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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04432623
Recruitment Status : Recruiting
First Posted : June 16, 2020
Last Update Posted : April 15, 2022
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Phoenicia BioScience

Study Description
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Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Beta Thalassemia Intermedia Sickle Cell Disease Drug: Benserazide Only Product Phase 1 Phase 2

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.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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Each higher dose level cohort will be enrolled after 2 weeks of treatment in the lower dose level. Additional doses or regimens may be added. Expansion cohorts at the most active dose will be evaluated.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Sequential Open Label Dose-Ranging Study of Safety, Pharmacokinetics, and Preliminary Activity of Benserazide in Subjects With Beta Thalassemia Intermedia
Actual Study Start Date : October 5, 2020
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Thalassemia

Arms and Interventions
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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


Outcome Measures
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Primary Outcome Measures :
  1. Safety and Tolerability [ Time Frame: 12 to 24 weeks ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  2. Maximum plasma concentration (Cmax) [ Time Frame: 4 weeks ]
    drug concentration (ng/ml)

  3. Minimum plasma drug concentration (Cmin) [ Time Frame: 4 weeks ]
    Minimum drug plasma concentration, (ng/ml)

  4. Plasma drug concentration over time [ Time Frame: 4 weeks ]
    area under the curve


Secondary Outcome Measures :
  1. F-cells [ Time Frame: 12 to 24 weeks ]
    % Red blood cells containing HbF

  2. HbF protein per cell [ Time Frame: 12 to 24 weeks ]
    Mean fluorescent intensity (MFI)

  3. Fetal hemoglobin (HbF) [ Time Frame: 12 to 24 weeks ]
    % and absolute (g/dl)

  4. Hemoglobin [ Time Frame: 16 to 24 weeks ]
    gram/dl


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Beta thalassemia intermedia (BTI) or (NTDT, Non-Transfusion Dependent Thalassemia) with at least one documented beta thalassemia mutation, including HbE beta thalassemia
  • >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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04432623


Contacts
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Contact: Susan Perrine, MD 617 335-7002 sperrine@bu.edu
Contact: Melissa Askin, RN 410 231-1512 Melissa.Askin@acroclinical.com

Locations
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United States, California
UCSF Benioff Children's Hospital at Oakland Recruiting
Oakland, California, United States, 94609
Contact: Sylvia Singer, MD    510-428-3169    Sylvia.Singer@UCSF.edu   
Contact: Diego Martinez Mendiola, BA    510- 428-3885 ext 5361    Diego.martinezmendiola@UCSF.edu   
Sub-Investigator: Ashtosh Lal, MD         
Sub-Investigator: Elliott P Vichinsky, MD         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Hanny Al-Samkari, MD    617-643-6214    hal-samkari@mgh.harvard.edu   
Susan Perrine Not yet recruiting
Weston, Massachusetts, United States, 02493
Contact: Susan Perrine, MD    617-335-7002    Sperrine@bu.edu   
United States, New York
Weil Cornell Medicine Recruiting
New York, New York, United States, 10065
Contact: Sujit Sheth, MD    212-746-3400    shethsu@med.cornell.edu   
Principal Investigator: Sujit Sheth, MD,MS         
Canada, Ontario
University Health Network and Toronto General Hospital Recruiting
Toronto, Ontario, Canada, M5G2C4
Contact: Kevin Kuo, MD    416 340-4800 ext 6729    Kevin.Kuo@uhn.ca   
Contact: RBCD Trial Info Cellphone    437 929-5158    rbcd.clinicaltrials@uhn.ca   
Sub-Investigator: Jacob Prendergast, MD         
Sponsors and Collaborators
Phoenicia BioScience
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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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
More Information
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Publications:

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Responsible Party: Phoenicia BioScience
ClinicalTrials.gov Identifier: NCT04432623    
Other Study ID Numbers: PB04-001
R33HL147845 ( U.S. NIH Grant/Contract )
First Posted: June 16, 2020    Key Record Dates
Last Update Posted: April 15, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Results will be provided in abstracts as the study is being conducted and in a publication after completion and analysis.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Phoenicia BioScience:
Non-transfusion dependent beta thalassemia
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Thalassemia
beta-Thalassemia
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
 Benserazide
Antiparkinson Agents
Anti-Dyskinesia Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Dopamine Agents
Neurotransmitter Agents
Physiological Effects of Drugs