Sirolimus in Treatment of Proteinuric Flares of Lupus Nephritis

A Pilot Study of Sirolimus in Treatment of Proteinuric Flares of Lupus Nephritis

This a single-centre, one-arm, open-label pilot study. Eligible patients with mild proteinuric flares of lupus nephritis Class III/IV±V are received sirolimus without changing previous immunosuppressive medication during 12-week follow-up.

Primary Objective:

• To investigate the efficacy of sirolimus for mild proteinuric flares in patients with Class III/IV±V lupus nephritis

Secondary Objective:

• To assess the safety and tolerability of sirolimus treatment for mild proteinuric flares in patients with Class III/IV±V lupus nephritis

Study Overview

• Status: Not yet recruiting
• Conditions: Lupus Nephritis; Immunosuppression; Effect of Drug
• Intervention / Treatment: Drug: Sirolimus

Detailed Description

Lupus nephritis is a common and serious complication of systemic lupus erythematosus (SLE). It often requires aggressive immunosuppressive therapy. Although majority of patients with severe lupus nephritis achieve a complete or partial remission after 6-month induction treatment, renal flares can still occur during maintenance therapy. Whether patients with mild proteinuric flares should receive intensive immunosuppressive therapy is unclear. In pathogenesis of SLE, T-cell dysfunction is attributed to the activation of the mammalian target of rapamycin (mTOR). Previous prospective and retrospective studies in SLE or lupus nephritis showed the effect of mTOR blockade on systemic disease activity index or severe lupus nephritis as initial or maintenance therapy.

Eligible subjects with biopsy-proven Class III/IV±V lupus nephritis(ISN/RPS 2003) are received oral sirolimus without change previous immunosuppressive therapy. We follow up the included patients at Week 2, Week 4, Week6, Week 8 and Week 12 regularly.

The investigator will actively detect and inquire about the occurrence of adverse events (AEs)/ severe adverse events (SAEs) at every visit/ contact during the study. The clinical trials insurance is prepaid by sponsor to cover the design risks of the protocol and liability/ compensation to the research subject for bodily injury or death resulting from their participation in the trial.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Chao Li, MD; Phone Number: 86-010-69155058; Email: superchad099@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Biopsy-proven Class III or IV±V lupus nephritis (ISN/RPS 2003 lupus nephritis classification) with biopsy performed within 48 weeks before inclusion.
• Males or females aged 18 to 60 years old at the time of screening.

• The mild proteinuric flare of lupus nephritis is defined as meeting all of the following criteria :

  1. Persistently increased proteinuria after complete remission, and 24-hr proteinuria≥1.0g/day or doubling of proteinuria after partial remission, and 24-hr proteinuria≥2.0g/day
  2. No hypoalbuminemia: serum albumin ≥35g/L
  3. Stable renal function: serum creatinine<25% increase above the level at the time of renal disease remission
• Eligible to sign informed-consent independently

Exclusion Criteria:

• Renal disease unrelated to SLE (e.g. diabetes mellitus, other glomerular or tubulointerstitial diseases, renovascular disease), or transplanted kidney
• Estimate glomerular filtration rate (eGFR by CKD-EPI)<45mL/min per 1.73m^2 at the time of screening
• Renal biopsy showing cellular of fibrocellular crescent in more than 25% of glomeruli
• Central nervous system (CNS) or other severe organ manifestations of lupus that necessitate aggressive immunosuppressive therapy on its own.
• Co-morbidities that require corticosteroid therapy (e.g. asthma, inflammatory bowel disease)
• Any increased dose of corticosteroids or other immunosuppressive medication including cyclophosphamide, mycophenolate, leflunomide, calcineurin inhibitors, azathioprine, methotrexate, or use of biological agents regardless of duration, with the past six months
• Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection history: seropositivity of HBV surface antigen (HBsAg) or HCV antibodies (HCV-Ab)
• Women who are pregnant or breastfeeding
• Women with childbearing potential or their male partners, who refuse to use an effective birth control method

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Sirolimus group; The initial dose of sirolimus is 1mg/day. And the serum trough level of sirolimus is monitored at Week 2, Week 4, Week 8, and Week 12，respectively. The target serum trough level of sirolimus is 5-8 ng/mL. The dose of sirolimus is titrated according to therapeutic drug level monitoring.; The previous immunosuppressive medication is not allowed to be changed during the 3-month follow-up, unless premature discontinuation from study.

Drug: Sirolimus; The daily dose of sirolimus is divided twice.; Other Names: Rapamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of patients achieving sustained Renal Response(RR)	Sustained RR is defined as satisfying all of the following criteria: 1)Proteinuria is improved by ≥50% compared with baseline 2)24-hr urine protein < 1g 3)Serum creatinine is not higher than 15% above baseline level 4)No occurrence of non-renal disease flare after achieving response to treatment.	at the end of 12 weeks (3 months) from baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete renal remission	24-hr urine protein<0.3g/day or urine Protein-Creatinine ratio (uPCR)<300mg/g; Serum creatinine not higher than 15% above baseline level	at the end of 12 weeks (3 months) from baseline
Partial renal remission	24-hr urine protein<3.5g/day or uPCR<3500mg/g; Serum creatinine not higher than 15% above baseline level	at the end of 12 weeks (3 months) from baseline
Rate of non-renal flare	Central nervous system or other severe organ manifestations of SLE that necessitate aggressive immunosuppressive therapy on its own	during the 3-month follow up
Safety and tolerability of study medications	The following parameters will be monitored: Increase of serum creatinine level>15% from baseline and whether it is reversible or irreversible; Episodes with sirolimus level above the target range; New-onset hypertension or worsening hypertensive control that required increase of antihypertensive medication; Infectious requiring hospitalization and the causative agents; Hospitalization episodes- cause, duration (days); Hypokalemia: serum potassium <3.5mmol/L; Metabolic acidosis with HCO3 <17mmol/L; New-onset hypercholesterolemia present at 3 months or beyond from baseline and/or addition of lipid-lowering drug(s).; Premature discontinuation from the study due to treating intolerance; Premature discontinuation from the study due to rapid disease progression or other reasons; Failure to adhere to the protocol defined corticosteroid reduction regimen; Other adverse clinical events or events considered clinically significant	during the 3-month follow up
Increase of serum creatinine level>15% from baseline	Increase of serum creatinine level (μmol/L)>15% from baseline and whether it is reversible or irreversible.	during the 3-month follow up
Episodes with sirolimus level above the target range	Episodes with sirolimus level above the target range（serum sirolimus trough level>8ng/mL) will be recorded.	during the 3-month follow up
New-onset hypertension or worsening hypertensive control that required increase of antihypertensive medication	Hypertension be diagnosed when a person's systolic blood pressure (SBP) in the office or clinic is ≥140 mm Hg and/or their diastolic blood pressure (DBP) is ≥90 mm Hg following repeated examination. New-onset hypertension or worsening hypertensive control that required increase of antihypertensive medication will be recorded.	during the 3-month follow up
Infection requiring hospitalization	Infection requiring hospitalization will be recorded including the site of infection, the causative agent and duration (days).	during the 3-month follow up
Hypokalemia	Serum potassium <3.5mmol/L	during the 3-month follow up
Hypercholesterolemia	New-onset hypercholesterolemia present during follow-up or beyond from baseline and/or addition of lipid-lowering drug(s)	during the 3-month follow up
Premature discontinuation from the study	The time of of discontinuation from study will be recorded, and the discontinuation is due to: treating intolerance; rapid disease progression; other reasons	during the 3-month follow up
Failure to adhere to the protocol	Failure to adhere to the protocol including: do not titer the dose of sirolimus following study protocol; increase the dose of other immunosuppressives personally without the permission of physician	during the 3-month follow up
Changes in Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI)	Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) assesses disease activity by scoring 24 weighted disease activity descriptors of SLE as "present" or "absent" in preceding 10 days. A patient's total score is the sum of all marked SLE-related descriptors; a total score ranges between 0 and 105, with a higher score representing a more significant degree of disease activity. Assessment scales of SELENA-SLEDAI is available online.	from baseline to end of 12 weeks
Changes in Physician Global Assessement (PGA)	The Physician Global Assessment (PGA) is a visual analog scale (VAS) using 3 benchmarks for assessing disease activity over the last 2 weeks. Mild flare will score 1.0 point, moderate flares will score a 2.0-2.5 point and severe flares will score a 3 on the 0-3 analog scale. PGA is available online.	from baseline to end of 12 weeks

Collaborators and Investigators

• Sponsor: Peking Union Medical College Hospital
• Collaborators: North China Pharmaceutical Group Corporation
• Investigators: Principal Investigator: Xue-mei Li, MD, Peking Union Medical College Hospital

Publications and helpful links

General Publications

• Yap DYH, Tang C, Chan GCW, Kwan LPY, Ma MKM, Mok MMY, Chan TM. Longterm Data on Sirolimus Treatment in Patients with Lupus Nephritis. J Rheumatol. 2018 Dec;45(12):1663-1670. doi: 10.3899/jrheum.180507. Epub 2018 Oct 1.
• Lai ZW, Kelly R, Winans T, Marchena I, Shadakshari A, Yu J, Dawood M, Garcia R, Tily H, Francis L, Faraone SV, Phillips PE, Perl A. Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial. Lancet. 2018 Mar 24;391(10126):1186-1196. doi: 10.1016/S0140-6736(18)30485-9. Epub 2018 Mar 15.
• Eriksson P, Wallin P, Sjowall C. Clinical Experience of Sirolimus Regarding Efficacy and Safety in Systemic Lupus Erythematosus. Front Pharmacol. 2019 Feb 6;10:82. doi: 10.3389/fphar.2019.00082. eCollection 2019.
• Esatoglu SN, Seyahi E. Is sirolimus a treatment option for patients with systemic lupus erythematosus? Clin Exp Rheumatol. 2019 Nov-Dec;37 Suppl 122(6):13. Epub 2019 Jul 12. No abstract available.
• Ma MKM, Yung S, Chan TM. mTOR Inhibition and Kidney Diseases. Transplantation. 2018 Feb;102(2S Suppl 1):S32-S40. doi: 10.1097/TP.0000000000001729.

Study record dates

Study Major Dates

• Study Start (Anticipated): June 30, 2021
• Primary Completion (Anticipated): June 30, 2023
• Study Completion (Anticipated): October 30, 2023

Study Registration Dates

• First Submitted: May 10, 2021
• First Submitted That Met QC Criteria: May 13, 2021
• First Posted (Actual): May 19, 2021

Study Record Updates

• Last Update Posted (Actual): May 19, 2021
• Last Update Submitted That Met QC Criteria: May 13, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Sirolimus; Lupus Nephritis; Renal Flare
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Kidney Diseases; Urologic Diseases; Connective Tissue Diseases; Glomerulonephritis; Lupus Erythematosus, Systemic; Nephritis; Lupus Nephritis; 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: HS-2743

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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