Main objective:The primary objective of the trial is to evaluate the efficacy of test investigational medicinal product (IMP) as compared to placebo IMP for the preventive treatment of chronic migraine (CM). Secondary objectives:To evaluate the…
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Brief title
Condition
- Headaches
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is the mean change from baseline (28-day baseline
period) in the monthly average number migraine days during the 12-week period
after the first dose of IMP.
Secondary outcome
The safety and tolerability endpoints are as follows:
• occurrence of adverse events throughout the trial, including local injection
site reaction/pain
• abnormal standard 12-lead electrocardiogram (ECG) findings
• changes from baseline in vital signs (systolic and diastolic blood pressure,
pulse, temperature, and respiratory rate), height, and weight measurements
• changes from baseline in clinical laboratory (serum chemistry, hematology,
coagulation, and urinalysis) test results
• abnormal physical examination findings
• suicidal ideation and behavior as suggested by the Columbia-Suicide Severity
Rating Scale (C SSRS)
The secondary efficacy endpoints are as follows:
• mean change from baseline (28-day baseline period) in monthly average number
of headache days of at least moderate severity during the 12 week period after
the first dose of IMP
• proportion of participants reaching at least 50% reduction inthe
monthly average number of migraine days during the
12-week period after the first dose of IMP
• mean change from baseline (28-day baseline period) in the monthly average
number of days of use of any acute headache medications during the 12-week
period after the first dose of IMP
• mean change from baseline (day 1) in migraine-related disability score, as
measured by the Pediatric Migraine Disability Assessment (PedMIDAS)
questionnaire, at 12 weeks after administration of the first dose of IMP
• mean change from baseline (day 1) in quality of life, as measured by the
Pediatric Quality of Life Inventory (PedsQL), at 12 weeks after administration
of the first dose of IMP
• 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.
Background summary
Fremanezumab is a humanized immunoglobulin G2 (IgG2) Δa/kappa monoclonal
antibody (mAb) derived from a murine precursor. In September 2018, fremanezumab
was approved in the United States of America (US) for the preventive treatment
of migraine in adults and marketed under the trade name AJOVY®. Fremanezumab
has also been approved in the European Union (EU) and a number of countries
worldwide. Fremanezumab is a potent, selective calcitonin gene-related peptide
(CGRP) binder and blocks both CGRP isoforms (α- and β-CGRP) from binding to the
CGRP receptor. While the precise mechanism of action by which fremanezumab
prevents migraine is unknown, it is believed that blocking CGRP prevents
activation of the trigeminal system. Fremanezumab is highly specific for CGRP
and does not bind to closely related family members (eg, amylin, calcitonin,
intermedin, and adrenomedullin). Two mutations were introduced into the
constant region of the fremanezumab heavy chain to limit antibody effector
functions. This loss of function prevents fremanezumab from stimulating
antibody-dependent cell-mediated cytotoxicity and
triggering complement-mediated lysis; these activities can lead to unwanted
consequences, such as cell lysis, opsonization, and
cytokine release and inflammation.
The safety and tolerability of fremanezumab (intravenous [iv] doses of 0.2 to
2000 mg and subcutaneous [sc] doses of 225 to 900 mg) as well as the
pharmacokinetic profile of 225 to 900 mg sc and iv have been well characterized
in the Phase 1 development program in adults.
Furthermore, the safety and effectiveness of fremanezumab have been
demonstrated in 2 Phase 2b trials and 3 Phase 3 trials in adult participants
with migraine. The 2 Phase 2b trials were a randomized, double-blind,
placebo-controlled Phase 2b trial of 2 sc dosing regimens of fremanezumab
(monthly fremanezumab at 900 mg or fremanezumab at 675 mg followed by monthly
fremanezumab at 225 mg) in participants with chronic migraine (CM) and a
randomized, double-blind, placebo-controlled Phase 2b trial of 2 sc dosing
regimens of fremanezumab (monthly fremanezumab at 675 or 225 mg) in
participants with episodic migraine (EM).
Two completed, randomized, double-blind, placebo-controlled Phase 3 trials
(Trials TV48125-CNS-30049 in CM and TV48125-CNS-30050 in EM and 1 completed,
randomized, double-blind Phase 3 long-term safety trial (Trial
TV48125-CNS-30051 in migraine [EM and CM]) were conducted to further evaluate
the efficacy, safety, and tolerability of various dose regimens of fremanezumab
in the preventive treatment of migraine. Additional trials within the migraine
development program of fremanezumab include the completed Phase 3b trial (Trial
TV48125-CNS-30068) in participants from the EU and US to evaluate the safety
and efficacy of fremanezumab in migraine participants who have failed multiple
preventive medications, 2 ongoing Phase 2b/3 trials in Japanese and Korean EM
and CM participants (Trials 406-102-00002 and 406-102-00001, respectively), and
1 ongoing long-term safety trial (Trial 406-102-00003) in CM and EM to evaluate
the safety and efficacy of fremanezumab. One Phase 4 trial (Trial
TV48125-MH-40142) was conducted to evaluate the efficacy and safety of
fremanezumab in adult participants with migraine and comorbid major depressive
disorder.
The pediatric migraine development program includes a completed Phase 1,
single-dose, open-label trial with administration of single sc doses of 75 mg
in pediatric participants with migraine 6 to 11 years of age, inclusive (Trial
TV48125-CNS-10141). Fremanezumab is further studied for the preventive
treatment of persistent posttraumatic headache (PPTH) in 1 Phase 2 trial (Trial
TV48125-CNS-20024) that is comparing the efficacy and safety of the sc dose
regimen of fremanezumab versus placebo in participants with PPTH. Fremanezumab
was being studied for the preventive treatment of cluster headache (CH) in 3
Phase 3 trials: Trial TV48125-CNS-30056 in participants with episodic CH, Trial
TV48125-CNS-30057 in participants with chronic CH, and a longterm safety Trial
TV48125-CNS-30058 in CH. All 3 trials were terminated by Teva because a
prespecified futility analysis showed that the primary endpoint of mean change
from baseline in the monthly average number of CH attacks during the 12-week
treatment period was unlikely to be met.
Migraine is a prevalent condition characterized by attacks of headache and
associated symptoms (such as nausea, photophobia, or phonophobia). Among
populations of children of all ages, migraine prevalence ranges from 8% to 11%
The prevalence of migraine is substantially lower among children younger than 7
years, ranging from 1% to 3%
The prevalence of migraine in children younger than 12 years is less than
one-third of the prevalence among adolescents
Therefore, the prevalence of migraine increases throughout childhood, with
estimates for adolescents comparable to the 12% to 15% prevalence estimates
cited for adult populations
Migraine has been classified by headache frequency in the International
Classification of Headache Disorders, 3 rd revision (ICHD-3) and is described
as EM, which is defined as headaches occurring on less than 15 days per month,
and CM, which is defined as headaches on at least 15 days per month for at
least 3 months, with the features of migraine on at least 8 days per month
Treatment options for migraine include non-pharmacological biobehavioral
strategies and pharmacological strategies. Topiramate is the only migraine
preventive medication approved for pediatric populations, but it is not
approved in all regions of the EU and is
limited to adolescents ages 12 through 17. Non-pharmacological strategies for
adults and children with migraine include sleep hygiene, exercise, dietary
modifications, biofeedback, and stress management (. Pharmacologic agents used
for the treatment of migraine can be classified as acute (ie, to alleviate the
acute migraine attack) or prophylactic (ie,preventing headache recurrence).
Preventive therapy is indicated for all individuals with CM and for those with
EM that have high frequency of attacks. If given during CM, prophylactic
treatments could revert the patients to EM and continue to provide benefit
after remission is achieved. Most specialists require that a child experience a
minimum of 1 headache per week or 3 to 4 headaches per month to justify
prophylactic medication. Children who report intensive and
prolonged headaches (lasting more than 48 hours), even if infrequent, may also
be offered prophylactic therapy. It is recommended that an adequate trial of at
least 6 to 8 weeks should be sustained before abandoning a treatment. Detailed
information on the test investigational medicinal product (IMP) (fremanezumab),
nonclinical pharmacokinetics, toxicology studies, and clinical trials/studies
are provided in the Investigator*s Brochure (IB).
Study objective
Main objective:
The primary objective of the trial is to evaluate the efficacy of test
investigational medicinal product (IMP) as compared to placebo IMP for the
preventive treatment of chronic migraine (CM).
Secondary objectives:
To evaluate the safety and tolerability of test IMP in the preventive treatment
of CM.
-To further demonstrate the efficacy of test IMP as compared to placebo IMP for
the preventive treatment of CM.
-To eevaluate the immunogenicity of test IMP and the impact of antidrug
antibodies (ADAs) on clinical outcomes in participants exposed to test IMP.
Study design
This is a 4-month, multicenter, randomized, double-blind, placebo-controlled,
parallel-group studytrial to evaluate the efficacy, safety, and tolerability of
2 different doses (dependent on partiecipants* body weight) of subcutaneous
(sc) fremanezumabtest investigational medicinal product (IMP) and placebo IMP.
Enrollment will include male and female partiecipants (6 to 17 years of age,
inclusive). The dose of test IMP will be determined by the participant*s weight
at randomization.
The trial consists of a screening visit, a 28-day baseline period, and a
12-week (84-day) treatment period, including a final evaluation at week 12
(end-of-treatment [EOT] visit, approximately 4 weeks [28 days] after the final
dose IMP).
Intervention
Participants will be randomly assigned in a 1:1 ratio between fremanezumabtest
IMP and placebo IMP treatment groups:
• monthly sc administration of test IMP
• monthly sc administration of matching placebo IMP
The dose of test IMP to be administered will be determined by the participant*s
weight at randomization (visit 2):
• participants weighing >=45.0 kg will receive monthly sc administration of test
IMP at 225 mg.
• participants weighing <45.0 kg will receive monthly sc administration of test
IMP at 120 mg.
Study burden and risks
Identified Risks:
The identified risks of fremanezumab are the following:
• Injection site induration
• Injection site erythema
• Injection site pruritus
• Injection site rash
• Injection site pain
None of these risks impact the benefit-risk profile.
Mild and moderate drug hypersensitivity events were observed infrequently and
with similar incidence in placebo and fremanezumab
in the clinical development program, but no anaphylaxis or severe
hypersensitivity reactions were seen. However, it cannot be
excluded that severe events may occur in the future. Additional information
regarding benefits and risks to participants may be found
in the IB.
In summary, the benefit and risk assessment for fremanezumab is favorable
following review of the observed clinical adult data.
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Listed location countries
Age
Inclusion criteria
a. The participants is a male or female between the ages of 6 to 17 years
(inclusive) on the day of randomization to test IMP/placebo IMP.
b. The 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.
c. [Revision 01]The participant has a clinical history of recurrent headache
consistent with the diagnosis of migraine for at least 6 months before
screening, consistent with ICHD-3 criteria, (Headache Classification Committee
of the IHS 2013), and a history of >=15 headache days per month on average
during the 3 months prior to screening (visit 1).
d. The participant or parent/caregiver has maintained a prospectively collected
headache diary during a 28-day baseline period in which headache days were
recorded on 15 or more days, and 8 or more of these headache days had at least
1 of the following migraine characteristics:
* head pain of moderate to severe intensity lasting for 2 or more hours in
duration and accompanied by either throbbing quality, predominantly unilateral
location, or aggravation with normal activities.
* headache is accompanied by a migraine-associated symptom, such as
photophobia, phonophobia, abdominal pain, nausea, or vomiting.
* headache is preceded by an aura, as described by ICHD-3 criteria.
* headache was treated by a nonsteroidal anti-inflammatory drug, paracetamol,
triptan, or ergot preparation.
e. This criterion was deleted
f. [Revision 01]Not using migraine preventive medications (listed in Section
13.8) or using no more than 2 migraine 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). A list of migraine preventive
medications allowed for any condition for the duration of the trial for
approximately 35% of participants
Note: A person is considered to be not using migraine preventive medications
(listed in Section 13.8) 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 Onabotulinum toxin A or B prior to screening
(visit 1). The use of other agents that are not included in Section 13.8 but
used for migraine prevention is permitted during the trial; however, these
participants will not be counted towards the approximately 35% participant
limit threshold.
g. 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 at baseline
or are sterile.
h. 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, starting at screening) 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.
i. 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 ofn21 out of 28 days (approximately 75% diary compliance).
j. The participant is in good health, as determined by a medical and
psychiatric history, medical examination, 12-lead electrocardiogram (ECG),
serum chemistry, hematology, coagulation, urinalysis, and serology.
k. The participant/caregiver must be willing and able to comply with trial
requirements and return to the clinic as required for the duration of the trial.
l. The participant weighs at least 17.0 kg on the day of randomization to test
IMP/placebo IMP.
m. The participant has a body mass index ranging from the 5th to 120% of the
95th percentile, inclusive, at screening, based on the local standard.
n. The participant has received all recommended age-appropriate vaccines
according to local standard of care and schedule prior to screening.
Exclusion criteria
a. The participant is 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.
b. The participant has used 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 of the
screening visit.
c. The participant has any clinically significant cardiovascular (including
congenital cardiac anomalies or thromboembolic events), endocrine,
gastrointestinal, genitourinary, hematologic, hepatic, immunologic, neurologic,
ophthalmic, pulmonary, renal disease, or complications of an infection, at the
discretion of the Investigator.
d. [Revision 01] The participant has a current history of a clinically
significant psychiatric condition, at the discretion of the investigator. Any
prior history of a suicide attempt, or a history of suicidal ideation with a
specific plan within the past 2 years must be excluded.
e. The participant has an ongoing infection or a known history of human
immunodeficiency virus (HIV) infection, tuberculosis, Lyme disease, chronic
hepatitis B or C, or a known active infection of COVID-19.
f. The participant has a past or current history of cancer.
g. The participant is pregnant or nursing.
h. The participant has a history of hypersensitivity reactions to injected
proteins, including mAbs, or a history of Stevens-Johnson Syndrome or toxic
epidermal necrolysis syndrome, or the participant is concomitantly using
lamotrigine.
i. The participant has participated in another trial of an IMP (or a medical
device) within the 30 days (or 90 days for biologics) or 5 half-lives previous
to the day of the screening visit (whichever is longer), or is currently
participating in another trial of an IMP (or a medical device).
j. The participant has had exposure to a mAb targeting the CGRP pathway
(erenumab, eptinezumab, galcanezumab, fremanezumab) during the 6 months
previous to the day of the screening visit.
k. Previous participation in the Phase 1 pharmacokinetics trial (Trial
TV48125-CNS-10141).
l. In the judgment of the Investigator, the participant has an abnormal finding
on the baseline 12-lead ECG considered clinically significant.
m. In the judgment of the Investigator, the participant has a significantly
abnormal finding during the 28-day baseline period, including hematology, blood
chemistry, coagulation tests, or urinalysis values/findings (abnormal tests may
be repeated for confirmation).
n. The participant has hepatic enzymes (alanine aminotransferase [ALT],
aspartate aminotransferase [AST], alkaline phosphatase [ALP]) more than 1.5×
the upper limitof normal (ULN) during the 28-day baseline period, after
confirmation in a repeat test, or suspected hepatocellular damage that fulfills
the criteria for Hy*s law.
o. The participant has serum creatinine more than 1.5× the ULN, clinically
significant proteinuria (urine dipstick +4), an estimated glomerular filtration
rate (eGFR) of <75 mL/min/1.73m 2, as calculated by the revised Schwartz
formula (eGFR=[0.413×Ht]/serum creatinine), or evidence of renal disease during
the 28-day baseline period.
p. The participant has any history of alcohol or drug abuse. The definition of
alcohol or drug abuse, including marijuana, is based on the Investigator's
clinical judgement.
q. In the judgment of the Investigator, the participant cannot fully
participate in or successfully complete the trial for its full duration for any
of the following reasons:
* The participant is mentally or legally incapacitated, or unable to give
assent/consent for any reason.
* The participant is in custody due to an administrative or a legal decision or
is in residential treatment.
* The participant /caregiver is unable to be contacted in case of emergency.
* The participant has any other condition, which, in the opinion of the
Investigator, makes the patient inappropriate for inclusion in the trial.
* The participant is a relative of a trial center or Sponsor employee who is
directly involved in the trial.
r. Vulnerable participants (eg, people kept in detention) whose vulnerability
is based on a condition other than the age required for trial eligibility.
s. The participant received a live attenuated vaccine (eg, intranasal flu
vaccine, and measles, mumps, and rubella vaccine) within the 12-week period
prior to screening.
Note: If a medical need arises during the trial, the participant may receive a
live attenuated vaccine.
t. The participant has a known hypersensitivity to the active substance or to
any of the excipients of the IMP.
u. The participant has a current or past medical history of hemiplegic
migraine.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-002053-33-NL |
| ClinicalTrials.gov | NCT04464707 |
| CCMO | NL74045.056.20 |