Führer 1998.

Methods	Duration From 1993 to 1997 (update 1993 to 2001) Randomization Allocation compatible with 'Mendelian randomization' Treatment Number of arms: 2 Type of intervention Test arm: MSD‐HSCT Control arm: IST Median follow‐up time Not reported
Participants	Setting Multi‐center study Germany and Austria Eligibility criteria Less than 17 years of age ("Two hundred and thirteen patients newly diagnosed with SAA younger than the age of 17 years"). "By biologic selection depending on the availability of an MSD, patients were assigned to either the BMT or the IST group." "The diagnosis of SAA was based on morphology and blood counts." "Fanconi anemia was excluded by chromosomal fragility test." Number of patients Total participants: N = 116 (update N = 213) HSCT arm: N = 28; 25 patients received HSCT from MSD, 3 patients received HSCT from other donors (update N = 67; 62 patients received MSD‐HSCT, in the remaining 5 patients, parents refused HSCT) IST arm: N = 86; 86 patients received ciclosporin and antilymphocyte globulin (update N = 146; 151 patients were treated with horse antithymocyte globulin and ciclosporin including 5 patients with an MSD who were assigned to the HSCT arm in the first place but changed treatment arm after the parents refused HSCT Age MSD‐HSCT arm: 10.1 (range 2.3 to 15.8) years IST arm: 9.1 (range 0.9 to 15.2) years Gender MSD‐HSCT arm: males 43% (12 of 28) patients IST arm: males 62% (53 of 86) patients Further inclusion criteria to define SAA Criteria for the diagnosis of SAA: "They all met the internationally accepted diagnostic criteria. Patients were stratified into 3 groups according to severity of disease. Severity depends on PMN counts (VSAA: PMN <200/μI; SAA: PMN <500/μI; not severe aplastic anemia: >500/μI)."
Interventions	Interval from diagnosis to treatment MSD‐HSCT arm: median 49 (range 18 to 272) days IST arm: median 23 (range 3 to 168) days MSD‐HSCT arm Patients received MSD‐HSCT from 1993 to 1997 (update 1993 to 2001) Interval from diagnosis to treatment: not reported Previous therapy: none reported Discontinuation of treatment not reported, no criteria defined Bone marrow was the stem cell source for all recipients IST arm Patients received IST from 1993 to 1997 (update 1993 to 2001) Interval from diagnosis to treatment: not reported Previous therapy: none reported Discontinuation of treatment not reported, no criteria defined ATG: treatment consisted of 1 dose of equine anti‐human thymocyte globulin per day (0.75 ml/kg/day) for 8 days Ciclosporin: treatment consisted of 2 doses per day (5 mg/kg/day) for at least 6 months
Outcomes	Primary outcome Overall survival Secondary outcomes Event‐free survival Treatment response New clonal disease after treatment
Notes	Financial support was provided by 2 pharmaceutical companies ("The SAA 94 study was supported by AMGEN andJMTIX"). Amgen Inc. is headquartered in Thousand Oaks, California, USA and a manufacturer of filgrastim, a human granulocyte colony‐stimulating factor (G‐CSF). The authors stated that G‐CSF was given in addition to IST but did not mention the manufacturer in the methods chapter. The type of support, such as providing G‐CSF or financial support, was not specified.
Risk of bias
Bias	Authors' judgement	Support for judgement
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding of outcome assessor was not reported for any outcome
Incomplete outcome data (attrition bias) All outcomes	High risk	In the 2005 update, 7.5% (5 of 67) patients assigned to the MSD‐HSCT group dropped out because the parents refused the treatment. "Sixty‐two patients received BMT after a conditioning treatment with ATG (...) and cyclophosphamide (...). In the remaining 5 patients, 3 with SAA and 2 with vSAA, parents refused BMT."
Selective reporting (reporting bias)	High risk	In the 2005 update, overall survival, secondary clonal disease or malignancies, and also relapse were not reported separately for the 2 distinct treatment groups. Rather, the results were presented for 2 subgroups according to disease severity. This was different from the earlier report of the same study published in 1998 covering the study period from 1993 to 1997. See Fig. 1 and Tab. 1 of the article. "In 137 (64%) of 213 patients very SAA was diagnosed. Within the BMT group, patients with very SAA (N = 40) and with SAA (N = 27) reached comparable survival rates (5‐year survival rate: very SAA 89% (95% CI 80% to 99%); SAA 96% (95% CI 89% to 100%)."
Other bias	High risk	Financial support was provided by 2 pharmaceutical companies. "The SAA 94 study was supported by AMGEN and JMTIX".
Comparable baseline characteristics	Low risk	There were no differences in baseline characteristics between the 2 treatment groups, in particular with reference to age. See Table 1 and Table 2 of the 1998 article.
Concurrent control	Low risk	Data for the control group were collected during the same time period as the data for the test group. "Two hundred and thirteen patients newly diagnosed with SAA younger than the age of 17 years in 53 centers in Germany and Austria were included in the study between November 1993 and December 2001."