A Safety and Efficacy Study of Oral Danazol (a Previously Approved Drug) in the Treatment of Diabetic Macular Edema.
Condition: Diabetic Macular Edema
MeSH terms: Macular Edema; Edema
Intervention: Danazol Capsules; Placebo
Intervention MeSH terms: Danazol
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 354.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: macular edema; diabetic

Summary:

      This study will evaluate the efficacy of ultra low dose danazol (Optina™) for the treatment
      of diabetic macular edema.
    

Eligibility 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 Exclusion Criteria:

          1. Macular edema considered to be due to a cause other than DME; e.g., cataract
             extraction, vitreo-retinal interface disease (a taut posterior hyaloid or epiretinal
             membrane)

          2. An ocular condition is present such that, in the opinion of the Investigator, VA would
             not improve from resolution of macular edema (e.g., foveal atrophy, closure of
             juxtafoveal capillaries, dense subfoveal hard exudates)

          3. An ocular condition (other than diabetic retinopathy) that, in the opinion of the
             Investigator, might affect macular edema or alter VA during the course of the study,
             e.g., vein occlusion, uveitis or other ocular inflammatory disease, Irvine-Gass
             Syndrome, etc.

          4. Substantial cataract that, in the opinion of the Investigator, is likely to interfere
             with ocular measurements or evaluations during this study

          5. History of treatment for DME at any time in the past 8 weeks (such as focal/grid
             macular photocoagulation, intravitreal or peribulbar corticosteroids, anti-vascular
             endothelial growth factor [VEGF drugs], or any other treatment). Note, the 28-day
             screening period allows subjects to be screened at 4 weeks post DME treatment and have
             a baseline visit 28 days later.

          6. History of panretinal scatter photocoagulation (PRP) within 4 months prior to
             randomization or anticipated need for PRP in the 6 months following randomization

          7. History of major ocular surgery (including cataract extraction, scleral buckle, any
             intraocular surgery, etc.) within prior 6 months or anticipated within the next 6
             months following randomization

          8. History of yttrium aluminum garnet (YAG) capsulotomy performed within 2 months prior
             to randomization

          9. Uncontrolled glaucoma (in Investigator's judgment) in the study eye

         10. Aphakia