Drug Therapy

When Do Efficacy Outcomes in Clinical Trials Correlate With Clinical Relevance? Analysis of Clindamycin Phosphate 1.2%–Benzoyl Peroxide 3.75% Gel in Moderate to Severe Acne Vulgaris

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Acne vulgaris (AV) is a common skin disease that is challenging to successfully treat due to its complex underlying pathophysiology and chronicity. Unrealistic expectations based on the desire for rapid and complete clearance or local tolerability reactions related to topical medications often lead to incomplete adherence with therapy, premature treatment cessation, and poor therapeutic outcomes. Despite stressing to patients the importance of compliance and the lag time of several weeks before visible improvement may be noted with treatments for AV, data on evaluation of the time taken to achieve a clinically meaningful improvement of AV that may be perceived by clinicians and patients are limited. Clindamycin phosphate 1.2%–benzoyl peroxide 3.75% (clindamycin-BP 3.75%) gel has been shown in pivotal trials to be effective and well tolerated in patients with moderate to severe AV. This article reviews a new concept referred to as time to onset of action (TOA), which is described in detail and illustrated using the pivotal trial data with clindamycin-BP 3.75% gel for treatment of AV.

Practice Points

  • Time to onset of action (TOA) refers to how long it takes after starting a therapy for a patient to perceive visible improvement.
  • Time to onset of action has been determined based on data to date to correlate overall with a 25% lesion reduction.
  • The TOA for clindamycin phosphate 1.2%–benzoyl peroxide 3.75% gel applied once daily based on analysis of pivotal trial data is 3 weeks or less depending on the severity of acne vulgaris at baseline.

 

References

Acne vulgaris (AV) is a common skin disease that usually presents in adolescence and can persist into adulthood. Some cases may start in adulthood, especially in women. Acne vulgaris remains a challenge to treat successfully, both in teenagers and adults. Unrealistic expectations that therapy will rapidly clear and sustain clearance of AV completely can lead to incomplete adherence or complete cessation of treatment.1-4 Local tolerability reactions also may decrease adherence to topical medications. Suboptimal adherence to medications for AV is one of the major reasons for treatment failure.5 Acne vulgaris can strongly influence psychological well-being and self-esteem.6 In general, severe AV causes more psychological distress, but the adverse emotional impact of AV can be independent of its severity.7

An effective relationship between the patient and his/her physician and staff is believed to be important in setting realistic expectations, optimizing adherence, and achieving a positive therapeutic outcome. One component related to setting reasonable expectations is the discussion about when the patient may begin to visibly perceive that the treatment regimen is working. This article evaluates the time course of a clinically meaningful response using pivotal trial data with clindamycin phosphate 1.2%–benzoyl peroxide 3.75% (clindamycin-BP 3.75%) gel for treatment of AV.

Are data available that evaluate the time course of a clinically relevant response to treatment of AV?

Unfortunately, data on what might be perceived as a clinically meaningful improvement in AV and how long it might take to achieve this treatment effect are limited. A meta-analysis of more than 4000 patients with moderate to severe AV suggested that a 10% to 20% difference in acne lesion counts from baseline as compared to a subsequent designated time point was clinically relevant.8 A review of 24 comparative studies of patients with mild to moderate AV used a primary outcome parameter of a 25% reduction in mean inflammatory lesion count to evaluate time to onset of action (TOA) to achieve a clinically meaningful benefit.9 This outcome was based on a previously identified threshold of clinical relevance and the authors’ clinical experience in a patient population with milder AV. In this same analysis, a difference of greater than 4 days between the active group and the vehicle group was considered to be relevant to the patient.9

A faster onset of visible improvement as perceived by the patient should be more desirable and is likely to improve treatment adherence, as long as it is not counterbalanced by an increase in adverse events.

What is meant by TOA?

Time to onset of action refers to the duration required to achieve a 25% mean lesion count reduction from baseline, which is believed to correlate with the time point at which many patients would be able to perceive visible improvement when viewing their full face. Therefore, TOA represents an attempt to correlate data that is quantitative (based on lesion count reduction) with what is likely to be the average time that a patient may qualitatively observe an initial visible improvement in their AV. This concept may be useful as a tool when communicating with AV patients but should not be used in a way that will overpromise and underdeliver; rather, it is a guide for discussion with the patient and with a parent or guardian when applicable.

Consistent with the comparative AV study analysis that evaluated TOA, a linear course of lesion reductions between the provided time intervals was assumed. In this linear model, the TOA was calculated using the 2 extracted lesion count values between which the 25% lesion reduction was achieved as well as their corresponding given time points.9 Differences between the results in the active and vehicle study arms were calculated for a number of determinants.

How was pivotal trial data with clindamycin-BP 3.75% gel used to assess TOA?

A total of 498 patients with moderate to severe AV were randomized (1:1) to receive clindamycin-BP 3.75% gel or vehicle in a multicenter, double-blind, controlled, 12-week, 2-arm study.10 Before randomization, patients were stratified by acne severity based on a static Evaluator’s Global Severity Score (EGSS) ranging from 0 (clear) to 5 (very severe). Specifically, moderate AV (EGSS of 3) was described as predominantly noninflammatory lesions with evidence of multiple inflammatory lesions; several to many comedones, papules, and pustules; and no more than 1 small nodulocystic lesion. Severe AV (EGSS of 4) was characterized by inflammatory lesions; numerous comedones, papules, and pustules; and possibly a few nodulocystic lesions.10

Male and female patients aged 12 to 40 years with moderate to severe AV—defined as 20 to 40 inflammatory lesions (papules, pustules, nodules), 20 to 100 noninflammatory lesions (comedones), and no more than 2 nodules—were included in the study. Standard washout periods were required for patients using prior prescription and over-the-counter acne treatments.10

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