NCT03877809

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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
26

participants targeted

Target at below P25 for phase_2

Timeline
Completed

Started Jun 2019

Typical duration for phase_2

Geographic Reach
1 country

2 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

March 14, 2019

Completed
4 days until next milestone

First Posted

Study publicly available on registry

March 18, 2019

Completed
3 months until next milestone

Study Start

First participant enrolled

June 27, 2019

Completed
2.8 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

April 30, 2022

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

April 30, 2022

Completed
Last Updated

January 23, 2024

Status Verified

January 1, 2024

Enrollment Period

2.8 years

First QC Date

March 14, 2019

Last Update Submit

January 22, 2024

Conditions

Beta-Thalassemia

Keywords

Fetal hemoglobinSirolimusRed Blood Cells

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 (10)

  • Change from baseline of fetal hemoglobin level

    180 days

  • Change from baseline of γ-globin expression

    360 days

  • Change from baseline of biomarkers for erythropoiesis

    360 days

  • Change from baseline of biomarkers for erythropoiesis

    360 days

  • Change from baseline of biomarkers for haemolysis

    360 days

  • +5 more secondary outcomes

Study Arms (1)

Open label trial

EXPERIMENTAL

Sirolimus 0.5 mg tablets

Drug: Sirolimus 0.5 mg

Interventions

Sirolimus 0.5 mgDRUG

Daily administration of 1 or more tablets

Open label trial

Eligibility Criteria

Age18 Years - 65 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

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 of 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;
  • +8 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (2)

Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology

Ferrara, 44121, Italy

Location

Department of Growth and Reproduction Azienda Ospedaliero-Universitaria S.Anna

Ferrara, 44124, Italy

Location

Related Publications (3)

  • Zuccato C, Cosenza LC, Zurlo M, Gasparello J, Papi C, D'Aversa E, Breveglieri G, Lampronti I, Finotti A, Borgatti M, Scapoli C, Stievano A, Fortini M, Ramazzotti E, Marchetti N, Prosdocimi M, Gamberini MR, Gambari R. Expression of gamma-globin genes in beta-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin). Ther Adv Hematol. 2022 Jun 21;13:20406207221100648. doi: 10.1177/20406207221100648. eCollection 2022.

    PMID: 35755297RESULT

  • Zurlo M, Finotti A, Gamberini MR, Gambari R. Co-Induction of ULK-1 and AHSP mRNAs in Erythroid Precursor Cells Isolated From a Sirolimus-Treated beta-Thalassemia Patient: A Case Report Study. Br J Biomed Sci. 2025 Jun 27;82:14311. doi: 10.3389/bjbs.2025.14311. eCollection 2025.

    PMID: 40655320DERIVED

  • Zurlo M, Nicoli F, Proietto D, Dallan B, Zuccato C, Cosenza LC, Gasparello J, Papi C, d'Aversa E, Borgatti M, Scapoli C, Finotti A, Gambari R. Effects of Sirolimus treatment on patients with beta-Thalassemia: Lymphocyte immunophenotype and biological activity of memory CD4+ and CD8+ T cells. J Cell Mol Med. 2023 Feb;27(3):353-364. doi: 10.1111/jcmm.17655. Epub 2023 Jan 10.

    PMID: 36625233DERIVED

MeSH Terms

Conditions

beta-Thalassemia

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

ThalassemiaAnemia, Hemolytic, CongenitalAnemia, HemolyticAnemiaHematologic DiseasesHemic and Lymphatic DiseasesHemoglobinopathiesGenetic Diseases, InbornCongenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

MacrolidesLactonesOrganic Chemicals

Study Design

Study Type
interventional
Phase
phase 2
Allocation
NA
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Model Details: Interventional, pilot, single centre, open-label phase II study with sirolimus in patients with transfusion dependent beta-thalassemia
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

March 14, 2019

First Posted

March 18, 2019

Study Start

June 27, 2019

Primary Completion

April 30, 2022

Study Completion

April 30, 2022

Last Updated

January 23, 2024

Record last verified: 2024-01

Data Sharing

IPD Sharing
Will share

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

Shared Documents
STUDY PROTOCOL, CSR
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(2)