Table 1

Recommendations for design of pivotal trials designed to show long-term efficacy and safety of AP systems

Design considerationRecommendationAlternativeComment
RCT typeParallelCrossoverCrossover design requires long washout for HbA1c outcome
Study populationRepresentative of population, patients who use multiple daily injections and continuous subcutaneous insulin infusion, with few exclusionsAdults only, high-risk patients excludedGiven the potential for off-label use, the FDA may not approve if the device is not demonstrated to be safe in a broad population and payers may limit coverage to only the population that was studied
Randomization (AP:control)2:11:12:1 randomization provides greater exposure to AP; 1:1 randomization will require a smaller sample size or give greater power for same sample size if equal variance
Control groupUsual careSAPBoth scientifically valid, usual care has numerous pragmatic advantages (see text)
Superiority vs. noninferioritySuperiorityNoninferiorityNoninferiority may be sufficient for approval but is not likely to drive reimbursement and adoption
Run-in periodBlinded CGMUnblinded CGM (SAP training)Unblinded run-in must be sufficient to achieve competency for SAP trial enrolling non-SAP users
Duration6–12 months3 months3 months minimum for HbA1c, longer duration shows continuation of use and durability of effect
Primary outcome(s)HbA1c, time <60 mg/dLHbA1c onlyHbA1c does not capture hypoglycemia; CGM more reliable and quantitative than participant recall