Low-dose Interleukin-2 Treatment on Polymyalgia Rheumatica

Phase 2

• Conditions: Polymyalgia Rheumatica
• Interventions: Drug: Interleukin-2

• Registration Number: NCT04062006
• Lead Sponsor: Peking University People's Hospital

Brief Summary

This study aims to explore the clinical and immunological efficacy of low-dose Interleukin-2 (IL-2) on polymyalgia rheumatica.

Detailed Description

The investigators designed a single center, open-label, prospective study that routinely administered low-dose IL-2 therapy to monitor the improvement of clinical and laboratory parameters to explore its efficacy and to observe changes in immune cell subsets and cytokines. One million units of Recombinant Human Interleukin-2 (rhIL-2) was administered subcutaneously five days every week for 4 weeks and then once a week for 8 weeks. All patients were followed up for 3 months after treatment.

Study Timeline

• Study First Submitted: 2019-08-18
• Study First Submitted QC: 2019-08-19
• Study First Posted: 2019-08-20
• Study Start: 2019-08-31
• Status Verified: 2019-09
• Last Update Submitted: 2019-09-01
• Last Update Posted: 2019-09-04
• Primary Completion: 2021-03-31
• Study Completion: 2021-06-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 15

Inclusion Criteria

1. Male or female, aged ≥50 years at screening visits

2. Diagnostics meet the 1986 Nancy recommendations

3. Apply glucocorticoids (≤10 mg/d prednisone or equivalent doses of other hormones), DMARDs (eg methotrexate, hydroxychloroquine, azathioprine, morphine, Ester, leflunomide, cyclosporine, etc.) must be stable for 4 weeks and do not increase hormone doses or other immunosuppressive agents throughout the study. If the enrolled doctor plans to stop using the current immunosuppressant or glucocorticoid, the elution period needs to be followed before enrollment. Each drug needs to meet the following elution period

   • Glucocorticoid-2 weeks
   • Immunosuppressants (including methotrexate, azathioprine, cyclosporine, tacrolimus, leflunomide, mycophenolate mofetil) - 4 weeks
   • Intravenous immunogloblin (IVIg) or cyclophosphamide - 2 months
   • Rituximab - 6 months
   • Other biological agents (infliximab, adalimumab, etanercept, anakinra, etc.) -12 weeks

4. The patient must be informed in writing of the consent to participate in the trial and the patient is expected to be able to comply with the requirements of the study follow-up plan and other protocols.

5. Excluding Horton syndrome

6. The amount of non-steroidal dose was stable 4 weeks before enrollment

Exclusion Criteria

Any subject meeting any of the following criteria should be excluded:

1. Use rituximab or other monoclonal antibodies within 6 months.
2. Received high doses of glucocorticoid (>10 mg/d) within 1 month.
3. Serious complications: including heart failure (≥ New York Heart Association (NYHA) class III), renal insufficiency (creatinine clearance ≤ 30 ml/min), liver dysfunction (serum Alanine transaminase (ALT) or aspartate aminotransferase (AST) greater than three times the upper limit of normal, or total bilirubin greater than Normal upper limit)
4. Other serious, progressive or uncontrollable hematology, gastrointestinal, endocrine, pulmonary, cardiac, neurological or brain disorders (including demyelinating diseases such as multiple sclerosis).
5. Known allergies, hyperreactivity or intolerance of IL-2 or its excipients.
6. Have a serious infection needing hospitalization (including but not limited to hepatitis, pneumonia, bacteremia, pyelonephritis, EB virus, tuberculosis infection), or use intravenous antibiotics to treat infection in 2 months before the enrollment.
7. Chest imaging showed abnormalities in malignant tumors or current active infections (including tuberculosis) within 3 months prior to the first use of the study drug.
8. Infection with HIV (HIV antibody positive serology) or hepatitis C (Hep C antibody positive serology). If seropositive, it is recommended to consult a doctor who has expertise in treating HIV or hepatitis C virus infection.
9. Any known history of malignancy in the past 5 years (except for non-melanoma skin cancer, non-melanoma skin cancer or cervical tumor without recurrence within 3 months after surgical cure prior to the first study preparation).
10. Uncontrolled mental or emotional disorders, including a history of drug and alcohol abuse over the past 3 years, may hinder the successful completion of the study.
11. Accept or expect to receive any live virus or bacterial vaccination within 3 months prior to the first injection of the study agent, during the study period, or within 4 months after the last injection of the study agent. Bacillus Calmette-Guerin (BCG) vaccine was inoculated within 12 months after screening.
12. Pregnant, lactating women (WCBP) are reluctant to use medically approved contraceptives during treatment and 12 months after treatment.
13. Men whose partners have fertility potential but are reluctant to use appropriate medically-accepted contraceptives during treatment and 12 months after the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Interleukin-2	Interleukin-2	low dose interleukin-2 injected subcutaneously, at a dose of 1 x 10\~6 IU/m2 five days per week for 4 weeks (day1-5, 8-12, 15-19, 22-26) and then once a week for 8 weeks (day33, 40, 47, 54, 61, 68, 75, 82).

Primary Outcome Measures

Name	Time	Method
Foxp3+Treg cells: change in percentage of total lymphocytes	week 12	Treg refers to regulatory T cells

Secondary Outcome Measures

Name	Time	Method
Physician's Global Disease Activity VAS	week12 and 24	Physician's Global Disease Activity (10 cm VAS assessing global disease activity from "No evidence of disease activity" to "Extremely active or severe disease activity"; Disease Activity being defined as potentially reversible pathology or physiology resulting from the polymyalgia rheumatica).
Patient's Global Disease Activity VAS	week12 and 24	Patient's Global Disease Activity (10 cm VAS assessing global disease activity from "No evidence of disease activity" to "Extremely active or severe disease activity"; Disease Activity being defined as potentially reversible pathology or physiology resulting from the polymyalgia rheumatica).
Cumulative dosages of glucocorticoids (GCs)	week 12 and 24	dosages of GCs
Safety and tolerability of interleukin-2 as assessed by incidence of adverse events reported and observed	up to 24 weeks	The investigators will report frequency of adverse events
Patient reported outcome 36-item Short Form Health Survey (SF-36)	wee12 and 24	Clinical studies 36-item Medical Outcomes Study Short-Form General Health Survey An instrument used to assess multidimensional health-related quality of life (QOL), which measures 8 health related parameters: physical function, social function, physical role, emotional role, mental health, energy, pain, general health perceptions; each parameter is scored from 0 to 100 Managed care 36-Item Short-Form Functional and Perceived Health Status Survey A questionnaire which measures health status; the SF-36 also includes a list of 18 self-reported chronic conditions
The proportion of patients with PMR-activity score (AS) < 1.5; 10; 17	week 12 and 24	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.
Proportion of patients with Low disease activity (PMR-AS<10) with steroid independence (GCs ≤5 mg absolute value) or decrease ≥ 10 mg	from week 0 to week 12 and 24	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.