A 3-arm Proof of Concept Study of AIN457, ACZ885 or Corticosteroids in Patients With Polymyalgia Rheumatica

Study Overview
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Brief Summary
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The study is a two-week, single-blinded, double-dummy, randomized, active-controlled, parallel group design, with a follow-up period up to a total study duration of 6-month, non-randomized, open-label phase to monitor safety, tolerability and, in responders, flare. It is a multicentric, multinational study. The protocol will seek to enroll a total of 30 patients, who will be randomized to the 3 arms at a ratio of 1:1:1. Patients will have a maximum screening period of 7 days with randomization at D1 for a dosing period of 15 days followed by a follow up-period of 154 days, or 4 months (112 days) after their last biologic dose, whichever is greater, and followed by unblinded re-dosing in the case of a disease flare.

Official Title
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A 2-week Single-blind, Randomized, 3-arm Proof of Concept Study of the Effects of AIN457 (Anti-IL17 Antibody), ACZ885 (Canakinumab, Anti-IL1b Antibody), or Corticosteroids in Patients With Polymyalgia Rheumatica, Followed by an Open Label Phase to Assess Safety and Long Term Efficacy

Conditions
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Polymyalgia Rheumatica, Inflammatory Diseases

Intervention / Treatment
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* Drug: AIN457
* Drug: ACZ885
* Drug: Prednisone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet all of the following features: Patients ≥ 50 and ≤ 85 years C-reactive protein (CRP) > 1.0 mg/dl OR erythrocyte sedimentation rate (ESR) > 30 mm/hr New bilateral shoulder and/or hip pain Early morning stiffness ≥ 60 min Duration of illness > 1 week A negative 5 U purified protein derivative skin test (PPD) skin test (≤ 5 mm induration) at screening Exclusion Criteria: Active infection or current use of antibiotics Known human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatits B virus (HBV) Previous therapy with methotrexate or other immunosuppressive agents within three months prior to baseline History of malignancy other than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix within five years prior to study entry Presence of rheumatoid arthritis or other inflammatory arthritic processes (features of Giant Cell Artertitis (GCA), spondyloarthropathies), connective tissue disease, drug-induced myopathies, endocrine disorders, neurological disorders, chronic pain syndromes, as assessed by base line screening including thyroid-stimulating hormone (TSH), creatine kinase (CK), rheumatoid factor (RF), cyclic citrullinated peptide (CCP), antinuclear antibodies (ANA), serum protein electrophoresis, urinalysis. Other protocol-defined inclusion/exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACZ885<br>On day 1, patients received a single intravenous dose of ACZ885 3mg/kg along with a placebo intravenous infusion in a double dummy manner to maintain the blind. On day 15, partial and complete responders continued in the open label phase of this treatment arm where they were eligible to receive one re-dose of ACZ885 upon confirmed disease flare. Non-responders started a 20 mg dose cycle of prednisone or prednisolone followed by standard steroid tapering. | Drug: AIN457<br>* 3 mg/kg<br>Drug: Placebo<br>* Matching placebo to AIN457, ACZ885 and prednisone<br>|
| Experimental: AIN457<br>On day 1, patients received a single intravenous dose of AIN457 3mg/kg along with a placebo intravenous infusion in a double dummy manner to maintain the blind. On day 15, partial and complete responders continued in the open label phase of this treatment arm where they were eligible to receive one re-dose of AIN457 upon confirmed disease flare. Non-responders started a 20 mg dose cycle of prednisone or prednisolone followed by standard steroid tapering. | Drug: ACZ885<br>* 3 mg/kg<br>* Other names: canakinumab;Drug: Placebo<br>* Matching placebo to AIN457, ACZ885 and prednisone<br>|
| Other: Prednisone<br>On day 1, patients received daily oral doses of prednisone 20 mg along with daily oral placebo doses to in a double-dummy manner to maintain the blind. On day 15, partial and complete responders continued in the study and tapered their steroid treatment according to standard care. Non-responders were discontinued from the study. | Drug: Prednisone<br>* 20 mg<br>Drug: Placebo<br>* Matching placebo to AIN457, ACZ885 and prednisone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Polymyalgia Rheumatica Activity Score (PMR-AS) | The efficacy of a single dose of AIN457 and ACZ885 (canakinumab) was measured by the polymyalgia rheumatica activity score. A composite PMR-AS was developed from the following components: measure of C-reactive protein (CRP), measure of Erythrocyte Sedimentation Rate (ESR), assessment of early morning stiffness, assessment of the patient's elevation on upper limbs, patient's assessment of pain, and physician's global assessment of disease activity. Treatment effect was measured by the percent reduction in PMR-AS. N=3 for the ACZ885 arm because CRP values at Day 15 were missing for 2 participants. | Baseline, Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Partial Clinical Response | The time to partial clinical response was assessed in patients who received a single dose of AIN457 or ACZ885 (canakinumab). Daily monitoring (home-based) of CRP was performed. This outcome shows the percentage of patients who achieved a partial clinical response at Day 15. A participant was defined as a partial responder if the participant had: >50% reduction in patient global assessment visual analogue scale (VAS) compared with baseline and morning stiffness < 60 minutes. | Day 15 | 
| Time to Complete Clinical Response | The time to complete clinical response was assessed in patients who received a single dose of AIN457 or ACZ885 (canakinumab). Daily monitoring (home-based) of CRP was performed. This outcome shows the percentage of patients who achieved a complete clinical response at Day 15. A participant was defined as a complete responder if the participant had: >70% reduction in patient global assessment VAS compared with baseline, morning stiffness < 30 min, CRP < 1.0 mg/dL and/or ESR < 30 mm/1st hr. | Day 15 | 
| Time to First Flare | This study was terminated because the data did not show that the two biologic treatments impacted PMR disease activity to the same degree as steroid treatment within a 2-week treatment period. Only 1 participant experienced a flare, in the AIN457 treatment group. The flare for this one participant occurred on study day 44 | 6 months | 
| Number of Flares Over a 6 Month Period | This study was terminated because the data did not show that the two biologic treatments impacted PMR disease activity to the same degree as steroid treatment within a 2-week treatment period. The summary statistics include patients with a valid measurements for the outcome measure. | 6 months | 
| Mean Steroid Dose Over a 6 Month Period | This study was terminated because the data did not show that the two biologic treatments impacted PMR disease activity to the same degree as steroid treatment within a 2-week treatment period. The summary statistics include patients with a valid measurements for the outcome measure. | 6 months | 
| Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Deaths |  | 6 months | 
| Comparison Between the Initial Response to AIN457 and ACZ885 and the Response After Re-dosing of AIN457 and ACZ885 - Assessed by the Number of Flares After Redosing. | One participant experienced one flare after initial dose but this participant had no flare after a redose. This patient was in the AIN457 arm. | 6 months | 
| Effect on Health-related Quality of Life Via the Short Form-36 (SF-36) Questionnaire | The Short Form-36 (SF-36) Questionnaire is a 36-item questionnaire yields an 8-scale health profile as well as summary measures of individual patients.. The scores range for each subscale from 0 to 10, and the composite score ranges from 0 to 100, with higher scores indicative of better health. | 6 months | 
| Effect on Health-related Quality of Life Via the Health Assessment Questionnaire (HAQ) | HAQ: The scores range from 0 (min) to 3 (max). Higher scores = more disability; lower scores = less disability. | baseline and at month 6 | 
| Effect on Health-related Quality of Life Via the Health Assessment Questionnaire (HAQ) - % Change From Baseline in the Standard Disability Score at EOS / Month 6 | HAQ: The scores range from 0 (min) to 3 (max). Higher scores = more disability; lower scores = less disability. | 6 months | 
| Pharmacokinetics of AIN457 and ACZ885 - Cmax |  | Day 15 | 
| Pharmacokinetics of AIN457 and ACZ885 - Tmax |  | Day 15 | 
| Pharmacokinetics of AIN457 and ACZ885 - AUCinf and AUClast |  | Day 15 | 
| Pharmacokinetics of AIN457 and ACZ885 - CL |  | Day 15 | 
| Pharmacokinetics of AIN457 and ACZ885 - Vz |  | Day 15 | 
| Pharmacokinetics of AIN457 and ACZ885 - T1/2 |  | Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Polymyalgia Rheumatica, Inflammatory Disease, Rheumatic Disease