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

Primary Purpose

Beta Thalassemia Intermedia, Sickle Cell Disease

Status

Recruiting

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Benserazide Only Product

About this trial

This is an interventional treatment trial for Beta Thalassemia Intermedia focused on measuring Non-transfusion dependent beta thalassemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

UCSF Benioff Children's Hospital at OaklandRecruiting
Massachusetts General HospitalRecruiting
Susan Perrine
Weil Cornell MedicineRecruiting
University Health Network and Toronto General HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Low dose

Middle dose

High dose 3 days per week

High dose 5 days per week

Sickle Cell Disease Arm

Arm Description

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

A middle dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 weeks

Highest dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 to 24 weeks

The highest dose, by mouth once per day on 5 days per week for 24 weeks

The most active dose given once per day on the most active regimen for up 24 weeks

Outcomes

Primary Outcome Measures

Safety and Tolerability

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Maximum plasma concentration (Cmax)

drug concentration (ng/ml)

Minimum plasma drug concentration (Cmin)

Minimum drug plasma concentration, (ng/ml)

Plasma drug concentration over time

area under the curve

Secondary Outcome Measures

F-cells

% Red blood cells containing HbF

HbF protein per cell

Mean fluorescent intensity (MFI)

Fetal hemoglobin (HbF)

% and absolute (g/dl)

Hemoglobin

gram/dl

Full Information

NCT ID

NCT04432623

First Posted

June 9, 2020

Last Updated

April 9, 2022

Sponsor

Phoenicia BioScience

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT04432623

Brief Title

The BENeFiTS Trial in Beta Thalassemia Intermedia

Acronym

PB04-001

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2022

Overall Recruitment Status

Recruiting

Study Start Date

October 5, 2020 (Actual)

Primary Completion Date

December 2023 (Anticipated)

Study Completion Date

December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Phoenicia BioScience

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Beta Thalassemia Intermedia, Sickle Cell Disease

Keywords

Non-transfusion dependent beta thalassemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

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)

Allocation

Non-Randomized

Enrollment

36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Low dose

Arm Type

Experimental

Arm Description

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

Arm Title

Middle dose

Arm Type

Experimental

Arm Description

A middle dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 weeks

Arm Title

High dose 3 days per week

Arm Type

Experimental

Arm Description

Highest dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 to 24 weeks

Arm Title

High dose 5 days per week

Arm Type

Experimental

Arm Description

The highest dose, by mouth once per day on 5 days per week for 24 weeks

Arm Title

Sickle Cell Disease Arm

Arm Type

Experimental

Arm Description

The most active dose given once per day on the most active regimen for up 24 weeks

Intervention Type

Drug

Intervention Name(s)

Benserazide Only Product

Intervention Description

Investigational drug

Primary Outcome Measure Information:

Title

Safety and Tolerability

Description

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Time Frame

12 to 24 weeks

Title

Maximum plasma concentration (Cmax)

Description

drug concentration (ng/ml)

Time Frame

4 weeks

Title

Minimum plasma drug concentration (Cmin)

Description

Minimum drug plasma concentration, (ng/ml)

Time Frame

4 weeks

Title

Plasma drug concentration over time

Description

area under the curve

Time Frame

4 weeks

Secondary Outcome Measure Information:

Title

F-cells

Description

% Red blood cells containing HbF

Time Frame

12 to 24 weeks

Title

HbF protein per cell

Description

Mean fluorescent intensity (MFI)

Time Frame

12 to 24 weeks

Title

Fetal hemoglobin (HbF)

Description

% and absolute (g/dl)

Time Frame

12 to 24 weeks

Title

Hemoglobin

Description

gram/dl

Time Frame

16 to 24 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Susan Perrine, MD

Phone

617 335-7002

sperrine@bu.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Melissa Askin, RN

Phone

410 231-1512

Melissa.Askin@acroclinical.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Susan Perrine, MD

Organizational Affiliation

Phoenicia BioScience

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Kevin Kuo, MD

Organizational Affiliation

University Health Network, Toronto General Hospital

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Sylvia Singer, MD

Organizational Affiliation

UCSF Benioff Children's Hospital at Oakland

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Hanny D Al-Samkari, MD

Organizational Affiliation

Massachusetts General Hospital

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Sujit Sheth, MD MS

Organizational Affiliation

Weill Medical College of Cornell University

Official's Role

Principal Investigator

Facility Information:

Facility Name

UCSF Benioff Children's Hospital at Oakland

City

Oakland

State/Province

California

ZIP/Postal Code

94609

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Sylvia Singer, MD

Phone

510-428-3169

Sylvia.Singer@UCSF.edu

First Name & Middle Initial & Last Name & Degree

Diego Martinez Mendiola, BA

Phone

510- 428-3885

Ext

5361

Diego.martinezmendiola@UCSF.edu

First Name & Middle Initial & Last Name & Degree

Ashtosh Lal, MD

First Name & Middle Initial & Last Name & Degree

Elliott P Vichinsky, MD

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Hanny Al-Samkari, MD

Phone

617-643-6214

hal-samkari@mgh.harvard.edu

Facility Name

Susan Perrine

City

Weston

State/Province

Massachusetts

ZIP/Postal Code

02493

Country

United States

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Susan Perrine, MD

Phone

617-335-7002

Sperrine@bu.edu

Facility Name

Weil Cornell Medicine

City

New York

State/Province

New York

ZIP/Postal Code

10065

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Sujit Sheth, MD

Phone

212-746-3400

shethsu@med.cornell.edu

First Name & Middle Initial & Last Name & Degree

Sujit Sheth, MD,MS

Facility Name

University Health Network and Toronto General Hospital

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G2C4

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Kevin Kuo, MD

Phone

416 340-4800

Ext

6729

Kevin.Kuo@uhn.ca

First Name & Middle Initial & Last Name & Degree

RBCD Trial Info Cellphone

Phone

437 929-5158

rbcd.clinicaltrials@uhn.ca

First Name & Middle Initial & Last Name & Degree

Jacob Prendergast, MD

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing 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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The BENeFiTS Trial in Beta Thalassemia Intermedia

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