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

• ClinicalTrials.gov Identifier: NCT04247750
• Recruitment Status: Recruiting
• First Posted: January 30, 2020
• Last Update Posted: November 12, 2021
• Sponsor: Università degli Studi di Ferrara
• Collaborators: Rare Partners srl Impresa Sociale; Azienda Ospedaliero, Universitaria Meyer; Azienda Ospedaliero, Universitaria Pisana
• Information provided by (Responsible Party): Maria Rita Gamberini, Azienda USL Ferrara

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Beta-Thalassemia	Drug: Sirolimus 0.5 mg	Phase 2

Detailed Description:

The general aim of this protocol is to demonstrate the applicability of a personalised and precision medicine approach in beta-thalassaemia; the clinical trial setting repurposes a drug, namely sirolimus. The presence of high Fetal Hemoglobin (HbF) levels is considered a condition predictive of a favourable outcome in thalassaemia. Its increase induced by pharmacological agents is considered a potential way to improve the clinical status of the patients. In terms of efficacy analysis, the investigators will focus their attention on HbF levels.

Primary objective:

• The suitability evaluation of sirolimus for the treatment of beta-thalassemia patients within the frame of a comprehensive project aimed at the reduction of their transfusions need, with consequent amelioration of their quality of life. The purpose can be achieved through increasing of HbF levels pharmacologically mediated, with verification of a prerequisite, namely the correlation between the induction of HbF in vitro and in vivo in single patients.

Secondary objectives:

• To assess the 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 the hematopoietic and immune system of thalassemia patients.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Interventional, pilot, open-label phase II study with sirolimus in patients with transfusion-dependent beta-thalassemia
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Treatment of Beta-thalassemia Patients With Rapamycin (Sirolimus): From Pre-clinical Research to a Clinical Trial" - "Trattamento di Pazienti Con Beta-talassemia Con Rapamicina (Sirolimus): Dalla Ricerca Pre-clinica ad Uno Studio Clinico
• Actual Study Start Date: April 13, 2021
• Estimated Primary Completion Date: April 30, 2022
• Estimated Study Completion Date: April 30, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Open label trial; Sirolimus 0.5 mg tablets	Drug: Sirolimus 0.5 mg; Daily administration of 1 or more tablets

Outcome Measures

Primary Outcome Measures :

1. 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 Outcome Measures :

1. Change from baseline of fetal hemoglobin level [ Time Frame: 90-180 days ]
   Fetal hemoglobin level in peripheral blood at days 90 and 180 compared to day 0, assessed through HPLC
2. Change from baseline of γ-globin expression [ Time Frame: 90-180-360 days ]
   Level of induction of the γ-globin expression at day 90, 180 and 360 compared to day 0
3. Change from baseline of biomarkers for erythropoiesis [ Time Frame: 180-360 days ]
   - Evaluation of the Reticulocytes number at day 180 and 360 compared to baseline.
4. Change from baseline of biomarkers for erythropoiesis [ Time Frame: 180-360 days ]
   - Evaluation of the Nucleated red blood cells number at day 180 and 360 compared to baseline.
5. Change from baseline of biomarkers for erythropoiesis [ Time Frame: 180-360 days ]
   - Evaluation of the erythropoietin level at day 180 and 360 compared to baseline.
6. Change from baseline of biomarkers for erythropoiesis [ Time Frame: 180-360 days ]
   - Evaluation of the serum transferrin receptor level at day 180 and 360 compared to baseline.
7. Change from baseline of biomarkers for haemolysis [ Time Frame: 180-360 days ]
   - - Evaluation of the biomarkers for haemolysis level at day 180 and 360 compared to baseline. Biomarkers will include: serum bilirubin level
8. Change from baseline of biomarkers for haemolysis [ Time Frame: 180-360 days ]
   - - Evaluation of the biomarkers for haemolysis level at day 180 and 360 compared to baseline. Biomarkers will include: serum lactate dehydrogenase (LDH) level
9. Change from baseline of tranfusion needs [ Time Frame: 360 days ]
   Measurement of the total blood quantity (in mL) transfused (day -360 to -180, day -180 to 0, day 0 to 180, day 180 to 360)
10. Change from baseline of tranfusion needs [ Time Frame: 360 days ]
    Recording of the number of transfusions done in a semester (day -360 to -180, day -180 to 0, day 0 to 180, day 180 to 360)
11. Change from baseline of Iron status [ Time Frame: 180-360 days ]
    • Evaluation of the intake of iron chelators at days 180 and 360 compared to baseline
12. Change from baseline of Iron status [ Time Frame: 90-180-360 days ]
    • Evaluation of serum ferritin level at day 90, 180 and 360 in comparison with day 0
13. Change from baseline of Immune function [ Time Frame: 90-360 days ]
    • Peripheral blood immunophenotype-Lymphocyte subsets at day 90 and 360 compared to day 0
14. Change from baseline of Immune function [ Time Frame: 90-360 days ]
    • Quantitative analysis of ImmunoglobulinG/ImmunoglobulinA/ImunoglobulinM at day 90 and 360 compared to day 0
15. Change from baseline of Quality of Life [ Time Frame: 360 days ]
    Evaluation of the patient quality of life at 6 and 12 months compared to baseline through Transfusion-dependent Quality of Life questionnaire (TranQol), measuring specifically the quality of life in patients with thalassemia. The TranQol is a disease-specific Quality of Life measure that has been shown to be valid and reliable (Klaassen et al, British Journal of Haematology, 2014, 164, 431-437). On a total scale of 0-100, higher values always represent a better outcome. The questions are grouped into four domains: physical health, emotional health, family functioning, and school and career functioning. The adult self-report questionnaires include a fifth category on sexual activity which is only one item. Subscales are summed

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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);

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 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;
• Current participation in another trial with an investigational drug or experimental device, or inclusion in another trial with an investigational drug or experimental device within the preceding month;
• Major surgery (including splenectomy) within 60 days before selection (patients must have fully recovered from any previous surgery);
• Iron chelation therapy changed in the last 3 months prior to selection (note that Deferiprone is not accepted as a chelation therapy drug in this study while Desferrioxamine and Deferasirox are tolerated at stable dose);
• Current treatment with macrolide antibiotics (clarithromycin);
• Pregnant or lactating women;
• History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the experimental drug;
• Treatment with live vaccines within 90 days preceding the selection;
• Subject with history or current malignancies (solid tumours and haematological malignancies) or presence of masses/tumour detected by ultrasound at selection;
• Subject with any significant medical condition and/or laboratory abnormality considered by the investigator as not adequately controlled at the time of selection.

Contacts and Locations

Contacts

Contact: Roberto Gambari, Ph.D.; 00390532974443; roberto.gambari@unife.it

Contact: Maria Rita Gamberini, MD; 00390532239549; m.gamberini@ospfe.it

Locations

Italy

University of Ferrara Department of Life Sciences and Biotechnology; Recruiting

Ferrara, FE, Italy, 44121

Contact: Roberto Gambari, PhD 00390532974443 roberto.gambari@unife.it

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

Ferrara, FE, Italy, 44124

Contact: Maria Rita Gamberini, Dr 00390532239549 m.gamberini@ospfe.it

Contact: Monica Fortini, BSc 00390532237349 frtmnc@unife.it

Thalassemia and Hemoglobinopathies Center Azienda Ospedaliero Universitaria Meyer; Recruiting

Firenze, Fi, Italy, 50139

Contact: Tommaso Casini, Dr 0039 055 5662580 tommaso.casini@meyer.it

Pediatric oncohematology Azienda Ospedaliero Universitaria Pisana Ospedale Santa Chiara; Recruiting

Pisa, Pi, Italy, 56126

Contact: Francesco Massei, Dr 0039 050 992842 f.massei@med.unipi.it

Sponsors and Collaborators

Università degli Studi di Ferrara

Rare Partners srl Impresa Sociale

Azienda Ospedaliero, Universitaria Meyer

Azienda Ospedaliero, Universitaria Pisana

More Information

• Responsible Party: Maria Rita Gamberini, Medical Director, Azienda USL Ferrara
• ClinicalTrials.gov Identifier: NCT04247750
• Other Study ID Numbers: 2018-001469-18 (EudraCT num)
• First Posted: January 30, 2020
• Last Update Posted: November 12, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: At the end of the study the study protocol and the clinical trial report will be available to other researchers. Publication of the data is planned
• Supporting Materials: 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

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Maria Rita Gamberini, Azienda USL Ferrara:

rapamycin; erythroid differentiation; γ-globin; fetal haemoglobin

Additional relevant MeSH terms:

Thalassemia; beta-Thalassemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Sirolimus; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs