A Study to Explore the Long-Term Safety and Efficacy of Fremanezumab (TEV-48125) for the Prevention of Cluster Headache (ENFORCE)
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| ClinicalTrials.gov Identifier: NCT03107052 |
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Recruitment Status :
Terminated
(The study was terminated after the episodic cluster study was terminated due to a pre specified futility analyses)
First Posted : April 11, 2017
Results First Posted : May 6, 2020
Last Update Posted : November 9, 2021
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Sponsor:
Teva Branded Pharmaceutical Products R&D, Inc.
Information provided by (Responsible Party):
Teva Branded Pharmaceutical Products R&D, Inc.
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Cluster Headache | Drug: Fremanezumab | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 275 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | A Multicenter, Double-Blind, Double-Dummy Study to Explore the Long-Term Safety and Efficacy of TEV-48125 for the Prevention of Cluster Headache |
| Actual Study Start Date : | April 27, 2017 |
| Actual Primary Completion Date : | June 11, 2019 |
| Actual Study Completion Date : | June 11, 2019 |
Resource links provided by the National Library of Medicine
MedlinePlus related topics:
Headache
Drug Information available for:
Fremanezumab
| Arm | Intervention/treatment |
|---|---|
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Experimental: Fremanezumab 225 mg Monthly
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.
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Drug: Fremanezumab
Fremanezumab
Other Name: TEV-48125 |
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Experimental: Fremanezumab 675/225 mg Monthly
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.
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Drug: Fremanezumab
Fremanezumab
Other Name: TEV-48125 |
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Experimental: Fremanezumab 675 mg Quarterly
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.
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Drug: Fremanezumab
Fremanezumab
Other Name: TEV-48125 |
Primary Outcome Measures :
- Number of Participants With Adverse Events (AEs) [ Time Frame: Baseline up to follow-up (Week 68) ]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.
- Number of Participants With Potentially Clinically Significant Abnormal Laboratory Results: Serum Chemistry [ Time Frame: Baseline up to end of treatment (Week 40) ]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.
- Number of Participants With Potentially Clinically Significant Abnormal Laboratory Results: Hematology [ Time Frame: Baseline up to end of treatment (Week 40) ]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.
- Number of Participants With Potentially Clinically Significant Abnormal Laboratory Results: Urinalysis [ Time Frame: Baseline up to end of treatment (Week 40) ]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.
- Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Coagulation Laboratory Test Results [ Time Frame: Baseline up to end of treatment (Week 40) ]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.
- Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values [ Time Frame: Baseline up to follow-up (Week 68) ]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.
- Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters [ Time Frame: Baseline up to follow-up (Week 68) ]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.
- Number of Participants With Abnormal Physical Examination Findings [ Time Frame: Baseline up to follow-up (Week 68) ]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.
- Number of Participants With Injection Site Reactions [ Time Frame: Baseline up to Week 36 ]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.
- Number of Participants With Hypersensitivity/Anaphylaxis Reactions [ Time Frame: Baseline up to Week 36 ]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.
- Number of Participants Who Received Concomitant Medications [ Time Frame: Baseline up to follow-up (Week 68) ]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.
- Number of Participants With Suicidal Ideation and Suicidal Behavior as Assessed by the Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) [ Time Frame: Baseline up to follow-up (Week 68) ]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.
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| Ages Eligible for Study: | 18 Years to 70 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- 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.
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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
Exclusion Criteria:
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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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03107052
Locations
Show 83 study locations
Sponsors and Collaborators
Teva Branded Pharmaceutical Products R&D, Inc.
Investigators
| Study Director: | Teva Medical Expert, MD | Teva Branded Pharmaceutical Products R&D, Inc. |
Study Documents (Full-Text)
Documents provided by Teva Branded Pharmaceutical Products R&D, Inc.:
Documents provided by Teva Branded Pharmaceutical Products R&D, Inc.:
Study Protocol [PDF] August 28, 2018
Statistical Analysis Plan [PDF] July 15, 2019
| Responsible Party: | Teva Branded Pharmaceutical Products R&D, Inc. |
| ClinicalTrials.gov Identifier: | NCT03107052 |
| Other Study ID Numbers: |
TV48125-CNS-30058 2016-003172-43 ( EudraCT Number ) |
| First Posted: | April 11, 2017 Key Record Dates |
| Results First Posted: | May 6, 2020 |
| Last Update Posted: | November 9, 2021 |
| Last Verified: | November 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Undecided |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Cluster Headache Headache Pain Neurologic Manifestations Trigeminal Autonomic Cephalalgias |
Headache Disorders, Primary Headache Disorders Brain Diseases Central Nervous System Diseases Nervous System Diseases |