Study of Efficacy and Safety of Canakinumab in Patients With Hereditary Periodic Fevers

Study Overview
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Brief Summary
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This study is to determine whether canakinumab is able to induce and maintain a clinically meaningful reduction of disease activity in participants with Hereditary Periodic Fevers (HPF) compared to placebo.

Detailed Description
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This study consists of 3 randomized cohorts (one per condition of colchicine resistant/intolerant Familial Mediterranean Fever (crFMF), Hyper Immunoglobulin D Syndrome (also known as mevalonate kinase deficiency (HIDS/MKD), and Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), and 4 study epochs: Epoch 1: a screening epoch to assess participant's eligibility; Epoch 2: a randomized treatment epoch of 16 weeks where participants are randomized to canakinumab 150 mg every 4 weeks (q4w) or to placebo to obtain efficacy and safety data in a double-blind placebo controlled parallel-arm setting. This epoch contained 2 possible escape options : early blinded escape option for non responders from Day 8 to Day 28 with here an add-on dose of 150mg canakinumab followed by blinded uptitration at the next scheduled visit (Day 29) late unblinded escape option for non responders from Day 29 to Day 112; with open-label uptitration Epoch 3: a randomized withdrawal epoch of 24 weeks where canakinumab responders from the randomized treatment epoch were re-randomized to canakinumab 150mg q8w or placebo to assess the potential for canakinumab to maintain clinical efficacy at a reduced dosing frequency; Epoch 4: an open-label treatment epoch of 72 weeks to collect long-term

Official Title
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A Randomized, Double-blind, Placebo Controlled Study of Canakinumab in Patients With Hereditary Periodic Fevers (TRAPS, HIDS, or crFMF), With Subsequent Randomized Withdrawal/Dosing Frequency Reduction and Open-label Long-term Treatment Epochs

Conditions
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Hereditary Periodic Fevers

Intervention / Treatment
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* Drug: Canakinumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Patient's written informed consent (or parent's written informed consent in case of pediatric patient) at screening - Male and female patients at least 2 years of age at the time of the screening visit. Male and female patients >28 days but <2 years eligible for open label treatment only. - Confirmed diagnosis and active flare at randomization - CRP >10mg/L at randomization Exclusion Criteria: - Use of the following therapies (within varying protocol defined timeframes): 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 - History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in - situ cervical cancer), treated or untreated - Significant medical diseases, including but not limited to the following: a. History of organ transplantation b. Elevated liver enzymes ≥3x ULN d. Increase in total bilirubin e. Serious hepatic disorder (Child-Pugh scores B or C) f. Chronic Kidney Disease 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 immunecompromise the patient and/or places the patient at unacceptable risk for immunomodulatory therapy - Live vaccinations within 3 months prior to the start of the trial, during the trial, and up to 3 months following the last dose

Ages Eligible for Study
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Minimum Age: 1 Month

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: crFMF: 150 mg<br>During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration. | Drug: Canakinumab<br>* Canakinumab solution for subcutaneous injection in vial which contained 150mg/mL canakinumab in 1 mL solution.<br>* Other names: ACZ885;|
| Placebo Comparator: crCMF: placebo<br>During epoch 2, participants received matching placebo to canakinumab 150 mg Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab. 150mg, participants were uptitrated to open-label canakinumab 300 mg. | Drug: Placebo<br>* Matching placebo to canakinumab solution for subcutaneous injection<br>|
| Experimental: HIDS/MKD: 150 mg<br>During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration. | Drug: Canakinumab<br>* Canakinumab solution for subcutaneous injection in vial which contained 150mg/mL canakinumab in 1 mL solution.<br>* Other names: ACZ885;|
| Placebo Comparator: HIDS/MKD: placebo<br>During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg. | Drug: Placebo<br>* Matching placebo to canakinumab solution for subcutaneous injection<br>|
| Experimental: TRAPS: 150 mg<br>During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing <= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration | Drug: Canakinumab<br>* Canakinumab solution for subcutaneous injection in vial which contained 150mg/mL canakinumab in 1 mL solution.<br>* Other names: ACZ885;|
| Placebo Comparator: TRAPS: placebo<br>During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing <= 40kg) between Day 8 and 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg. | Drug: Placebo<br>* Matching placebo to canakinumab solution for subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Resolution of Initial Flare and Absence of New Flares up to the End of the Randomized Treatment Epoch (16 Weeks) | Resolution of the initial disease flare is defined as: Physician's Global Assessment of Disease activity (PGA) <2 and C-reactive protein (CRP) within normal range (<= 10 mg/L) or reduction by at least 70% from baseline. The PGA was evaluated by the investigator based on a 5-point scale: 0 = None (no) disease associated with clinical signs and symptoms; 1 = minimal disease associated signs and symptoms; 2 = mild disease associated signs and symptoms; 3 = moderate disease associated signs and symptoms; and 5 = severe disease associated signs and symptoms. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieve Physician's Global Assessment (PGA) < 2 | The PGA was evaluated by the investigator based on a 5-point scale: 0 = None (no) disease associated with clinical signs and symptoms; 1 = minimal disease associated signs and symptoms; 2 = mild disease associated signs and symptoms; 3 = moderate disease associated signs and symptoms; and 5 = severe disease associated signs and symptoms. | 16 weeks | 
| Percentage of Participants With the Serologic Remission | Serologic remission was defined as C-reactive protein <= 10 mg/L. | 16 weeks | 
| Percentage of Participants With Normalized Serum Amyloid A (SAA) Level | Normalized SAA was defined as SAA <= 10 mg/L. | 16 weeks | 
| Percentage of Participants of Canakinumab Responders From Epoch 2 Who Maintained a Clinically Meaningful Response (Absence of New Flares) (40 Weeks) | A responder was defined as a participant who had no flare between week 16 and week 40. | 40 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Canakinumab, interleukin-1, Hereditary Periodic Fevers, auto-inflammatory diseases