DMD杜氏肌萎缩症基因型和运动功能

Examples of Trial Designs Incorporating Genotypically Mixed or Unmatched Controls (A) Hypothetical randomized, parallel group, blinded platform trial of multiple genotype-specific investigational therapies. In this hypothetical platform trial, patients are enrolled from 4 genotype groups (A–D) that are each amenable to 1 of 4 trialed genotype-specific investigational therapies. Patients in each genotype group are blinded to treatment assignment and randomly assigned to 1 of the 4 genotype-specific therapies or to a mixed-genotype common placebo arm in a 4:1 ratio. Comparisons of each genotype-specific therapy vs placebo are based on the shared, genotype-mixed control arm, adjusting for the genotype mix as outlined in Figure 5. This trial design could include strictly concurrent genotype-specific treatment groups (e.g., if run by a single sponsor with a multigenotype pipeline) or could admit nonconcurrent genotype-specific treatment arms (e.g., including different mechanisms and drug developers over time). The use of a shared, genotype-mixed control arm enables blinding and may reduce the overall sample size needed and the number of patients from each genotype group that are required to be assigned to placebo. (B) Hypothetical hybrid trial of a genotype-specific investigational therapy using (1) randomized genotype-matched, (2) external genotype-unmatched or (3) external mixed genotype controls. A trial of a genotype-specific investigational therapy may include different control groups: (1) concurrent, randomized, and blinded genotype-matched controls (possibly with a 1:4 or other reduced ratio of those receiving control vs active therapy), (2) external, genotype-unmatched controls, or (3) external, mixed genotype controls. Hybrid control groups can be composed of type (1) in addition to type (2) and/or type (3). Comparisons of the genotype-specific investigational therapy vs these external or hybrid control groups will require adjustment for genotype differences between groups as outlined in Figure 5 and consideration of the risk of bias due to lack of randomization and lack of blinding. In the absence of randomization, comparisons should adjust for baseline prognostic factors to mitigate the risk of bias. Bias due to unmeasured confounding cannot be ruled out in these designs, but the impacts of different magnitudes of confounding on treatment effects may be explored.⁴⁸ The risks of unblinded designs should be considered carefully, and in light of evidence showing that functional outcomes in DMD have not differed between blinded placebo arms, natural history, and real-world settings, and that adjustment for strong baseline prognostic factors can mitigate bias.⁴⁹ Inclusion of at least some randomized and blinded controls is preferred to allow direct assessment of these risks of bias.