Interventions for focal segmental glomerulosclerosis in adults

Elisabeth M Hodson; Aditi Sinha; Tess E Cooper

doi:10.1002/14651858.CD003233.pub3

. 2022 Feb 28;2022(2):CD003233. doi: 10.1002/14651858.CD003233.pub3

Interventions for focal segmental glomerulosclerosis in adults

Elisabeth M Hodson ^1,^2,^✉, Aditi Sinha ³, Tess E Cooper ^1,²

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC8883337 PMID: 35224732

Abstract

Background

Focal segmental glomerulosclerosis (FSGS) can be separated into primary, genetic or secondary causes. Primary disease results in nephrotic syndrome while genetic and secondary forms may be associated with asymptomatic proteinuria or with nephrotic syndrome. Overall only about 20% of patients with FSGS experience a partial or complete remission of nephrotic syndrome with treatment. FSGS progresses to kidney failure in about half of the cases. This is an update of a review first published in 2008.

Objectives

To assess the benefits and harms of immunosuppressive and non‐immunosuppressive treatment regimens in adults with FSGS.

Search methods

We searched the Cochrane Kidney and Transplant Register of Studies to 21 June 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria

Randomised controlled trials (RCTs) and quasi‐RCTs of any intervention for FSGS in adults were included. Studies comparing different types, routes, frequencies, and duration of immunosuppressive agents and non‐immunosuppressive agents were assessed.

Data collection and analysis

At least two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random‐effects model and results were expressed as a risk ratio (RR) for dichotomous outcomes, or mean difference (MD) for continuous data with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results

Fifteen studies (560 participants) were included. No studies specifically evaluating corticosteroids compared with placebo or supportive therapy were identified. Studies evaluated participants with steroid‐resistant FSGS. Five studies (240 participants) compared cyclosporin with or without prednisone with different comparators (no specific treatment, prednisone, methylprednisolone, mycophenolate mofetil (MMF), dexamethasone). Three small studies compared monoclonal antibodies (adalimumab, fresolimumab) with other agents or placebo. Six single small studies compared rituximab with tacrolimus, cyclosporin plus valsartan with cyclosporin alone, MMF with prednisone, chlorambucil plus methylprednisolone and prednisone with no specific treatment, different regimens of dexamethasone and CCX140‐B (an antagonist of the chemokine receptor CCR2) with placebo. The final study (109 participants) compared sparsentan, a dual inhibitor of endothelin Type A receptor and of the angiotensin II Type 1 receptor, with irbesartan. In the risk of bias assessment, seven and five studies were at low risk of bias for sequence generation and allocation concealment, respectively. Four studies were at low risk of performance bias and 14 studies were at low risk of detection bias. Thirteen, six and five studies were at low risk of attrition bias, reporting bias and other bias, respectively.

Of five studies evaluating cyclosporin, four could be included in our meta‐analyses (231 participants). Cyclosporin with or without prednisone compared with different comparators may increase the likelihood of complete remission (RR 2.31, 95% CI 1.13 to 4.73; I² = 1%; low certainty evidence) and of complete or partial remission (RR 1.64, 95% CI 1.10 to 2.44; I² = 19%) but not of partial remission (RR 1.36, 95% CI 0.78 to 2.39, I² = 22%). In Individual studies, cyclosporin with prednisone versus prednisone may increase the likelihood of partial (49 participants: RR 7.96, 95% CI 1.09 to 58.15) or complete or partial remission (49 participants: RR 8.85, 95% CI 1.22 to 63.92) but not of complete remission. The remaining individual comparisons may make little or no difference to the likelihood of complete remission, partial remission or complete or partial remission compared with no treatment, methylprednisolone, MMF, or dexamethasone. Individual study data and combined data showed that cyclosporin may make little or no difference to the outcomes of chronic kidney disease or kidney failure. It is uncertain whether cyclosporin compared with these comparators in individual or combined analyses makes any difference to the outcomes of hypertension or infection.

MMF compared with prednisone may make little or no difference to the likelihood of complete remission (33 participants: RR 1.05, 95% CI 0.58 to 1.88; low certainty evidence), partial remission, complete or partial remission, glomerular filtration rate, or infection. It is uncertain whether other interventions make any difference to outcomes as the certainty of the evidence is very low. It is uncertain whether sparsentan reduces proteinuria to a greater extent than irbesartan.

Authors' conclusions

No RCTs, which evaluated corticosteroids, were identified although the KDIGO guidelines recommend corticosteroids as the first treatment for adults with FSGS. The studies identified included participants with steroid‐resistant FSGS. Treatment with cyclosporin for at least six months was more likely to achieve complete remission of proteinuria compared with other treatments but there was considerable imprecision due to few studies and small participant numbers. In future studies of existing or new interventions, the investigators must clearly define the populations included in the study to provide appropriate recommendations for patients with primary, genetic or secondary FSGS.

Plain language summary

Immunosuppressive treatment for focal segmental glomerulosclerosis in adults

What is the issue?

Nephrotic syndrome is a condition where the kidneys leak protein from the blood into the urine. Focal segmental glomerulosclerosis (FSGS) defined on kidney biopsy is an uncommon cause of nephrotic syndrome disease but it progresses to kidney failure in about half of all cases. It can be divided into three groups ‐ primary FSGS (thought to be due to a factor circulating in the blood that damages the kidneys), genetic (secondary to mutations in one or more genes), and secondary to other causes, including certain infections. Treatments aim to reduce the amount of protein in the urine completely or partly to increase the time before kidney failure develops.

What did we do?

We looked at all randomised controlled trials (RCTs) which examined therapy with prednisone or other agents which affect the immune system such as cyclosporin and mycophenolate mofetil and other agents with or without steroid therapy.

What did we find?

We found 15 studies involving 553 participants. In five studies cyclosporin was compared with different treatments. Combining four studies (231 participants) showed that cyclosporin was more effective than these other treatments in achieving complete remission of nephrotic syndrome. The studies were too small and lasted for too short a time to determine if cyclosporin reduced the risk of kidney failure. Nine small studies examined different medicines that suppress the body's immune system. None of these treatments reduced the amount of protein in the urine.

Conclusions

We found limited information that cyclosporin may reduce the amount of protein in the urine in some people with FSGS but the data are uncertain because the studies enrolled too few participants. We need new agents for the treatment of FSGS with nephrotic syndrome to prevent kidney failure.

Summary of findings

Summary of findings 1. Cyclosporin versus different comparators for focal segmental glomerulosclerosis in adults.

Cyclosporin versus different comparators for focal segmental glomerulosclerosis (FSGS) in adults
Patient or population: adults with FSGS Setting: nephrology departments Intervention: cyclosporin with or without prednisone Comparison: different comparators (supportive treatment, prednisone, methylprednisolone, MMF, dexamethasone)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with different comparators	Risk with Cyclosporin	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Complete remission of proteinuria Follow‐up: 6 to 12 months	73 per 1000	168 per 1000 (82 to 344)	RR 2.31 (1.13 to 4.73)	231 (4)	⊕⊕⊝⊝ LOW ¹
Partial remission of proteinuria Follow‐up: 6 to 12 months	218 per 1000	297 per 1000 (170 to 521)	RR 1.36 (0.78 to 2.39)	231 (4)	⊕⊕⊝⊝ LOW ¹
Complete or partial remission Follow‐up: 6 to 12 months	291 per 1000	477 per 1000 (320 to 710)	RR 1.64 (1.10 to 2.44)	231 (4)	⊕⊕⊝⊝ LOW ¹
Chronic kidney disease Follow‐up: 6 to 12 months	209 per 1000	174 per 1000 (73 to 410)	RR 0.83 (0.35 to 1.96)	231 (4)	⊕⊕⊝⊝ LOW ¹
Kidney failure Follow‐up: 6 to 12 months	145 per 1000	80 per 1000 (22 to 291)	RR 0.55 (0.15 to 2.00)	231 (4)	⊕⊕⊝⊝ LOW ¹
Adverse effects: hypertension Follow‐up: 6 to 12 months	Data not pooled**	Data not pooled	‐‐	187 (2)	⊕⊝⊝⊝ VERY LOW ^{1 2}
Adverse effects: infection Follow‐up: 6 to 12 months	Data not pooled	Dat not pooled	‐‐	157 (2)	⊕⊕⊝⊝ LOW ¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  Adverse effects were not pooled due to the inconsistency between the studies  CI: Confidence interval; RR:** Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Study name	Serum albumin		Urinary protein excretion		Included participants as reported by authors
Study name	Treatment group	Control group	Treatment group	Control group	Included participants as reported by authors
Cyclosporin studies
Bhaumik 2002	‐‐	‐‐	‐‐	‐‐	All had nephrotic syndrome
Cattran 1999	3.1 ± 0.9 g/dL	3.0 ± 0.9 g/dL	6.9 g/24 hours	8.7 g/24 hours	All had nephrotic syndrome
FSGS‐CT 2011	3.0 g/dL (IQR 2.3 to 3.7)	2.7 g/dL (IQR 2‐3.5)	UPCR: 1 to 1.9 g/g in 20 UPCR: > 1.9 g/g in 47	UPCR: 1 to 1.9 g/g in 13 UPCR: > 1.9 g/g in 53	Did not specifically state that all included participants had nephrotic syndrome
Ponticelli 1993a	‐‐	‐‐	167 ± 56 mg/m²/hour (4.0 g/day)	116 ± 34 mg/m²/hour (2.78 g/day)	All had nephrotic syndrome
Walker 1990	‐‐	‐‐	‐‐	‐‐	All had nephrotic syndrome
Other studies
Cho 2019	‐‐	‐‐	9.6 (8.1 to 12.2) g/day (mean for all patients)	Not separated for groups	All had nephrotic syndrome
Dasgupta 2020	2.84 ± 0.58 g/dL	2.54 ± 0.57 g/dL	6.31 ± 2.27 g/24 hours	7.01 ± 2.35 g/24 hours	All had nephrotic syndrome
DUET 2017	‐‐	‐‐	UPCR: 3.61 (0.4‐18.7) g/g (median/range)	UPCR: 3.12 (0.9‐10.7) g/g (median/range)	Did not specifically state that all included participants had nephrotic syndrome. Entry criteria required UPCR > 1g/g
FONT I 2009	2.1 ± 1 g/dL Adalimumab	2.3 ± 1 g/dL Rosiglitazone	UPCR: 15.9 ± 10.4 g/g Adalimumab	UPCR: 5.5 ± 2.6 g/g Rosiglitazone	Did not specifically state that all included participants had nephrotic syndrome. Entry criteria required UPCR > 1g/g
FONT II 2011	2.40 g/dL (IQR 2.10 ‐ 3.50) Adalimumab or galactose or standard therapy	Data not separated for groups	UPCR: 4.93 g/g (IQR 3.3 to 11.5)	Data not separated for groups	Did not specifically state that all included participants had nephrotic syndrome. Entry criteria required UPCR > 1g/g
Imbasciati 1980	‐‐	‐‐	‐‐	‐‐	All had nephrotic syndrome
LUMINA‐1 2018	‐‐	‐‐	‐‐	‐‐	Did not specifically state that all included participants had nephrotic syndrome. Entry criteria required UPCR > 1g/g
Quintaes 2000	2.52 ± 1.3 g/L	2.18 ± 1.0 g/L	6.3 ± 2.7 g/24 hours	10.83 ± 4.1 g/24 hours	All had nephrotic syndrome
Senthil Nayagam 2008	‐‐	‐‐	UPCR: 4.68 ± 1.82 mg/mg (baseline for 17 FSGS and 11 MN)	UPCR: 4.95 ± 1.65 mg/mg (baseline for 16 FSGS and 10 MN)	All had nephrotic syndrome
Vincenti 2017	‐‐	‐‐	UPCR: 5.92 (2.6,17.3) mg/mg UPCR: 6.46 (1.3, 15.9) mg/mg	UPCR: 6.41 (2.2, 13.7) mg/mg	Did not specifically state that all included participants had nephrotic syndrome. Entry criteria required UPCR ≥ 3 mg/mg in > 1 urine specimen

Date	Event	Description
10 January 2022	New search has been performed	New studies and interventions included
10 January 2022	New citation required but conclusions have not changed	New studies included, however no change to conclusions
17 May 2018	Amended	Amended search strategies
27 March 2008	Amended	Converted to new review format.

Databases	Search Terms
CENTRAL	MeSH descriptor: [Glomerulosclerosis, Focal Segmental] explode all trees focal segmental glomerulosclerosis:ti,ab,kw (Word variations have been searched) focal sclerosing glomerulonephritis:ti,ab,kw (Word variations have been searched) "Focal glomerulosclerosis" or "segmental glomerulosclerosis":ti,ab,kw (Word variations have been searched) fsgs or fsgn:ti,ab,kw (Word variations have been searched) {or #1‐#5}
MEDLINE (OVID)	Glomerulosclerosis, Focal Segmental/ (fsgs or fsgn).tw. focal segmental glomerulosclerosis.tw. focal sclerosing glomerulonephritis.tw. (Focal glomerulosclerosis or segmental glomerulosclerosis).tw. or/1‐5
EMBASE (OVID)	focal glomerulosclerosis/ focal segmental glomerulosclerosis.tw. focal sclerosing glomerulonephritis.tw. "focal and segmental glomerulosclerosis".tw. focal glomerulus sclerosis.tw. fsgs.tw. or/1‐6

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Complete remission of proteinuria	4	231	Risk Ratio (M‐H, Random, 95% CI)	2.31 [1.13, 4.73]
1.1.1 Cyclosporin versus supportive treatment at 12 months	1	19	Risk Ratio (M‐H, Random, 95% CI)	4.55 [0.25, 83.70]
1.1.2 Cyclosporin + prednisone versus prednisone at 6 months	1	49	Risk Ratio (M‐H, Random, 95% CI)	2.67 [0.11, 62.42]
1.1.3 Cyclosporin + prednisone versus IV methylprednisolone at 6 months	1	25	Risk Ratio (M‐H, Random, 95% CI)	2.31 [0.55, 9.74]
1.1.4 Cyclosporin + prednisone versus mycophenolate mofetil + dexamethasone + prednisone at 12 months	1	138	Risk Ratio (M‐H, Random, 95% CI)	2.14 [0.87, 5.24]
1.2 Partial remission of proteinuria	4	231	Risk Ratio (M‐H, Random, 95% CI)	1.36 [0.78, 2.39]
1.2.1 Cyclosporin versus no treatment	1	19	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.36, 3.97]
1.2.2 Cyclosporin + prednisone versus prednisone	1	49	Risk Ratio (M‐H, Random, 95% CI)	7.96 [1.09, 58.15]
1.2.3 Cyclosporin + prednisone versus IV methylprednisolone	1	25	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.51, 3.74]
1.2.4 Cyclosporin + prednisone versus mycophenolate + dexamethasone + prednisone	1	138	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.61, 1.93]
1.3 Complete or partial remission	4	231	Risk Ratio (M‐H, Random, 95% CI)	1.64 [1.10, 2.44]
1.3.1 Cyclosporin versus supportive treatment	1	19	Risk Ratio (M‐H, Random, 95% CI)	1.80 [0.63, 5.16]
1.3.2 Cyclosporin + prednisone versus prednisone	1	49	Risk Ratio (M‐H, Random, 95% CI)	8.85 [1.22, 63.92]
1.3.3 Cyclosporin + prednisone versus IV methylprednisolone	1	25	Risk Ratio (M‐H, Random, 95% CI)	1.69 [0.92, 3.12]
1.3.4 Cyclosporin + prednisone versus mycophenolate + dexamethasone + prednisone	1	138	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.90, 2.10]
1.4 Chronic kidney disease	4	231	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.35, 1.96]
1.4.1 Cyclosporin versus supportive treatment	1	19	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.04, 2.39]
1.4.2 Cyclosporin + prednisone versus prednisone	1	49	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.72, 1.94]
1.4.3 Cyclosporin + prednisone versus IV methylprednisolone	1	25	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.08, 1.24]
1.4.4 Cyclosporin + prednisone versus mycophenolate mofetil + dexamethasone + prednisone	1	138	Risk Ratio (M‐H, Random, 95% CI)	2.29 [0.46, 11.41]
1.5 Kidney failure	4	231	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.15, 2.00]
1.5.1 Cyclosporin versus supportive treatment	1	19	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.01, 6.62]
1.5.2 Cyclosporin + prednisone versus prednisone	1	49	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.13, 0.98]
1.5.3 Cyclosporin + prednisone versus IV methylprednisolone	1	25	Risk Ratio (M‐H, Random, 95% CI)	0.23 [0.03, 1.79]
1.5.4 Cyclosporin + prednisone versus mycophenolate mofetil + dexamethasone + prednisone	1	138	Risk Ratio (M‐H, Random, 95% CI)	4.58 [0.55, 38.22]
1.6 Adverse effects: hypertension	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.6.1 Cyclosporin + prednisone versus prednisone	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.6.2 Cyclosporin + prednisone versus mycophenolate mofetil + dexamethasone + prednisone	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.7 Adverse effects: infection	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.7.1 Cyclosporin versus supportive treatment	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.7.2 Cyclosporin + prednisone versus mycophenolate mofetil + dexamethasone + prednisone	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.8 Adverse effects: total hospitalisations	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.8.1 Cyclosporin + prednisone versus IV methylprednisolone	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.8.2 Cyclosporin + prednisone versus mycophenolate mofetil + dexamethasone + prednisone	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.9 Adverse effects: GI disturbances	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.9.1 Cyclosporin + prednisone versus prednisone	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.9.2 Cyclosporin + prednisone versus mycophenolate mofetil + dexamethasone + prednisone	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Remission	1	34	Risk Ratio (M‐H, Random, 95% CI)	1.42 [0.49, 4.16]
2.1.1 Complete remission at 6 months	1	17	Risk Ratio (M‐H, Random, 95% CI)	4.50 [0.25, 81.76]
2.1.2 Partial remission at 6 months	1	17	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.37, 3.76]
2.2 Protein excretion at 6 months	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2.3 Biochemical outcomes at 6 months	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2.3.1 Serum albumin g/dL	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2.3.2 Serum creatinine µmol/L	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
3.1 Kidney outcomes	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1.1 Complete remission at 6 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1.2 Partial remission at 6 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1.3 Complete or partial remission at 6 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1.4 Doubling of serum creatinine at 6 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
4.1 Kidney outcomes	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.1.1 Complete remission at 6 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.1.2 Partial remission at 6 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.1.3 Complete or partial remission at 6 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.2 Adverse effects	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.2.1 Infection	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.3 GFR	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
4.3.1 MMF versus prednisolone	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
5.1 Partial remission at 48 weeks	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.2 GFR	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
5.3 24‐hour urine protein excretion	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
5.4 Adverse effects	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.4.1 serious adverse effects	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.4.2 Mood swings	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.4.3 Infection	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
6.1 Remission of proteinuria by 12 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6.1.1 Complete remission at 12 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6.1.2 Partial remission at 12 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6.1.3 Complete or partial remission at 12 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6.2 Relapse by 12 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6.3 Adverse effects	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6.3.1 Worsening hypertension	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6.3.2 Infection	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6.3.3 Diabetes	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6.3.4 Doubling of serum creatinine	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

*Study characteristics*
Methods	Study design: parallel, open‐label RCT Study duration: 50 months (January 1996 to March 2000) Follow‐up period: 6 months
Participants	Country: India Setting: single centre Inclusion criteria: aged 3 to 49 years with biopsy‐proven primary FSGS with nephrotic syndrome, resistant to therapy with oral prednisolone at 2 mg/kg for 8 weeks Number: treatment group (13); control group (12) Mean age ± SD (years): not reported Sex (M/F): not reported Exclusion criteria: not reported
Interventions	Treatment group CSA (oral): 1 to 4 mg/kg/day Prednisolone (oral): 10 to 40 mg/day Duration: at least 6 months Control group Methylprednisolone (IV): 250 to 750 mg/day for 7 days followed by weekly administration Duration: at least 12 weeks Co‐interventions ACEi and lipid‐lowering therapies; dietary protein intake restricted to 0.8 to 1 g/kg/day
Outcomes	Number with complete remission Number with a decline in proteinuria from baseline and stable SCr Change in CrCl from baseline Occurrence of ESKD within 3 years Number requiring hospitalisation for therapy‐related adverse events
Notes	Abstract‐only publication Funding source: not reported Definitions of complete and partial remission not provided The time at which the outcome was measured was not specified but presumed to be 6 months
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not specified: '... were randomised for two treatment options...'
Allocation concealment (selection bias)	Unclear risk	Method not specified: '... were randomised for two treatment options...'
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study. While the laboratory measure is unlikely to be influenced by lack of blinding, the time point of outcome assessment is not defined and is susceptible to bias in an open‐label study
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients were accounted for
Selective reporting (reporting bias)	Unclear risk	Pre‐specified outcomes not reported in available abstract
Other bias	Unclear risk	Funding source not reported; full manuscript was not published; trial not registered and no published protocol available

*Study characteristics*
Methods	Study design: placebo‐controlled RCT Study duration: not reported Follow‐up period: unclear but at least 104 weeks for remission of proteinuria and average of 200 weeks for kidney function
Participants	Countries: Canada; USA Setting: international (12 sites) Inclusion criteria: 18 to 70 years; biopsy‐proven FSGS; no response to oral prednisolone at ≥ 1 mg/kg/days for ≥ 8 weeks; proteinuria ≥3.5 g/day or ≥ 50 mg/kg; CrCl ≥ 42 mL/min/1.73 m²; BP ≤ 135/90 mm Hg; dietary protein intake ≤ 0.8 g/kg Number: treatment group (26), control group (23) Mean age ± SD (years): treatment group (38 ± 10); control group (40 ± 14) Sex (M/F): treatment group (17/9); control group (17/6) Exclusion criteria: biopsy suggestive of collapsing glomerulopathy or segmental sclerosis secondary to another disease; women unwilling to take effective birth control measures; comorbidity with expected survival < 2 years; serious systemic infection; daily therapy with NSAIDS; DM; obesity; unilateral renal artery stenosis; immunosuppressive therapy, plasma exchanges or anti‐lymphocyte products in the last 6 months
Interventions	Treatment group CSA: 3.5 mg/kg/day in 2 divided doses; CSA dose adjusted to maintain whole blood 12‐hour trough level between 125 and 225 mg/L Prednisone: 0.15 mg/kg/day (maximum daily dose of 15 mg) Duration: 26 weeks, CSA then tapered over 4 weeks to discontinue Control group Placebo: 0.035 mL/kg/day in 2 divided doses Prednisone: 0.15 mg/kg/day (maximum daily dose of 15 mg) Duration: 26 weeks, placebo then tapered over 4 weeks to discontinue Co‐interventions Participants already on ACEi or ARBs could remain on these medications but these medications could not be commenced during the study
Outcomes	Number with complete or partial remission of proteinuria by week 26 Complete remission: proteinuria ≤ 0.3 g/day and stable kidney function (defined as CrCl within 15% of baseline value); assessed at 26, 52, 78 and 104 weeks Partial remission: 50% reduction in proteinuria and ≤ 3.5 g/day with stable kidney function; assessed at 26, 52, 78 and 104 weeks Time to a reduction in CrCl by 50% from baseline; time to doubling of baseline SCr Number with ESKD, defined as CrCl < 12 mL/min, the start of dialysis, or transplantation Early stop points of study medication Confirmed ≥ 30% rise in SCr (SCr not improved by two 25% reductions in medication dose over 4 weeks); doubling of baseline liver enzymes; intolerable adverse effects; complete remission of proteinuria achieved and persisted for ≥ 1 month period
Notes	Prior to randomisation, both placebo and treatment groups received prednisone (treatment group, mean dose 120 mg/kg over mean duration of 13 weeks and control group, mean dose 100 mg/kg over 14 weeks and 11 patients (control group (5), treatment group (6)) had received a course of a cytotoxic agent (CPA (9), AZA (2)) in a dose of 1 to 3 mg/kg for a mean of 2 months All patients were followed for an average of 200 weeks Funding source: Kidney Foundation of Canada and Norvatis Canada Ltd
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was performed by the clinical coordinating center from a table of random numbers and was stratified by center in blocks of two to ensure a balance between groups"
Allocation concealment (selection bias)	Low risk	Central randomisation Quote: "Randomization was performed by the clinical coordinating center from a table of random numbers and was stratified by center in blocks of two to ensure a balance between groups"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "The patients were masked in regards to active versus placebo assignment, but the physicians were not, for safety reasons and because the end points were objective and measured centrally by a lab masked to patient designation"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The patients were masked in regards to active versus placebo assignment, but the physicians were not for safety reasons and because the end points were objective and measured centrally by a lab masked to patient designation"
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants accounted for; therapy discontinued only as per pre‐specified stopping rules
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Unclear risk	Supported by the Kidney Foundation of Canada and Norvatis Canada Ltd

*Study characteristics*
Methods	Study design: phase 3, parallel, open‐label RCT Duration: not reported Follow‐up period: 48 weeks
Participants	Country: USA Setting: multicentre (number of sites not reported) Inclusion criteria: biopsy‐proven MCD or FSGS and nephrotic range proteinuria (> 3.5 g/1.73 m²/day) despite maximum tolerated therapy with ACEi or ARB for > 4 weeks and oral glucocorticoid therapy (at > 0.5 mg/kg daily or on alternate days for < 8 weeks); CKD‐EPI eGFR ≥ 40 mL/min/1.73 m²; BP controlled adequately; tuberculosis ruled out adequately (e.g. by negative PPD test within 3 months of study entry); among sexually active women of reproductive age group, willingness to maintain an effective birth control regimen and with a negative urine pregnancy test Number: treatment group 1 (4); treatment group 2 (3; 4 patients randomised, one withdrew before taking medication and not included in results) Mean age ± SD (years): treatment group 1 (38 ± 8); treatment group 2 (30 ± 5) Sex (M/F): treatment group 1 (2/2); treatment group 2 (2/1) Pathology: 6 patients had FSGS and 1 had MCD Exclusion criteria: adaptive FSGS (as suggested by near normal serum albumin levels despite nephrotic‐range proteinuria, enlarged glomeruli, perihilar sclerosis and hyalinosis, and limited podocyte foot process effacement); medication‐associated FSGS (e.g., with therapy with lithium or interferon‐alpha); poorly controlled DM or hypertension (> 25% of values > 125/75 mm Hg); infection with HIV, HCV or HBV or untreated tuberculosis; pregnancy or lactation
Interventions	Treatment group 1 Dexamethasone (oral, pulse): 50 mg/m² at 2 doses once every 2 weeks for 12 weeks, then at 25 mg/m² at 2 doses every 2 weeks for 48 weeks Treatment group 2 Dexamethasone (oral, pulse): 50 mg/m² at 4 doses every 4 weeks for 12 weeks, then at 25 mg/m² at 4 doses every 4 weeks for 48 weeks Co‐interventions Antihypertensives as required to control BP, other than newly initiated ACEi, ARB, or non‐dihydropyridine calcium channel blockers) Daily supplementation of 1500 mg elemental calcium and 800 units of vitamin D
Outcomes	Complete or partial remission at 48 weeks Follow‐up data at 2 years, last follow‐up (5.4 years) Urine protein/24 hours at 48 weeks Follow‐up data at 2 years, last follow‐up (5.4 years) CKD‐EPI eGFR at 48 weeks Follow‐up data at 2 years, last follow‐up (5.4 ye Adverse events Definitions Complete remission: proteinuria < 0.3 g/day Partial remission: proteinuria < 3.5 g/day and ≥ 50% decline with preserved eGFR (> 60/75% of baseline) Limited response: proteinuria > 3.5 g/day with ≥ 50% decline from baseline No response: all outcomes other than complete, partial, or limited response
Notes	Study terminated because of insufficient enrolment (only 7 of proposed 70) Funding source: National Institute of Diabetes and Digestive and Kidney Disease, Intramural Research Program (ZO1‐DK04312), NIH Clinical Center Pharmacy
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quotes: "Randomised/parallel assignment." "... subjects were randomised to 2 doses every 2 weeks or 4 doses every 4 weeks"; "Subjects were randomised (1: 1) using a stratified block design to 2 doses every 2 weeks versus 4 doses every 4 weeks for both periods"
Allocation concealment (selection bias)	Unclear risk	Quotes: "Randomised/parallel assignment. ." "...subjects were randomised to 2 doses every 2 weeks or 4 doses every 4 weeks"; "Subjects were randomised (1: 1) using a stratified block design to 2 doses every 2 weeks versus 4 doses every 4 weeks for both periods"; No other information provided
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Remission confirmed by 24‐hour urine collection for protein. Laboratory measure unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	Only 8 participants enrolled; one of 8 participants randomised (to treatment group 2) withdrew before taking medication and was excluded
Selective reporting (reporting bias)	Unclear risk	All pre‐specified outcomes were reported but not always reported separately for RCT and for another non‐randomised study
Other bias	Low risk	National Institute of Diabetes and Digestive and Kidney Disease, Intramural Research Program (ZO1‐DK04312), NIH Clinical Center Pharmacy

*Study characteristics*
Methods	Study design: parallel, open‐label RCT Time frame: February 2016 to December 2018 Follow‐up period: 12 months
Participants	Country: India Setting: single centre Inclusion criteria: 18 to 60 years with SRNS, biopsy‐proven MCD/FSGS, GFR > 30 mL/min; on biopsy tubular atrophy and Interstitial fibrosis < 25%, receiving the maximum tolerated dose of ACEi/ARB; failed to respond to up to 16 weeks of prednisone therapy Number (randomised/analysed): treatment group 1 (10/10); treatment group 2 (5/5) Mean age ± SD (years): treatment group 1 (34.1 ± 10.14); treatment group 2 (36.2 ± 13.04) Sex (M/F): treatment group 1 (8/2); treatment group 2 (3/2) Pathology on biopsy (FSGS/MCD): treatment group 1 (9/1); treatment group 2 (4/1) Exclusion criteria: active infection; DM; hepatitis; HIV; abnormal liver function tests' pregnancy; cancer; chronic diarrhoea; collapsing FSGS; secondary FSGS; therapy within 6 months with other immunosuppressants; serious infection episode in past 12 months
Interventions	Treatment group 1 TAC: 0.075 mg/kg in 2 doses. Dose adjusted to levels of 5 to 10 ng/mL and then to 3 to 6 ng/mL when patient in remission. TAC ceased after 6 months if no response Treatment group 2 Rituximab: 375 mg/m² 4 doses at weekly intervals. Further dose given if no response after 6 months
Outcomes	Complete remission at 12 months Partial remission at 12 months Relapse at 6 to 12 months Number failing therapy Adverse effects
Notes	Presumed to be primary FSGS. No information provided on genetic studies Funding source: no funding obtained for study
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "...were randomised using random numbers table in 2:1 distribution to receive tacrolimus or rituximab"
Allocation concealment (selection bias)	Unclear risk	No information provided on whether participant allocation to treatment groups was concealed
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	End point of proteinuria determined by UPCR measured in a laboratory and so unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants completed the study
Selective reporting (reporting bias)	Low risk	Reported expected outcomes
Other bias	Low risk	No funding obtained for study

Outcome or subgroup title	No. of studies	Statistical method	Effect size
7.1 Partial remission at 16 weeks	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
7.1.1 Fresolimumab 1 mg versus placebo	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
7.1.2 Fresolimumab 4 mg versus placebo	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
8.1 Partial remission at 8 weeks	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
8.2 Adverse effects	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
8.2.1 Drug‐related adverse effects	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
8.2.2 Need to cease medication because of adverse effects	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

*Study characteristics*
Methods	Study design: phase 2, parallel RCT Time frame: December 2013 to June 2016 (enrolment period April 2014 to April 2016) Follow‐up period: 8 weeks
Participants	Countries: USA, Belgium, Czech Republic, Italy Setting: international (55 sites) Inclusion criteria: 8 to 75 years (18 to 75 years in Europe); biopsy‐proven primary FSGS or identified podocyte mutation; UPCR ≥ 1.0 g/g, eGFR > 30 mL/min/1.73 m², BP > 100/60 mm Hg and < 145/96 mm Hg in adults; BP > 90/60 mm Hg and < 95th percentile for age, sex, and height in children; immunosuppressive regimen stable for > 1 month and unlikely to change in next 8 weeks; among those who received rituximab or CPA, therapy completed > 3 months before enrolment in the study Number: 109 randomised Adults/children: treatment groups 1‐3 (60/13); control group (26/10) Age (range): 8 to 71 years Sex (M/F): treatment groups 1‐3 (41/32); control group (19/17) Exclusion criteria: secondary FSGS; DM; significant cardiac (heart failure, coronary artery disease or cardiac conduction defects), cerebrovascular (stroke or transient ischaemic attack) or hepatobiliary (e.g., jaundice, hepatitis, cholelithiasis) disease; malignancy; transplantation; anaemia; hyperkalaemia; BMI > 40; pregnancy or lactation; other investigational drugs in previous 28 days; previous sparsentan; unwilling to comply; specified thresholds of N‐terminal prohormone of brain natriuretic peptide for eGFR categories; drug or alcohol abuse
Interventions	Treatment group Sparsentan (dual endothelin and ARB) 200 mg, 400 mg, or 800 mg orally once/day for 8 weeks Participants weighing ≤ 50 kg received half dose in each group Groups combined for comparison Control group (ARB) Irbestartan (oral): 300 mg once/day for 8 weeks Dose was 150 mg during the first week and for participants weighing ≤ 50 kg Co‐interventions Not reported During a subsequent open‐label, phase, sparsentan was given for 144 weeks to both groups
Outcomes	Change in UPCR from baseline at 8 weeks For FSGS: partial remission defined as UPCR ≤ 1.5 g/g with > 40% reduction at 8 weeks Changes to baseline albumin, 24‐hour urinary protein, GFR, BP, SCr, lipid profiles QoL (SF36 in adults; PEDsQL version 4.0 in < 18 years)
Notes	Includes some participants without nephrotic syndrome at study entry Data from the three intervention groups (sparsentan) was pooled to compare against control (irbesartan) Outcome of FSGS partial remission endpoint was defined later; not included in the original protocol on clinicaltrials.gov Randomisation proceeded in progressive dosing cohorts Full analysis set: all randomised patients who received at least one dose of study drug and had at least one post‐baseline efficacy evaluation Efficacy evaluation set: all patients who received at least one dose of study drug and had both baseline and week 8 UPCR measurements Safety analysis set: all randomised patients who received at least one dose of study drug and had at least one post‐baseline safety evaluation The study had a double‐blind phase for 8 weeks followed by an open‐label extension during which all patients continued on, or changed to. sparsentan and were followed to 144 weeks Funding source: Retrophin Inc. (San Diego, CA)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	At week 0, a computer‐generated randomisation sequence, via an interactive Web response system, used to randomise patients (3:1) to receive sparsentan or irbesartan
Allocation concealment (selection bias)	Low risk	At week 0, a computer‐generated randomisation sequence, via an interactive Web response system, used to randomise patients (3:1) to receive sparsentan or irbesartan
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Both medications were encapsulated in grey gelatin capsules Quote: "Investigators, participants, caregivers, and the study sponsor were blinded to treatment allocations until database extraction and unblinding at the completion of the 8‐week, double‐blind treatment period."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Both medications were encapsulated in grey gelatin capsules Quote: "Investigators, participants, caregivers, and the study sponsor were blinded to treatment allocations until database extraction and unblinding at the completion of the 8‐week, double‐blind treatment period."
Incomplete outcome data (attrition bias) All outcomes	Low risk	94% completed the double‐blind period and data on the primary outcome was reported on 96/109 (88%)
Selective reporting (reporting bias)	High risk	Primary outcome of change in proteinuria could not be included in meta‐analysis. Additional analysis (not pre‐specified) and adverse effects could be included in meta‐analyses
Other bias	High risk	Trial organised by Retrophin Inc. (San Diego, CA)

*Study characteristics*
Methods	Study design: phase 1, parallel RCT Time frame: not reported Follow‐up period: 16 weeks
Participants	Country: USA Setting: multicentre (number of sites not reported) Inclusion criteria: 2 to 41 years with biopsy‐confirmed primary FSGS and initial steroid resistance; steroid resistance (UPCR > 1.0 g/g after 4 weeks of steroid therapy), persistent proteinuria (UPCR > 1.0 g/g) and eGFR > 40 mL/min/1.73 m²; patients were admitted who failed treatment in the FSGS‐CT Study 2011 or were ineligible for FSGS‐CT Study because of previous use of study interventions; patients off all immunosuppressive agents for at least 4 weeks. Inclusion criteria assumed to be the same as FSGS‐CT study Number (randomised/completed 16 weeks): treatment group 1 (10/9); treatment group 2 (11/10) Mean age ± SD (years): treatment group 1 (16.8 ± 9.0); treatment group 2 (15.4 ± 6.2) Sex (M/F): treatment group 1 (2/8); treatment group 2 (8/3) Exclusion criteria (assumed to be the same as FSGS‐CT study): secondary FSGS; allergic to the study medications; obesity; ANC < 2000/mm³; HCT < 28%; uncontrolled hypertension; DM; active or serious infection; cirrhosis or chronic active liver disease; history of significant GI disorder; organ transplantation; history of malignancy; participation in another therapeutic trial within 30 days before randomisation; lactation, pregnancy, child‐bearing age and refused birth control
Interventions	Treatment group 1 Adalimumab (SC): 24 mg/m² (maximum 40 mg/dose) on alternate weeks for 16 weeks for a maximum of 40 mg Treatment group 2 Rosiglitazone (oral): 3 mg/m² twice/day for 16 weeks Co‐interventions ACEi or ARB with unchanged dosage, diuretics, low‐dose prednisolone, lipid‐lowering agents
Outcomes	Per cent reduction in proteinuria, eGFR and SCr at 16 weeks Serum albumin Blood glucose Adverse events
Notes	Did not specifically state that all participants had nephrotic syndrome 4/9 participants had a reduction in proteinuria of 50% with adalimumab at 16 weeks. One adverse effect probably related to adalimumab 2/10 participants had a reduction in proteinuria of 40% with rosiglitazone at 16 weeks. 3 adverse effects possibly related to rosiglitazone Data was not added to meta‐analysis as outcomes differed between groups. Information on methods/results requested from authors but none received Funding source: grants from the NIH–NIDDK (5R21‐DK070341), and the GCRC program of the Division of Research Resources, NIH RR00046 (UNC) and NIH RR018535 (North Shore Long Island Jewish Health System)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Patients were randomised to receive adalimumab or rosiglitazone. No other information provided
Allocation concealment (selection bias)	Unclear risk	Patients were randomised to receive adalimumab or rosiglitazone. No other information provided
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Primary outcomes were laboratory‐based and unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	9% did not complete the study; 1/11 did not complete rosiglitazone arm; 1/10 did not complete adalimumab arm
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Low risk	This work was supported by grants from the NIH–NIDDK (5R21‐DK070341), and the GCRC program of the Division of Research Resources, NIH RR00046 (UNC) and NIH RR018535 (North Shore Long Island Jewish Health System)

*Study characteristics*
Methods	Study design: parallel RCT Time frame: November 2004 to November 2009 Follow‐up period: 78 weeks
Participants	Country: USA Setting: multicentre (66 sites) Inclusion criteria: aged 2 to 40 years with SRNS; with biopsy‐confirmed primary FSGS and initial steroid resistance; steroid resistance (UPCR > 1.0 g/g after 4 weeks of steroid therapy), persistent proteinuria (UPCR > 1.0 g/g) and eGFR > 40 mL/min/1.73 m² Number: treatment group 1 (66); treatment group 2 (72) Age (< 18 years/≥ 18 years): 93/45 Sex (M/F): 73/65 Exclusion criteria: secondary FSGS; previous therapy with sirolimus, CSA, TAC, MMF or AZA; treatment with CPA, chlorambucil, levamisole, methotrexate, or nitrogen mustard within 30 days of enrolment; received > 3 pulses of methylprednisolone; allergic to the study medications; obesity; ANC < 2000/mm³; HCT < 28%; uncontrolled hypertension; DM; active or serious infection; cirrhosis or chronic active liver disease; history of significant GI disorder; organ transplantation; history of malignancy; participation in another therapeutic trial within 30 days before randomisation; lactation, pregnancy, child‐bearing age and refused birth control
Interventions	Treatment group 1 Dexamethasone (oral pulse): 0.9 mg/kg/day (max 40 mg) daily on 2 consecutive days at the start of weeks 1 to 8, then daily on 2 consecutive days at the start of every second week in weeks 10 to 26, then every 4 weeks from week 30 to 50, for a total of 46 doses (over 12 months) MMF: 25 to 36 mg/kg/day (max 2 g/day) divided into 2 divided doses for 12 months Treatment group 2 CSA: 5 to 6 mg/kg/day (max initial dose 250 mg/day) in 2 divided doses for 12 months. CSA dose adjusted to achieve a 12‐hour trough concentration of 100 to 250 ng/mL Co‐interventions Prednisone (or prednisolone for children taking liquid preparation): 0.3 mg/kg/dose (max 15 mg) every other day for the first 6 months of the treatment period Lisinopril: 0.36 ± 0.12 (range 0.04 to 0.56) mg/kg/day for 18 months Losartan: 1.10 ± 0.50 (range 0.55 to 2.69) mg/kg/day for patients intolerant of ACEi Additional antihypertensive therapies were not restricted by study protocol
Outcomes	Complete remission: UPCR < 0.2 g/g at 52 weeks (outcomes 1 and 2 on ordinal classification of proteinuria primary outcome) Partial remission: UPCR < 50% of baseline at 52 weeks (outcome 3) No remission at 52 weeks (outcome 4 to 6) Treatment failure with no remission at 26 weeks (outcomes 5, 6) or no remission at 52 weeks (outcome 4) or reached protocol defined stop point Persistence of complete or partial remission between weeks 52 to 78 following cessation of treatment (outcomes 1 to 3 on the ordinal classification of proteinuria secondary outcome) Adverse events
Notes	138 participants aged 2 to 40 years (but no difference in results of subgroup analysis by age) Could include some participants without nephrotic syndrome Stop points: 50% decline in baseline GFR to ≤ 75 mL/min/1.73 m², dialysis, pregnancy, pre‐specified medication‐related toxicity Exclusions post‐randomisation but pre‐intervention: none Additional data requested from authors: breakdown of data to paediatric and adult data; no data received Funding source: NIH funding
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation schedules using randomly permuted blocks of random sizes were prepared by the Data Coordinating centre stratified by eGFR, race
Allocation concealment (selection bias)	Low risk	Study investigators were blinded to randomised schedules
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Open‐label study; lack of blinding could influence patient management differently between treatment groups
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study investigators were blinded to results of interim analyses done for the Data and Safety Monitoring Board Laboratory values for primary outcomes and some secondary outcomes are unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	Minimal participants were lost to follow‐up/did not attend assessments (< 1%); all patients included in outcome measurement
Selective reporting (reporting bias)	Low risk	All expected outcomes (remission, relapse, adverse effects) were reported
Other bias	Low risk	NIH funded

*Study characteristics*
Methods	Design: parallel, open‐label RCT Duration: not reported Follow‐up period: 6 months
Participants	Country: Italy Setting: multicentre (number of sites not reported) Inclusion criteria: biopsy‐proven FSGS, nephrotic syndrome, SCr < 2 mg/dL Number: treatment group (8), control group (7) Median age, range (years): treatment group (41, 30 to 51); control group (41.5, 19 to 66) Sex (M/F): treatment group (5/3); control group (5/2) Exclusion criteria: FSGS secondary to systemic disease, drugs or toxins; or contraindication to use of steroids or cytostatic therapies (DM, peripheral arteriopathies, infections or severe hypertension)
Interventions	Treatment group Methylprednisolone (IV): 1 g (15 to 20 mg/kg)/day for 3 days followed by oral prednisolone at 0.5 mg/kg/day for 1 month, followed by oral chlorambucil at 0.2 mg/kg/day for the next month; the course was repeated consecutively for a total duration of 6 months Control group No specific treatment Co‐interventions Not reported
Outcomes	Complete remission: proteinuria < 100 mg/day Partial remission: persistent proteinuria but < 50% of baseline value and worsening kidney function
Notes	Reported results are defined as "preliminary" No length of follow‐up provided Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Patients ... were randomly allocated to treatment or control groups"
Allocation concealment (selection bias)	Unclear risk	Quote: "Patients ... were randomly allocated to treatment or control groups"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Remission confirmed by 24‐hour urine protein. Laboratory investigation and unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	Unclear risk	No information on adverse effects and limited information on other outcomes
Other bias	Unclear risk	Insufficient information to permit judgement

*Study characteristics*
Methods	Study design: phase 2, parallel RCT Study duration: March 2018 to February 2020 Follow‐up period: 12 weeks
Participants	Country: North America, Europe and Australia Setting: international (number of sites not reported) Inclusion criteria: 18 to 75 years with primary FSGS based on renal biopsy or high‐risk genetic variant; eGFR > 30 mL/min/1.73m²; on stable therapy with ACEi or ARB; immunosuppressive or immunomodulatory therapy stable for at least 4 weeks prior to screening and projected to remain stable through study week 12; UPCR ≥ 1 g/g at screening Number: 46 Mean age ± SD (years): not reported Sex (M/F): not reported Exclusion criteria: pregnant or nursing; organ transplantation; on an organ transplant waiting list or anticipated organ transplant within 6 months of screening; anti‐CD20 monoclonal antibodies within 20 months of screening; plasmapheresis within 12 weeks of screening; BMI ≥ 40; participation in any clinical study of an investigational product within 12 weeks or 5 half‐lives of screening; on dialysis or likely to require dialysis during the blinded treatment phase of the study; cancer within 5 years of screening; HBV, HCV, or HIV; kidney disease associated with disorders other than FSGS that is active or has significant risk of progressing during the course of the study; Disorders that are associated with FSGS lesions; tuberculosis; liver disease; Hb < 8 g/dL; platelets < 50,000, ANC < 1000 cells/µL; QTcF greater than 450 msec; alcohol or illicit drug abuse or of lithium, pamidronate and interferon; GI conditions that may interfere with study medication compliance; known hypersensitivity to CCX140‐B or inactive ingredients of the CCX140‐B tablets; systemic disorder other than FSGS that requires, or is expected to require, systemic glucocorticoids or immune modulators during the study; presence of any medical condition or disease which, in the opinion of the Investigator, may place the subject at unacceptable risk for study participation; taking strong CYP3A4 inducers or strong CYP3A4 inhibitors within 2 weeks prior to screening; taking lithium, interferon, NSAIDS
Interventions	Treatment group 1 CCX140‐B: 5 mg once/day for 12 weeks Treatment group 2 CCX140‐B: 10 mg twice/day for 12 weeks Treatment group 3 CCX140‐B: 15 mg twice/day for 12 weeks Control group Placebo for 12 weeks Co‐interventions Not reported
Outcomes	Change in UPCR eGFR using the CKD‐EPI Cystatin C, CKD‐EPI creatinine equation, CKD‐EPI creatinine‐cystatin C equation and MDRD creatinine equation
Notes	Completion date March 2020 Preliminary results from company https://www.chemocentryx.com/pipeline/chronic-kidney-disease/. Information on methods from NCT03536754 Funding source: Chemocentryx
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised, placebo‐controlled, phase 2
Allocation concealment (selection bias)	Low risk	Randomised, placebo‐controlled, phase 2
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Triple (participant, care provider, investigator)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Triple (participant, care provider, investigator)
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Incomplete information
Selective reporting (reporting bias)	High risk	No data reported
Other bias	High risk	Study supported by Chemocentryx

*Study characteristics*
Methods	Study design: cross‐over RCT Study duration of recruitment: not reported Follow‐up period: not reported
Participants	Country: Australia Setting: single centre Inclusion criteria: biopsy‐proven, steroid‐resistant FSGS and nephrotic syndrome Number: 9 Mean age ± SD (years): not reported Sex (M/F): not reported Exclusion criteria: not reported
Interventions	Treatment group CSA: 2 to 6 months and then crossed over; dose not provided Control group No specific treatment Co‐interventions All participants received warfarin
Outcomes	Serum albumin UPCR SCr
Notes	Abstract‐only publication Serum albumin increased and urinary protein decreased with CSA compared with control period. No patient had complete resolution of nephrotic syndrome. No numerical results provided Duration of follow‐up: unclear
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Participants allocated "at random to treatment". Cross‐over study
Allocation concealment (selection bias)	Unclear risk	Participants allocated "at random to treatment". Cross‐over study
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome defined by 24‐hour urine protein excretion
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Abstract‐only publication. Unclear if all participants completed study
Selective reporting (reporting bias)	High risk	No report of adverse effects
Other bias	Unclear risk	Abstract‐only publication

Study	Reason for exclusion
Chan 2007	Wrong population: IMN. The authors had planned to include participants with FSGS or IMN according to the protocol (NCT00404833) However because of difficulty in recruitment of participants with FSGS, the study was not undertaken in participants with FSGS (Information from chief investigator Professor Daniel TM Chan)
GloMY 2010	Terminated study: RCT comparing MMF with prednisolone in patients with FSGS terminated in 2012 because of insufficient enrolment
Heering 2004	Said to be RCT but some participants in the control group (chlorambucil) moved into the experimental group (CSA). Some participants were analysed in both groups. Unclear whether remission of proteinuria in the control group occurred during control therapy or after transfer to experimental therapy
Liu 2006	Terminated study: RCT comparing TAC in patients with FSGS terminated in 2012 because of insufficient enrolment
Liu 2016c	Wrong population: RCT but population included patients with several different types of glomerulonephritis and the results for FSGS cannot be separated
NCT01451489	Terminated study: Study comparing TAC with CPA terminated due to inadequate recruitment. 70 patients enrolled of 130 estimated
Ren 2013	Wrong population: RCT includes both patients with steroid‐sensitive and steroid‐resistant disease and the groups cannot be separated
Trachtman 2011	Unclear methodology: phase 1 study of fresolimumab in participants with FSGS. While entry to 2 of 4 groups was randomised, unclear how participants were allocated to the remaining groups

Methods	Study design: parallel, open‐label RCT
Participants	Inclusion criteria: 18 to 60 years at onset of signs or symptoms of FSGS; urine protein ≥ 3.5 g/24 hours; eGFR ≥ 40 mL/min/1.73 m²; SCr < 2.5 mg/dL; biopsy confirmed as idiopathic FSGS (including all subtypes); willingness to follow the clinical trial protocol, including medications, and baseline and follow‐up visits and procedures Number: 67 adult participants; original estimated enrolment 90 participants Exclusion criteria: secondary FSGS; prior therapy with sirolimus, CSA, MMF, AZA, cytoxan, chlorambucil, levamisole, methotrexate, or nitrogen mustard in the last 90 days; active/serious infection; malignancy; previously diagnosed as DM type 1 or 2, or abnormal carbohydrate tolerance; peripheral white blood cells < 3000/µL; clinical evidence of cirrhosis or chronic active liver diseases; history of significant GI disorder; allergy to study medications; inability to consent/assent
Interventions	Treatment group 1 Prednisone: 60 mg/m² for 8 weeks then Tripterygium wilfordii 120 mg/day plus prednisone 30 mg/day for 12 weeks Treatment group 2 Prednisone: 30 mg/m² for 8 weeks then Tripterygium wilfordii 120 mg/day plus prednisone 30 mg/day for 12 weeks
Outcomes	Primary outcome to measure efficacy and safety of prednisone and Tripterygium wilfordii
Notes	Study commenced January 2009 and completed in 2011. No publication of results identified Principal Investigator Zhi‐hong Liu, M.D, Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine

PERMALINK

Interventions for focal segmental glomerulosclerosis in adults

Elisabeth M Hodson

Aditi Sinha

Tess E Cooper

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. Cyclosporin versus different comparators for focal segmental glomerulosclerosis in adults.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

1. Serum and urine protein levels at presentation of FSGS.

Cyclosporin studies

Immunosuppressive agents

Other interventions

Ongoing studies

Studies awaiting classification

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Cyclosporin versus corticosteroids with/without other immunosuppressive agents

Complete remission of proteinuria

1.1. Analysis.

Partial remission of proteinuria

1.2. Analysis.

Complete or partial remission

1.3. Analysis.

Chronic kidney disease or kidney failure

1.4. Analysis.

1.5. Analysis.

Adverse effects

1.6. Analysis.

1.7. Analysis.

Methods	Study design: parallel RCT
Participants	Inclusion criteria: urinary protein ≥ 1.0 g/24 hours; biopsy‐proven FSGS; age ≥ 16years; understanding of the content of this study; signing informed consent form; adherence to drug‐taking and being able to be long‐term followed up Number: 40 adult participants Exclusion criteria: sharp deterioration of kidney function; refractory hypertension; secondary FSGS; serious disease of the liver; active stage of viral hepatitis; or AST; ALT ≥ 2.5 times of baseline; serious myelosuppression; unable to be long‐term followed up
Interventions	Treatment group Prednisone Initial 3 months, prednisone dosage is 30 mg/day In the following 4 to 6 months, prednisone dose decreased to 20 mg/day, then tapered gradually to 10 mg/day TAC the initial dosage is 0.2 mg/kg/day, twice/day The maintenance dosage is adjusted to the serum concentration of TAC (is maintained at the level of 6 to 10 μg/L) MMF Initial dosage is 1.0 g twice/day, then reduce to 0.75 g, twice/day after 3 months Control group Prednisone In the initial 16 to 24 weeks, prednisone is given at the full dose of 1mg/kg/day, then tapered gradually; the whole course of treatment is 52 weeks
Outcomes	Proteinuria at 16 to 24 weeks
Notes	Estimated completion date December 2012. No information provided after August 2009 so status of study unknown Request for more information sent to Dr Gui on July 30, 2020

Study name	ACTION. Safety and effectiveness of propagermanium (CCR2 receptor antagonist) in focal segmental glomerulosclerosis participants receiving irbesartan (AT1R receptor antagonist) to test the hypothesis that simultaneous antagonism of the angiotensin II receptor type 1 (AT1R) and the chemokine receptor 2 (CCR2) is beneficial in patients with primary FSGS
Methods	Double‐blind, placebo‐controlled, cross‐over RCT
Participants	Adults (18 to 80 years) with primary FSGS, who are already on irbesartan 300 mg/day for at least 3 months; eGFR > 25 mL/min/1.73 m² Mean of 2 UPCR values (screening and baseline) of ≥ 1326 mg/g (150 mg/mmol)
Interventions	Group 1 Treatment period 1: one propagermanium capsule twice/day for 16 weeks followed by a 6‐week washout period Treatment period 2: placebo capsule twice/day for 16 weeks Group 2 Treatment period 1: placebo capsule twice/day for 16 weeks followed by a six week washout period Treatment period 2: one propagermanium capsule twice/day for 16 weeks
Outcomes	Adverse effects Degree of proteinuria
Starting date	8 November 2018
Contact information	Dr Simon Roger, Gosford Research
Notes	Estimated completion date: June 2020. Confirmed that study completed but results not yet analysed. Information from Dr Simon Roger, chief investigator

Study name	Study of sparsentan in patients with primary focal segmental glomerulosclerosis (FSGS) (DUPLEX)
Methods	Multicentre, double‐blind, parallel, active‐control RCT
Participants	300 patients aged 8 to 75 years (USA); 18 to 75 years (outside USA) with biopsy‐proven FSGS or documentation of a genetic mutation in a podocyte protein associated with FSGS, UPCR > 1.5 g/g and GFR > 30 mL/min/1.73m² at screening Excluded if FSGS due to other conditions; rituximab, abatacept in previous 3 months; DM; cardiac/cerebrovascular disease, liver disease
Interventions	Intervention Sparsentan: 400 mg/day; titrating to 800 mg/day from week 108 to 112 Comparator Irbesartan 300 mg/day to week 108 to 112
Outcomes	Primary outcomes Slope of eGFR from 8 to 108 weeks Proportion of patients achieving a UPCR ≤ 1.5 g/g and a > 40% reduction from baseline in UPCR at week 36 Secondary outcomes Percentage change in eGFR from 6 weeks post‐randomisation at week 108 Percentage change in eGFR from baseline to 4 weeks post‐cessation of treatment at week 112
Starting date	March 29, 2018
Contact information	Study Director: Radko Komers, MD, PhD
Notes	Expected completion December 2022

Study name	Randomised controlled trial to evaluate rituximab compared with high dose prednisone (standard therapy) in patients with minimal change disease or focal segmental glomerulosclerosis
Methods	Parallel, open‐label RCT
Participants	40 patients aged >18 years Persistent proteinuria ≥ 2 g/ 24 hours or a UPCR ≥ 2 g/10 mmol (2 g/g) after 8 weeks of treatment with high dose prednisone 1 mg/kg/day (max 80 mg/day) Idiopathic nephrotic syndrome caused by biopsy‐proven MCD or FSGS
Interventions	Treatment group Rituximab (IV): 375 mg/m²on day 0 and day 14. B‐cells will be monitored weekly, and if no complete depletion is achieved, additional dose(s) of rituximab will be given at a weekly interval until complete B cell depletion (maximum of 2 additional doses) Control group Prednisone: 1 mg/kg/day (max 80 mg/day) for 8 weeks
Outcomes	Primary outcome Proportion of patients reaching complete remission defined as proteinuria < 0.3 g/day or < 300 mg/g Secondary outcomes Proportion of patients reaching partial remission defined as proteinuria < 3.5 g/24 hours or < 3.5 g/g and 50% lower than baseline proteinuria Late complete or partial remission Time to remission Time to relapse Proportion with relapse Proportion requiring additional immunosuppression
Starting date	22 August 2018
Contact information	Jeroen Deegens, MD,PhD. Jeroen.Deegens@radboudumc.nl; +31243614761
Notes	Estimated completion date 22 January 2021

Study name	PODOCYTE: treatment of treatment resistant or treatment intolerant idiopathic focal and segmental glomerulosclerosis
Methods	Parallel group RCT of patients with FSGS, who have achieved remission with 23 weeks of H.P. Acthar® Gel (repository corticotropin injection, RCI). Quadruple blind
Participants	,About 236 patients with nephrotic range proteinuria will be treated with RCI Those with complete, partial, or fractional decrease in proteinuria will be randomised Subjects who do not achieve remission may continue RCI in an open‐label extension
Interventions	Treatment group RCI 80 U twice/week or 24 weeks Control group Placebo for 24 weeks
Outcomes	Number maintaining remission Number with partial or fractional decrease in proteinuria achieving complete remission
Starting date	May 16, 2016. Estimated completion date June 2021
Contact information	Susan Vanmeter, Mallinckrodt Pharmaceuticals, Ellicott City,MD; Brad Rovin, Ohio State University Wexner Medical Center, Columbus, Ohio
Notes	NCT02633046

Study name	A Phase II randomised, placebo‐controlled, double‐blind, parallel arms with switchover, pilot study to evaluate the efficacy and safety of intravenous abatacept in treatment resistant nephrotic syndrome (focal segmental glomerulosclerosis/minimal change disease)
Methods	Placebo‐controlled RCT (quadruple blind)
Participants	Planned enrolment: 90 participants aged ≥ 6 years with treatment‐resistant nephrotic syndrome due to MCD or FSGS (collapsing FSGS excluded), GFR ≥ 45 mL/min/1.73 m² Exclusions: patients with recurrence of disease post‐transplant; secondary treatment‐resistant nephrotic syndrome, DM, chronic heart failure, BMI > 40, recent or chronic infection Patients stratified for age (< 18 and ≥ 18), APOL1 risk status Actual enrolment: 36 participants
Interventions	Group 1 16‐week parallel arms comparing IV abatacept and placebo (normal saline) on days 1, 14, 28 and then every 28 days Group 2 16‐week cross‐over with placebo group receiving abatacept and abatacept group receiving placebo Group 3 169‐day abatacept extension with all receiving abatacept Group 4 Weight‐tiered dose of abatacept from 500 to 1000 mg. Children < 18 years weighing < 75 kg will receive 10 mg/kg/dose Group 4 Standard immunosuppression (CNI, MMF, prednisone) unchanged in 1 month; ACEi, ARB
Outcomes	Difference in % of participants who achieve a renal response by 113 days (end of first 16‐week, parallel study). Renal response defined as a ≥ 50% reduction in UPCR from baseline to day 113 with UPCR < 3g/g and eGFR > 90 mL/min/1.73m² (if below normal at baseline, remaining ≥ 75% of baseline Change in proteinuria, GFR, remission, quality of life (PROMIS), adverse events
Starting date	1 March 2016. Actual completion date 28 January 2020. No results available
Contact information	Anna Greka: agreka@bwh.harvard.edu
Notes	27 study sites. NCT02592798. Sponsor: Bristol‐Myers Squibb

Study name	TURING. The use of rituximab in the treatment of nephrotic glomerulonephritis
Methods	Double‐blind, placebo‐controlled, phase III RCT to assess efficacy and safety of rituximab in de novo or relapsing nephrotic syndrome with biopsy‐proven MCD or FSGS previously treated with corticosteroids and CNIs
Participants	112 participants aged ≥ 16 years with nephrotic syndrome secondary to primary MCD or FSGS Minimum follow‐up 24 months
Interventions	Treatment group Rituximab 1 g at baseline, day 14 and at week 26 Control group Placebo at baseline, day 14 and at week 26
Outcomes	Primary outcomes Proportion achieving complete or partial remission, relapse Secondary outcomes Adverse effects, kidney function, change in proteinuria, health status
Starting date	01/11/2018. Estimated completion date 30/12/2025
Contact information	Dr Lisa Willcocks 01223 245151; Dr Megan Griffith 02083835272. Cambridge Clinical Trials Unit: add‐tr.turing@nhs.net
Notes	Eudrac 2018‐004611‐50; ISRCTN 16948923