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

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ClinicalTrials.gov Identifier: NCT04432623

Recruitment Status : Recruiting

First Posted : June 16, 2020

Last Update Posted : April 15, 2022

See Contacts and Locations

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborator:

National Heart, Lung, and Blood Institute (NHLBI)

Information provided by (Responsible Party):

Phoenicia BioScience

Tracking Information

First Submitted Date ^ICMJE

June 9, 2020

First Posted Date ^ICMJE

June 16, 2020

Last Update Posted Date

April 15, 2022

Actual Study Start Date ^ICMJE

October 5, 2020

Estimated Primary Completion Date

December 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

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

Original Primary Outcome Measures ^ICMJE

Safety and Tolerability [ Time Frame: 12 weeks ]
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Plasma drug concentration over time [ Time Frame: 4 weeks ]
area under the curve
Maximum plasma concentration (Cmax) [ Time Frame: 4 weeks ]
drug concentration (ng/ml)
Minimum plasma drug concentration (Cmin) [ Time Frame: 4 weeks ]
Minimum drug plasma concentration, (ng/ml)

Change History

Current Secondary Outcome Measures ^ICMJE

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

Original Secondary Outcome Measures ^ICMJE

Fetal hemoglobin (HbF) [ Time Frame: 12 weeks ]
% and absolute (g/dl)
Hemoglobin [ Time Frame: 16 weeks ]
gram/dl
F-cells [ Time Frame: 12 weeks ]
% Red blood cells containing HbF
HbF protein per cell [ Time Frame: 12 weeks ]
Mean fluorescent intensity (MFI)
Lactate dehydrogenase (LDH) [ Time Frame: 12 weeks ]
U/L

Current Other Pre-specified Outcome Measures

Not Provided

Original Other Pre-specified Outcome Measures

Not Provided

Descriptive Information

Brief Title ^ICMJE

The BENeFiTS Trial in Beta Thalassemia Intermedia

Official Title ^ICMJE

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

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.

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 Type ^ICMJE

Interventional

Study Phase ^ICMJE

Phase 1
Phase 2

Study Design ^ICMJE

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

Condition ^ICMJE

Beta Thalassemia Intermedia
Sickle Cell Disease

Intervention ^ICMJE

Drug: Benserazide Only Product

Investigational drug

Study Arms ^ICMJE

Experimental: Low dose
A low dose, by mouth, once per day, on Monday, Wednesday, and Friday for 12 weeks

Intervention: Drug: Benserazide Only Product
Experimental: Middle dose
A middle dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 weeks

Intervention: Drug: Benserazide Only Product
Experimental: High dose 3 days per week
Highest dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 to 24 weeks

Intervention: Drug: Benserazide Only Product
Experimental: High dose 5 days per week
The highest dose, by mouth once per day on 5 days per week for 24 weeks

Intervention: Drug: Benserazide Only Product
Experimental: Sickle Cell Disease Arm
The most active dose given once per day on the most active regimen for up 24 weeks

Intervention: Drug: Benserazide Only Product

Publications *

* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ^ICMJE

Recruiting

Estimated Enrollment ^ICMJE

Original Estimated Enrollment ^ICMJE

Same as current

Estimated Study Completion Date ^ICMJE

December 2023

Estimated Primary Completion Date

December 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

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

Sex/Gender ^ICMJE

Sexes Eligible for Study:

All

Ages ^ICMJE

18 Years and older (Adult, Older Adult)

Accepts Healthy Volunteers ^ICMJE

Contacts ^ICMJE

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

Listed Location Countries ^ICMJE

Canada, United States

Removed Location Countries

Administrative Information

NCT Number ^ICMJE

NCT04432623

Other Study ID Numbers ^ICMJE

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

Has Data Monitoring Committee

Yes

U.S. FDA-regulated Product

Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No

IPD Sharing Statement ^ICMJE

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.

Current Responsible Party

Phoenicia BioScience

Original Responsible Party

Same as current

Current Study Sponsor ^ICMJE

Phoenicia BioScience

Original Study Sponsor ^ICMJE

Same as current

Collaborators ^ICMJE

National Heart, Lung, and Blood Institute (NHLBI)

Investigators ^ICMJE

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

PRS Account

Phoenicia BioScience

Verification Date

April 2022

^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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