possible within a 5-minute period, pre- and post-application on days 1 and 15). An additional single set of triplicate ECGs was captured at week 12. Clinically significant ECG changes from baseline were recorded as AEs.
Tolerability
Tolerability assessments included local skin condition (LSC), local skin reactions (LSRs), and scarring. Before the first berdazimer gel, 10.3% application at baseline, investigators assessed LSC in the designated treatment areas, including individual features of erythema, flaking/scaling crusting, swelling, vesiculation/ pustulation, and erosion/ulceration. The pre-application LSC captured the patient’s skin condition as it related to MC lesions before exposure to berdazimer gel, 10.3%.
LSRs were assessed 30 minutes post-application on day 1 and before in-clinic berdazimer gel, 10.3% application on days 8 and 15 of the PK period. LSRs were evaluated at each clinic visit during the extension period. Investigators rated LSRs on individual features including erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration and reported clinically significant LSRs (including any LSR suggestive of allergic contact dermatitis) as AEs. For both LSC and LSR assessments, each component was evaluated on a 0 to 4 scale, with higher numbers indicating more severe reactions. The highest possible LSC and LSR composite scores were 24. Scar/keloid/hypertrophic scar formation were assessed at the day 15 PK visit and through week 12 of the extension. All scars, including molluscum pitted scars, developing after baseline were reported as AEs and assessed by the investigator for treatment relatedness.
Effectiveness
Medication effectiveness was assessed by counting the number of active (raised, palpable, treatable) molluscum lesions per treatment area at each visit.
Statistical and Data Analyses
Study populations
The intention-to-treat (ITT) population included all enrolled patients. The safety population included all patients who received at least 1 application of berdazimer gel, 10.3%. The PK population included all patients in the safety population who had at least 1 post-application blood draw for hMAP3 and/or nitrate analysis.
Sample size
A minimum of 24 and a maximum of 36 patients ≥6 months of age were to be enrolled. The sample size was not based on statistical considerations; rather, the number of patients planned for enrollment was considered sufficient to achieve the study objectives. At least 6 patients ≥6 years of age and at least 6 patients <6 years of age were to be enrolled. Additional recruitment efforts were made to enroll patients <2 years of age.
Pharmacokinetic analyses
The primary endpoint was the PK profile of hMAP3 and nitrate as markers for systemic exposure to berdazimer sodium after topical application of berdazimer gel, 10.3% to approximately 484 cm2 once daily. Plasma hMAP3 and nitrate concentrations were determined using validated liquid chromatography tandem mass spectrometry (LC/MS-MS) analytic methods with a lower limit of quantitation (LLOQ) of 5 ng/mL for hMAP3 and 300 ng/mL for nitrate. All patients in the PK population with at least 1 quantifiable hMAP3 and/or nitrate concentration were included in the PK analyses. Calculation of area under the plasma concentration-time curve (AUC) required the 1-hour, 3-hour (all patients), and 6-hour (patients ≥6 years of age) samples to be quantifiable. For calculation of mean concentrations and generation of mean concentration-versus-time profiles, all below the lower limit of quantitation (BLQ) values were set to 0 except when an individual BLQ value fell between 2 quantifiable values, in which case the value was treated as missing data.
The following standard PK parameters were calculated for days 1 and 15 using noncompartmental analysis implemented within a validated installation of Phoenix® WinNonlin® V8.1.: maximum observed plasma concentration value (Cmax); time to Cmax (Tmax); AUC from time 0 to 3 hours post-application (AUC0-3); and AUC from 0 to 6 hours post-application (AUC0-6).
Safety
All AEs that occurred during the study were recorded and classified based on Medical Dictionary for Regulatory Activities (MedDRA) terminology. Treatment-emergent AEs (TEAEs) were defined as AEs with an onset on or after the first application of berdazimer gel 10.3%. TEAEs were summarized by MedDRA preferred term, severity, relationship to berdazimer gel, 10.3% (causality), and seriousness. TEAE severity and causality were determined by investigators.
Statistical analyses
Descriptive statistics were used to summarize PK parameters and safety, tolerability, and effectiveness data. For continuous variables, descriptive statistics included the number of patients with non-missing values, mean, standard deviation, median, minimum, and maximum values. For categorical variables, descriptive statistics included counts and percentages of patients who were in the category or each possible value. Descriptive statistical analyses and tabulations were performed using SAS® software Version 9.4 or higher (SAS Institute Inc., Cary, NC).
Tolerability
Tolerability assessments included local skin condition (LSC), local skin reactions (LSRs), and scarring. Before the first berdazimer gel, 10.3% application at baseline, investigators assessed LSC in the designated treatment areas, including individual features of erythema, flaking/scaling crusting, swelling, vesiculation/ pustulation, and erosion/ulceration. The pre-application LSC captured the patient’s skin condition as it related to MC lesions before exposure to berdazimer gel, 10.3%.
LSRs were assessed 30 minutes post-application on day 1 and before in-clinic berdazimer gel, 10.3% application on days 8 and 15 of the PK period. LSRs were evaluated at each clinic visit during the extension period. Investigators rated LSRs on individual features including erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration and reported clinically significant LSRs (including any LSR suggestive of allergic contact dermatitis) as AEs. For both LSC and LSR assessments, each component was evaluated on a 0 to 4 scale, with higher numbers indicating more severe reactions. The highest possible LSC and LSR composite scores were 24. Scar/keloid/hypertrophic scar formation were assessed at the day 15 PK visit and through week 12 of the extension. All scars, including molluscum pitted scars, developing after baseline were reported as AEs and assessed by the investigator for treatment relatedness.
Effectiveness
Medication effectiveness was assessed by counting the number of active (raised, palpable, treatable) molluscum lesions per treatment area at each visit.
Statistical and Data Analyses
Study populations
The intention-to-treat (ITT) population included all enrolled patients. The safety population included all patients who received at least 1 application of berdazimer gel, 10.3%. The PK population included all patients in the safety population who had at least 1 post-application blood draw for hMAP3 and/or nitrate analysis.
Sample size
A minimum of 24 and a maximum of 36 patients ≥6 months of age were to be enrolled. The sample size was not based on statistical considerations; rather, the number of patients planned for enrollment was considered sufficient to achieve the study objectives. At least 6 patients ≥6 years of age and at least 6 patients <6 years of age were to be enrolled. Additional recruitment efforts were made to enroll patients <2 years of age.
Pharmacokinetic analyses
The primary endpoint was the PK profile of hMAP3 and nitrate as markers for systemic exposure to berdazimer sodium after topical application of berdazimer gel, 10.3% to approximately 484 cm2 once daily. Plasma hMAP3 and nitrate concentrations were determined using validated liquid chromatography tandem mass spectrometry (LC/MS-MS) analytic methods with a lower limit of quantitation (LLOQ) of 5 ng/mL for hMAP3 and 300 ng/mL for nitrate. All patients in the PK population with at least 1 quantifiable hMAP3 and/or nitrate concentration were included in the PK analyses. Calculation of area under the plasma concentration-time curve (AUC) required the 1-hour, 3-hour (all patients), and 6-hour (patients ≥6 years of age) samples to be quantifiable. For calculation of mean concentrations and generation of mean concentration-versus-time profiles, all below the lower limit of quantitation (BLQ) values were set to 0 except when an individual BLQ value fell between 2 quantifiable values, in which case the value was treated as missing data.
The following standard PK parameters were calculated for days 1 and 15 using noncompartmental analysis implemented within a validated installation of Phoenix® WinNonlin® V8.1.: maximum observed plasma concentration value (Cmax); time to Cmax (Tmax); AUC from time 0 to 3 hours post-application (AUC0-3); and AUC from 0 to 6 hours post-application (AUC0-6).
Safety
All AEs that occurred during the study were recorded and classified based on Medical Dictionary for Regulatory Activities (MedDRA) terminology. Treatment-emergent AEs (TEAEs) were defined as AEs with an onset on or after the first application of berdazimer gel 10.3%. TEAEs were summarized by MedDRA preferred term, severity, relationship to berdazimer gel, 10.3% (causality), and seriousness. TEAE severity and causality were determined by investigators.
Statistical analyses
Descriptive statistics were used to summarize PK parameters and safety, tolerability, and effectiveness data. For continuous variables, descriptive statistics included the number of patients with non-missing values, mean, standard deviation, median, minimum, and maximum values. For categorical variables, descriptive statistics included counts and percentages of patients who were in the category or each possible value. Descriptive statistical analyses and tabulations were performed using SAS® software Version 9.4 or higher (SAS Institute Inc., Cary, NC).
RESULTS
Demographics and Baseline Characteristics
Thirty-four patients were enrolled at 5 clinical centers in the US between September 16, 2019 and February 4, 2020, and all were
Thirty-four patients were enrolled at 5 clinical centers in the US between September 16, 2019 and February 4, 2020, and all were
