GCs Sparing Regimen in PMR
Study Details
Study Description
Brief Summary
Glucocorticoids are the cornerstone treatment for polymyalgia rheumatica but induce adverse events. The efficacy of the candidate drug Tofacitinib has not yet been demonstrated in controlled studies. The aim of the study is to investigate the efficacy and safety of Tofacitinib as a glucocorticoid sparing agent in patients with refractory polymyalgia rheumatica.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
A two-stage, phase 2 clinical trial was conducted to test whether tofacitinib would take into effect as a glucocorticoid sparing agent in patients with refractory polymyalgia rheumatica. Tofacitinib was given at the dose of 10mg daily through the 24 weeks. Patients were to receive prednisone in a dosage of 15mg daily (or equivalent oral GCs) at baseline and tapered to 2.5mg or less daily within 20 weeks. The primary endpoint was the response to treatment, defined as the achievement of sustained low disease activity (PMR-AS<7) with GC independence (prednisone≤2.5mg daily or equivalent oral GCs) for 4 weeks before week 24.
The trial will be conducted following a two-stage Simon minimax design. After 8 participants have completed their 24-week follow up there will be an interim analysis. If there are 3 or more failures out of these 8 then the trial will stop with the conclusion that the study of Tofacitinib should be abandoned. If there are fewer than 3 failures then the study will continue until a further 6 participants have received treatment, giving a total sample size of 14. If amongst these 14 participants there are 4 or more failures then it will be concluded that the further study of Tofacitinib should be abandoned. If further study of the drug is not abandoned at either the interim of the final analysis, then a recommendation to conduct a comparative, randomized phase III trial will be made.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Tofacitinib+Prednisone Tofacitinib was given at the dose of 10mg daily through the 24 weeks. Prednisone (or equivalent oral GCs) of 15 mg daily at baseline was tapered to 2.5 mg or less within 20 weeks. The PMR-AS was determined every two weeks; if≤10 the dosage was decreased by 2.5mg every two weeks; and if >17, the dosage was increased to previous dosage; if 10≤PMR-AS≤17, the dosage was maintained at previous stable dose. |
Drug: Tofacitinib 5 MG
Oral tofacitinib at the dose of 5mg twice a day was given for 24 weeks. Prednisone (or equivalent oral GCs) of 15 mg daily at baseline was tapered to 2.5 mg or less within 20 weeks. The PMR-AS was determined every two weeks; if≤10 the dosage was decreased by 2.5mg every two weeks; and if >17, the dosage was increased to previous dosage; if 10≤PMR-AS≤17, the dosage was maintained at previous stable dose.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Response to treatment [24 week]
Response to treatment is defined as the achievement of sustained low disease activity (PMR-AS<7) with GC independence (≤2.5mg/d) for 4 weeks before week 24
Secondary Outcome Measures
- Time till GC-free low disease activity within 24w [24 week]
Time till GC-free low disease activity (PMR-AS<7) within 24 weeks
- Time till first relapse within 24w [24 week]
Time till first relapse (PMR-AS ≥7) within 24w
- Cumulative GC dose at 24w [24 week]
Cumulative glucocorticoids dose over time
- Proportion of patients with sustained remission for 4 weeks before week 24 [24 week]
Proportion of patients with sustained remission (PMR-AS <1.5) with GC independence (≤2.5mg/d) for 4 weeks before week 24
- Incidence of adverse events (AEs) and Serious AEs (SAEs) [24 week]
Incidence of adverse events (AEs) and Serious AEs (SAEs) within 24 weeks
- Change of disease activity by PMR-AS [24 week]
Change of disease activity by PMR-AS within 24 weeks
- Assessment of quality of life using the MHAQ [24 week]
The Modified Health Assessment Questionnaire (MHAQ), reduced the number of items from 20 in the original HAQ to eight, and improved the feasibility in clinical practice when screening patients. The MHAQ score is calculated as the mean of the scores for each activity. Total score is between 0.0-3.0, in 0.125 increments. Higher scores indicate worse function and greater disability. MHAQ scores <0.3 are considered normal.
- Assessment of quality of life using the EQ-5D [24 week]
Health quality assessed by EuroQol five dimensions questionnaire. It is a preference-based measure that can be regarded as a continuous outcome scored on a -0.59 to 1.00 scale, with 1.00 indicating 'full health' and 0 representing dead.
- Circulating serum cytokines, immunoregulators, and inflammatory parameters [24 week]
On the circulating serum cytokines and immunoregulators (IL-6, IL-1, BLyS/BAFF, IL-6 receptor, gp130) and B cells receptors and on the phenotype of circulating T- and B-cells between baseline and W4, W12, W24. On inflammatory parameters (CRP and ESR) every 2 weeks.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Female or male between 50 and 85 years.
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PMR according to the American College of Rheumatology (ACR)/European league Against Rheumatism (EULAR) 2012 PMR core (essential) classification criteria.
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Patients must have erythrocyte sedimentation rate ≥20 mm/hr and/or C-reactive protein ≥8 mg/L associated with PMR disease activity within 12 weeks prior to screening.
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Active PMR（PMR-AS>10) with prednisone of at least 7.5 mg/day (or equivalent) and not exceeding 20 mg/day within 4 weeks of screening.
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Patient is willing and able to take prednisone of 15 mg/day at baseline.
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Signed written informed consent.
Exclusion Criteria:
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Presence of any other connective tissue disease, such as but not limited to giant-cell arteritis, systemic lupus erythematosus, systemic sclerosis, vasculitis, myositis, mixed connective tissue disease, and ankylosing spondylitis.
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Concurrent diagnosis of active fibromyalgia, rhabdomyolysis or neuropathic muscular diseases.
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Organ transplant recipient.
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Any prior (within the defined period below) or concurrent use of immunosuppressive therapies but not limited to any of the following: (1) Any prior use of tumor necrosis factor inhibitors, anti-IL-6 agents or Janus kinase inhibitor; (2) Alkylating agents including cyclophosphamide within 6 months of baseline; (3) Cell-depletion agents (e.g., anti CD20) without evidence of recovery of B cells to baseline level; (4) Abatacept within 8 weeks of baseline; (5) Cyclosporine, azathioprine or mycophenolate mofetil or leflunomide within 4 weeks of baseline; (6) Unstable methotrexate (MTX) dose and/or MTX dose >15mg/week within 3 months of baseline; (7) Concurrent use of systemic GCs for conditions other than PMR.
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Evidence (as assessed by the investigator) of active infection, presence of hepatitis B surface antigen or hepatitis C antibody in blood, HIV positivity.
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Patients with a history of active or recurrent herpes zoster.
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Patients who have had surgery within 4 weeks of screening or planned surgery during study.
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Malignancy within 5 years prior to screening, except for non-melanoma skin cancer.
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Pregnant or breastfeeding woman.
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Any medical condition that could interfere with the implementation or interpretation of the study or with the safety of the patient during the study.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Ren Ji Hospital | Shanghai | China | 201112 |
Sponsors and Collaborators
- RenJi Hospital
Investigators
- Study Chair: Ting Li, MD, RenJi Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- GCs sparing regimen in PMR