Thomas R. Fleming’s research while affiliated with University of Washington and other places

In randomized clinical trials, stopping study medication, use of rescue treatment, and other intercurrent events can complicate interpretation of results. The ICH E9(R1) Addendum on estimands stimulated important cross‐disciplinary discussions on trial objectives. Unfortunately, with influence of the Addendum, many trials have proposed analyzing primary endpoints using “while on treatment”, “hypothetical”, or “principal stratum” strategies that handle intercurrent events in ways that use post‐randomization outcomes to exclude information from randomized participants and don't preserve integrity of randomization, or that don't reliably capture the intervention's meaningful net effects. These approaches have inherent limitations in ability to draw scientifically rigorous inference on clinically relevant causal effects important for decisions about adopting interventions. We describe advantages of trials with standard‐of‐care control arms targeting estimands using “treatment policy” approaches for intercurrent events, while potentially incorporating other meaningful intercurrent events, such as death, into the primary endpoint applying a composite strategy. Well‐designed and ‐conducted trials targeting such estimands achieve scientifically rigorous causal inference through analyzes that protect the integrity of randomization. Such estimands also provide meaningful information relevant to real‐world settings because they (1) are unconditional in nature i.e., they don't condition on post‐treatment circumstances that might not be many participants' experiences; and (2) properly evaluate the experimental intervention within a regimen that includes possible ancillary care that would be clinically appropriate in real‐world settings. We hope to add clarity about appropriate strategies for intercurrent events and how to improve design, conduct, and analysis of clinical trials to address questions of greatest clinical importance reliably.

Background/Objectives: The aim of this study was to estimate the effect of a 6 months’ treatment course of the innate immune modulator NP001 (a pH-adjusted intravenous formulation of purified sodium chlorite), on disease progression, as measured by overall survival (OS) in patients with amyotrophic lateral sclerosis. Methods: Blinded survival data were retrospectively collected for 268 of the 273 patients who had participated in two phase 2 placebo-controlled clinical trials of NP001 (ClinicalTrials.gov: NCT01281631 and NCT02794857) and received at least one dose of either 1 mg/kg or 2 mg/kg of NP001 as chlorite based on actual body weight, or placebo. Kaplan–Meier methods were used on the intent-to-treat population to estimate survival probabilities. Results: In the overall population, the median OS was 4.8 months (2.7 years [95% CI: 2.3, 3.5] in the 2 mg/kg NP001group and 2.3 years [95% CI: 1.8, 2.9] in the placebo group). Hazard ratio (HR): 0.77 (95% CI: 0.57, 1.03), p = 0.073. Among patients aged ≤ 65 years, the median OS for the 2 mg/kg NP001 group was 10.8 months (3.3 years [95% CI: 2.4, 3.8] in the 2 mg/kg NP001 group and 2.4 years [95% CI: 1.7, 3.3] in the placebo group). HR: 0.69 (95% CI: 0.50, 0.95). No differences were observed in the 1 mg/kg NP001 group or in patients aged > 65 years. Conclusions: The findings from this study suggest that a 6 months’ treatment course of NP001 resulted in a 4.8-month increase in overall survival in patients with ALS. The findings from this study indicate that targeting inflammation associated with the innate immune system may provide a pathway for new therapeutic options for the treatment of ALS.

Clinical trials in pulmonary arterial hypertension (PAH) have led to the approval of several effective treatments that improve symptoms, exercise capacity and clinical outcomes. In phase 3 clinical trials, primary end-points must reflect how a patient “feels, functions or survives”. In a rare disease like PAH, with an ever-growing number of treatment options and numerous candidate therapies being studied, future clinical trials are now faced with challenges related to sample size requirements, efficiency and demonstration of incremental benefit on traditional end-points in patients receiving background therapy with multiple drugs. Novel clinical trial end-points, innovative trial designs and statistical approaches and new technologies may be potential solutions to tackle the challenges facing future PAH trials, but these must be acceptable to patients and regulatory bodies while preserving methodological rigour. In this World Symposium on Pulmonary Hypertension task force article, we address emerging trial end-points and designs, biomarkers and surrogate end-point validation, the concept of disease modification, challenges and opportunities to address diversity and representativeness, and the use of new technologies such as artificial intelligence in PAH clinical trials.

Clinical trials investigating novel or high-risk interventions often use data monitoring committees (DMCs) to ensure that the participants' best interests are safeguarded. The typical DMC charter describes procedures by which the DMC operates, including important details concerning organizational structure, membership, meeting frequency, statistical monitoring guidelines, and contents of DMC reports for interim review. These charters, however, are not routinely publicly available; in some cases, their access could be important to the interpretation of trial results. We recommend including DMC charters for such trials in ClinicalTrials.gov at the time of trial completion; trial protocols, informed consent documents, and statistical analysis plans are already available in this repository.