Phase II Randomized Study of Methylprednisolone Hemisuccinate and Methoxsalen in Grade II Acute Graft-Versus-Host Disease Post-Allogeneic Stem Cell Transplantation

The primary objective of this study is to compare the percentage of patients who are not in treatment failure at 6 months from the start of treatment for **acute graft-versus-host disease** (GVHD) between the conventional treatment arm, which involves corticosteroids alone, and the experimental arm, which combines corticosteroids with extracorporeal photopheresis (ECP). This comparison is clinically relevant as it aims to determine the efficacy of adding ECP to the standard corticosteroid treatment in improving patient outcomes in acute GVHD, a condition that can significantly impact morbidity and mortality following allogeneic stem cell transplantation.

Secondary objectives include:

• Comparison of the two groups on the cumulative dose of steroids over time.
• Comparison on the incidence rate of infections, including bacteremia, septicemia, fungal infections, parasite, and virus reactivation.
• Comparison on the incidence of thrombotic complications.
• Comparison on the incidence and severity of chronic GVHD.
• Comparison on the non-relapse mortality rate.
• Comparison on the incidence of disease relapse.
• Comparison on disease-free survival (DFS).
• Comparison on overall survival.
• Comparison on health-related quality of life.
• Comparison on immune reconstitution, including T, B, NK cells, and gamma globulins.

These secondary objectives are crucial for understanding the broader impacts of the treatment strategies on patient health and quality of life, as well as their potential to reduce complications and improve long-term outcomes in patients with acute GVHD.

The clinical trial involves **adult patients** who have undergone an allogeneic hematopoietic stem cell transplantation and present with Grade II acute graft-versus-host disease (GVHD) with skin and/or upper gastrointestinal involvement. The study population includes both male and female participants over the age of 18, who are not considered part of a vulnerable population. Participants are required to have a leukocyte count greater than 1.5 G/L and platelet count over 30 G/L, with a hematocrit level above 27%, as per the latest blood test results. The trial is conducted in transplant centers within hematology departments, and participants must have a peripheral or central venous access suitable for performing photopheresis sessions. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific inclusion criteria, including the ability to start extracorporeal photopheresis (ECP) therapy within three days post-randomization and the requirement for first-line therapy to treat acute GVHD. Participants must be affiliated with a social security scheme or be beneficiaries of such a scheme.

The clinical trial is a multi-center, randomized, phase II study designed to compare the efficacy of corticosteroids alone versus corticosteroids combined with **extracorporeal photopheresis** (ECP) as a first-line treatment for Grade II acute graft-versus-host disease (GVHD) with skin involvement following allogeneic stem cell transplantation. The trial employs a double-blind, controlled methodology to ensure unbiased results. The estimated duration of the trial is from March 2024 to September 2026, with participant involvement expected to last up to 12 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 18 years, recent allogeneic hematopoietic stem cell transplantation, and the presence of Grade II acute GVHD. Following randomization, participants will be assigned to either the conventional treatment arm (corticosteroids alone) or the experimental arm (corticosteroids plus ECP). The study includes regular follow-up visits to monitor treatment efficacy and safety, with assessments at 1, 2, 3, 6, and 12 months post-randomization. The end-of-study visit will occur at 12 months, or earlier if the participant experiences treatment failure or other conditions necessitating early termination, such as severe adverse events or withdrawal of consent.

The primary endpoint is the percentage of patients without treatment failure at 6 months, defined by survival, absence of hematological disease relapse, no requirement for new acute GVHD treatment, and no initiation of systemic treatment for chronic GVHD. Secondary endpoints include the cumulative dose of steroids, incidence of infections and thromboembolic complications, severity of chronic GVHD, non-relapse mortality, disease-free survival, overall survival, quality of life scores, and immune reconstitution. Participants may be terminated early from the study if they do not meet the inclusion criteria, experience significant adverse effects, or choose to withdraw consent.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **SOLUMEDROL** 500 mg, a **methylprednisolone hemisuccinate** formulation, is provided as a powder for solution for injection. It is administered via injection with a maximum daily dose of 500 mg, and the treatment period is limited to 3 days. This medication is produced by Pfizer Holding France and is used as a comparator in the study.

**Uvadex** 20 micrograms/mL, containing the active substance **methoxsalen**, is a solution for blood fraction modification. It is used extracorporeally in conjunction with the Therakos Cellex photopheresis system, a class IIb medical device. The maximum daily dose is 0.2 mg/mL, and the treatment can extend up to 12 months. This product is manufactured by Therakos Europe Ltd and serves as an auxiliary treatment in the trial.

**CORTANCYL** 20 mg, a **prednisone** tablet, is administered orally. The maximum daily dose is 2 mg/kg, with a treatment duration of up to 3 days. This medication is produced by Cheplapharm Arzneimittel GmbH and is used as a comparator in the study.

**Noxafil** 40 mg/mL, an oral suspension containing **posaconazole**, is administered orally with a maximum daily dose of 40 mg. The treatment period is limited to 3 days. This product is manufactured by Merck Sharp & Dohme BV and is utilized as a test treatment in the trial.

Participant compliance with the dosing schedules is monitored throughout the study to ensure adherence to the prescribed treatment regimens. The trial aims to compare the efficacy of corticosteroids alone versus corticosteroids combined with extracorporeal photopheresis in treating Grade II acute graft-versus-host disease with skin involvement.

Efficacy in this clinical trial will be assessed by comparing the percentage of patients who do not experience treatment failure at 6 months from the start of treatment for **acute graft-versus-host disease (GVHD)**. The primary endpoint is defined by the absence of treatment failure, which includes being alive, not experiencing a relapse of the hematological disease, not requiring a new line of treatment for acute GVHD, and not initiating systemic treatment for chronic GVHD. This will be evaluated in both the conventional treatment arm (corticosteroids alone) and the experimental arm (corticosteroids plus extracorporeal photopheresis).

Secondary endpoints include the mean cumulative dose of steroids over specified time periods, the cumulative incidence rate of infections at 6 and 12 months, and the incidence of thromboembolic complications at 3 months. Additionally, the incidence and severity of chronic GVHD, non-relapse mortality rate, incidence of underlying disease relapse, disease-free survival, and overall survival will be assessed at 6 and 12 months. Health-related quality of life will be measured using the French validated FACT-BMT (version 4.0) at 3, 6, and 12 months post-transplant. Immune reconstitution will be evaluated based on peripheral blood testing for various immune cell types at 3, 6, and 12 months, depending on usual practices at each center.