Trial Outcomes & Findings for Pharmacokinetics, Safety, and Efficacy Trial of WR 279,396 (Paromomycin + Gentamicin Topical Cream) and Paromomycin Topical Cream for the Treatment of Cutaneous Leishmaniasis in Panama (NCT NCT01083576)

NCT ID: NCT01083576

Last Updated: 2015-07-16

Results Overview

Number of participants who had initial clinical cure (100% re-epithelialization of index lesion by Day 63) OR initial clinical improvements (\> 50% re-epithelialization of index lesion followed by Day 63 by 100% re-epithelialization of the index lesion on or before Day 100), AND no relapse of index lesion.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 30 participants
• Primary outcome timeframe: 168 days
• Results posted on: 2015-07-16

Participant Flow

Participant milestones

Measure	Paromomycin Alone Treatment Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated cutaneous leishmaniasis (CL) lesions once daily for 20 days	WR 279,396 WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Overall Study STARTED	15	15
Overall Study COMPLETED	9	14
Overall Study NOT COMPLETED	6	1

Reasons for withdrawal

Measure	Paromomycin Alone Treatment Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated cutaneous leishmaniasis (CL) lesions once daily for 20 days	WR 279,396 WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Overall Study Treatment Failure	6	1

Baseline Characteristics

Pharmacokinetics, Safety, and Efficacy Trial of WR 279,396 (Paromomycin + Gentamicin Topical Cream) and Paromomycin Topical Cream for the Treatment of Cutaneous Leishmaniasis in Panama

Baseline characteristics by cohort

Measure	Paromomycin Alone Treatment n=15 Participants Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	WR 279,396 n=15 Participants WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	Total n=30 Participants Total of all reporting groups
Age, Continuous	24.0 years STANDARD_DEVIATION 16.2 • n=5 Participants	25.5 years STANDARD_DEVIATION 15.9 • n=7 Participants	24.7 years STANDARD_DEVIATION 15.8 • n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	11 Participants n=7 Participants	24 Participants n=5 Participants
Race/Ethnicity, Customized Mestizo	14 Participants 100 • n=5 Participants	15 Participants 93.3 • n=7 Participants	29 Participants n=5 Participants
Race/Ethnicity, Customized Other	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	15 Participants n=5 Participants	15 Participants n=7 Participants	30 Participants n=5 Participants

PRIMARY outcome

Timeframe: 168 days

Population: All randomized subjects were included in the mITT Analysis. All subjects met criteria for the evaluable subset.

Number of participants who had initial clinical cure (100% re-epithelialization of index lesion by Day 63) OR initial clinical improvements (> 50% re-epithelialization of index lesion followed by Day 63 by 100% re-epithelialization of the index lesion on or before Day 100), AND no relapse of index lesion.

Outcome measures

Measure	Paromomycin Alone Treatment n=15 Participants Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	WR 279,396 n=15 Participants WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Number of Participants Who Obtained Final Clinical Cure of Index Lesion	9 Participants	13 Participants

SECONDARY outcome

Timeframe: 168 days

Population: All randomized subjects were included in the mITT Analysis. All subjects met criteria for the evaluable subset.

Final cure as defined by the primary outcome measure AND and cure of all other lesions by Day 168. (100% re-epithelialization of all ulcerated lesions and resolution of all other type of lesions)

Outcome measures

Measure	Paromomycin Alone Treatment n=15 Participants Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	WR 279,396 n=15 Participants WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Number of Participants Who Obtained a Modified Final Clinical Cure of All Lesions	8 Participants	13 Participants

SECONDARY outcome

Timeframe: 20 days

Population: Adults ages \>= 17 years

Proportion of subjects with any detectable Paromomycin or Gentamicin plasma levels on a study day when blood for PK was collected

Outcome measures

Measure	Paromomycin Alone Treatment n=8 Participants Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	WR 279,396 n=9 Participants WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Detectable Paromomycin or Gentamicin Plasma Levels Any detectable gentamicin	0 Participants	1 Participants
Detectable Paromomycin or Gentamicin Plasma Levels Any detectable paromomycin	8 Participants	8 Participants

SECONDARY outcome

Timeframe: Day 4 to Day 28

Population: Adults ages \>= 17 years

Paromomycin plasma concentrations following administration of paromomycin alone or WR 279,396 in adults

Outcome measures

Measure	Paromomycin Alone Treatment n=8 Participants Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	WR 279,396 n=9 Participants WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Paromomycin Plasma Concentrations in Adults Day 28	0 ng/mL Standard Deviation 0	0 ng/mL Standard Deviation 0
Paromomycin Plasma Concentrations in Adults Day 4	0 ng/mL Standard Deviation 0	17.8 ng/mL Standard Deviation 38.0
Paromomycin Plasma Concentrations in Adults Day 7	13.1 ng/mL Standard Deviation 37.1	17.6 ng/mL Standard Deviation 34.9
Paromomycin Plasma Concentrations in Adults Day 12	6.6 ng/mL Standard Deviation 18.8	26.4 ng/mL Standard Deviation 40.8
Paromomycin Plasma Concentrations in Adults Day 17	44.0 ng/mL Standard Deviation 49.8	26.3 ng/mL Standard Deviation 52.3
Paromomycin Plasma Concentrations in Adults Day 20	54.6 ng/mL Standard Deviation 48.4	31.4 ng/mL Standard Deviation 47.8

SECONDARY outcome

Timeframe: Days 1 and 20

Population: Children ages 7 to 16

Paromomycin plasma concentrations 4 hours following administration of paromomycin alone or WR 279,396 in children

Outcome measures

Measure	Paromomycin Alone Treatment n=7 Participants Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	WR 279,396 n=6 Participants WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Paromomycin Plasma Concentrations in Children Study Day 1	116.3 ng/mL Standard Deviation 83.6	98.6 ng/mL Standard Deviation 132.3
Paromomycin Plasma Concentrations in Children Study Day 20	992.7 ng/mL Standard Deviation 1149.7	634.2 ng/mL Standard Deviation 426.2

SECONDARY outcome

Timeframe: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20

Population: Adults with measurable samples.

Cmax of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

Outcome measures

Measure	Paromomycin Alone Treatment n=8 Participants Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	WR 279,396 n=9 Participants WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Pharmacokinetic Parameter: Cmax Day 1	219.0 ng/mL Standard Deviation 294	121 ng/mL Standard Deviation 106
Pharmacokinetic Parameter: Cmax Day 20	751.0 ng/mL Standard Deviation 609.0	561.0 ng/mL Standard Deviation 560.0

SECONDARY outcome

Timeframe: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20

Population: Adults ages \>= 17 years with measurable samples. Both groups had only 6 measureable samples each on Day 1.

Tmax of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

Outcome measures

Measure	Paromomycin Alone Treatment n=8 Participants Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	WR 279,396 n=8 Participants WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Pharmacokinetic Parameter: Tmax Day 1	2.7 hr Standard Deviation 1.2	2.8 hr Standard Deviation 2.6
Pharmacokinetic Parameter: Tmax Day 20	2.2 hr Standard Deviation 0.8	2.2 hr Standard Deviation 1.4

SECONDARY outcome

Timeframe: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20

Population: Adults ages \>= 17 years with measurable samples.

Area under the curve (AUC) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

Outcome measures

Measure	Paromomycin Alone Treatment n=8 Participants Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	WR 279,396 n=9 Participants WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Pharmacokinetic Parameter: Area Under the Curve (AUC) Day 1	1571 ng*hr/mL Standard Deviation 1850	863.4 ng*hr/mL Standard Deviation 974.0
Pharmacokinetic Parameter: Area Under the Curve (AUC) Day 20	5603 ng*hr/mL Standard Deviation 4050	4740 ng*hr/mL Standard Deviation 3987

SECONDARY outcome

Timeframe: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20

Population: Adults ages \>= 17 years with measurable samples. Paromomycin Alone Treatment had only 5 measureable samples on Day 1, and WR 279,396 had only 4 measureable samples on Day 20.

t(1/2) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

Outcome measures

Measure	Paromomycin Alone Treatment n=7 Participants Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	WR 279,396 n=8 Participants WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Pharmacokinetic Parameter: t(1/2) Day 1	7.03 hr Standard Deviation 7.67	4.0 hr Standard Deviation 1.9
Pharmacokinetic Parameter: t(1/2) Day 20	5.3 hr Standard Deviation 2.1	7.0 hr Standard Deviation 3.6

SECONDARY outcome

Timeframe: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20

Population: Adults ages \>= 17 years with measurable samples.

Maximum observed plasma concentration divide by topical dose (Cmax/D) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

Outcome measures

Measure	Paromomycin Alone Treatment n=8 Participants Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	WR 279,396 n=9 Participants WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Pharmacokinetic Parameter: Cmax/D Day 1	104.0 1/ML Standard Deviation 104.0	61.3 1/ML Standard Deviation 64.0
Pharmacokinetic Parameter: Cmax/D Day 20	227 1/ML Standard Deviation 71	179 1/ML Standard Deviation 128

SECONDARY outcome

Timeframe: Days 1 and 20

Population: Adults ages \>= 17 years with measurable samples.

Area under the plasma concentration-time curve over 24 hrs divided by topical dose (AUC/D) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

Outcome measures

Measure	Paromomycin Alone Treatment n=8 Participants Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	WR 279,396 n=9 Participants WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Pharmacokinetic Parameter: AUC/D Day 1	715.2 hr/ML Standard Deviation 748.1	345.9 hr/ML Standard Deviation 303.9
Pharmacokinetic Parameter: AUC/D Day 20	1725 hr/ML Standard Deviation 530	1380 hr/ML Standard Deviation 631

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 1 and Day 20

Population: All randomized subjects were included in the mITT Analysis. All subjects met criteria for the evaluable subset.

Blood creatinine was measured to assess possible nephrotoxicity associated with aminoglycosides

Outcome measures

Measure	Paromomycin Alone Treatment n=15 Participants Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	WR 279,396 n=15 Participants WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Serum Creatinine Levels Study Day 1	0.83 mg/dL Standard Deviation 0.23	0.79 mg/dL Standard Deviation 0.27
Serum Creatinine Levels Study Day 20	0.77 mg/dL Standard Deviation 0.26	0.76 mg/dL Standard Deviation 0.22

Adverse Events

Paromomycin Alone Treatment

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

WR 279,396

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Paromomycin Alone Treatment n=15 participants at risk Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated CL lesions once daily for 20 days	WR 279,396 n=15 participants at risk WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
General disorders Application site erythema	13.3% 2/15	20.0% 3/15
General disorders Application site oedema	20.0% 3/15	13.3% 2/15
General disorders Application site pain	33.3% 5/15	6.7% 1/15
Infections and infestations Superinfection bacterial	0.00% 0/15	6.7% 1/15
Infections and infestations Folliculitis	6.7% 1/15	0.00% 0/15
Infections and infestations Mucocutaneous leishmaniasis	6.7% 1/15	6.7% 1/15
Skin and subcutaneous tissue disorders Burning sensation	0.00% 0/15	6.7% 1/15
Skin and subcutaneous tissue disorders Dermatitis contact	53.3% 8/15	40.0% 6/15

Additional Information

Director, Division of Regulated Activites and Compliance

US Army Medical Materiel Development Activity (USAMMDA)

Phone: 301-619-0197

Email: usarmy.detrick.medcom-usammda.mbx.usamrmc-regulatory-affairs@mail.mil

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place