Challenges in designing a randomized, double-blind noninferiority trial for treatment of acne: The SD-ACNE trial

Abstract

Background/aims: Excessive use of antibiotics has led to development of antibiotic resistance and other antibiotic-associated complications. Dermatologists prescribe more antibiotics per clinician than any other major specialty, with much of this use for acne. Alternative acne treatments are available but are used much less often than antibiotics, at least partially because dermatologists feel that they are less effective. Spironolactone, a hormonal therapy with antiandrogen effects that can address the hormonal pathogenesis of acne, may represent a therapeutic alternative to oral antibiotics for women with acne. However, the comparative effects of spironolactone and oral antibiotics in the treatment of acne have not been definitively studied. The Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation (SD-ACNE) trial aims to answer whether spironolactone, in addition to standard topical therapy, is noninferior to doxycycline (an oral antibiotic) for women with acne. Several interesting challenges arose in the development of this study, including determining acceptability of the comparative regimens to participating dermatologists, identifying data to support a noninferiority margin, and establishing a process for unblinding participants after they completed the study while maintaining the blind for study investigators.

Methods: We present the scientific and clinical rationale for the decisions made in the design of the trial, including input from key stakeholders through a Delphi consensus process.

Results: The Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation trial (NCT04582383) is being conducted at a range of community and academic sites in the United States. To maximize external validity and inform clinical practice, the study is designed with broad eligibility criteria and no prohibition of use of topical medications. Participants in the trial will be randomized to receive either spironolactone 100 mg/day or doxycycline hyclate 100 mg/day for 16 weeks. The primary outcome is the absolute decrease in inflammatory lesion count, and we have established a noninferiority margin of four inflammatory lesions. Secondary outcomes include the percentage of participants achieving Investigator Global Assessment success, change in quality of life, and microbiome changes and diversity.

Conclusions: The Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation trial will have substantial implications for the treatment of acne and antibiotic stewardship. In addition, this study will provide important information on the effect of these systemic agents on the development of changes to the microbiome and antibiotic resistance in a healthy population of patients.

Keywords: Acne; antibiotic resistance; antibiotics; doxycycline; microbiome; spironolactone.

Figure 1.. Study Flow Overview

IGA: Investigator Global Assessment; DLQI: Dermatology Life Quality Index; PGA: Patient Global Assessment

Figure 2.. PRECIS-2 Diagram

Eligibility (4) – Downgraded for excluding those on other systemic treatments as sometimes spironolactone and oral antibiotics will be combind in clinical practice; Recruitment (3) – Downgraded as using advertising (flyers, posting on local clinical trial recruitment platforms) as well as providing financial incentives for participating in the trial; Setting (4) – Downgraded as study visits are separate from standard care visits, but similarly conducted in outpatient setting; Organization (4) – Downgraded as participants receive the medication from the study team rather than from a traditional pharmacy due to the need for blinding; Follow-Up (4) - Downgraded since visits are more frequent than what is sometimes done in standard care (follow-up at 3-4 months).