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Supporter terminated study due to slow subject accrual secondary to COVID pandemic limiting travel to research site.
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Diamond Blackfan anemia (DBA) is a rare inherited pure red cell aplasia. The two main non-stem cell transplant therapeutic options are corticosteroids and red blood cell (RBC) transfusions. About 80% of DBA patients initially respond to corticosteroids, however, half of the patients cannot continue due to side effects or loss of response. These patients are then typically dependent on RBC transfusions throughout life. Each of these treatments is fraught with many side effects and significant morbidity and mortality are potential consequences of hematopoietic stem cell transplantation (SCT). The majority of individuals with DBA have mutations in genes encoding structural proteins of the small or large ribosomal subunit leading to deficiency of the particular ribosomal protein (RP). Using the RP deficient zebrafish embryo model, high throughput drug screens have demonstrated a strong hematologic response to several calmodulin inhibitors. One of these chemicals is trifluoperazine (TFP). TFP treatment of a mouse model of DBA also increased the red blood cell count and the hemoglobin (Hb) levels in the mice. TFP is a FDA-approved typical antipsychotic agent that has been available since 1958 with a well-known safety profile. In the United States, TFP is approved for the short-term treatment of generalized non-psychotic anxiety; treatment or prevention of nausea and vomiting of various causes; and, management of psychotic disorders.
This study aims to determine the safety/tolerability of TFP in adult subjects with DBA. TFP's expected dose-limiting toxicity is primarily neurologic (extrapyramidal) when used long-term at typical anti-psychotic doses (range 10-50 mg daily). Non-neurologic adverse effects in subjects with DBA have not been investigated. We will perform a dose escalation study to define the safety and tolerability of lower doses of this agent in subjects with DBA. To mitigate the potential risks of administering TFP to this new population, we will (1) start dosing at dose levels well below those prescribed for psychosis, (2) dose escalate to a maximum of 10 mg daily (the lowest dose typically prescribed for psychosis), and (3) perform weekly safety monitoring. Given the positive signal in DBA animal models and the 60-year clinical experience with higher doses of TFP, this drug warrants a trial in humans to assess tolerability in DBA.
This is a dose escalation safety/tolerability study to evaluate the presence of TFP-related adverse events in DBA subjects, and to determine the maximum tolerated dose (MTD) of TFP in DBA.
If tolerated, this trial will support either a proof of concept trial of low-dose TFP in DBA, or the advancement of a chemically modified TFP-like drug (to alleviate the neurologic toxicity) for the treatment of DBA.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort A | Experimental | Cohort A: Three subjects will receive Trifluoperazine (TFP) 1 mg PO daily.
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| Cohort B | Experimental | Cohort B: Three subjects will receive TFP 2 mg PO daily.
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| Cohort C | Experimental | Cohort C: Three subjects will receive TFP 5 mg PO daily.
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Trifluoperazine | Drug | Trifluoperazine (TFP)1mg, 2mg, 5mg, or 10mg will be given once daily by mouth for 21 days |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Treatment-related Adverse Events as Assessed by the Simpson-Angus Scale and CTCAE v4.0 | Each subject will undergo weekly safety assessment using the Simpson-Angus Extrapyramidal Side Effects Scale to determine the safety of TFP in this new population of patients. The subjects will also undergo weekly bloodwork to evaluate for any liver or kidney abnormalities as well as a complete blood count and reticulocyte count. All dosed subjects will be followed for an additional 1 week after discontinuing study drug (post-study safety follow-up). There will be no more than 6 subjects enrolled at any particular time. Treatment will be discontinued for any subject if their Hb is > 12 gm/dL , and not associated with RBC transfusions. | The subjects will be evaluated weekly for 4 weeks after the start of the 21-day course, 3 weeks while on the study drug and one week after completion. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Adrianna Vlachos, MD | Northwell Health | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Boston Children's hospital | Boston | Massachusetts | 02115 | United States | ||
| The Feinstein Institute for Medical Research |
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| ID | Title | Description |
|---|---|---|
| FG000 | Cohort A | Cohort A: Three subjects will receive Trifluoperazine (TFP) 1 mg PO daily.
Trifluoperazine: Trifluoperazine (TFP)1mg, 2mg, 5mg, or 10mg will be given once daily by mouth for 21 days |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Cohort A | Cohort A: Three subjects will receive Trifluoperazine (TFP) 1 mg PO daily.
Trifluoperazine: Trifluoperazine (TFP)1mg, 2mg, 5mg, or 10mg will be given once daily by mouth for 21 days |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Treatment-related Adverse Events as Assessed by the Simpson-Angus Scale and CTCAE v4.0 | Each subject will undergo weekly safety assessment using the Simpson-Angus Extrapyramidal Side Effects Scale to determine the safety of TFP in this new population of patients. The subjects will also undergo weekly bloodwork to evaluate for any liver or kidney abnormalities as well as a complete blood count and reticulocyte count. All dosed subjects will be followed for an additional 1 week after discontinuing study drug (post-study safety follow-up). There will be no more than 6 subjects enrolled at any particular time. Treatment will be discontinued for any subject if their Hb is > 12 gm/dL , and not associated with RBC transfusions. | One subject received study drug. The other subject did not receive study drug. | Posted | Count of Participants | Participants | The subjects will be evaluated weekly for 4 weeks after the start of the 21-day course, 3 weeks while on the study drug and one week after completion. |
|
4 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cohort A | Cohort A: Three subjects will receive Trifluoperazine (TFP) 1 mg PO daily.
Trifluoperazine: Trifluoperazine (TFP)1mg, 2mg, 5mg, or 10mg will be given once daily by mouth for 21 days |
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Protocol closed early due to slow accrual secondary to COVID travel restrictions.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Adrianna Vlachos, MD | Feinstein Institutes for Medical Research | 5165623757 | avlachos@northwell.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 14, 2020 | Nov 22, 2021 | Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Sep 18, 2018 | May 23, 2019 | ICF_000.pdf |
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| ID | Term |
|---|---|
| D029503 | Anemia, Diamond-Blackfan |
| D012010 | Red-Cell Aplasia, Pure |
| ID | Term |
|---|---|
| D029502 | Anemia, Hypoplastic, Congenital |
| D000741 | Anemia, Aplastic |
| D000740 | Anemia |
| D006402 | Hematologic Diseases |
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| ID | Term |
|---|---|
| D014268 | Trifluoperazine |
| ID | Term |
|---|---|
| D010640 | Phenothiazines |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D006575 | Heterocyclic Compounds, 3-Ring |
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Dose escalation study
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| Cohort D | Experimental | Cohort D: Three subjects will receive TFP 10 mg PO daily.
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| Manhasset |
| New York |
| 11030 |
| United States |
| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG000 |
| Cohort A |
Cohort A: Three subjects will receive Trifluoperazine (TFP) 1 mg PO daily.
Trifluoperazine: Trifluoperazine (TFP)1mg, 2mg, 5mg, or 10mg will be given once daily by mouth for 21 days |
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| 0 |
| 1 |
| 0 |
| 1 |
| 0 |
| 1 |
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| D006425 |
| Hemic and Lymphatic Diseases |
| D000080984 | Congenital Bone Marrow Failure Syndromes |
| D000080983 | Bone Marrow Failure Disorders |
| D001855 | Bone Marrow Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D000072471 |
| Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |