Testing SIROLIMUS in Beta-thalassemia Transfusion Dependent Patients (THALA-RAP)

NCT04247750 | Unknown Phase 2 DMC

• 1 other identifier: 2018-001469-18 (EudraCT num)
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 4

Brief Summary

In β-thalassaemia and Sickle Cell Disease (SCD), a significant production of fetal haemoglobin (HbF) may reduce the severity of clinical course and reactivation of γ-globin gene expression in adulthood. HbF induction is one of the best strategies to ameliorate the characteristic symptoms of these diseases. Hydroxyurea (HU) is the only medication, approved by the US Food and Drug Administration, inducing HbF. However, treatments with HU induce sufficient HbF levels in only half of the patients, and side effects including leukopenia and neutropenia are frequently reported. Therefore, novel therapeutic inducers must be identified to develop a personalized treatment in β-thalassaemia and sickle cell anaemia. The availability of new treatments depends on drugs already approved for other indications, and on pharmacokinetics and pharmacovigilance already assessed. Rapamycin (as Sirolimus) is an immunosuppressant agent, approved by the FDA for acute rejection prevention in renal transplant recipients. The ability of this drug to induce γ-globin gene expression in erythroleukemia cell line and erythroid precursors cells (ErPCs) in ß-thalassaemia patients is already known. A clinical investigation on the effects of sirolimus in ß-Thalassaemia aims to evaluate several parameters related to red blood cell status and HbF levels and is a first step for the full clinical development in this new indication.

Conditions

Beta-Thalassemia

Keywords

rapamycin; erythroid differentiation; γ-globin; fetal haemoglobin

Outcome Measures

Primary Outcomes (1)

• Change from baseline of fetal hemoglobin level

  Fetal hemoglobin level in peripheral blood at day 360 compared to day 0, assessed through high pressure liquid chromatography (HPLC)

  360 days

Secondary Outcomes (15)

• Change from baseline of fetal hemoglobin level

  90-180 days

• Change from baseline of γ-globin expression

  90-180-360 days

• Change from baseline of biomarkers for erythropoiesis

  180-360 days

• Change from baseline of biomarkers for erythropoiesis

  180-360 days

• Change from baseline of biomarkers for erythropoiesis

  180-360 days

Study Arms (1)

Open label trial

EXPERIMENTAL

Sirolimus 0.5 mg tablets

Drug: Sirolimus 0.5 mg

Interventions

Sirolimus 0.5 mg DRUG

Daily administration of 1 or more tablets

Open label trial

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients over 18 years of age;
• Patients able to understand the informed consent and to sign it before any study procedure;
• Patients with β0/β0 and β+/β0 thalassaemia genotype;
• Documented diagnosis of major or intermediate thalassemia transfusion-dependent (number of transfusions not less than 8 over the past 12 months before selection);
• On regular transfusion since at least 6 years;
• Splenectomy performed at least 60 days before selection or spleen largest dimensions \< 20 cm as detected by abdominal echography;
• Female participants who are surgically sterilised/hysterectomised or post-menopausal for longer than 2 years or female participants of childbearing potential using and/or willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or using any other method considered sufficiently reliable by the investigator in individual cases. Patients must be counselled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of sirolimus;
• Patient willing to follow all the study requirements and perform all the study visits and to cooperate with the investigator;
• Patient followed by the same clinical site since at least 6 months.
• Note that patients will be treated with oral sirolimus only in the case their Erythroid Precursor Cells (ErPCs) are responsive to the in vitro treatment with sirolimus according to laboratory-specific definition (≥ 20% increase of HbF in comparison with samples not treated with sirolimus);

You may not qualify if:

• 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 to selection;
• Positivity for human immunodeficiency virus (HIV) antibody, active hepatitis B (HBV) or hepatitis C (HCV) as demonstrated by the presence of hepatitis B surface antigen (HBsAg) and a positive HCV-RNA test, HBcAb and HBV-DNA positivity
• White blood cell \[WBC\] count \<3000 cells per μL and/or Granulocytes \<1500/mm3;
• Total cholesterol \> 240 mg/dl;
• Triglycerides \> 200 mg/dl;
• Proteinuria with urinary protein \>1g/24 hrs;

Sponsors & Collaborators

• Università degli Studi di Ferrara: lead
• Rare Partners srl Impresa Sociale: collaborator
• Meyer Children's Hospital IRCCS: collaborator
• Azienda Ospedaliero, Universitaria Pisana: collaborator

Study Sites (4)

University of Ferrara Department of Life Sciences and Biotechnology

Ferrara, FE, 44121, Italy

RECRUITING

Day Hospital Thalassaemia and Haemoglobinopathies (DHTE) - Azienda Ospedaliero-Universitaria S.Anna of Ferrara

Ferrara, FE, 44124, Italy

RECRUITING

Thalassemia and Hemoglobinopathies Center Azienda Ospedaliero Universitaria Meyer

Florence, Fi, 50139, Italy

RECRUITING

Pediatric oncohematology Azienda Ospedaliero Universitaria Pisana Ospedale Santa Chiara

Pisa, Pi, 56126, Italy

RECRUITING

MeSH Terms

Conditions

beta-Thalassemia

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Thalassemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Central Study Contacts

Roberto Gambari, Ph.D.

CONTACT

00390532974443; roberto.gambari@unife.it

Maria Rita Gamberini, MD

CONTACT

00390532239549; m.gamberini@ospfe.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Director

Model Details: Interventional, pilot, open-label phase II study with sirolimus in patients with transfusion-dependent beta-thalassemia

Study Record Dates

• First Submitted: January 8, 2020
• First Posted: January 30, 2020
• Study Start: April 13, 2021
• Primary Completion: April 30, 2022
• Study Completion: April 30, 2022
• Last Updated: November 12, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: After completion of the Clinical Study Report preparation
• Access Criteria: Free availability of the publication. Free availability of the study protocol upon request

Locations

IT (4)