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

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

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

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

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.

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.

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.

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.

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

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.

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.

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.

Proportion of patients with platelet count higher or equal than 30x109/L and at least double than baseline.

Patients with platelet count between 100x109/L and 30x109/L and at least doubled from baseline and absence of bleeding symptoms.

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.

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

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

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.

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.

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.

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.

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

- 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

- The maximum number of consecutive days with platelet count ≥100x109/L in the total sample and in the absence of any rescue treatment

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

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

The total number od days with platelet count ≥100x109/L in the total sample and in the absence of any rescue treatment

The total number od days with platelet count ≥100x109/L in the total sample and in the absence of any rescue treatment

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

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

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.

The results will be shared with the investigators involved in the study, and will be shared when the analysis of the results is performed.