A Study to Explore the Long-Term Safety and Efficacy of Fremanezumab (TEV-48125) for the Prevention of Cluster Headache

NCT03107052 | Terminated Phase 3 Results FDA Drug

• 2 other identifiers: TV48125-CNS-300582016-003172-43
• Study Type: interventional
• Target: 275
• Locations: 12 countries
• Sites: 83

Brief Summary

This is a 68-week study to evaluate the long-term safety and efficacy of fremanezumab in participants with cluster headache (CH). Participants who complete the pivotal studies TV48125-CNS-30056 (NCT02945046) and TV48125-CNS-30057 (NCT02964338) and enroll into the current study will visit the investigational center for investigational medicinal product (IMP) administration, safety and efficacy assessments, and blood and urine collections for pharmacokinetics, immunogenicity (anti-drug antibodies \[ADAs\]), and biomarker analyses. Participants will return to the investigational center for a follow-up visit to evaluate ADAs, fremanezumab concentrations, biomarkers, and safety (adverse events and concomitant medications) approximately 7.5 months after the last dose of IMP.

Conditions

Cluster Headache

Outcome Measures

Primary Outcomes (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. 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 refers to the baseline values from the pivotal studies.

  Baseline up to follow-up (Week 68)

• Number of Participants With Potentially Clinically Significant Abnormal Laboratory Results: Serum Chemistry

  Serum chemistry tests with potentially clinically significant abnormal findings included: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH) each ≥3\*upper limit of normal (ULN); Blood urea nitrogen (BUN) ≥10.71 millimole (mmol)/L; Bilirubin (Total) ≥34.2 micromole/liter (umol/L); and Creatinine ≥177 umol/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

  Baseline up to end of treatment (Week 40)

• Number of Participants With Potentially Clinically Significant Abnormal Laboratory Results: Hematology

  Hematology tests with potentially clinically significant abnormal findings included: hemoglobin less than or equal to (≤)115 grams (g)/L (males) or ≤95 g/L (females), leukocytes count ≥20\*10\^9/L or ≤3\*10\^9/L, eosinophils ≥10%, hematocrit \<0.37 L/L (males) and \<0.32 L/L (females), platelets count ≥700\*10\^9/L or ≤75\*10\^9/L, absolute neutrophil count (ANC) ≤1\*10\^9/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

  Baseline up to end of treatment (Week 40)

• Number of Participants With Potentially Clinically Significant Abnormal Laboratory Results: Urinalysis

  Urinalysis laboratory tests with potentially clinically significant abnormal findings included: haemoglobin, urine glucose, ketones, urine total protein each ≥2 unit (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 refers to the baseline values from the pivotal studies.

  Baseline up to end of treatment (Week 40)

• Number of Participants With Shift From Baseline to Endpoint (Last Assessment) 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 refers to the baseline values from the pivotal studies.

  Baseline up to end of treatment (Week 40)

• Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values

  Potentially clinically significant abnormal vital signs findings included: Pulse rate ≥120 beats per minute (bpm) and increase from baseline of ≥15 bpm, or ≤50 bpm and decrease from baseline of ≥15 bpm; Systolic blood pressure ≤90 millimeters of mercury (mmHg) and decrease from baseline of ≥20 mmHg, or ≥180 mmHg and increase from baseline of ≥20 mmHg; Diastolic blood pressure ≤50 mmHg and decrease from baseline of ≥15 mmHg, or ≥105 mmHg and increase from baseline of ≥15 mmHg; Temperature \>38.3 degrees celsius (°C). A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

  Baseline up to follow-up (Week 68)

• 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 refers to the baseline values from the pivotal studies.

  Baseline up to follow-up (Week 68)

• Number of Participants With Abnormal Physical Examination Findings

  A complete physical examination included the following organ systems: general appearance; head, eyes, ears, nose, and throat; chest and lungs; heart; abdomen; musculoskeletal; skin; lymph nodes; and neurological. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

  Baseline up to follow-up (Week 68)

• 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, rash, warmth, and pruritus. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

  Baseline up to Week 36

• Number of Participants With Hypersensitivity/Anaphylaxis Reactions

  A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.

  Baseline up to Week 36

• Number of Participants Who Received Concomitant Medications

  Concomitant medications included: agents acting on the renin-angiotensin system, all other therapeutic products (homeopathic), allergens, analgesics, anesthetics, anti-parkinson drugs, antianemic preparations, antibacterials, antibiotics and chemotherapeutics for dermatological use, antidiarrheals, intestinal antiinflammatory/antiinfective agents, antiemetic, antiepileptics, antifungals for dermatologiocal use, antigout preparations, antihemorrhagics, antihistamines for systemic use, antihypertensives, antiinflammatory and antirheumatic products, antimycotics for systemic use, antipruritics, antipsoriatics, antivirals for systemic use, beta blocking agents, blood substitutes and perfusion solutions, cardiac therapy, corticosteroids, cough and cold preparations, diagnostic radiopharmaceuticals, diuretics, thyroid therapy, urologicals, vaccines, psycoleptics, psycoanaleptics, ophthalmologicals, muscle relaxants, drugs used in diabetes. Baseline refers to values from the pivotal studies.

  Baseline up to follow-up (Week 68)

• 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 refers to the baseline values from the pivotal studies.

  Baseline up to follow-up (Week 68)

Study Arms (3)

Fremanezumab 225 mg Monthly

EXPERIMENTAL

Participants with ECH or CCH who received fremanezumab at 900 mg intravenous (IV) infusion at Week 0 and fremanezumab at 225 mg subcutaneous (SC) injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; will receive fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 milliliter {mL}\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection (225 mg/1.5 mL) at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.

Drug: Fremanezumab

Fremanezumab 675/225 mg Monthly

EXPERIMENTAL

Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; will receive fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36.

Drug: Fremanezumab

Fremanezumab 675 mg Quarterly

EXPERIMENTAL

Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; will receive fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 an 36; and single placebo SC injections at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.

Drug: Fremanezumab

Interventions

Fremanezumab DRUG

Fremanezumab

Also known as: TEV-48125

Fremanezumab 225 mg Monthly; Fremanezumab 675 mg Quarterly; Fremanezumab 675/225 mg Monthly

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The participant completes either the Phase 3 pivotal study for ECH (Study TV48125-CNS-30056) or the Phase 3 pivotal study for CCH (Study TV48125-CNS-30057) without important protocol deviations related to participant safety and participant compliance.
• Prior to 15 June 2018, participants from the ECH study and the CCH study were enrolled. After 15 June 2018, only participants who participated in the ECH study (Study TV48125-CNS-30056) will be enrolled for active treatment.
• In addition, participants who do not complete the pivotal efficacy studies, and participants who complete the pivotal efficacy studies but will not continue treatment during this long-term safety study, will be offered to enroll in this study for the purpose of evaluating ADAs, and safety (adverse events and concomitant medications) approximately 7.5 months after administration of the last dose of the IMP.
• Additional criteria apply, please contact the investigator for more information

You may not qualify if:

• Any finding that, in the judgment of the investigator, is a clinically significant abnormality, including serum chemistry, hematology, coagulation, and urinalysis test values (abnormal tests may be repeated for confirmation)
• Additional criteria apply, please contact the investigator for more information

Sponsors & Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.: lead

Study Sites (83)

Teva Investigational Site 13834

Phoenix, Arizona, 85018, United States

Location

Teva Investigational Site 13819

Canoga Park, California, 91303, United States

Location

Teva Investigational Site 13811

Santa Monica, California, 90404, United States

Location

Teva Investigational Site 13823

Stanford, California, 94305, United States

Location

Teva Investigational Site 13837

Aurora, Colorado, 80045, United States

Location

Teva Investigational Site 13814

Colorado Springs, Colorado, 80918, United States

Location

Teva Investigational Site 13836

Denver, Colorado, 80218, United States

Location

Teva Investigational Site 13813

Englewood, Colorado, 80113, United States

Location

Teva Investigational Site 13821

New Haven, Connecticut, 06510-2483, United States

Location

Teva Investigational Site 13812

Stamford, Connecticut, 06905, United States

Location

Teva Investigational Site 13810

Gainesville, Florida, 32607, United States

Location

Teva Investigational Site 13815

Orlando, Florida, 32806, United States

Location

Teva Investigational Site 13829

Ormond Beach, Florida, 32174, United States

Location

Teva Investigational Site 13830

St. Petersburg, Florida, 33709, United States

Location

Teva Investigational Site 13842

Tampa, Florida, 33612, United States

Location

Teva Investigational Site 13840

Tampa, Florida, 33634, United States

Location

Teva Investigational Site 13833

Columbus, Georgia, 31904, United States

Location

Teva Investigational Site 13826

Chicago, Illinois, 60614, United States

Location

Teva Investigational Site 13818

Ann Arbor, Michigan, 48104, United States

Location

Teva Investigational Site 13835

Las Vegas, Nevada, 89106, United States

Location

Teva Investigational Site 13832

Las Vegas, Nevada, 89113, United States

Location

Teva Investigational Site 13831

Lebanon, New Hampshire, 03756, United States

Location

Teva Investigational Site 13820

Princeton, New Jersey, 08540, United States

Location

Teva Investigational Site 13827

Albuquerque, New Mexico, 87102, United States

Location

Teva Investigational Site 13816

Amherst, New York, 14226, United States

Location

Teva Investigational Site 13817

New York, New York, 10019, United States

Location

Teva Investigational Site 13809

Raleigh, North Carolina, 27607, United States

Location

Teva Investigational Site 13839

Salisbury, North Carolina, 28144, United States

Location

Teva Investigational Site 13825

Cleveland, Ohio, 44195, United States

Location

Teva Investigational Site 13824

Philadelphia, Pennsylvania, 19107, United States

Location

Teva Investigational Site 13841

Richmond, Texas, 77307, United States

Location

Teva Investigational Site 13822

Virginia Beach, Virginia, 23454, United States

Location

Teva Investigational Site 78120

Auchenflower, 4066, Australia

Location

Teva Investigational Site 78118

Clayton, 3168, Australia

Location

Teva Investigational Site 78123

Melbourne, 3004, Australia

Location

Teva Investigational Site 78122

Parkville, 3050, Australia

Location

Teva Investigational Site 78121

Randwick, 2031, Australia

Location

Teva Investigational Site 11132

Newmarket, Ontario, L3Y5G8, Canada

Location

Teva Investigational Site 11130

Calgary, Canada

Location

Teva Investigational Site 40030

Helsinki, 00180, Finland

Location

Teva Investigational Site 40031

Oulu, 90100, Finland

Location

Teva Investigational Site 40029

Turku, 20100, Finland

Location

Teva Investigational Site 32666

Berlin, 10117, Germany

Location

Teva Investigational Site 32667

Bochum, 44787, Germany

Location

Teva Investigational Site 32660

Essen, 45147, Germany

Location

Teva Investigational Site 32665

Hamburg, 20246, Germany

Location

Teva Investigational Site 32662

Kiel, 24149, Germany

Location

Teva Investigational Site 32661

Königstein im Taunus, 61462, Germany

Location

Teva Investigational Site 32663

Rostock, 18147, Germany

Location

Teva Investigational Site 80124

Ashkelon, 7830604, Israel

Location

Teva Investigational Site 80122

Hadera, 3810101, Israel

Location

Teva Investigational Site 80125

Holon, 58100, Israel

Location

Teva Investigational Site 80121

Jerusalem, 9112001, Israel

Location

Teva Investigational Site 80123

Netanya, 4244916, Israel

Location

Teva Investigational Site 80120

Ramat Gan, 5265601, Israel

Location

Teva Investigational Site 80127

Tel Aviv, 64239, Israel

Location

Teva Investigational Site 80126

Tel Aviv, 6812509, Israel

Location

Teva Investigational Site 30190

Milan, 20133, Italy

Location

Teva Investigational Site 30192

Modena, 41124, Italy

Location

Teva Investigational Site 30194

Napoli, 80131, Italy

Location

Teva Investigational Site 30193

Pavia, 27100, Italy

Location

Teva Investigational Site 30191

Rome, 00161, Italy

Location

Teva Investigational Site 30189

Rome, 00163, Italy

Location

Teva Investigational Site 38118

Leiden, 2333 ZA, Netherlands

Location

Teva Investigational Site 38119

Nijmegen, 6532 SZ, Netherlands

Location

Teva Investigational Site 38117

Zwolle, 8025 AB, Netherlands

Location

Teva Investigational Site 53380

Bialystok, 15-402, Poland

Location

Teva Investigational Site 53383

Krakow, 31-505, Poland

Location

Teva Investigational Site 53379

Krakow, 33-332, Poland

Location

Teva Investigational Site 53382

Lodz, 90-338, Poland

Location

Teva Investigational Site 53381

Szczecin, 70-111, Poland

Location

Teva Investigational Site 31211

Galdakao, 48960, Spain

Location

Teva Investigational Site 31214

Madrid, 28034, Spain

Location

Teva Investigational Site 31213

Seville, 41013, Spain

Location

Teva Investigational Site 31212

Valladolid, 47003, Spain

Location

Teva Investigational Site 31215

Zaragoza, 50009, Spain

Location

Teva Investigational Site 42047

Huddinge, 141 86, Sweden

Location

Teva Investigational Site 42045

Vällingby, 162 68, Sweden

Location

Teva Investigational Site 34224

Glasgow, G51 4TF, United Kingdom

Location

Teva Investigational Site 34222

Liverpool, L9 7LJ, United Kingdom

Location

Teva Investigational Site 34223

London, SE1 9RT, United Kingdom

Location

Teva Investigational Site 34220

London, W6 8RF, United Kingdom

Location

Teva Investigational Site 34221

Oxford, OX3 9DU, United Kingdom

Location

MeSH Terms

Conditions

Cluster Headache

Interventions

fremanezumab

Condition Hierarchy (Ancestors)

Trigeminal Autonomic Cephalalgias; Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Limitations and Caveats

The study was terminated after the ECH study (TV48125-CNS-30056) was terminated due to a pre specified futility analyses.

Results Point of Contact

• Title: Director, Clinical Research
• Organization: Teva Branded Pharmaceutical Products, R&D Inc.

USMedInfo@tevapharm.com

1-888-483-8279

Study Officials

• Teva Medical Expert, MD

  Teva Branded Pharmaceutical Products R&D, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 23, 2017
• First Posted: April 11, 2017
• Study Start: April 27, 2017
• Primary Completion: June 11, 2019
• Study Completion: June 11, 2019
• Last Updated: November 9, 2021
• Results First Posted: May 6, 2020

Record last verified: 2021-11

Locations

IL (8); PL (5); IT (6); US (32); GB (5); FI (3); ES (5); DE (7); AU (5); NL (3); SE (2); CA (2)