Atherosclerosis, Cerebrovascular Accident, Ischemia, Myocardial Infarction
Conditions
Brief summary
This study is designed to evaluate the long-term ocular safety of SCH 530348 (vorapaxar) in participants with established atherosclerotic disease who are enrolled into the TRA 2°P - TIMI 50 Study (P04737) (NCT00526474).
Interventions
DRUGVorapaxar 2.5 mg
Vorapaxar 2.5 mg oral tablet
DRUGPlacebo
matching placebo oral tablet
Sponsors
The TIMI Study Group
Duke Clinical Research Institute
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Evidence or a history of atherosclerosis involving the coronary, cerebral, or peripheral vascular systems
Exclusion criteria
* The study will include participants who meet none of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Develop Vacuolization in the Inner Nuclear Layer (INL) of the Retina as Measured by Ocular Coherence Tomography (OCT) | Up to 12 months | Vacuolization is defined as the presence of more than one vacuole (defined as a clear, round structure in the INL of the retina of at least 30 microns in diameter) compared to baseline in either the left or right eye as evaluated by ocular coherence tomography (OCT). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Have a Decrease in Visual Acuity Score of at Least Seven Letters From Baseline | Baseline and 4, 8 and 12 months | Visual acuity was assessed in both eyes by best corrected visual acuity following standardized refraction. The best corrected visual acuity score is the number of letters on a standard visual acuity testing chart read correctly by a participant. A decrease in best corrected visual acuity score in the left and/or right eye indicates a worsening of vision. |
| Number of Participants With Change From Baseline of Center Foveal Thickness of Greater Than 15 Microns as Measured by OCT | Baseline and 4, 8 and 12 months | Center foveal thickness measured by OCT was evaluated for a change from baseline in greater than 15 microns in either the left or right eye. |
| Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by OCT | Baseline and 4, 8 and 12 months | Individual OCT abnormalities were scored as 0=not present or 1=present. The total number of possible abnormalities present was 84 (42 possible abnormalities per eye). Data are for the left and right eyes combined (score range: 0 to 84). Change from Baseline at a given timepoint was calculated as Timepoint Score minus Baseline Score. A smaller score indicates fewer graded abnormalities. |
| Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by Fundus Photography | Baseline and 4, 8 and 12 months | Individual fundus photography abnormalities were scored as 0=not present or 1=present. The total number of possible abnormalities present was 48 (24 possible abnomalities per eye). Data are for the left and right eyes combined (score range: 0 to 48). Change from Baseline at a given timepoint was calculated as Timepoint Score minus Baseline Score. A smaller score indicates fewer graded abnormalities. |
Participant flow
Recruitment details
Participants were recruited from participants enrolled in Study SCH 530348 P04737 (NCT00526474) and met the inclusion/exclusion criteria for this study.
Pre-assignment details
A total of 258 particpants were referred to opthalmology sites, 65 of whom did not particpate in this study (P05138) beyond the screening visit and were not included in the analysis of ocular safety. A total of 193 participants were included in the analysis of ocular safety.
Participants by arm
| Arm | Count |
|---|---|
| Vorapaxar Participants receive a vorapaxar 2.5 mg tablet administered orally once daily for 1 year | 98 |
| Placebo Participants receive a matching placebo tablet to vorapaxar administered orally once daily for 1 year | 95 |
| Total | 193 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Referral Screening Period | Adverse Event | 0 | 1 |
| Referral Screening Period | Did Not Meet Protocol Eligibility | 36 | 24 |
| Referral Screening Period | Did Not Wish To Continue | 3 | 1 |
| Study Treatment Period | Adverse Event | 7 | 3 |
| Study Treatment Period | Did Not Meet Protocol Eligibility | 2 | 0 |
| Study Treatment Period | Noncompliance with Protocol | 0 | 1 |
| Study Treatment Period | Withdrawal by Subject | 8 | 12 |
Baseline characteristics
| Characteristic | Vorapaxar | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 56.6 years STANDARD_DEVIATION 10.1 | 55.3 years STANDARD_DEVIATION 11.7 | 55.9 years STANDARD_DEVIATION 10.9 |
| Sex: Female, Male Female | 27 Participants | 26 Participants | 53 Participants |
| Sex: Female, Male Male | 71 Participants | 69 Participants | 140 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Number of Participants Who Develop Vacuolization in the Inner Nuclear Layer (INL) of the Retina as Measured by Ocular Coherence Tomography (OCT)
Vacuolization is defined as the presence of more than one vacuole (defined as a clear, round structure in the INL of the retina of at least 30 microns in diameter) compared to baseline in either the left or right eye as evaluated by ocular coherence tomography (OCT).
Time frame: Up to 12 months
Population: The analysis population consisted of all participants who took at least one dose of study medication, and had a baseline and at least one post-baseline vacuolation assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vorapaxar | Number of Participants Who Develop Vacuolization in the Inner Nuclear Layer (INL) of the Retina as Measured by Ocular Coherence Tomography (OCT) | 4 months (n=91, n=86) | 1 participants |
| Vorapaxar | Number of Participants Who Develop Vacuolization in the Inner Nuclear Layer (INL) of the Retina as Measured by Ocular Coherence Tomography (OCT) | 8 months (n=86, n=80) | 1 participants |
| Vorapaxar | Number of Participants Who Develop Vacuolization in the Inner Nuclear Layer (INL) of the Retina as Measured by Ocular Coherence Tomography (OCT) | 12 months (n=77, n=78) | 0 participants |
| Placebo | Number of Participants Who Develop Vacuolization in the Inner Nuclear Layer (INL) of the Retina as Measured by Ocular Coherence Tomography (OCT) | 8 months (n=86, n=80) | 0 participants |
| Placebo | Number of Participants Who Develop Vacuolization in the Inner Nuclear Layer (INL) of the Retina as Measured by Ocular Coherence Tomography (OCT) | 4 months (n=91, n=86) | 0 participants |
| Placebo | Number of Participants Who Develop Vacuolization in the Inner Nuclear Layer (INL) of the Retina as Measured by Ocular Coherence Tomography (OCT) | 12 months (n=77, n=78) | 0 participants |
Secondary
Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by Fundus Photography
Individual fundus photography abnormalities were scored as 0=not present or 1=present. The total number of possible abnormalities present was 48 (24 possible abnomalities per eye). Data are for the left and right eyes combined (score range: 0 to 48). Change from Baseline at a given timepoint was calculated as Timepoint Score minus Baseline Score. A smaller score indicates fewer graded abnormalities.
Time frame: Baseline and 4, 8 and 12 months
Population: The analysis population consisted of all participants who took at least one dose of study medication, and had a baseline and at least one post-baseline numerical score of graded abnormalities assessment as measured by fundus photogrpahy.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vorapaxar | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by Fundus Photography | Baseline score (n=91, n=87) | 4.1 score on a scale | Standard Error 0.4 |
| Vorapaxar | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by Fundus Photography | 8 months change (n=86, n=80) | -0.4 score on a scale | Standard Error 0.4 |
| Vorapaxar | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by Fundus Photography | 4 months change (n=90, n=86) | -0.2 score on a scale | Standard Error 0.4 |
| Vorapaxar | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by Fundus Photography | 12 months change (n=76, n=77) | -0.6 score on a scale | Standard Error 0.5 |
| Placebo | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by Fundus Photography | 4 months change (n=90, n=86) | -0.4 score on a scale | Standard Error 0.3 |
| Placebo | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by Fundus Photography | Baseline score (n=91, n=87) | 3.9 score on a scale | Standard Error 0.4 |
| Placebo | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by Fundus Photography | 12 months change (n=76, n=77) | -0.3 score on a scale | Standard Error 0.5 |
| Placebo | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by Fundus Photography | 8 months change (n=86, n=80) | -0.6 score on a scale | Standard Error 0.4 |
Secondary
Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by OCT
Individual OCT abnormalities were scored as 0=not present or 1=present. The total number of possible abnormalities present was 84 (42 possible abnormalities per eye). Data are for the left and right eyes combined (score range: 0 to 84). Change from Baseline at a given timepoint was calculated as Timepoint Score minus Baseline Score. A smaller score indicates fewer graded abnormalities.
Time frame: Baseline and 4, 8 and 12 months
Population: The analysis population consisted of all participants who took at least one dose of study medication, and had a baseline and at least one post-baseline numerical score of graded abnormalities assessment by OCT.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vorapaxar | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by OCT | Baseline score (n=92, n=87) | 3.1 score on a scale | Standard Error 0.3 |
| Vorapaxar | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by OCT | 4 months change (n=91, n=86) | 0.2 score on a scale | Standard Error 0.3 |
| Vorapaxar | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by OCT | 8 months change (n=86, n=80) | 0.6 score on a scale | Standard Error 0.3 |
| Vorapaxar | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by OCT | 12 months change (n=77, n=78) | 0.2 score on a scale | Standard Error 0.3 |
| Placebo | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by OCT | 12 months change (n=77, n=78) | 0.0 score on a scale | Standard Error 0.3 |
| Placebo | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by OCT | 4 months change (n=91, n=86) | 0.7 score on a scale | Standard Error 0.3 |
| Placebo | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by OCT | Baseline score (n=92, n=87) | 3.4 score on a scale | Standard Error 0.4 |
| Placebo | Change From Baseline in the Numerical Score of Graded Abnormalities as Measured by OCT | 8 months change (n=86, n=80) | 0.9 score on a scale | Standard Error 0.3 |
Secondary
Number of Participants Who Have a Decrease in Visual Acuity Score of at Least Seven Letters From Baseline
Visual acuity was assessed in both eyes by best corrected visual acuity following standardized refraction. The best corrected visual acuity score is the number of letters on a standard visual acuity testing chart read correctly by a participant. A decrease in best corrected visual acuity score in the left and/or right eye indicates a worsening of vision.
Time frame: Baseline and 4, 8 and 12 months
Population: The analysis population consisted of all participants who took at least one dose of study medication, and had a baseline and at least one post-baseline visual acuity score.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vorapaxar | Number of Participants Who Have a Decrease in Visual Acuity Score of at Least Seven Letters From Baseline | 4 months (n=90, n=86) | 10 participants |
| Vorapaxar | Number of Participants Who Have a Decrease in Visual Acuity Score of at Least Seven Letters From Baseline | 8 months (n=86, n=80) | 10 participants |
| Vorapaxar | Number of Participants Who Have a Decrease in Visual Acuity Score of at Least Seven Letters From Baseline | 12 months (n=78, n=78) | 7 participants |
| Placebo | Number of Participants Who Have a Decrease in Visual Acuity Score of at Least Seven Letters From Baseline | 4 months (n=90, n=86) | 8 participants |
| Placebo | Number of Participants Who Have a Decrease in Visual Acuity Score of at Least Seven Letters From Baseline | 8 months (n=86, n=80) | 8 participants |
| Placebo | Number of Participants Who Have a Decrease in Visual Acuity Score of at Least Seven Letters From Baseline | 12 months (n=78, n=78) | 9 participants |
Secondary
Number of Participants With Change From Baseline of Center Foveal Thickness of Greater Than 15 Microns as Measured by OCT
Center foveal thickness measured by OCT was evaluated for a change from baseline in greater than 15 microns in either the left or right eye.
Time frame: Baseline and 4, 8 and 12 months
Population: The analysis population consisted of all participants who took at least one dose of study medication, and had a baseline and at least one post-baseline center point thickness assessment by OCT.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vorapaxar | Number of Participants With Change From Baseline of Center Foveal Thickness of Greater Than 15 Microns as Measured by OCT | 4 months (n=91, n=86) | 27 participants |
| Vorapaxar | Number of Participants With Change From Baseline of Center Foveal Thickness of Greater Than 15 Microns as Measured by OCT | 8 months (n=86, n=80) | 23 participants |
| Vorapaxar | Number of Participants With Change From Baseline of Center Foveal Thickness of Greater Than 15 Microns as Measured by OCT | 12 months (n=77, n=78) | 19 participants |
| Placebo | Number of Participants With Change From Baseline of Center Foveal Thickness of Greater Than 15 Microns as Measured by OCT | 12 months (n=77, n=78) | 29 participants |
| Placebo | Number of Participants With Change From Baseline of Center Foveal Thickness of Greater Than 15 Microns as Measured by OCT | 4 months (n=91, n=86) | 28 participants |
| Placebo | Number of Participants With Change From Baseline of Center Foveal Thickness of Greater Than 15 Microns as Measured by OCT | 8 months (n=86, n=80) | 26 participants |