September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Potential Beneficial Effect of Low Dose Danazol in Combination With Renin Angiotensin System Inhibitors in Diabetic Macular Edema: a 12-week Double Blind Randomized Controlled Trial
Author Affiliations & Notes
  • Michael Singer
    Med Ctr Ophthalmology Assoc, San Antonio, New York, United States
  • Alessandro Orlando
    Trauma Research, Swedish Medical Center, Englewood, Colorado, United States
    Trauma Research, St. Anthony Hospital, Lakewood, Colorado, United States
  • Vaughan Clift
    Ampio Pharmaceuticals, Englewood, Colorado, United States
  • David Bar-Or
    Ampio Pharmaceuticals, Englewood, Colorado, United States
    Trauma Research, Swedish Medical Center, Englewood, Colorado, United States
  • Footnotes
    Commercial Relationships   Michael Singer, Ampio (F); Alessandro Orlando, Ampio Pharmaceuticals, Inc. (C); Vaughan Clift, Ampio Pharmaceuticals, Inc. (E), Ampio Pharmaceuticals, Inc. (I), Ampio Pharmaceuticals, Inc. (S); David Bar-Or, Ampio Pharmaceuticals, Inc. (I), Ampio Pharmaceuticals, Inc. (E), Ampio Pharmaceuticals, Inc. (P), Ampio Pharmaceuticals, Inc. (S)
  • Footnotes
    Support  Research support from Ampio to conduct the study
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 3250. doi:
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      Michael Singer, Alessandro Orlando, Vaughan Clift, David Bar-Or; Potential Beneficial Effect of Low Dose Danazol in Combination With Renin Angiotensin System Inhibitors in Diabetic Macular Edema: a 12-week Double Blind Randomized Controlled Trial. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3250.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Anti-VEGFs improve diabetic macular edema (DME) by reducing vascular permeability, but only act through a single pathway, VEGF-A. Low-dose danazol has been shown to decrease vascular permeability via multiple higher-order pathways in in-vivo and in-vitro DME models. The objectives of this study were to evaluate the efficacy and safety of low-dose danazol in DME, and identify a target population for future trials.

Methods : Patients with DME were enrolled in a randomized controlled trial across 21 sites. Subjects were treated twice-daily for 12 weeks with oral 0.5mg danazol/BMI, 1mg danazol/BMI or placebo. Primary and secondary outcomes were change from baseline in best-corrected visual acuity (BCVA, ETDRS letters) and central retinal thickness (CRT, μm). A mixed-model analysis of covariance, adjusting for baseline values examined these outcomes; interactions with BMI, and renin-angiotensin system (RAS) inhibitors were examined using similar models. Responder rates (≥5 letter gain) were compared using chi-squared tests.

Results : 425 eyes were included: placebo=142, 0.5mg danazol/BMI=141, 1mg danazol/BMI=142. 53% of subjects had failed anti-VEGF therapy. There were no overall differences between groups in change from baseline in BCVA or CRT (p=0.29, p=0.64), because the changes were dependent on BMI (p-interactions=0.06, 0.13). The 0.5mg danazol/BMI dose was optimal in BMIs 27.72–31.31 (neyes=110), and depended on RAS inhibitor use (p-interaction=0.10)–results are presented for this BMI subgroup. 60% of eyes treated with 0.5mg danazol/BMI + RAS inhibitors regained ≥5 letters, compared to 27% in placebo (p=0.02). 0.5mg danazol/BMI + RAS inhibitors had significantly larger improvements in BCVA and CRT, than placebo + RAS inhibitors (BCVA diff.=5.1 letters, p=0.01; CRT diff.=-59.3μm, p=0.03); similar, significant improvements were seen in patients refractory to anti-VEGF therapy. No significant changes in BCVA or CRT was seen in the placebo + RAS inhibitor or the 0.5mg danazol/BMI + no RAS inhibitors groups. No serious drug-related adverse events were seen.

Conclusions : Combined low-dose danazol and RAS inhibitors shows promise as a painless, safe and efficacious oral rescue medication for DME, and will be confirmed in future trials and formulated to work across all BMIs.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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