Methods

Trial design: randomised controlled trial

Trial grouping: parallel group

Participants

Baseline characteristics

GH group

Gender: male (n = 6), female (n = 4)

Age (mean (SD): 11.66 (0.96) years

Height SDS (mean (SD): ‐3.15 (0.29)

Height velocity (mean (SD): 2.47 (0.48) cm/year

Height velocity SDS (mean (SD): ‐3.42 (0.79)

Bone age (mean (SD): 7.86 (0.52) years

Hemoglobin (mean (SD): 10.22 (2.3) g/dL

Ferritin (mean (SD): 1466.20 (260.82) ng/mL

Plasma zinc (mean (SD): 91.82 (11.22) μg/dL

FBG (mean (SD): 70.20 (9.18) mg/dL

OGTT sum (mean (SD): 347.70 (39.23) mg/dL

Thyroxine (mean (SD):8.3 (1.1)μg/dL

TSH (mean (SD): 3.33 (3.1) mU/mL

IGF‐1 (mean (SD)): 47.44 (9.96) ng/mL

Control group (no GH therapy)

Gender: male (n = 10), female (n = 0)

Age (mean (SD): 11.17 (0.89) years

Height SDS (mean (SD): ‐2.79 (0.17)

Height velocity (mean (SD): 2.86 (0.39) cm/year

Height velocity SDS (mean (SD): ‐3.32 (0.63)

Bone age (mean (SD): 7.85 (0.61) years

Hemoglobin (mean (SD): 9.50 (1.82) g/dL

Ferritin (mean (SD): 1602.20 (234.15) ng/mL

Plasma zinc (mean (SD): 104.10 (20.27) μg/dL

FBG (mean (SD): 73.71 (11.82) mg/dL

OGTT sum (mean (SD): 340.71 (31.76) mg/dL

Thyroxine (mean (SD): 8.14 (2.2) μg/dL

TSH (mean (SD): 3.27 (1.2) mU/mL

IGF‐1 (mean (SD): 47.79 (11.43) ng/mL

Inclusion criteria: homozygous β thalassemia, short stature (height below – 2 SD for age, height velocity below 25th percentile and bone age delay of more than 2 years).

Exclusion criteria: biochemical decompensated clinical hypothyroidism (low thyroxine, elevated basal TSH) and glucose intolerance (fasting glucose >115 mg/dL, OGTT sum >400 mg/dL, 2 hour OGTT >140 mg/dL).

Pre‐treatment: no major differences between groups with the exception of the gender distribution between both groups.

Comment: it was unclear whether the participants fulfilled the diagnostic criteria of having GH deficiency, as their GH status at baseline was not available.

Interventions

GH group: recombinant GH (Genotropin, Pharmacia) administered subcutaneously on a daily basis at a dose of 0.7 IU/kg per week for a duration of 12 months in addition to standard treatment

Control group: standard treatment

Outcomes

Height velocity (cm/year): continuous data, fully reported, measured in cm/year

Height velocity SDS: continuous data, fully reported

Change from baseline to final visit in height velocity SDS: continuous data

Height SDS: continuous data

Change from baseline to final visit in height SDS: continuous data

Number of participants with adverse events (esp glucose tolerance and thyroid function): dichotomous data

FBG (mg/dL): continuous data

OGTT sum (mg/dL): continuous data

Identification

Sponsorship source: supported in part by Pharmacia‐Upjohn and Ankara Thalassemia Society

Country: Turkey

Setting: paediatric department of a tertiary hospital

Authors name: Ayten Arcasoy (first author)

Institution: Department of Pediatrics, Divisions of Pediatric Hematology and Pediatric Endocrinology, Faculty of Medicine, Ankara University, Ankara, Turkey

Email: [email protected] (Corresponding author Dr Merih Berberolu)

Address: 59. Sokak 10/6 Emek, 06510 Ankara, Turkey

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Randomization of the patients was made with closed envelopes for each patient."

Judgement comment: methods of random sequence generation was not stated.

Allocation concealment (selection bias)

Unclear risk

Comment: sealed envelopes were used for the concealment of allocation as the authors stated that "Randomization of the patients was made with closed envelopes". However, it was not stated if these envelopes were opaque to fully conceal the allocation.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: although not clearly stated, blinding of participants and personnel appeared highly unlikely, as GH was administered subcutaneously. However, we considered the lack of blinding to be unlikely to affect the growth outcomes in this particular group of patients, as the growth of this group of children was not known to be readily influenced by any form of known co‐intervention.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: it was not stated who the assessors of the growth outcomes were, and whether the assessors were blinded to the allocation status of the participants. However, we considered this as unlikely to influence the growth outcomes, which were objectively measured.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: the authors stated that all 20 participants were followed up till trial completion, although it was unclear whether all data were available for analysis for all participants at all periods of measurement.

Selective reporting (reporting bias)

Low risk

Comment: the main outcomes defined in the review methodology (growth response and side effects) were reported in sufficient detail. In terms of growth response, the height and height velocity measurements and SDSs were reported with means and standard deviations after the 12‐month period as defined in the methodology. The side effects which were reported such as effects on glucose metabolism and thyroid function are reasonable given the relatively short period of the trial.

Other bias

Unclear risk

Comment: there was a gender imbalance in the 2 groups (10 males in the control group and six boys and four girls in the intervention group) which may raise issues in the applicability of the evidence. The trial was sponsored by a pharmaceutical company but there is no clear evidence that this affect the overall risk of bias in the trial.