PBA Use for Treatment of ATF6-/- Patients
|
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT04041232 |
|
Recruitment Status :
Not yet recruiting
First Posted : August 1, 2019
Last Update Posted : February 5, 2021
|
Sponsor:
Columbia University
Information provided by (Responsible Party):
Columbia University
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
Brief Summary:
Some patients with achromatopsia, an inherited disorder characterized by partial or complete loss of color vision, carry mutations in ATF6. ATF6 is a gene that is responsible for coding a protein that acts in response to endoplasmic reticulum (ER) stress. When the ATF6 protein is mutated, retinal function decreases, contributing to color blindness. The study aims to investigate whether an already FDA-approved drug, glycerol phenylbutyrate (PBA), can improve retinal function inpatients with achromatopsia caused by ATF6 mutations. Patients will be instructed to take three doses of PBA per day at equally divided time intervals and rounded up to the nearest 0.5 mL. The total dose of PBA will be 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) and will not exceed 17.5 mL/day (19 g/day). Their condition will be monitored over the course of a minimum of 3 clinic visits that will consist of a number of retinal function tests, fundus examinations, and imaging procedures. Findings from the study could elucidate the potential for PBA to serve as a treatment for patients with ATF6-mediated a chromatopsia.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| ACHROMATOPSIA 7 Achromatopsia | Drug: PBA | Early Phase 1 |
ATF6 has been described as an endoplasmic reticulum (ER) stress-regulated transmembrane protein that activates the transcription of molecular chaperones in response to ER stress. Patients harboring mutations in ATF6 present with decreased retinal function and are diagnosed with achromatopsia. The investigator's research group has previously demonstrated that administration of glycerol phenylbutyrate (PBA), a fatty acid compound that facilitates protein folding, can lead to enhanced retinal function in mice that are homozygous for the ATF6 mutation. This study will investigate the effects of PBA administration in two patients who carry ATF6-/- mutations and a diagnosis of achromatopsia. Enrolled subjects will undergo a minimum of 3 clinic visits that consist of a complete ophthalmic examination (best-corrected visual acuity, intraocular pressure, anterior segment examination, slit lamp and binocular fundus examination), a visual functioning questionnaire, color vision tests, contrast sensitivity tests, retinal imaging (optical coherence tomography, short wavelength autofluorescence and near-infrared autofluorescence), a macular sensitivity test (Nidek microperimetry) and full-field electroretinogram (ffERG). A blood draw will be performed at each visit to test for any indications of adverse effects from drug use. Subjects will be instructed to take 3 doses of PBA per day, totaling to a dose of 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day).
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 2 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Intervention Model Description: | Two patients will receive PBA as treatment for ATF6-/- Achromatopsia. |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Evaluation of Glycerol Phenylbutyrate (PBA) Use in Endoplasmic Reticulum Stress Reduction in ATF6-/- Patients |
| Estimated Study Start Date : | May 2021 |
| Estimated Primary Completion Date : | December 2021 |
| Estimated Study Completion Date : | March 2022 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
|
Experimental: PBA treatment of ATF6-/- Achromatopsia
Patients will be monitored at the baseline visit, followed by a second and third visit that will be 1 and 3 months after the initial visit. Patients will complete a standard visual functioning questionnaire and undergo a complete ophthalmic evaluation at each visit. Other visual assessments will consist of color vision testing, contrast sensitivity, retinal imaging, and macular sensitivity testing using microperimetry. Full-field electroretinogram will also be performed at the baseline visit and after 1 and 3 months of PBA use. If improvement in retinal function is observed, an additional ophthalmic evaluation will be conducted after 6 months of PBA use. A blood draw will be performed at each visit to test for any indications of adverse effects from drug use.
|
Drug: PBA
Glycerol phenylbutyrate (PBA) is a triglyceride that consists of three molecules of phenylbutrate linked to a glycerol backbone. It is a nitrogen-binding agent that has been approved by the Food and Drug Administration (FDA) for the treatment of urea cycle disorders. Oral supplementation of PBA demonstrated no severe side effects, and are found to be therapeutically effective in reducing ER stress. Patients will be instructed to take three doses of PBA per day at equally divided time intervals and rounded up to the nearest 0.5 mL. The total dose of PBA will be 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day) and will not exceed 17.5 mL/day (19 g/day).
Other Name: Glycerol Phenylbutyrate |
Primary Outcome Measures :
- Changes in best corrected visual acuity (BCVA) [ Time Frame: Baseline, 1 month, 3 months, 6 months post-PBA use ]to measure changes in vision at each time point
- Changes in contrast sensitivity [ Time Frame: Baseline, 1 month, 3 months, 6 months post-PBA use ]using Pelli Robson charts
- Changes in color vision [ Time Frame: Baseline, 1 month, 3 months, 6 months post-PBA use ]using D50
- Changes in macular sensitivity [ Time Frame: Baseline, 1 month, 3 months, 6 months post-PBA use ]using microperimetry (Nidek)
- Changes in retinal imaging [ Time Frame: After 1 and 3 months of PBA use. If changes in retinal function is observed, an additional ophthalmic evaluation will be conducted after 6 months of PBA use ]including optical coherence tomography (OCT), short wavelength autofluorescence (SW-AF), and near-infrared autofluorescence (NIR-AF)
- Changes in Full-field Electroretinogram (ffERG) X [ Time Frame: After 1 and 3 months of PBA use. If changes in retinal function is observed, an additional ophthalmic evaluation will be conducted after 6 months of PBA use ]to measure changes in rod and cone traces
Secondary Outcome Measures :
- Changes in intraocular pressure [ Time Frame: Baseline, 1 month, 3 months, 6 months post-PBA use ]part of full ophthalmic evaluation
- Changes in anterior segment [ Time Frame: After 1 and 3 months of PBA use. If changes in retinal function is observed, an additional ophthalmic evaluation will be conducted after 6 months of PBA use ]part of full ophthalmic evaluation
- Changes observed in posterior segment (slit lamp and binocular fundus examination) [ Time Frame: After 1 and 3 months of PBA use. If changes in retinal function is observed, an additional ophthalmic evaluation will be conducted after 6 months of PBA use ]part of full ophthalmic evaluation
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Patients harboring mutations in ATF6 present with decreased retinal function
Exclusion Criteria:
- Patients who are minors
- Patients who are pregnant
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04041232
Contacts
| Contact: Stephen Tsang, MD | 212-342-1189 | sht2@cumc.columbia.edu | |
| Contact: Karen Park | ksp2117@cumc.columbia.edu |
Locations
| United States, New York | |
| Edward S. Harkness Eye Institute | |
| New York, New York, United States, 10032 | |
| Contact: Stephen Tsang, MD 212-342-1189 sht2@cumc.columbia.edu | |
| Principal Investigator: Stephen Tsang, MD | |
Sponsors and Collaborators
Columbia University
Investigators
| Principal Investigator: | Stephen Tsang, MD | Professor of Ophthalmology and Professor of Pathology and Cell Biology |
| Responsible Party: | Columbia University |
| ClinicalTrials.gov Identifier: | NCT04041232 |
| Other Study ID Numbers: |
AAAR9833 |
| First Posted: | August 1, 2019 Key Record Dates |
| Last Update Posted: | February 5, 2021 |
| Last Verified: | February 2021 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | No |
Keywords provided by Columbia University:
|
achromatopsia PBA ATF6 color blindness |
Additional relevant MeSH terms:
|
Color Vision Defects Vision Disorders Sensation Disorders Neurologic Manifestations Nervous System Diseases Cone Dystrophy |
Eye Diseases, Hereditary Eye Diseases Glycerol Cryoprotective Agents Protective Agents Physiological Effects of Drugs |