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. 2020 Mar 12;2020(3):CD003965. doi: 10.1002/14651858.CD003965.pub3

Cruzado 2011.

Methods
  • Study design: parallel, 2‐arm RCT

  • Time frame: July 2006 to August 2009

  • Duration of follow‐up: 12 months

Participants
  • Setting: multicentre (3 sites)

  • Country: Spain

  • Inclusion criteria: biopsy proven IgAN diagnosed in the previous 3 months; age 18‐ to 70‐years old; absence of known hepatic, cardiac, pulmonary or intestinal disease; GFR estimated by Cockcroft‐Gault formula within 30 to 60 mL/min/1.73 m2; proteinuria >1 g/day; hypertension defined as SBP >140 mmHg or DBP >90 mmHg associated with proteinuria between 0.3 to 1 g/day

  • Number (analysed/randomised): treatment group (14/14); control group (9/9)

  • Mean age ± SD (years): treatment group (42 ± 11); control group (50 ± 9)

  • Sex (M/F): treatment group (12/2); control group (7/2)

  • Exclusion criteria: positive serology for HIV or hepatitis B virus infection or hepatitis C virus infection; treatment with steroids or any other immunosuppressant in the 2 previous years; evidence of active infection; pregnancy at the time of inclusion in the study; GFR < 30 mL/min/1.73 m2; serum bilirubin > 2 mg/dL; ALT and AST 2 times higher than the normal upper limit; DM; poor controlled hypertension or evidence or suspicion of renovascular disease; thrombocytopenia < 100,000/mm3 or total neutrophil counts < 2000/mm3; triglycerides > 4.6 mmol/L; cholesterol > 7.8 mmol/L; LDL > 5.2 mmol/L; systemic IgAN forms, i.e. HSP, IgAN secondary forms; cases presented in the form of rapidly progressive kidney failure; extra capillary proliferation > 50% at renal biopsy; use of any other medication under research; cancer diagnosis in the 5 previous years, except suitably removed skin basal cell carcinoma; known intolerance to sirolimus or macrolides

Interventions Treatment group
  • Sirolimus: initially 1 mg/day. Blood concentrations were monitored and the dose adjusted to be within 4 to 8 ng/mL


Control group
  • Usual care


Co‐interventions
  • Enalapril (and other antihypertensive medications) to lower BP < 130/80 mmHg

  • Atorvastatin to lower total cholesterol levels < 4.2 mmol/L

Outcomes
  • Variation of haematuria

  • Proteinuria

  • Change in the GFR

  • BP

  • Renal histology

  • Adverse events

  • ESKD ("dialysis‐free")

Notes
  • This research was performed in the context of The Red de Investigacio´n Renal (REDinREN, ISCIII 06/0016)

  • The study was approved by The Spanish Drug Agency

Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Insufficient information to permit judgement
Allocation concealment (selection bias) Unclear risk Permuted‐block randomisation with a block size of six and an allocation ratio of 1:1
Blinding of participants and personnel (performance bias) 
 All outcomes High risk Open‐label study
Blinding of outcome assessment (detection bias) 
 All outcomes High risk Blinding of outcome assessment not specifically reported. Key outcomes were objective laboratory measures and were unlikely to be affected by any knowledge of treatment allocation. Reporting of adverse events may have been influenced by knowledge of treatment allocation
Incomplete outcome data (attrition bias) 
 All outcomes Low risk All patient data were available
Selective reporting (reporting bias) Low risk All relevant outcomes, except death, were reported
Other bias High risk Recruitment terminated early due to lack of recruitment (achieved recruitment of 23 out of 30 planned participants). Participants in control group were older (imbalance of baseline characteristics)