The Combination of ATRA and Danazol as Second-line Treatment in Adult Immune Thrombocytopenia

Study Overview
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Brief Summary
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Randomized, open-label, multicentre study to compare the efficacy and safety of ATRA plus danazol with danazol monotherapy in patients with corticosteroid-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 corticosteroid-resistant or relapsed ITP is not well understood; thus, treatment remains a great challenge. 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 ATRA+danazol and danazol monotherapy group. Platelet count, bleeding and other symptoms were evaluated before and after treatment. Adverse events are also recorded throughout the study, in order to compare the efficacy and safety of ATRA plus danazol with danazol monotherapy in patients with corticosteroid-resistant/relapsed ITP.

Official Title
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The Combination of Oral All-trans Retinoic Acid and Danazol vs Danazol as Second-line Treatment in Adult Immune Thrombocytopenia: a Multicenter, Randomized, Open-label Trial

Conditions
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Autoimmune Thrombocytopenia

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary immune thrombocytopenia (ITP) confirmed by excluding other supervened causes of thrombocytopenia; Platelet count of less than 30×109/L at enrolment 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. 18 years older. 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 Unable to do blood routine test for the sake of time, distance, economic issues or other reasons.

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: All-trans retinoic acid ＆Danazol<br>Danazol 400mg po and ATRA 10mg bid po | Drug: All-trans retinoic acid<br> <br> * Other names: Retinoid acid;Drug: Danazol<br> <br> * Other names: Danol;|
| Active Comparator: Danazol<br>Danazol 400mg po | Drug: Danazol<br> <br> * Other names: Danol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the sustained platelet response at the 12-month follow-up | 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 12-month follow-up. | From the start of study treatment (Day 1) up to the end of Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response | The number of participants with platelet count >=30×10^9/L at least once and at least a doubling of the baseline platelet count without the administration of any other platelet increasing therapy | From the start of study treatment (Day 1) up to the end of Month 12 | 
| primary response rate at 4 weeks | The number of participants with platelet count >=30×10^9/L and at least a doubling of the baseline platelet count without the administration of any other platelet increasing therapy at week 4 of treatment | From the start of study treatment (Day 1) up to week 4 of treatment | 
| primary response rate at 8 weeks | The number of participants with platelet count >=30×10^9/L and at least a doubling of the baseline platelet count without the administration of any other platelet increasing therapy at week 8 of treatment | From the start of study treatment (Day 1) up to week 8 of treatment | 
| time to response | Time to response was defined as the time from starting treatment to the time to achieve the response. | From the start of study treatment (Day 1) up to the end of month 12 | 
| duration of response | Duration of response was measured from the achievement of response to the loss of response. | From the start of study treatment (Day 1) up to the end of month 12 | 
| reduction in bleeding symptoms | Changes of bleeding after treatment. Bleeding was defined in accordance with the WHO bleeding scale (0, no bleeding; 1, petechiae; 2, mild blood loss; 3, gross blood loss; and 4, debilitating blood loss). | From the start of study treatment (Day 1) up to the end of month 12 | 
| safety | All patients were assessed for safety every week during the first 8 weeks of treatment, and at 2-week intervals thereafter. Adverse events were scaled according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | From the start of study treatment (Day 1) up to the end of follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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All-trans retinoic acid, primary immune thrombocytopenia, corticosteroid-resistant, refractory, danazol