Clinical Trials Logo

Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT04247750
Other study ID # 2018-001469-18 (EudraCT num)
Secondary ID
Status Recruiting
Phase Phase 2
First received
Last updated
Start date April 13, 2021
Est. completion date April 30, 2022

Study information

Verified date November 2021
Source Università degli Studi di Ferrara
Contact Roberto Gambari, Ph.D.
Phone 00390532974443
Email roberto.gambari@unife.it
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Recruiting
Enrollment 45
Est. completion date April 30, 2022
Est. primary completion date April 30, 2022
Accepts healthy volunteers No
Gender All
Age group 18 Years to 65 Years
Eligibility 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 ß0/ß0 and ß+/ß0 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.

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Sirolimus 0.5 mg
Daily administration of 1 or more tablets

Locations

Country Name City State
Italy Day Hospital Thalassaemia and Haemoglobinopathies (DHTE) - Azienda Ospedaliero-Universitaria S.Anna of Ferrara Ferrara FE
Italy University of Ferrara Department of Life Sciences and Biotechnology Ferrara FE
Italy Thalassemia and Hemoglobinopathies Center Azienda Ospedaliero Universitaria Meyer Firenze Fi
Italy Pediatric oncohematology Azienda Ospedaliero Universitaria Pisana Ospedale Santa Chiara Pisa Pi

Sponsors (4)

Lead Sponsor Collaborator
Università degli Studi di Ferrara Azienda Ospedaliero, Universitaria Meyer, Azienda Ospedaliero, Universitaria Pisana, Rare Partners srl Impresa Sociale

Country where clinical trial is conducted

Italy, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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 Change from baseline of fetal hemoglobin level Fetal hemoglobin level in peripheral blood at days 90 and 180 compared to day 0, assessed through HPLC 90-180 days
Secondary Change from baseline of ?-globin expression Level of induction of the ?-globin expression at day 90, 180 and 360 compared to day 0 90-180-360 days
Secondary Change from baseline of biomarkers for erythropoiesis - Evaluation of the Reticulocytes number at day 180 and 360 compared to baseline. 180-360 days
Secondary Change from baseline of biomarkers for erythropoiesis - Evaluation of the Nucleated red blood cells number at day 180 and 360 compared to baseline. 180-360 days
Secondary Change from baseline of biomarkers for erythropoiesis - Evaluation of the erythropoietin level at day 180 and 360 compared to baseline. 180-360 days
Secondary Change from baseline of biomarkers for erythropoiesis - Evaluation of the serum transferrin receptor level at day 180 and 360 compared to baseline. 180-360 days
Secondary Change from baseline of biomarkers for haemolysis - - Evaluation of the biomarkers for haemolysis level at day 180 and 360 compared to baseline. Biomarkers will include: serum bilirubin level 180-360 days
Secondary Change from baseline of biomarkers for haemolysis - - Evaluation of the biomarkers for haemolysis level at day 180 and 360 compared to baseline. Biomarkers will include: serum lactate dehydrogenase (LDH) level 180-360 days
Secondary Change from baseline of tranfusion needs 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) 360 days
Secondary Change from baseline of tranfusion needs 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) 360 days
Secondary Change from baseline of Iron status • Evaluation of the intake of iron chelators at days 180 and 360 compared to baseline 180-360 days
Secondary Change from baseline of Iron status • Evaluation of serum ferritin level at day 90, 180 and 360 in comparison with day 0 90-180-360 days
Secondary Change from baseline of Immune function • Peripheral blood immunophenotype-Lymphocyte subsets at day 90 and 360 compared to day 0 90-360 days
Secondary Change from baseline of Immune function • Quantitative analysis of ImmunoglobulinG/ImmunoglobulinA/ImunoglobulinM at day 90 and 360 compared to day 0 90-360 days
Secondary Change from baseline of Quality of Life 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 360 days
See also
  Status Clinical Trial Phase
Completed NCT00069862 - Iron Balance Study of DFO and GT56-252 in Patients With Transfusional Iron Overload Secondary to Beta-Thalassemia Phase 1/Phase 2
Completed NCT00733811 - Efficacy Study of the Use of Sequential DFP-DFO Versus DFP Phase 4
Completed NCT05506358 - Evaluation of Low-cost Techniques for Detecting Sickle Cell Disease and β-thalassemia in Nepal and Canada N/A
Withdrawn NCT04938635 - Efficacy and Safety Study of Multiple Doses of VIT-2763 in Adults With Transfusion-dependent Beta-thalassemia Phase 2
Active, not recruiting NCT03655678 - A Safety and Efficacy Study Evaluating CTX001 in Subjects With Transfusion-Dependent β-Thalassemia Phase 2/Phase 3
Completed NCT06239389 - Comparison Of Efficacy And Safety Of Thalidomide Vs Hydroxyurea In Thalassemia Patients: A Single-Centre Pilot Study. Phase 2
Recruiting NCT05635266 - Tissue Repository Providing Annotated Biospecimens for Approved Investigator-directed Biomedical Research Initiatives
Completed NCT03271541 - A Study of Bitopertin (RO4917838) in Adults With Non-Transfusion-Dependent (NTD) Beta-Thalassemia Phase 2
Terminated NCT02274233 - Safety and Pharmacokinetic Study of Escalating Doses of SP-420, an Iron Chelator, in Patients With β-Thalassemia Phase 1
Completed NCT01206075 - Evaluating the Safety and Effectiveness of Mozobil Mobilization in Adults With Beta-Thalassemia Major N/A
Recruiting NCT05567458 - A Study to Evaluate Luspatercept (ACE-536) in Chinese Participants Who Require Regular Red Blood Cell Transfusions Due to Beta (β)-Thalassemia. Phase 2
Enrolling by invitation NCT03655223 - Early Check: Expanded Screening in Newborns
Completed NCT03961828 - Hyalornic Acid Level in β-Thalassemic Children Treated for Hepatitis C Virus Phase 4
Recruiting NCT06065189 - Base-edited Autologous Hematopoietic Stem Cell Transplantation in Treating Patients With β-thalassemia Major Early Phase 1
Recruiting NCT04143724 - Study of Safety & PK of Luspatercept (ACE-536) in Pediatric Participants With Beta (β)-Thalassemia Phase 2
Terminated NCT03381833 - A Study With LJPC-401 for the Treatment of Myocardial Iron Overload in Patients With Transfusion-Dependent Beta Thalassemia Phase 2
Completed NCT02268409 - ACE-536 Extension Study - Beta Thalassemia Phase 2
Not yet recruiting NCT01996683 - Efficacy and Safety of Efficacy and Safety of Continued Iron Chelation Therapy In Poly-transfused Thalassemia Patients With Low Serum Ferritin (< 500 ng/ml) N/A
Active, not recruiting NCT01016093 - Zoledronic Acid for the Prevention of Bone Loss Post-bone Marrow Transplantation for Thalassemia Major Patients Phase 2/Phase 3
Completed NCT01039636 - Safety and Pharmacokinetic Study of Escalating Multiple Doses of an Iron Chelator in Patients With Iron Overload Phase 1