Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes

Abstract

It has been 100 years since the life-saving discovery of insulin, yet daily management of type 1 diabetes (T1D) remains challenging. Even with closed-loop systems, the prevailing need for persons with T1D to attempt to match the kinetics of insulin activity with the kinetics of carbohydrate metabolism, alongside dynamic life factors affecting insulin requirements, results in the need for frequent interventions to adjust insulin dosages or consume carbohydrates to correct mismatches. Moreover, peripheral insulin dosing leaves the liver underinsulinized and hyperglucagonemic and peripheral tissues overinsulinized relative to their normal physiologic roles in glucose homeostasis. Disease-modifying therapies (DMT) to preserve and/or restore functional β-cell mass with controlled or corrected autoimmunity would simplify exogenous insulin need, thereby reducing disease mortality, morbidity, and management burdens. However, identifying effective DMTs for T1D has proven complex. There is some consensus that combination DMTs are needed for more meaningful clinical benefit. Other complexities are addressable with more innovative trial designs and logistics. While no DMT has yet been approved for marketing, existing regulatory guidance provides opportunities to further "de-risk" development. The T1D development ecosystem can accelerate progress by using more innovative ways for testing DMTs for T1D. This perspective outlines suggestions for accelerating evaluation of candidate T1D DMTs, including combination therapies, by use of innovative trial designs, enhanced logistical coordination of efforts, and regulatory guidance for expedited development, combination therapies, and adaptive designs.

Figure 1

Daunting “square peg” challenges and “rounding” opportunities for the clinical trials ecosystem for DMTs in T1D are best addressed collectively in trials design. For disease risks, broad expert consensus exists that combination DMTs will be needed for durable, more clinically meaningful effects. Baseline biomarkers are available as stratification factors to ameliorate heterogeneity issues. The potential exists for extensive, systematic biomarker data mining and validation across trials to rapidly inform progress and define decision criteria for subsequent trials. Available biomarkers have shown correlation with important clinical outcomes, and further biomarker research/validation can be incorporated into clinical program plans and platform protocols for careful dose selection, early proof of concept, and confirmatory clinical efficacy. C-peptide AUC is a widely accepted clinical end point and can be used at 6-month intervals. Factors to manage trial risks are broader use of adaptive designs, early dose-finding designs, factorial designs, and platform protocols for purpose-built speed and efficiency. In terms of logistical risks, platform protocols are working well in other indications (e.g., pancreatic cancer), with emerging efforts in T1D via INNODIA, T1DUK, and Global Platform for the Prevention of Autoimmune Diabetes. Global, adaptive platform protocols are needed for early (phase 1/2a) and late (phase 2b/3) product development. Concerning regulatory risks, T1D qualifies as a serious disease, availing expedited regulatory support. Adaptive designs have been well accepted in other indications, and there are multiple facilitative regulatory guidelines for treatment combinations.

Figure 2

Conceptual comparison of traditional and innovative program plans for a combination DMT in new-onset T1D to achieve a New Drug Application (NDA) or Biologics Licensing Application (BLA). Both programs provide randomized, treatment-masked phase 2 and phase 3 designs, with inferences powered for 0.5 SD effect sizes for main effect tests (phase 2: 85% power; phase 3: 90% power). The innovative program plan makes full use of the adaptive designs and logistics ideas described here. The phase 2 factorial design provides inferences for A and B main effects as well as an estimate of synergy sufficient to support a conditional power calculation for a phase 3 A+B versus SOC/placebo inference. First, a SAD–MAD combination trial with constituent 1 and constituent 2 would initiate the clinical program (program month 1). Positive interim results from an interim analysis of the SAD–MAD cohorts (3-month safety and robust early biomarker effects) could support application for breakthrough designation (program month 9). Second, a phase 2/3 adaptive trial of constituent 1 and constituent 2, where the phase 2 portion is a 2 × 2 factorial design, including the combination group, the two monotherapy groups, and a placebo group, initiated based on 6-month follow-up data from the last SAD–MAD dose–escalation cohort (no later than program month 15). The phase 3 portion would be a two-group comparison of the combination versus placebo, initiated based on a phase 2 interim safety and efficacy analysis (of accrued safety data and 6-month stimulated C-peptide AUC) at program month 30. Both the SAD–MAD study and the phase 2/3 study would be planned for up to 3 years of follow-up. However, the decision point for starting the phase 3 portion would be positive phase 2 interim safety and efficacy analysis at 15 months from phase 2 first patient first visit (program month 30). This information, along with longer-term SAD–MAD follow-up data, may then support an application for accelerated approval. The marketing application would be based on a phase 3 interim analysis planned at the 1-year follow-up. With the results supporting expedited review for accelerated approval, the marketing application could be as early as program month 45. Final approval (following an earlier conditional approval) might be based on the 3-year follow-up results from the phase 2/3 design (at program month 70). The traditional program is exemplified by typical “white space” between studies and parallel phase 2 and 3 designs where synergy is not estimable.