Clinical trial NCT04892212: Sirolimus in Treatment of Proteinuric Flares of Lupus Nephritis
Official title: A Pilot Study of Sirolimus in Treatment of Proteinuric Flares of Lupus Nephritis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Lupus Nephritis
Immunosuppression
Effect of Drug
Keywords: Sirolimus
Lupus Nephritis
Renal Flare
Lead sponsor: Peking Union Medical College Hospital
Sponsor class: OTHER
Collaborators: name: North China Pharmaceutical Group Corporation
First posted: 2021-05-19
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility criteria: 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

Primary outcomes:
measure: The number of patients achieving sustained Renal Response(RR)
timeFrame: at the end of 12 weeks (3 months) from baseline
Secondary outcomes:
measure: Complete renal remission
timeFrame: at the end of 12 weeks (3 months) from baseline
measure: Partial renal remission
timeFrame: at the end of 12 weeks (3 months) from baseline
measure: Rate of non-renal flare
timeFrame: during the 3-month follow up
measure: Safety and tolerability of study medications
timeFrame: during the 3-month follow up
measure: Increase of serum creatinine level>15% from baseline
timeFrame: during the 3-month follow up
measure: Episodes with sirolimus level above the target range
timeFrame: during the 3-month follow up
measure: New-onset hypertension or worsening hypertensive control that required increase of antihypertensive medication
timeFrame: during the 3-month follow up
measure: Infection requiring hospitalization
timeFrame: during the 3-month follow up
measure: Hypokalemia
timeFrame: during the 3-month follow up
measure: Hypercholesterolemia
timeFrame: during the 3-month follow up
measure: Premature discontinuation from the study
timeFrame: during the 3-month follow up
measure: Failure to adhere to the protocol
timeFrame: during the 3-month follow up
measure: Changes in Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI)
timeFrame: from baseline to end of 12 weeks
measure: Changes in Physician Global Assessement (PGA)
timeFrame: from baseline to end of 12 weeks
Other outcomes:
Locations:
Study officials:
affiliation: Peking Union Medical College Hospital
name: Xue-mei Li, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.