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. 2021 Mar 4;2021(3):CD013498. doi: 10.1002/14651858.CD013498.pub2

Risk of bias for analysis 1.24 Mild/moderate hypoglycaemia.

Study Bias
Randomisation process Deviations from intended interventions Missing outcome data Measurement of the outcome Selection of the reported results Overall
Authors' judgement Support for judgement Authors' judgement Support for judgement Authors' judgement Support for judgement Authors' judgement Support for judgement Authors' judgement Support for judgement Authors' judgement Support for judgement
Subgroup 1.24.1 Adults
Bartley 2008 Low risk of bias Randomisation was carried out using a telephone randomisation system (Interactive Voice Response System (IVRS)). There were no relevant baseline imbalances. Low risk of bias Open‐label trial design. A modified intention‐to‐treat analysis was applied (all randomised participants exposed to at least one dose of trial product). Low risk of bias Withdrawals and reasons for withdrawal were documented, did not differ substantially between intervention groups and did not appear to be related to health status. Modified intention‐to‐treat analysis (ITT) was used as the primary analysis for both efficacy and safety. Missing observations were considered missing at random in all analyses. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions. Low risk of bias Data from full clinical study report. Only one measurement and result provided for the time point selected by review authors. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions.
Kobayashi 2007 Low risk of bias Randomised, multi‐centre, open‐labelled, parallel‐group trial. No details were provided in the clinical study synopsis. Because this study was performed in cooperation with Novo Nordisk it is likely that randomisation and concealment of allocation were performed adequately. There were no relevant baseline imbalances. Low risk of bias Open‐label trial design. All participants who received at least one dose of trial product were included in the safety analysis. For all efficacy endpoints the analysis was performed on the full analysis set (FAS). Low risk of bias Withdrawals and reasons for withdrawal were documented, did not differ substantially between intervention groups and did not appear to be related to health status. All participants who received at least one dose of trial product were included in the safety analysis. For all efficacy endpoints the analysis was performed on the full analysis set (FAS). The FAS consisted of all randomised participants who had any available efficacy data after receiving the trial product. The last observation carried forward (LOCF) approach was used for all endpoints at week 48 for participants who had at least one valid post‐baseline measurement. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions. Low risk of bias Data from clinical study synopsis and some translated pages from the clinical study report. Only one measurement and result provided for the time point selected by review authors. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions.
Russell‐Jones 2004 Low risk of bias Randomisation was carried out using a telephone randomisation system, the Interactive Voice Response System (IVRS). Block randomisation within individual trial sites was handled by the system. There were no relevant baseline imbalances. Low risk of bias Open‐label trial design. A modified intention‐to‐treat analysis was applied (all participants exposed to at least one dose of trial product). Low risk of bias Withdrawals and reasons for withdrawal were documented, did not differ substantially between intervention groups and did not appear to be related to health status. Modified intention‐to‐treat analysis (ITT) set was used (all exposed participants were analysed). Missing observations were considered missing at random in all analyses. All primary and secondary efficacy analyses were based on the ITT analysis set. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions. Low risk of bias Data from full clinical study report. Only one measurement and result provided for the time point selected by review authors. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions.
Standl 2004 Low risk of bias Randomisation was carried out using a telephone randomisation system (Interactive Voice Response System (IVRS)). There were no relevant baseline imbalances. Low risk of bias Open‐label trial design. A modified intention‐to‐treat analysis was applied (all randomised participants exposed to at least one dose of trial product). Low risk of bias Withdrawals and reasons for withdrawal were documented, did not differ substantially between intervention groups and did not appear to be related to health status. Modified intention‐to‐treat analysis set was used (all exposed participants were analysed). Missing observations were considered missing at random in all analyses. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions. Low risk of bias Data from full clinical study report. Only one measurement and result provided for the time point selected by review authors. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions.
Vague 2003 Low risk of bias Randomisation was carried out using a telephone randomisation system (Interactive Voice Response System (IVRS)). There were no relevant baseline imbalances. Low risk of bias Open‐label trial design. A modified intention‐to‐treat analysis was applied (all randomised participants exposed to at least one dose of trial product). Low risk of bias Withdrawals and reasons for withdrawal were documented, did not differ substantially between intervention groups and did not appear to be related to health status. Modified intention‐to‐treat analysis set was used (all exposed participants were analysed). Missing observations were considered missing at random in all analyses. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions. Low risk of bias Data from full clinical study report. Only one measurement and result provided for the time point selected by review authors. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions.
Subgroup 1.24.2 Children
NCT00605137 Low risk of bias Randomisation codes were prepared by a responsible person for randomisation and carried out by the registration centre. Randomisation was stratified by type of bolus insulin. Minor baseline differences did not indicate a problem with randomisation. Low risk of bias Open‐label trial design. For all efficacy endpoints the analyses were performed on a full analysis set (FAS), i.e. all randomised participants who had any available efficacy data after receiving the trial product. Low risk of bias Withdrawals and reasons for withdrawal were documented, did not differ substantially between intervention groups and did not appear to be related to health status. For all efficacy endpoints the analyses were performed on a full analysis set (FAS), i.e. all randomised participants who had any available efficacy data after receiving the trial product. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions. Low risk of bias Data from study protocol, clinical study synopsis and some translated pages of the clinical study report. Only one measurement and result provided for the time point selected by review authors. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions.
Robertson 2007 Low risk of bias Randomisation was carried out using a telephone randomisation system (Interactive Voice Response System (IVRS)). There were no relevant baseline imbalances. Low risk of bias Open‐label trial design. A modified intention‐to‐treat analysis was applied (all randomised participants exposed to at least one dose of trial product). Low risk of bias Withdrawals and reasons for withdrawal were documented, did not differ substantially between intervention groups and did not appear to be related to health status. Modified intention‐to‐treat analysis set was used (all exposed participants were analysed). Missing observations were considered missing at random in all analyses. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions. Low risk of bias Data from full clinical study report. Only one measurement and result provided for the time point selected by review authors. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions.
Thalange 2013 Low risk of bias Randomisation was carried out using a telephone/web based randomisation system called Interactive Voice Response System (IVRS)/Interactive Web Response System (IWRS). Stratification was applied by age group (2‐5 and 6‐16 years old). There were no relevant baseline imbalances. Low risk of bias Open‐label trial design. A modified intention‐to‐treat analysis was applied (all participants exposed to at least one dose of trial product with a post‐baseline observation). Low risk of bias Withdrawals and reasons for withdrawal were documented, did not differ substantially between intervention groups and did not appear to be related to health status. Modified intention‐to‐treat analysis set was used (all exposed participants were analysed). Missing observations were considered missing at random in all analyses. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions. Low risk of bias Data from full clinical study report. Only one measurement and result provided for the time point selected by review authors. Some concerns Open‐label design. Outcome measure could have been influenced by knowledge of the intervention received. It it unlikely that there were strong beliefs in beneficial or harmful effects of the interventions.