Steroid-refractory Diamond-Blackfan Anemia (DBA)Phase 1/2NCT05828108

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

A Phase 1/2 study testing Bitopertin in people with Steroid-refractory Diamond-Blackfan Anemia (DBA), run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

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. Read more about this study

Who is it for?: Ages 18 to 100 years
Conditions the study is for: Steroid-refractory Diamond-Blackfan Anemia (DBA)
What is being tested?: Bitopertin
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 15 participants
Where: 1 siteUnited States
Study dates: 25 Jul 2023to 28 Aug 2025
Phase: Phase 1/2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 100 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

To be eligible to participate in this study, an individual must meet all of the following criteria:
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:
familial history
gene mutation testing demonstrating a known disease-causing mutation or a mutation of disease-associated gene in combination with clinical characteristics of DBA
Patients with late-onset DBA (diagnosed after the third year of life) may also be included if (but only if) gene mutation testing confirms a disease-causing mutation, as above.
Clinically-significant anemia as defined as either:

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hemoglobin less than 9.0 g/dL
red cell transfusion of at least 2 units PRBC for adults in the eight weeks prior to study enrollment
Relapsed and/or steroid-refractory disease or patient intolerance of systemic corticosteroids
Age >= 18 years at the time of consent
Although all patients without a molecular diagnosis (i.e., genetic testing positive for a disease- causing lesion) will undergo targeted gene panel testing for mutations in all known genes associated with DBA , the diagnosis of DBA is a clinical one, and as such, consent and enrollment does not require results from these genetic tests in the absence of any features that would suggest an alternative diagnosis (e.g., Fanconi Anemia, Dyskeratosis Congenita, etc.).

Who cannot join

An individual who meets any of the following criteria will be excluded from participation in this study:
Treatment with androgens (danazol or oxymetholone) or corticosteroids less than 4 weeks prior to initiating bitopertin.
-Stable physiologic dose steroid replacement for adrenal insufficiency or other similar conditions is not an exclusion criterium.
Hypersensitivity to bitopertin or its components
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
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

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Life expectancy of less than 3 months from any cause
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).
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.
Evidence for MDS or AML as defined by WHO criteria, or any active malignancy or likelihood of recurrence of malignancies within 12 months
Patients who have received chemotherapeutic treatment or other specific antineoplastic drugs or radiation therapy within 6 months of study entry
Female subjects who are nursing or pregnant (positive serum or urine beta-human chorionic gonadotrophin (beta-hCG) pregnancy test) at screening/baseline visit
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
<1%), for example hormone vaginal ring or transdermal hormone contraception.
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.
-Women are considered post-menopausal and not of childbearing potential if they have had over 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile age appropriate (e.g., generally 40-59 years), history of vasomotor symptoms (e.g., hot flushes) in the absence of other medical justification or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment should she be considered not of childbearing potential.
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.
Active alcohol/drug abuse.
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.
Unable to take the oral study drug.
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.

Trial locations and contacts

1 site in 1 country.

United States1 site

National Institutes of Health Clinical Center
Bethesda, Maryland, 20892

Other trials in United States

About this study

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

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.

Read the detailed description

Study Description:

Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by selective erythroid defects. In DBA, a defect in erythroid ribosome biosynthesis creates an asynchrony between protein synthesis of globin chains and heme, wherein the continued production of free heme without sufficient globin is toxic to cells. Bitopertin prevents the uptake of glycine through the GlyT1 transporter reducing the synthesis of 5- aminolevulinic acid, the rate-limiting step in heme synthesis, which in turn leads to a significant reduction in intracellular heme.

We hypothesize that bitopertin will rescue DBA by rebalancing heme and globin chain production and reducing the toxicity to the hematopoietic cells that the excess heme causes. Thus, we propose a phase I/II (pilot), single-arm, intra-patient dose-escalation trial of bitopertin for the treatment of steroid-refractory DBA.

Objectives:

Primary Objective: Efficacy of bitopertin in treating Diamond- Blackfan anemia

Secondary Objectives:

Examine the safety and tolerability of bitopertin in treating Diamond-Blackfan anemia.
Examine the maintenance of response and relapse rates of Diamond-Blackfan anemia during long-term bitopertin use
Examine the effects of long-term treatment of Diamond-Blackfan anemia with bitopertin on clonal evolution, survival, and health- related quality of life metrics

Tertiary/Exploratory Objectives:

Evaluate the impact of bitopertin on stem cell and erythroid cell dynamics in the Diamond-Blackfan anemia through correlative and translational studies
Examine the pharmacology of bitopertin in Diamond-Blackfan anemia

Endpoints:

Primary endpoint:

-response rate from drug initiation until 8 months (32 weeks) as measured by an increase in pre-transfusion hemoglobin and/or either decrease in transfusion rate or transfusion-independence

Secondary endpoints:

toxicity profile at 8 months (CTCAE criteria)
intra-patient maximum tolerated dose at 8 months (32 weeks) from drug initiation
response rate after 3 months (12 weeks) at the maximum tolerated dose
response rate 3 years post-primary endpoint (extension)
rate of relapse ongoing for up to 3 years, beginning 8 months (32 weeks) from drug initiation as demonstrated by new or increasing transfusion requirements and/or according to clinical outcome
rate of clonal evolution on bitopertin annually for up to 3 years, beginning 8 months (32 weeks) from drug initiation as measured by karyotypic, histologic, and flow cytometric changes
rate of overall survival ongoing for up to 3 years, beginning 8 months (32 weeks) from drug initiation according to clinical outcomes
Health-related quality of life (HRQL) annually for up to 3 years, beginning 8 months (32 weeks) from drug initiation based on questionnaire-based inventory of HRQL

Conditions: Steroid-refractory Diamond-Blackfan Anemia (DBA)
Being tested: Bitopertin
Keywords: Inherited Bone Marrow Failure Syndrome, Erythroid Aplasia, Iron Homeostasis, Ribosomopathy, Heme Synthesis, Hemoglobin Synthesis
Medical subject headings: Congenital Bone Marrow Failure Syndromes, Anemia, Aplastic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

BitopertinDrug
Dose Escalation: Monthly (every 4 weeks) up to a maximum dose of 60 mg bitopertin (5 mg, 10mg, 20mg, 40mg, 60mg). At each monthly (4 week) interval, a complete blood count (CBC) with differential and a reticulocyte analysis (including reticulocyte hemoglobin) will be collected prior to taking the higher dose. If the absolute reticulocyte count (ARC) is 60,000 /microL or higher, the subject will hold at the current dose level (or return to that level if escalation has already occurred) for an additional 4 weeks. If, after 8 weeks at that dose, response criteria are met this will be considered the minimum effective dose (MED) and shall be the treatment dose throughout the remainder of the study unless modifications are indicated.

Study groups in NCT05828108
Study group	Role	What they receive
Steroid Refractory Diamond-Blackfan Anemia in Bitopertin	Experimental	Participants with refractory Diamond-Blackfan Anemia will receive oral bitopertin once daily with dose escalation every 4 weeks (5 mg, 10 mg, 20 mg, 40 mg, up to a maximum of 60 mg). If response criteria are met after 8 weeks at a given dose level, that dose will be designated the minimum effective dose (MED) and continued for the remainder of the study unless dose modification is clinically indicated. Receives: Drug: Bitopertin

What is being measured

The primary outcome is the main question the study is designed to answer.

Number of Participants With Response
Response was defined as either an increase in hemoglobin or a decrease in transfusion rate. Robust response was defined as achievement of transfusion independence.
Measured: Up to 32 Weeks

Secondary outcomes (6)

Response Rate
Response was defined as either an increase in hemoglobin or a decrease in transfusion rate. Robust response was defined as achievement of transfusion independence.
Measured: 12 weeks
Rate of Relapse
Relapse as demonstrated by new or increasing transfusion requirements and/or according to clinical outcome
Measured: Up to 32 weeks
Number of Participants Tolerating Study Drug
Intra-patient dose escalation occurred every 4 weeks (5 mg, 10 mg, 20 mg, 40 mg, up to a maximum of 60 mg). Tolerability was defined as achieving a maximum tolerated dose of up to 60 mg daily without unacceptable toxicity or intolerance.
Measured: Up to 32 Weeks
Number of Treatment-Related Adverse Events (AEs), Including Serious Adverse Events (SAEs) by Dose Levels
Safety was assessed by the number and severity of treatment-related adverse events at each dose level using the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.
Adverse events were graded as follows: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe or medically significant), Grade 4 (life-threatening), and Grade 5 (death related to adverse event).
Measured: Up to 32 Weeks
Rate of Clonal Evolution
Rates of clonal evolution on bitopertin as measured by karyotypic, histologic, and flow cytometric changes
Measured: Up to 32 weeks
Number of Participants Surviving
Rate of overall survival according to clinical outcomes. Overall survival is defined as the number of participants alive following initiation of treatment.
Measured: 32 Weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

25 Jul 202328 Aug 2025

First posted25 Apr 2023
Study start25 Jul 2023
Primary completion28 Aug 2025
Study completion28 Aug 2025

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Steroid-refractory Diamond-Blackfan Anemia (DBA)Studies of the same condition, open and under way.
More trials run by National Heart, Lung, and Blood Institute (NHLBI)The sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrolment: 15 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT05828108
Sponsor's protocol ID: 10001528
Other IDs: 001528-H
Status last verified: Jun 2026
First submitted: 22 Apr 2023
Last updated: 30 Jun 2026
Results posted: Yes, on ClinicalTrials.gov
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: We will generate data as specified by the clinical protocol, including patient characteristics/demographics and primary/secondary outcomes. To protect research participant identities, individual de-identified data points will be made available. Sufficient data produced in the course of the project will be preserved. Sufficient data produced will also be shared except if limited by patient request (i.e., informed consent), federal or local laws and regulations (e.g., Health Insurance Portability and Accountability Act/HIPAA), or within the embargo period specified by the Cooperative Research and Development Agreement (CRADA) associated with this project (HL-CTCR-22-08002). The project does not involve any data collection instruments that would limit accessibility or interpretation of the scientific data. To facilitate interpretation of the data, applicable protocol case report form templates, protocol, and data dictionaries, will be shared and associated with the relevant datasets.

Publications

Young DJ, Machado TR, Cowling BC, Doty RT, Venugopal S, Wu CO, Abkowitz JL, Savage W, Dunbar CE. Results from the first clinical trial of bitopertin for steroid-relapsed/refractory Diamond-Blackfan anemia. Blood Red Cells Iron. 2026 Sep;2(3):100090. doi: 10.1016/j.brci.2026.100090. Epub 2026 Jul 8.
PubMed 42583025