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Efficacy and Safety of Sirolimus in Active Systemic Lupus Erythematosus (SiroLupus)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04582136
Recruitment Status : Unknown
Verified October 2020 by Xiaofeng Zeng, Chinese SLE Treatment And Research Group.
Recruitment status was:  Not yet recruiting
First Posted : October 9, 2020
Last Update Posted : October 9, 2020
Sponsor:
Collaborators:
Beijing Municipal Science & Technology Commission
North China Pharmaceutical Group Corporation
Information provided by (Responsible Party):
Xiaofeng Zeng, Chinese SLE Treatment And Research Group

Brief Summary:
This is a multi-center, double-blinded, randomized, placebo-controlled, phase 2 study to evaluate the efficacy and safety of sirolimus administered in addition to standard therapy, in patients with active SLE disease.

Condition or disease Intervention/treatment Phase
Systemic Lupus Erythematosus Drug: Sirolimus Drug: Placebo Phase 2

Detailed Description:

This study is a multi-center, double-blinded, randomized, placebo-controlled, phase 2 clinical trial to assess the safety and efficacy of sirolimus in patients with active systemic lupus erythematosus despite receiving standard background therapy.

Six large rheumatological referring centers across from China will participate in the study.

The study is divided into two phases. The first phase is a 24-week randomized, double-blinded, placebo-controlled trial, from which the primary end point will be generated, and the second phase is a 24-week open-labeled extension trial.

The study enrolls SLE patients between 18~65 years old who have SLEDAI-2K score ≥4 (not including scores for anti-dsDNA antibody and hypocomplementemia), despite conventional treatment (e.g., immunosuppressants, antimalarial drugs, glucocorticoids, NSAIDs, anti-hypertensive drugs, and/or topical medications). In addition, subjects must be serologically active (positive anti-dsDNA antibody and/or hypocomplementemia.

Subjects will be randomly assigned by 1:1 ratio to receive sirolimus (1.5mg/day) or placebo for the first 24-week phase. In the second 24-week open-labeled phase, sirolimus patients receive the same dose of sirolimus, and placebo group are switched to receive sirolimus at 1.5mg/day

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 146 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Efficacy and Safety of Sirolimus in Patients With Active Systemic Lupus Erythematosus Despite Standard of Care: a Multi-center, Double Blinded, Randomized, Placebo-controlled, Phase 2 Trial
Estimated Study Start Date : November 2020
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : November 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lupus
Drug Information available for: Sirolimus

Arm Intervention/treatment
Experimental: Sirolimus plus SOC
Sirolimus plus standard therapy (SOC) for SLE; Generic name: sirolimus (0.5mg capsule); Dosage: 1.5mg/day; Administration route: Oral
Drug: Sirolimus
In the double-blinded phase, sirolimus 1.5mg/day plus SOC is administered throughout 24 weeks; in the open-label extension period, patients who opt to participate continue on sirolimus 1.5mg/day plus SOC for an additional 24 weeks.
Other Name: rapamycin

Placebo Comparator: Placebo plus SOC
Placebo plus standard therapy (SOC) for SLE; Drug: Placebo comparator plus SOC; Administration route: Oral
Drug: Placebo
In the double-blinded phase, placebo plus SOC is administered throughout 24 weeks; in the open-label extension period, patients who opt to participate are switched to receive sirolimus 1.5mg/day plus SOC for an additional 24 weeks.




Primary Outcome Measures :
  1. The Proportion of Patients Who Achieve an SLE Responder Index-4 (SRI-4) Composite Response at Week 24 [ Time Frame: 24 weeks ]
    SLE responder index-4 (SRI-4), is a composite outcome includes all of the following outcomes: a reduction of SLEDAI-2K ≥ 4 points, no new BILAG A organ domain scores and no more than 1 new BILAG B organ domain scores, and no worsening of PGA (increase < 0.3).


Secondary Outcome Measures :
  1. Change From Baseline in Complement Level at Week 24 [ Time Frame: 24 weeks ]
    Serum complement refers to C3 and C4, which are both detected in the central lab.

  2. Change From Baseline in Titers of Anti-dsDNA Antibody at Week 24 [ Time Frame: 24 weeks ]
    Anti-dsDNA antibody is detected in the central lab using chemiluminiscence.

  3. Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) Score at Week 24 [ Time Frame: 24 weeks ]
    The SLEDAI-2K is an established, validated SLE activity index. It is based on the presence of 24 features in 9 organ systems and measures disease activity in SLE patients in the previous 30 days. It is weighted according to the feature. Features are scored by the assessing physician if present within the last 30 days with more severe features having higher scores, and then simply added to determine the total SLEDAI 2K score, which ranges from 0 to 105, with higher scores representing increased disease activity.

  4. Change From Baseline in Physician's Global Assessment of Disease Activity (PGA) Score at Week 24 [ Time Frame: 24 weeks ]
    PGA is recorded on a visual analogue scale (VAS; 0.0 to 10.0 centimeter [cm]). The scale for the physician's assessment ranges for 'no lupus activity' (0.0) to 'extremely active lupus' (10.0).

  5. Number of Participants With BILAG-based Combined Lupus Assessment (BICLA) Response at Week 24 [ Time Frame: 24 weeks ]
    BICLA response defined as participants meeting following criteria: 1. BILAG improvement (all BILAG A scores at baseline improved to either B, C or D and all BILAG B scores at baseline improved to C or D and no worsening in disease activity defined as no new BILAG A scores and <= 1 new BILAG B score) and 2. no worsening of total SLEDAI-2K from baseline 3. < 1 cm increase in PGA and 4. no treatment failure criteria met. BILAG: assesses disease extent, severity (range: A [severe] to E [no disease]). SLEDAI-2K: assesses improvement in disease activity (range: 0 to 105; higher score = higher severity). PGA: assesses worsening in participant's general health status (0.0= 'no lupus activity' to 10.0 = 'extremely active lupus').


Other Outcome Measures:
  1. Change From Baseline in SLE Disease Activity Score (SLE-DAS) at Week 24 [ Time Frame: 24 weeks ]
    SLE-DAS is a newly developed tools to assess SLE disease activity. It is a multinomial that includes 17 clinical or laboratory indices: arthritis, swollen joint count, mucocutaneous vasculitis, localized cutaneous rash, generalized cutaneous rash, alopecia, mucosal ulcers, hypocomplementaemia, increased anti-dsDNA antibody, proteinuria, thrombocytopenia, leucopenia, neuropsychiatric involvement, systemic vasculitis, cardiac/pulmonary involvement, myositis, serositis, and haemolytic anaemia.

  2. Percentage of Patients With Clinical Remission at week 24 [ Time Frame: 24 weeks ]
    Clinical remission is defined as clinical SLEDAI-2K (cSLEDAI-2K, excluding items from hypocomplementemia or positive anti-dsDNA antibody) = 0 AND that allowable dose of glucocorticoids is ≤ 5 mg/day prednisone (or equivalent)

  3. Percentage of Patients With Lupus Low Disease Activity State (LLDAS) at week 24 [ Time Frame: 24 weeks ]
    LLDAS is defined as: (1) SLE Disease Activity Index (SLEDAI)-2K ≤4, with no activity in major organ systems (renal, central nervous system (CNS), cardiopulmonary, vasculitis, fever) and no haemolytic anaemia or gastrointestinal activity; (2) no new lupus disease activity compared with the previous assessment; (3) a Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment (scale 0-3) ≤1; (4) a current prednisolone (or equivalent) dose ≤7.5 mg daily; and (5) well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents.

  4. Percentage of Patients With Hypocomplementemia returned to normal at week 24 [ Time Frame: 24 weeks ]
    Percentage of patients whose hypocomplementemia are returned to normal (C3>0.90g/L AND C4>0.10g/L)

  5. Percentage of Patients With Anti-dsDNA Antibody decreased to negative at week 24 [ Time Frame: 24 weeks ]
    Percentage of Patients With Anti-dsDNA Antibody decreased to <10 IU/ml.

  6. Change From Baseline in Urine Protein/Creatine Ratio (PCR) Among Patients With Baseline PCR >500mg/g at Week 24 [ Time Frame: 24 weeks ]
    PCR is detected in the central lab

  7. The Time to First BILAG Flare [ Time Frame: 24 weeks ]
    First BILAG flare is defined as at least one new BILAG A score or at least two new BILAG B scores

  8. Proportions of Patients With an SRI-5 and SRI-6 Response at Week 24 [ Time Frame: 24 weeks ]
    The definitions of SRI-5 and SRI-6 is similar with SRI-4 except for a reduction of SLEDAI-2K ≥ 5 points or ≥ 6 points respectively

  9. Proportion of Patients With No Worsening in BILAG at Week 24 [ Time Frame: 24 weeks ]
    No worsening in BILAG is defined as no new BILAG A score and no more than one new BILAG B score

  10. Proportions of Patients With No Worsening in PGA at Week 24 [ Time Frame: 24 weeks ]
    No increase in PGA scores

  11. Change From Baseline in 36-Item Short Form Survey (SF-36) [ Time Frame: 24 weeks ]
    As a concise health questionnaire, SF-36 comprehensively summarizes the quality of life of the subjects from eight aspects: physiological function, physiological function, physical pain, general health status, energy, social function, emotional function and mental health.

  12. Change From Baseline in Lupus Patient-Reported Outcome tool (LupusPRO) [ Time Frame: 24 weeks ]
    LupusPRO is a valid and reliable patient-reported health outcome targeting towards measuring health (HRQOL) and non-health related quality of life (Non HRQOL) among patients with systemic lupus erythematosus (SLE). It assess the quality of life from 14 aspects: lupus syptoms, cognition, lupus medications, procreation, physical health, sleep, vitality, pain, emotional health, body image, desires-goals, social-support, coping, satisfaction with care.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age between 18~65 years;
  • Fulfilling the 2012 SLICC criteria for SLE; time from SLE diagnosis ≥ 3 months;
  • Active disease as defined by a SLEDAI-2K score of ≥4 (not including scores for anti-dsDNA antibody and hypocomplementemia) at screening;
  • Serologically active defining as positive anti-dsDNA antibody (>10IU/ml) or hypocomplementemia (C3<0.90g/L)
  • Before the first dose of sirolimus, a stable regimen of oral corticoids (0-20 mg/day, prednisone or equivalent) ≥4 weeks; doses of antimalarials, or immunosuppressive agents (mycophenolate mofetil [MMF]/mycophenolic acid [MPA] ≤1.5g/day, or MTX ≤15mg/week) are required to be stable for at least 12 weeks prior to first dose). In addition, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, NSAIDs or other analgesics should be stable for at least 2 weeks.

Exclusion Criteria:

  • Concomitant connective tissue disease or inflammatory disease that might confound efficacy assessments, e.g., systemic sclerosis, rheumatoid arthritis, dermatomyositis/polymyositis, etc;
  • Neuropsychiatric SLE;
  • Severe active lupus nephritis (urinary protein ≥3.5g/24h or urine protein/creatine ration> 3500mg/g or eGFR < 60ml/1.73m2/min);
  • Pregnant or breast-feeding women;
  • Previous treatment with sirolimus or allergic to sirolimus;
  • Intravenous CTX within 6 months of enrollment;
  • Intravenous immunoglobulin or prednisone dose >100mg/day within 3 months;
  • Calcineurin inhibitors (e.g., tacrolimus or cyclosporin A) within 1 month;
  • Traditional Chinese Herb (such as Tripterygium wilfordii Hook F) within 1 month;
  • Concurrent active or uncontrolled infection (such as tuberculosis and hepatitis) requiring antibiotics or antivirus;
  • WBC count <3×10^9/L;
  • Abnormal biochemical indices including: alanine transaminase (ALT) or aspartate aminotransferase (AST) >1.5 times upper limit of laboratory reference range; total bilirubin or blood lipid (including total cholesterol, triglycerides, and low-density lipoprotein) >2 times upper limit of laboratory reference range;
  • Subjects has certain conditions that may lead to dropping out of the study in advance or that may bring risk to subjects themselves if they participate in the study. This is judged by experienced clinicians.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04582136


Contacts
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Contact: Mengtao Li, MD +86 13911788572 mengtao.li@cstar.org.cn
Contact: Liying Peng, MD +86 15201435661 liying_penguin@163.com

Sponsors and Collaborators
Chinese SLE Treatment And Research Group
Beijing Municipal Science & Technology Commission
North China Pharmaceutical Group Corporation
Investigators
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Principal Investigator: Xiaofeng Zeng, MD Chinese SLE Treatment and Registration Group
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Responsible Party: Xiaofeng Zeng, Director of Rheumatology and Immunology Department Chinese Academy of Medical Sciences &Peking Union Medical College Hospital, Chinese SLE Treatment And Research Group
ClinicalTrials.gov Identifier: NCT04582136    
Other Study ID Numbers: CSTAR_RCT_SLE_001
First Posted: October 9, 2020    Key Record Dates
Last Update Posted: October 9, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: all IPD that underlie results in a publication
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: IPD will be available when the study result is published.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Xiaofeng Zeng, Chinese SLE Treatment And Research Group:
mTOR
systemic lupus erythematosus
SLE
lupus erythematosus
sirolimus
rapamycin
Additional relevant MeSH terms:
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Lupus Erythematosus, Systemic
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs