Low-dose Recombinant Human IL-2 for the Treatment of Rheumatoid Arthritis

Phase 2

Completed

Conditions: Rheumatoid Arthritis

Interventions: Drug: hrIL-2 active
Drug: hrIL-2 placebo
Drug: MTX
Drug: Folic Acid
Drug: Loxoprofen

Registration Number: NCT02467504

Lead Sponsor: Peking University People's Hospital

Brief Summary: Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease, characterized by symmetric poly-arthritis usually involving the small joints of the hands and feet. In addition, various extra-joint manifestations may develop. Several immunomodulating agents have been attempted in the treatment of RA without achieving satisfactory results. Dysfunction of regulatory T (Treg) cells has been detected in diverse autoimmune diseases, which can be promoted by interleukin-2 (IL-2). The investigators hypothesized that low-dose IL-2 could be a novel therapy in active RA patients. This clinical study will test the efficacy and safety of low dose IL-2 treatment in RA. The investigators perform a single-centre, double-blind pilot trial with hrIL-2 in RA. The investigators evaluate the effectiveness and safeness of low-dose hrIL-2 for RA by randomized controlled study (hrIL-2 (N = 23) + Methotrexate (MTX)+ Loxoprofen versus placebo+MTX + Loxoprofen group (N = 24)).

Detailed Description: Each RA patients (n=47) with DAS\>3.2 received low-dose IL-2+MTX+ Loxoprofen or placebo+MTX + Loxoprofen (active group: placebo group =1:1, 1 million units every other day subcutaneously (hrIL-2 1×106, ip, Qod) for a period of 14 days. After a 14-day rest, another cycle started) for 3 cycles. The end points were safety and clinical and immunologic response.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 47

Inclusion Criteria

Male or female ≥18 and ≤70 years of age at time of screening
Diagnosed with rheumatoid arthritis
Must have active disease with DMARDs (Disease Modifying Anti-Rheumatic Drugs) except MTX, the doses had been stable for at least 3 months before baseline
Moderate or severe rheumatoid arthritis during screening, as defined by a disease activity score (28 joint) calculated using the C-reactive protein formula (DAS28-ESR) > 3.2
Have given written informed consent

Exclusion Criteria

Patient presenting or having a history of other inflammatory joint disease
Patient with ongoing or previous Stevens-Johnson syndrome, toxic epidermal necrolysis or erythema multiforme
Patient with significantly impaired bone marrow function or significant anaemia, leucopenia or thrombocytopenia due to causes or other than active rheumatoid arthritis
Persistent infection or severe infection within 3 months before enrollment,
Uncontrolled hypertension, uncontrolled diabetes, unstable ischemic heart disease, active inflammatory bowel disease, active peptic ulcer disease, terminal illness or other medical condition which, in the opinion of the investigator, would put the patient at risk to participate in the study,
Clinically relevant cardiovascular, hepatic, neurological, endocrine, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult
Severe hypoproteinemia (e.g., in case of severe liver disease or nephrotic syndrome) with serum albumin < 30 g/L
Moderate or severe impairment of renal function, as known by serum creatinine > 133μmol/L (or 1.5 mg/dl)
Patient with history of recent and clinically significant drug or alcohol abuse
Impairment of liver function or persisting ALT (SGPT) elevations of more than 2-fold the upper limit of normal
Known HIV positive status
Known positive serology for hepatitis B or C
Patient with hypersensitivity to any of the excipients in the tablets of methotrexate
Pregnancy
Breastfeeding
Women of childbearing potential, except if they fulfill specific conditions,
Men wishing to father children during the course of the study or within the 24 months thereafter (or 3 month with the washout procedure)
Patient with a congenital or acquired severe immuno-deficiency, a history of cancer or lymphoproliferative disease, or any patient who has received total lymphoid irradiation.
Enrollment in any other clinical trial involving off-label use of an investigational drug or device, or enrollment in any other type of medical research
Any active infection (including chronic or localized infections) for which anti-infectives were indicated within 28 days prior to first investigational product dose
BMI(body mass index) under 18.5 kg/m2 or more than 30 kg/m2
The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Experimental	hrIL-2 active	hrIL-2 active (1 million U doses of hrIL-2s.c.injection) MTX Folic acid Loxoprofen
Experimental	MTX	hrIL-2 active (1 million U doses of hrIL-2s.c.injection) MTX Folic acid Loxoprofen
Experimental	Folic Acid	hrIL-2 active (1 million U doses of hrIL-2s.c.injection) MTX Folic acid Loxoprofen
Experimental	Loxoprofen	hrIL-2 active (1 million U doses of hrIL-2s.c.injection) MTX Folic acid Loxoprofen
Placebo Comparator	hrIL-2 placebo	hrIL-2 placebo (1 million U doses of placebo s.c.injection) MTX Folic acid Loxoprofen
Placebo Comparator	MTX	hrIL-2 placebo (1 million U doses of placebo s.c.injection) MTX Folic acid Loxoprofen
Placebo Comparator	Folic Acid	hrIL-2 placebo (1 million U doses of placebo s.c.injection) MTX Folic acid Loxoprofen
Placebo Comparator	Loxoprofen	hrIL-2 placebo (1 million U doses of placebo s.c.injection) MTX Folic acid Loxoprofen

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Achieving DAS28 Remission.	week 24	DAS 28 remission is defined by a disease activity score (28 joint) calculated using the erythrocyte sedimentation rate (DAS28-ESR) of less than 2.6
Percentage of Participants Meeting the American College of Rheumatology 20% Response Criteria	week 12, week 24	The assessments are based on a 20% or greater improvement from Baseline in the number of tender joints, a 20%, or more improvement in the number of swollen joints, and a 20% or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP).
The Change From Baseline of Clinical Disease Activity Index (CDAI)	week 12, week 24	Clinical Disease Activity Index(CDAI), the minimum is 0, the maximum is 76. higher scores mean a worse outcome. The change of from baseline of CDAI, the minimum is -76, the maximum is 76. higher scores mean a worse outcome.
The Change From Baseline of Simplified Disease Activity Index (SDAI)	week 12, week 24	Simplified Disease Activity Index(SDAI). the minimum is 0, the maximum is 96. higher scores mean worse outcome. The change from baseline of SDAI. the minimum is -96, the maximum is 96. higher scores mean worse outcome.

Secondary Outcome Measures

Name	Time	Method
Erythrocyte Sedimentation Rate (ESR)	week 12, week 24
Percentage of Participants Achieving a Good or Moderate European League Against Rheumatism (EULAR) Response	week 12, week 24	Good response is defined as: DAS28-ESR ≤ 3.2 and decrease from Baseline by \> 1.2. moderate response is defined as achievement of one of the following: DAS28-ESR ≤ 3.2 and decrease from Baseline \> 0.6 and ≤ 1.2 DAS28-ESR \> 3.2 and ≤ 5.1 and decrease from Baseline \> 0.6 DAS28-ESR \> 5.1 and decrease from Baseline \>1.2.
Percentage of Participants Meeting the 2011 American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) Remission Criteria Simplified for Clinical Practice	week 12, week 24	The 2011 ACR/EULAR remission criteria simplified for clinical practice is defined as:Tender Joint Count (TJC) ≤ 1, Swollen Joint Count (SJC) ≤ 1 and Patient's Global Assessment of Disease Activity (PtGADA) ≤ 1.
Number of Participants With Adverse Events	Up to week 24	adverse events includes injection site reactions, influenza-like symptoms, infection, fever, tumor, cardiovascular event, drug-induced liver and kidney damage.
Percentage of Participants Meeting the American College of Rheumatology 70% Response Criteria	week 12, week 24	The assessments are based on a 70% or greater improvement from Baseline in the number of tender joints, a 70%, or more improvement in the number of swollen joints, and a 70% or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP).
The Change From Baseline of a Health Assessment Questionnaire- Disability Index (HAQ-DI)	week 12, week 24	The domains of the HAQ-DI are dressing and grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. The total score ranges from 0 to 3 with lower scores meaning lower disability. The change from baseline of HAQ-DI, minimum is -3, the maximum is 3. higher scores mean a worse outcome.
Percentage of CD4+ Treg Cells	week 12, week 24	analysis regulatory CD4+ T(Treg) cells before and during IL-2 treatment. P values\<0.05 are considered statistically significant.
C Reactive Protein (CRP)	week 12, week 24
The Change From Baseline of Physician's Global Assessment of Disease Activity (PhGADA)	week 12, week 24	VAS score from 0 to 100 for Physician's Global Assessment of Disease Activity higher scores mean a worse outcome. The change from baseline, the minimum is -100, the maximum is 100.
Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]-2	week 24	In the last month, number of work days missed, number of work days with reduced productivity. In the last month, number of days with no household work, number of days with reduced household work productivity, number of days with hired outside help, number of days missed of family/social/leisure activities in the last month.higher scores mean a worse outcome.
Percentage of Participants Achieving DAS28 Low Disease Activity.	week 12, week 24	Low disease activity is defined by a disease activity score (28 joint) calculated using the erythrocyte sedimentation rate (DAS28-ESR) of less than 3.2
The Scores of SF-36 Quetionnaire	week 12, week 24	Score ranging from 0 to 100 with higher scores a better outcome.
Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]	week 24	The Arthritis interference in the last month with work productivity is measured on a scale that ranges from 0 (no interference) to 10 (complete interference). The Arthritis interference in the last month with household work productivity is measured on a scale that ranges from 0 (no interference) to 10 (complete interference).higher scores mean a worse outcome.
The Change From Baseline of Patient's Assessment of Arthritis Pain (PtAAP)	week 12, week 24	VAS score from 0 to 100 for Patient's Assessment of Arthritis Pain higher scores mean a worse outcome. The change from baseline of PtAAP, the minimum is -100, the maximum is 100.
Percentage of Participants Meeting the American College of Rheumatology 50% Response Criteria	week 12, week 24	The assessments are based on a 50% or greater improvement from Baseline in the number of tender joints, a 50%, or more improvement in the number of swollen joints, and a 50% or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP).
The Change From Baseline of Patient's Global Assessment of Disease Activity (PtGADA)	week 12, week 24	VAS score from 0 to 100 for Patient's Global Assessment of Disease Activity Higher scores mean a worse outcome. The change from baseline of PtGADA, the minimum is -100, the maximum is 100. Higher scores mean a worse outcome.