Beta-ThalassemiaPhase 2THALA-RAPNCT04247750
Testing SIROLIMUS in Beta-thalassemia Transfusion Dependent Patients (THALA-RAP)
A Phase 2 study testing Sirolimus 0.5 mg in people with Beta-Thalassemia, run by Università degli Studi di Ferrara at 4 sites in Italy.
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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Beta-Thalassemia
- What is being tested?
- Sirolimus 0.5 mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 45 participants
- Where
- 4 sitesItaly
- Study dates
- 13 Apr 2021to 30 Apr 2022
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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;
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- 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);
Who cannot join
- 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;
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- 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.
Trial locations and contacts
4 sites in 1 country.
Italy4 sites, 4 recruiting
- Recruiting
University of Ferrara Department of Life Sciences and Biotechnology
Ferrara, FE, 44121
Roberto Gambari, PhD, 00390532974443, roberto.gambari@unife.it
- Recruiting
Day Hospital Thalassaemia and Haemoglobinopathies (DHTE) - Azienda Ospedaliero-Universitaria S.Anna of Ferrara
Ferrara, FE, 44124
Maria Rita Gamberini, Dr, 00390532239549, m.gamberini@ospfe.it
Monica Fortini, BSc, 00390532237349, frtmnc@unife.it
- Recruiting
Thalassemia and Hemoglobinopathies Center Azienda Ospedaliero Universitaria Meyer
Florence, Fi, 50139
Tommaso Casini, Dr, 0039 055 5662580, tommaso.casini@meyer.it
- Recruiting
Pediatric oncohematology Azienda Ospedaliero Universitaria Pisana Ospedale Santa Chiara
Pisa, Pi, 56126
Francesco Massei, Dr, 0039 050 992842, f.massei@med.unipi.it
About this study
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
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.
Read the 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.
- Conditions
- Beta-Thalassemia
- Being tested
- Sirolimus 0.5 mg
- Keywords
- rapamycin, erythroid differentiation, γ-globin, fetal haemoglobin
- Medical subject headings
- beta-Thalassemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sirolimus 0.5 mgDrug
Daily administration of 1 or more tablets
| Study group | Role | What they receive |
|---|---|---|
| Open label trial | Experimental | Sirolimus 0.5 mg tablets Receives: Drug: Sirolimus 0.5 mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
Measured: 360 days
Secondary outcomes (15)
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
Measured: 90-180 days
Change from baseline of γ-globin expression
Level of induction of the γ-globin expression at day 90, 180 and 360 compared to day 0
Measured: 90-180-360 days
Change from baseline of biomarkers for erythropoiesis
- Evaluation of the Reticulocytes number at day 180 and 360 compared to baseline.
Measured: 180-360 days
Change from baseline of biomarkers for erythropoiesis
- Evaluation of the Nucleated red blood cells number at day 180 and 360 compared to baseline.
Measured: 180-360 days
Change from baseline of biomarkers for erythropoiesis
- Evaluation of the erythropoietin level at day 180 and 360 compared to baseline.
Measured: 180-360 days
Change from baseline of biomarkers for erythropoiesis
- Evaluation of the serum transferrin receptor level at day 180 and 360 compared to baseline.
Measured: 180-360 days
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
Measured: 180-360 days
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
Measured: 180-360 days
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)
Measured: 360 days
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)
Measured: 360 days
Change from baseline of Iron status
- Evaluation of the intake of iron chelators at days 180 and 360 compared to baseline
Measured: 180-360 days
Change from baseline of Iron status
- Evaluation of serum ferritin level at day 90, 180 and 360 in comparison with day 0
Measured: 90-180-360 days
Change from baseline of Immune function
- Peripheral blood immunophenotype-Lymphocyte subsets at day 90 and 360 compared to day 0
Measured: 90-360 days
Change from baseline of Immune function
- Quantitative analysis of ImmunoglobulinG/ImmunoglobulinA/ImunoglobulinM at day 90 and 360 compared to day 0
Measured: 90-360 days
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
Measured: 360 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jan 2020
- Study start13 Apr 2021
- Primary completion30 Apr 2022 (estimated)
- Study completion30 Apr 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Beta-ThalassemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Interventional, pilot, open-label phase II study with sirolimus in patients with transfusion-dependent beta-thalassemia
- Masking
- None (open label)
- Enrolment
- 45 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Università degli Studi di Ferrara
- Sponsor type
- University, hospital or other
- Collaborators
- Rare Partners srl Impresa Sociale, Meyer Children's Hospital IRCCS, Azienda Ospedaliero, Universitaria Pisana
- Responsible party
- Principal investigator, Maria Rita Gamberini, Azienda USL Ferrara
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04247750
- Sponsor's protocol ID
- 2018-001469-18 (EudraCT num)
- Other IDs
- 2018
- Acronym
- THALA-RAP
- Status last verified
- Nov 2021
- First submitted
- 8 Jan 2020
- Last updated
- 12 Nov 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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
Study at a glance
From the registry record, last updated by the sponsor on 12 Nov 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04247750
- Acronym / sponsor ID
- THALA-RAP / 2018-001469-18 (EudraCT num)
- Conditions
- Beta-Thalassemia
- Keywords
- rapamycin, erythroid differentiation, γ-globin, fetal haemoglobin
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 45 participants (estimated)
- Lead sponsor
- Università degli Studi di FerraraUniversity, hospital or other
- Collaborators
- Rare Partners srl Impresa Sociale, Meyer Children's Hospital IRCCS, Azienda Ospedaliero, Universitaria Pisana
- Study start
- 13 Apr 2021 (actual)
- Primary completion
- 30 Apr 2022 (estimated)
- Study completion
- 30 Apr 2022 (estimated)
- First posted
- 30 Jan 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Interventional, pilot, open-label phase II study with sirolimus in patients with transfusion-dependent beta-thalassemia
| Arm | Type | Receives |
|---|---|---|
| Open label trial | Experimental | Drug: Sirolimus 0.5 mgSirolimus 0.5 mg tablets |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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;
Key exclusion criteria (24 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sirolimus 0.5 mgDaily administration of 1 or more tablets | Drug | Open label trial |
Primary outcome
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)
15 secondary outcomes
Change from baseline of fetal hemoglobin level
Time frame: 90-180 days
Change from baseline of γ-globin expression
Time frame: 90-180-360 days
Change from baseline of biomarkers for erythropoiesis
Time frame: 180-360 days
Change from baseline of biomarkers for erythropoiesis
Time frame: 180-360 days
Change from baseline of biomarkers for erythropoiesis
Time frame: 180-360 days
Change from baseline of biomarkers for erythropoiesis
Time frame: 180-360 days
Change from baseline of biomarkers for haemolysis
Time frame: 180-360 days
Change from baseline of biomarkers for haemolysis
Time frame: 180-360 days
Change from baseline of tranfusion needs
Time frame: 360 days
Change from baseline of tranfusion needs
Time frame: 360 days
Change from baseline of Iron status
Time frame: 180-360 days
Change from baseline of Iron status
Time frame: 90-180-360 days
Change from baseline of Immune function
Time frame: 90-360 days
Change from baseline of Immune function
Time frame: 90-360 days
Change from baseline of Quality of Life
Time frame: 360 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Nov 2021.
- Individual participant dataSharing planned: Yes. 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
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Sirolimus 0.5 mg in people with Beta-Thalassemia, run by Università degli Studi di Ferrara at 4 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 12 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Roberto Gambari, Ph.D. (00390532974443, roberto.gambari@unife.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change from baseline of fetal hemoglobin level (time frame: 360 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Nov 2021.