Evaluation of Intravenous Human Normal Immunoglobulin, Oral Prednisone, and High-Dose Dexamethasone in Adult Immune Thrombocytopenia with Bleeding

The primary objective of this study is to demonstrate the **non-inferiority** in terms of short-term response of oral **dexamethasone** administered at 40 mg on days 1 to 4 compared to intravenous immunoglobulin (IVIg) given at 1 g/kg on days 1 and 2, in combination with **prednisone** (1 mg/kg per day for 3 weeks) in adult patients with **immune thrombocytopenia** (ITP) with mild to severe bleeding manifestations. This is clinically relevant as it aims to establish an effective and potentially more convenient treatment regimen for ITP, which could improve patient compliance and outcomes.

Secondary objectives include:

• To compare the initial rate of complete response (CR) in the two arms and the delay to obtain a CR.
• To compare the duration of the response in the two arms.
• To assess the acceptability and feasibility of the protocol by comparing the proportion of early treatment switches (before day 5) across arms.
• To estimate the interaction between treatment effect and the severity/risk of bleeding.
• To compare the initial response on bleeding manifestations in both arms.
• To compare the duration of hospital stay in the two arms.
• To compare the efficacy (overall response rate) at Day 28 and 6 months in the two arms.
• To compare the safety profile in the two arms.
• To estimate the incremental (decremental) cost-effectiveness of dexamethasone versus IVIg at 6 months, given the non-inferiority design, with the hypothesis that dexamethasone is cheaper and non-inferior in cost-effectiveness compared to IVIg.
• To assess whether the presence of anti-platelet antibodies is associated with the outcome (chronic or cured) at 6 months in the two arms.

The clinical trial involves **adult patients** diagnosed with **immune thrombocytopenia (ITP)**, characterized by mild to severe bleeding manifestations. The study population includes both male and female participants, aged between 18 and 80 years. Participants are required to have a platelet count of ≤ 20 x 10⁹/L and exhibit any cutaneous and/or mucosal bleeding manifestations. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria include individuals affiliated with a social security regime and those who have provided written consent. The trial population encompasses a vulnerable group, and the study does not impose specific lifestyle considerations such as diet or physical activity. The inclusion criteria allow for both newly diagnosed and relapsed cases of ITP, ensuring a diverse representation of the disease's progression.

The clinical trial is designed to evaluate the **non-inferiority** of oral **dexamethasone** compared to intravenous **immunoglobulin** (IVIg) in combination with **prednisone** for adult patients with **immune thrombocytopenia** (ITP) exhibiting mild to severe bleeding manifestations. This is a randomized, multicenter trial with a double-blind, controlled design. The trial is expected to last approximately 18 months, with an estimated recruitment start date of April 7, 2022, and an estimated end date of October 7, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-80 years), diagnosis of ITP, platelet count ≤ 20 x 10⁹/L, and the presence of bleeding manifestations. Following the screening, eligible participants will be randomized into one of the treatment arms. The trial involves a treatment period where participants receive either oral dexamethasone at 40 mg on days 1 to 4 or IVIg at 1 g/kg on days 1 and 2, combined with prednisone at 1 mg/kg per day for 3 weeks.

Follow-up visits will be conducted to monitor the time to achieve an initial response, defined as a platelet count ≥ 30 x 10⁹/L with at least a doubling of the baseline value, and to assess the absence of new bleeding and the use of other ITP-directed therapies. Secondary endpoints include the time to achieve a complete response, duration of overall response, and the number of new bleeding manifestations. The end-of-study visit will occur at 6 months, where the rates of response and complete response, as well as adverse events, will be evaluated.

Participant involvement is expected to last for the duration of the treatment and follow-up period, totaling approximately 6 months. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or the need for alternative ITP-directed therapies not included in the treatment arm. The trial aims to provide valuable insights into the efficacy and safety of the treatment regimens for ITP, contributing to improved patient management strategies.

The clinical trial involves the administration of **Neofordex 40 mg tablets**, which contain the active substance **dexamethasone**. This medication is provided in tablet form and is administered orally. The dosing regimen for dexamethasone is 40 mg per day, given on days 1 to 4 of the treatment cycle. The maximum total dose over the treatment period is 320 mg, with a maximum treatment duration of 8 days. Dexamethasone is a chemical substance classified under the ATC code H02AB02 and is used as a test treatment in this study.

Another treatment used in the trial is **prednisone**, which is administered in conjunction with intravenous immunoglobulin (IVIg). Prednisone is given orally at a dosage of 1 mg/kg per day for a duration of 3 weeks, with a maximum total dose of 21 mg/kg. Prednisone is a chemical substance, and its administration is intended to complement the effects of IVIg in the treatment of immune thrombocytopenia (ITP). The ATC code for prednisone is H02AB07.

The study also includes the use of **human normal immunoglobulin (IV)**, administered intravenously. The dosing schedule for IVIg is 1 g/kg on days 1 and 2, with a maximum total dose of 2000 mg/kg over the treatment period. This treatment is classified under the ATC code J06BA02 and is derived from a structurally diverse substance, specifically blood-derived immunoglobulins. IVIg serves as a comparator treatment in the trial, aiming to evaluate its efficacy in combination with prednisone against the test treatment of high-dose dexamethasone.

Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the time to achieve an initial response (R) within 5 days, defined as a platelet count of at least 30 x 10⁹/L with at least a doubling of the baseline value, in the absence of new bleeding and without the use of any other immune thrombocytopenia (ITP) directed therapies. Secondary endpoints include the time to achieve an initial complete response (CR), defined by a platelet count greater than 100 x 10⁹/L, and the duration of overall response from Day 1 to the end of the study (6 months). Additional secondary endpoints involve the proportion of early treatment switches, the number of new bleeding manifestations, rates of response and complete response at 28 days and 6 months, and the number of days of hospitalization.

Bleeding manifestations will be assessed using the score reported by Khellaf et al. The trial will also evaluate the number of adverse events, the incremental cost-effectiveness ratio expressed in cost per responder at 6 months, and the comparison of the number of responders and outcomes at 6 months in patients with positive and negative anti-platelet antibodies. Efficacy parameters will be collected and analyzed at specified time points, including Day 1, Day 5, Day 28, and at 6 months, to ensure comprehensive assessment of treatment effects in both trial arms.