Minocycline Extended-Release Comparison with Doxycycline for the Treatment of Rosacea: A Randomized, Head-to-Head, Clinical Trial

Abstract

Objective: Minocycline efficacy for the treatment of papulopustular rosacea (PPR) has not been evaluated in clinical trials at levels demonstrated to stay below the antimicrobial threshold. We assessed the efficacy, safety, and dose response of DFD-29, a minocycline extended-release oral capsule. Two studies are reported (NCT03340961).

Methods: A single-center open-label, three-arm, Phase I pharmacokinetic study randomized 24 healthy subjects aged 18 to 45 years to receive 21 days of once-daily dosing with DFD-29 40 or 20mg, or doxycycline 40mg. Blood samples were collected over 24 hours on Days 1 and 21 to plot mean plasma concentration levels. A multicenter Phase II clinical trial randomized 205 subjects with mild-to-severe PPR 1:1:1:1 to receive once-daily DFD-29 40 or 20mg, doxycycline 40mg, or placebo for 16 weeks. Co-primary endpoints were the proportion of subjects achieving treatment success (IGA grade 0 or 1 and ≥2-grade improvement) at Week 16, and a reduction in total inflammatory lesion count at Week 16.

Results: Pharmacokinetic analysis demonstrated that minocycline plasma levels of DFD-29 40mg were approximately half those of doxycycline 40mg after 21 days, with DFD-29 20mg even lower, demonstrating a dose response. In the Phase II trial, DFD-29 40mg met both co-primary endpoints, achieving IGA treatment success in 66.0 percent subjects versus 11.5 percent placebo (p<0.0001), 31.9 percent DFD-29 20mg (p=0.007), and 33.3 percent doxycycline 40mg (p<0.0010), and a mean reduction in lesion counts of -19.2 versus -7.3 placebo (p<0.0001), -12.6 DFD-29 20mg (p=0.0070), and -10.5 doxycycline 40mg (p=0.0004).

Limitations: MIC values and plasma concentrations shown for antibacterial threshold data are mean values; fast absorbers/slow metabolizers could exceed the threshold, causing resistance selection pressure.

Conclusion: DFD-29 40mg demonstrated significantly greater efficacy than placebo, DFD-29 20mg, and doxycycline 40mg at plasma concentrations predicted to be below the antimicrobial threshold for the treatment of PPR.

Keywords: Rosacea; doxycycline; minocycline; papulopustular rosacea.

Conflict of interest statement

DISCLOSURES: Dr. Tsianakas has received honoraria as a consultant and speaker from Novartis, Sanofi-Aventis, UCB, Pfizer, Kyowa Kirin, Beiersdorf, Janssen-Cilag, Almirall, Celgene, and LEO Pharma. Dr. Baldwin has received honoraria from Galderma, Mayne, Ortho-Dermatologics, Almirall, EPI Health, and Sun. Dr. Pieber has nothing to disclose. Dr. Feichtner has nothing to disclose. The remaining authors are all employees of Dr Reddy’s Laboratories.

Copyright © 2021. Matrix Medical Communications. All rights reserved.

Figures

FIGURE 1A.

Mean (±SD) plasma profiles of DFD-29 (minocycline) and doxycycline on Day 1

FIGURE 1B.

Mean (±SD) plasma profiles of DFD-29 (minocycline) and doxycycline on Day 21

FIGURE 2.

Phase II study subject disposition and analysis sets. aITT population included all randomized subjects dispensed the study drug; FAS included all randomized subjects with at least one post-baseline efficacy assessment; Safety population included all randomized subjects with at least one post-baseline safety assessment; PP population included all subjects who completed the study without protocol deviations

FIGURE 3A.

Proportion of subjects achieving treatment success for IGA (defined as a ≥2-grade reduction from baseline with grade 0 or 1 at end of study) at Week 16. FAS shown. χ2 test using MI for missing data.

FIGURE 3B.

Mean reduction in total of papules, pustules, and nodules from baseline to Week 16. FAS shown with SD. Mixed model using MI for missing data.

FIGURE 4.

Median change in total RosaQoL score at Week 16. Mean score reduction from baseline shown. ITT population. Kruskal–Wallis test.