A Review of Current Studies Evaluating Treatment of Paroxysmal Nocturnal Hematuria (PNH): Examining the Changing Landscape in PNH Study Design

Background:Paroxysmal nocturnal hematuria (PNH) is a rare acquired nonmalignant hematologic disorder due to deficiency of the GPI-linked complement regulators on the membrane of red blood cells making them vulnerable to complement-mediated damage. It is characterized by hemolytic anemia and thrombosis. The prevalence of PNH is 10-20 per million, without an association by sex, race, ethnicity, or geography. The first therapy for PNH was Eculizumab, a C5 inhibitor, in 2007. Eculizumab's approval was based on one phase 3 trial - superiority randomized placebo-controlled trial. The primary endpoints for the study were hemoglobin stabilization and number of packed red blood cells transfused. In the last two decades, there have been several studies evaluating treatment for PNH including the development of novel agents targeting the complement cascade. We aim to comprehensively review therapeutic clinical trials for PNH registered with ClinicalTrials.gov and changes in the clinical trial design landscape for emerging therapeutics.

Methods: Therapeutic trials for PNH registered on ClinicalTrials.gov up to 15 March 2024 were examined for study designs, treatment strategies, main inclusion criteria and efficacy endpoints. Particular importance was placed on studies associated with novel therapy approval.

Results:A total of 145 clinical trials for PNH were extracted on ClinicalTrials.gov up to 15 March 2024. These trials can be further delineated into phases: 9.7% phase 1, 3.4% phase 1/2, 36.6% phase 2, 24.8% phase 3, and 2.1% phase 4. Most of these trials were interventional studies (interventional 80%, observational 17.2%, and expanded access 2.8%). In terms of allocation, 31.9% were randomized, 24.1% were non-randomized, 2.6% were missing allocation information, and 41.4% allocation was not applicable. In terms of intervention models, 3.4% utilized crossover design, 31% parallel model, 12.9% sequential model, 48.3% single group, and 4.3% using another model. In terms of masking, 81.9% of interventional trials had no masking, 1.7% were single blind, 4.3% were double blind, 0.9% triple blind, 8.6% quadruple blind, and 2.6% missing. While evaluating studies resulting in novel therapies for PNH, we found that all currently available therapies work by modulating complement activation. The first two approved drugs for PNH (Eculizumab and Ravulizumab) worked on C5, while subsequent approved therapies Pegcetacoplan and Iptacopan act on C3, with Iptacopan being a factor B inhibitor. With exception of the first study with Eculizumab, all studies have not employed masking in their design and have been open labeled. The studies focus on hemoglobin stabilization, LDH, and number of transfusions as endpoints.

Conclusions:Over the past two decades several clinical trials have been done evaluating PNH treatment with the approval of four therapies - Eculizumab, Ravulizumab, Pegcetacoplan, and Iptacopan. In the vast majority of trials masking was not done, and the trials largely utilized parallel model or single group model for intervention model. When looking at studies that resulted in approval of medications, all trials' primary endpoints were objective measures - hemoglobin stabilization, number of transfusions, and LDH. Iptacopan stands among the current treatments available in that it can be administered orally. With these considerations in mind, future trials for PNH might be improved by masking involved in study design. This would allow for better assessing patient-reported and quality of life measures such as a “Functional Assessment of Chronic Illness Therapy” (FACIT) score. Future studies might also assess modulation of other components of the complement cascade and different formulations for administration.

No relevant conflicts of interest to declare.