A Trial to Test if Fremanezumab is Effective in Preventing Migraine in Children and Adolescents

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Teva Branded Pharmaceutical Products R&D LLC

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

14 Oct 2020 → 23 Dec 2025

Decision date (initial)

2024-10-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Teva Branded Pharmaceutical Products LLC

External identifiers

EU CT number

2024-512837-34-00

EudraCT number

2019-002056-16

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Safety, Prophylaxis

To evaluate the long-term safety and tolerability of subcutaneous test IMP in the preventive treatment of migraine in pediatric participants 6 to 17 years of age (inclusive at enrollment in the pivotal trial)

Secondary objectives 2

1. To evaluate the efficacy of subcutaneous test IMP in pediatric participants with migraine
2. To evaluate the immunogenicity of test IMP and the impact of ADAs on clinical outcomes in pediatric participants exposed to test IMP

Conditions and MedDRA coding

Episodic and Chronic Migraine

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001877-PIP01-15

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 22

1. Participants Rolling Over from the Pivotal Efficacy Trials may be included only if they meet all of the following criteria: Completion of the pivotal efficacy trial and in the opinion of the Investigator/Sponsor able to complete the trial in a safe and compliant way
2. Participant's parent(s) or legal guardian(s) must give written informed consent, and the participant must give assent (in accordance with local regulations) Note: In some countries, participants aged 15 to 17 years (inclusive) may give written informed consent; however, the participant's parent(s) or legal guardian(s) must be informed, per local regulations.
3. Participant may continue with a stable dose/regimen of the preventive medication they were taking during the pivotal efficacy trials
4. Willing and able to comply with trial restrictions and to remain at the clinic for the required duration during the trial period and willing to return to the clinic for the follow-up evaluation as specified in this protocol
5. Participant continues to meet appropriate criteria carried forward from the pivotal efficacy trial, as follows:
6. Females who are postmenarchal or ≥12 years of age may be included only if they have a negative beta-human chorionic gonadotropin (β-HCG) test before day 1 or are sterile
7. Females who are postmenarchal or ≥12 years of age and sexually active must use highly effective birth control methods with their male partners for the duration of the trial (ie, at least 2 months before day 1) and for 6 months after the last dose of IMP. Males who are sexually active with female partners must use a condom for the duration of the trial and for 6 months after the last administration of IMP
8. Receipt of all recommended age-appropriate vaccines according to local standard of care and schedule
9. Good health, determined by a medical and psychiatric history, medical examination, 12-lead ECG, serum chemistry, hematology, coagulation, urinalysis, and serology
10. Weight of at least 17.0 kg on the day of trial enrollment
11. BMI ranging from the 5th to 120% of the 95th percentile, incl. at day1, based on the local standard Participants Rolling Over from Trial TV48125-CNS-10141: may be included only if they meet all of the following criteria
12. Participants Rolling Over from Trial TV48125-CNS-10141: may be included only if they meet all of the following criteria; Participant is male/female, 6 - 17 years old (inclusive)
13. Written informed consent is obtained from each participant's parent or legal guardian and written assent (according to local regulations) is obtained from each participant. Note: In some countries, participants aged 15 to 17 years (inclusive) may give written informed consent; however, the participant's parent(s) or legal guardian(s) must be informed, per local regulations. Note: In some countries, participants aged 15 to 17 years (inclusive) may give written informed consent; however, the participant's parent(s) or legal guardian(s) must be informed, per local regulations
14. 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)
15. Females who are postmenarchal or ≥12 years of age may be included only if they have a negative β-HCG test before day 1 or are sterile
16. Females who are postmenarchal or ≥12 years of age and sexually active must use highly effective birth control methods with their male partners for the duration of the trial (ie, at least 2 months before day 1) and for 6 months after the last dose of the IMP. Males who are sexually active with female partners must use a condom for the duration of the trial and for 6 months after the last administration of the IMP
17. The participant has received all recommended age-appropriate vaccines according to local standard of care and schedule
18. The participant is in good health as determined by a medical and psychiatric history, medical examination, 12-lead ECG, serum chemistry, hematology, coagulation, urinalysis, and serology
19. The participant/caregiver must be willing and able to comply with trial requirements and to remain at the clinic for the required duration during the trial period, and willing to return to the clinic for the followup evaluation as specified in this protocol
20. Weight of at least 17.0 kg on the day of trial enrollment
21. BMI ranging from the 5th to 120% of the 95th percentile, inclusive, at screening, based on the local standard.
22. 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 day 1 Participants Rolling Over from the Pivotal Efficacy Trials: Remainder of criteria applies as per the trial protocol

Exclusion criteria 32

1. Participants from the Pivotal Efficacy Trials (any criteria met): Significant abnormal finding on trial entry (e.g. hematology), repeat abnormal tests for confirmation
2. Pregnant or nursing
3. Abnormal clinically significant finding on day 1 12-lead ECG
4. One of the following criteria is met:
5. The participant is regularly using medications containing opioids (including codeine) or barbiturates (including Fiorinal®, Fioricet®, or any other combination containing butalbital) for the treatment of migraine during the 3 months prior to the day of the screening visit.
6. Use of an intervention/device (eg, scheduled nerve block or transcranial magnetic stimulation) for the treatment of migraine or in the head or neck area for any condition during the 2 months prior to the day 1
7. Any clinically significant disease (e.g. cardiovascular), or complications of an infection
8. History of clinically significant psychiatric condition/history of a suicide attempt/history of suicidal ideation with a specific plan within the past 2 years, at the discretion of the investigator
9. Ongoing infection/known history of e.g. HIV infection/tuberculosis, Lyme disease, chronic hepatitis B or C, or a known infection of coronavirus disease 2019 (COVID-19)
10. Past or current history of cancer
11. History of hypersensitivity reactions to injected proteins, incl. mAbs, history of Stevens-Johnson Syndrome, toxic epidermal necrolysis syndrome, or the participant in concomitantly using lamotrigine
12. Current participation in another IMP/medical device trial
13. Hepatic enzymes (ALT, AST, ALP) > 1.5× ULN after a repeat test confirmation, or suspected hepatocellular damage (fulfilling Hy's law)
14. Serum creatinine > 1.5× the ULN, clinically significant proteinuria (urine dipstick +4), an estimated glomerular filtration rate (eGFR) of <75 mL/min/1.73 m2, as calculated by the revised Schwartz formula (eGFR=[0.413×Ht]/serum creatinine), or evidence of renal disease
15. Participant cannot fully participate in/successfully complete the trial for its full duration for any of the following reasons: -In custody due to an administrative or a legal decision or in residential treatment; -Participant/caregiver unable to be contacted in case of emergency; -Presence of any other condition, which makes the participant inappropriate for trial inclusion; -Participant is a relative of a trial center or sponsor employee who is directly involved in the trial
16. Vulnerable participants (eg, people in detention) that are vulnerable due to other conditions than age
17. Receipt of a live attenuated vaccine (eg, intranasal flu vaccine) within the 12-week period prior to day 1. Note: If a medical need arises during the trial, the participant may receive a live attenuated vaccine.
18. The participant has a known hypersensitivity to the active substance or to any of the excipients of the trial drug.
19. The participant has a current or past medical history of hemiplegic migraine.
20. Participants from Trial TV48125-CNS-10141 (any criteria met): Use of an intervention/device for the treatment of migraine or in the head or neck area for any condition during the 2 months prior to day 1.
21. Any clinically significant disease (e.g. cardiovascular)/complications of an infection
22. Current history of clinically significant psychiatric condition/history of a suicide attempt/suicidal ideation with a specific plan within the past 2 years, at discretion of investigator
23. Ongoing infection/known history of e.g. HIV infection/tuberculosis/Lyme disease/chronic hepatitis B or C, COVID-19
24. Past or current history of cancer
25. Pregnant or nursing
26. History of hypersensitivity reactions to injected proteins, incl. mAbs/history of Stevens-Johnson Syndrome/toxic epidermal necrolysis syndrome, or participant is concomitantly using lamotrigine
27. Participation in another trial of an IMP/medical device within 30 days/ 90 days for biologics or 5 half-lives previous to screening visit day (whichever is longer) or current participation in another trial of an IMP/medical device
28. Exposure to a mAb targeting the calcitonin gene-related peptide pathway (erenumab, eptinezumab, galcanezumab, fremanezumab) during the 6 months prior to screening visit day
29. Abnormal finding on day 1 12-lead ECG considered clinically significant
30. Clinically significant abnormal finding on screening visit day, incl. hematology, blood chemistry, coagulation tests, urinalysis values/findings (repeat abnormal tests for confirmation)
31. Hepatic enzymes (ALT, AST, ALP) > 1.5× the ULN on screening visit day after confirmation in a repeat test/suspected hepatocellular damage (fulfilling Hy's law)
32. Serum creatinine > 1.5× the ULN, clinically significant proteinuria (urine dipstick +4), an estimated glomerular filtration rate (eGFR) of <75 mL/min/1.73 m2, as calculated by the revised Schwartz formula (eGFR=[0.413×Ht]/serum creatinine), or evidence of renal disease on the day of the screening visit. Remainder of criteria applies as per the trial protocol

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. Safety: Occurrence of adverse events throughout the trial, including local injection site reactions/pain
2. Changes from baseline in clinical laboratory (serum chemistry, hematology, coagulation, and urinalysis) test results and height and weight measurements taken at V5, V8, and at the end of treatment (V11)
3. Abnormal standard 12-lead electrocardiogram findings at each trial visit up to the end of treatment (V11)
4. Changes from baseline in vital signs (pulse, systolic and diastolic blood pressure, temperature, and respiratory rate) at each trial visit up to the end of treatment (V11)
5. Abnormal physical examination findings at trial visits V6, V7, V11, and V12
6. Suicidal ideation and behavior as suggested by the Columbia-Suicide Severity Rating Scale throughout the trial

Secondary endpoints 7

1. Efficacy: Mean change from baseline (defined as the original baseline from the EM and CM studies) in the number of headache days of at least moderate severity during the 4-week periods after V2, V6, and V10
2. Mean change from baseline (defined as the original baseline from the EM and CM studies) in the number of migraine days during the 4-week periods after V2, V6, and V10
3. Proportion of participants reaching at least 50% reduction in the number of migraine days during the 4-week periods after V2, V6, and V10
4. Proportion of participants reaching at least 50% reduction in the number of headache days of at least moderate severity during the 4- week periods after V2, V6, and V10
5. Mean change from baseline (defined as the original baseline from the EM and CM studies) in the number of days of use of any acute headache medications during the 4-week periods after V2, V6, and V10
6. Mean change from baseline (day 1) in migraine-related disability score, as measured by the PedMIDAS questionnaire at V5, V8, V11, and V12
7. Proportion of participants developing ADAs throughout the trial. The impact of ADAs on safety and efficacy will be analyzed if the number of ADA-positive participants allows

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Teva Branded Pharmaceutical Products R&D LLC

Sponsor organisation

Teva Branded Pharmaceutical Products R&D LLC

Address

145 Brandywine Parkway

City

West Chester

Postcode

19380-4245

Country

United States

Scientific contact point

Organisation

Teva Branded Pharmaceutical Products R&D LLC

Contact name

Medical Information

Public contact point

Organisation

Teva Branded Pharmaceutical Products R&D LLC

Contact name

Medical Information

Third parties 4

Locations

6 EU/EEA countries · 23 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 50 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications