Artificial pancreas treatment for outpatients with type 1 diabetes: systematic review and meta-analysis

Abstract Objective To evaluate the efficacy and safety of artificial pancreas treatment in non-pregnant outpatients with type 1 diabetes. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Medline, Embase, Cochrane Library, and grey literature up to 2 February 2018. Eligibility criteria for selecting studies Randomised controlled trials in non-pregnant outpatients with type 1 diabetes that compared the use of any artificial pancreas system with any type of insulin based treatment. Primary outcome was proportion (%) of time that sensor glucose level was within the near normoglycaemic range (3.9-10 mmol/L). Secondary outcomes included proportion (%) of time that sensor glucose level was above 10 mmol/L or below 3.9 mmol/L, low blood glucose index overnight, mean sensor glucose level, total daily insulin needs, and glycated haemoglobin. The Cochrane Collaboration risk of bias tool was used to assess study quality. Results 40 studies (1027 participants with data for 44 comparisons) were included in the meta-analysis. 35 comparisons assessed a single hormone artificial pancreas system, whereas nine comparisons assessed a dual hormone system. Only nine studies were at low risk of bias. Proportion of time in the near normoglycaemic range (3.9-10.0 mmol/L) was significantly higher with artificial pancreas use, both overnight (weighted mean difference 15.15%, 95% confidence interval 12.21% to 18.09%) and over a 24 hour period (9.62%, 7.54% to 11.7%). Artificial pancreas systems had a favourable effect on the proportion of time with sensor glucose level above 10 mmol/L (−8.52%, −11.14% to −5.9%) or below 3.9 mmol/L (−1.49%, −1.86% to −1.11%) over 24 hours, compared with control treatment. Robustness of findings for the primary outcome was verified in sensitivity analyses, by including only trials at low risk of bias (11.64%, 9.1% to 14.18%) or trials under unsupervised, normal living conditions (10.42%, 8.63% to 12.2%). Results were consistent in a subgroup analysis both for single hormone and dual hormone artificial pancreas systems. Conclusions Artificial pancreas systems are an efficacious and safe approach for treating outpatients with type 1 diabetes. The main limitations of current research evidence on artificial pancreas systems are related to inconsistency in outcome reporting, small sample size, and short follow-up duration of individual trials.


Intervention
• Any closed-loop delivery system, defined as a system utilising a control algorithm, which autonomously increases and decreases insulin delivery based on real-time sensor glucose concentrations, assessed either during daytime, overnight period, or the day-and-night period.

Comparators
• Any type of insulin based therapy, including multiple daily injections (MDI), insulin pump therapy, sensor-augmented insulin pump therapy, sensor-augmented insulin pump with a low glucose suspend (LGS) feature.

Outcomes
Primary outcome: Proportion of time that glucose level was within the near normoglycaemic range (3.9 -10 mmol/l) (both overnight, and during a 24h period).
Secondary outcomes: • % of time during day and night (24h) or night only that glucose level was below 3.9 mmol/l • % of time during day and night (24h) or night only that glucose level was above 10 mmol/l • area under the curve (AUC) of glucose < 3.5 mmol/l • low blood glucose index (LBGI) • Mean blood glucose levels • HbA1c • Insulin amount administered

Study design
Randomised controlled trials, with parallel group or cross-over design, irrespective of duration of intervention.

Search strategy
Search strategy based only on the intervention (Closed-loop system) and a filter for randomised trials, to avoid missing potentially relevant studies, as recommended in the Centre for Reviews and Dissemination (CRD) guidance for undertaking reviews in health care and the Cochrane Handbook. We will use search terms that have been identified from initial scoping searches, target references and browsing of database thesauri (i.e. Medline MeSH and Embase Emtree). We have developed search strategies specifically for each database based on the search features and controlled vocabulary of every individual bibliographic database. We will search the following databases and resources (via relevant interfaces): • Cochrane Database of Systematic Reviews (CDSR) (Wiley Online Library) • Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley Online Library) We will also look for completed and on-going trials by searching the NIH ClinicalTrials.gov (http://www.clinicaltrials.gov/) trial registry.
We will impose no restrictions based on language or publication status. References identified will be imported in Endnote reference management software for de-duplication. Finally, we will export potentially eligible records to Covidence™ for further handling (screening and data extraction).

Study selection & data collection
All records will be screened via Covidence™, by two reviewers, working independently, and disagreements will be arbitrated by a senior team member. Initially, records will be screened at title and abstract level. Full texts for potentially eligible studies will be imported into Covidence™ and screened as described previously. Finally, we will extract data for the following variables: study and participant baseline characteristics, details for the interventions (i.e. single-hormone, algorithm utilised) and comparators, and clinical outcomes. Data will be extracted by two reviewers, using a piloted, data extraction form. Disagreements will be resolved by consensus or following discussion with a senior reviewer. For crossover studies that report their results as parallel group trials, we will use appropriate methodology to impute within-patient differences.

Study quality assessment
We will assess the methodological quality of included RCTs using the Cochrane Risk of Bias Tool. For crossover studies we will use a modified version to assess a series of methodological challenges that are linked with this specific design. We will use results for descriptive purposes to provide an evaluation of the overall quality of the included studies, but also to inform a sensitivity analysis. Quality assessment will be undertaken by two independent reviewers, and disagreements will be resolved by consensus or arbitrated by a third reviewer.

Methods of analysis
We will combine data both from parallel group and cross-over studies if appropriate. We will calculate mean differences with 95% confidence intervals, using an inverse-variance weighted random effects model.

Subgroup analyses
Depending on accrued evidence, for the primary outcome we plan to conduct subgroup analyses based on mode of intervention (overnight or 24h use of closed-loop delivery system), and type of closed-loop (single vs dual-hormone closed-loop).

Sensitivity analyses
We will do sensitivity analysis for the primary outcome excluding trials at unclear or high risk of bias, trials conducted at other settings than home or hotel, and supervised trials.

Investigation of heterogeneity
We will assess presence of statistical heterogeneity by means of the chi-square-based Cochran Q test and the magnitude of heterogeneity by means of the I 2 statistic, with P values < 0.10 and I 2 > 50% respectively representing high heterogeneity. All analyses will be undertaken in Revman.
This protocol was submitted as a module assignment for the Systematic Review module for an MSc on Medical Research Methodology at Aristotle University Thessaloniki, and internally peer reviewed.

Protocol and
registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. 3, appendix 1 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. 4 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. 3, 4 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. Appendix 3 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). 4 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. 4, appendix 4 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 4

Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

Study selection
17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. 5, Figure 1 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

Data extraction form
For every trial we extracted the following information: We also extracted data (see below) for the following outcomes:

Identifier
• % of overnight time glucose was between 3.9 -10.0 mmol/l • % of day and overnight time (24h) glucose was between 3.9 -10.0 mmol/l • % of overnight time glucose was below 3.9 mmol/l • % of day and overnight time (24h) glucose was below 3.9 mmol/l