The PROLONG Trial - Rituximab Maintenance Therapy in ITP

This study is a two phase study that aims to evaluate if low-dose Rituximab maintenance therapy may prolong the the effect of Rituximab in immune thrombocytopenia.

This is a multi-center, international, randomized, two-phase study:

First phase (induction phase) is open-label, hypothesis-generating, involving 1:1 randomization into: rituximab (group 1) or rituximab plus dexamethasone (group 2) to determine if the response to rituximab can be improved by the addition of dexamethasone.

Second Phase (maintenance phase) is the main part of the study, involving 1:1 double-blind randomization into low dose rituximab or placebo to determine if the response achieved in the first phase can be prolonged by administrating maintenance treatment with low dose rituximab.

Primary objective:

To determine if maintenance therapy with low-dose rituximab is superior to placebo in prolonging responses among ITP patients who achieved an initial response with rituximab.

Secondary objectives:

1. To explore if the initial overall response rate, at week 24, can be improved by at least 10% by adding dexamethasone to rituximab (induction phase).
2. To assess the safety of study treatment, especially infectious episodes (induction \& maintenance phases).
3. To assess bleeding complications during the study (induction \& maintenance phases).
4. To assess the use of rescue medications and other platelet-elevating therapies during the study (induction \& maintenance phases).
5. To determine rate of Complete Response (CR) during induction phase and sustained CR during maintenance phase (induction \& maintenance phases).
6. To determine the duration of overall response and CR (induction \& maintenance phases).
7. To assess health-related quality of life and fatigue (induction \& maintenance phases).

Eligibility Criteria:
Inclusion Criteria First randomization (Induction phase):

1. Male or female aged ≥18 years.
2. Diagnosis of primary ITP of less than one year duration having a platelet count of ≤ 30 x109/L measured within 4 weeks prior to inclusion with failure to achieve initial response or relapse either after one cycle of dexamethasone (40 mg daily for 4 days) or 4 weeks with any other steroid (prednisone or prednisolone). Platelet count between 31 to 50 x109/L is accepted if higher platelet count is required due to concomitant antiplatelet therapy or bleeding.
3. Scheduled intravenous treatment of rituximab.
4. Signed and dated written informed consent.
5. Females of child-bearing potential accepting to follow effective contraceptive methods for at least 12 months following the last administration of rituximab or placebo.

Inclusion criteria second randomization (maintenance phase):

1. Completion of the induction phase (phase 1) of the study.
2. Sustained response at the end of phase 1.
3. Randomization within 4 weeks after the completion of phase 1, i.e. between week 24 and 28.

Exclusion Criteria first randomization (Induction phase):

1. Previous treatment for ITP with: rituximab, other immune suppressants (including mycophenolate mofetil, aziothioprin, cyclosporine), chemotherapy or splenectomy.
2. Pregnancy or lactation.
3. Known active gastro-duodenal ulcer.
4. Secondary ITP: ITP associated with lymphoma, chronic lymphocytic leukemia, autoimmune disorders such as, common variable immune deficiency, human immunodeficiency virus, or hepatitis C or thrombocytopenia associated with myeloid dysplasia.
5. Concomitant autoimmune hemolytic anemia.
6. History of any major cardiovascular event within the 6 months prior to randomization, including but not limited to: myocardial infarction, unstable angina, cerebrovascular accident, or New York Heart Association Class III or IV heart failure.
7. Active hepatitis B virus or patients with positive HBsAG or HBcAB.
8. Patients with active severe infection, including systemic mycotic infections or a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection.
9. Known allergy and/or sensitivity or contraindication to rituximab or dexamethasone or any of the ingredients.
10. Patients in a severely immune compromised state.
11. Known contraindication to a treatment with any proton-pump inhibitor.
12. Active malignancy or history of malignant disease during the last 2 years except cured skin cancer.
13. Patients with history of poor compliance or history of alcohol/drug abuse or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent.

Exclusion criteria second randomization (maintenance phase) 14. Severe allergic reaction or serum sickness due to rituximab in phase 1 of the study.

15. Pregnancy. 16. Treatment with rescue medication after week 18. 17. Patients refusing to continue in the study (withdrawal of consent). 18. Splenectomy performed for any cause.

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