The Combination of Low-dose Rituximab and ATRA as the Treatment of Steroid-resistant/Relapse Immune Thrombocytopenia

Study Overview
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Brief Summary
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Randomized, open-label, multicentre study to assess the efficacy and safety of the combination of low-dose rituximab and ATRA in patients with steroid-resistant/relapsed ITP.

Detailed Description
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Immune thrombocytopenia (ITP) is a severe bleeding disorder. Approximately 2/3 of patients achieve remission from first-line therapies. However, the underlying mechanism of steroid-resistant or relapsed ITP is not well understood; thus, treatment remains a great challenge. Rituximab has been shown to partly improve the complete remission rate of ITP. All-trans retinoic acid (ATRA) has an immunomodulatory effect on haematopoiesis, making it a possible treatment option. A multicentre prospective study was performed in non-splenectomized ITP patients who were either resistant to a standard dose of corticosteroids or had relapsed. Patients were randomized to the low-dose rituximab+ATRA and the low-dose rituximab monotherapy groups. Platelet count, bleeding and other symptoms were evaluated before and after treatment. Interim analysis was scheduled at 50% through recruitment. Adverse events are also recorded throughout the study, in order to assess the efficacy and safety of the combination of low-dose rituximab and ATRA in patients with steroid-resistant/relapsed ITP.

Official Title
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The Combination of Low-dose Rituximab and All-trans Retinoic Acid as the Treatment of Steroid-resistant/Relapse Immune Thrombocytopenia: a Multicenter, Randomized, Open-label Trial

Conditions
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Immune Thrombocytopenia

Intervention / Treatment
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* Drug: Rituximab
* Drug: All-trans retinoic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ITP confirmed by excluding other supervened causes of thrombocytopenia; Platelet count of less than 30×10^9/L at enrollment; Patients who did not achieve a sustained response to treatment with full dose corticosteroids for a minimum duration of 4 weeks or who relapsed during steroid-tapering or after its discontinuation; ECOG<2. Exclusion Criteria: Secondary immune thrombocytopenia (e.g., patients with HIV, HCV, Helicobacter pylori infection or patients with systemic lupus erythematosus) Congestive heart failure Severe arrhythmia Nursing or pregnant women Aspartate aminotransferase and alanine transaminase levels ≥ 3×the upper limit of the normal threshold criteria Creatinine or serum bilirubin levels each 1•5 times or more than the normal range Active or previous malignancy Patients with other diseases were undergoing treatment with immunosuppressants Patients with ITP had received rituximab

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: low-dose rituximab & ATRA<br>rituximab 100mg once weekly for 6 weeks and oral all-trance retinoid acid 20mg/m^2 qd for 12 weeks. | Drug: Rituximab<br>* Low-dose rituximab was used in combination with ATRA or as the monotherapy<br>Drug: All-trans retinoic acid<br>* ATRA was used in combination with low-dose rituximab<br>|
| Active Comparator: low-dose rituximab<br>rituximab 100mg once weekly for 6 weeks | Drug: Rituximab<br>* Low-dose rituximab was used in combination with ATRA or as the monotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response | The number of participants (responders) with platelet count >=30x10^9/L and at least a 2-fold increase in the baseline count (PR) or a platelet count >=100x10^9/L (CR) and the absence of bleeding, without rescue medication at 1-year follow-up. Interim analysis was scheduled at 50% through recruitment. | From the start of study treatment (Day 1) up to the end of Year 1 | 
| sustained response | The number of participants that can maintain the platelet count > 30 x 109/L, an absence of bleeding events, and without requirement for any other ITP-specific treatment for 6 consecutive months after achievement of response. Interim analysis was scheduled at 50% through recruitment. | From the start of study treatment (Day 1) up to the end of Year 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| complete response | The number of participants (responders) with platelet count>=100x10^9/L (CR) and the absence of bleeding, without rescue medication at 1-year follow-up. Interim analysis was scheduled at 50% through recruitment. | From the start of study treatment (Day 1) up to the end of Year 1 | 
| time to response | Time to response was defined as the time from starting treatment to the time to achieve the response. Interim analysis was scheduled at 50% through recruitment. | From the start of study treatment (Day 1) up to the end of Year 1 | 
| duration of response | Duration of response was measured from the achievement of response to the loss of response. Interim analysis was scheduled at 50% through recruitment. | From the start of study treatment (Day 1) up to the end of Year 1 | 
| incidence of adverse events | All patients were assessed for adverse events every week during the first 4 weeks of treatment, and at 2-weeks interval for the following 5 months, and monthly thereafter. Adverse events were scaled according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Interim analysis was scheduled at 50% through recruitment. | From the start of study treatment (Day 1) up to the end of Year 1 | 
| Initial response | The number of patients who achieve response at 4 weeks following treatment | From the start of study treatment (Day 1) up to the end of Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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all-trans retinoid acid, rituximab, steroid-resistant, refractory, low-dose