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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Systemic Lupus Erythematosus
• Intervention / Treatment: Drug: Sirolimus; Drug: Placebo

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

• Study Type: Interventional
• Enrollment (Estimated): 146
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Mengtao Li, MD; Phone Number: +86 13911788572; Email: mengtao.li@cstar.org.cn
• Study Contact Backup: Name: Liying Peng, MD; Phone Number: +86 15201435661; Email: liying_penguin@163.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100053
      • Recruiting
      • Peking Union Medical College Hospital
      • Contact: Mengtao Li, MD; Phone Number: +8613911788572
  • Guangdong
    • Shenzhen, Guangdong, China
      • Recruiting
      • ShenZhen People's Hospital
      • Contact: Dongzhou Liu, MD
  • Henan
    • Zhengzhou, Henan, China
      • Recruiting
      • The First Affiliated Hospital of Zhengzhou University
      • Contact: Shengyun Liu, MD; Phone Number: 13837192659
  • Jiangxi
    • Nanchang, Jiangxi, China
      • Recruiting
      • The Second Affiliated Hospital of Nanchang University
      • Contact: Xingwang Duan, MD
  • Liaoning
    • Shenyang, Liaoning, China
      • Recruiting
      • The First Hospital of China Medical University
      • Contact: Pinting Yang, MD
  • Yunnan
    • Kunming, Yunnan, China
      • Recruiting
      • First Affiliated Hospital of Kunming Medical University
      • Contact: Jian Xu, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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;
• Any condition that may require multiple courses of systemic corticosteroids (e.g., uncontrolled asthma, COPD);
• Major surgery within the past month;
• Suffering from malignant tumors or a history of malignant tumors within 5 years before screening, or a history of lymphoproliferative diseases: Patients with previously treated cutaneous squamous cell carcinoma and basal cell carcinoma without evidence of recurrence are allowed to enroll; and Patients with cervical cancer in situ who have documented formal surgical cure are allowed to enroll;
• Previous stem cell transplantation (including hematopoietic stem cell transplantation and mesenchymal stem cell transplantation);
• Have a history of splenectomy;
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Proportion of Patients Who Achieve an SLE Responder Index-4 (SRI-4) Composite Response at Week 24	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).	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Complement Level at Week 24	Serum complement refers to C3 and C4, which are both detected in the central lab.	24 weeks
Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) Score at Week 24	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.	24 weeks
Change From Baseline in Physician's Global Assessment of Disease Activity (PGA) Score at Week 24	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).	24 weeks
Number of Participants With BILAG-based Combined Lupus Assessment (BICLA) Response at Week 24	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').	24 weeks
Change From Baseline in Titers of Anti-dsDNA Antibody at Week 24	Anti-dsDNA antibody is detected in the central lab using chemiluminescence.	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With Clinical Remission at week 24	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)	24 weeks
Percentage of Patients With Lupus Low Disease Activity State (LLDAS) at week 24	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.	24 weeks
Percentage of Patients With Hypocomplementemia returned to normal at week 24	Percentage of patients whose hypocomplementemia are returned to normal (C3>0.90g/L AND C4>0.10g/L)	24 weeks
Percentage of Patients With Anti-dsDNA Antibody decreased to negative at week 24	Percentage of Patients With Anti-dsDNA Antibody decreased to <10 IU/ml.	24 weeks
Change From Baseline in Urine Protein/Creatine Ratio (PCR) Among Patients With Baseline PCR >500mg/g at Week 24	PCR is detected in the central lab	24 weeks
The Time to First BILAG Flare	First BILAG flare is defined as at least one new BILAG A score or at least two new BILAG B scores	24 weeks
Proportions of Patients With an SRI-5 and SRI-6 Response at Week 24	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	24 weeks
Proportion of Patients With No Worsening in BILAG at Week 24	No worsening in BILAG is defined as no new BILAG A score and no more than one new BILAG B score	24 weeks
Proportions of Patients With No Worsening in PGA at Week 24	No increase in PGA scores	24 weeks
Change From Baseline in SLE Disease Activity Score (SLE-DAS) at Week 24	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.The SLE-DAS is a continuous disease activity score with higher values signifying greater disease activity.	24 weeks
Change From Baseline in 36-Item Short Form Survey (SF-36)	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. SF-36 scores range from 0 (maximum disability) to 100 (no disability).	24 weeks
Change From Baseline in Lupus Patient-Reported Outcome tool (LupusPRO)	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 symptoms, cognition, lupus medications, procreation, physical health, sleep, vitality, pain, emotional health, body image, desires-goals, social-support, coping, satisfaction with care. The score range of LupusPRO is from 0 to 100 points, where higher scores represent better quality of life, while lower scores indicate poorer quality of life.	24 weeks

Collaborators and Investigators

• Sponsor: Chinese SLE Treatment And Research Group
• Collaborators: Beijing Municipal Science & Technology Commission; North China Pharmaceutical Group Corporation
• Investigators: Principal Investigator: Xiaofeng Zeng, MD, Chinese SLE Treatment and Registration Group

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2021
• Primary Completion (Estimated): October 31, 2024
• Study Completion (Estimated): May 1, 2025

Study Registration Dates

• First Submitted: October 3, 2020
• First Submitted That Met QC Criteria: October 3, 2020
• First Posted (Actual): October 9, 2020

Study Record Updates

• Last Update Posted (Actual): February 8, 2024
• Last Update Submitted That Met QC Criteria: February 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: systemic lupus erythematosus; SLE; mTOR; sirolimus; rapamycin; lupus erythematosus
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Connective Tissue Diseases; Lupus Erythematosus, Systemic; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: CSTAR_RCT_SLE_001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: all IPD that underlie results in a publication
• IPD Sharing Time Frame: IPD will be available when the study result is published.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• 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