Diabetic Macular Edema
Conditions
Keywords
macular edema, diabetic
Brief summary
This study will evaluate the efficacy of ultra low dose danazol (Optina™) for the treatment of diabetic macular edema.
Detailed description
A Randomized, Placebo-Controlled, Parallel, Double-Masked Study to Evaluate the Efficacy and Safety of Two Doses of Oral Optina™ in Adult Patients With Diabetic Macular Edema. The primary trial objective is to evaluate the efficacy of two oral BMI-related doses (0.5 mg per body mass index (BMI), 1.0 mg per BMI per day) of Optina™ in improving visual acuity (VA) compared to placebo. The secondary objectives are to evaluate the efficacy of two oral BMI-related doses of Optina™ on change in central macular thickness (CMT) and VA responder status compared to placebo, and to assess the safety and tolerability of two oral BMI-related doses of Optina™ compared to placebo.
Interventions
DRUGDanazol Capsules
DRUGPlacebo
Sponsors
Ampio Pharmaceuticals. Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Study Level Inclusion Criteria: 1. Subject is willing and able to provide informed consent for study participation 2. Male or female 18 years or older with Type 1 or 2 diabetes mellitus \[defined as a self-report of diabetes accompanied by treatment (insulin or diet) or a history of fasting plasma glucose ≥ 7.0 mmo/l (126 mg/dl) or 2-hr plasma glucose ≥ 11.1 mmo/l (200 mg/dl)\] 3. Female subjects of childbearing potential must have a negative pregnancy test within 7 days prior to randomization and must agree to utilize a reliable form of effective contraception (hormonal or barrier method; abstinence) throughout the study and for 90 days after the last dose of study medication. Childbearing potential is defined as women who have had menses within the past 12 months, who have not had tubal ligation or bilateral oophorectomy \[Note: patients using contraceptive methods containing progesterone (including a progesterone IUD) for 90 days prior to randomization or planning to use progesterone contraceptive methods (including a progesterone IUD) during the study drug treatment period are not eligible for enrollment.\] Should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately 4. Enrollment in this study is contraindicated for pregnant or lactating women. Thus, female patients who are postmenopausal without a menstrual period for ≥ 12 months, surgical sterility, not pregnant and not breast feeding for 90 days prior to randomization can be enrolled 5. At least one eye meets the study eye criteria for inclusion in the study (see Study Eye Inclusion Criteria, below) 6. Stable diabetic and metabolic control (no major changes in diabetic or lipid reducing medications for 3 months prior to start of this study as determined by the Investigator) Study Eye Inclusion Criteria (if both eyes meet criteria, both eyes will be study eyes) 1. Change in VA within previous 12 months reasonably believed to be associated with diabetic macular edema (DME) in the opinion of the Investigator 2. Best-corrected visual acuity (BCVA) in accordance with early treatment diabetic retinopathy study (ETDRS) letter score of ≥24 (e.g., 20/320 or better) and ≤78 (e.g., 20/32 or worse) 3. Definite retinal thickening ≥275 microns on spectral-domain optical coherence tomography (OCT) due to DME involving the center of the macula on clinical exam in the opinion of the Investigator 4. Media clarity, pupillary dilation, and patient cooperation sufficient for adequate fundus photographs 5. Assessment by the Investigator that focal photocoagulation can be deferred safely for 16 weeks Study Level
Exclusion criteria
1. Known allergy to any danazol (Cyclomen® or Danocrine®) or any other non-medicinal component of the danazol test drug (cornstarch, lactose, magnesium stearate, gelatin, and talc) (Note: Lactose intolerance is not a contraindication to ingesting the small amount of lactose contained in oral medications) 2. Known allergy to any component of the placebo test drug (lactose, magnesium stearate, and gelatin) 3. History of systemic (e.g., oral, intravenous, intramuscular, subcutaneous, intra-uterine, epidural, bursal, or implanted) androgens, progesterone or corticosteroids (including topical ophthalmic corticosteroids preparations within 4 months prior to randomization (topical non-ophthalmic corticosteroids are not excluded) 4. Blood pressure \>180/110 mm Hg (in cases where either or both of the systolic or diastolic limits are exceeded, blood pressure can be re-measured after 10 minutes rest period for inclusion in the study) 5. HbA1c greater than 11% or consistent HbA1c values in a similar range for the last 6 months. 6. Carcinoma of the breast 7. Prostate cancer 8. Androgen-dependent tumor 9. Undiagnosed abnormal genital bleeding 10. Genital neoplasia 11. Currently taking warfarin (coumadin), carbamazepine, phenytoin, phenobarbital cyclosporin or tacrolimus 12. Females who are pregnant or planning pregnancy in the 6-month period after randomization (Note: Enrollment in this study is contraindicated for pregnant or lactating women) 13. Females breast feeding or breast feeding in the 90 days prior to randomization (Note: Enrollment in this study is contraindicated for pregnant or lactating women) 14. Use of any hormonal therapies including hormone replacement therapy (HRT) and contraceptive medications that contain progesterone within 3 months before randomization (Note: patients on pure estrogen or estradiol replacement therapy can be enrolled in the study) 15. Unstable cardiovascular disease or a history of significant heart disease (including unstable angina, acute coronary syndrome, myocardial infarction, or history of coronary revascularization procedure) within 6 months before randomization 16. Any condition that, in the opinion of the Investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure and glycemic control). Patients in poor glycemic control who, within the last 3 months, using a new type of insulin (for example, changing to or adding a short acting insulin from a longer-acting insulin), or increased the daily dose ≥ 50%, initiated intensive insulin treatment such as an insulin pump or additional daily injections or plan to do so in the next 3 months should not be enrolled. 17. Significant hepatic disease (defined as aspartate aminotransferase, alanine aminotransferase or alkaline phosphatase \[ALP\], more than twice the upper limit of normal) where, in the opinion of the Investigator, danazol might be contraindicated 18. Significant renal disease (defined as serum creatinine ≥ 2.5 mg/dl, history of renal transplant, or undergoing dialysis at screening) where, in the opinion of the Investigator, danazol might be contraindicated 19. Changes in anti-hypertensive medication within 3 months before randomization (except for dosage adjustments that are considered minor in the opinion of the Investigator) 20. Major surgery (e.g., head and neck, chest, abdomen, gastrointestinal, genitourinary or central nervous system) within past 28 days or anticipated in the next 6 months 21. History of acute intermittent porphyria, any thrombosis or thromboembolic disease or pseudotumor cerebri 22. Participation in an investigational trial within 30 days of study entry that involved treatment with any drug that has not received regulatory approval at the time of study entry 23. Patient is expecting to move out of the area of the clinical center during the next 6 months Study Eye
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Best Corrected Visual Acuity (BCVA) | Determined at Baseline and Week 12 | Change from baseline score to the week 12 score in the number of letters read on an eye chart in accordance with Early Treatment Diabetic Retinopathy Study (ETDRS) of the Intent to Treat (ITT) population of all treated subjects. A positive number indicates more letters could be read. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Central Macular Thickness (CMT) | Determined at Baseline and Week 12 | A measured change from baseline to week 12 of central macular thickness of the Intent to Treat population of all treated subjects. A negative difference in Central Macular Thickness constitutes a reduction in retinal thickness. Increase in Central Macular Thickness is caused by diabetic macular edema. A greater negative value indicates a greater reduction in swelling. |
Participant flow
Recruitment details
Subjects were recruited for study enrollment from a population of subjects being seen by clinicians participating in the investigational trial. Recruitment occurred from February 2013 to June 2014.
Pre-assignment details
Standard of care treatment for diabetes will not be withheld during the study.
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Danazol 0.5 mg/BMI/day of Danazol administered as 2 capsules twice daily (total of 4 capsules/day) for 12 weeks. | 117 |
| Low Dose Danazol 0.5 mg/BMI/day of Danazol administered as 2 capsules twice daily (total of 4 capsules/day) for 12 weeks. | 141 |
| High Dose Danazol 1.0 mg/BMI/day of Danazol administered as 2 capsules twice daily (total of 4 capsules/day) for 12 weeks. | 117 |
| High Dose Danazol 1.0 mg/BMI/day of Danazol administered as 2 capsules twice daily (total of 4 capsules/day) for 12 weeks. | 142 |
| Placebo Placebo capsules administered as 2 capsules twice daily (total of 4 capsules/day) for 12 weeks. | 120 |
| Placebo Placebo capsules administered as 2 capsules twice daily (total of 4 capsules/day) for 12 weeks. | 142 |
| Total | 779 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 6 | 5 |
| Overall Study | Lost to Follow-up | 2 | 1 | 3 |
| Overall Study | Non-compliance | 0 | 1 | 2 |
| Overall Study | Other | 9 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 4 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 7 | 3 | 2 |
Baseline characteristics
| Characteristic | Low Dose Danazol | Total | Placebo | High Dose Danazol |
|---|---|---|---|---|
| Age, Continuous | 64.2 Years STANDARD_DEVIATION 11.2 | 63.1 Years STANDARD_DEVIATION 10.3 | 62.4 Years STANDARD_DEVIATION 10.6 | 62.7 Years STANDARD_DEVIATION 8.8 |
| Best Corrected Visual Acuity (BCVA) | 63.8 Letters Correctly Read STANDARD_DEVIATION 11.2 | 63.4 Letters Correctly Read STANDARD_DEVIATION 11 | 62.7 Letters Correctly Read STANDARD_DEVIATION 11.6 | 63.6 Letters Correctly Read STANDARD_DEVIATION 10.2 |
| Body Mass Index (BMI) | 32.3 kg/m^2 STANDARD_DEVIATION 7.1 | 32.3 kg/m^2 STANDARD_DEVIATION 6.9 | 32.3 kg/m^2 STANDARD_DEVIATION 6.8 | 32.2 kg/m^2 STANDARD_DEVIATION 6.9 |
| Central Macular Thickness | 438.6 micrometers (μm) STANDARD_DEVIATION 132.8 | 430.1 micrometers (μm) STANDARD_DEVIATION 127.6 | 426.8 micrometers (μm) STANDARD_DEVIATION 126.9 | 423.3 micrometers (μm) STANDARD_DEVIATION 120.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants | 86 Participants | 31 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 89 Participants | 268 Participants | 89 Participants | 90 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 3 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 7 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 30 Participants | 7 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 4 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 97 Participants | 308 Participants | 109 Participants | 102 Participants |
| Region of Enrollment United States | 117 participants | 354 participants | 120 participants | 117 participants |
| Sex: Female, Male Female | 58 Participants | 177 Participants | 68 Participants | 51 Participants |
| Sex: Female, Male Male | 59 Participants | 177 Participants | 52 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 117 | 0 / 117 | 0 / 120 |
| other Total, other adverse events | 32 / 117 | 34 / 117 | 48 / 120 |
| serious Total, serious adverse events | 14 / 117 | 7 / 117 | 12 / 120 |
Outcome results
Primary
Change in Best Corrected Visual Acuity (BCVA)
Change from baseline score to the week 12 score in the number of letters read on an eye chart in accordance with Early Treatment Diabetic Retinopathy Study (ETDRS) of the Intent to Treat (ITT) population of all treated subjects. A positive number indicates more letters could be read.
Time frame: Determined at Baseline and Week 12
Population: Intent to Treat (ITT)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low Dose Danazol | Change in Best Corrected Visual Acuity (BCVA) | 1.0 Letters Correctly Read |
| High Dose Danazol | Change in Best Corrected Visual Acuity (BCVA) | 0.8 Letters Correctly Read |
| Danazol Combined (0.5 mg / BMI and 1.0 mg / BMI Dose) | Change in Best Corrected Visual Acuity (BCVA) | 0.9 Letters Correctly Read |
| Placebo | Change in Best Corrected Visual Acuity (BCVA) | 2.5 Letters Correctly Read |
p-value: 0.16ANCOVA
p-value: 0.07ANCOVA
p-value: 0.03ANCOVA
Secondary
Change in Central Macular Thickness (CMT)
A measured change from baseline to week 12 of central macular thickness of the Intent to Treat population of all treated subjects. A negative difference in Central Macular Thickness constitutes a reduction in retinal thickness. Increase in Central Macular Thickness is caused by diabetic macular edema. A greater negative value indicates a greater reduction in swelling.
Time frame: Determined at Baseline and Week 12
Population: Intent to Treat (ITT)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low Dose Danazol | Change in Central Macular Thickness (CMT) | -6.0 micrometers (μm) |
| High Dose Danazol | Change in Central Macular Thickness (CMT) | -2.8 micrometers (μm) |
| Danazol Combined (0.5 mg / BMI and 1.0 mg / BMI Dose) | Change in Central Macular Thickness (CMT) | -4.4 micrometers (μm) |
| Placebo | Change in Central Macular Thickness (CMT) | -17.5 micrometers (μm) |
p-value: 0.42ANCOVA
p-value: 0.28ANCOVA
p-value: 0.14ANCOVA