Sirolimus in Treatment of Proteinuric Flares of Lupus Nephritis

Chinese Academy of Medical Sciences & Peking Union Medical College

Status and phase: Unknown; Phase 3; Phase 2

Conditions: Lupus Nephritis; Immunosuppression; Effect of Drug

Treatments: Drug: Sirolimus

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT04892212

HS-2743

Details and patient eligibility

About

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

Full 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.

Enrollment: 20 estimated patients

Sex: All

Ages: 18 to 60 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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20 participants in 1 patient group

Sirolimus group

Experimental group

Description:

1. 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. 2. The previous immunosuppressive medication is not allowed to be changed during the 3-month follow-up, unless premature discontinuation from study.

Treatment:

Drug: Sirolimus