Study of Tocilizumab to Treat Polymyalgia Rheumatica

Study Overview
=================
Brief Summary
-----------------
This is a fifteen-month open label, Phase IIa clinical trial is being conducted to assess the tolerability, safety and efficacy of a medication called Tocilizumab (Actemra®) in patients with polymyalgia rheumatica (PMR).

Detailed Description
-----------------
This fifteen-month open label, Phase IIa clinical trial is being conducted to assess the tolerability, safety and efficacy of a medication called Tocilizumab (Actemra®) in patients with polymyalgia rheumatica (PMR). The typical symptoms of PMR are muscle pain and stiffness in the shoulder, neck or hip region. Steroids have traditionally been used to treat this condition with great success, although long courses of steroids, up to 2 years in many cases, are often required. This can result in many unwanted side effects including diabetes, high blood pressure, heart disease, cataracts, weak bones with fractures, weak muscles, skin bruising, difficulty sleeping and mood disturbances. In this trial, the steroid dosage will be decreased much more quickly than what is done in routine clinical practice; there is an expectation that steroid therapy will be withdrawn within six months. Tocilizumab is a medication already on the market that has been FDA approved in the US and Japan for the treatment of rheumatoid arthritis, and in Japan it is also approved for certain types of juvenile idiopathic arthritis (which is like rheumatoid arthritis in children) and Castleman's disease (which is a rare disease that causes enlarged lymph nodes). It is not FDA approved to treat polymyalgia rheumatica at this time. In this study, it will be given as an intravenous infusion once a month for a treatment period of one year. Experiments done on the blood of patients with PMR show one particular cytokine or small molecule that circulates throughout the body, interleukin-6, to be elevated in this disease. Tocilizumab is a medication that is designed to specifically block this cytokine. The co-primary endpoints for this study include efficacy, as well as evaluations of safety and tolerability. Efficacy will be defined by the proportion of patients in Disease Remission (DR) off corticosteroids, without relapse or recurrence, at six months from trial entry Safety and tolerability of Tocilizumab will be evaluated during the fifteen-month study period by the monitoring of adverse events and immunogenicity surveillance Disease Remission (DR) will be defined as the disappearance of signs and symptoms of polymyalgia rheumatica (aching and stiffness of the shoulder, hip girdle, or both) with normalization of erythrocyte sedimentation rate (ESR<30 mm/hr) and c-reactive protein (CRP ≤1.0 mg/dl), unless elevation of ESR and/or CRP are attributable to causes other than PMR (i.e., infection).

Official Title
-----------------
Phase IIa of Tocilizumab In the Treatment of Polymyalgia Rheumatica

Conditions
-----------------
Polymyalgia Rheumatica (PMR)

Intervention / Treatment
-----------------
* Drug: Tocilizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Disease- Specific Inclusion Criteria: Patients must meet the following inclusion criteria to be eligible for study entry: Diagnosed with polymyalgia rheumatica and enrolled within one month of diagnosis. Disease Specific Exclusion Criteria: Patients will be excluded from the study based on the following criteria: Symptoms or diagnosis of temporal arteritis, including headache, jaw claudication, hyperesthesia of scalp, abnormal palpated temporal artery, visual disturbances, temporal artery biopsy positivity Concurrent rheumatoid arthritis Presence of rheumatoid factor and CCP Other inflammatory arthritis or other connective tissue diseases, such as but not limited to systemic lupus erythematosus, systemic sclerosis, vasculitis, polymyositis, dermatomyositis, mixed connective tissue disease Treatment of polymyalgia rheumatica with more than 20mg of daily prednisone or its equivalent at the time of screening Treatment with more than 30mg of daily prednisone or its equivalent since diagnosis. Treatment with 30mg of daily prednisone or its equivalent since diagnosis for more than 2 weeks. More than 4 weeks of corticosteroid therapy prior to enrollment History of bowel perforation within the past five years. Active diverticulitis. Pre-existing or recent onset demyelinating disorders

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab<br>This is a single-arm study. All subjects will receive the active study treatment for 12 months, and will then be evaluated for 3 months of long-term follow-up. | Drug: Tocilizumab<br>* Tocilizumab is a humanized anti-interleukin-6 receptor antibody that has been FDA approved for the treatment of rheumatoid arthritis (RA). This molecule binds to the IL-6 binding site of human IL-6 receptor, and competitively inhibits IL-6 signaling.<br>* Other names: Actemra;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients in Disease Remission at Six Months From Trial Entry | The co-primary endpoints for this study include efficacy: • Efficacy will be defined by the proportion of patients in Disease Remission (DR) off corticosteroids, without relapse or recurrence, at six months from trial entry Relapse was defined as the reappearance of signs and symptoms of PMR, accompanied by an increasing erythrocyte sedimentation rate and/or C-reactive protein level attributable to disease activity. Recurrence was similarly defined as the return of PMR symptoms in conjunction with elevations in levels of inflammation markers, occurring 1 month after discontinuation of glucocorticoid therapy. | Six months | 
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | The co-primary endpoints for this study include evaluations of safety and tolerability: • Safety and tolerability of Tocilizumab will be evaluated during the fifteen-month study period by the monitoring of adverse events and immunogenicity surveillance | 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Able to Achieve Disease Remission (DR) Off Corticosteroids, Without Disease Relapse or Recurrence |  | 12 and 15 months from trial entry | 
| Proportion of Patients Who Develop Disease Relapses | Relapse was defined as the reappearance of signs and symptoms of PMR, accompanied by an increasing erythrocyte sedimentation rate and/or C-reactive\ protein level attributable to disease activity. Recurrence was similarly defined as the return of PMR symptoms in conjunction with elevations in levels of inflammation markers, occurring 1 month after discontinuation of GC therapy. | 6, 12 and 15 months from trial entry | 
| The Cumulative Dose of Prednisone |  | 6, 12 and 15 months from trial entry | 
| Total Number of Relapses/Recurrences |  | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PMR, POLYMYALGIA RHEUMATICA, Tocilizumab, Hospital for Special Surgery, HSS, Robert Spiera