Systemic Lupus Erythematosus
Conditions
Keywords
SLE, IL-2
Brief summary
This clinical study will test the efficacy and safety of low dose IL-2 treatment in Systemic lupus erythematosus.
Detailed description
Systemic lupus erythematosus (SLE) is a chronic autoimmune syndrome affecting various organs. While available therapies, such as corticosteroids and immunosuppressive agents have improved the outcome of patients, there remains a significant unmet need for safe and more effective treatments. Dysfunction of regulatory T (Treg) cells has been detected in diverse autoimmune diseases, which can be promoted by interleukin-2 (IL-2). We hypothesized that low-dose IL-2 could be a novel therapy in active SLE patients. This is a single center, uncontrolled, open-label study to assess the efficacy/safety of low dose IL-2 plus standard therapy in active SLE. Methods: Each SLE patients (n=40) with Scores\>=8 on the Safety of Estrogens in Lupus Erythematosus National Assessment (AELENA) version of the SLE Disease Activity Index (SLEDAI) that was refractory or relaps to glucocorticoid therapy received low-dose IL-2 (1 million units every other day subcutaneously (HrIL-2 1X 106, ip, Qod) for a period of 14 days. After a 14-day rest, another cycle started) for 3-6 cycles according to the situation of the disease. The end points were safety and clinical and immunologic response. Expected Results: This trail will define low-dose IL-2 plus standard therapy is efficacy and safety with active lupus patients, which could be relevant to the amelioration the abnormity of T help cells in SLE patients.
Interventions
DRUGInterleukin-2
Patients receive low dose recombinant human Interleukin-2（HrIL-2） (1 million units every other day subcutaneously (HrIL-2 1X 106, ip, Qod) for a period of 14 days. After a 14-day rest, another cycle started) for 3-6 courses according to the situation of the disease.
Sponsors
Monash University
Peking University People's Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Meet the American College of Rheumatology criteria for the diagnosis of SLE. * Under standard treatment (≥ 2 months) at the time of inclusion * Background treatment failed to control flares or to permit prednisone tapering * With at least one of the following manifestations: thrombocytopenia, disease-associated rash, mouth ulcer, non-infectious type of fever, active vasculitis, renal disorder(proteinuria\>0.5g/day), neuropsychiatric SLE. * Positive for at least one of the following laboratory tests: ANA\>1:160, anti-dsDNA, immunoglobulin\>20g/L, decreased C3 or C4, leukopenia\<3×10\^9/L, thrombocytopenia\<100×10\^9/L; * SLE disease activity index(SLEDAI) ≥ 8. * Negative HIV test. * Negative for hepatitis B and C virus. * Written informed consent form.
Exclusion criteria
* Sever chronic liver, kidney, lung or heart dysfunction; (heart failure (≥ grade III NYHA), hepatic insufficiency (transaminases\> 3N) ) * Serious infection such as bacteremia, sepsis; * Cancer or history of cancer cured for less than five years (except in situ carcinoma of the cervix or Basocellular carcinoma); * High-dose steroid pulse therapy (\>1.5mg/kg) or IV bolus of corticosteroids in the last 2 months. * History of administration of rituximab or other biologics; * Purified protein derivative (tuberculin) \>10mm * Mental disorder or any other chronic illness or drug-abuse that could interfere with the ability to comply with the protocol or to give information; * Inability to comply with IL-2 treatment regimen.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Were SLE Responders (SRI) | week 2，week 4，week 6，week 8，week 10 | SRI response was defined as (1) a ≥ 4-point reduction in SELENA-SLEDAI score, (2) no new BILAG A score or ≤ 1 new BILAG B score, and (3) no deterioration from baseline in the physician's global assessment by ≥ 0.3 points. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immunological Responses | week 0 and week 10 | Analysis regulatory CD4+ T (Treg) cells , interleukin 17 (IL-17)-producing helper T (Th17) cells and follicular helper T (Tfh) cells before and during IL-2 treatment. P values below 0.05 are considered statistically significant in this study. |
| The Immunologic Impact of Low Dose IL-2 Treatment in SLE Patients | week 0 and week 10 | Laboratory measures were detected, including, C3, C4 and anti-dsDNA titres. |
| SELENA SLEDAI Score | week 0, week 10 | Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) change. The higher the score represent the worse of the disease. The total score ranges from 0 to 105 points, score\> 8 means the disease is moderate-to-severe active. |
| Number of Relapses | 24 weeks | Relapses mean that if the patient's SELENA SLEDAI Score is lower than 4 during the treatment, while the SELENA SLEDAI Score increase after stopping using the study drugs in 3 months. |
| Safety Assessment | up to Day 180 | Adverse events includes injection site reactions, influenza-like symptoms, infection, fever, tumor, cardiovascular event，drug-induced liver and kidney damage. |
Countries
China
Participant flow
Recruitment details
Between August 2013 and May 2014,38 patients completed three cycles of recombinant human IL-2 (rhIL-2) in Dept. of Rheumatology and Immunology, Peking University People's Hospital. Patients were permitted changes in background therapy according to the treating physician's advice.
Pre-assignment details
All the patients showed poor efficacy at least 4 weeks of stable routine treatment at the time of enrollment. Two of the enrolled patients withdrew from the study at week 8: one changed to the belimumab treatment by personal preference; the other elected changed to the cyclophosphamide treatment to reduce the frequency of hospital visits.
Participants by arm
| Arm | Count |
|---|---|
| Interleukin-2 Interleukin-2 to treat activated SLE.
Interleukin-2: Patients receive low dose recombinant human Interleukin-2（HrIL-2） (1 million units every other day subcutaneously (HrIL-2 1X 106, ip, Qod) for a period of 14 days. After a 14-day rest, another cycle started) for 3-6 courses according to the situation of the disease. | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 2 |
Baseline characteristics
| Characteristic | Interleukin-2 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 38 Participants |
| Age, Continuous | 31 years |
| Region of Enrollment China | 38 partiipants |
| SELENA-SLEDAI score | 11.35 score STANDARD_DEVIATION 3.71 |
| Sex: Female, Male Female | 36 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 5 / 38 |
| serious Total, serious adverse events | 0 / 38 |
Outcome results
Primary
Number of Participants Who Were SLE Responders (SRI)
SRI response was defined as (1) a ≥ 4-point reduction in SELENA-SLEDAI score, (2) no new BILAG A score or ≤ 1 new BILAG B score, and (3) no deterioration from baseline in the physician's global assessment by ≥ 0.3 points.
Time frame: week 2，week 4，week 6，week 8，week 10
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SRI Results | Number of Participants Who Were SLE Responders (SRI) | Week 2 | 12 participants |
| SRI Results | Number of Participants Who Were SLE Responders (SRI) | Week4 | 27 participants |
| SRI Results | Number of Participants Who Were SLE Responders (SRI) | Week 6 | 33 participants |
| SRI Results | Number of Participants Who Were SLE Responders (SRI) | week 8 | 34 participants |
| SRI Results | Number of Participants Who Were SLE Responders (SRI) | week 10 | 34 participants |
Secondary
Immunological Responses
Analysis regulatory CD4+ T (Treg) cells , interleukin 17 (IL-17)-producing helper T (Th17) cells and follicular helper T (Tfh) cells before and during IL-2 treatment. P values below 0.05 are considered statistically significant in this study.
Time frame: week 0 and week 10
Population: regulatory CD4+ T (Treg) cells , interleukin 17 (IL-17)-producing helper T (Th17) cells and follicular helper T (Tfh) cells
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| SRI Results | Immunological Responses | Week 0 | 10.6 Percentage of CD4+ T cells |
| SRI Results | Immunological Responses | Week 10 | 17.5 Percentage of CD4+ T cells |
| Immunological Responses 2 | Immunological Responses | Week 0 | 3.93 Percentage of CD4+ T cells |
| Immunological Responses 2 | Immunological Responses | Week 10 | 2.1 Percentage of CD4+ T cells |
| Immunological Responses 3 | Immunological Responses | Week 0 | 4.09 Percentage of CD4+ T cells |
| Immunological Responses 3 | Immunological Responses | Week 10 | 2.63 Percentage of CD4+ T cells |
Comparison: Comparing the data between baseline and week 10.p-value: <0.01Wilcoxon (Mann-Whitney)
Secondary
Number of Relapses
Relapses mean that if the patient's SELENA SLEDAI Score is lower than 4 during the treatment, while the SELENA SLEDAI Score increase after stopping using the study drugs in 3 months.
Time frame: 24 weeks
Secondary
Safety Assessment
Adverse events includes injection site reactions, influenza-like symptoms, infection, fever, tumor, cardiovascular event，drug-induced liver and kidney damage.
Time frame: up to Day 180
Secondary
SELENA SLEDAI Score
Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) change. The higher the score represent the worse of the disease. The total score ranges from 0 to 105 points, score\> 8 means the disease is moderate-to-severe active.
Time frame: week 0, week 10
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| SRI Results | SELENA SLEDAI Score | Week 0 | 11.35 score | Standard Deviation 3.71 |
| SRI Results | SELENA SLEDAI Score | Week 10 | 3.775 score | Standard Deviation 2.27 |
Secondary
The Immunologic Impact of Low Dose IL-2 Treatment in SLE Patients
Laboratory measures were detected, including, C3, C4 and anti-dsDNA titres.
Time frame: week 0 and week 10
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| SRI Results | The Immunologic Impact of Low Dose IL-2 Treatment in SLE Patients | Week 0 | 0.42 g/L |
| SRI Results | The Immunologic Impact of Low Dose IL-2 Treatment in SLE Patients | Week 10 | 0.75 g/L |
| Immunological Responses 2 | The Immunologic Impact of Low Dose IL-2 Treatment in SLE Patients | Week 0 | 0.075 g/L |
| Immunological Responses 2 | The Immunologic Impact of Low Dose IL-2 Treatment in SLE Patients | Week 10 | 0.157 g/L |
| Immunological Responses 3 | The Immunologic Impact of Low Dose IL-2 Treatment in SLE Patients | Week 0 | 417.9 g/L |
| Immunological Responses 3 | The Immunologic Impact of Low Dose IL-2 Treatment in SLE Patients | Week 10 | 105.1 g/L |