Statistical analysis
The original sample size of the study was set up to have 80% power to detect a treatment effect of between 1·1 points and 1·3 points on the primary efficacy outcome at a two-sided significance level (α) of 0·05. The original study hypothesis was that there would be a difference between the CAP-1002 and placebo groups of greater than a 1-point change from baseline at the 12-month timepoint in functional capacity as assessed by the mid-level elbow dimension of PUL 1.2. The original study protocol included targeted enrolment of 84 patients to ensure 76 evaluable patients. All statistical tests were two-sided and p values of 0·05 or less were considered statistically significant. The primary efficacy outcome was the only outcome prespecified for formal statistical testing at the conclusion of the study, so other reported p values are considered nominal values unadjusted for multiple testing. Secondary and exploratory outcomes were evaluated in a similar manner to the primary outcome. The safety population was defined as all individuals who received an investigational product. The intention-to-treat population, in which all efficacy outcomes were evaluated, was defined as all individuals who were randomised.
A parametric linear mixed model repeated measures (MMRM) was the prespecified analysis originally performed for all primary, secondary, and exploratory endpoints of the study. A blinded 6-month interim analysis was prespecified after 20 patients were enrolled for futility, because this was the first trial to evaluate repeated intravenous administration of CAP-1002. Due to funding constraints, the trial sponsor elected to pause enrolment in the trial before the interim analysis for futility. Based on the interim analysis and review by the data safety monitoring board, which supported lack of concerning safety signals and lack of futility, the sponsor elected to amend the protocol to reduce enrolment to the 20 already randomised patients. The decision was made to not enrol the full 84-patient cohort due to important input from the US Food and Drug Administration, which recommended transitioning as quickly as possible to a phase 3 trial that would be powered based on the forthcoming 12-month HOPE-2 trial data. All HOPE-2 patients were offered treatment beyond 12 months in an open-label extension protocol (ClinicalTrials.gov, NCT04428476).
Because of the smaller sample size, model residuals were inspected and found to fail the normality assumptions for a parametric MMRM (appendix p 14). Therefore, HOPE-2 data were fitted using a non-parametric version of the prespecified model with change from baseline and baseline values converted to a percentile rank over all timepoints and at baseline (appendix pp 15–16). For a given outcome, this is generated by calculating the percentile rank of each change-from-baseline value relative to all observed change-from-baseline values for the same outcome (across all patients and all post-baseline observation times). The percentile ranked change from baseline was treated as the dependent variable in the regression. This modelling approach was used for primary, secondary, and exploratory endpoints. For PUL and cardiac MRI outcomes, a global statistical test18 was calculated as the averaged percentile ranked change from baseline. Analyses were performed with SAS software, version 9.4. This trial is registered with ClinicalTrials.gov, NCT03406780.
The above is from the lancet re the CAP HOPE-2 results. Basically the trial was designed from data gained by mouse study, and reliant on 84 participants. Due to CAP being a small bio tech company, when an opportunity to fast track approval was offered, they cut this trial to 20 participants. This meant that the data gained would no longer fit the trial design model, so it was "fitted" or "normalised" to better fit end points.
The methodbof dosing for this drug requires hospitalisation, and high dosage of steroids (higher than normal SOC) at various points prior to and after infusion, to prevent any anaphylaxis. They also infuse a one off dose into the cardiac artery to help the heart. The high dose steroid is an FDA requirement for safety following an adverse event in one trial patient.
The CAP trial is for non-ambulant boys aged over 10yrs of age, with end points aimed at upper body strength using PUL2. They have a pretty restrictive screening profile for the trial, with the aim of showing delay in reduced mobility.
Cost of this treatment would be significantly more than that of ATL1102 due to it being more intrusive with hospitalisation being required, and the requirements for high dose steriods.
This treatment is also aimed at the reduction of inflammation rather than increasing dystrophin. Although they refer to the present trial as a phase 3 trial, it is effectively the same as the ANP phase 2b trial, as they are both looking for an accelerated approval pathway. Trial designs are very similar, as both are double blinded placebo controlled, followed with extension trial.
ATL1102, aimed at CD49+, would seem to have more platform drug potential, I say that based purely on the targeted bio markers. However, CAP haven't researched other applications for their drug yet.
Both drugs seem to hold potential. Endpoints for both arent too far apart. And recent trials tend to suggest that the treatment of fibrosis, which both drugs do, may be the key for DMD.
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