COMPLETED

Study of the Selective GlyT1 Inhibitor Bitopertin for Steroid-Refractory Diamond-Blackfan Anemia

Conditions

Steroid-refractory Diamond-Blackfan Anemia (DBA)Inherited Bone Marrow Failure Syndrome Erythroid Aplasia Iron Homeostasis Ribosomopathy Heme Synthesis Hemoglobin Synthesis

Quick Navigation

Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

Background: Diamond-Blackfan anemia (DBA) is an inherited disease that affects the bone marrow. People with DBA have chronic anemia that can be severe. Many must have frequent transfusions of red blood cells. Current treatments for DBA all have risks of serious side effects. Better treatments are needed. Objective: To test a new drug (bitopertin) in people with DBA. Eligibility: People aged 18 or older with DBA. Design: Participants will be screened. They will have a physical exam; they will have blood tests and a test of their heart function. They will have a bone marrow biopsy: An area of their hip will be numbed, and a needle will be inserted to remove a sample of tissue from inside the bone. Bitopertin is a pill taken by mouth. Participants will take the drug once a day every day for 8 months. They will start with a low dose of the drug; the dosage may increase gradually over time. They will keep a diary to record each dose. Participants will have blood tests every 4 weeks. This may be done in the clinic. Participants may also have telehealth visits; they can have blood drawn at a local lab and sent to the researchers. The bone marrow biopsy and other tests will be repeated after 8 months. Participants who have a positive response to bitopertin will be invited to enter an extended phase of the trial. They may continue to take the drug for 3 more years. Those who choose not to continue in the extended phase may have a follow-up visit 6 months after they stop taking the drug.

Official Title

A Phase I/II, Intra-Patient Dose-Escalation Study of the Selective GlyT1 Inhibitor, Bitopertin for Steroid-Refractory Diamond-Blackfan Anemia.

Quick Facts

Study Start:2023-07-25

Study Completion:2025-08-25

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:COMPLETED

Study ID

NCT05828108

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.

Ages Eligible for Study:18 Years to 100 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
1. Diamond-Blackfan anemia defined as chronic anemia presenting on or before the third year of life, associated with reticulocytopenia and greatly reduced or absent bone marrow erythroid precursors, supported by, but not requiring either: 1. familial history 2. gene mutation testing demonstrating a known disease-causing mutation or a mutation of disease-associated gene in combination with clinical characteristics of DBA 2. Clinically-significant anemia as defined as either: 1. hemoglobin less than 9.0 g/dL 2. red cell transfusion of at least 2 units PRBC for adults in the eight weeks prior to study enrollment 3. Relapsed and/or steroid-refractory disease or patient intolerance of systemic corticosteroids 4. Age \>= 18 years at the time of consent	1. Treatment with androgens (danazol or oxymetholone) or corticosteroids less than 4 weeks prior to initiating bitopertin. 2. Hypersensitivity to bitopertin or its components 3. Patient Health Questionnaire-8 (PHQ-8) score greater than or equal to 10 or imminent suicidal risk identified by the Columbia-Suicide Severity Rating Scale (C-SSRS) as defined as suicidal ideation with intent (grade 4 or 5) within the last year or any suicidal behavior within the last five years 4. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient s ability to tolerate protocol therapy 5. Life expectancy of less than 3 months from any cause 6. History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following: * Recent myocardial infarction (within last 6 months), * Uncontrolled congestive heart failure, * Unstable angina (within last 6 months), * Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third-degree AV block without a pacemaker.) * Long QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome or additional risk factors for cardiac repolarization abnormality, as determined by the investigator * Impaired cardiac function such as corrected QTc\>450msec using Fridericia correction on the screening ECG, other clinically significant cardio-vascular disease (e.g., uncontrolled hypertension, history of labile hypertension), history of known structural abnormalities (e.g. cardiomyopathy). 7. Known active or uncontrolled infections not adequately responding to appropriate therapy. * Note, HIV infection is not exclusive of trial participation if the infection is effectively controlled with medications not known to interfere with bitopertin metabolism or be metabolized by pathways known to be altered by bitopertin. HIV RNA viral load must be undetectable at the time of enrollment, and CD4 cell count must be \>= 200/microL. Patients must remain on antiretroviral therapy throughout study participation and must be periodically monitored for suppression of viral load and CD4 cell count. * If drug-drug interactions between antiretroviral (e.g. HIV), antiviral (e.g., hepatitis), or antifungal medications and bitopertin are suspected (such as lopinavir, ritonavir or other strong CYP3A4 inhibitors), these must be addressed by a qualified clinical pharmacist or pharmacologist, and any changes to antiretroviral therapy need to be approved in consultation with an Infectious Disease and/or HIV specialist prior to enrollment. 8. Evidence for MDS or AML as defined by WHO criteria, or any active malignancy or likelihood of recurrence of malignancies within 12 months 9. Patients who have received chemotherapeutic treatment or other specific antineoplastic drugs or radiation therapy within 6 months of study entry 10. Female subjects who are nursing or pregnant (positive serum or urine beta-human chorionic gonadotrophin (beta-hCG) pregnancy test) at screening/baseline visit 11. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, not using highly effective methods of contraception during dosing and for 30 days after the last dose of bitopertin. Highly effective contraception methods include: * Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post- ovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Male sterilization (at least 6 months prior to screening). For female patients on the study the vasectomized male partner should be the sole partner for that patient. * Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate * In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. * Sexually active males unless they use a condom during intercourse while taking the study treatment and for 30 days after stopping study treatment and should not father a child in this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via seminal fluid. 12. Active alcohol/drug abuse. 13. Unable to understand the investigational nature of the study or give informed consent and does not have a legally authorized representative or surrogate that can provide informed consent. 14. Unable to take the oral study drug. 15. Concurrent participation in an investigational study within 30 days prior to enrollment or within 5-half-lives of the study drug, whichever is longer. Note: parallel enrollment in a disease registry is permitted.

Inclusion Criteria

Exclusion Criteria

1. Diamond-Blackfan anemia defined as chronic anemia presenting on or before the third year of life, associated with reticulocytopenia and greatly reduced or absent bone marrow erythroid precursors, supported by, but not requiring either:
1. familial history
2. gene mutation testing demonstrating a known disease-causing mutation or a mutation of disease-associated gene in combination with clinical characteristics of DBA
2. Clinically-significant anemia as defined as either:
1. hemoglobin less than 9.0 g/dL
2. red cell transfusion of at least 2 units PRBC for adults in the eight weeks prior to study enrollment
3. Relapsed and/or steroid-refractory disease or patient intolerance of systemic corticosteroids
4. Age \>= 18 years at the time of consent

1. Treatment with androgens (danazol or oxymetholone) or corticosteroids less than 4 weeks prior to initiating bitopertin.
2. Hypersensitivity to bitopertin or its components
3. Patient Health Questionnaire-8 (PHQ-8) score greater than or equal to 10 or imminent suicidal risk identified by the Columbia-Suicide Severity Rating Scale (C-SSRS) as defined as suicidal ideation with intent (grade 4 or 5) within the last year or any suicidal behavior within the last five years
4. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient s ability to tolerate protocol therapy
5. Life expectancy of less than 3 months from any cause
6. History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following:
* Recent myocardial infarction (within last 6 months),
* Uncontrolled congestive heart failure,
* Unstable angina (within last 6 months),
* Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third-degree AV block without a pacemaker.)
* Long QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome or additional risk factors for cardiac repolarization abnormality, as determined by the investigator
* Impaired cardiac function such as corrected QTc\>450msec using Fridericia correction on the screening ECG, other clinically significant cardio-vascular disease (e.g., uncontrolled hypertension, history of labile hypertension), history of known structural abnormalities (e.g. cardiomyopathy).
7. Known active or uncontrolled infections not adequately responding to appropriate therapy.
* Note, HIV infection is not exclusive of trial participation if the infection is effectively controlled with medications not known to interfere with bitopertin metabolism or be metabolized by pathways known to be altered by bitopertin. HIV RNA viral load must be undetectable at the time of enrollment, and CD4 cell count must be \>= 200/microL. Patients must remain on antiretroviral therapy throughout study participation and must be periodically monitored for suppression of viral load and CD4 cell count.
* If drug-drug interactions between antiretroviral (e.g. HIV), antiviral (e.g., hepatitis), or antifungal medications and bitopertin are suspected (such as lopinavir, ritonavir or other strong CYP3A4 inhibitors), these must be addressed by a qualified clinical pharmacist or pharmacologist, and any changes to antiretroviral therapy need to be approved in consultation with an Infectious Disease and/or HIV specialist prior to enrollment.
8. Evidence for MDS or AML as defined by WHO criteria, or any active malignancy or likelihood of recurrence of malignancies within 12 months
9. Patients who have received chemotherapeutic treatment or other specific antineoplastic drugs or radiation therapy within 6 months of study entry
10. Female subjects who are nursing or pregnant (positive serum or urine beta-human chorionic gonadotrophin (beta-hCG) pregnancy test) at screening/baseline visit
11. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, not using highly effective methods of contraception during dosing and for 30 days after the last dose of bitopertin. Highly effective contraception methods include:
* Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post- ovulation methods) and withdrawal are not acceptable methods of contraception
* Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
* Male sterilization (at least 6 months prior to screening). For female patients on the study the vasectomized male partner should be the sole partner for that patient.
* Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate
* In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
* Sexually active males unless they use a condom during intercourse while taking the study treatment and for 30 days after stopping study treatment and should not father a child in this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via seminal fluid.
12. Active alcohol/drug abuse.
13. Unable to understand the investigational nature of the study or give informed consent and does not have a legally authorized representative or surrogate that can provide informed consent.
14. Unable to take the oral study drug.
15. Concurrent participation in an investigational study within 30 days prior to enrollment or within 5-half-lives of the study drug, whichever is longer. Note: parallel enrollment in a disease registry is permitted.

Contacts and Locations

Principal Investigator

David J Young, M.D.

PRINCIPAL_INVESTIGATOR

National Heart, Lung, and Blood Institute (NHLBI)

Study Locations (Sites)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892

United States

Collaborators and Investigators

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

David J Young, M.D., PRINCIPAL_INVESTIGATOR, National Heart, Lung, and Blood Institute (NHLBI)

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 Registration Dates

Study Start Date2023-07-25

Study Completion Date2025-08-25

Study Record Updates

Study Start Date2023-07-25

Study Completion Date2025-08-25

Terms related to this study

Keywords Provided by Researchers

Inherited Bone Marrow Failure Syndrome
Erythroid Aplasia
Iron Homeostasis
Ribosomopathy
Heme Synthesis
Hemoglobin Synthesis

Additional Relevant MeSH Terms

Steroid-refractory Diamond-Blackfan Anemia (DBA)