Migraine
Conditions
Keywords
episodic migraine, chronic migraine
Brief summary
The primary objective of the study is to evaluate the long-term safety and tolerability of subcutaneous fremanezumab in the preventive treatment of migraine in pediatric participants 6 to 17 years of age (inclusive at enrollment in the pivotal study). Secondary objectives are to evaluate the efficacy of subcutaneous fremanezumab in pediatric participants with migraine and to evaluate the immunogenicity of fremanezumab and the impact of ADAs on clinical outcomes in pediatric participants exposed to fremanezumab. The total duration of the study is planned to be up to 84 months.
Detailed description
The study population will be composed of 3 subgroups of participants as follows: * Participants rolling over from the pivotal Phase 3 pediatric efficacy studies (Studies TV48125-CNS-30082 and TV48125-CNS-30083) * Participants rolling over from the Phase 1 pediatric pharmacokinetic study (Study TV48125-CNS-10141) * Participants rolling over from the pivotal Phase 3 pediatric efficacy studies (Studies TV48125-CNS-30082 and TV48125-CNS-30083) for safety follow-up and antidrug antibody (ADA) evaluation only
Interventions
DRUGFremanezumab
Participants weighing ≥ threshold will receive Dose A subcutaneously monthly. Participants weighing \< threshold will receive Dose B subcutaneously monthly. Subcutaneously monthly, confirmed or adjusted, as appropriate, based on the participant's weight every 3 months.
Sponsors
Teva Branded Pharmaceutical Products R&D LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
Inclusion Criteria for Participants Rolling Over from the Pivotal Efficacy Studies (TV48125-CNS-30082 or TV48125-CNS-30083): * Participants have completed the pivotal efficacy study and, in the opinion of the Investigator or the Sponsor, are able to complete the study in a safe and compliant way. * Participants may continue with a stable dose/regimen of the preventive medication they were taking during the pivotal efficacy studies. * The participant continues to meet appropriate criteria carried forward from the pivotal efficacy study/ * The participant has received all recommended age-appropriate vaccines according to local standard of care and schedule. * The participant weighs at least 17.0 kg on the day of study enrollment. NOTE: Additional criteria apply; please contact the investigator for more information. Inclusion Criteria for Participants Rolling Over from the Phase 1 Pediatric Pharmacokinetic Study (Study TV48125-CNS-10141): * The participant/caregiver has demonstrated compliance with the electronic headache diary during the 28-day baseline period by entry of headache data on a minimum of 21 out of 28 days (approximately 75% diary compliance). * The participant has received all recommended age-appropriate vaccines according to local standard of care and schedule. * The participant weighs at least 17.0 kg on the day of study enrollment. * The participant has a body mass index ranging from the 5th to 120% of the 95th percentile, inclusive, on the day of study enrollment. * Not using preventive medications or using no more than 2 preventive medications for migraine or other medical condition, as long as the dose and regimen have been stable for at least 2 months prior to screening (visit 1). NOTE: Additional criteria apply; please contact the investigator for more information. Inclusion Criteria for Participants Rolling Over from the Pivotal Efficacy Studies (TV48125-CNS-30082 and TV48125-CNS-30083) for Safety and antidrug antibody (ADA) Assessment Only: • Participants may be included in this study if they sign and date the informed consent document or upon consent of a parent or guardian, if the participant is younger than the age of consent, accompanied by assent of the participant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | Day 1 up to Day 393 | An AE was defined as any untoward medical occurrence in a participant who received the study drug without regard to possibility of causal relationship. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in the Reported AE section. |
| Number of Participants With Potentially Clinically Significant Abnormal Laboratory (Serum Chemistry, Hematology, Coagulation, and Urinalysis) Results | Day 1 up to Day 253 | Serum chemistry tests with clinically significant abnormal findings included: alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase ≥2\*upper limit of normal (ULN); gamma glutamyl transferase ≥3\* ULN; bilirubin ≥34.2 micromole/liter (umol/L); and urea nitrogen ≥9 umol/L. Hematology tests with clinically significant abnormal findings included: hemoglobin ≤100 grams (g)/L (female) or ≤100 g/L (male), hematocrit \<0.32 L/L (male), leukocytes ≤3\*10\^9 cells/L or ≥20\*10\^9 cells/L, neutrophils ≤1\*10\^9 cells/L, eosinophils/leukocytes ≥10%, and platelets ≤75x10\^9/L. Coagulation parameter test with clinically significant abnormal findings included: prothrombin international normalized ratio (INR) \>1.5. Urinalysis laboratory tests with clinically significant abnormal findings included: urine protein and urine glucose ≥2 units (U) increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
| Number of Participants With Shift From Baseline to Last Assessment in Electrocardiogram (ECG) Findings (Assessed by Investigator) | Baseline to last assessment (up to Day 253) | The number of participants with a shift from Baseline (Normal, Abnormal CS \[Clinically Significant\], or Abnormal NCS \[Not Clinically Significant\]) in any of the following ECG parameters is reported by treatment group: Heart rate, PR interval, QRS interval, RR interval, QT interval, QT interval corrected using the Bazett's formula (QTcB), and QT interval corrected using the Fridericia formula (QTcF). Last assessment was defined as the last observed postbaseline interpretation. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
| Number of Participants With Shift From Baseline to Last Assessment in ECG Findings (Assessed by Cardiologist) | Baseline to last assessment (up to Day 253) | The number of participants with a shift from Baseline (Normal or Abnormal) in any of the following ECG parameters is reported by treatment group: Heart rate, PR interval, QRS interval, RR interval, QT interval, QTcB, and QTcF. Last assessment was defined as the last observed postbaseline interpretation. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
| Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | Day 1 up to Day 253 | Potentially clinically significant abnormal vital signs findings included any one of the following: Pulse rate ≥120 beats per minute (bpm) and increase from baseline of ≥15 bpm, or ≤50 bpm and decrease from baseline of ≥15 bpm, or ≤60 bpm and decrease from baseline of ≥15 bpm; systolic blood pressure ≤80 millimeters of mercury (mmHg) and decrease of ≥20 mmHg, or ≤85 mmHg and decrease of ≥20 mmHg, or ≥150 mmHg and increase of ≥20 mmHg; diastolic blood pressure ≤37 mmHg and decrease of ≥15 mmHg, or ≤44 mmHg and decrease of ≥15 mmHg, or ≥100 mmHg and increase of ≥15 mmHg, or ≥93 mmHg and increase of ≥15 mmHg; respiratory rate \<15 or \<10 breaths/minute; and body temperature ≥38.3 degrees Celsius and change ≥1.1 degrees Celsius. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
| Number of Participants With Shift From Baseline to Last Assessment in Physical Examination Findings | Baseline to last assessment (up to Day 393) | The number of participants with a shift from Baseline (Normal or Abnormal) in any of the following organ systems examination is reported by treatment group: general appearance; head, eyes, ears, nose, and throat (HEENT); chest and lungs; cardiovascular; abdomen; musculoskeletal; skin; lymph nodes; neurological, and extremities/back. Last assessment was defined as the last observed postbaseline interpretation. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
| Number of Participants With Suicidal Ideation or Behavior, as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) | Day 1 up to Day 393 | C-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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in the Monthly Average Number of Headache Days of at Least Moderate Severity | Baseline, Months 1, 5, and 9 | A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) where the participant reported either of the following: A day with headache pain that lasted ≥2 hours with a peak severity of at least moderate severity or a day where the participant used acute headache medication (triptans or ergots) to treat a headache of any severity or duration. Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over 4-week period/number of days with assessments recorded in in electronic diary \[e-diary\] for 4-week period) \* 28. |
| Mean Change From Baseline in the Monthly Average Number of Migraine Days | Baseline, Months 1, 5, and 9 | A migraine day was defined as a day with at least one of the following: A calendar day (0:00 to 23:59) demonstrating ≥2 consecutive hours of a headache meeting criteria for migraine with or without aura, or a calendar day (0:00 to 23:59) demonstrating ≥2 consecutive hours of a headache meeting criteria for probable migraine, a migraine subtype where only 1 migraine criterion was missing, or a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine specific medications (triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over 4-week period/number of days with assessments recorded in e-diary for 4-week period) \* 28. |
| Percentage of Participants Reaching at Least 50% Reduction From Baseline in the Monthly Average Number of Migraine Days | Months 1, 5, and 9 | A migraine day was defined as a day with at least one of the following: A calendar day (0:00 to 23:59) demonstrating ≥2 consecutive hours of a headache meeting criteria for migraine with or without aura, or a calendar day (0:00 to 23:59) demonstrating ≥2 consecutive hours of a headache meeting criteria for probable migraine, a migraine subtype where only 1 migraine criterion was missing, or a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine specific medications (triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over 4-week period/number of days with assessments recorded in e-diary for 4-week period) \* 28. |
| Percentage of Participants Reaching at Least 50% Reduction From Baseline in the Monthly Average Number of Headache Days of at Least Moderate Severity | Months 1, 5, and 9 | A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) where the participant reported either of the following: A day with headache pain that lasted ≥2 hours with a peak severity of at least moderate severity or a day where the participant used acute headache medication (triptans or ergots) to treat a headache of any severity or duration. Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over 4-week period/number of days with assessments recorded in in electronic diary \[e-diary\] for 4-week period) \* 28. |
| Mean Change From Baseline in the Monthly Average Number of Days of Use of Any Acute Headache Medications | Baseline, Months 1, 5, and 9 | Participants recorded any headache medications (name of drug, number of tablets/capsules, and the dose in milligrams per tablet/capsule) taken each day in their electronic headache diary device. Acute headache medication included triptans and ergot compounds. Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over 4-week period/number of days with assessments recorded in e-diary for 4-week period) \* 28. |
| Mean Change From Baseline in Migraine-related Disability Score, as Measured by the Pediatric Migraine Disability Assessment (PedMIDAS) Questionnaire | Baseline, Months 3, 6, 9, and 14 | The PedMIDAS is a scale developed to assess headache-related disability which can be self-administered by the participant or administered by a caregiver. It has been validated in participants aged 4 to 18 years and includes 3 subscales: the impact of headache on school performance (range of scores 0-92), disability at home (range of scores 0-92), social/sport functioning (range of scores 0-92). The subscales are added to get the total score with a range 0 to 276. The total score was used for grading of disability, with 4 score categories of 0 to 10, 11 to 30, 31 to 50, and 51-276 interpreted as disability grades 1 (little or no disability), 2 (mild disability), 3 (moderate disability), and 4 (severe disability), respectively. Higher total scores indicated severe disability. The change from baseline score is reported with a range of -276 to 276 with higher scores indicating more severe disability. |
| Number of Participants Developing Antidrug Antibodies (ADAs) Throughout the Study | Day 1 up to Day 393 | Number of participants who developed ADAs were reported. |
Countries
Canada, Finland, Germany, Israel, Italy, Netherlands, Poland, Spain, United States
Contacts
STUDY_DIRECTORTeva Medical Expert, MD
Teva Branded Pharmaceutical Products R&D LLC
Participant flow
Pre-assignment details
A total of 499 participants were enrolled and evaluated in the trial.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 14.0 years STANDARD_DEVIATION 2.64 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 364 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 11 Participants |
| Race/Ethnicity, Customized Race Other | 6 Participants |
| Race/Ethnicity, Customized Race Unknown or Not Reported | 16 Participants |
| Race/Ethnicity, Customized Race White | 402 Participants |
| Sex: Female, Male Female | 327 Participants |
| Sex: Female, Male Male | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 100 | 0 / 399 |
| other Total, other adverse events | 56 / 100 | 229 / 398 |
| serious Total, serious adverse events | 4 / 100 | 17 / 398 |
Outcome results
None listed