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    • 专利摘要:
    USE OF BOTULINIC TOXIN FOR CHRONIC MIGRAINE PROPHYLAXIS AND COMPOSITION TO PROPHILATICALLY TREAT PATIENTS WITH CHRONIC MIGRAINE.The present invention relates to disorders such as headaches that can be treated by administering a botulinum toxin to a patient suffering from them, such as a migraine headache. A combined fixed-site / fixed-dose paradigm and an optional variable dosage of follow-up pain and injection site is described to optimize the clinical effectiveness of administering botulinum toxin to patients suffering from chronic migraine. The injection schedule requires a minimum dose of 155 U using a fixed site injection regimen, fixed dose at 31 to 39 sites through 7 head / neck muscles, namely the frontal, corrugator, proximal, occipital, paraspinal muscles, temporal, trapezius and cervical.
    公开号:BR112012024920A2
    申请号:R112012024920-7
    申请日:2011-03-29
    公开日:2020-08-25
    发明作者:Catherine C. Turkel；Sheena K. Aurora；David W. Dodick；Mitchell F. Brin
    申请人:Allergan, Inc.；
    IPC主号:
    专利说明:

    Invention Patent Descriptive Report for "USE OF BOTULINICAL XINA FOR CHRONIC MIGRAINE PROPHYLAXIS AND
    COMPOSITION TO PROPERLY TREAT PATIENTS WITH CHRONIC MIGRAINE ". Cross Reference to Related Orders This order claims the benefit of Provisional Order US 61 / 319,230, filed on March 30, 2010, and 61 / 320,667, filed on April 2, 2010, all incorporated entirely by reference Field Modalities of the present invention relate to the treatment of various diseases, especially for administration by injection using botulinum neurotoxin protocols Background It is known that botulinum toxin can be used to treat a variety of disorders. include US Patent 5,714,468 (migraine) issued on February 3, 1998; published patent application US 2005019132 (headache), serial number 11 / 039,506, filed on January 18, 2005; US published patent 20050191320 (headache from overuse of medication), serial number 10 / 789,180, filed February 26, 2004, and US Patent
    7,811,587 (neuropsychiatric disorders), issued on October 12, 2010, all incorporated entirely by reference. An example of a disease treatable with botulinum toxins is chronic migraine (EC), a disabling headache disorder that affects 1.3% to 2.4% of the general population, and considered the most common type of chronic headache primary daily rate in the United States. EC is linked to suffering, disability and overuse of medication, and only a third of patients with EC use prophylactic headache medication. Few preventive headache treatments have been investigated in patients with EC. Thus, there remains a need for optimized and targeted methodologies for the treatment of this disease, in particular, specific and useful injection and dosing paradigms for the use of botulinum toxin for the treatment of CS.
    | 2067 | - ”Another condition favorable to treatment with botulinum toxin is Headache Disorder due to Excessive Medication Use (MOU). He | í has been described as a headache, rhythmic, self-medication cycle | 7 - sustainable characterized by daily or almost daily headache with the resistant and predictable use of essential medicines.
    Evidence of the existence of MOU is widely reported in the medical literature.
    Summary In one embodiment, the present invention describes a method for prophylactically treating a headache of a patient suffering from migraine, chronic headaches, the method consisting essentially of local administration of a botulinum neurotoxin to the frontal muscles, corrugator, prostate, occipital, temporal, trapezius and cervical paravertebral regions of the patient suffering from migraine headache, in which the botulinum neurotoxin is administered, to the frontal in about twenty units divided into four injection sites , for the corrugator of about ten uni-; activities divided between two injection points; to the wax in about five units for an injection site, to the occiput in about thirty L units divided between six injection points, for about forty units divided between the eight injection points; to the temporal in about forty units divided between the eight injection points up to fifty units divided between the 10 injection points, to the trapezoid in about thirty units divided between the six injection sites of up to about fifty units divided between the ten injection points and for the cervical paravertebral muscles in about twenty units divided between four injection sites, and in which the botulinum neurotoxin is injected at 31-39 injection sites.
    Brief Description of the Figures The following drawings are presented to illustrate the features and characteristics of modalities of the present invention.
    Figure 1 is a graph that shows the results (average variation in the number of headaches for a period of thirty days) of a study
    ND 1 ——— ADDDÓDDDDO O A o 3/67 of the clinician performed by using BOTOXº to treat migraines among other things, which shows that patients had less headaches] after the administration of BOTOX.
    In the data shown in the figures, the! 4> patients had been administered BOTOX on days 0, 90 and 180.. Figure 2 is a graph showing the results (mean variation in the number of days of patients who were simultaneously taking medication to relieve acute headache for a period of thirty days) from a clinical study with BOTOX to inter alia treat migraines, showing that patients had fewer days, when they were taking “acute headache relief medication after administration of BOTOX . Figure 3 is a graph showing a comparison between the percentage of patients (some who had been given BOTOXº and some who had been given a placebo), who were over a period of thirty days of using narcotic drugs to control pain acute head.
    Figure 3 shows a decrease in the use of narcotics in patients treated with BOTOX.
    Figure 4 is a graph showing a decrease in the percentage of patients who had acute headache under excessive use of “medication during a period of thirty days after the administration of BOTOX : Figure 5 is a graph showing a decrease in the percentage of patients who had demonstrated excessive use of triptan in a period of thirty days after the administration of BOTOX.
    Figure 6 comprises two graphs showing the average change in the number of headaches experienced by patients over a period of thirty days after the administration of BOTOX in which patients either had no MOU ("no MOU"; graph on the left) or patients who had an MOU disorder (graph on the right). "> = 15 diase2> days / week" are criteria used to determine that the patient had a disorder MOU, MOU and MOD are synonymous terms.
    By definition, a patient has a MOU disorder, if he or she takes a medication
    «Acute tion, 15 or more days a month and at least twice a week, in the week that they are experiencing acute pain.
    : Figure 7 comprises two graphs, which show the average change from baseline in the frequency of headaches per period of 30 days in patients using (graph A) and not using (graph B) prophylactic pain medications head at the start of the study, for a combined population of patients. The Y axis represents the average variation in the number of headaches over a period of thirty days. "n" indicates the number of patients in the sample of patients evaluated.
    Figure 8 comprises two graphs showing the average change in the number of headaches experienced by patients during a period of thirty days after the administration of BOTOXº, in which patients used or not concurrently used with other prophylaxis treatment. headache (on the left side of the graph) or patients | 15 did not simultaneously use another prophylactic treatment for headache and had a MOU disorder (graph on the right side).
    Figure 9 comprises two graphs showing the average change in the number of headaches experienced by patients during a period of thirty days after the administration of BOTOXº, in which patients used or not concurrently used with another migraine prophylaxis treatment. and do not have an MOU disorder (left side graph) or patients did not simultaneously use another prophylactic treatment of headache and had an MOU disorder (right side graph). Figure 10 is a graph of bars that show the percentage of patients over a period of thirty days after the administration of BO-TOXPº, who also used an opioid medication for acute headache.
    | Figure 11 is composed of two graphs that show the average change in the number of headaches experienced by patients during a period of thirty days after the administration of BOTOXº, in which the patients were patients on medication or excessive use of triptan ( on the left side of the graph) or patients did not use medication or
    tryptane (graph on the right side). . Figure 12 comprises two graphs showing the change: mean baseline (after administration of BOTOX ) In number of 4 days with acute headache (analgesic) with medication use by - patient parts, where patients were or patients with excessive use of triptan medication (left graph) or patients who did not use excessive triptan medication (graph on the right). Figure 13 comprises, on the left side, a schematic view of the left side of the human muscular anatomy from the shoulders upwards, with a schematic view of the back on the right side.
    Figure 14 comprises two graphs showing the average change from baseline in the frequency of headaches over a period of thirty days for placebo non-responders (A) and responders (B). Figure 15 shows the average change from baseline in the frequency of headaches over a 30-day period for a combined population of patients.
    Figure 16 comprises two graphs showing the change x mean of the baseline in the number of days of use of analgesic drugs for acute headache for a period of 30 days for patients who use (graph A) and do not use (graph A) graph B) prophylactic medications headache at the beginning of the study, for a grouped population of patients.
    Figure 17 illustrates an example of fixed locations for which doses of botulinum toxin are administered to a patient (in this case, in the supine and seated positions), according to a one-step injection procedure.
    Description In certain embodiments, the dose of a botulinum toxin used in accordance with the modalities of the present invention is less than the amount of botulinum toxin that would be used to paralyze a musician, because 80 the intention of a method according to the modalities of The present invention is not to paralyze the muscle, but to reduce the sensory pain produced by the sensory neurons located inside or over a muscle, or inside or under the skin. = The following definitions are applied here: '"About" means approximately or almost, and in the context O of a numeric value or range defined here, it means + 10% of the numeric value or range recited or claimed.
    "Relief" means a reduction in the occurrence of a headache, pain or symptom of a headache. Thus, relief includes some reduction, significant reduction, almost total reduction, and total reduction. A relief effect may not appear clinically for 1 to 7 days after administration of a clostridial toxin to a patient or some time later. "Botulinum toxin" means a botulinum neurotoxin as' either pure or complex, native, recombinant or modified toxin, and includes botulinum toxin type A, type B, type C1, type D, type E, type F and type G. As used herein, this term does not exclude neurotoxins, such as cytotoxic botanical toxin C; and C3. º "Local administration" means the administration of a pharmaceutical agent to or in the vicinity of a patient's muscle or subcutaneous site via a non-systemic route. Thus, local administration excludes systemic routes of administration, such as intravenous or oral administration.
    "Peripheral administration" means administration to a location away from a symptomatic location, as opposed to a local administration.
    "MOU" means headache from excessive medication or medication - headache from overuse.
    "Treating" or "treating" means relieving (or eliminating) at least one of the symptoms (such as, for example, headache), either temporarily or permanently. This can include prophylactic applications to prevent at least one of the headache symptoms.
    Here, modalities of a paradigm for the administration of botulinum neurotoxins are described. In some modalities, the method may include specific injection sites and dosage quantities for
    botulinum xin in the treatment of various disorders, including, for example, ”EC, MOU, ND's, and the like. In certain embodiments of the invention, the disorder can be treated by intramuscular administration of toxin in specific amounts or ranges of values to specific locations within the upper part of the patient's trunk. In certain embodiments, such locations may include, for example, the head, the neck, one or both shoulders, in either the anterior or posterior positions. Botulinum toxin can be a type A, type B, type C1, type D, type E, type F, or type G botulinum toxin or any combination of these. Botulinum neurotoxin can be made recombinant botulinum neurotoxins made, such as, botanical toxin produced by E. coli.
    In addition, the botulinum neurotoxin can be a modified: neurotoxin, which is a botulinum neurotoxin, which has at least one of its deleted, modified or substituted amino acids, compared to the native toxin or the modified botulinum neurotoxin can be one. produced recombinant botulinum neurotoxin or its derivative or fragment. In certain embodiments, the modified toxin has an altered ability interest cell of a neuronal or non-neuronal cell interest. This altered ability is achieved through substitution the naturally occurring domain of interest for a botulinum toxin with a domain of interest that shows selective binding activity for a non-botulinum toxin receptor present in a non-botulinum toxin target cell, such modifications to a target domain result in a modified toxin, which is able to selectively bind to a non-botulinum toxin receptor (target receptor) present in a non-botulinum toxin (redirected) target cell. The modified botulinum toxin with a targeting activity to a cell target of non-botulinum toxin can bind to a receptor present in the target cell of non-botulinum toxin, translate to the cytoplasm, and exert its proteolytic effect on the target cell's SNARE complex. In essence, a light chain botulinum toxin comprising an enzyme domain is intracellularly distributed to any desired cell, selecting the appropriate domain of interest.
    Botulinum toxins for use in accordance with the present invention can be stored in vacuum lyophilized form, dried in containers under vacuum pressure, or as stable liquids. Before lyophilizing the botulinum toxin, they can be combined with pharmaceutically acceptable excipients, stabilizers and / or vehicles, such as, for example, albumin, or the like. In embodiments containing albumin, albumin can be, for example, human serum albumin or the like. The lyophilized material can be reconstituted with a suitable liquid, such as, for example, water, saline, or the like to create a solution or composition containing the botulinum toxin to be administered "to the patient.
    The amount of botulinum toxin administered, according to a method within the scope of the modalities of the invention can vary according to the particular characteristics of the pain to be treated, including its gravity and other various variables of the patient, including height, weight,. age and responsiveness to therapy. To guide the professional, typically no less than about 1 unit and no more than about '25 units of a botulinum toxin type A (such as BOTOX) is administered by injection per treatment session. patient. For a type of botulinum toxin type A, such as DYSPORTº, no less than about 2 units and no more than about 125 units of type A botulinum toxin are administered by injection, per patient treatment session. For a botulinum toxin type B, such as MYOBLOC *, no less than about 40 units and no more than about 1500 units of botulinum toxin type B are administered by injection, per patient treatment session.
    Preferably, for BOTOX no less than about 2 units and no more than about 20 units of a botulinum toxin type A are administered by injection per patient treatment session; for DYSPORTº no less than about 4 units, and no more than about 100 units are administered by injection per patient treatment session; and, for MYOBLOCº, no less than about 80 units and no more than about 1000 units are administered by injection, through the patient's treatment session.
    More preferably, for BOTOX º, no less than about 5 units and no more than about 15 units of a botanical toxin type A; for DYSPORTº no less than about 20 units and no more than about 75 units and, for MYOBLOCº, no less than about 200 units, and no more than about 750 units are,. respectively, administered by injection site, per patient treatment session.
    In general, the total amount of BOTOXS, DYSPORT or MYOB- 'LOCº, suitable for administration to a patient, according to the methods of the invention described here should not be more than about 300 units, about 1,500 units or about 15,000 units, respectively, per treatment session.
    The effects of treatment with botulinum toxin may persist. between about 1 month and 5 years.
    The modalities of the invention provide a fixed injection targeting paradigm aimed at a specific set of muscles with a specific minimum number and volume of injection, and also have the object of additional / optional administration of additional botulinum toxin to the specific site. of selected muscles.
    In one embodiment, the fixed dosage (that is, a minimum dosage amount, according to fixed amounts and locations specified in a package insert or prescription information) of botulinum toxin is administered to the frontal, corrugator, prostate, occipital, temporal muscle, trapezius and cervical paravertebral of a patient, plus a variable amount of botulinum toxin can be added to four or less than seven of the head / neck area, such that the total amount of botulinum toxin administered does not exceed a maximum total dose as indicated. in the package insert or prescription information that accompanies a medication containing botulinum toxin.
    Botulinum toxin can be selected from the group consisting of botulinum toxin types A, BC, D / E, Fe G.
    Botulinum toxin type A is a preferred botulinum toxin.
    Botox toxin
    can be administered in an amount of between about 1 unit and about 3,000 units, or between about 2 units and about 2000 units, or between about 5 and about 1000 units of units, or VU between about 10 to about 500 units of units, or between about 15 units and about 250 units, or between about 20 units and about 150 units, or between 25 units and about 100 units, or between about of 30 units and about 75 units, or between about 35 and about 50 units of units, or you like them, and for the relief of symptoms they can persist for between about 1 month and about 5 years.
    In one embodiment, a method is described that uses a dose 7 and injection paradigm of 155 units of BOTOXS (typically supplied as 100 units of Clostridium botulinum GC type A neurotoxin complex, with 0.5 mg human serum albumin, and 0.9 mg of sodium chloride in a sterile solution, in a state of vacuum drying for reconstitution), administered as 31 fixed sites, with fixed dose injections (5 units per) and an optional 40 units in up to eight additional injection sites using a persistent pain regimen per treatment cycle (for up to '39 injection sites and up to 195 units in total). The total dose is divided by 7 muscles in the head / neck and is repeated every 12 weeks.
    In one embodiment, a method for the treatment of a migraine, such as, for example, EC, may include the administration of a botulinum toxin to 31 fixed injection sites in seven head / neck muscles. Optionally, up to 8 additional injection sites in three specific muscles, where these three muscles are a subset of the seven muscles above the head / neck, the muscles are administered using a continuation of the pain regimen to provide dose / muscle flexibility for the three muscles, to meet the individual needs of patients. In particular modalities, a minimum of 155 units of a botulinum toxin type A, up to about 195 units of a botulinum toxin type A, are administered, according to a particular injection paradigm described here.
    In a specific modality, to a method for the treatment of
    EC comprises the stage of local administration of a botulinum neurotoxin to the frontal, corrugator, proximal, occipital, temporal, trapezoid and cervical paravertebral muscle of the patient with MS, such that the botulinum neurotoxin "OR is administered to the frontal muscle in about of 20 units divided into four injection sites, for the corrugator of about 10 units divided between two injection sites, for the proximal to about five units for an injection site, for the occipital to about 30 divided units ] between six injection points, for about 40 units divided into eight injection sites; at the time of about 40 units divided between eight injection points, up to 50 units divided between 10 injection sites, - for the trapezoid in about of 30 units divided between six injection points, up to about 50 units divided between 10 injection points, and 'for cervical paraspinal muscles by about 20 units divided into four the injection sites, such that the total amount of botulinum neurotoxin is administered from about 155 units to about. 195 units injected at 31-39 injection sites, respectively.
    In one aspect, modalities of the present invention are based on the discovery that botulinum toxin can be used to treat a patient with MOU to reduce both (a) the number of headaches experienced by the patient (see figure 1 ) and (b) the daily use of acute headache medication by the patient (figure 2). In particular, it has been found (see figure 3) that botulinum toxin can be used to reduce patients' use of narcotic pain medication.
    Additionally, it was found that patients who used excess pain relief medication experienced a significant reduction in the use of such medications after treatment with botulinum toxin (see figure 4). It was also found that there was a significant reduction in the consumption of triptan medication in patients who were overusing triptan medication (see figure 5). The modalities of the invention can also be used as part of a detoxification protocol, in which a patient who is being cured of drugs for acute pain is facilitated in this objective, the ad-
    concomitant administration of a botulinum toxin. Additional embodiments 2 of the present invention can be used in the treatment of other chronic pain conditions, including, for example, back pain, neuropathic pain, VU allodynia, fibromyalgia, and the like.
    In one embodiment, a method for treating a MOU patient may involve administering a botulinum toxin to 31 fixed injection sites in seven head / neck muscles. Optionally, up to 8 additional injection sites in three specific muscles, where these three muscles are a subset of the seven above the head / neck, muscles are administered using a continuation of the pain regimen to 'provide dose flexibility / muscle for the three muscles, to meet the individual needs of patients. In particular modalities, a minimum of 155 units of a botulinum toxin type A, up to about 195 units of a botulinum toxin type A, are administered, according to a particular injection paradigm described here. . In a specific embodiment, a method for the treatment of MOU comprises the stage of local administration of a botulinum neurotoxin to the frontal muscle, corrugator, proximal, occipital, temporal, trapezius and cervical paravertebral muscles of the patient MOU, such that the botulinum neurotoxin is administered to the frontal muscle in about 20 units divided into four injection sites, to the corrugator of about 10 units divided between two injection sites, to the proximal to about five units to an injection site , for the occiput to about 30 units divided between six injection points, to about 40 units divided into eight injection sites; to the storm of about 40 units divided between the eight injection points, up to 50 units divided between 10 injection sites, for the trapezoid in about 30 units divided between the six injection points, up to about 50 units divided between 10 points injection, and for cervical paraspinal muscles in about 20 units divided into four injection sites, such that the total amount of botulinum neurotoxin is administered from about 155 units to about 195 units injected in 31 at 39 injection sites, respectively.
    In one embodiment, a method for the treatment of healthy depression may include the administration of a botulinum toxin to 31 fixed injection sites in seven head / neck muscles. Optionally, up to 8 additional CU injection sites in three specific muscles, where these three muscles are a subset of the seven above the head / neck, the muscles are administered using a continuation of the pain regimen to provide dose / muscle flexibility for the three muscles, to meet the individual needs of patients. In particular modalities, a minimum of 155 units of a botulinum toxin type A, up to about 195 units of a botulinum toxin type A, are administered, according to a particular injection paradigm described here.
    In a specific embodiment, a method for the treatment of DN, such as, for example, depression, to a patient in need of it comprises the stage of local administration of a botulinum neurotoxin to the frontal, corrugator, prostate, occipital muscle , temporal,. trapezius and cervical paravertebral muscles of the patient, in such a way that the botulinum neurotoxin is administered to the frontal muscle in about 20 'units divided into four injection sites, for the corrugator of about 10 units divided between two injection sites, for the proximal to about five units for an injection site, for the occiput to about 30 units divided into six injection points, to about 40 units divided into eight injection points, to the temporal in about 40 divided units in eight injection points, up to 50 units divided between ten injection sites, for the trapezoid in about 30 units divided into six injection points, up to about 50 units divided between 10 injection points, and for the paraspinal muscles cervical cells in about 20 units divided into four injection sites, so that the total amount of botulinum neurotoxin is administered from about 155 units to about 195 units are injected at 31 to 39 injection sites, respectively. Significantly, a method within the scope of the present invention can provide improved patient function. "Improved patient function" can be defined as an improvement measured by factors such as reduced pain, reduced time spent in bed, increased locomotion, healthier attitude, more varied lifestyle and / or healing allowed by VU normal muscle tone .
    Improved patient function can be measured with a better quality of life (QOL) or Quality related to Health and Life (QVS). QOL can be assessed, for example, using SF-12 or SF-36 research and health scoring procedures, or Migraine Specific Quality of Life (MSQ) questionnaires. The SF-36 assesses a patient's physical and mental health in the eight domains of physical functioning, limitations due to physical problems, social functioning, bodily pain, general mental health, limitations due to emotional problems, vitality and general health perceptions .
    Scores obtained can be compared to the published values available for various populations in general and the patient.
    The Migraine Specific Quality life questionnaire version 2.1 is one of the most used specific migraine tools. disease assessment of migraine impact on HRQoL.
    The MSQ measures the impact of migraine on the patient's HRQoL over the past 4 weeks in three dimensions: Role-Restrictive Function (RR), Role-Preventive Function (RP), and Emotional Function (EF). The MSQ was developed from an item-based analysis of migraine literature and validated in a clinical sample of 458 new and stable MS patients.
    In the validation study, the MSQ revealed high internal consistency (Cronbach a = 0.79 to 0.85), a moderate to strong convergent validity, as well as an adequate discriminant validity.
    Martin and 21 colleagues conducted a study — a multicenter study that most supported the evidence of high internal consistency (Cronbach a = 0.86 to 0.96), strong reliability and good validity of the MSQ item
    14 among the 267 participants.
    The following non-limiting examples provide those skilled in the art with certain preferred methods for the treatment of chronic migraine within the scope of the present description and are not intended to limit the scope of the invention.
    In the following examples, several modes of non-systemic administration of a Clostridium neurotoxin may
    can be accomplished. For example, by intramuscular injection, subcutaneous + injection or implantation of a controlled-release implant.
    EXAMPLES VU The following non-limiting examples provide those skilled in the art with certain preferred methods for treating conditions within the scope of the modalities of the present invention and are not intended to limit the scope of the invention. Example 1 - Botulinum Toxin Therapy type A for Headache Associated with Chronic Migraine In the similar, multicenter, randomized, placebo-controlled design, phase 3 studies, 1384 adults with EC were randomized to onabotulinumtoxinA (botulinum toxin type A) (n = 688) or place- 'bo (n = 696). Both studies consisted of a screening period of 28 base days (hereinafter referred to as baseline), 24 weeks, double-blind (DB) phase (2 injection cycles), and one 32 weeks, phase. open label (OL) (3 treatment cycles). Study visits took place every 4 weeks and patients used a telephone diary daily: to record their headache symptoms and acute pain medications. Participants were men or women aged 18 to 65 years with a history of migraine from the diagnostic criteria listed in CIC-II (2004) Section 1, Migraine, with the exception of "complicated migraine", and with headache occurring 2 15 days / month with at least 50% of headache days being migraine or probable migraine days. Botulinum toxin type A blocks the release of neurotransmitters associated with the genesis of pain. As confirmed by preclinical and clinical trials, the presumed mechanism for prophylaxis is headache, blocking peripheral signals to the central nervous system inhibiting central sensitization. The fixed in-place approach described here distributes botulinum toxin type A to the muscles and skin in the distribution of V1 and C2 nerve innervation. Based on analyzes of safety, tolerability and effectiveness of the dosing paradigms explored in previous studies, the
    instant injection system was developed.
    In this example, the particular neurotoxin + botulinum used is onabotulinumtoxinA (BOTOX® Allergan Inc., Irvine CA). Injection goals included the muscles: Frontal VU, Corrugator, and Procerus: In previous trials, patients most often reported the frontal / glabellar region as the origin and end of their headache; these and other trials showed that all 3 muscles required injections for maximum effectiveness.
    Temporal: In previous tests, the temporal region was the second most frequent site cited as the beginning and end of the headache.
    According to one aspect of the present description, a minimum dose of 20 units on each side and an additional dose of up to 10 units (pain management strategy) total (administered to one or both sides, in increments] units) is administered to that muscle.
    Cervical paraspinal muscles: In previous trials, patients indicated that their headache often started and / or - ended at the back of the head (in the occiput and / or the neck). To maintain efficacy and improve overall tolerability (lower incidence of neck pain, neck stiffness, and neck muscle weakness), in one aspect, the instant injection paradigm includes the recommendations of: (a) injections for the upper part of the neck (cervical spinal muscles) at the base of the skull, (b) do not use a follow-up injection scheme in the neck area, (c) maintain superficial injections and (d) reduce the total dose injected into the neck to a fixed location, with a fixed dose of 20 total units for this group of muscles (10 units on each side of the head). Accordingly, this dose adjustment has been shown to be successful and safe, since only one patient here needed to wear a soft collar compared to 10 in previous studies.
    Occipital: In previous trials, the occipital was the third most frequently reported site for pain.
    In a previous study, which explored the following pain strategy, the occipital dose was fixed at 20 units (10 units on each side), while the highest dose allowed in this muscle in another study was 30 units (15 units each side). = The total dose administered to the neck was reduced and, consequently, to ensure that there was not enough "back of the head" for VU to ensure the effective, minimum dose administered to the occipital muscle was 30 units (15 units on each side); injection sites have been standardized and located mainly above the occipital crest to reduce the risk of weakening the neck; optional next pain dosage with an additional up to 10 units was allowed.
    Trapezoid: In previous trials, about 20% to 30% of patients reported that their headache started and / or ended in the trapezius.
    Optional pain-following injections occurred frequently for this muscle group.
    Although not a safety concern in general, the incidence of the arm (shoulder), increased pain with higher doses, and therefore it was determined that a preferred dosing regimen for the trapezius muscle would be normalized to one dose minimum of 30 units - (15 units on each side) and allow optional pain follow-up injections for a maximum dose of 50 units, if clinically necessary. 'Masseter: The masseter muscle was not included as a group of target muscles for injection in the instantaneous paradigm, as surprisingly injections into the masseter do not help in the treatment of migraine headaches.
    In one aspect, from the previous trials, the highest total dose per injection cycle evaluated was 260 units, and the lowest dose was 105 units (one trial), while the dose groups in the second trial include 225 units, 150 units and 75 units.
    When assessing the dose response in the assay for tolerability, it was determined that the total ideal dose for maximizing efficacy and tolerability was within the range of> 150 and <200 units.
    In the present example, the subjects were randomly assigned blindly (1: 1) to onabotulinumtoxinA (BOTOX) (155 units) or with placebo, administered as 31 fixed-dose, fixed-dose (IM) intramuscularly via seven specific muscle areas of the head
    çal / neck (frontal, corrugator, procerus, temporal, occipital, cervical paravertebral 2, and trapezius) (figure 17): Frontal! 20 units (two houses on each side: total of 4 locations); Corrugator * 10 units (1 site on each side: total VU of 2 sites) procero 5 units (1 site); occipital * 30 units (3 places of —called: total6 places); temporal! 40 units (4 locations on each side: a total of 8 locations); trapeze! 30 units (3 houses on each side: total of 6 locations); cervical paravertebral muscles! 20 units (two houses on each side: total of 4 locations). Total dose range: 155 units. Each IM injection site = 0.1 mL = 5 U onabotulinumtoxinA (BOTOX). (* Doses distributed bilaterally.). Up to an additional 40 units of onabotulinumtoxinA or placebo can be administered between the 3 muscle groups (occipital, temporal, or trapezius; total of 8 sites), using a defined, follow-a-paradigm protocol. pain (figure 17). The maximum dose was 195 units in 39 locations. The dose range per injection cycle was 155 units to 195 - units every 12 weeks for 5 cycles.
    In the practice of this example, doctors were instructed according to the following: dosage / administration: each bottle of 100 units of onabotulinumtoxinA (BOTOX) or placebo was diluted with 2 mL of normal preservative saline, resulting in a concentration of 5 units / 0.1 mL. Doses of 155 units to 195 units or placebo were administered intramuscularly using a sterile 30 gauge needle, 1.27 cm (0.5 inch) (with a Luer Lock tip) with injections of 0.1 mL (5 units ) by location. A 2.54 cm (1 inch) needle was allowed, at the discretion of the physician in the neck region for patients with thick neck muscles. Guidelines for administering onabotulinumtoxinA were as follows: Gloves should be worn during administration of the treatment and, prior to injection, the skin should be cleaned, in accordance with normal practice for intramuscular injection (eg with alcohol), the needle it must be inserted into the muscle with the bevel upwards, at about a 45 degree angle, once inserted, the needle hub must be held with one hand while the plunger is pulled back slightly with the other hand to avoid torque and blood return, respectively. If the blood twitches. the needle must be reinserted into the muscle, the plunger must be pushed to deliver 0.1 mL (5 units) to each location. VU The following is an example of a useful form of injection for .— 5 administration of botulinum toxin, in accordance with the present description. Anatomical injection sites follow distributions and areas innervated by the first division of the trigeminal nerve and the second cervical nerve. : In an exemplary paradigm, a doctor palpates each muscle (bilaterally, if applicable) before the injection to check muscle delineation and determine the presence of muscle tenderness and / or pain 'that requires additional treatment. The patients were supinated by injections in the corrugator (2 injections, one on each side), proximal (1 injection, midline), frontal (4 injections, two on each side), and temporal (8 injections, four on each side) side), in this sequence (figure 17). The patients were seated for occipital injections (6 injections, three on each side), cervical paravertebrals (4 injections, two on each side) and trapezius (6 injections, three on each side), in this sequence (figure 17) . If necessary, additional injections into the 'temporal, occipital and trapezius muscles were allowed, using the optional pain tracking paradigm (figure 17).
    Post-administration, patients were observed for 10-15 minutes after treatment and were instructed not to rub or massage the affected areas for 24 hours and were advised that all bumps on the forehead should disappear within approximately 2 hours. . Patients were warned that they might need and should use their medications for acute headache pain and to return 4 weeks apart and keep a pain diary.
    Grouped analyzes showed statistically significant differences favoring the dose disclosed here from 155 to 195 units over placebo at all time points in the double-blind phase, through headache measures of multiple symptoms, including the primary end point combined change from baseline in the frequency of 24-week headache days: -8.4 onabotulinumtoxinA / -6.6 place-
    bo, p <0.001. - Each and every feature described herein, and a combination of each of two or more of such features, is included within the scope of the modalities of the present invention, provided that the features included in such a combination are not mutually incompatible.
    Example 2 - Botulinum Toxin Therapy type A for Headache and a Probable Headache Disorder from Overuse of Medication A clinical study was conducted with patients who complained of headache and who took frequent acute pain medications, such as narcotics and triptans to control pain.
    Botulinum toxin (BO- 'TOX9) was administered to patients on day 0, day 90 and day 180. BOTOXº injections were administered intramuscularly in an average of 20 separate injections for each patient in each of the three sessions injection.
    BOTOXº was administered to up to seven different muscles. - From 105 to 260 units of BOTOX was administered to each patient in each of the three treatment sessions.
    It was found 1 that patients experienced a reduction both in (a) the number of headaches experienced by patients (figure 1), and, (b) the daily use of acute headache medication by these patients (figure 2). In particular, it was found (figure 3) that botulinum toxin can reduce the use of narcotic pain medication by these patients.
    Additionally, it was found that the use of a botulinum toxin in patients who were overusing pain relief medication resulted in a significant reduction in the use of such drugs (see figure 4). It was also found that there was a significant reduction in medication intake in patients with excessive use of triptan (figure 5). Thus, this clinical study showed that, surprisingly, a botulinum toxin can be used to treat a headache disorder from overuse of medication (MOU) (see figure 6). The study also demonstrated (see figure 7) that botulinum toxin was more effective in patients who were not using a simultaneous headache prophylaxis treatment, regardless of any issue + overuse of medication.
    In addition, the same study showed (see figures 8 and 9) that the botulinum toxin CU was more effective in patients who were not using a simultaneous headache prophylaxis treatment and overused medication.
    This is a breakthrough in addition to our discovery that botulinum toxin can be used to treat acute headaches in a patient who were overusing medication, regardless of the fact that the patient is being treated with monotherapy with botulinum toxin, or that he or she is being treated for headache with other headache prophylaxis drugs.
    On the other hand, with regard to the use of acute medication i in patients (and not excessive, but any use), the study showed that the treatment of headaches with botulinum toxin resulted in a significant decrease in the use of drugs by these patients (see, for example, on day 210, figure 10). Finally, and significantly, the study also showed (see 'figures 11 and 12) that, after treatment with a botulinum toxin, there was a greater decrease in the frequency of acute headache and the number of days of analgesic medications were needed in patients who made excessive use of triptan medication for headache in the baseline, compared with patients who did not use excessive triptan.
    This indicates that triptans are most effective for treating headache when used in conjunction with a botulinum toxin.
    Thus, a method for increasing the effectiveness of a triptan to treat a headache can be accomplished using a triptan and a botulinum toxin concurrently to treat a headache. : Clinically, overuse of triptan medication seems to actually cause or exacerbate the headache, rather than the headache relief that can result from using normal triptan.
    Therefore, it was a surprising discovery, as established by figures 11 and 12, to verify that the administration of a botulinum toxin helps to avoid headaches in a population of patients who have headaches, more frequent headaches or exacerbated headaches due to excessive use of triptan medication. This discovery is demonstrated by the VU results of studies and patient observations that show that patient-testriptan MOU required less triptan medication after the administration of botulinum toxin. Example 3 - Botulinum Toxin Therapy type A for Chronic Headache This study evaluated the potential benefit of BOTOX in the prophylaxis of headache in the adult population with daily chronic headache.
    The term chronic daily or near-daily headache has been used to: 'refer to very frequent headache (16 or more days of headache in a month) in relation to a systemic or structural disease (Silberstein and] Lipton , 2001). The main requirement for entry into the study was the primary headache disorder with> 16 days of headache per month by history and confirmed by the electronic diary during the baseline. Headache disorder could include any combination of episodic / chronic tension headache, migraines with or without aura, and / or migraine '(as defined by the IHS criteria [IHS Headache Classification Subcommittee, 1988, revised in 2004], and / or chronic headache per day, as defined by Silberstein and Lipton, 2001).
    One study was conducted with a multicenter, double-blind, randomized, placebo-controlled study of parallel groups of multiple treatments with BOTOXº for the prophylactic treatment of headaches in a chronic migraine population. The total duration of the study for each patient was 11 months. Patients were selected on day -60 (base period). During this period, data were collected daily from the patient in relation to the specific characteristics of his episodes of headache and headache from medication use for 30 days through electronic telephone diaries. After the initial period, patients returned on day -30 (Treatment 1) to the placebo run in this period. In this visit, patients who met the inclusion / exclusion criteria were injected with a single-blind placebo, and
    specified characteristics of his headache episodes for 30 days «through electronic diaries. Treatment 1 injections were in a minimum of six muscle areas and 23 to 58 injection sites within those CU areas, which depend on the location and intensity of the pain. The investigator also had the option to inject into the masseter, if the patient was experiencing muscle pain.
    After 30 days (on day 0) patients returned to be ranked for treatment 2. Before the draw, using the diary information collected during the management during the placebo period, patients were classified as a placebo responder if they had <16 days' of headache or had> 30% decrease from baseline in the frequency of headache days. All other patients were considered placebo non-responders. Patients within each stratum (responders, non-responders) were randomized to receive BO-TOXº or placebo on day 0 (Treatment 2). - Patients received additional treatments on Day 90 (Treatment 3) and 180 days (Treatment 4). Patients returned for follow-up visits at 30-day intervals after each treatment until day 270. If a patient left the study, at any appointment prior to Day 270 (departure), all exit procedures and assessments were to be completed in visit. For treatments 2, 3 and 4, were the patients injected with BOTOX or placebo using the same dose and volume and in the same muscle and local areas as in treatment 1. The study visit schedule and measurements are shown in Table 2.
    The study was randomized and double-blind to minimize the influence of the investigator and patient. The blind spot was ensured by the similarity in the appearance of the study medication bottles and which require a person in each study center, who was not involved in another study medication reconstitution study and filling syringes for injection. A placebo-controlled, parallel-group design eliminated possible confounding effects that are inherent in other study models.
    In contrast to the fixed local approach / treatment of fixed dosage - used in previous clinical studies in the episodic migraine population, physicians participating in this study were allowed to use VU a more individualized and tailored treatment approach, depending on location of the patient's headache. Specifically, doctors had the opportunity to determine the number of injection sites and the dosage within a specified protocol range to be administered during the specified areas of the frontal and posterior muscle of the head and neck, depending on the location and severity of a patient's headache. Maximum doses allowed in this study were also * higher than those used in previous studies, due to the addition of a larger injection in the posterior pericranial muscles and neck.
    Due to the high rate of response to placebo seen in previous studies, a period of placebo execution was implemented at present - a study to stratify patients into two groups (placebo responders and non-responders). During the placebo period, patients were not informed if they were injected with BOTOX or placebo. In addition, the study protocol was changed to include three double-blind treatment cycles.
    Efficacy criteria were as follows. For the main variable, a difference of 3 days without headache between BOTOX "and placebo in the mean change from baseline in the frequency of free headache days per month on day 180 was considered clinically significant.
    * All patients included in this study met, at least, the following inclusion criteria: male or female, aged 18 to 65 years; + Primary headache disorder with> 16 days of headache per month per story and confirmed by the diary during the baseline, which can include any combination of migraines with or without tension headache, aura, episodic / chronic and / or migraine (as defined in 1988 by the IHS criteria) (Headache Classification Subcommittee of the IHS, 1988); > * willing and able to give written informed consent; DV * stable medical condition; - stable chronic medications, if applicable, including prophylactic medications for non-acute migraine, by, at. least 3 months immediately prior to Day -60; * willing and able to stay on current medications * - during the course of the study; * willing and able to complete the entire course of the study and to "comply with the study instructions, including daily telephone system. A range of unit doses to be injected into each muscle area] has been defined, with the exception of the occipital muscle where The number of injection sites (total 23 to 58 injection sites) within the specific muscle area (6 to 7 muscle areas) and injected dose (105 U to 260 U) were determined by the physician, based on the pattern of pain distribution and the severity of pain in the particular muscle area. Patients were injected into a minimum of 6 muscle areas, which included the frontal / glabellar, occipital, temporal, semispinalis, splenic capitis and trapezius, as specified in Table 1 and figure 13. Injection into the masseter muscle was optional. Patients were injected with the same dose and in the same muscle zones and locations for treatments 1,2,3, and 4. Whenever possible, treatments for each p patient was performed by the same doctor throughout the study.
    Table 1 Study dose of Medicines and Injection Sites [FoGaRer | 25-20 | No [35 [os | and [Om TO, [ema | as [sm | 39-50 [asseteriopoonan | - 025 | sm | o-so | units | o [Cspenus cats | sto sm] o20 [Faasenaeta [O ro6260 Note: Patients were injected with BOTOXº or placebo into specific muscles at doses determined by the investigator.
    º Patients randomized to the placebo group received the U of BOTOX .
    - 5 Each bottle of BOTOXº contained 100 U of botulinum toxin type A, 0.5 mg of albumin (human), and sodium chloride 0.9 mg of a sterile solution, vacuum-dried without preservative. Each placebo bottle contained 0.9 mg sodium chloride of a sterile solution, vacuum-dried form without preservative. The bottles were stored in a freezer. 10 between -20ºC and -5ºC before use. Instructions for reconstitution with the diluent, 0.9% sterile saline solution (without preservatives), for injection. were provided in the protocol.
    In this study, in contrast to the fixed-site / fixed-dose treatment approach used in previous studies, physicians were empowered to use a more individualized or tailored patient treatment approach. Specifically, the number of injection sites (23-58 injection sites) within each specified muscle area (6-7 muscle areas) and the injected dose (total dose of 105-260 U) were determined by the doctor, based on in the distribution of the usual standard pain and the intensity of pain in the patient's particular muscle area. During the course of the study, the protocols were modified to include a total of 3 treatment cycles (after the placebo execution) and the location primary end was changed to Day 180, in relation to placebo to placebo stratum non-responder. At the time these changes were put in place, a significant number of individuals left the original study at the planned 120 Day time point.
    Enrollment has been extended to ensure that at least 90 non-responder place-patients (45 per treatment group) were available for Day 180 analysis. CU The use of any concomitant medication (eg, prescription or over-the-counter) , including herbal remedies) was recorded on the patient's CRF along with the reason for the medication being taken. In addition, medications that the patient had taken for the treatment of headaches since his 7 days before the -60 day were recorded on the appropriate medication- * - CRF. During the study, the patient reported any use of concomitant medication for the treatment of headache using the daily electronic telephone diary.
    Patients undergoing concomitant therapies were maintained at a stable dose and dose regimen during the study, particularly with regard to the use of prophylactic medications for non-acute migraine. Medicines that were considered necessary for the good- patient data could be given at the investigator's discretion. The administration of all drugs was to be reported in the CRFs.
    'Efficacy measures The headache patient's initial / final time, maximum and average severity of headaches, location and type of headache, the effect on physical activity, presence of aura, presence of symptoms associated with headache (nausea, vomiting, photo / phonophobia), headache and medications and doses used. The main measure of effectiveness was the change from baseline in the frequency of headache in free days over a period of 30 days. The preliminary visit to determine effectiveness was Day 180, with the assessment reflecting the period 30 days earlier. Baseline for effectiveness measures was defined as the frequency of headache-free days during the first 30 days of the screening period. A difference of 3 days without headache between BO-TOXº and placebo in the mean change from baseline in the frequency of headache-free days for a period of 30 days on day 180 was considered clinically significant.
    The measure of secondary efficacy was the proportion of patients with - a 50% or more decrease from baseline in the frequency of headache days for a period of 30 days, on Day 180. Other variables of effectiveness were the following: * the proportion of patients with a baseline reduction of 50% or more in the frequency of headaches for a period of 30 days; «The frequency of headaches, of any severity (for a period of 30 days); * the frequency of migraines, of any severity (per period of 3090 days); '' * the proportion of patients with a baseline reduction of 50% or more in the frequency of migraine for a period of 30 days; Ú * the proportion of patients with a baseline reduction of two or more migraines for a period of 30 days; * moderate to severe frequency of migraine (for a period of 30 days); * patient's overall assessment of response to baseline treatment, as follows: -4 = very marked worsening (about 100% worse or higher) -3 = marked worsening (about 75% worse) | -2 = moderate worsening (about 50% worse) -1 = slight worsening (about 25% worse) 0 = unchanged + 1 = slight improvement (about 25% improvement) +2 = moderate improvement (about 50 % improvement) + 3 = marked improvement (about 75% improvement) +4 = clearance of signs and symptoms (about 100% improvement) * the number of days per 30-day period with headaches without migraine; * maximum and medium headache severity (none, mild, moderate, severe);
    * the number of days that the acute headache medication was used during the study, and * the number of uses (ingestion) of acute CU headache mediation during the study.
    Assessment Schedule The frequency and timing of study visits and measurements are shown in Table 2 below.
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    The primary efficacy variable was the change in the frequency of + free headache days from an initial period of 30 days (Day -60 to -31 day). Days of free headache in each 30-day period were determined based on data recorded in the electronic telephone diary.
    The data recorded in the diaries included date and time of headache onset and date and time of end of headache, and the following characteristics of headache: normal headache (mild, moderate, severe), worsening headache (mild, moderate, severe); head side (unilateral / bilateral); type of pain (pulsating / throbbing or pressing / squeezing), and effect of physical activity on pain (worse, not worse). It also included symptoms of headache: Aura (yes or no); activity interference (yes or no), and other symptoms (nausea, vomiting, sensitivity to light [hotophobia, sensitivity to noise [honophobia]). The diary data also included acute medication, for headache (yes or no) and the name and dose of the medication. . Of the 571 patients examined and evaluated throughout the day - 60 to -30 day initial period, 355 were enrolled / randomized on Day O.
    At the end of the execution period (Day 0), 279 patients were classified as placebo non-responders and 76 responders as placebo. Subsequently, patients were randomized into each stratum (placebo non-responders and placebo responders) to receive the BOTOXº or placebo.
    Within the non-responder placebo stratum, 134 patients received BOTOX and 145 patients received placebo.
    Within the placebo responder stratum, 39 patients received BOTOX "and 37 patients received placebo.
    A total of 76.9% of patients (273/355) completed the study, including 132 patients who completed the original protocol, requiring only post-randomization treatment.
    Of patients who were discontinued early (22.8% [81/355]): 5.1% (18/355) due to lack of effectiveness, 1.4% (5/355) due to adverse effects, 0.3 % (1/355) due to the inability to follow the study instructions, 1.1% (4/355), for personal reasons, and 2.8% (10/355) were lost by. side dish.
    There were no significant differences between treatment groups in demographic characteristics.
    Overall, patients were 19 to 65 years old (mean 43.5 years), 84.5% (300/355) were female, and 87.9% (312/355) were Caucasian. .
    There were no significant differences between treatment groups in terms of baseline characteristics (Table 3). Table 3 Characteristics of the baseline (as treated population) o Line characteristics of 05 ions Total Placebo P-Value N = 182) =: base (N = 173) () (N = 355) Years since the beginning, mean | 11904224) | 1420125) | 1450124) | 0.655º * (SD) (given at the beginning, average of 27.5 (12.3) | 292 (136) | 284 (13.0) | 0.301º years (SD) Frequency of migraine - likely / migraines by 30 day period in 11.2 (6.6) 10.8 (7.9) 11.0 (7.3) 0.274 baseline Use of prophylactic treatment hp 56 (32, 71 (39.0) A ly Pain experience of ca-> 0.999 0 (O,),) menstrual period, n (%) 0.0) 00.0) 00.0) h Baseline score 55.3 (49, 9.8 (59, .6 (55,, 997 MIDAS, mean (SD) Employer | ua Score of baseline inventories for bells of 7.8 (6.9) 7.9 (6.8) 7.8 ( 6.9) | 0.847º depression, mean (SD) Total mean dose for 190.8 AI SD = standard deviation, NA = not applicable, MIDAS = Migraine Disability Assessment à P-value for comparisons of treatments of the Wilcoxon rank-sum test. ValorP- for comparisons of treatments of the chi-square test or Fisher's exact test.
    The most common places where the headache historically started and ended, as reported by patients at the beginning of the study, are shown in Table 4. VÀ Table 4 —Localondea Headache Historically Begins and Ends Reported at baseline ((%) Number of patients)] BOTOKo Placebo Total Location 105 U to 260 U P-Value = EE EEA o ea. where the pain started: mena | And where the pain ended | | In the analysis of the frequency of headaches over a period of 30 days, a statistically significant change in the frequency of headaches over a period of 30 days was observed in Days 30, 60, 150, 180,210, and 240 for placebo non-responders and on day 180 for the answering boards (Table 5). Figure 14 shows the average baseline and the average changes from baseline in the frequency of headaches over a period of 30 days for placebo non-responders and placebo responders.
    Table 5 - Mean (standard deviation) at the beginning and change from the initial value in the frequency of headaches for a period of 30 days for placebo non-responders VU and placebo responders for time | (N = 134) | (N = 145) (N = 39) (N = 37) base - es Thesis [2069 | om [6769 [leave] om | : [Pam] 2562 [306] om [7662 [sea] sz | [Da1so | s360 [2662 | 000 [2562 [sleep] os | | [atso [8165 | 2168 | 003 [sum [week] with | [eace] [71Ça | 4165 | 0065 | s76D | 8209 | 08 | Source: tables 14,2-12,3e14,2-12,4. * comparison between treatment using Wilcoxon rank-sun tests.
    In the analysis of other protocol variables designated as efficacy, there were statistically significant differences between BOTOXº and placebo in the group of non-responders and responders. In addition, the patient subgroups for which they were identified, there was a consistently better response to BOTOX "than to the placebo.
    Frequency of headaches, Combined Population A statistically significant change in the frequency of headaches over a period of 30 days was observed at various time points (Days 30, 60, 150, 180, 210, and 240) (Table 6). Figure 15 shows the average baseline and the average changes from the baseline in frequency. headaches for a period of 30 days.
    Did the analysis of the frequency of headaches show statistically significant differences between CÀU BOTOXS and the placebo that favored BOTOX , | Table 6 Mean (standard deviation) at the beginning and change from the initial value in the frequency of headaches for a period of 30 days; Combined Population rose Es | a | ee Time period p-value N = 173 N = 182 Placebo
    [Ban] 7a6n | 4260 | om | [ax [ro | sis | oo |
    * comparison between treatment using Wilcoxon rank-sun tests. - As can be seen in Table 6 and Figure 15, the time of the first statistically significant difference between the treatment groups in the frequency of headaches for a period of 30 days was 30 days after the first placebo treatment after execution, At this point in time, was there a significant difference (p = 0.021) between BOTOX and placebo showing a rapid onset of the effect.
    Were the mean changes from baseline 4.1 to BOTOX and -2.7 for placebo. - Table 7: Number (percentage) of patients with a 50% decrease in the line of knowledge of CU or more of headaches for a period of 30 days; Combined Population. [PRmPo [love | aemo | om | [Deo [measure | measure | os | : [an [semen | craves | 0352 | : om Theses | ema | 05 | | [—Bazo [Gems | sameso | o206 | 2nd comparison between the treatment of Person's chi-square test or Fisher's exact test. ” Number of patients with response / number of patients evaluated in the time period (in percentage). Table 8 shows the average baseline and average changes from baseline in the frequency of headaches over a 30-day period for patients who completed 2 and 3 treatment cycles after the placebo execution period.
    The 138 patients (69 BOTOX, 69 placebo) who completed three treatment cycles had a sustained response to treatment.
    During the 270-day treatment period the response to treatment with BOTOX generally continued to improve, while response to placebo treatment remained relatively stable.
    Table 8 ”Mean (standard deviation) at the beginning and change from the initial value in the frequency of headaches for a period of 30 days for patients who completed VU 2 or 3 injection cycles after running the placebo; Combined Population. | emanated [Paserçaaa from after execution of Pla- | after Pla-'s execution: cebo cebo [Cem [Siza | mere [rot noso | fresh [erme "| p-value p-value time N = 72 N = 79 N = 69 N = 69
    ESFIRINCIFINCO, base (7.5) (8.3) (7.5) (8.1) '[aso Tazea | ss6O] 0072 [476] 3160] 0006 | [biaso [5363 [3569] 0037 [5369 | 9768] 000 | | | Diai2o | -58662) | -3668)] 0023 [-57662) 36660] 0036 | i [Diatao [7168 [276] oo [7169/2763] 000 | [niaz4o [ramn 516] with [79 so6a | 002 | * comparison between the treatment of a Wilcoxon rank-sum test.
    Table 9 presents the average baseline and the mean changes: days from the baseline in the number of headaches, lasting> 4 hours and <4 hours per 30-day period. During the 270-day treatment period, in 4-hour headaches 2, were the baseline changes in headache count significantly higher for BOTOX than for placebo at all return visits (p <0.044, Table 14.5-325). A significant difference between groups was not seen on any return visit for headaches <4 hours in duration. ”- 'Table 9 Average baseline and Change from baseline in frequency of headache VU pain to headache with Duration 2 4 hours and <4 hours per 30 day period. [Ear [mer] tion> 4 Hours tion <4 Hours
    EARAFAÇIRAÇRADCA P-value P-value º * detempo | N = 173 | N = 182 N = 173, | N = 182
    FADIDIDDIEIC [beso] 28 [| 12 | om] 12 [| 5 [os] [Dao | as [no [om | 14 [xs [or | [aso [| a3 | 20 [om | 16 | 17 [086 | : [Demo] if | 20 | oo] ts | o | om): [Basso] 28 | 28 [00 | 20 | 8 | oso6 | [sinks] 46 | 22 | 0005 | 25 | 16 | ot | [Diaz] s1 | 24 | 0003 | 23 | 17 | 0688 | [Dazeo | Sa [so | oo | 27 | 21 | 030 | [Deo] ss [21 [om [| 24 | 22 | os | º comparison between the treatment of a Wilcoxon rank-sum test. Efficacy variables for which there are clinically significant differences between BOTOX and placebo in this subpopulation subgroup included: a 50% reduction from the baseline in the frequency of headaches over a 30-day period, a 30% reduction from the baseline in the frequency of headaches over a 30-day period; frequency of migraines or probable migraines for a period of 30 days, and the number of days and number of uses of analgesic medication for acute headache for a period of 30 days.
    Table 10 - Baseline characteristics of patients using and not using prophylactic medications for headache at baseline; Combined population. [Fo | Baseline prophylactic headache medications in 'BOTOX Features "| BOTOX placebo º | Baseline placebo (N = 117) | (N = 111) | P-Value | (N = 56) | ( N = 71) | P-value Age, mean 422 42.5 0.978 * 44.4 46.5 years (SD) (104) | (11.5), (8.5) (10.3) Sex, n (%) 'Male 11 (9.4) 2 11 (19.6) | 11 (15.5) | 0.540 »(19.8) Female 106 89 45 60' in (90.6) | (80, 2) (804) | (84.5) Race, n (%), 102 EX) b 52 65> 0.999 Caucasian (87.2) | (838) | 996 | 1929) | (91.5) Z -; 15 18 Non-Caucasian (12.8) (16.2) 4 (7.1) | 6 (8.5) Years from the beginning, 15.3 14.3 13.8 14.2 0.864 Mean (SD ) (13.2) (12.8) (10.7) (12.1) 'Age at onset, mean 26.2 27.6 30.1 31.8 0.407th day of years (SD) (12 , 2) (13.1) (12.1) (13.9) 'Prophylactic headache medications, n (%) Beta blockers NA NA NA IS 21 0.901 eta D'oq 186) | ( 296) '18 calcium channel blockers NA NA NA 9161) (25.4) 0.204;; 23 27 Anticonvulsants NA NA NA (411) (38.0) 0.727; Only 31 43 Antidepressants NA NA NA N A (85.4) (60.6) 0.655 MI- baseline. 54.0 55.7 58.0 66.1 at DAS score, mean (44.4) (60.3) (59.7) (58.8) 0.264 (SD) Depression signs inventory score | 6.9 (6.6) | 7.8 (7.0) | 0.945º | 9.5 (7.4) | 8.6 (6.4) | 0.739 healthy, mean (SD)
    SD = standard deviation, NA = not applicable, NC = not calculated. - P-value for comparisons of treatments from the Wilcoxon rank-sum test. P-value "for comparisons of chi-square treatments or Fisher's exact CU test.
    The mean baseline and mean baseline changes for each time point for assessing the frequency of headache days per 30-day period are shown in Table 11 and figure 16 for the patient populations in use and not using prophylactic headache medications at first. The types of prophylactic headache medications used at the beginning of the study included beta blockers, calcium channel blockers, anticonvulsants and antidepressants (excluding serotonin reabsorption inhibitors [eg Prosacº] since Ú there is no no evidence of any effect on headache for this class). Table 11. Mean (standard deviation) at the beginning and change from the initial value in the frequency of headaches for a period of 30 days due to the use of prophylactic medications: Headache at baseline; Combined Population. [The seara seem | sm o e Es ET | N = 566 N = 71 N = 117 N = 111:
    EXRRORHO [es Tasun [2667] 08 [3760 [2569] 000 | [Da & [250 | a65uo | the [sen 2067 | 0005 | [Dam [ssa [2009] 025 | ss6o [ssa] om | [Dersa [s76n [2769 | the [7862 [456 | 00 | [De1so [6660 [asun | oo [7560 [267 | 000 |
    [UU eestessneemen rhinestones postpones prophylactic headache medications at baseline. sm Ng »* comparison between the treatment of a Wilcoxon rank-sum test.
    For patients using antidepressants at the beginning of the study: (31 BOTOX, 43 placebo) there were no statistically significant differences between the treatment groups at any point in time, except for the '5 210 days (p = 0.048), in the change baseline in the frequency of headaches for a period of 30 days.
    From day 120 to 270 days, the reduction - mean of the baseline was greater for BOTOXº for 1.6-3.7 headaches for a period of 30 days.
    For patients who did not use antidepressants at the beginning of the study, from the 60th to the 270th day, the average reduction. 10 from the baseline was higher for BOTOXº by 1.7-3.6 headaches for a period of 30 days.
    Was the change from baseline significantly higher (p <0.020) than BOTOX on Days 30, 60 and 180. The percentages of patients at each assessment time with at least a 50% reduction from baseline in the frequency of headaches for a period of 30 days (defined as a response) are shown in Table 12 for patients using and not using prophylactic headache medications at the beginning of the study.
    For patients using prophylactic headache medications at the beginning of the study, there were no statistically significant differences between BOTOXS and placebo.
    For patients who do not use prophylactic medications for headache at baseline, from day 150 to 270 days, at least 50% of patients treated with BOTOX responded to treatment.
    The differences between BOTOXº and placebo were statistically significant on days 150 and 210. At these time points, the response rate for BOTOXSº was greater than the response rate for placebo by at least 20%.
    Table 12 »Number (percentage) of patients with a baseline decrease of 50% or more in headaches for a period of 30 days due to the use of prophylactic medications Headache at baseline; Combined Population.
    Fo | Use of prophylactic headache medications in the baseline BOTOXº period | BOTOX Placebo "| Placeb: tem) P-value icebo Da PO N = 56 | ne7z | VOOMPO | oa | mean | Vier Treatment 1: Placebo (followed by a run period of 30) Case of 4/56 7M 0754 194117 | 130741 »o o o, Placebo (7.1%) (9.9%) (16.2%) (11.7%) - R 10.56 17/71 35/116 30/111 (17, 9%) (23.9%) | 0205 (30.2%) (27.0%) 6,500 15/54 20/66 45/110 29/100 i 0.762 Gram) | (603%) E (409%) | (29.0%) 15/53 22/63 39/96 27/94 'ji Aa (28.3%) (34.9%) (40.6%) (28.7%) 0.085. Treatment 3 17/34 17/39 16/46 11/43 4 | pero | 60.0%) | (436%) 48%) | (256%) 13/30 19/38 25/45 14/42 Day 150 (43 , 3%) (50.0%) (55.6%) (33.3%) Day 180 16/28 15/38 23/44 15/41 (57.1%) (39.5%) (52 , 3%) (36.6%) Treatment 4 '18/29 17/38 22/41 11/89 sink 210 (62.1%) (44.7%) EI (53.7%) (28.2 %) 0.021 18/29 17/35 21/41 15/36 (62.1%) | (48.6%) 0: 289 (51.2%) | (41.7%) 16/29 19/33 24/40 19/36 j 849 Pia27o | 552%) | (67.6%) (60.0%) | (62.8%) * comparison between treatment using Person's chi-square test or Fisher's exact test. number of patients with response / number of patients evaluated in the time period (in percentage).
    The percentages of patients at each assessment time with ”at least a 30% reduction from baseline in the frequency of headaches over a period of 30 days are shown in Table 13 for patients using and not using medications prophylactics of headache at the beginning For patients using prophylactic headache medications at the beginning of the study, were no statistically significant differences between BOTOX and the placebo.
    For patients who do not use prophylactic medications for headache at baseline, from day 30 to day 270 at least 50% of patients treated with BOTOX 'had at least a 30% reduction in the frequency of headaches over a period of 30 days.
    The differences between BOTOXº and placebo were statistically significant on Days 30, 60, 150, 180 and 210. At these time points, the response rates for Botox were higher than the response rates for 16-day placebo. , 4 to 26.2%. . Table 13 Number (Percentage) of patients with a baseline decrease of '30% or more of headaches for a period of 30 days due to the use of prophylactic medications Headache at baseline; Combined Population. [use if prophylactic medications for granddaughter headache if thesis | | PAess sme Tres Tvs "| soroe [Press [vos]. 'EXSEADADIFIAFIC:
    ps Use prophylactic headache medications at baseline. [Im No o. 20/34 23/39 26/46 20/43 At 18/30 26/38 35/45 24/42. 20/28 24/38 33/44 20/41: 23/29 22/38 28/41 18/39 (79.3%) FEFICGIFIFIDI. 22/29 23/35 31/41 22/36 ': 20/29 23/33 30/40 23/36
    EXBFAFIDIFIAFADS: º comparison between the treatment using Person's chi-square test. - The analysis of the frequency of headaches for a period of 30 days for patients who were 10 to 20 years old and> 20 years old since the beginning of the disease are shown in Table 14. The response to BOTOX was consistently better than the response to placebo over the treatment period for patients with disease onset 10 to 20 years, with a statistically significant difference only on Day 180 and for patients with disease onset of> 20 years, with statistical significance differences on Days 30, 60 and 210. Of note is the observation that, for subgroups of patients> 20 years old, the response to placebo treatment was consistently and considerably less compared to the response to treatment for subgroups of patients aged 10 to 20 years.
    Table 14 + Baseline Average (Standard Deviation) and change in the initial value in the frequency of headaches for a period of 30 days per time of onset of CU disease (10 to 20 and> 20 years); Combined Population. [coa dsene Ts20ans | disease code> 20aros - | time N = 53 N = 53 N = 46 N = 48 base - [Bs Tssso [36 | om | 4760 [7562 | 00 | [aso | 4960 [4169 | 0269 | sema | 1862] 00 | “= [Ba [4069 | a4uo | 00 [sata [2662 | oo | [Demo | s269 [256] 0205 [sin | 256] om | : [Datso [7762 [5760 | 026 [s360 (2560 | 01 | [Det [s16A [4862 | 0065 [6169 [2563] 005 | | * comparison between treatment by a Wilcoxon rank-sum test.
    The analysis of the frequency of headaches per 30-day period of headache frequency at baseline (20 to 24 and 25 to 30 days of headache) are summarized in Table 15. The response to BOTOX was consistently better than the response to placebo over the treatment period for patients with a baseline day-headache frequency of 20 to 24, with statistically significant differences on days 60 and 180, and for patients with a baseline headache of 25 days to 30 days, with statistically significant differences on Days 30, 60, and 180. At each time point, the difference between mean changes for BOTOX "and placebo were higher for patients with a baseline frequency of headache
    25 to 30. + Table 15 Mean (standard deviation) at the beginning and change from the initial value in the frequency of CU headaches for a period of 30 days for patients with Day-Frequency headache from 20 to 24 and 25 to 30 for a period of 30 days at the beginning; Combined Population [| SEADE | sas peicisaesndas 20 to 24 for a period of 30 days 25 to 30 for a period of 30 days time N = 53 N = 54 N = 70 N = 81 | [Bas Ts7en 3269] 026 [356 [1209] 00 | [weight [ss6n 2760 | 006 [2062 [1469] 006 | | : [Dem [556 [2660] 016 [3167 [2569] o | [beto [2060 | ss6nm] 017 5265 | 2769 | 005 | [isteo [es60 | sum] 006 [sum | 256a] with | * comparison between the treatment of a Wilcoxon rank-sum test.
    Frequency of headaches per baseline of overuse of medication Analgesic for acute headache Overuse of medication was defined as the use of any acute analgesic medication for 2 15 days and 2 2 days / week.
    Based on this definition, for patients who did not overuse acute analgesic drugs at the beginning of the study, no statistically significant differences were observed between BOTOXº and the placebo in terms of baseline changes in the frequency of headaches per period 30 days at any point of time (Table 16). For patients + with an excess of acute analgesic drugs at baseline, except for Day 90, the difference in baseline reduction was significantly higher CU for BOTOX than placebo. Were the average baseline reductions greater for BOTOX for 2.0-5.6 headaches in all periods, except day 90 (Table 16). Table 16 Mean (standard deviation) at the beginning and change from the initial value in the frequency of headaches for a period of 30 days for patients with excessive use of analgesic medication acute headache (No, Yes) at the beginning; - Combined population.
    EE REIS 1 gesico for> 15 Days and> 2 Gesico for> 15 Days as / Week, No e> = 2 Days / Week, Yes' Period | BOTOXº | Placebo a | BOTOX | Base placebo: [Ben Tas [2860] 032 [3560 [2509] 00 | [aso [2063 [2769] 076 [ssa (2662 | 000 | [Demo Tases [266] os [269] ss6A] com | | Datso [sun | so67 | os | 2269 2362] 00 | [aro [sun | sa60 | oo [16 266] 00 | [os2 Tosa [4407] os [2579 | ss6] oo | * comparison between treatment of a Wilcoxon rank-sum test Types of Headaches Each headache was classified as a migraine (ICHD 1) or not migraine (ICHD 2; example, tension-type headache).
    of patients had at least one migraine during the »baseline period, which suggests that all patients may actually have a migraine diagnosis, although this diagnosis has not been recognized by the investigator for all patients .
    During the study, patients experienced migraines and non-migraine headaches.
    Most headaches in both treatment groups were classified as migraine (by ICHD criteria). Migraine The average baseline and mean baseline changes in the frequency of migraine headaches (ICHD 1.1 or 1.2) or 'likely migraine (ICHD 1.5.1) for a period of 30 days are shown in Table 17 At all time points the decrease from baseline was' greater for BOTOXº compared to placebo and were significantly greater (p <0.048) on days 120, 180, and 210. At that time the mean decrease from baseline was higher for BOTOXº by 1.6-2.8 headaches.
    Table 17 'Mean (standard deviation) at the beginning and change from the initial value in the frequency of migraine and headaches of probable migraine for a period of days; Combined Population. [snoring | ES | and | ves | Time period P-value N = 173 N = 182 [BRs TT ss | 276 | 0 [act q mrs | 76 | and [stop TT ss6a [son | om ç N = 173 N = 182 th comparison between the treatment of a Wilcoxon rank-sum test.
    Non-Migraine Headaches The average frequency of non-migraine headaches over a period of 30 days at baseline was 2.3 and 1.8 on BOTOX and placebo, - 5 respectively.
    Were there no statistically significant differences (p = 0.065) between BOTOX and the placebo regarding changes from baseline in the 'frequency of non-migraine headaches for a period of 30 days in all periods, except day 90 (p = 0.034). At all times after the execution period, the mean baseline reductions were - 10 largest for BOTOXº by 0.3-1.0 headaches without migraine.
    On day 90, the average reduction was 1.0 for BOTOX and 0.2 for placebo. 'MOU There were few statistically significant differences between treatment groups for the use of any acute headache medication (eg, triptans, opioids, etc.) during a 30-day treatment period.
    There was also no statistically significant difference between the group differences for the individual categories of medication, that is, Ergotamines, triptans, simple analgesics, or antiemetics.
    There were significant differences between the opioid treatment groups on day 210 (11.4% [8/70], BOTOX , 24.7% [19/77] placebo, p = 0.038 and for combination therapies on day 210 ( 34.3% [24/70] BOTOXº, 18.2% [14/77] placebo, p = 0.026) and 240 days (32.9% [23/70] BOTOXº, 18.3% [13/71 placebo] ], p = 0.048 The baseline characteristics of patients with excessive use without overuse of analgesic medication acute headache at baseline are summarized in Table 18. Acute patients with overuse of analgesic headache medications were significantly older at the beginning of the study (mean age 45.6 versus 41.6 years, p = 0.001), otherwise there were no statistically significant differences between the demographic characteristics of pain relievers headache in excess and without excess at the beginning of the study.
    Table 18 Baseline characteristics of patients with and without overuse of analgesic headache medication at baseline; Combined Population.
    Excessive use of analgesic medication. of headache at baseline. Line feature | n = 70s | 187 Base P-Value Jd o O | "Age, mean in years 45.6 (9.6) 41.6 (11.0) 0.001 * (SD) - Sex, n (%) Male 32 (19.0) 23 (12.3) 0.079 º. Female 136 (81 , 0) 164 (87.7) Race, n (%) Caucasian 151 (89.9) 161 (86.1) 0.275 º Non-Caucasian 17 (10.1) 26 (13.9) “| Years from the beginning , mean (SD) 15.7 (12.6) 13.5 (12.2) 0.075 Age at onset, mean in b years (SD) 29.3 (12.4) 27.5 (13, 4) 0.153 Prophylactic and headache medications, n (26) 61 (36.3) 66 (35.3) 0.842 Beta blockers 16 (9.5) 21 (11.2) 0.599 * 4 and 4 channel blockers calcium 14 (8.3) 13 (7.0) 0.624 Anticonvulsants 23 (13.7) 27 (14.4) 0.840 º Antidepressants 38 (22.6) 36 (19.3) 0.435 * Baseline score> MIDAS, mean (SD) SAS 54.7) 60.6 (55.2) Baseline score of signs inventory of 7.9 (6.6) 7.8 (7.1) 0.577 * depression, mean (SD)
    º overuse = use for 2 15 days and 2 2 days / week> P P-value for comparisons of treatments of the Wilcoxon rank-sum test.
    CU º P-value for comparisons of treatments of chi-square test or Fisher's exact test. In all post-times of baseline points, in BO-TOXº compared to the placebo group, there was a great decrease in the number of use of analgesic medications for acute headache, with a statistically significant difference at 90 days and 210 (p <0.047). This was also observed in the analysis of the average number of days of. Analgesic drugs for acute headache were used, with statistically significant differences on days 90, 180, 210, and 240 (p <'0.033). Table 19 Mean (standard deviation) at the beginning and change from the initial value of the Number of 7 Uses and days of use of analgesic drugs for acute headache for a period of 30 days for patients who do not use prophylactic drugs for headache at baseline; Combined Population | | anita burns in awe | agtecas acer docmteta ato Analgesics for acute headache | nalgesics of acute headache time N = 117 N = 111 N = 117 | NEH [es Temo] Ea [26 [69 [ssen] 1 |
    | | aesd ar ads cmeçsana | aagecas air aorto coa açuês | Acute pain relievers | pain relief from acute headache. time N = 117 N = 111 N = 117 N = 111 the BRes Tesa rna] in [76 [16 | 005 | [Tsscan peace | e569 | om | ese) a77o] 00% | [eace [ssasa e2ma] oo [without 5203] 00% | comparison between the treatment of a Wilcoxon rank-sum test. Overall, 97.7% (347/355) of patients received acute headache medications, while in the study, with similar proportions in each treatment group: 98.3% (170/173) of patients in the '5 BOTOXº group and 97.3% (177/182) in the placebo group. Overall, 87.6% (311/355) of patients received concomitant medications (with the exception of acute headache medications), - with similar proportions in each treatment group: 90.2%. (156/173) of patients in the BOTOX group and 85.2% (155/182) in the '10 placebo group. : A total of 35.8% (127/355) of patients were taking medication for headache prophylaxis during baseline. These included 10.4% (37/355) in beta blockers, 7.6% (27/355 in calcium channel blockers, 14.1% (50/355) in anticonvulsants, and 20.8%
    15. (74/355) in antidepressants. There were no statistically significant differences between the BOTOX progestins and placebo groups in the number of patients taking any of the aforementioned prophylactic headache medications. During the placebo execution period (first treatment cycle 1, Day -30 to Day 0) all patients received placebo on day -
    30. On day O, patients were randomized to receive three cycles of treatment for intramuscular injections of BOTOX or placebo. Of the 355 patients who participated in the study, 173 received 105 U and 260 U BO-TOXº and placebo received 182. The maximum dose of BOTOX "that the patients could have received, according to the protocol was 260 U per» treatment cycle. for each of the 3 treatment cycles for a total cumulative exposure of 780 U. "Dose The mean (median) of the total dose of BOTOXº for the second, third and fourth treatment cycles was 190.8 U (200 U), 190 , 9 U (200 U), and 190.5 (200 U), respectively.
    The average and median doses of BOTOXº injected into each muscle group during the second, third and fourth treatment cycles are shown in Table 20, Of note is the observation that the optional masseter injection was administered in less than half: of the patients in both the BOTOXº and placebo groups.
    Table 20 | Ú Average (median) doses of BOTOX injected by muscle group per treatment cycle. - (Dose interval treatment 2 treatment 3 treatment 4 allowed) (Day 0) (Day 90) (Day 180) Note: During treatment cycle 1, all patients were treated with placebo. . The numerical average (mean) of the sites injected with BOTOXº per muscle group for the first, second and third injections are shown in Table 21.
    Table 21 x Average (median) of the Number of Sites injected by Botoxº per muscle group per treatment cycle. VC Injected Muscle (Inter-Cycle Cycle of "treatment 2 treatment 3 treatment 4 dose allowable) (Day 0) (Day 90) (Day 180) Masseter (optional; | Splenius capitis (10 a - Note: During treatment cycle 1, all patients were treated with placebo., The significant and consistent efficacy favoring BOTOXº over placebo was observed for the change from baseline in the - frequency of headaches for a period of 30 days. alterations were observed in the group of non-responding placebo strata and in the respondent placebo, in the data obtained, and in the subgroup of patients with baseline headache without prophylactic treatment. is a preferred primary endpoint in migraine trials (European Medicines Assessment Agency, 2003). Recent prophylactic migraine treatment approved by the FDA North American has also established efficacy by measuring a change in frequency headache (Depakote bula, 2003).
    Significant differences were found between the groups that favored BOTOXº in the percentage of patients with a baseline decrease of at least 50% or more, for each period of 30 days in the number of headaches, on Day 180 (54.2 % vs 38.0%, p = 0.046) and
    210 days (57.1% vs 36.4%, p = 0.012). In addition, the percentage of patients with a 50% decrease in headaches over a 30-day period occurred in more than 50% of patients on days 150, 180, 210, 240, and VU 270 in the BOTOX group , while this level was reached only on Day 270 in the placebo group.
    Example 4 - Type A Botulinum Toxin Injection Paradigm to Treat Chronic Migraine A clinical study was conducted to develop and optimize a dosage and administration paradigm for the injection of botulinum toxin, useful in the treatment of migraine, particularly chronic migraine.
    This one . study developed a new method and selection of muscles to be injected, minimum doses, as well as optional, maximum dose and number of injection sites per muscle were specified in the present study.
    In this study, a preferred formulation of botulinum toxin (BOTOX) was used. The present injection paradigm is particularly useful for the treatment of migraine patients with 15 or more days of headache over a period of 28 days.
    In one aspect (double blind phase) the study compared the administration of botulinum toxin, according to this injection and dosing paradigm, with placebo, as well as a prophylactic treatment for patients with migraine headache with 15 or more days of headache for a period of 4 weeks.
    It has been found that injection, in a preferred embodiment, from a minimum of 31 to a maximum of 39 injection sites, a minimum dose of 155 to 195 units of maximal administration of the to-: 25 — botulinum x type A injection paradigm ( here BOTOX) detailed below, provided very positive and effective clinical results for treated patients.
    In a modality of a dosing paradigm used in Example 3, the administration of 155 to 195 units (units in 31-39 injection sites) per treatment cycle was repeated every 12 weeks, up to a maximum of 5 treatment cycles. injection.
    This injection paradigm, in a modality, required a minimum required dose of 155U using a fixed site, a fixed dose injection regime in 31 sites across the 7 head / neck muscles. An optional additional dose of botulinum toxin up to x 40U (up to a maximum of 8 sites), using a pain-following regimen, provided flexibility in muscle dosing for all 3 muscles (poral, occipital and trapezius VU) ) to satisfy the needs of individual patients. By using a portion of the regimen following the additional pain, optional in this new injection paradigm for these three muscles (temporal, occipital and trapezius), the optional and additional botulinum toxin it was administered unilaterally or bilaterally to one or even three of the specific muscle areas of the head / neck (temporal and / or occipital and / or trapezius).
    With reference to figure 17, an example of fixed locations for which doses of botulinum toxin were administered to patients (here administered in a supine and sitting position, for example), according to S with an aspect of a injection paradigm, are described. In figure 17, in each indicated location, 0.1 mL = 5U of botulinum toxin type A was administered. Abbreviations used in figure 17 (in each of the mid- muscles) means FSFD = fixed-dose fixed site, FTP = following optional pain (sites and amounts of botulinum toxin administered, using: part of following the optional injection paradigm pain, are detailed below). : It was determined that the frontal / glabellar region was the most frequent place where the headache started and ended. It was determined that to ensure consistency, efficacy and standardization of treatment, three muscles (frontal, corrugator and proterus) were selected to be included as part of the 31 fixed sites and the fixed dosing muscles of the Example 2 injection paradigm. In order to reduce the potential for focal adverse events, such as eyelid ptosis, a total dose of 35U was determined to be the most advantageous. In addition, the exact number and locations for injection into these muscles have been specified to ensure optimal tolerability and specifically to minimize eyelid ptosis. Indeed, did the injection method specified in these muscles achieve these goals since the statistically significant separation from placebo in various measures of headache symptoms with an overall rate of eyelid ptosis for patients treated with BOTOX in the double-blind phase, placebo-controlled was found.
    In the injection of these superficial muscles, the needle was kept preferably superficial VU to avoid hitting the periosteum.
    In one aspect, a total of two injections were given to the corrugator muscle, one on each side of the forehead (figure 17, A). The injection site is located approximately 1.5 cm (1 finger wide) above the upper medial border of the orbital crest (bone mark). The thumb was placed under the corrugator muscle and the administration is done with the needle tilted upwards and away from the eye (towards the forehead), to prevent eyelid ptosis.
    In another aspect, a. The procerus may have an injection site, which is at the midline on the forehead about 1.5 cm above the midline and with the upper medial aspect of the 'orbital crest (bone mark) of each eye (figure 17, B). This injection site is substantially halfway between the two injections of the corrugator.
    In the frontal injection, the needle does not need to be directed upwards for these injections.
    A total of four injections (2 on the left and 2 on the right) were given to the frontal.
    For the two medial injection sites, an imaginary line that takes the part of the medial edge of the eyebrow to about 1.5 'cm (a finger width) from the corrugator injection site is a useful method for determining the needle position (figure 17, C). The lateral injection sites were parallel and approximately 1.5 cm lateral to the medial injection sites.
    As for the temporal, which determined that the temporal area was the second most frequent place where the headache started and ended. —Fixed dose and fixed site regimen for this muscle was used in the present injection paradigm.
    Since this muscle is a common predominant pain location for many patients, a minimum dose of 20 units on each side (40 minimum units total) was determined, and an additional dose of up to 10 total units (administered to a or both sides in 5 unit increments) for this muscle group was allowed to use in a pain-following strategy.
    The temporal area received a minimum total of 8 injections, 4 on each side (figure 17, D). In addition, up to 2 additional injections using the follow-a-pain paradigm option were used.
    Before any injection, the muscles on both sides of the head were palpated for feeling or pain.
    Clenching of the patient's teeth assisted by a medical doctor - in locating the anterior aspect of the temporal muscle, which was then palpated.
    The first injection was done just behind this point, trying to stay behind the hairline.
    The second injection was approximately 0.5 cm and 1.5 cm superior posterior to the first injection in the medial aspect of the muscle.
    The third injection site was parallel and about 1.5 cm posterior to the second injection.
    The fourth fixed injection site was 1.5 cm below and is perpendicular to the second injection, for the medial aspect of the muscle.
    If additional injections (using the follow-a-pain aspect and this B injection paradigm of Example 2) of botulinum toxin were used, additional injection sites (instead of increasing the injection volume to the 4 fixed sites) were performed . - With regard to the cervical paravertebral muscle group (neck muscles), it was determined that the headache often "started and / or stopped at the back of the head (or in the occiput and / or neck) Thus, it was determined that for the injection paradigm used in this example, the injections were given in the upper part of the neck (cervical paravertebral muscles above the occipital crest), at the base of the skull, instead of in the middle region of the neck ( to avoid neck pain and neck stiffness), and thus, a pain-following injection regimen was not allowed in the neck region, and the injections were more superficial, rather than inserted deep into the neck muscles. (in a preferred embodiment, the length of the injection needle and gauge were standardized at 1.27 cm (0.5 inch) and gauge 30, respectively) and the total injected dose to the neck region was reduced.
    Thus, the global dose for the cervical paravertebral muscle group was a fixed site, the total fixed dose of —20U for this muscle group (10U on each side of the head divided into four sites (5 U per site, figure 17 F)). It was determined that this dose is sufficient from the point of view of efficacy and this particular dose in the neck
    result in less or no neck pain, less or no neck stiffness and decreased the risk of excessive neck muscle weakness, which improved the overall tolerability profile while maintaining efficacy. VU Starting from the left side, the injection sites of the cervical paravertebral muscle group were located by palpation of the cervical spine and it was preferable not to go too deep into the cervical paravertebral and trapezius muscles with the injections (1 needle hub , 27 cm (0.5 inch) serves as a relatively "depth" precision guide). The first injection was administered lateral to the midline, about 3-5 centimeters below the occipital protuberance. A second injection was administered at. same side, 1 cm lateral and superior to that of the first injection (diagonally in relation to the ear, from the first injection). This procedure was repeated symmetrically, on the contralateral side, for a total of four injections (fixed points).
    Regarding the trapezius, it was determined that the headache with. frequency started and / or ended on the trapezoid. Thus, the dosage regimen for the trapezius muscle was standardized to a minimum dose of 30 'U (15 U on each side) (to avoid / minimize pain in the arm (shoulder)), with the additional option for treatment of following pain, at a maximum dose of 50U (ie, an additional 20 units and up to 10 global locations), if clinically necessary. Thus, the upper portions of the trapezius were palpated to identify areas of sensitivity and / or pain. Beginning on the left side, the muscle was visually divided into three sections. in one modality, the first trapezius injection was administered in the lateral aspect of the muscle. Moving medially, the middle portion of the trapezius was administered the second injection, while the third injection was administered medially and superiorly within the third section of the muscle. This procedure was repeated symmetrically, on the contralateral side, for a total of six injections (figure 17, G.). According to one aspect of the optional follow-a-pain dosing paradigm, an additional 4 injections were, if necessary, distributed between the right and left trapezius muscles in the domains identified as having maximum sensitivity.
    The inferior-medial portions of the + trapezius muscle were avoided to limit the possibility of neck weakness. 'OR Regarding the occiput, it was determined that the occiput was a more frequent third place in which the headache started and ended.
    According to one aspect of our new injection and dosing paradigm, the minimum dose administered to the occiput was 30U at 6 injection sites in the occiput, located mainly above the occipital crest, which reduces the risk of weakening the neck.
    It was also determined that, in order to treat possible complaints of a predominant pain in the back of the head, additional follow-up dosing was allowed in the occipital. 'Before injecting the occipital area, both the left and right sides were palpated to identify areas of tenderness and / or pain.
    To locate the injection sites in the occipital, the ex-occipital protuberance. tender was touched.
    The sites are superior to the supranuchal ridge on both sides of this protuberance.
    In one embodiment, three injections were 'administered to the right and left occipital muscles, for a total of six injections (figure 17, E). As an example, the first injection was given just above the occipital protuberance along the supranuchal crest and about 1 cm to the left / right (as the side) of the external occipital protuberance.
    The second injection was given approximately 1 cm to the left / right and about 1 cm above the first injection.
    The third injection was given 1 cm medial and 1 cm above the site of the first injection.
    According to and in one aspect of a modality, the dosing paradigm following the optional pain, in an additional 2 injections were, if necessary, distributed between the right and left occipital muscles (1 injection on each side, or two 1-sided injections) in areas that have been identified as having maximum sensitivity.
    In one embodiment of the present invention, the masseter muscle was not included as a group of target muscles for injection at the time of the injection / dosing paradigm used.
    It was surprisingly
    Since some patients had pain in the masseter region, Ns as part of the symptoms of chronic migraine, the injection of botulinum toxin into the masseter muscle was not necessary to obtain positive CU results for clinicians. Headache.
    Thus, this paradigm, which uses a combination of fixed and pain-based locations for the administration of botulinum toxin, provides an optimal distribution of botulinum toxin, such as a type A botulinum toxin, based on the symptoms of the individual patient. .
    Thus, in a modality, the minimum fixed dose of 155U and the fixed number of injection sites (31 sites), divided between 7 specific ones. muscles of the head and neck (referred to as a 'fixed location, fixed dose regimen) (Table 23) were tested. Interestingly, this protocol also' enabled a follow-up regimen outlined and modified to an additional 40U divided by 3 specific muscles: temporal (up to an additional total 10U in up to 2 more locations), occipital (up to an additional total 10U in. Up to 2 more locations) and trapezius (up to an additional total of 20U in an additional up to four (Table 24). As indicated below, the 'follow-a-pain' portion regime was not required, nor was there a requirement to standardize the use of follow-a-pain from one injection cycle to another injection cycle ( toxin administered every 12 weeks).
    The global study was a multicenter, double-blind, randomized, placebo-controlled, clinical study of parallel groups with an open label extension phase, and was conducted for 60 weeks (including an initial phase of 4 weeks, followed by a 24-week, double-blind treatment phase, before patients enter an open, 32-week extension phase. Patients were randomized / stratified after an initial 4-week phase, in which patients who meet the inclusion / exclusion criteria were assigned a randomization number provided through a telephone exchange randomization system.
    Patients were classified as overuse of medication ("yes"), which meet one or more of these categories.
    Table 22 * Overuse criteria General: combined at least> 10 days per month and at least 2 two categories between ergotamines, | days a week triptan, painkillers' combination of painkillers as a category) and opioids. days a week: days a week days a week] days a week sica days a week Within each stratum, the patient was randomly allocated to receive botulinum toxin or placebo in a 1: 1 ratio. As for the dose and dose regimen, two sessions (2) in the double-blind treatment phase and three (3) treatment sessions in the open label extension were performed.
    In the double-blind phase, all patients received a minimum dose of 155 U of botulinum toxin or placebo administered as 31 fixed site, fixed dose injections through seven (7) specific head / neck muscle zones listed in Table 23. In addition In addition, at the doctor's discretion, additional injections of botulinum toxin or placebo were administered unilaterally or bilaterally, with a pain-following paradigm in up to three (3) specific muscle areas of the head / neck | (temporal, occipital, and / or trapezius). According to one modality, the dosage and the number of possible injection sites are described below in the form of a table:
    Table 23 oo Required dose using a fixed-site injection, Fixed dose.
    Ps gal / neck Number of units | Number of units | Number of units per muscle (number- | per muscle (number- | per muscle (number of injection sites | | of injection sites | of injection sites *) tion) [Po and sara hunger | Gees | see | 306 | : In | neither | rem | behold 1 Cervical Paraespi- 10 (2 sites) 10 (2 sites) 20 (4 sites) nhal [reemnimo D E esuantess injection site 1 = 0.1 mL = 5 U of botulinum toxin type A or O U of the 'placebo group.
    - 5 optional additional injections (that is, in addition to those detailed in Table 23) were not required to be consistent across treatment visits, with respect to dose or number of injection sites (as they were administered on a case-by-case and at the doctor's discretion, but not exceeding the maximum allowed dose (ie 195 units).
    It was determined that the doctor took into account what the patient reported at the usual predominant pain site, severity of muscle sensitivity during palpation of the muscle before injection, and better judgment by the doctor about the potential benefit of doses specific muscles (for example, large muscle size) in determining how many additional units to inject above the minimum value set for the particular muscle region (for example, temporal and / or occipital and / or trapezius) . Thus, in one example, the minimum total dose was 155 U with 31 head / neck injections and the maximum total dose was 195 U with 39 head / neck injections.
    Table 24 E Optional additional dosage using an injection paradigm | following-a-pain: 'TOTAL RIGHT LEFT Head area / - | Location Number Number | Number of neck units per - | units per - | usual pain or units per muscle (node- - | muscle (num- - | sensitivity - | muscle (number of sites | number of sites | in probing the number of injection sites ”) of injection of injection *) Uilocal ( up to Left side 2 locations) Uoca! (0.50u10U SU / location (up to ia. Both la- 5U. 5 U (1 location) (1 location) Í 5 U / location (up to Left side 2 locations) 0 , 50u 10U 2 s SUNocal (up to 2 | | aqodirito | (0.1or210- Local time) sas) 'Both la- | sU 5 U (1 place) (1 place)' 5 Uflocal (up to 4 places) 5 Ullocal ( until Left side 5 U (1 place) 3 places) 5 Ullocal (up to 4 places) 0, 5, 10, 15 or Trapezoid o 20U 5 U (1 place) 5 Ullocal (up to 3 | Right side 0. 1,2 , 3 locations) (0, 1,2, 3 or 4 locations) 5 Ullocal (up to | 5 U / local (up to 2 2 locations) locations) Both sides stretchers Do = [EU 1 js Injection site 1 = 0, 1 ml = 5 U of botulinum toxin type A or OU of the placebo group ”Additional maximum dose distributed unilaterally or bilaterally, is as follows: occipital = 10 U, Temporal = 10 U, Tr apezium = 20 U.
    During the initial phase of this example (Week 4 to Day 0), the patient had »at least 15 days of headache and at least 4 headache episodes of any type, each with a minimum duration * ú. 4 hours. At least 50% of headache episodes were classified as migraine (ICHD-II 1.1 or 1.2) or probable migraine (ICHD-II
    1.6). After the 4-week baseline phase, potential patients returned to the investigators office to qualify for entry into the 24-week, double-blind treatment phase. Women of childbearing potential had a negative urine pregnancy test before entering the 4-week baseline phase and even before the first injection of the study drug on Day 0.
    Thus, and as an example, a combined paradigm of fixed Ú site and following-pain of botulinum toxin dosage and administration sites having a minimum number of head, neck and shoulder areas to be administered with a minimal amount of botulinum toxin, along with a subset of those head, neck and shoulder areas to which additional botulinum toxin can be administered (up to a maximum recommended dosage), such as a maximum dosage listed in a package insert or prescription information is described.
    权利要求:
    Claims (8)
    [1]
    1. Method for prophylactically treating a headache in a patient with chronic migraine headaches, characterized by the fact that it consists essentially of: local administration of a botulinum neurotoxin to the frontal paraspinal muscles, corrugator, prostate, occipital, temporal, trapezius and cervical of the patient suffering from migraine headache; in which botulinum neurotoxin is administered to the frontal spinal muscles in about twenty units divided between four injection sites; to the corrugator in about ten units divided between two injection sites; to the wax in about five units for an injection site; to the occiput in about thirty units divided among six injection sites to about forty units divided among eight injection sites; the temporal in about forty units divided between eight injection sites up to fifty units divided among ten injection sites; the trapezoid in about thirty units divided among six injection sites up to about fifty units divided among ten injection sites and the cervical in about twenty units divided among four injection sites; in which botulinum neurotoxin is injected at 31 to 39 injection sites.
    [2]
    Method according to claim 1, characterized in that the total amount of botulinum neurotoxin administered is from about 155 units to about 195 units of onabotulinumtoxinA.
    [3]
    3. Method according to claim 1, characterized by the fact that the botulinum neurotoxin is type B.
    [4]
    4. Method according to claim 1, characterized by the fact that the botulinum neurotoxin is type E.
    [5]
    5. Method according to claim 1, characterized by the fact that the botulinum neurotoxin is type A.
    [6]
    6. Use of a botulinum neurotoxin, characterized by the fact that it is for the preparation of a composition to prophylactically treat a headache in a patient with chronic migraine headaches, formulated to be administered locally called botulinum neurotoxin to the frontal paraspinal muscles , corrugator, proximal, occipital, temporal, tracheal and cervical of the patient suffering from migraine headache; in which botulinum neurotoxin is administered to the frontal spinal muscles in about twenty units divided between four injection sites; to the corrugator in about ten units divided between two injection sites; to the wax in about five units for an injection site; to the occiput in about thirty units divided among six injection sites to about forty units divided among eight injection sites; the temporal in about forty units divided between eight injection sites up to fifty units divided among ten injection sites; to the trapezoid in about thirty units divided among six injection sites to about fifty units divided among ten injection sites and to the cervical in about twenty units divided among four injection sites; in which botulinum neurotoxin is injected at 31 to 39 injection sites.
    [7]
    7. Composition to prophylactically treat a headache in a patient with chronic migraine headaches, characterized by the fact that it comprises a botulinum neurotoxin, in which the botulinum neurotoxin is onabotulinumtoxinA, type A, type B and type E.
    [8]
    8. Invention, in any form of its embodiments or in any applicable category of claim, for example, of product or process or use encompassed by the matter initially described, revealed or illustrated in the patent application.
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    法律状态:
    2020-09-08| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-11-17| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2021-05-04| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2021-05-25| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-11-09| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|
    2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    2022-02-15| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    US31923010P| true| 2010-03-30|2010-03-30|
    US61/319,230|2010-03-30|
    US32066710P| true| 2010-04-02|2010-04-02|
    US61/320,667|2010-04-02|
    PCT/US2011/030370|WO2011123456A1|2010-03-30|2011-03-29|Botulinum toxin dosage regimen for chronic migraine prophylaxis|
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