The primary objective of this study is to demonstrate the efficacy of fremanezumab in the prevention of CCH in adult patients:- The primary efficacy endpoint of this study is the mean change from baseline (run-in period) in the monthly average…
ID
Source
Brief title
Condition
- Headaches
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• the proportion of patients with a >=50% reduction from baseline (run-in
period) in the monthly average number of cluster headache (CH) attacks over the
12 week period after the administration of the first dose of the IMP, ie, based
on week 0 to 12 data
• the mean change from baseline (run-in period) in the number of CH attacks
during the 4 week period after administration of the first dose of the IMP, ie,
based on week 0 to 4 data
• the mean change from baseline (run-in period) in the number of CH attacks
during the 4 week period after administration of the third dose of the IMP, ie,
based on week 8 to 12 data
• the mean change from baseline (run-in period) in the weekly average number of
days with use of cluster-specific acute headache medications (triptans and
ergot compounds) during the 12 week period after administration of the first
dose of the IMP, ie, based on week 0 to 12 data
• the mean change from baseline (run-in period) in the weekly average number of
days oxygen is used to treat CCH during the 12-week period after administration
of the first dose of the IMP, ie, based on week 0 to 12 data
• assessment of patient*s perceived improvement, as measured by the
Patient-Perceived Satisfactory Improvement (PPSI) at 1, 4, 8, and 12 weeks
after administration of the first dose of the IMP relative to baseline (day 0)
Secondary outcome
- occurrence of adverse events throughout the study
- clinical laboratory (serum chemistry, hematology,
coagulation, and urinalysis) test results at each visit
- vital signs (systolic and diastolic blood pressure,
oral temperature, and pulse rate) measurements at
each visit. Note: Oxygen saturation will be
measured in cases of suspected anaphylaxis and
severe hypersensitivity. Respiratory rate will also
be measured in these cases but not as a standard
vital sign.
- 12-lead electrocardiogram (ECG) findings at
screening, baseline, and week 12
- use of concomitant medication during the study
- clinically significant changes in physical
examinations, including body weight
- injection site reaction (ie, erythema, induration, and
ecchymosis) and injection site pain assessments
- occurrence of hypersensitivity/anaphylaxis
reactions
- suicidal ideation and behavior as measured by the
electronic Columbia Suicide Severity Rating Scale
(eC-SSRS)
Background summary
This is a 16-week study to evaluate the efficacy and safety of 2 dose regimens
of fremanezumab versus placebo in adult patients for the
prevention of CCH. Patients who provide written informed consent and complete a
screening visit (visit 1) will enter a run-in period lasting at least 4 weeks
(+3 days) during which they will enter baseline CH attack information into an
electronic diary device daily. Patients will return to
the study center after completing the run-in period (visit 2 [week 0]), and
patients who continue to meet eligibility requirements will be randomized to
receive test IMP (fremanezumab 900-mg iv or 675-mg sc followed by
fremanezumab 225-mg sc monthly) or placebo IMP (placebo iv and sc
followed by single placebo doses sc monthly). An EOT visit will occur
approximately 4 weeks after the administration of the last dose of IMP to
evaluate ADAs, fremanezumab concentrations, biomarkers, and safety.
Efficacy will be evaluated using CH attack data entered daily throughout the
treatment period in an electronic diary and administration of questionnaires to
evaluate CH-related disability, change in quality of life, health status, and
satisfaction with treatment. The safety of fremanezumab in patients with CH
will be evaluated through adverse event and concomitant medication inquiries,
ECGs, vital signs measurements, clinical laboratory tests, physical
examinations, injection site reaction/pain assessments, assessments for
anaphylaxis and hypersensitivity, and administration of the e-CSSRS. In
addition, blood will be collected for pharmacokinetics, immunogenicity,
biomarker, and pharmacogenomics (unless not allowed per local regulation)
analyses, and urine will be collected for biomarker analysis.
Study objective
The primary objective of this study is to demonstrate the efficacy of
fremanezumab in the prevention of CCH in adult patients:
- The primary efficacy endpoint of this study is the mean change from baseline
(run-in period) in the monthly average number of cluster headache (CH) attacks
during the 12-week period after administration of the first dose of the
investigational medicinal product (IMP), ie, based on week 0 to 12 data
A secondary objective of this study is to further demonstrate the efficacy of
fremanezumab in the prevention of CCH in adult patients:
- the proportion of patients with a >=50% reduction from baseline (run-in
period) in the monthly average number of cluster headache (CH) attacks over the
12 week period after the administration of the first dose of the IMP, ie, based
on week 0 to 12 data
- the mean change from baseline (run-in period) in the number of CH attacks
during the 4-week period after administration of the first dose of the IMP, ie,
based on week 0 to 4 data
- the mean change from baseline (run-in period) in the number of CH attacks
during the 4-week period
after administration of the third dose of the IMP, ie, based on week 8 to 12
data
- the mean change from baseline (run-in period) in the weekly average number of
days with use of
cluster-specific acute headache medications (triptans and ergot compounds)
during the 12-week period after administration of the first dose of the IMP,
ie, based on week 0 to 12 data
- the mean change from baseline (run-in period) in the weekly average number of
days oxygen is used
to treat CCH during the 12-week period after administration of the first dose
of the IMP, ie, based on week 0 to 12 data
- assessment of patient*s perceived improvement, as measured by the
Patient-Perceived Satisfactory Improvement (PPSI) at 1, 4, 8, and 12 weeks
after administration of the first dose of the IMP relative to baseline (day 0)
A secondary objective of this study is to evaluate the safety of fremanezumab
in adult patients with CCH.
• occurrence of adverse events throughout the study
• clinical laboratory (serum chemistry, hematology, coagulation, and
urinalysis) test results at each visit
• vital signs (systolic and diastolic blood pressure, oral temperature, and
pulse rate) measurements at each visit. Note: Oxygen saturation will be
measured in cases of suspected anaphylaxis and severe hypersensitivity.
Respiratory rate will also be measured in these cases but not as a standard
vital sign.
• 12 lead electrocardiogram (ECG) findings at screening, baseline, and week 12
• use of concomitant medication during the study
• clinically significant changes in physical examinations, including body
weight
• injection site reaction (ie, erythema, induration, and ecchymosis) and
injection site pain assessments
• occurrence of hypersensitivity/anaphylaxis reactions
• suicidal ideation and behavior as measured by the electronic Columbia Suicide
Severity Rating Scale (eC-SSRS)
Study design
This is a 16-week, multicenter, randomized, double-blind, double-dummy,
placebo-controlled,
parallel-group study to compare the efficacy and safety of 2 dose regimens of
fremanezumab versus
placebo in adult patients for the prevention of CCH. The study will consist of
a screening visit, a
run-in period lasting approximately 4 weeks (+3 days), and a 12-week
double-blind treatment
period. During the course of any CH attack, patients will be allowed to use
acute medications to treat acute headaches, as needed.
Patients will complete a screening visit (visit 1) after providing written
informed consent, and
eligible patients will enter a run-in period lasting at least 4 weeks (+3 days)
during which they
will enter baseline CH attack information into an electronic diary device
daily. Patients will
return to the study center after completing the run-in period (visit 2 [week
0]). Patients who had
at least 10 CH attacks during the run-in period and who continue to meet
eligibility criteria
(including entry of CH attack information in an electronic diary, demonstrating
compliance for
85% of days during the run-in period) will be randomly assigned at visit 2
(week 0) in a
1:1:1 ratio to 1 of 3 treatment groups.
Intervention
Patients will complete a screening visit (visit 1) after providing written
informed consent, and eligible patients will enter a run-in period lasting at
least 4 weeks (+3 days) during which they will enter baseline CH attack
information into an electronic diary device daily. Patients will
return to the study center after completing the run-in period (visit 2 [week
0]). Patients who had at least 10 CH attacks during the run-in period and who
continue to meet eligibility criteria (including entry of CH attack information
in an electronic diary, demonstrating compliance for
85% of days during the run-in period) will be randomly assigned at visit 2
(week 0) in a 1:1:1 ratio to 1 of 3 treatment groups.
In order to maintain blinding throughout the study, the number of infusions and
injections at each visit will be the same for all patients regardless of the
treatment group to which they are randomized. Thus, all patients will receive
an iv infusion of test IMP or placebo IMP followed
by 3 sc injections of test IMP or placebo IMP at visit 2 (week 0), and all
patients will receive single sc injections of test IMP or placebo IMP at visits
3 and 4 (weeks 4 and 8, respectively).
Patients will also return for an end of treatment (EOT) visit, approximately 4
weeks after the administration of the last dose of IMP, in order to evaluate
antidrug antibodies (ADAs), fremanezumab concentrations, biomarkers, and safety
assessments.
The fremanezumab doses, regimens, and routes of administration to be evaluated
in this double-blind, double-dummy, placebo-controlled study were selected on
the basis of 3 key factors. First, simulations suggest that Cmax is the most
significant pharmacokinetic parameter in
the efficacy of fremanezumab (in migraine). As CH is considered one of the most
severe forms of pain a person can experience, treatments that provide quick and
lasting relief (ie, for the duration of the cluster period) are a priority for
this patient population. Second, the biological nature of
the disease mandates the need for any treatment to desensitize the third order
neuron, not the second (as is the case in migraine), suggesting that high
levels of blockade at the first neuron would be necessary. Third, the favorable
safety profile of the drug and calculated safety margins
based modelling and simulations, as well as clinical and nonclinical safety
data on exposure, suggest that the proposed doses, regimens, and routes of
administration will not present any safety concerns.
In the current study, high doses are planned for the first dose (900 mg iv or
675 mg sc) in order to provide a rapid response, especially following iv
infusion where higher peak plasma concentrations (Cmax) generally occur at or
shortly after the end of infusion (median tmax values
of 1.0 to 5.0 hours after starting the iv infusion) compared with 96 to 108
hours postdose for sc injections. The 2 forms of loading dose will provide data
to confirm the benefit of either the iv or sc as loading dose. Monthly doses of
fremanezumab at 225 mg sc were added to both the initial
dose of 900 mg iv and 675 mg sc for maintenance of efficacy. Based on
modelling, the inclusion of a loading dose should allow patients to reach
steady state faster. The monthly doses of 225 mg sc in this CCH population will
account for the continuous attacks, with less than 1 month free of
headaches between attacks, seen with this CH form.
Study burden and risks
Risks associated to the study drug
Like all medicines, fremanezumab , can cause side effects, although not
everybody experiences them. The possible discomforts, side effects and risks
related to fremanezumab treatment are not all known yet. The study drug is
generally well tolerated. A total of 484 subjects/patients (118 healthy
subjects and 366 patients with migraine) have been treated with at least 1 dose
of fremanezumab in the past in clinical trials. Also there are other 5 ongoing
trials with the study drug for migraines. This section describes the most
frequent side effects which occurred in subjects who were treated with
fremanezumab :
- Injection site disorders/reactions in some of the patients that received
fremanezumab as subcutaneous injections:
• injection site erythema (redness of the skin that is often a sign of
infection or inflammation), (15 patients on fremanezumab versus 5 patients on
placebo).
• injection site pain (38 patients on fremanezumab versus 13 patients on
placebo).
• injection site pruritus (itchiness) , (7 patients on fremanezumab versus 0 on
placebo).
• injection site dermatitis (inflammation of the skin), (3 patients on
fremanezumab versus 0 on placebo).
• drug hypersensitivity (was observed in one patient treated with intravenous
administration (infusion related reaction) and one patient with subcutaneous
injection of fremanezumab)
- Infusion-related reaction for patients treated with intravenous fremanezumab:
• administration site pain
• infusion-related reaction
Other reported side effects were headache, back pain, and upper respiratory
tract infection. Potential risks of taking study drug include perivascular
inflammation, development of antidrug antibodies (ADAs), raised liver enzymes,
and cardiovascular effects (e.g. on blood pressure, heart rate, other).
Taking certain other medicines together with fremanezumab may increase the
chance of unwanted effects. The risk will depend on how much of each medicine
you take every day, and on how long you take the medicines together.
Like in the case of infusion of any drug of this class, there is the infusion
associated risk of fever, headache, nausea, vomiting or hypotension.
Risks associate to blood drawn
Blood samples will be collected during this study. A needle is inserted into a
vein in your arm and a small blood sample is withdrawn. Although one blood draw
is usually sufficient, a second one may be necessary if the first is not
successful. Collecting blood samples may cause fainting and some pain and/or
bruising at the site on your arm where the blood was taken. In rare occasions,
infection may occur.
Pregnancy
Information for women:
The risks of taking fremanezumab to pregnant women or an unborn baby are
unknown. For this reason, women must have a pregnancy test before the study
starts and again just before receiving fremanezumab. Women who or
breast-feeding cannot be in this study. Women must not become pregnant during
this study.
Information for men:
Men should keep in mind that their partner must not become pregnant during the
study. Inform your partner about this.
The effects of the study drug on the male reproductive system are not known at
this time, and contraceptive methods should be used throughout the study and
for 7,5 months after completion of the study.
Moores Road 41
Frazer, Pennsylvania 19355
US
Moores Road 41
Frazer, Pennsylvania 19355
US
Listed location countries
Age
Inclusion criteria
a. Patients are capable of giving signed informed consent as described in Appendix D
which includes compliance with the requirements and restrictions listed in the
informed consent form (ICF) and in this protocol.
b. The patient is a man or woman 18 to 70 years of age, inclusive
c. The patient has history of CCH according to ICHD-3 beta criteria (Headache
Classification Committee of the IHS 2013) for >=12 months prior to screening
including the following:
Attacks of severe, strictly unilateral pain, which is orbital, supraorbital, temporal
or in any combination of these sites, lasting 15 to 180 minutes and occurring from
once daily every other day to 8 times a day for more than half of the time when
the disorder is active.
The pain is associated with at least 1 of the following symptoms or signs:
ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhea,
forehead and facial sweating, miosis and/or ptosis and/or eyelid edema, and/or
sense of restlessness or agitation.
CH attacks occurring for more than 1 year without remission, or with remission
periods lasting less than 1 month.
d. The patient has a total body weight of >=45 kg.
e. The patient is not using or using <= 2 concomitant medications that are
commonly prescribed as preventive treatments for CH (Appendix H), regardless of
the indication for which the medication was prescribed. Patients must be on a stable
dose and regimen for at least 2 weeks prior to screening and throughout the study.
f. If a patient is receiving Botox, it should be in a stable dose regimen, considered as having >=2 cycles of Botox prior to screening. The patient should not receive Botox during the run-in period up to the evaluation period (12 weeks) where the primary endpoint is evaluated.
g. The patient demonstrated compliance with the electronic headache diary during the
run-in period by entry of headache data on 85% of days during the run-in period.
h. The patient has at least 10 CH attacks during the run-in period.
i. The patient is in good health in the opinion of the investigator as determined by a
medical and psychiatric history; medical examination; 12-lead ECG; and serum
chemistry, hematology, coagulation, and urinalysis.
j. Women may be included only if they have a negative serum beta-human chorionic
gonadotropin (β-HCG) test at screening, are sterile, or postmenopausal, and are not lactating. Definitions of sterile and postmenopausal are given in Appendix E.
k. Women of childbearing potential (WOCBP) whose male partners are potentially
fertile (ie, no vasectomy) must use highly effective birth control methods for the
duration of the study (ie, starting at screening) and for 7.5 months after
discontinuation of IMP.
l. Men must be sterile, or if they are potentially fertile/reproductively competent (not
surgically [eg, vasectomy] or congenitally sterile) and their female partners are of
childbearing potential, must agree to use, together with their female partners, acceptable birth
control methods for the duration of the study and for 7.5 months after discontinuation
of the IMP. Definitions of women of non-childbearing potential, sterile women, and postmenopausal women; male
contraception; and highly effective and acceptable birth control methods including
examples are given in Appendix E.
m. The patient must be willing and able to comply with study restrictions, to remain at
the clinic for the required duration during the study period and to return to the clinic
for the follow-up evaluations, as specified in this protocol.
Exclusion criteria
a. The patient has used systemic steroids for any medical reason (including treatment of the current CH cycle ) within <=7 days prior to screening.
b. The patient reports using butalbital on more than 7 days during the 4 weeks prior to
screening or using butalbital on more than 10 days during the screening/run-in period.
c. The patient reports using opioids on more than 15 days during the 4 weeks prior to
screening or using opioids on more than 15 days during the screening/run-in period.
d. The patient has used an intervention/device (eg, scheduled nerve blocks) for headache
during the 4 weeks prior to screening.
e. The patient has clinically significant hematological, renal, endocrine, immunologic, pulmonary,
gastrointestinal, genitourinary, cardiovascular, neurologic, hepatic, or ocular disease, at the
discretion of the investigator.
f. The patient has evidence or medical history of clinically significant psychiatric issues
determined at the discretion of the investigator.
g. The patient has a history of any suicide attempt in the past or current active suicidal
ideation, as measured by the eC-SSRS.
h. The patient has a history of clinically significant cardiovascular disease or vascular
ischemia (such as myocardial, neurological [eg, cerebral ischemia], peripheral
extremity ischemia, or other ischemic event) or thromboembolic events (arterial or
venous thrombotic or embolic events), such as cerebrovascular accident (including
transient ischemic attacks), deep vein thrombosis, or pulmonary embolism.
i. The patient has a past or current history of cancer or malignant tumor in the past 5 years, except for appropriately treated non-melanoma skin carcinoma.
j. The patient is pregnant or lactating.
k. The patient has a history of hypersensitivity reactions to injected proteins, including
monoclonal antibodies.
l. The patient has participated in a clinical study of a new chemical entity or a
prescription medicine within 2 months or 5 half-lives before administration of the
first dose of the IMP, whichever is longer.
m. The patient has participated in a clinical study of a monoclonal antibody within 3 months or 5 half-lives before administration of the first dose of the IMP, whichever is longer, unless it is
known that the patient received placebo during the study.
n. The patient has a history of prior exposure to a monoclonal antibody targeting the
CGRP pathway (AMG 334, ALD304, LY2951742, or fremanezumab). If patient has participated in a clinical study with any of these monoclonal antibodies, it has to be confirmed that the patient received placebo in order to be eligible for this study.
o. The patient has any finding in the baseline 12-lead ECG considered clinically
significant in the judgment of the investigator.
p. The patient has 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).
q. The patient has hepatic enzymes (alanine aminotransferase [ALT] and aspartate
aminotransferase [AST]) >1.5 × the upper limit of normal (ULN) range after
confirmation in a repeat test, or the patient has suspected hepatocellular damage that
fulfills criteria for Hy*s law at screening.
r. The patient has serum creatinine >1.5 × the ULN or evidence of clinically significant
renal disease in the judgement of the investigator.
s. The patient cannot participate or successfully complete the study, in the opinion of
their healthcare provider or the investigator, for any of the following reasons:
mentally or legally incapacitated or unable to give consent for any reason
in custody due to an administrative or a legal decision, under tutelage, or being
admitted to a sanitarium or social institution unable to be contacted in case of emergency
has any other condition, which, in the opinion of the investigator, makes the patient inappropriate for inclusion in the study
u. The patient is an employee of the sponsor/participating study center who is directly
involved in the study or is the relative of such an employee.
v. The patient has an active implant for neurostimulation used in the treatment of CH.
w. The patient is a member of a vulnerable population (eg, people kept in detention).
x. The patient has a history of alcohol and/or drug abuse that in the investigator*s opinion could interfere with the study evaluations or the patient*s safety.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
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 | EUCTR2016-003171-21-NL |
| CCMO | NL59637.058.17 |