Evaluation of Daratumumab in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Placebo-Controlled, Double-Blind Phase II Trial

The primary objective of this study is to evaluate the **efficacy** of **daratumumab** compared to placebo in reducing symptoms of **Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)** in subjects with moderate to severe manifestations of the condition. This is clinically relevant as it aims to determine the potential therapeutic benefit of daratumumab, an anti-CD38 antibody, in alleviating the debilitating symptoms associated with ME/CFS, which currently lacks effective treatment options.

Secondary objectives include:

• Evaluating the efficacy of daratumumab versus placebo in reducing core ME/CFS symptoms and improving physical function and activity level.
• Assessing the safety and toxicity profile of daratumumab compared to placebo in subjects with moderate to severe ME/CFS.

The clinical trial involves participants diagnosed with **Myalgic Encephalomyelitis/Chronic Fatigue Syndrome** (ME/CFS), specifically targeting individuals with moderate to severe symptoms. The study population includes both male and female subjects, aged between 18 to 64 years, who are generally not considered part of a vulnerable population. Participants are required to have a defined onset of ME/CFS following an initial infection or other immunological trigger, with the condition persisting for at least two years. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Lifestyle considerations such as diet and physical activity are not detailed in the available data. Key inclusion criteria include a negative serum pregnancy test for women of childbearing potential and the use of highly effective contraception. The selection process ensures that participants meet the Canadian consensus criteria for ME/CFS, with NK-cell numbers at baseline being a significant factor. The sponsor has not disclosed additional details regarding the selection process or specific lifestyle factors.

The clinical trial is designed to evaluate the efficacy of **daratumumab** versus placebo in reducing symptoms of **Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)** in subjects with moderate to severe disease. This study is a randomized, placebo-controlled, and double-blind phase II trial. The trial is expected to commence recruitment on May 19, 2025, and conclude by December 31, 2030. Participants will be involved in the study for a maximum treatment period of 26 weeks, with follow-up extending to 60 weeks to assess both primary and secondary endpoints.

Study visits are structured to ensure comprehensive data collection and participant safety. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, disease duration, and baseline **NK-cell** numbers. Following successful screening, participants will be randomized to receive either the investigational product or placebo via subcutaneous injection. Regular follow-up visits will occur throughout the treatment period to monitor the course of the **DSQ-SF** total score and other secondary endpoints, including the **SF-36 Physical Function** score and safety assessments according to **CTCAE ver. 5.0**. The end-of-study visit will finalize data collection and ensure participant well-being post-treatment.

Participants are expected to adhere to the study protocol for the entire duration unless specific conditions necessitate early termination. Such conditions include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial's design and methodology are structured to maintain scientific rigor and ensure the reliability of the results, contributing valuable insights into the management of ME/CFS.

The clinical trial involves the administration of **Hyaluronidase 1500 I.U. Powder for Solution for Injection/Infusion**. This experimental medication is provided in the form of a powder that is reconstituted into a solution for injection or infusion. The active substance, **hyaluronidase**, is a mixture used to enhance the dispersion and absorption of other injected drugs. The pharmaceutical form is a solution for injection, and the route of administration is via subcutaneous injection. The maximum daily dose is 1500 IU, with a total maximum dose of 7500 IU over a treatment period of 26 weeks. The product is manufactured by WOCKHARDT UK LTD and is not a pediatric formulation.

Another experimental medication used in the trial is **DARZALEX 1800 mg solution for injection**, which contains the active substance **daratumumab**. Daratumumab is a monoclonal antibody targeting CD38, classified as a protein of other origin. The pharmaceutical form is a solution for injection, administered subcutaneously. The maximum daily dose is 1800 mg, with a total maximum dose of 9000 mg over a 26-week treatment period. This product is manufactured by JANSSEN-CILAG INTERNATIONAL NV and is also not a pediatric formulation.

The trial is designed as a randomized, placebo-controlled, and double-blind phase II study, aiming to evaluate the efficacy of daratumumab versus placebo in reducing symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in subjects with moderate to severe ME/CFS. Compliance with the dosing schedule and administration is monitored throughout the study to ensure adherence to the protocol.

The efficacy of the investigational product, **daratumumab**, will be assessed in a randomized, placebo-controlled, double-blind phase II clinical trial targeting patients with moderate to severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The primary endpoint for evaluating efficacy is the course of the DSQ-SF total score from baseline through follow-up until week 60. Secondary endpoints include the course of the modified DSQ-SF score, SF-36 Physical Function (SF-36 PF), FUNCAP total score, and steps per 24 hours, all measured from baseline until week 60. Additionally, overall response is defined as a decrease of 25 points in the DSQ-SF score from baseline to the time interval 28 to 48 weeks after the start of the intervention. Safety and toxicity will be continuously recorded through the 60-week follow-up according to CTCAE version 5.0.