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PBA Use for Treatment of ATF6-/- Patients

Primary Purpose

ACHROMATOPSIA 7, Achromatopsia

Status
Not yet recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
PBA
Sponsored by
Columbia University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for ACHROMATOPSIA 7 focused on measuring achromatopsia, PBA, ATF6, color blindness

Eligibility Criteria

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

Inclusion Criteria:

  • Patients harboring mutations in ATF6 present with decreased retinal function

Exclusion Criteria:

  • Patients who are minors
  • Patients who are pregnant

Sites / Locations

  • Edward S. Harkness Eye Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

PBA treatment of ATF6-/- Achromatopsia

Arm Description

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.

Outcomes

Primary Outcome Measures

Changes in best corrected visual acuity (BCVA)
to measure changes in vision at each time point
Changes in contrast sensitivity
using Pelli Robson charts
Changes in color vision
using D50
Changes in macular sensitivity
using microperimetry (Nidek)
Changes in retinal imaging
including optical coherence tomography (OCT), short wavelength autofluorescence (SW-AF), and near-infrared autofluorescence (NIR-AF)
Changes in Full-field Electroretinogram (ffERG) X
to measure changes in rod and cone traces

Secondary Outcome Measures

Changes in intraocular pressure
part of full ophthalmic evaluation
Changes in anterior segment
part of full ophthalmic evaluation
Changes observed in posterior segment (slit lamp and binocular fundus examination)
part of full ophthalmic evaluation

Full Information

First Posted
July 31, 2019
Last Updated
March 15, 2023
Sponsor
Columbia University
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1. Study Identification

Unique Protocol Identification Number
NCT04041232
Brief Title
PBA Use for Treatment of ATF6-/- Patients
Official Title
Evaluation of Glycerol Phenylbutyrate (PBA) Use in Endoplasmic Reticulum Stress Reduction in ATF6-/- Patients
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
May 2023 (Anticipated)
Primary Completion Date
March 2024 (Anticipated)
Study Completion Date
March 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Columbia University

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.
Detailed Description
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ACHROMATOPSIA 7, Achromatopsia
Keywords
achromatopsia, PBA, ATF6, color blindness

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Model Description
Two patients will receive PBA as treatment for ATF6-/- Achromatopsia.
Masking
None (Open Label)
Allocation
N/A
Enrollment
2 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
PBA treatment of ATF6-/- Achromatopsia
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
PBA
Other Intervention Name(s)
Glycerol Phenylbutyrate
Intervention Description
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).
Primary Outcome Measure Information:
Title
Changes in best corrected visual acuity (BCVA)
Description
to measure changes in vision at each time point
Time Frame
Baseline, 1 month, 3 months, 6 months post-PBA use
Title
Changes in contrast sensitivity
Description
using Pelli Robson charts
Time Frame
Baseline, 1 month, 3 months, 6 months post-PBA use
Title
Changes in color vision
Description
using D50
Time Frame
Baseline, 1 month, 3 months, 6 months post-PBA use
Title
Changes in macular sensitivity
Description
using microperimetry (Nidek)
Time Frame
Baseline, 1 month, 3 months, 6 months post-PBA use
Title
Changes in retinal imaging
Description
including optical coherence tomography (OCT), short wavelength autofluorescence (SW-AF), and near-infrared autofluorescence (NIR-AF)
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
Title
Changes in Full-field Electroretinogram (ffERG) X
Description
to measure changes in rod and cone traces
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
Secondary Outcome Measure Information:
Title
Changes in intraocular pressure
Description
part of full ophthalmic evaluation
Time Frame
Baseline, 1 month, 3 months, 6 months post-PBA use
Title
Changes in anterior segment
Description
part of full ophthalmic evaluation
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
Title
Changes observed in posterior segment (slit lamp and binocular fundus examination)
Description
part of full ophthalmic evaluation
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients harboring mutations in ATF6 present with decreased retinal function Exclusion Criteria: Patients who are minors Patients who are pregnant
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Stephen Tsang, MD
Phone
212-342-1189
Email
sht2@cumc.columbia.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Laura Jenny
Email
lj2539@cumc.columbia.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephen Tsang, MD
Organizational Affiliation
Columbia University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Edward S. Harkness Eye Institute
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stephen Tsang, MD
Phone
212-342-1189
Email
sht2@cumc.columbia.edu
First Name & Middle Initial & Last Name & Degree
Stephen Tsang, MD

12. IPD Sharing Statement

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PBA Use for Treatment of ATF6-/- Patients

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