Exudative Macular Degeneration
Conditions
Keywords
VEGF, PDGF, AMD
Brief summary
The objective of this study is to evaluate the safety and preliminary biologic activity/efficacy of X-82 in patients with wet Age-related Macular Degeneration (AMD). Preliminary efficacy will be assessed by change from baseline in visual acuity, fluorescein leakage, retinal thickness and fibrosis, if detectable, based on fundus examination, fundus photography, fluorescein angiography and optical coherence tomography (OCT).
Interventions
DRUGX-82 oral
X-82 oral for 24 weeks or until unacceptable toxicity develops
Rescue treatment with intravitreal ranibizumab (Lucentis) as needed
Sponsors
Tyrogenex
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Active choroidal neovascularization (CNV) associated with AMD, as evidenced on fluorescein angiography (FA) and OCT. 2. No previous treatment with anti-VEGF therapy or prior anti-VEGF therapy with evidence of response to treatment and the need for additional treatment. 3. Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA 20/32 to 20/320 in the study eye(s). 4. Adequate bone marrow function. 5. PT within the institutional upper limit of normal. 6. Adequate hepatic function. 7. Adequate renal function; serum creatinine. 8. Ability to swallow oral medication. 9. Age ≥ 50 years. 10. Willing and able to provide written informed consent, comply with the investigational study protocol and return for all study visits.
Exclusion criteria
1. Previous treatment with photodynamic therapy (PDT) within 4 months of screening in the study eye. 2. CNV due to causes other than AMD. 3. Geographic atrophy involving the foveal center in the study eye. 4. Any retinal vascular disease or retinal degeneration other than AMD in the study eye. 5. In the opinion of the investigator, any significant disease in the study eye that could compromise best-corrected visual acuity. 6. Cataract surgery in the study eye within three months of screening. 7. Trabeculectomy or aqueous shunt or valve in the study eye. 8. Intraocular surgery in the study eye within three months of screening; Nd:YAG capsulotomy or laser iridotomy within 30 days of screening. 9. Inadequate pupillary dilation or significant media opacities in the study eye. 10. Use of any investigational agent or participation in any other clinical trial of an investigational agent or investigational therapy within thirty (30) days of baseline with the exception of subjects who are participating in the AREDS2 study. 11. Females of child bearing potential that are pregnant or not using medically acceptable contraception; males unwilling to take adequate contraceptive measures. Females that are breastfeeding are also excluded. 12. Serious allergy to or prior significant adverse reaction to fluorescein. 13. Undiagnosed acute illness first observed during screening or between screening and baseline, or severe concurrent medical conditions that, in the investigators judgment, represent a safety concern. 14. Severe cardiac disease, symptomatic congestive heart failure, unstable angina, acute coronary syndrome, myocardial infarction or coronary artery revascularization, or arterial thrombosis within 12 months of start of study drug, inadequately controlled hypertension, or ventricular tachyarrhythmias requiring ongoing treatment. 15. QTc ≥450 msec or subjects with a history of risk factors for Torsades de Pointes or other clinically significant ECG abnormalities as determined by the investigator. 16. Stroke or transient ischemic attack within 12 months of trial entry. 17. Clinically significant impaired renal or hepatic function. 18. Any major surgical procedure within one month of trial entry. 19. Presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of X-82. 20. Receiving treatment with anti-coagulants other than 325 mg of aspirin per day. 21. Serious active infection, other serious medical condition or any other condition that would impair the ability of the subject to administer the investigational drug or to adhere to the study protocol requirements. 22. Presence of any condition which, in the judgment of the investigator, would prevent the subject from completing the study. 23. No herbal medications with the exception of bilberry are allowed within 7 days of start of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Visual Acuity at 6 Months | 6 months | The best corrected visual acuity by the Early Treatment Diabetic Retinopathy Study (ETDRS) method was determined at baseline and at various times during the study. The ETDRS method records the number of letters of decreasing size on a chart that a subject can read from a defiend distance. During the study the ETDRS visual acuity was used to monitor the need for rescue therapy. The primary endpoint of the study was the change from baseline visual ETDRS visual acuity at 6 months. It was calculated by subtracting the baseline visual acuity from the visual acuity at 6 months for each individual subject. A positive change from baseline indicates improvement in visual acuity. |
Countries
United States
Participant flow
Recruitment details
Subjects with wet age related macular degeneration were enrolled at 5 US retinal clinics between November 2012 and March 2015
Pre-assignment details
110 subjects were screened for entry into the study. 52 did not meet inclusion criteria, 19 declined to participate and 4 were excluded for other reasons
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation of X-82 and Ranibizumab Rescue Groups of participants were assigned to 1 of 6 X-82 doses over 24weeks,with an additional 4 weeks for follow-up. The dose escalated from one level to the next in the absence of any dose-limiting toxicity (DLT) defined as a drug-related safety event during the first 2 weeks of treatment that was severe enough to require removal of the participant from the study.
The escalating X82 oral dose regimens were 50 mg alternate days, 50 mg daily, 100 mg alternate days, 100mg daily, 200mg daily, and 300mg daily. | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 | 1 | 2 | 2 |
| Overall Study | Protocol Violation | 0 | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Dose Escalation of X-82 and Ranibizumab Rescue |
|---|---|
| Age, Continuous | 76.8 years STANDARD_DEVIATION 8.5 |
| Best corrected visual acuity | 62.4 Number of letters STANDARD_DEVIATION 12.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 33 Participants |
| Region of Enrollment United States | 35 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 35 |
| other Total, other adverse events | 28 / 35 |
| serious Total, serious adverse events | 3 / 35 |
Outcome results
Primary
Change From Baseline Visual Acuity at 6 Months
The best corrected visual acuity by the Early Treatment Diabetic Retinopathy Study (ETDRS) method was determined at baseline and at various times during the study. The ETDRS method records the number of letters of decreasing size on a chart that a subject can read from a defiend distance. During the study the ETDRS visual acuity was used to monitor the need for rescue therapy. The primary endpoint of the study was the change from baseline visual ETDRS visual acuity at 6 months. It was calculated by subtracting the baseline visual acuity from the visual acuity at 6 months for each individual subject. A positive change from baseline indicates improvement in visual acuity.
Time frame: 6 months
Population: The mean and standard deviation was calculated for all subjects who completed 6 months of treatment with oral X82
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Completers | Change From Baseline Visual Acuity at 6 Months | 3.8 number of letters | Standard Deviation 9.6 |