FormalPara Key Points

The most bothersome aspects for patients/caregivers are molluscum contagiosum lesion visibility and contagiousness.

Lesion count reductions are meaningful to patients/caregivers, even when complete clearance is not achieved.

1 Introduction

Molluscum contagiosum (MC), a common, highly contagious viral skin infection caused by the molluscipoxvirus [1], replicates only in human skin cells and has the unique ability to produce proteins that enable the virus to evade the host’s immune surveillance system [2, 3]. Molluscum contagiosum manifests as clusters of small raised firm bumps on infected skin and is especially common in younger children [4, 5]. Molluscum contagiosum lesions may be widespread, affecting sensitive body areas, causing pain, irritation, and redness, and if scratched, autoinoculation and heightened communicability [1]. Molluscum contagiosum infections may clear without treatment yet can persist for months or years [6]. Indeed, prolonged duration and visibility of MC lesions coupled with the potential to spread the virus can create psychosocial distress and anxiety [5] for both the patient and caregiver.

Currently, there is lack of consensus regarding treatment approaches to MC [7] and there is no US Food and Drug Administration (FDA)-approved prescription medication. Therefore, many healthcare providers take a watch-and-wait strategy with an estimated 74% of patients with MC left untreated [8]. It is unknown what impact the lack of a MC therapeutic intervention has on patient/caregiver physical and/or psychosocial well-being.

Berdazimer gel, 10.3% (SB206) is a novel, topical, nitric oxide-releasing agent under investigation as a first-in-class therapy for the treatment of MC [9,10,11,12]. The Berdazimer Sodium In Molluscum Patients with Lesions (B-SIMPLE4) pivotal phase III trial of berdazimer gel, 10.3% (ClinicalTrials.gov identifier: NCT04535531) enrolled the largest-ever cohort of patients with MC in a clinical trial (N = 891) with the results showing favorable efficacy and tolerability [9,10,11,12].

Capturing the patient experience and integrating the patient voice in dermatologic clinical trials have been a collaborative effort led by the FDA, patient advocacy groups, and the pharmaceutical industry [13]. Therefore, to better understand patients’ and caregivers’ experiences with the MC disease state and MC therapeutic strategies, patient-experience data (PED), including participant-reported and investigator-reported perception of complete clearance and participant-reported and investigator-reported Global Impression of Change (GIC), were collected in B-SIMPLE4. In addition, a qualitative exit interview was conducted with a subset of B-SIMPLE4 patients and caregivers. The objective of the exit interview was to gather input from patients and caregivers on the most bothersome signs and symptoms of MC, the psychosocial aspects of MC, expectations regarding clinical trial participation, and the meaningfulness of changes in MC lesion count and location, with special attention given to the impact of a reduced lesion count in the absence of complete clearance.

2 Methods

2.1 PED Assessments and Population

Briefly, B-SIMPLE4 was a multicenter, double-blind, vehicle-controlled, parallel-group (1:1) randomized clinical trial of the efficacy and safety of berdazimer gel, 10.3% applied topically once daily for 12 weeks [9]. The study methodology, eligibility criteria, patient disposition, and efficacy and safety results for B-SIMPLE4 have been published [9]. For the PED, B-SIMPLE4 included participant and investigator perceptions of MC lesion clearance at baseline and weeks 12 and 24. These assessments were based on participants’ (including patients and caregivers) and investigators’ perception of lesion clearance rather than a formal lesion count. For the GIC ratings, participants and investigators reported their overall impression of change from baseline in the patient’s overall MC condition at weeks 12 and 24 on a scale from 1 (very much improved) to 7 (very much worse) using a non-validated scale.

2.2 Exit Interview Study Design and Population

For the qualitative exit interview, all English-speaking B-SIMPLE4 participants at select sites who had less than complete MC lesion clearance from baseline to their week 12 visit as determined by the investigator were eligible for qualitative exit interviews. The goal was to engage ~ 30 participants (balanced between berdazimer gel, 10.3% and placebo groups), including ~ 20 participants with lesion count reductions that ranged from 75 to < 100% and approximately three to four participants with reductions in each of the following ranges: from 50 to < 75%, 25 to < 50%, and 0 to < 25%. The 60-min qualitative interviews of participants (patients or caregivers were interviewed, depending on patient age) were conducted using an interview guide by one of two RTI Health Solutions staff members via telephone 2–4 weeks after their week 12 visit.

2.3 Analyses

2.3.1 PED Analyses

For the PED from B-SIMPLE4, the participant-reported and investigator-reported perceptions of complete lesion clearance and participant-reported and investigator-reported GIC were summarized descriptively.

2.3.2 Exit Interview Analyses

For the exit interview, each semi-structured interview began with a brief overview of the interview process and a few general questions intended to prompt participants to discuss symptoms and impacts of MC. Additionally, patients were asked specifically what their treatment expectations were before entering the clinical trial and what their experiences were during the trial. Caregivers were asked specifically what their treatment expectations were before entering the clinical trial and what their child’s experiences were during the trial. Finally, interview participants were queried about various treatment benefits and outcomes, including any improvements observed, and the importance and meaningfulness of those improvements.

Exit interview data were systematically collected from study participants as field notes captured in Microsoft Excel (Microsoft Corporation, Redmond, WA, USA) and audio files. After interviews concluded, all audio files were transcribed verbatim and prepared for qualitative analysis.

The qualitative analysis of exit interviews was facilitated by a coding software (ATLAS.ti 9; Atlas.ti Scientific Software Development GmbH, Berlin, Germany), using a coding framework that was developed and adapted as the analysis progressed and emerging themes were incorporated. Interview results were analyzed using a thematic analysis approach [14]. Using the transcripts and interviewer field notes, dominant trends in each interview were identified and compared across interviews [15] to describe themes and the relative importance of concepts described by interview participants. This analytical process generated themes or patterns in the way interview participants described their observations and experiences.

3 Results

3.1 B-SIMPLE4 PED

3.1.1 Participant-Reported and Investigator-Reported Perception of Lesion Clearance

Among all B-SIMPLE4 participants who completed the participant-reported assessment of lesion clearance, complete clearance was reported by 37% (145/391) of the berdazimer group at week 12 and 60% (226/374) at week 24 compared with 20% (79/390) of the vehicle group at week 12 and 46% (174/378) at week 24 (Fig. 1A). This trend was also consistent with investigators’ perception of complete clearance, which was reported for 37% (147/393) of the berdazimer group at week 12 and 61% (230/378) at week 24 compared with 22% (89/396) of the vehicle group at week 12 and 47% (177/379) at week 24 (Fig. 1B).

Fig. 1
figure 1

Participant (a) and investigator (b) perceptions of complete lesion clearance

Full size image

3.1.2 Participant-Reported and Investigator-Reported GIC

At week 12 of B-SIMPLE4, 82% (322/392) of participants in the berdazimer group and 60% (237/394) in the vehicle group reported their MC lesions were either very much improved or much improved on the GIC, for a difference between groups of 22 percentage points (Fig. 2A). The 35 and 25% of vehicle patients who reported their lesions were very much improved or much improved at week 12, respectively, may reflect the typically self-limiting nature of MC. However, at week 24, there continued to be a difference between groups (12 percentage points) with more berdazimer (84% [313/374]) than vehicle (71% [270/378]) participants reporting their lesions were either very much improved or much improved (Fig. 2A). Results for the investigator-reported GIC were similar (Fig. 2B). For participants with a ≥ 75% reduction in MC lesion count from baseline at week 12, almost all felt improvement regardless of treatment assignment (Table 1).

Fig. 2
figure 2

Global Impression of Change over time. a Participant-reported Global Impression of Change and b investigator-reported Global Impression of Change

Full size image
Table 1 Participant-reported Global Impression of Change by lesion reduction at week 12
Full size table

3.2 Exit Interviews

3.2.1 Baseline Demographic and Clinical Characteristics

Qualitative interviews were conducted with 30 English-speaking participants (two patients and 28 caregivers) from 16 US clinical trial sites. Baseline demographic and clinical characteristics are presented in Table 2. Most participants lived in the Southern region of the USA, and all participants were white.

Table 2 Participant characteristics reported at the time of the interview
Full size table

The mean duration of MC at baseline (as reported by participants) was 20.2 months. The mean number of lesions estimated by participants at the time of B-SIMPLE4 study entry was 21.7. The recruitment target for different ranges of lesion reduction at week 12 was generally met (Fig. 3). Participants were also balanced by treatment group, with 15 from the berdazimer gel, 10.3% group, and 15 from the vehicle group interviewed.

Fig. 3
figure 3

Participant-reported reduction in lesion count at the time of the interview. One participant in the 0–24% category reported an overall increase in lesion count. Participants were selected for interviews based on the investigator-determined reduction in lesion count, these numbers represent the participant-reported reduction in lesion count

Full size image

3.2.2 Signs and Symptoms of MC

Participants described their MC lesions as bumps, spots, rashes, and warts. Caregivers frequently reported use of the term “bumps” by their child to describe lesions. Participants also reported various attributes of MC lesions including location, size, number, contagiousness, and visibility.

The most frequently reported MC-related signs and symptoms were itch, scarring, and pain (Table 3). Additionally, some participants spontaneously reported the terms pustules or inflammation, sores or blisters, and bleeding when describing their MC lesions. Participants could distinguish between MC-related signs and symptoms and adverse events associated with study medication.

Table 3 Signs, symptoms, and characteristics of molluscum contagiosum reported by participants
Full size table

The two patient participants indicated visibility and contagiousness as the most bothersome aspects of MC (Table 3). Similarly, caregivers most frequently reported visibility and contagiousness as the most bothersome aspect of their child’s MC. Of note, two caregivers reported that nothing about their child’s MC bothered them.

3.2.3 Impacts of MC

The most frequently reported impacts of MC were psychosocial, including self-consciousness, embarrassment, and worrying about others noticing or commenting on lesions (Table 4). Other impacts reported by ≥ 20% of participants included having to avoid certain clothing and physical activity limitations. One participant each reported impact on mood (annoying), social relationships, work, interpersonal relationships, and sleep. Caregiver impacts of MC focused on the time required to apply the study medicine and the time and effort needed to clean household surfaces to prevent viral spread.

Table 4 Impacts of molluscum contagiosum reported by participants
Full size table

3.2.4 Clinical Trial Participation Expectations

The two patients and 26 of 28 caregivers reported that lesion clearance was an expectation of study participation before enrolling in B-SIMPLE4. Additionally, two caregivers reported an expectation of preventing MC recurrence. Other reasons caregivers provided for deciding to enroll their children in B-SIMPLE4 were trying something new in hopes of treating their child’s MC and the possibility of a quicker resolution of their child’s MC.

3.2.5 Improvements During the Course of the Clinical Trial

The most frequently reported improvement was a reduction in lesion number, reported by 28 of 30 participants (two patients and 26 caregivers [93%]). Although participants were selected based on less than complete lesion clearance as assessed by the investigator, six (20%) participants reported complete clearance at the time of the interview. The two caregivers who did not report lesion count improvement reported no change in lesion count (n = 1; 3%) or an increase in lesion count (n = 1; 3%). Other reported improvements were a shorter duration of healing (n = 4; 13%), a reduction in lesion size (n = 4; 13%), and less inflammation (n = 2; 7%). Improvements in spreading, redness, itch, and swelling were each reported by one caregiver.

3.2.6 Improvement in Most Bothersome Symptom and Impact

Of the 24 participants who reported a most bothersome sign or symptom, 21 (88%) stated that the sign or symptom had improved during the study. Of the 22 participants who reported a most bothersome impact, 19 (86%) reported that the impact had improved during the study.

3.2.7 Change in Lesion Number

For the 28 participants who reported a reduction in lesions, the average was 18 fewer lesions, which represented a 76% decrease from the baseline lesion count (Table 5). Of these 28 participants, 22 (79%) reported that the decrease represented “many less” lesions and 6 (21%) reported “less” lesions at study end, compared with the baseline lesion count.

Table 5 Participant-reported change in lesion count since study initiation
Full size table

3.2.8 Meaningfulness of Change in Lesion Count and Lesion Location

Of 30 participants, 23 (77%) reported a meaningful change in lesion count since study initiation, and 25 (83%) reported a change in lesion location during the study. Of these 25 participants, 14 (56%) reported the change in lesion location had not been as important or as meaningful as the reduction in lesion number, whereas 11 (44%) reported the change in lesion location had been meaningful because of reduced visibility and less irritation or discomfort.

3.2.9 Level of Satisfaction with Any Changes Since Study Initiation

Overall, 26 of 30 participants reported being very satisfied (n = 18; 60%) or satisfied (n = 8; 27%) with any MC lesion changes since study initiation (range of percent improvement in lesion count from baseline as reported by participants at the time of the interview: 23–100%). Of the remaining four participants, three (10%) reported being neither satisfied nor dissatisfied, and one (3%) reported being dissatisfied. Twenty-one caregivers provided a satisfaction rating from their child’s perspective: 17 (57%) said their child was “very satisfied” (n = 12; 40%) or “satisfied” (n = 5; 17%), and four said their child was “neither satisfied nor dissatisfied” (n = 2; 7%) or “dissatisfied” (n = 2; 7%).

3.2.10 Changes in Lesion Count and Location in Participants with Less Than Complete Clearance

Of the 28 participants who reported a lesion count reduction, 22 (79%) reported less than complete clearance. For these 22 participants, the mean lesion count reduction was 14, representing a mean percentage decrease from baseline of 70%. When probed, these participants described the change as “many less” (n = 16; 73%) or “less” (n = 6; 27%) lesions compared with baseline. Of these 22 participants, 17 (77%) reported that the reduction in lesion number was meaningful and 11 (50%) reported that the change in lesion location was meaningful. Consistent with GIC results captured in the full B-SIMPLE4 sample, most of these participants (n = 19; 86%) reported being “very satisfied” (n = 13; 68%) or “satisfied” (n = 6; 32%) with MC lesion changes during the clinical trial. Patient and caregiver quotes grouped by interview topics are shown in Table 6.

Table 6 Select quotes grouped by interview topic
Full size table

4 Discussion

Patient experiences are becoming increasingly important in the understanding of skin disease burden and unmet therapeutic needs [13]. Indeed, patients’ views of their symptoms and how symptoms may affect their daily lives are instrumental in treatment decisions in dermatology [13]. Although healthcare providers may be aware of the bothersome symptomology of dermatologic diseases, the impact on patient and/or caregiver quality of life is not well understood. Patient-centric assessments can measure what is important to patients and generate information on patient perceptions regarding the clinical benefit of an experimental medication that goes beyond overt physical changes in severity or lesion count as evaluated by a clinical investigator [13].

Molluscum contagiosum, although one of the most common skin diseases affecting children, has not been widely investigated in clinical trials or through qualitative research. The B-SIMPLE4 trial provided the opportunity to query study patients and/or their caregivers on the impact of MC and a topical clinical intervention. Findings from the exit interviews revealed that lesion location, number, and size, as well as pain, scarring, itching, visibility, and contagiousness, were of concern to patients and caregivers, with visibility and contagiousness being the most bothersome. The most common psychosocial concerns were self-consciousness, embarrassment, and worry about others noticing or commenting on MC lesions.

In the absence of either FDA-approved medications or standard-of-care guidelines for MC, many clinicians adopt a watch-and-wait strategy. Many of the exit interview participants reported being motivated to participate in B-SIMPLE4 because of a desire to try an investigational topical treatment that might result in partial or complete lesion clearance. Availability of new treatment options will likely be welcomed by clinicians and patients [16, 17].

Indeed, participants who experienced partial or complete MC lesion clearance were satisfied with their clinical trial participation. Additionally, participants with less than complete clearance reported that the change in lesion count since study initiation was meaningful. These results highlight the importance of lesion count reductions to patients with MC and caregivers, even when complete clearance is not achieved. The PED indicated that nearly 40% of B-SIMPLE4 participants who received berdazimer gel, 10.3% perceived complete clearance by week 12, indicating that some may have perceived lesion resolution at week 12 as complete clearance even when the complete clearance rate was 34% based on investigator lesion counts in the primary study [9]. In addition, some patients who participated in the exit interview may have achieved complete clearance at the time of the interview, which occurred 2–4 weeks after the week 12 visit. Despite actual lesion counts, most participants reported their MC was much or very much improved by week 12. The nearly identical scores between participant-reported GIC and investigator-reported GIC were notable.

4.1 Limitations

Because the B-SIMPLE4 study was designed to fulfill regulatory requirements for marketing authorization, the exit interviews conducted as a substudy may not be an optimal setting to fully capture experiences of a wide range of patients with MC. All exit interview patients were white as the majority of B-SIMPLE4 patients were white [9]; therefore, results may not be generalizable to the general population of patients with MC. In addition, most exit interview participants were caregivers, and therefore the patient experience was primarily reported by caregivers. In addition, the sample size was small (n = 30), though reasonable for a qualitative design. Despite these limitations, the study provided valuable qualitative data on both patient and caregiver experiences with MC treatment. The research methodology and analysis were guided by established qualitative research practices and followed FDA guidance [18,19,20]. To expand upon study findings and further confirm these results, additional qualitative research is needed in a more diverse group of patients with MC and their caregivers. Additionally, qualitative interviews should be conducted in patients less than 11 years of age who are able to self-report on their experiences with MC so that information can be gathered directly from the patient perspective. Finally, although B-SIMPLE4 included two PED assessments, development of a fit-for-purpose patient-reported outcome measure for patients with MC may be a worthy endeavor that would allow for the comparison of patient-reported outcomes between treatment groups in future, randomized controlled intervention trials.

5 Conclusions

The PED and exit interviews revealed important factors motivating MC patients/caregivers to participate in clinical trials that might result in complete, partial, or accelerated MC lesion clearance. The underlying drivers appear to be related to the desire to mitigate both physical and psychosocial MC symptomology. Although statistical success of a clinical trial in patients with MC is typically measured by complete lesion clearance, patients/caregivers may be satisfied with partial clearance. Indeed, the PED results and interviews reveal the importance of a reduction in MC lesion count, with or without complete clearance, which highlights the need to involve patients/caregivers in defining therapeutic “success.”