Primary: The primary objective of the randomized treatment epoch and for the overall study is to demonstrate that subcutaneous canakinumab administered every 4 weeks is superior to placebo in achieving a clinically meaningful reduction of disease…
ID
Source
Brief title
Condition
- Other condition
- Congenital and hereditary disorders NEC
Synonym
Health condition
erfelijke periodieke koortssyndromen (TRAPS, HIDS of crFMF)
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Physician*s global assessment of disease activity.
Secondary outcome
CRP, SAA, responders in Epoch 2 who maintain a clinically meaningful response
when switched to canakinumab every 8 weeks compared to placebo in epoch 3.
Adverse events. PK/PD.
Background summary
Hereditary Periodic Fevers is a group of rare orphan diseases and consists of 4
separate conditions: Cryopyrin Associated Periodic Syndrome (CAPS), TNF
receptor Associated Periodic Syndrome (TRAPS), Hyper IgD Syndrome (HIDS) and
Familial Mediterranean Fever (FMF). There are currently no approved treatments
for TRAPS, HIDS and colchicine resistant FMF (crFMF).
A key feature of these conditions is the recurrent episodes of systemic
inflammation with high fever that is accompanied by characteristic signs and
symptoms like serositis, neutrophilic rash, muco-cutaneous ulcers,
arthralgia/arthritis, and aseptic meningitis/headaches.
Canakinumab is a fully human monoclonal anti-human interleukin-1* (IL-1*)
antibody. Canakinumab is designed to bind to human IL-1* blocking the
interaction of this cytokine to its receptors, thus functionally neutralizing
the bioactivity of this cytokine, IL-1* is recognized as one of the principal
pro inflammatory cytokines in a variety of inflammatory conditions. Canakinumab
is registered for the treatment of adults with CAPS, gout and of Systemic
Juvenile Idiopathic Arthritis.
The purpose of this study is to determine whether canakinumab is able to induce
and maintain a clinically meaningful reduction of disease activity in a greater
proportion of patients with TRAPS, HIDS, or crFMF compared to placebo. It is
further to determine whether, in patients responding to the initial dosing
regimen, canakinumab will maintain its clinical efficacy if administered at a
reduced dosing interval.
The study protocol allows the inclusion of minors.
Amendment 2 is issued to address the request from the Paediatric Committee at
the EMA in to include patients >28 days in this clinical trial compared to
previously *2 years of age. Patients >28 days but <2 years old will enter the
study directly into the open-label arm of Epoch 2, but won*t be considered
toward the total number of patients enrolled for the primary efficacy and
safety analyses. In addition, this amendment provides more clarity on patient*s
management for randomized and non- andomized cohorts in accordance with
clinical practice.
It is unlikely that patients <2 years will be included in NL.
Study objective
Primary: The primary objective of the randomized treatment epoch and for the
overall study is to demonstrate that subcutaneous canakinumab administered
every 4 weeks is superior to placebo in achieving a clinically meaningful
reduction of disease activity defined as resolution of the index flare at Day
15 and no new disease flares over 16 weeks of treatment.
Secondary:
* Percentage of patients who achieve a Physician Global Assessment of Disease
Activity <2 (*minimal* or *none*) at Week 16
* Percentage of patients with the serologic remission at Week 16 (defined as
CRP <10 mg/L)
* Percentage of patients with normalized Serum Amyloid A level at Week 16
(defined as SAA <10 mg/L)
* Percentage of responders in Epoch 2 who maintain a clinically meaningful
response (absence of new flares) when switched to canakinumab every 8 weeks
compared to placebo in epoch 3
* Long-term safety and tolerability and immunogenicity
* Pharmacokinetics/pharmacodynamics
Study design
This study consists of 3 cohorts (one cohort per condition: TRAPS, HIDS and
crFMF), and 4 study epochs.
Each cohort will follow the same study design across the 4 epochs:
1. Screening (max 12 weeks).
2. A randomized treatment epoch (canakinumab s.c. every 4 weeks versus placebo)
of 16 weeks which will provide efficacy and safety data in a double-blind
placebo-controlled parallel-arm setting. This randomized treatment epoch will
include 2 possible escape options:
* Blinded escape.
* Open-label treatment.
3. A randomized withdrawal epoch of 24 weeks for responders.
4. An open-label treatment epoch of 72 weeks to collect long-term safety data
for canakinumab.
180 patients (25 in NL).
Intervention
Treatment with canakinumab (in double blind epoch canakinumab or placebo).
Study burden and risks
Risk: Adverse effects of study medication.
Burden: Study duration approx. 2 years. 25 visits.
Injections with canakinumab/placebo every 4 weeks during approx. 88 weeks (if
no withdrawal in epoch 3). In case of dose increase 2 injections per visit. In
case of withdrawal: injections every 8 weeks during 24 weeks.
Physical examination approx. 22 times.
Blood tests (approx. 17 ml/visit for adults) approx. 24 times. For children the
amount of blood to be taken will be adjusted.
ECG 5 times.
Questionnaires (SF12 en Sheehan disability) 6 times.
Electronic diary (sign and symptoms) during part 1 and 2.
Optional pharmacogenetic research (10 ml blood).
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
* Male or female patients at least 2 years of age. Patients >28 days but <2 years old with bodyweight *3.75 kg at the time of the screening visit will be enrolled in the open label arm only.
* Confirmed diagnosis of TRAPS, HIDS or crFMF at screening.
* Active flare of TRAPS, HIDS or crFMF as evidenced by *mild*, *moderate* or *severe* disease activity (Physician*s Global Assessment of Disease Activity *2) at randomization.
* CRP >10mg/L (normal CRP range *10 mg/L) at randomization.
Exclusion criteria
* Use of the following therapies (within varying protocol defined timeframes, see also protocol page 28-29): Corticosteroids, anakinra, canakinumab, rilonacept, tocilizumab, TNF inhibitors, abatacept, tofacitinib, rituximab, leflunomide, thalidomide, cyclosporine, intravenous immunoglobulin, 6-merceptopurine, azathioprine, cyclophosphamide, or chlorambucil, , any other investigational biologics
* Significant medical diseases, including but not limited to the following:
a) History of organ transplantation
b) Elevated ALT *3x ULN
c) Elevated AST *3x ULN
d) Increase in total bilirubin CTC Grade *2
e) Serious hepatic disorder (Child-Pugh scores B or C)
f) Chronic Kidney Disease NKF stages *4
g) Thyroid disease
h) Diagnosis of active peptic ulcer disease
i) Coagulopathy
j) Significant CNS effects including vertigo and dizziness
* Any conditions or significant medical problems which immunocompromise the patient and/ or places the patient at unacceptable risk for immunomodulatory therapy, e.g.
a) Absolute neutrophil count decreased as per CTC Grade *1
b) Thrombocytopenia CTC * Grade 1
c) Any active or recurrent bacterial, fungal (with exception of onychomycosis) or viral infection
d) HIV, Hepatitis B or C
e) Tuberculosis
f) Requirement for administration of antibiotics against latent TB
g) Clinical evidence or history of multiple sclerosis or other demyelinating diseases, or Felty*s syndrome
* Live vaccinations within 3 months prior to the start of the trial, during the trial, and up to 3 months following the last dose
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 |
|---|---|
| Other | Clinicaltrials.gov; NCT02059291 |
| EudraCT | EUCTR201300429135-NL |
| CCMO | NL49974.091.14 |