A Natural History of the Progression of Stargardt Disease: Retrospective and Prospective Studies (ProgSTAR)

• ClinicalTrials.gov Identifier: NCT01977846
• Recruitment Status: Completed
• First Posted: November 7, 2013
• Results First Posted: November 1, 2019
• Last Update Posted: November 1, 2019
• Sponsor: Foundation Fighting Blindness
• Collaborator: United States Department of Defense
• Information provided by (Responsible Party): Foundation Fighting Blindness

• Study Type: Observational
• Study Design: Observational Model: Case-Only; Time Perspective: Other
• Condition: Stargardt Disease
• Enrollment: 259

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Retrospective Cohort	Prospective Cohort
Arm/Group Description	Patients with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Participant's data are from clinical examinations and central reading center (RC) grading of retinal imaging (fundus auto-fluorescence, and spectral domain optical coherence tomography (OCT).	Patients with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Participant's data are from standardized clinical examinations and central reading center (RC) grading of retinal imaging (fundus auto-fluorescence, spectral domain optical coherence tomography (OCT) and micro-perimetry (optional).
Period Title: Total Study - Retrospective
Started	251	0
Completed	251	0
Not Completed	0	0
Period Title: Total Study - Prospective
Started	0	259
Completed	0	230
Not Completed	0	29
Reason Not Completed
Death	0	1
Lost to Follow-up	0	8
Withdrawal by Subject	0	13
Not available at time of visit	0	5
No show	0	1
Protocol Violation	0	1

Baseline Characteristics

Arm/Group Title		Retrospective Cohort	Prospective Cohort	Total
Arm/Group Description		Subjects with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Clinical data from multiple centers extracted from medical records. Participants were to have at least two visits with at least one of the study image modalities (fundus auto-fluorescence, micro-perimetry, or spectral domain optical coherence tomography (OCT))	Multicenter prospective longitudinal cohort. Patients with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Participants were to have standardized visits at baseline and every 6 months for 24 months. Participant's data are from clinical examinations and central RC grading of retinal imaging (fundus auto-fluorescence, spectral domain optical coherence tomography (OCT)) and micro-perimetry.	Total of all reporting groups
Overall Number of Baseline Participants		251	259	510
Baseline Analysis Population Description		In Retrospective cohort, 251 participants contributed 433 eyes. In Prospecitive cohort, 259 participants contributed 489 eyes.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	251 participants	259 participants	510 participants
	<=18 years	69 27.5%	51 19.7%	120 23.5%
	Between 18 and 65 years	179 71.3%	201 77.6%	380 74.5%
	>=65 years	3 1.2%	7 2.7%	10 2.0%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	251 participants	259 participants	510 participants
	Female	149 59.4%	141 54.4%	290 56.9%
	Male	102 40.6%	118 45.6%	220 43.1%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Race	Number Analyzed	251 participants	259 participants	510 participants
	White/Middle Eastern	174 69.3%	222 85.7%	396 77.6%
	Black or African American	14 5.6%	20 7.7%	34 6.7%
	Asian/Indian	10 4.0%	10 3.9%	20 3.9%
	Other	5 2.0%	1 0.4%	6 1.2%
	More than one race	2 0.8%	2 0.8%	4 0.8%
	Don't know/missing	46 18.3%	4 1.5%	50 9.8%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	251 participants	259 participants	510 participants
United States		90	137	227
United Kingdom		79	30	109
France		49	48	97
Germany		33	44	77

Outcome Measures

1. Primary Outcome

Title	Yearly Progression Rate of Atrophic Lesions Using Fundus Autofluorescence (FAF) Images
Description	Yearly increase in area of decreased auto-fluorescence (DAF) which is defined as the sum of definite and questionable decreased auto-fluorescence
Time Frame	2-12 years

Outcome Measure Data

Analysis Population Description

Eyes of participants with at least 2 visits with gradable fundus auto-fluorescence images with atrophic lesions present

Arm/Group Title	Retrospective Cohort	Prospective Cohort
Arm/Group Description:	Subjects with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Clinical data from multiple centers extracted from medical records. Participants were to have at least two visits with at least one of the study image modalities (fundus auto-fluorescence, micro-perimetry, or spectral domain optical coherence tomography (OCT))	Multicenter prospective longitudinal cohort. Patients with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Participants were to have standardized visits at baseline and every 6 months for 24 months. Participant's data are from clinical examinations and central RC grading of retinal imaging (fundus auto-fluorescence, spectral domain optical coherence tomography (OCT)) and micro-perimetry.
Overall Number of Participants Analyzed	215	259
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	386	489
Mean (95% Confidence Interval); Unit of Measure: mm^2/year
	0.35; (0.28 to 0.43)	0.64; (0.57 to 0.71)

2. Secondary Outcome

Title	Yearly Rate of Loss of Retinal Sensitivity as Measured by Scotopic Microperimetry (MP)
Description	The yearly rate of change in retinal sensitivity. Sensitivity tested with a Nidek MP-1 machine using a modified Humphrey 10-2 grid. The sensitivity was the average sensitivity from a 68-points test pattern (Prospective cohort only)
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Microperimetry data are available for only the Prospective cohort at centers with required equipment

Arm/Group Title	Retrospective Cohort	Prospective Cohort
Arm/Group Description:	Subjects with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Clinical data from multiple centers extracted from medical records. Participants were to have at least two visits with at least one of the study image modalities (fundus auto-fluorescence, micro-perimetry, or spectral domain optical coherence tomography (OCT))	Multicenter prospective longitudinal cohort. Patients with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Participants were to have standardized visits at baseline and every 6 months for 24 months. Participant's data are from clinical examinations and central RC grading of retinal imaging (fundus auto-fluorescence, spectral domain optical coherence tomography (OCT)) and micro-perimetry.
Overall Number of Participants Analyzed	0	238
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	0	449
Mean (95% Confidence Interval); Unit of Measure: dB/year
		-0.76; (-0.87 to -0.66)

3. Secondary Outcome

Title	Yearly Rate of Visual Acuity Loss
Description	Yearly change of visual acuity. Visual acuity measures of best-corrected or presenting VA extracted from medical record charts. Prospective cohort is best-corrected visual acuity using Early-Treatment Diabetic Retinopathy study methods
Time Frame	2-12 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Retrospective Cohort	Prospective Cohort
Arm/Group Description:	Subjects with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Clinical data from multiple centers extracted from medical records. Participants were to have at least two visits with at least one of the study image modalities (fundus auto-fluorescence, micro-perimetry, or spectral domain optical coherence tomography (OCT))	Multicenter prospective longitudinal cohort. Patients with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Participants were to have standardized visits at baseline and every 6 months for 24 months. Participant's data are from clinical examinations and central RC grading of retinal imaging (fundus auto-fluorescence, spectral domain optical coherence tomography (OCT)) and micro-perimetry.
Overall Number of Participants Analyzed	176	259
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	332	489
Mean (95% Confidence Interval); Unit of Measure: logMAR/year
	0.030; (0.026 to 0.043)	0.011; (0.004 to 0.018)

4. Secondary Outcome

Title	Difference in the Rate of Retinal Sensitivity Change Per Year Between Photopic and Scotopic Micro-perimetry Testing
Description	Difference in the yearly rate of change in retinal sensitivity under photopic and scotopic conditions. Sensitivity tested with a Nidek MP-1. Scotopic sensitivity was obtained using a 40 points test pattern, and photopic sensitivity was obtained using a 68 points test pattern in a subset of Prospective cohort patients
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Photopic microperimetry was obtained in a subset of patients, in a single designated study eye

Arm/Group Title	Retrospective Cohort	Prospective Cohort
Arm/Group Description:	Subjects with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Clinical data from multiple centers extracted from medical records. Participants were to have at least two visits with at least one of the study image modalities (fundus auto-fluorescence, micro-perimetry, or spectral domain optical coherence tomography (OCT))	Multicenter prospective longitudinal cohort. Patients with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Participants were to have standardized visits at baseline and every 6 months for 24 months. Participant's data are from clinical examinations and central RC grading of retinal imaging (fundus auto-fluorescence, spectral domain optical coherence tomography (OCT)) and micro-perimetry.
Overall Number of Participants Analyzed	0	118
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	0	118
Mean (95% Confidence Interval); Unit of Measure: dB/year
		-0.78; (-1.16 to -0.41)

5. Secondary Outcome

Title	Yearly Rate of Loss of Overall Retinal Thickness
Description	Yearly decrease of overall retinal thickness using spectral domain optical coherence tomography (SD-OCT) scans from a 20° x 20° scan area centered on the fovea. Data are only available for the Prospective cohort.
Time Frame	Participants followed at Baseline, 6 months, 12 months and 24 months

Outcome Measure Data

Analysis Population Description

All visits of eligible eyes of the 258 participants with gradable overall thickness. Only OCT scans with adequate and fair quality are included

Arm/Group Title	Prospective Cohort
Arm/Group Description:	Multicenter prospective longitudinal cohort. Patients with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). OCT scans were graded by a central reading center.
Overall Number of Participants Analyzed	258
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	487
Mean (95% Confidence Interval); Unit of Measure: microns/year
	-2.85; (-3.19 to -2.52)

6. Secondary Outcome

Title	Yearly Rate of Loss of Outer Ring Retinal Thickness
Description	Yearly decrease of outer ring retinal thickness using SD-OCT scans from a 20° x 20° scan area centered on the fovea. Outer ring defined as ETDRS fields 1-4.
Time Frame	Participants followed at Baseline, 6 months, 12 months and 24 months

Outcome Measure Data

Analysis Population Description

All visits of eligible eyes of the 258 participants with gradable thickness in the outer ring. Only OCT scans with adequate and fair quality are included

Arm/Group Title	Prospective Cohort
Arm/Group Description:	Multicenter prospective longitudinal cohort. Patients with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). OCT scans were graded by a central reading center.
Overall Number of Participants Analyzed	258
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	487
Mean (95% Confidence Interval); Unit of Measure: microns/year
	-2.84; (-3.19 to -2.50)

7. Secondary Outcome

Title	Yearly Rate of Loss of the Inner Ring Retinal Thickness
Description	Yearly decrease of the inner ring retinal thickness using SD-OCT scans from a 20° x 20° scan area centered on the fovea. Inner ring defined as ETDRS fields 5-8. Data are only available for the Prospective cohort.
Time Frame	Participants followed at Baseline, 6 months, 12 months and 24 months

Outcome Measure Data

Analysis Population Description

All visits of eligible eyes of the 258 participants with gradable thickness in the inner ring. Only OCT scans with adequate and fair quality are included

Arm/Group Title	Prospective Cohort
Arm/Group Description:	Multicenter prospective longitudinal cohort. Patients with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). OCT scans were graded by a central reading center.
Overall Number of Participants Analyzed	258
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	487
Mean (95% Confidence Interval); Unit of Measure: microns/year
	-3.20; (-3.68 to -2.72)

8. Secondary Outcome

Title	Yearly Rate of Loss of the Central Ring Retinal Thickness
Description	Yearly decrease of the central ring retinal thickness using SD-OCT scans from a 20° x 20° scan area centered on the fovea. Central area defined as ETDRS fields 9. Data are only available for the Prospective cohort.
Time Frame	Participants followed at Baseline, 6 months, 12 months and 24 months

Outcome Measure Data

Analysis Population Description

All visits of eligible eyes of the 258 participants with gradable thickness in the inner ring. Only OCT scans with adequate and fair quality are included

Arm/Group Title	Prospective Cohort
Arm/Group Description:	Multicenter prospective longitudinal cohort. Patients with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). OCT scans were graded by a central reading center.
Overall Number of Participants Analyzed	258
Overall Number of Units Analyzed; Type of Units Analyzed: Eyes	487
Mean (95% Confidence Interval); Unit of Measure: microns/year
	-2.24; (-3.06 to -1.42)

Adverse Events

Time Frame	Adverse events were not collected in this natural history study
Adverse Event Reporting Description	As there was no intervention in this study, adverse events were not collected
Arm/Group Title	Retrospective Cohort	Prospective Cohort
Arm/Group Description	Subjects with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Clinical data from multiple centers extracted from medical records. Participants should had at least two visits with at least one of the study image modalities (fundus auto-fluorescence, micro-perimetry, or spectral domain optical coherence tomography (OCT)). Adverse events were not collected	Multicenter prospective longitudinal cohort. Patients with at least two pathogenic mutations in the ABCA4 gene (or one mutation, but the clinical phenotype of flecks at the level of the RPE typical for STGD1). Participants had standardized visits at baseline and every 6 months for 24 months. Participant's data are from clinical examinations and central RC grading of retinal imaging (fundus auto-fluorescence, spectral domain optical coherence tomography (OCT)) and micro-perimetry. Adverse events were not collected
All-Cause Mortality
	Retrospective Cohort	Prospective Cohort
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/251 (0.00%)	1/259 (0.39%)
Serious Adverse Events
	Retrospective Cohort	Prospective Cohort
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/0	0/0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Retrospective Cohort	Prospective Cohort
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/0	0/0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Chief Scientific Officer
• Organization: Foundation Fighting Blindness
• Phone: 410-423-0600
• EMail: info@FightBlindness.org

Publications of Results:

Strauss RW, Ho A, Muñoz B, Cideciyan AV, Sahel JA, Sunness JS, Birch DG, Bernstein PS, Michaelides M, Traboulsi EI, Zrenner E, Sadda S, Ervin AM, West S, Scholl HP; Progression of Stargardt Disease Study Group. The Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Studies: Design and Baseline Characteristics: ProgStar Report No. 1. Ophthalmology. 2016 Apr;123(4):817-28. doi: 10.1016/j.ophtha.2015.12.009. Epub 2016 Jan 16.

Kong X, Strauss RW, Michaelides M, Cideciyan AV, Sahel JA, Muñoz B, West S, Scholl HP; ProgStar Study Group. Visual Acuity Loss and Associated Risk Factors in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 2). Ophthalmology. 2016 Sep;123(9):1887-97. doi: 10.1016/j.ophtha.2016.05.027. Epub 2016 Jul 2.

Kong X, Strauss RW, Cideciyan AV, Michaelides M, Sahel JA, Munoz B, Ahmed M, Ervin AM, West SK, Cheetham JK, Scholl HPN; ProgStar Study Group. Visual Acuity Change over 12 Months in the Prospective Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study: ProgStar Report Number 6. Ophthalmology. 2017 Nov;124(11):1640-1651. doi: 10.1016/j.ophtha.2017.04.026. Epub 2017 May 23.

Strauss RW, Muñoz B, Ho A, Jha A, Michaelides M, Cideciyan AV, Audo I, Birch DG, Hariri AH, Nittala MG, Sadda S, West S, Scholl HPN; ProgStar Study Group. Progression of Stargardt Disease as Determined by Fundus Autofluorescence in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 9). JAMA Ophthalmol. 2017 Nov 1;135(11):1232-1241. doi: 10.1001/jamaophthalmol.2017.4152.

Kong X, Fujinami K, Strauss RW, Munoz B, West SK, Cideciyan AV, Michaelides M, Ahmed M, Ervin AM, Schönbach E, Cheetham JK, Scholl HPN; ProgStar Study Group. Visual Acuity Change Over 24 Months and Its Association With Foveal Phenotype and Genotype in Individuals With Stargardt Disease: ProgStar Study Report No. 10. JAMA Ophthalmol. 2018 Aug 1;136(8):920-928. doi: 10.1001/jamaophthalmol.2018.2198.

Other Publications:

Schönbach EM, Ibrahim MA, Strauss RW, Birch DG, Cideciyan AV, Hahn GA, Ho A, Kong X, Nasser F, Sunness JS, Zrenner E, Sadda SR, West SK, Scholl HPN; Progression of Stargardt Disease Study Group. Fixation Location and Stability Using the MP-1 Microperimeter in Stargardt Disease: ProgStar Report No. 3. Ophthalmol Retina. 2017 Jan - Feb;1(1):68-76. doi: 10.1016/j.oret.2016.08.009. Epub 2016 Oct 31.

Kong X, West SK, Strauss RW, Munoz B, Cideciyan AV, Michaelides M, Ho A, Ahmed M, Schönbach EM, Cheetham JK, Ervin AM, Scholl HPN; ProgStar study group. Progression of Visual Acuity and Fundus Autofluorescence in Recent-Onset Stargardt Disease: ProgStar Study Report #4. Ophthalmol Retina. 2017 Nov - Dec;1(6):514-523. doi: 10.1016/j.oret.2017.02.008. Epub 2017 Apr 28.

Strauss RW, Muñoz B, Ho A, Jha A, Michaelides M, Mohand-Said S, Cideciyan AV, Birch D, Hariri AH, Nittala MG, Sadda S, Scholl HPN; ProgStar Study Group. Incidence of Atrophic Lesions in Stargardt Disease in the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study: Report No. 5. JAMA Ophthalmol. 2017 Jul 1;135(7):687-695. doi: 10.1001/jamaophthalmol.2017.1121.

Schönbach EM, Wolfson Y, Strauss RW, Ibrahim MA, Kong X, Muñoz B, Birch DG, Cideciyan AV, Hahn GA, Nittala M, Sunness JS, Sadda SR, West SK, Scholl HPN; ProgStar Study Group. Macular Sensitivity Measured With Microperimetry in Stargardt Disease in the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study: Report No. 7. JAMA Ophthalmol. 2017 Jul 1;135(7):696-703. doi: 10.1001/jamaophthalmol.2017.1162.

• Responsible Party: Foundation Fighting Blindness
• ClinicalTrials.gov Identifier: NCT01977846
• Other Study ID Numbers: FFBCRI-PROGSTAR-01/02
• First Submitted: October 31, 2013
• First Posted: November 7, 2013
• Results First Submitted: May 30, 2018
• Results First Posted: November 1, 2019
• Last Update Posted: November 1, 2019