Back to resultsSirolimus in Treatment of Proteinuric Flares of Lupus Nephritis
Primary Purpose
Lupus Nephritis, Immunosuppression, Effect of Drug
Status
Not yet recruiting
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Sirolimus
Sponsored by
About this trial
This is an interventional treatment trial for Lupus Nephritis focused on measuring Sirolimus, Lupus Nephritis, Renal Flare
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 :
- 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
- No hypoalbuminemia: serum albumin ≥35g/L
- 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
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Sirolimus group
Arm Description
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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
Partial renal remission
24-hr urine protein<3.5g/day or uPCR<3500mg/g
Serum creatinine not higher than 15% above baseline level
Rate of non-renal flare
Central nervous system or other severe organ manifestations of SLE that necessitate aggressive immunosuppressive therapy on its own
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
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.
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.
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.
Infection requiring hospitalization
Infection requiring hospitalization will be recorded including the site of infection, the causative agent and duration (days).
Hypokalemia
Serum potassium <3.5mmol/L
Hypercholesterolemia
New-onset hypercholesterolemia present during follow-up or beyond from baseline and/or addition of lipid-lowering drug(s)
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
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
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.
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.
Full Information
NCT ID
NCT04892212
First Posted
May 10, 2021
Last Updated
May 13, 2021
Sponsor
Peking Union Medical College Hospital
Collaborators
North China Pharmaceutical Group Corporation
1. Study Identification
Unique Protocol Identification Number
NCT04892212
Brief Title
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
2. Study Status
Record Verification Date
May 2021
Overall Recruitment Status
Not yet recruiting
Study Start Date
June 30, 2021 (Anticipated)
Primary Completion Date
June 30, 2023 (Anticipated)
Study Completion Date
October 30, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Peking Union Medical College Hospital
Collaborators
North China Pharmaceutical Group Corporation
4. Oversight
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
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lupus Nephritis, Immunosuppression, Effect of Drug
Keywords
Sirolimus, Lupus Nephritis, Renal Flare
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Sirolimus group
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamycin
Intervention Description
The daily dose of sirolimus is divided twice.
Primary Outcome Measure Information:
Title
The number of patients achieving sustained Renal Response(RR)
Description
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.
Time Frame
at the end of 12 weeks (3 months) from baseline
Secondary Outcome Measure Information:
Title
Complete renal remission
Description
24-hr urine protein<0.3g/day or urine Protein-Creatinine ratio (uPCR)<300mg/g
Serum creatinine not higher than 15% above baseline level
Time Frame
at the end of 12 weeks (3 months) from baseline
Title
Partial renal remission
Description
24-hr urine protein<3.5g/day or uPCR<3500mg/g
Serum creatinine not higher than 15% above baseline level
Time Frame
at the end of 12 weeks (3 months) from baseline
Title
Rate of non-renal flare
Description
Central nervous system or other severe organ manifestations of SLE that necessitate aggressive immunosuppressive therapy on its own
Time Frame
during the 3-month follow up
Title
Safety and tolerability of study medications
Description
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
Time Frame
during the 3-month follow up
Title
Increase of serum creatinine level>15% from baseline
Description
Increase of serum creatinine level (μmol/L)>15% from baseline and whether it is reversible or irreversible.
Time Frame
during the 3-month follow up
Title
Episodes with sirolimus level above the target range
Description
Episodes with sirolimus level above the target range（serum sirolimus trough level>8ng/mL) will be recorded.
Time Frame
during the 3-month follow up
Title
New-onset hypertension or worsening hypertensive control that required increase of antihypertensive medication
Description
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.
Time Frame
during the 3-month follow up
Title
Infection requiring hospitalization
Description
Infection requiring hospitalization will be recorded including the site of infection, the causative agent and duration (days).
Time Frame
during the 3-month follow up
Title
Hypokalemia
Description
Serum potassium <3.5mmol/L
Time Frame
during the 3-month follow up
Title
Hypercholesterolemia
Description
New-onset hypercholesterolemia present during follow-up or beyond from baseline and/or addition of lipid-lowering drug(s)
Time Frame
during the 3-month follow up
Title
Premature discontinuation from the study
Description
The time of of discontinuation from study will be recorded, and the discontinuation is due to:
treating intolerance
rapid disease progression
other reasons
Time Frame
during the 3-month follow up
Title
Failure to adhere to the protocol
Description
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
Time Frame
during the 3-month follow up
Title
Changes in Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI)
Description
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.
Time Frame
from baseline to end of 12 weeks
Title
Changes in Physician Global Assessement (PGA)
Description
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.
Time Frame
from baseline to end of 12 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
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 :
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
No hypoalbuminemia: serum albumin ≥35g/L
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Chao Li, MD
Phone
86-010-69155058
Email
superchad099@hotmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Xue-mei Li, MD
Organizational Affiliation
Peking Union Medical College Hospital
Official's Role
Principal Investigator
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
30275264
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.
Results Reference
background
PubMed Identifier
29551338
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.
Results Reference
background
PubMed Identifier
30787878
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.
Results Reference
background
PubMed Identifier
31376256
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.
Results Reference
background
PubMed Identifier
29369972
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.
Results Reference
background
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Sirolimus in Treatment of Proteinuric Flares of Lupus Nephritis
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