treatment of MC. During the initial 2-week PK period, the patients received treatment under maximal use conditions. The study was conducted in patients with the upper range of MC severity to maximize the potential for medication absorption.
Ethics
The study protocol and all study materials were approved by an institutional review board before study initiation. The study was conducted in accordance with the United States (US) 21 Code of Federal Regulations, the International Conference on Harmonization guidelines, current Good Clinical Practice principles, the Declaration of Helsinki, and local regulatory requirements. All patients/caregivers provided written informed consent/assent before enrollment.
Patients
Males and females at least 6 months of age and weighing at least 10 kg who had more than 20 raised and palpable MC lesions and a treatment area totaling a body surface area (BSA) of 484 cm2 at baseline were eligible to enroll. Exclusion criteria included: i) sexually transmitted MC; ii) MC only in the periocular area; iii) significant eczema or injury on designated medication application areas; iv) a confirmed methemoglobin level of >3.0% at baseline using a pulse co-oximeter; and v) primary source of drinking water was well water (due to the potential for elevated nitrate levels). Patients receiving current treatment for MC at the time of the screening visit could enter a wash out period of up to 14 days before the baseline visit.
Interventions
The 12-week study was divided into a 2-week PK period and a 10-week treatment extension period. All patients who completed the PK period could choose to enroll in the treatment extension period. The PK period included a screening visit followed by 3 clinic visits at days 1 (baseline), 8, and 15. The treatment extension period included 3 clinic visits at weeks 4, 8, and 12.
From days 1 to 15 (PK period), caregivers applied berdazimer gel, 10.3% once daily to a total treatment area of 484 cm2, comprised of up to 4 areas on the body that included as many MC lesions as possible. Caregivers were instructed to cut a 22 cm x 22 cm piece of cardstock in up to 4 pieces to cover as many lesions as possible. Study site staff documented all treatment areas and marked the selected treatment areas on each patient with a surgical marker so caregivers would know where to apply berdazimer gel, 10.3%. A 3-mg quantity of study medication was considered sufficient to cover the total treatment area(s) for all patients. Caregivers applied berdazimer gel, 10.3% (berdazimer sodium gel plus hydrogel) to the designated treatment areas immediately following admixture. Berdazimer gel, 10.3% was applied once daily throughout the PK period even if lesions cleared. Lesions outside the selected treatment area or within periocular areas (ie, within 2 cm from the edge of the eye) were not treated. On days 1, 8, and 15, study site staff applied berdazimer gel, 10.3%. Patients/caregivers applied all other doses at home.
In the 10-week treatment extension period, berdazimer gel, 10.3% was applied to all individual treatable lesions and approximately 1 cm surrounding each lesion, excluding periocular areas. New lesions that appeared during the extension period were treated. Treatment continued until complete clearance or week 12, whichever came first. If lesions cleared between visits, the patient/caregiver continued treating until the next study visit, at which time the investigator confirmed clearance and discontinued berdazimer gel, 10.3% treatment.
Assessments
Pharmacokinetic
For patients <6 years, blood samples for determination of plasma hydrolyzed N-methylaminopropyl-trimethoxysilane (hMAP3) and nitrate concentrations were collected pre-application and 1-hour post-application on day 1, and pre-application and 1- and 3-hours post-application on day 15. For patients ≥6 years, blood samples were collected pre-application and 1-, 3-, and 6-hours post-application on days 1 and 15. The pre-application blood draw on day 1 was used to determine baseline hMAP3 and nitrate levels. hMAP3 is a silicon-containing hydrolyzed monomer of the polymeric berdazimer drug substance. For approximately 24 hours before the day 1 and day 15 visits, and continuing until after the final blood draw on both days, all patients and mothers of breastfed patients were instructed to adhere to a low nitrate diet (guidelines provided).
Compliance
During the PK period (days 1-15), caregivers recorded the time of berdazimer gel, 10.3% application in a diary. During the treatment extension period, caregivers only recorded whether berdazimer gel, 10.3% was applied.
Safety
Safety assessments included monitoring and reporting of adverse events (AEs) throughout the study, clinical laboratory measurements, percent blood methemoglobin at every visit, vital sign measurements, and physical examination findings. On days 1 and 15, methemoglobin was measured at the same time with PK blood draw using a Masimo Rainbow® SET® Rad- 57™ pulse co-oximeter. Any clinically significant changes in laboratory values, vital signs, and methemoglobin levels were recorded as AEs. Patients with persistent methemoglobin levels >5% (confirmed by a second reading within 0.5% of initial reading within 30 minutes) at any post-baseline assessment were discontinued from the study.
Assessment of 12-lead electrocardiogram (ECG) parameters was based on triplicate ECGs (3 readings as close together as
Ethics
The study protocol and all study materials were approved by an institutional review board before study initiation. The study was conducted in accordance with the United States (US) 21 Code of Federal Regulations, the International Conference on Harmonization guidelines, current Good Clinical Practice principles, the Declaration of Helsinki, and local regulatory requirements. All patients/caregivers provided written informed consent/assent before enrollment.
Patients
Males and females at least 6 months of age and weighing at least 10 kg who had more than 20 raised and palpable MC lesions and a treatment area totaling a body surface area (BSA) of 484 cm2 at baseline were eligible to enroll. Exclusion criteria included: i) sexually transmitted MC; ii) MC only in the periocular area; iii) significant eczema or injury on designated medication application areas; iv) a confirmed methemoglobin level of >3.0% at baseline using a pulse co-oximeter; and v) primary source of drinking water was well water (due to the potential for elevated nitrate levels). Patients receiving current treatment for MC at the time of the screening visit could enter a wash out period of up to 14 days before the baseline visit.
Interventions
The 12-week study was divided into a 2-week PK period and a 10-week treatment extension period. All patients who completed the PK period could choose to enroll in the treatment extension period. The PK period included a screening visit followed by 3 clinic visits at days 1 (baseline), 8, and 15. The treatment extension period included 3 clinic visits at weeks 4, 8, and 12.
From days 1 to 15 (PK period), caregivers applied berdazimer gel, 10.3% once daily to a total treatment area of 484 cm2, comprised of up to 4 areas on the body that included as many MC lesions as possible. Caregivers were instructed to cut a 22 cm x 22 cm piece of cardstock in up to 4 pieces to cover as many lesions as possible. Study site staff documented all treatment areas and marked the selected treatment areas on each patient with a surgical marker so caregivers would know where to apply berdazimer gel, 10.3%. A 3-mg quantity of study medication was considered sufficient to cover the total treatment area(s) for all patients. Caregivers applied berdazimer gel, 10.3% (berdazimer sodium gel plus hydrogel) to the designated treatment areas immediately following admixture. Berdazimer gel, 10.3% was applied once daily throughout the PK period even if lesions cleared. Lesions outside the selected treatment area or within periocular areas (ie, within 2 cm from the edge of the eye) were not treated. On days 1, 8, and 15, study site staff applied berdazimer gel, 10.3%. Patients/caregivers applied all other doses at home.
In the 10-week treatment extension period, berdazimer gel, 10.3% was applied to all individual treatable lesions and approximately 1 cm surrounding each lesion, excluding periocular areas. New lesions that appeared during the extension period were treated. Treatment continued until complete clearance or week 12, whichever came first. If lesions cleared between visits, the patient/caregiver continued treating until the next study visit, at which time the investigator confirmed clearance and discontinued berdazimer gel, 10.3% treatment.
Assessments
Pharmacokinetic
For patients <6 years, blood samples for determination of plasma hydrolyzed N-methylaminopropyl-trimethoxysilane (hMAP3) and nitrate concentrations were collected pre-application and 1-hour post-application on day 1, and pre-application and 1- and 3-hours post-application on day 15. For patients ≥6 years, blood samples were collected pre-application and 1-, 3-, and 6-hours post-application on days 1 and 15. The pre-application blood draw on day 1 was used to determine baseline hMAP3 and nitrate levels. hMAP3 is a silicon-containing hydrolyzed monomer of the polymeric berdazimer drug substance. For approximately 24 hours before the day 1 and day 15 visits, and continuing until after the final blood draw on both days, all patients and mothers of breastfed patients were instructed to adhere to a low nitrate diet (guidelines provided).
Compliance
During the PK period (days 1-15), caregivers recorded the time of berdazimer gel, 10.3% application in a diary. During the treatment extension period, caregivers only recorded whether berdazimer gel, 10.3% was applied.
Safety
Safety assessments included monitoring and reporting of adverse events (AEs) throughout the study, clinical laboratory measurements, percent blood methemoglobin at every visit, vital sign measurements, and physical examination findings. On days 1 and 15, methemoglobin was measured at the same time with PK blood draw using a Masimo Rainbow® SET® Rad- 57™ pulse co-oximeter. Any clinically significant changes in laboratory values, vital signs, and methemoglobin levels were recorded as AEs. Patients with persistent methemoglobin levels >5% (confirmed by a second reading within 0.5% of initial reading within 30 minutes) at any post-baseline assessment were discontinued from the study.
Assessment of 12-lead electrocardiogram (ECG) parameters was based on triplicate ECGs (3 readings as close together as
