Romiplostim Plus Dexamethasone vs Dexamethasone in Patients With Newly Diagnosed Primary Immune Thrombocytopenia

Study Overview
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Brief Summary
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Phase III, open-labeled, randomized and multicenter clinical trial to evaluate the superiority of romiplostim plus dexamethasone vs dexamethasone alone in patients with newly diagnosed primary immune thrombocytopenia

Detailed Description
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The main objective of the study is to evaluate the superiority of romiplostim plus dexamethasone versus dexamethasone alone in the treatment of primary immune thrombocytopenia, with sustained response to any ITP treatment and without World Health Organization grade 2 or higher bleeding, after six months from cessation of treatment. Maximum time on treatment with romiplostim will be 12 months (365 days). Then, patients will be followed up for 6 additional months (180 days) after stopping romiplostim. Clinical rules are included if romiplostim dose should be modified or finished. In case of dexamethasone, no dose adjustment is permitted. The evaluation of romiplastim plus dexamethasone´s superiority in different periods and platelet count, proportion of patients with complete response (CR), global response (GR), early response (ER) and initial response (IR); time to loss of response (LoR), adverse events, quality of life and healthcare resources use are included as secondary objectives.

Official Title
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A Multicentre, Randomized, Open-label Study of Romiplostim Plus Dexamethasone vs Dexamethasone in Patients With Newly Diagnosed Primary Immune Thrombocytopenia

Conditions
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Primary Immune Thrombocytopenia

Intervention / Treatment
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* Drug: romiplostim plus dexamethasone
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Main inclusion criteria: Age ≥ 18 years of age at the time of signing informed consent. Newly diagnosis of primary ITP according to the International Working Group assessment [1] and previously untreated for ITP. Platelet counts <30x109/L or ITP with platelet counts <50x109/L and concomitant bleeding symptoms. Serum creatinine concentration ≤1.5 mg/dL. Main exclusion criteria: World Health Organization's performance status >2. Previous therapy with rituximab (within 3 months previous of study enrollment), corticosteroids or, therapy with other immunomodulating agents within 1 month before of enrolment;,prior use of hematopoietic analogs and or fostamatinib for any other reason despite ITP three months before enrolment. Previous use of romiplostim, polyethylene glycol-recombinant human megakaryocyte growth and development factor, Eltrombopag, recombinant human anti-thrombopoietin, or any platelet-producing agent three months before enrolment. Alkylating agents within 8 weeks before the screening visit or anticipated use during the time of the proposed study. Splenectomy within 3 months of the screening visit or planned splenectomy during study period. Abnormal renal function (serum creatinine > 1.5 mg/dL). Active hepatic disease (evidenced by alanine aminotransferase [ALT] or aspartate aminotransferase [AST] levels >5 times the upper limit of normal (it will only be necessary to determine one of the two transaminases Severe chronic liver disease as evidenced by, but not limited to, any of the following: International Normalized Ratio >1.4, hypoalbuminemia, portal vein hypertension including presence of otherwise unexplained splenomegaly and history of esophageal varices. Patients with known immunoglobulin M seropositive tests for cytomegalovirus and/or Epstein-Barr virus in the previous month. Patients with an active viral infection at screening with: Hepatitis B Virus, Hepatitis C Virus, detectable virus charge of HIV. Intolerance to dexamethasone. History of a bone marrow stem cell disorder. Active or prior malignancy except adequately treated (ie, complete surgical excision with negative margins) basal cell carcinoma. History of helicobacter pylori by urea breath test or stool antigen test within 6 months of enrollment, if available. History of myelodysplastic syndrome, systemic lupus erythematosus, or autoimmune cytopenia. History of antiphospholipid antibody syndrome. History of disseminated intravascular coagulation, hemolytic uremic syndrome, or thrombotic thrombocytopenic purpura. History of deep or superficial venous thromboembolism in the last 12 months or stroke, acute ischaemic heart disease or acute peripheral vascular disease in the last 6 months. Hypersensitivity to any recombinant Escherichia coli-derived product (eg, Infergen, Neupogen, Somatropin, and Actimmune) or known sensitivity to any of the products to be administered during dosing Currently enrolled in another investigational device or drug study or < 30 days since ending another investigational device or drug studies, or receiving other investigational agents. Will have any other investigational procedures performed while enrolled in this clinical study. Pregnant or breastfeeding, or planning to become pregnant or breastfeed during treatment or within 1 month after the end of treatment. Female subject of childbearing potential is not willing to use, in combination with her partner, an acceptable method of effective contraception during treatment and for 1 month after the end of treatment. Females of childbearing potential should only be included after a negative, pregnancy test. Will not be available for protocol-required study visits, to the best of the subject's and investigator's knowledge. Any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures. Other serious comorbidities at investigator criteria.

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
Interventional Model Description: Parallel Assignment Randomized 1:1
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: romiplostim plus dexamethasone (ROM + DEX)<br>Dexamethasone 40 mg daily x 4 days only in the first cycle and subcutaneous romiplostim weekly for up to 12 months Romiplostim: The starting dose should be 3 mcg/kg/week. It could be start during de 4 days of dexamethasone. Patients will weekly receive dose increases of romiplostim in increments of 1 mcg/kg up to a maximum dose of 10 mcg/kg in an attempt to reach a target platelet count higher than 50x109/L. Otherwise, if platelets are lower than 50x109/L treatment with romiplostim will go on until Day 365 since randomization. | Drug: romiplostim plus dexamethasone<br>* Patients will be reviewed weekly for 8 weeks (56 days). After Week 8, patients will be reviewed every 2 weeks (14 days) for 8 additional weeks and then monthly until Week 52 (365 days) from randomization.<br>* Other names: ROM + DEX;|
| Active Comparator: Dexamethasone (DEX)<br>Dexamethasone 40 mg daily x 4 days for up to 3 cycles every 14 to 28 days | Drug: Dexamethasone<br>* Patients will be reviewed weekly until the completion of dexamethasone cycles and for a minimum of 8 weeks (56 days). After that, every 2 weeks (14 days) for 8 additional weeks and then monthly until Week 52 (365 days) from randomization.<br>* Other names: DEX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients achieving sustain response out of treatment with platelets higher or equal than 30x109/L for 6 months (Sustained Response Off any ITP Treatment) | Proportion of patients with platelets higher or equal than 50x109/L in the absence of any ITP treatment including any rescue treatment for at least 6 consecutive months (≥180 days) from treatment cessation and without World Health Organization grade 2 or more bleeding | 180 days after treatment withdrawal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients achieving sustain response out of treatment with platelets higher or equal than 30x109/L for 6 months in the absence of any ITP treatment including any rescue treatment. | Proportion of patients with platelets higher or equal than 30x109/L in the absence of any ITP treatment including any rescue treatment for at least 6 consecutive months (≥180 days) from treatment cessation and without World Health Organization grade 2 or more bleeding. | 180 days after treatment withdrawal | 
| Proportion of patients achieving sustain response out of treatment with platelets higher or equal than 30x109/L for 12 months in the absence of any ITP treatment including any rescue treatment. | Proportion of patients with platelets higher or equal than 30x109/L in the absence of any ITP treatment including any rescue treatment for at least 12 consecutive months (≥365 days) from treatment cessation and without World Health Organization grade 2 or more bleeding. | 365 days after treatment withdrawal | 
| Proportion of patients achieving sustain response out of treatment with platelets higher or equal than 50x109/L for 12 months in the absence of any ITP treatment including any rescue treatment. | Proportion of patients with platelets higher or equal than 50x109/L in the absence of any ITP treatment including any rescue treatment for at least 12 consecutive months (≥365 days) from treatment cessation and without World Health Organization grade 2 or more bleeding. | 365 days after treatment withdrawal | 
| Proportion of patients with early response (ER) | Proportion of patients with platelet count higher or equal than 30x109/L and at least double than baseline. | Day 7 | 
| Proportion of patients with initial response (IR) | Proportion of patients with platelet count higher or equal than 30x109/L | Day 30 | 
| Proportion of patients with complete response (CR) | Patients with platelet count ≥100x109/L and absence of bleeding symptoms. | Day 180, Day 365, Day 545 | 
| Proportion of patients with response (R) | Patients with platelet count between 100x109/L and 30x109/L and at least doubled from baseline and absence of bleeding symptoms. | Day 180, Day 365, Day 545 | 
| Proportion of patients with global response (GR) | Patients with platelet count ≥100x109/L and absence of bleeding symptoms or platelet count between 100x109/L and 30x109/L and at least doubled from baseline and absence of bleeding symptoms. | Day 180, Day 365, Day 545 | 
| Proportion of patients with targeted range (TR) | Patients with platelet count between ≥30x109/L and ≤400x109/L. | Day 180, Day 365, Day 545 | 
| Time to loss of response (LoR) in patients who achieved response in both arms. | Number of days from the first time the patient achieved a platelet count ≥30x109/L until platelet count dropped below 30x109/L measured on 2 occasions with more than 1 day apart or presence of bleeding | In every study visit, assessed up to 545 days | 
| Proportion of patients requiring any rescue treatment | Proportion of patients who need rescue treatments in each arm and total patients | In every study visit, assessed up to 545 days | 
| Proportion and time to treatment failures | Proportion of patients who need rescue treatments and And the number of days they needed treatment | In every study visit, assessed up to 545 days | 
| Proportion of patients with adverse events (AEs), including serious adverse events (SAEs) and laboratory safety parameters. | AEs will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Bleeding events will be carefully monitored | In every study visit, assessed up to 545 days | 
| Changes in patients bleeding | For the assessment of the of the patients' bleeding will be used immune thrombocytopenia-bleeding assessment tool (ITP-BAT): bleeding signs/symptoms are grouped in three domains (skin, visible mucosae and organs) and is graded from 0 (No) to 4. | Screning, Day 1, Week 8, Week 12, Moth 6, Moth 12 and End of study Visit | 
| Changes in patients' quality of life- Short Form-36 Health Survey | For the assessment of the quality of life during the study will be used Short-Form-36 Health Survey: is a 36-item scale constructed to survey health-related 8 domains: limitations in physical activities due to health problems; limitations in social activities due to physical or emotional problems; limitations unusual role activities due to physical health problems; bodily pain; general mental health (psychological distress and well-being); limitations unusual role activities due to emotional problems; vitality (energy and fatigue); and general health perceptions. | Day 1, Week 8, Day 180, Day 365 and Day 545 | 
| Changes in patients' quality of life- FACIT-F | For the assessment of the quality of life during the study will be used FACIT-F (Fatigue Scale): is a short scale, 13-item, easy to administer tool that measures an individual's level of fatigue during their usual daily activities over the past week.The level of fatigue is measured by recording item responses ona 4-point Likert scale ranging from 0 not at all to 4 very much. | Day 1, Week 8, Day 180, Day 365 and Day 545 | 
| Changes in patients' quality of life- ITP-Patient Assessment Questionnaire | For the assessment of the quality of life during the study will be used ITP-Patient Assessment Questionnaire): is a disease-specific instrument that was designed to measure the QoL of adult patients with immune thrombocytopenia. The instrument comprises 38 items completed by male respondents and 44 items completed by female respondents. | Day 1, Week 8, Day 180, Day 365 and Day 545 | 
| Healthcare resources use (HRU) | The data collected may be used to conduct exploratory economic analyses and may include: Number of outpatient visits, Number of home health care Number of Hospitalization Duration of medical care visits (days) Number of Emergency room visits Number of diagnostic procedures Number of medical care visits | In every study visit, assessed up to 545 days | 
| Loss of productivity | Number of days of absenteeism from school or work and associated cost | In every study visit, assessed up to 545 days | 
| Maximum number of consecutive days with platelet response | - The maximum number of consecutive days with platelet count between 100x109/L and 30x109/L in the total sample and in the absence of any rescue treatment | In every study visit, assessed up to 545 days | 
| Maximum number of consecutive days with platelet complete response (CR) | - The maximum number of consecutive days with platelet count ≥100x109/L in the total sample and in the absence of any rescue treatment | In every study visit, assessed up to 545 days | 
| Maximum number of consecutive days with platelet global response (GR) | The maximum number of consecutive days with platelet count ≥100x109/L or platelet count between 100x109/L and 30x109/L in the total sample and in the absence of any rescue treatment | In every study visit, assessed up to 545 days | 
| Maximum number of consecutive days with platelet targeted range (TR) | The maximum number of consecutive days with platelet count between ≥30x109/L and ≤400x109/ L in the total sample and in the absence of any rescue treatment | In every study visit, assessed up to 545 days | 
| Total number of days with platelet response | The total number od days with platelet count ≥100x109/L in the total sample and in the absence of any rescue treatment | In every study visit, assessed up to 545 days | 
| Total number of days with platelet complete response (CR) | The total number od days with platelet count ≥100x109/L in the total sample and in the absence of any rescue treatment | In every study visit, assessed up to 545 days | 
| Total number of days with platelet global response (GR | The total number od days with platelet count ≥100x109/L or platelet count between 100x109/L and 30x109/L in the total sample and in the absence of any rescue treatment | In every study visit, assessed up to 545 days | 
| Total number of days with platelet targeted range (TR) | The total number od days with platelet count between ≥30x109/L and ≤400x109/ L in the total sample and in the absence of any rescue treatment | In every study visit, assessed up to 545 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Romiplostim, Dexamethasone