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| ID | Type | Description | Link |
|---|---|---|---|
| 2016-003171-21 | EudraCT Number |
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Futility analysis revealed that the primary endpoint is unlikely to be met. There were no safety concerns observed with fremanezumab treatment in the trial.
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The purpose of the current study is to evaluate the efficacy and safety of Fremanezumab (TEV-48125), in the prevention of CCH in adult participants.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8. |
|
| Fremanezumab 675/225/225 mg | Experimental | Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 milligrams (mg) as 3 subcutaneous injections (225 mg/1.5 milliliters [mL]) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
|
| Fremanezumab 900/225/225 mg | Experimental | Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fremanezumab | Drug | Fremanezumab will be administered as per the dose and schedule specified in the respective arms. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Mean Change From Baseline in the Overall Monthly Average Number of CH Attacks Up to Week 12 | A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. Least Squares (LS) mean calculated using analysis of covariance (ANCOVA) model with baseline preventive medication use (yes or no), sex, region (United States [US]/Canada or other), and treatment as fixed effects and the baseline number of CH attacks as a covariate. Change from baseline in the overall monthly average number of CH attacks during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported. | Baseline Period (from at least Week -4 to Week 0), Up to Week 12 |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants With a ≥50% Reduction From Baseline in the Monthly Average Number of CH Attacks Up to Week 12 | A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. |
Not provided
Inclusion Criteria:
The participant has a history of CCH according to the International Classification of Headache Disorders - 3 beta criteria (Headache Classification Committee of the International Headache Society [IHS] 2013) for greater than or equal to (≥)12 months prior to screening.
The participant has a total body weight of ≥45 kilograms (kg) (99 pounds [lbs]).
The participant is in good health in the opinion of the Investigator.
Women of childbearing potential (WOCBP) whose male partners are potentially fertile (that is, no vasectomy) must use highly effective birth control methods for the duration of the study.
Men must be sterile, or if they are potentially fertile/reproductively competent (not surgically [for example, vasectomy] or congenitally sterile) and their female partners are of childbearing potential, must agree to use, together with their female partners, acceptable birth control.
If a participant is receiving Botox, it should be in a stable dose regimen, which is considered as having ≥2 cycles of Botox prior to screening. The participant should not receive Botox during the run-in period up to the evaluation period (12 weeks) where the primary endpoint is evaluated.
Exclusion Criteria:
The participant has used systemic steroids for any medical reason (including treatment of the current cluster headache (CH) cycle within less than or equal to (≤)7 days prior to screening. The participant has used an intervention/device (for example, scheduled nerve blocks) for headache during the 4 weeks prior to screening.
The participant has clinically significant hematological, renal, endocrine, immunologic, pulmonary, gastrointestinal, genitourinary, cardiovascular, neurologic, hepatic, or ocular disease at the discretion of the Investigator.
The participant has evidence or medical history of clinically significant psychiatric issues determined at the discretion of the Investigator.
The participant has a past or current history of cancer or malignant tumor in the past 5 years, except for appropriately treated non-melanoma skin carcinoma.
The participant is pregnant or lactating.
The participant has a history of hypersensitivity reactions to injected proteins, including monoclonal antibodies.
The participant has participated in a clinical study of a monoclonal antibody within 3 months or 5 half-lives before administration of the first dose of the investigational medicinal product (IMP), whichever is longer, unless it is known that the participant received placebo during the study.
The participant has a history of prior exposure to a monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) pathway (AMG 334, ALD304, LY2951742, or fremanezumab). If participant has participated in a clinical study with any of these monoclonal antibodies, it has to be confirmed that the participant received placebo in order to be eligible for this study.
The participant is an employee of the sponsor/participating study center who is directly involved in the study or is the relative of such an employee.
The participant has an active implant for neurostimulation used in the treatment of CH.
The participant is a member of a vulnerable population (for example, people kept in detention).
The participant has a history of alcohol abuse prior to screening and/or drug abuse that in the Investigator's opinion could interfere with the study evaluations or the participant's safety.
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| Name | Affiliation | Role |
|---|---|---|
| Teva Medical Expert, MD | Teva Branded Pharmaceutical Products R&D, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Teva Investigational Site 13834 | Phoenix | Arizona | 85018 | United States | ||
| Teva Investigational Site 13819 |
A total of 259 participants were randomly assigned with stratification based on sex, country, and baseline concomitant preventive medication use (yes/no) to either placebo, fremanezumab 675/225/225 milligrams (mg), or fremanezumab 900/225/225 mg treatment groups in a 1:1:1 ratio.
Participants with a history of chronic cluster headache (CCH) were enrolled. Eligible participants entered baseline cluster headache (CH) attack information into an electronic diary device daily for greater than or equal to (≥)4 weeks during the Baseline Period.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8. |
| FG001 | Fremanezumab 675/225/225 mg |
| Title | Milestones | Reasons Not Completed | ||||
|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 1, 2017 | Jul 16, 2019 |
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|
| Placebo | Drug | Placebo matching to fremanezumab will be administered as per the schedule specified in the respective arms. |
|
| Baseline Period (from at least Week -4 to Week 0) up to Week 12 |
| Mean Change From Baseline in the Monthly Average Number of CH Attacks at Week 4 and Week 12 | A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) ≥1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. Mean change from baseline in monthly average number of CH attacks during 4-week period after administration of first dose of study drug (based on Week 0 to 4 data) and during 4-week period after administration of third dose of study drug (based on Week 8 to 12 data) is reported. | Baseline Period (from at least Week -4 to Week 0), Week 4 and Week 12 |
| Mean Change From Baseline in the Overall Weekly Average Number of Days With Use of Cluster-Specific Acute Headache Medications (Triptans and Ergot Compounds) Up to Week 12 | A maximum of 2 concomitant preventive medications for CH were allowed during the study. Participants must have been on a stable dose and regimen of the concomitant medication for at least 2 weeks before screening and throughout the study. Baseline data and the mean change from baseline in the overall weekly average number of days with the use of cluster-specific acute headache medications (triptans and ergot compounds) during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported. | Baseline Period (from at least Week -4 to Week 0), Up to Week 12 |
| Mean Change From Baseline in the Weekly Average Number of Days Oxygen Was Used to Treat CCH Up to Week 12 | Baseline data and the mean change from baseline in the overall weekly average number of days oxygen was used to treat CCH during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported. | Baseline Period (from at least Week -4 to Week 0), Up to Week 12 |
| Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 | The PPSI assessment was developed to measure pain intensity and was adjusted for CH symptoms improvement. Participants marked the level of CH-associated pain and indicated if pain is "1=much worse," "2=moderately worse," "3=slightly worse," "4=unchanged," "5=slightly improved," "6=moderately improved," or "7=much improved" compared with 4 weeks prior. PPSI was defined as the change in pain that corresponds with a minimal rating of "5=slightly improved." Data at Week 1 was recorded on Day 7 in the electronic diary device at home. Week 12 data also included assessment at the early withdrawal visit for participants who discontinued the study early. | Baseline and Weeks 1, 4, 8, and 12 |
| Number of Participants With Adverse Events (AEs) | An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the Investigator on a scale of mild, moderate and severe, with severe as an AE that prevents usual activities. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 12 |
| Number of Participants With Potentially Clinically Significant Laboratory (Serum Chemistry, Hematology, and Urinalysis) Abnormal Results | Serum chemistry, hematology, urinalysis laboratory tests with potentially clinically significant abnormal findings included: Alanine Aminotransferase (units/liter [U/L]) ≥3*upper limit of normal (ULN); Aspartate Aminotransferase (U/L) ≥3*ULN; Bilirubin (Total) ≥34.2 micromole/liter (umol/L); Blood Urea Nitrogen ≥10.71 millimole (mmol)/L; Creatinine ≥177 umol/L; Gamma Glutamyl Transferase (U/L) ≥3*ULN; hemoglobin less than (<)115 grams (g)/L (males) or less than or equal to (≤)95 g/L (females); leukocytes ≥20*10^9/L or ≤3*10^9/L; Eosinophils/Leukocytes ≥10%; Hematocrit <0.37 L/L (males) and <0.32 L/L (females); platelets ≥700*10^9/L or ≤75*10^9/L; blood ≥2 unit increase from baseline; urine glucose (milligrams/decilitre [mg/dL]) ≥2 U increase from baseline; ketones (mg/dL) ≥2 U increase from baseline; urine protein (mg/dL) ≥2 U increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 12 |
| Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results | Coagulation parameters included: prothrombin time (PT) (seconds) and prothrombin international normalized ratio (INR). Shifts represented as Baseline - endpoint value (last observed post-baseline value). Shifts from baseline to endpoint were summarized using participant counts grouped into three categories: - Low (below normal range) - Normal (within the normal range of 9.4 to 12.5 seconds) - High (above normal range). Missing PT and prothrombin INR shift data are also presented. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 12 |
| Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values | Potentially clinically significant abnormal vital signs findings included: pulse rate ≤50 beats/minute (bpm) and decrease of ≥15 bpm, or ≥120 bpm and increase of ≥15 bpm; systolic blood pressure ≤90 millimeters of mercury (mmHg) and decrease of ≥20 mmHg, or ≥180 mmHg and increase of ≥20 mmHg; diastolic blood pressure ≤50 mmHg and decrease of ≥15 mmHg, or ≥105 mmHg and increase of ≥15 mmHg; respiratory rate <10 breaths/minute; and body temperature ≥38.3 degrees centigrade and change of ≥1.1 degrees centigrade. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 12 |
| Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters | ECG parameters included: heart rate, PR interval, QRS interval, QT interval corrected using the Fridericia formula (QTcF), QT interval corrected using the Bazett's formula (QTcB) and RR interval. Shifts represented as Baseline - endpoint value (last observed post-baseline value). Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding. Missing ECG shift data are also presented. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline to Week 12 |
| Number of Participants With Injection Site Reactions | Number of participants who reported treatment-emergent injection site reactions are summarized. Preferred terms from Medical Dictionary for Regulatory Activities (MedDRA) version 18.1 were offered without a threshold applied. Injection site reactions included injection site erythema, induration, pain, haemorrhage, bruising, hypersensitivity, swelling, rash, and flushing. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 12 |
| Number of Participants With Suicidal Ideation and Suicidal Behavior as Assessed by the Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) | eC-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. Suicidal behavior was defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation was defined as a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent. | Baseline up to Week 12 |
| Canoga Park |
| California |
| 91303 |
| United States |
| Teva Investigational Site 13811 | Santa Monica | California | 90404 | United States |
| Teva Investigational Site 13823 | Stanford | California | 94305 | United States |
| Teva Investigational Site 13837 | Aurora | Colorado | 80045 | United States |
| Teva Investigational Site 13814 | Colorado Springs | Colorado | 80918 | United States |
| Teva Investigational Site 13836 | Denver | Colorado | 80218 | United States |
| Teva Investigational Site 13813 | Englewood | Colorado | 80113 | United States |
| Teva Investigational Site 13821 | New Haven | Connecticut | 06510-2483 | United States |
| Teva Investigational Site 13812 | Stamford | Connecticut | 06905 | United States |
| Teva Investigational Site 13810 | Gainesville | Florida | 32607 | United States |
| Teva Investigational Site 13815 | Orlando | Florida | 32806 | United States |
| Teva Investigational Site 13829 | Ormond Beach | Florida | 32174 | United States |
| Teva Investigational Site 13830 | St. Petersburg | Florida | 33709 | United States |
| Teva Investigational Site 13840 | Tampa | Florida | 33634 | United States |
| Teva Investigational Site 34222 | Augusta | Georgia | 30901 | United States |
| Teva Investigational Site 13833 | Columbus | Georgia | 31904 | United States |
| Teva Investigational Site 13826 | Chicago | Illinois | 60614 | United States |
| Teva Investigational Site 13818 | Ann Arbor | Michigan | 48104 | United States |
| Teva Investigational Site 13835 | Las Vegas | Nevada | 89106 | United States |
| Teva Investigational Site 13832 | Las Vegas | Nevada | 89113 | United States |
| Teva Investigational Site 13831 | Lebanon | New Hampshire | 03756 | United States |
| Teva Investigational Site 13820 | Princeton | New Jersey | 08540 | United States |
| Teva Investigational Site 13827 | Albuquerque | New Mexico | 87102 | United States |
| Teva Investigational Site 13816 | Amherst | New York | 14226 | United States |
| Teva Investigational Site 13817 | New York | New York | 10019 | United States |
| Teva Investigational Site 13809 | Raleigh | North Carolina | 27607 | United States |
| Teva Investigational Site 13839 | Salisbury | North Carolina | 28144 | United States |
| Teva Investigational Site 13825 | Cleveland | Ohio | 44195 | United States |
| Teva Investigational Site 13824 | Philadelphia | Pennsylvania | 19107 | United States |
| Teva Investigational Site 13841 | Richmond | Texas | 77307 | United States |
| Teva Investigational Site 13822 | Virginia Beach | Virginia | 23454 | United States |
| Teva Investigational Site 78120 | Auchenflower | 4066 | Australia |
| Teva Investigational Site 78118 | Clayton | 3168 | Australia |
| Teva Investigational Site 78123 | Melbourne | 3004 | Australia |
| Teva Investigational Site 78122 | Parkville | 3050 | Australia |
| Teva Investigational Site 78121 | Randwick | 2031 | Australia |
| Teva Investigational Site 11132 | Newmarket | Ontario | L3Y5G8 | Canada |
| Teva Investigational Site 11130 | Calgary | T3M 1M4 | Canada |
| Teva Investigational Site 11131 | Toronto | H3A 2B4 | Canada |
| Teva Investigational Site 40030 | Helsinki | 00180 | Finland |
| Teva Investigational Site 40031 | Oulu | 90100 | Finland |
| Teva Investigational Site 40029 | Turku | 20100 | Finland |
| Teva Investigational Site 32666 | Berlin | 10117 | Germany |
| Teva Investigational Site 32667 | Bochum | 44787 | Germany |
| Teva Investigational Site 32660 | Essen | 45147 | Germany |
| Teva Investigational Site 32665 | Hamburg | 20246 | Germany |
| Teva Investigational Site 32662 | Kiel | 24149 | Germany |
| Teva Investigational Site 32661 | Königstein im Taunus | 61462 | Germany |
| Teva Investigational Site 32663 | Rostock | 18147 | Germany |
| Teva Investigational Site 80124 | Ashkelon | 7830604 | Israel |
| Teva Investigational Site 80122 | Hadera | 3810101 | Israel |
| Teva Investigational Site 80125 | Holon | 58100 | Israel |
| Teva Investigational Site 80121 | Jerusalem | 9112001 | Israel |
| Teva Investigational Site 80123 | Netanya | 4244916 | Israel |
| Teva Investigational Site 80120 | Ramat Gan | 5265601 | Israel |
| Teva Investigational Site 80127 | Tel Aviv | 64239 | Israel |
| Teva Investigational Site 80126 | Tel Aviv | 6812509 | Israel |
| Teva Investigational Site 30190 | Milan | 20133 | Italy |
| Teva Investigational Site 30192 | Modena | 41124 | Italy |
| Teva Investigational Site 30194 | Naples | 80131 | Italy |
| Teva Investigational Site 30193 | Pavia | 27100 | Italy |
| Teva Investigational Site 30191 | Rome | 00161 | Italy |
| Teva Investigational Site 30189 | Rome | 163 | Italy |
| Teva Investigational Site 38118 | Leiden | 2333 ZA | Netherlands |
| Teva Investigational Site 38119 | Nijmegen | 6532 SZ | Netherlands |
| Teva Investigational Site 38117 | Zwolle | 8025 AB | Netherlands |
| Teva Investigational Site 53380 | Bialystok | 15-402 | Poland |
| Teva Investigational Site 53383 | Krakow | 31-505 | Poland |
| Teva Investigational Site 53379 | Krakow | 33-332 | Poland |
| Teva Investigational Site 53382 | Lodz | 90-338 | Poland |
| Teva Investigational Site 53381 | Szczecin | 70-111 | Poland |
| Teva Investigational Site 31211 | Galdakao | 48960 | Spain |
| Teva Investigational Site 31214 | Madrid | 28034 | Spain |
| Teva Investigational Site 31213 | Seville | 41013 | Spain |
| Teva Investigational Site 31212 | Valladolid | 47003 | Spain |
| Teva Investigational Site 31215 | Zaragoza | 50009 | Spain |
| Teva Investigational Site 42047 | Huddinge | 141 86 | Sweden |
| Teva Investigational Site 42045 | Vällingby | 162 68 | Sweden |
| Teva Investigational Site 34224 | Glasgow | G51 4TF | United Kingdom |
| Teva Investigational Site 34220 | London | W6 8RF | United Kingdom |
| Teva Investigational Site 34223 | London | WC1N 3BG | United Kingdom |
| Teva Investigational Site 34221 | Oxford | OX2 6HE | United Kingdom |
Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 milliliters [mL]) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
| FG002 | Fremanezumab 900/225/225 mg | Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
|
| Safety Analysis Set | All randomized participants who received at least 1 dose of study drug. |
|
| Full Analysis Set | ITT analysis set, received ≥1 dose of study drug, ≥10 days of postbaseline efficacy assessments |
|
| COMPLETED |
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| NOT COMPLETED |
|
|
Intent-to-treat analysis set included all randomized participants.
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8. |
| BG001 | Fremanezumab 675/225/225 mg | Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
| BG002 | Fremanezumab 900/225/225 mg | Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Number | participants |
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| Number of CH Attacks During the Baseline Period | CH attack defined as a severe/very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15-180 minutes with either or both of following 2 categories: 1) ≥1 of following symptoms/signs, ipsilateral to headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in ear; -miosis and/or ptosis. 2) sense of restlessness or agitation. Baseline period (≥4 weeks) defined as date informed consent was signed up to day before first dose of study drug. | Mean | Standard Deviation | CH attacks |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Mean Change From Baseline in the Overall Monthly Average Number of CH Attacks Up to Week 12 | A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. Least Squares (LS) mean calculated using analysis of covariance (ANCOVA) model with baseline preventive medication use (yes or no), sex, region (United States [US]/Canada or other), and treatment as fixed effects and the baseline number of CH attacks as a covariate. Change from baseline in the overall monthly average number of CH attacks during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported. | Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment. | Posted | Least Squares Mean | Standard Error | CH attacks/month | Baseline Period (from at least Week -4 to Week 0), Up to Week 12 |
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| Secondary | Percentage of Participants With a ≥50% Reduction From Baseline in the Monthly Average Number of CH Attacks Up to Week 12 | A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. | Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment. | Posted | Number | percentage of participants | Baseline Period (from at least Week -4 to Week 0) up to Week 12 |
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| Secondary | Mean Change From Baseline in the Monthly Average Number of CH Attacks at Week 4 and Week 12 | A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) ≥1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. Mean change from baseline in monthly average number of CH attacks during 4-week period after administration of first dose of study drug (based on Week 0 to 4 data) and during 4-week period after administration of third dose of study drug (based on Week 8 to 12 data) is reported. | Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment. Here, 'Number analyzed' signifies participants evaluable at specified timepoint. | Posted | Mean | Standard Deviation | CH attacks/month | Baseline Period (from at least Week -4 to Week 0), Week 4 and Week 12 |
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| Secondary | Mean Change From Baseline in the Overall Weekly Average Number of Days With Use of Cluster-Specific Acute Headache Medications (Triptans and Ergot Compounds) Up to Week 12 | A maximum of 2 concomitant preventive medications for CH were allowed during the study. Participants must have been on a stable dose and regimen of the concomitant medication for at least 2 weeks before screening and throughout the study. Baseline data and the mean change from baseline in the overall weekly average number of days with the use of cluster-specific acute headache medications (triptans and ergot compounds) during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported. | Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment. | Posted | Mean | Standard Deviation | days of use/week | Baseline Period (from at least Week -4 to Week 0), Up to Week 12 |
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| Secondary | Mean Change From Baseline in the Weekly Average Number of Days Oxygen Was Used to Treat CCH Up to Week 12 | Baseline data and the mean change from baseline in the overall weekly average number of days oxygen was used to treat CCH during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported. | Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment. | Posted | Mean | Standard Deviation | days of use/week | Baseline Period (from at least Week -4 to Week 0), Up to Week 12 |
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| Secondary | Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 | The PPSI assessment was developed to measure pain intensity and was adjusted for CH symptoms improvement. Participants marked the level of CH-associated pain and indicated if pain is "1=much worse," "2=moderately worse," "3=slightly worse," "4=unchanged," "5=slightly improved," "6=moderately improved," or "7=much improved" compared with 4 weeks prior. PPSI was defined as the change in pain that corresponds with a minimal rating of "5=slightly improved." Data at Week 1 was recorded on Day 7 in the electronic diary device at home. Week 12 data also included assessment at the early withdrawal visit for participants who discontinued the study early. | Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment. | Posted | Count of Participants | Participants | Baseline and Weeks 1, 4, 8, and 12 |
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| Secondary | Number of Participants With Adverse Events (AEs) | An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the Investigator on a scale of mild, moderate and severe, with severe as an AE that prevents usual activities. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Safety population included all randomized participants who received at least 1 dose of study drug. | Posted | Count of Participants | Participants | Baseline up to Week 12 |
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| Secondary | Number of Participants With Potentially Clinically Significant Laboratory (Serum Chemistry, Hematology, and Urinalysis) Abnormal Results | Serum chemistry, hematology, urinalysis laboratory tests with potentially clinically significant abnormal findings included: Alanine Aminotransferase (units/liter [U/L]) ≥3*upper limit of normal (ULN); Aspartate Aminotransferase (U/L) ≥3*ULN; Bilirubin (Total) ≥34.2 micromole/liter (umol/L); Blood Urea Nitrogen ≥10.71 millimole (mmol)/L; Creatinine ≥177 umol/L; Gamma Glutamyl Transferase (U/L) ≥3*ULN; hemoglobin less than (<)115 grams (g)/L (males) or less than or equal to (≤)95 g/L (females); leukocytes ≥20*10^9/L or ≤3*10^9/L; Eosinophils/Leukocytes ≥10%; Hematocrit <0.37 L/L (males) and <0.32 L/L (females); platelets ≥700*10^9/L or ≤75*10^9/L; blood ≥2 unit increase from baseline; urine glucose (milligrams/decilitre [mg/dL]) ≥2 U increase from baseline; ketones (mg/dL) ≥2 U increase from baseline; urine protein (mg/dL) ≥2 U increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Safety population included all randomized participants who received at least 1 dose of study drug. | Posted | Count of Participants | Participants | Baseline up to Week 12 |
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| Secondary | Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results | Coagulation parameters included: prothrombin time (PT) (seconds) and prothrombin international normalized ratio (INR). Shifts represented as Baseline - endpoint value (last observed post-baseline value). Shifts from baseline to endpoint were summarized using participant counts grouped into three categories: - Low (below normal range) - Normal (within the normal range of 9.4 to 12.5 seconds) - High (above normal range). Missing PT and prothrombin INR shift data are also presented. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Safety population included all randomized participants who received at least 1 dose of study drug. Here, 'Number analyzed' signifies participants evaluable at the timepoint. | Posted | Count of Participants | Participants | Baseline up to Week 12 |
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| Secondary | Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values | Potentially clinically significant abnormal vital signs findings included: pulse rate ≤50 beats/minute (bpm) and decrease of ≥15 bpm, or ≥120 bpm and increase of ≥15 bpm; systolic blood pressure ≤90 millimeters of mercury (mmHg) and decrease of ≥20 mmHg, or ≥180 mmHg and increase of ≥20 mmHg; diastolic blood pressure ≤50 mmHg and decrease of ≥15 mmHg, or ≥105 mmHg and increase of ≥15 mmHg; respiratory rate <10 breaths/minute; and body temperature ≥38.3 degrees centigrade and change of ≥1.1 degrees centigrade. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Safety population included all randomized participants who received at least 1 dose of study drug. | Posted | Count of Participants | Participants | Baseline up to Week 12 |
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| Secondary | Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters | ECG parameters included: heart rate, PR interval, QRS interval, QT interval corrected using the Fridericia formula (QTcF), QT interval corrected using the Bazett's formula (QTcB) and RR interval. Shifts represented as Baseline - endpoint value (last observed post-baseline value). Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding. Missing ECG shift data are also presented. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Safety population included all randomized participants who received at least 1 dose of study drug. Here, 'Number analyzed' signifies participants evaluable at the timepoint. | Posted | Count of Participants | Participants | Baseline to Week 12 |
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| Secondary | Number of Participants With Injection Site Reactions | Number of participants who reported treatment-emergent injection site reactions are summarized. Preferred terms from Medical Dictionary for Regulatory Activities (MedDRA) version 18.1 were offered without a threshold applied. Injection site reactions included injection site erythema, induration, pain, haemorrhage, bruising, hypersensitivity, swelling, rash, and flushing. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Safety population included all randomized participants who received at least 1 dose of study drug. | Posted | Count of Participants | Participants | Baseline up to Week 12 |
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| Secondary | Number of Participants With Suicidal Ideation and Suicidal Behavior as Assessed by the Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) | eC-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. Suicidal behavior was defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation was defined as a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent. | Safety population included all randomized participants who received at least 1 dose of study drug. | Posted | Count of Participants | Participants | Baseline up to Week 12 |
|
Baseline up to Week 12
Safety population included all randomized participants who received at least 1 dose of study drug.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8. | 0 | 83 | 2 | 83 | 18 | 83 |
| EG001 | Fremanezumab 675/225/225 mg | Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. | 0 | 88 | 2 | 88 | 22 | 88 |
| EG002 | Fremanezumab 900/225/225 mg | Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. | 0 | 87 | 3 | 87 | 19 | 87 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastric haemorrhage | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Pancreatitis acute | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Infusion site necrosis | General disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Cholecystitis | Hepatobiliary disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Anaphylactic reaction | Immune system disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Cellulitis | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
| |
| Pelvic abscess | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
| |
| Conversion disorder | Psychiatric disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Hospitalisation | Surgical and medical procedures | MedDRA 18.1 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Injection site erythema | General disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Injection site induration | General disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Injection site pain | General disorders | MedDRA 18.1 | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
|
Futility analysis revealed that the primary endpoint is unlikely to be met. There were no safety concerns observed with fremanezumab treatment in the trial.
Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Director, Clinical Research | Teva Branded Pharmaceutical Products, R&D Inc. | 1-888-483-8279 | USMedInfo@tevapharm.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 19, 2018 | Jul 16, 2019 | SAP_001.pdf |
| ID | Term |
|---|---|
| D003027 | Cluster Headache |
| ID | Term |
|---|---|
| D051303 | Trigeminal Autonomic Cephalalgias |
| D051270 | Headache Disorders, Primary |
| D020773 | Headache Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C000604315 | fremanezumab |
Not provided
Not provided
Not provided
| Male |
|
| Black or African American |
|
| Asian |
|
| American Indian or Alaska native |
|
| Native Hawaiian or other Pacific Islander |
|
| Middle Eastern |
|
| Not Hispanic or Latino |
|
| Hispanic or Latino |
|
| Missing Ethnicity |
|
| 0.3047 |
Threshold for significance at 0.05 level. |
| LS mean difference |
| -3.3 |
| 2-Sided |
| 95 |
| -9.59 |
| 3.01 |
| Other |
| OG002 | Fremanezumab 900/225/225 mg | Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
|
|
Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
| OG002 | Fremanezumab 900/225/225 mg | Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
|
|
| OG002 | Fremanezumab 900/225/225 mg | Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
|
|
Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
|
|
| OG002 | Fremanezumab 900/225/225 mg | Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
|
|
| OG002 | Fremanezumab 900/225/225 mg | Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
|
|
Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
| OG002 | Fremanezumab 900/225/225 mg | Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
|
|
| OG002 | Fremanezumab 900/225/225 mg | Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
|
|
| OG002 | Fremanezumab 900/225/225 mg | Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
|
|
| OG002 | Fremanezumab 900/225/225 mg | Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
|
|
Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
|
|
| OG002 | Fremanezumab 900/225/225 mg | Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. |
|
|