A Personalized Medicine Approach for Beta-thalassemia Transfusion Dependent Patients: Testing SIROLIMUS in a First Pilot Clinical Trial
Overview
- Phase
- Phase 2
- Intervention
- Sirolimus 0.5 mg
- Conditions
- Beta-Thalassemia
- Sponsor
- Rare Partners srl Impresa Sociale
- Enrollment
- 26
- Locations
- 2
- Primary Endpoint
- Change from baseline of fetal hemoglobin level
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
Beta-thalassemias are hereditary blood disorders caused by reduced or absent synthesis of hemoglobin beta chains, with variable outcomes ranging from severe anemia to clinically asymptomatic individuals. Treatment is symptomatic and thalassemia is a major unmet medical need. Survival is increased, even in patients needing transfusions, in comparison with a few years ago, but the quality of life is poor for many patients. In some patients, an anomalous expression of gamma-globin genes has been observed, with a consequent rise in Fetal Hemoglobin levels. The patients displaying a clinical phenotype known as Hereditary Persistence of Fetal Hemoglobin (HPFH) exhibit a positive clinical status. To mimick HPFH, several compounds able to induce expression of fetal hemoglobins (HbF) have been evaluated. Within this framework, sirolimus is particularly interesting as an inducer of HbF. It has been used for many years for different indications and the available preclinical evidence warrant the start of a clinical development plan in thalassemia. The investigators propose a clinical trial in beta-thalassemia patients, designed to evaluate the effect of sirolimus on several parameters related to red blood cell status and to the level of HbF in particular, as a first step for the full clinical development in this new indication.
Detailed Description
The general aim of the protocol is to demonstrate the applicability of a personalised and precision medicine approach in beta-thalassemia in a clinical trial setting for a repurposed drug, namely sirolimus. The presence of high level of Fetal Hemoglobin (HbF) is considered a condition predictive of a favourable outcome in thalassemia and its increase induced by pharmacological agents is considered a potential way to improve clinical status of the patients. In the present trial, in terms of efficacy analysis, the investigators will focus their attention on HbF levels. Primary objective: • To evaluate the suitability of sirolimus for the treatment of beta-thalassemia patients within the frame of a comprehensive project aimed to the reduction of their transfusions need (consequently ameliorating their quality of life). This goal can be obtained through a pharmacologically mediated increased level of HbF, with a prerequisite to be verified, namely the correlation between induction of HbF in vitro and in vivo in single patients. Secondary objectives: * To assess safety of sirolimus and correlation between administered dose and blood levels in beta-thalassemia patients, * To assess the influence of sirolimus on transfusion regimen * To assess the effect of sirolimus on hematopoietic and immune system of thalassemia patients.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- •Patient treated with hydroxyurea at selection visit or in the last 6 months;
- •Ongoing treatment with drugs possibly affecting sirolimus actions;
- •Documented aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3x Upper Limit of Normal (ULN) at selection;
- •Documented Platelet count \<150.000/microliter and \>1.000.000/microliter at selection;
- •Heart failure as classified by the New York Heart Association (NYHA) classification 3 or higher;
- •Uncontrolled hypertension defined as systolic blood pressure (BP) ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg;
- •Significant arrhythmia requiring treatment,
- •Corrected QT interval\> 450 msec on selection ECG;
- •Ejection fraction \<50% by echocardiogram, multiple gated acquisition scan or cardiac magnetic resonance;
- •Myocardial infarction within 6 months prior of selection;
Arms & Interventions
Open label trial
Sirolimus 0.5 mg tablets
Intervention: Sirolimus 0.5 mg
Outcomes
Primary Outcomes
Change from baseline of fetal hemoglobin level
Time Frame: 360 days
Fetal hemoglobin level in peripheral blood at day 360 compared to day 0, assessed through high pressure liquid chromatography (HPLC)
Secondary Outcomes
- Change from baseline of biomarkers for haemolysis(360 days)
- Change from baseline of Iron status(360 days)
- Change from baseline of biomarkers for erythropoiesis(360 days)
- Change from baseline of γ-globin expression(360 days)
- Change from baseline of fetal hemoglobin level(180 days)
- Change from baseline of tranfusion needs(360 days)
- Change from baseline of Immune function(360 days)
- Change from baseline of Quality of Life(360 days)