| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Episodic and Chronic Migraine |
|
| E.1.1.1 | Medical condition in easily understood language |
| Episodic and Chronic Migraine |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066636 |
| E.1.2 | Term | Chronic migraine |
| E.1.2 | System Organ Class | 100000004852 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10082019 |
| E.1.2 | Term | Episodic migraine |
| E.1.2 | System Organ Class | 100000004852 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the longterm safety and tolerability of subcutaneous fremanezumab in the preventive treatment of migraine in pediatric patients 6 to 17 years of age (inclusive at enrollment in the pivotal study) |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the efficacy of subcutaneous fremanezumab in pediatric patients with migraine
-To evaluate the immunogenicity of fremanezumab and the impact of ADAs on clinical outcomes in pediatric patients exposed to fremanezumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients Rolling Over from the Pivotal Efficacy Studies may be included only if they meet all of the following criteria:
a. Completion of the pivotal efficacy study and in the opinion of the
Investigator/Sponsor able to complete the study in a safe and compliant way
b. Patient’s parent(s) or legal guardian(s) must give written informed consent, and the patient must give assent (in accordance with local regulations) Note: In some countries, patients aged 15 to 17 years (inclusive) may give written informed consent; however, the patient’s parent(s) or legal guardian(s) must be informed, per local regulations.
c. Patients may continue with a stable dose/regimen of the preventive medication they were taking during the pivotal efficacy studies
d. Willing and able to comply with study restrictions and to remain
at the clinic for the required duration during the study period and willing to return to the clinic for the follow-up evaluation as specified in this protocol
e. Patient continues to meet appropriate criteria carried forward from the pivotal efficacy study, as follows:
f. 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
g. 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 study (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 study and for 6 months after the last administration of IMP
h. Receipt of all recommended age-appropriate vaccines according to local standard of care and schedule
i. Good health, determined by a medical and psychiatric history,
medical examination, 12-lead ECG, serum chemistry, hematology, coagulation, urinalysis, and serology
j. Weight of at least 17.0 kg on the day of study enrollment
k. BMI ranging from the 5th to 120% of the 95th percentile, incl. at day 1, based on the local standard
Patients Rolling Over from Study TV48125-CNS-10141: may be included only if they meet all of the following criteria
a. Patient is male/female, 6 - 17 years old (inclusive)
b. Written informed consent is obtained from each patient's parent or legal guardian and written assent (according to local regulations) is obtained from each patient. Note: In some countries, patients aged 15 to 17 years (inclusive) may give written informed consent; however, the patient’s parent(s) or legal guardian(s) must be informed, per local regulations.
c. The patient/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)
d. 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
e. 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 study (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 study and for 6 months after the last administration of the IMP
f. The patient has received all recommended age-appropriate vaccines according to local standard of care and schedule
g. The patient is in good health as determined by a medical and psychiatric history, medical examination, 12-lead ECG, serum chemistry, hematology, coagulation, urinalysis, and serology
h. The patient/caregiver must be willing and able to comply with study requirements and to remain at the clinic for the required duration during the study period, and willing to return to the clinic for the follow-up evaluation as specified in this protocol
i. Weight of at least 17.0 kg on the day of study enrollment
j. BMI ranging from the 5th to 120% of the 95th percentile, inclusive, at screening, based on the local standard.
k. 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
Note: A person is considered to be not using preventive medications when at least 5 half-lives have passed since the last use of the medication prior to screening (visit 1) or at least 4 months have passed since the last use of Onabotulinium toxin A or B prior to screening (visit 1).
Patients Rolling Over from the Pivotal Efficacy Studies: Remainder of
criteria applies as per the study protocol
|
|
| E.4 | Principal exclusion criteria |
Patients from the Pivotal Efficacy Studies (any criteria met):
a. Significant abnormal finding on study entry (e.g. hematology), repeat abnormal tests for confirmation
b. Pregnant or nursing
c. Abnormal clinically significant finding on day 1 12-lead ECG
d. One of the following criteria is met:
e. Use of medications containing opioids (incl. codeine), barbiturates (incl. Fiorinal®, any other combination containing butalbital) for migraine treatment during the 3 months prior to screening visit day
f. Use of an intervention/device (eg, scheduled nerve block) for the treatment of migraine or in the head or neck area for any condition during the 2 months prior to the day 1
g. Any clinically significant disease (e.g. cardiovascular), or complications of an infection
h. 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.
i. 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)
j. Past or current history of cancer
k. History of hypersensitivity reactions to injected proteins, incl. mAbs, history of Stevens-Johnson Syndrome, toxic epidermal necrolysis syndrome, or the patient in concomitantly using lamotrigine.
l. Current participation in another IMP/medical device study
m. Hepatic enzymes (ALT, AST, ALP) > 1.5× ULN after a repeat test confirmation, or suspected hepatocellular damage (fulfilling Hy’s law)
n. Serum creatinine > 1.5× the ULN, clinically significant proteinuria (urine dipstick +4), an estimated glomerular filtration rate of
<75 mL/min/1.73m2, as calculated by the revised Schwartz formula (eGFR=[0.413×Ht]/serum creatinine), or evidence of renal disease
o. Patient cannot fully participate in/successfully complete the study for its full duration for any of the following reasons:
-In custody due to an administrative or a legal decision or in residential treatment
-Patient/caregiver unable to be contacted in case of emergency
-Presence of any other condition, which makes the patient inappropriate for study inclusion
-Patient is a relative of a study center or sponsor employee who is directly involved in the study
p. Vulnerable patients (eg, people in detention) that are vulnerable due to other conditions than age
q. Receipt of a live attenuated vaccine (eg, intranasal flu vaccine) the 12-week period prior to day 1. Note: If a medical need arises during the study, the patient may receive a live attenuated vaccine.
r. The patient has a known hypersensitivity to the active substance or to any of the excipients of the study drug.
s. The patient has a current or past medical history of hemiplegic
migraine.
Patients from Study TV48125-CNS-10141 (any criteria met):
a. Use of an intervention/device (eg, scheduled nerve block) for the treatment of migraine or in the head or neck area for any condition during the 2 months prior to day 1.
b. Any clinically significant disease (e.g. cardiovascular)/complications of an infection
c. 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
d. Ongoing infection/known history of e.g. HIV infection/tuberculosis/Lyme disease/chronic hepatitis B or C, COVID-19
e. Past or current history of cancer
f. Pregnant or nursing.
g. History of hypersensitivity reactions to injected proteins, incl. mAbs/history of Stevens-Johnson Syndrome/toxic epidermal necrolysis syndrome, or patient is concomitantly using lamotrigine
h. Participation in another study 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 study of an IMP/medical device
i. Exposure to a mAb targeting the calcitonin gene-related peptide pathway (erenumab, eptinezumab, galcanezumab, fremanezumab) during the 6 months prior to screening visit day
j. Abnormal finding on day 1 12-lead ECG considered clinically significant
k. Clinically significant abnormal finding on screening visit day, incl. hematology, blood chemistry, coagulation tests, urinalysis values/findings (repeat abnormal tests for confirmation)
l. 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)
m. Serum creatinine > 1.5× the ULN, clinically significant proteinuria (urine dipstick +4), an estimated glomerular filtration rate of
<75 mL/min/1.73m2, 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.
n. The patient has any history of alcohol or drug abuse
Remainder of criteria applies as per the study protocol
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety:
-Occurrence of adverse events throughout the study, including local injection site reactions/pain
-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)
-Abnormal standard 12-lead electrocardiogram findings at each study visit up to the end of treatment (V11)
-Changes from baseline in vital signs (pulse, systolic and diastolic blood pressure, temperature, and respiratory rate) at each study visit up to the end of treatment (V11)
-Abnormal physical examination findings at study visits V6, V7, V11, and V12
-Suicidal ideation and behavior as suggested by the Columbia-Suicide Severity Rating Scale throughout the study
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| -Safety will be assessed throughout the study |
|
| E.5.2 | Secondary end point(s) |
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
-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
-Proportion of patients reaching at least 50% reduction in the number of migraine days during the 4-week periods after V2, V6, and V10
-Proportion of patients 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
-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
-Mean change from baseline (day 1) in migraine-related disability score, as measured by the PedMIDAS questionnaire at V5, V8, V11, and V12
-Proportion of patients developing ADAs throughout the study. The impact of ADAs on safety and efficacy will be analyzed if the number of ADA-positive patients allows
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Efficacy will be assessed through
V11 (end of treatment)
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Israel |
| Finland |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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