The BENeFiTS Trial in Beta Thalassemia Intermedia (PB04-001)

April 1, 2024 updated by: Phoenicia BioScience

A Phase 1b Sequential Open Label Dose-Ranging Study of Safety, Pharmacokinetics, and Preliminary Activity of Benserazide in Subjects With Beta Thalassemia Intermedia and Sickle Cell Disease

Beta-thalassemias and hemoglobinopathies are serious inherited blood diseases caused by abnormal or deficiency of beta A chains of hemoglobin, the protein in red blood cells which delivers oxygen throughout the body.The diseases are characterized by hemolytic anemia, organ damage, and early mortality without treatment. Increases in another type of (normal) hemoglobin, fetal globin (HbF), which is normally silenced in infancy, reduces anemia and morbidity. Even incremental augmentation of fetal globin is established to reduce red blood cell pathology, anemia, certain complications, and to improve survival.

This trial will evaluate an oral drug discovered in a high throughput screen, which increases fetal globin protein (HbF and red blood cells expressing HbF)and messenger ribonucleic acid (mRNA) to high levels in anemic nonhuman primates and in transgenic mice. The study drug acts by suppressing 4 repressors of the fetal globin gene promoter in progenitor cells from patients. The drug has been used for 50 years in a combination product for different actions - to enhance half-life and reduce side effects of a different active drug- and is considered safe for long-term use.

This trial will first evaluate 3 dose levels in small cohorts of nontransfused patients with beta thalassemia intermedia. The most active dose will then be evaluated in larger subject groups with beta thalassemia and other hemoglobinopathies, such as sickle cell disease.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The study will first evaluate 3 doses of the investigational drug which are considered safe with chronic use in a combination therapeutic used widely for a different disease in Europe and Canada. The doses to be studied are human equivalent doses of doses that are active in nonhuman primates in inducing high level fetal globin messenger ribonucleic acid (mRNA), protein, and proportions of red blood cells expressing fetal globin protein (F-cells). Additive effects are observed with hydroxyurea in sickle cell patients' cells in vitro.

The study will first evaluate the study therapeutic in male and female patients who are 18 years and older. After a screening period to obtain baseline medical and laboratory data, the study drug will be taken by mouth once per day, every other day. The first dose will be taken in a clinical unit, and thereafter will be taken at home for 12 weeks. Laboratory tests, physical exams, and tolerability will be assessed 6 times over 4 months, including for one month after completion of dosing.

The cohorts will be enrolled sequentially. Each new cohort will begin after the prior lower dose cohort has received 2 weeks of treatment without serious adverse events related to the study drug. The dose that increases fetal globin assays to the highest degree will be evaluated in a larger group of subjects with beta thalassemia intermedia and a groups with sickle cell disease. Other regimens or test doses may be added as needed to identify an active dose and regimen. The study drug is expected to be safe when added to most other medications used to treat thalassemia.

Study Type

Interventional

Enrollment (Estimated)

36

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Susan Perrine, MD
  • Phone Number: 617 335-7002
  • Email: sperrine@bu.edu

Study Contact Backup

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5G2C4
        • Recruiting
        • University Health Network and Toronto General Hospital
        • Contact:
        • Contact:
  • United States
    • California
      • Oakland, California, United States, 94609
        • Completed
        • UCSF Benioff Children's Hospital at Oakland
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Completed
        • Massachusetts General Hospital
      • Weston, Massachusetts, United States, 02493
        • Active, not recruiting
        • Susan Perrine
    • New York
      • New York, New York, United States, 10065
        • Completed
        • Weil Cornell Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Beta thalassemia intermedia (BTI) or (NTDT, Non-Transfusion Dependent Thalassemia) with at least one documented beta thalassemia mutation, including HbE beta thalassemia or an established diagnosis of sickle cell disease
  • >18 years of age at time of consent
  • Average of 2 total hemoglobin (Hgb) levels between 6.0 and 10.0 g/dL in the preceding 6 months
  • Able and willing to give consent and comply with all study procedures
  • If female and of childbearing potential, must have a documented negative pregnancy test prior to entry and agree to use one or more locally medically accepted methods of contraception

Exclusion Criteria:

  • Red blood cell (RBC) transfusion within 2 months prior to administration of study medication
  • Participating in a chronic transfusion program
  • Pulmonary hypertension requiring oxygen therapy
  • Use of erythropoiesis stimulating agents within 90 days of first dose
  • Transaminases > 3 times upper limit of institution normal (ULN)
  • Total and direct bilirubin > 3 times institution ULN unless due solely to hemolysis
  • Known infection with HIV or hepatitis C (untreated)
  • Fever > 38.5°C in the week prior to first administration of study medication
  • History of osteoporosis or osteomalacia with a fragility fracture
  • Received other investigational systemic therapy within 30 days prior to first dose
  • Narrow angle glaucoma
  • Currently pregnant or breast feeding a child
  • Known current drug or alcohol abuse
  • Taking monoamine oxidase inhibitors
  • Other co-morbidity that substantially increases subject risk for the study per Investigator discretion

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Low dose
A low dose, by mouth, once per day, on Monday, Wednesday, and Friday for 12 weeks
Drug: Benserazide Only Product
Investigational drug
Experimental: Middle dose
A middle dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 weeks
Drug: Benserazide Only Product
Investigational drug
Experimental: High dose 3 days per week
Highest dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 to 24 weeks
Drug: Benserazide Only Product
Investigational drug
Experimental: High dose 5 days per week
The highest dose, by mouth once per day on 5 days per week for 24 weeks
Drug: Benserazide Only Product
Investigational drug
Experimental: Sickle Cell Disease Arm
The most active dose given once per day on the most active regimen for up 24 weeks
Drug: Benserazide Only Product
Investigational drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety and Tolerability
Time Frame: 12 to 24 weeks
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
12 to 24 weeks
Maximum plasma concentration (Cmax)
Time Frame: 4 weeks
drug concentration (ng/ml)
4 weeks
Plasma drug concentration over time
Time Frame: 4 weeks
Area under the curve
4 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
F-cells
Time Frame: 12 to 24 weeks
% Red blood cells containing HbF
12 to 24 weeks
HbF protein per cell
Time Frame: 12 to 24 weeks
Mean fluorescent intensity (MFI)
12 to 24 weeks
Fetal hemoglobin (HbF)
Time Frame: 12 to 24 weeks
% and absolute (g/dl)
12 to 24 weeks
Hemoglobin
Time Frame: 16 to 24 weeks
gram/dl
16 to 24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Phoenicia BioScience

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Study Director: Susan Perrine, MD, Phoenicia BioScience
  • Principal Investigator: Kevin Kuo, MD, University Health Network, Toronto General Hospital
  • Principal Investigator: Sylvia Singer, MD, UCSF Benioff Children's Hospital at Oakland
  • Principal Investigator: Hanny D Al-Samkari, MD, Massachusetts General Hospital
  • Principal Investigator: Sujit Sheth, MD MS, Weill Medical College of Cornell University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 5, 2020

Primary Completion (Estimated)

December 31, 2024

Study Completion (Estimated)

February 28, 2025

Study Registration Dates

First Submitted

June 9, 2020

First Submitted That Met QC Criteria

June 11, 2020

First Posted (Actual)

June 16, 2020

Study Record Updates

Last Update Posted (Actual)

April 3, 2024

Last Update Submitted That Met QC Criteria

April 1, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PB04-001
  • R33HL147845 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Results will be provided in abstracts as the study is being conducted and in a publication after completion and analysis.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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