Composite endpoint to evaluate complement inhibition therapy in patients with paroxysmal nocturnal hemoglobinuria

Abstract

This study developed and explored a novel composite endpoint to assess the overall impact that treatment can have on patients living with paroxysmal nocturnal hemoglobinuria (PNH). Candidate composite endpoint variables were selected by a group of experts and included: lactate dehydrogenase levels as a measure of intravascular hemolysis; complete terminal complement inhibition; absence of major adverse vascular events, including thrombosis; absence of any adverse events leading to death or discontinuation of study treatment; transfusion avoidance; and improvements in fatigue-related quality of life as determined by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. From these variables, a novel composite endpoint was constructed and explored using data collected in the ravulizumab PNH Study 301 (NCT02946463). Thresholds were defined and reported for each candidate variable. Five of the six candidate variables were included in the final composite endpoint; the FACIT-Fatigue score was excluded. Composite endpoint criterion was defined as patients meeting all five selected individual component thresholds. All patients in the ravulizumab arm achieved complete terminal complement inhibition and a reduction in lactate dehydrogenase levels; 51.2% and 41.3% of patients in the ravulizumab arm and eculizumab arm, respectively, achieved all composite endpoint component thresholds (treatment difference: 9.4%; 95% confidence interval: −3.0, 21.5).The composite endpoint provided a single and simultaneous measurement of overall benefit for patients receiving treatment for PNH. Use of the composite endpoint in future PNH research is recommended to determine clinical benefit, and its use in health technology assessments should be evaluated.

Paroxysmal nocturnal hemoglobinuria: Where we stand

“…Patient representatives are especially relevant when it comes to ultra‐orphan disease such as PNH. At the same time health authorities require clinical studies to demonstrate patient relevant outcomes 128 and to define optimal endpoints 129 including adequate QoL tools 130,131 . This demands interaction with patient representatives at the corporate and the academic level and the development of strategies employed already in the area of malignant diseases 132,133 …”

Paroxysmal nocturnal hemoglobinuria: Where are we going

“…We unfortunately still do not have any effective tools to identify sub‐optimal responders prior to initiation of C5 inhibitors. This will determine if the choice of initial therapy would be C5 inhibition or proximal inhibition, as a significant proportion of patients initiated on eculizumab/ravulizumab continue to remain well, with good hemoglobin and quality of life 78 . The lack of Phase 3 data of upstream complement inhibition in complement inhibitor naïve PNH patients makes it difficult to recommend C3 inhibitors as initial therapy for all patients with PNH.…”