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From short-term benefits to long-term outcomes: the evolution of clinical trials in pulmonary arterial hypertension.

ABSTRACT: Abstract Over the past 2 decades, major advances in our understanding of pulmonary arterial hypertension (PAH) have led to the development of new targeted therapeutics and management strategies that have provided benefits to patients with this devastating disease. Despite such improvements, no therapies are curative, and PAH remains a progressive disease associated with high morbidity and suboptimal survival in many patients. Clinical research in PAH is currently at a crossroads. To move forward, not only are new therapies needed, but novel approaches to clinical trial design are also required. Trials should be designed to assess the longer-term benefits of investigational therapies in what has become a chronic disease. Moreover, there is a need to consider moving away from short-term trials that use markers such as the 6-minute walk distance as a measure of exercise capacity as primary end points to longer-term, event-driven trials with composite end points made up of clinically relevant measures that better reflect the ultimate goals of reducing morbidity and mortality. A shift in trial design may also be useful in overcoming some of the muted results from recent pivotal phase III studies of combination therapy by allowing the potential of these regimens to be more comprehensively assessed.

SUBMITTER: Chakinala MM

PROVIDER: S-EPMC4070802 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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From short-term benefits to long-term outcomes: the evolution of clinical trials in pulmonary arterial hypertension.

Chakinala Murali M MM Barst Robyn R

Pulmonary circulation 20130901 3

Abstract Over the past 2 decades, major advances in our understanding of pulmonary arterial hypertension (PAH) have led to the development of new targeted therapeutics and management strategies that have provided benefits to patients with this devastating disease. Despite such improvements, no therapies are curative, and PAH remains a progressive disease associated with high morbidity and suboptimal survival in many patients. Clinical research in PAH is currently at a crossroads. To move forward ...[more]

PMID: 24618537

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Project description:Rationale: Event-driven primary endpoints are increasingly used in pulmonary arterial hypertension clinical trials, substantially increasing required sample sizes and trial lengths. The U.S. Food and Drug Administration advocates the use of prognostic enrichment of clinical trials by preselecting a patient population with increased likelihood of experiencing the trial's primary endpoint.Objectives: This study compares validated clinical scales of risk (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, the French score, and Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management [REVEAL] 2.0) to identify patients who are likely to experience a clinical worsening event for trial enrichment.Methods: Baseline data from three pulmonary arterial hypertension clinical trials (AMBITION [a Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension], SERAPHIN [Study of Macitentan on Morbidity and Mortality in Patients with Symptomatic Pulmonary Arterial Hypertension], and GRIPHON [Selexipag in Pulmonary Arterial Hypertension]) were pooled and standardized. Receiver operating curves were used to measure each algorithm's performance in predicting clinical worsening within the pooled placebo cohort. Power simulations were conducted to determine sample size and treatment time reductions for multiple enrichment strategies. A cost analysis was performed to illustrate potential financial savings by applying enrichment to GRIPHON.Measurements and Main Results: All risk algorithms were compared using area under the receiver operating curve and substantially outperformed prediction per New York Heart Association Functional Class. The REVEAL 2.0's risk grouping provided the greatest time and sample size savings in AMBITION and GRIPHON for all enrichment strategies but lacked appropriate inputs (i.e., N-terminal-proB-type natriuretic peptide) to perform as well in SERAPHIN. Cost analysis applied to GRIPHON demonstrated the greatest financial benefit by enrolling patients with a REVEAL score ≥8.Conclusions: This preliminary study demonstrates the feasibility of risk algorithms for pulmonary arterial hypertension trial enrichment and a need for further investigation.

Project description:Limited data about the long-term prognosis and response to therapy in pulmonary arterial hypertension patients with World Health Organization functional class I/II symptoms are available. PubMed and Embase were searched for publications of observational registries and randomized, controlled trials in pulmonary arterial hypertension patients published between January 2001 and January 2018. Eligible registries enrolled pulmonary arterial hypertension patients ≥18 years, N > 30, and reported survival by functional class. Randomized, controlled trial inclusion criteria were pulmonary arterial hypertension patients ≥18 years, ≥6 months of treatment, and morbidity, mortality, or time to worsening as end points reported by functional class. The primary outcomes were survival for registries and clinical event rates for randomized, controlled trials. Separate random effects models were calculated for registries and randomized, controlled trials. Four randomized, controlled trials (n = 2482) and 10 registries (n = 6580) were included. Registries enrolled 9%-47% functional class I/II patients (the vast majority being functional class II) with various pulmonary arterial hypertension etiologies. Survival rates for functional class I/II patients at one, two, and three years were 93% (95% confidence interval (CI): 91%-95%), 86% (95% CI: 82%-89%), and 78% (95% CI: 73%-83%), respectively. The hazard ratio for the treatment effect in randomized, controlled trials overall was 0.61 (95% CI: 0.51-0.74) and 0.60 (95% CI: 0.44-0.82) for functional class I/II patients and 0.62 (95% CI: 0.49-0.78) for functional class III/IV. The calculated risk of death of 22% within three years for functional class I/II patients underlines the need for careful assessment and optimal treatment of patients with functional class I/II disease. The randomized, controlled trial analysis demonstrates that current medical therapies have a beneficial treatment effect in this population.

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From short-term benefits to long-term outcomes: the evolution of clinical trials in pulmonary arterial hypertension.

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From short-term benefits to long-term outcomes: the evolution of clinical trials in pulmonary arterial hypertension.

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