Phase 3 Study to Evaluate WR 279,396 vs. Paromomycin Alone to Treat Cutaneous Leishmaniasis (in Tunisia)

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

U.S. Army Medical Research and Materiel Command

ClinicalTrials.gov Identifier:

NCT00606580

First received: January 21, 2008

Last updated: June 11, 2014

Last verified: June 2014

History of Changes

Results First Received: May 12, 2014

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double Blind (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition:	Cutaneous Leishmaniasis
Interventions:	Drug: WR 279,396 topical cream Drug: Paromomycin Alone topical cream Drug: Vehicle placebo cream

Participant Flow

Hide Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

Description

WR 279,396 Topical Treament

WR 279,396 topical cream (15% paromomycin + 0.5% gentamicin topical cream)

WR 279,396 topical cream: WR 279,396 is a topical antibiotic cream containing 15% paromomycin and 0.5% gentamicin that will be applied to each lesion once a day and covered with a sterile gauze and tape dressing.

Paromomycin Alone Topical Treatment

Paromomycin Alone topical cream (15% paromomycin topical cream)

Paromomycin Alone topical cream: The antibiotic paromomycin 15% in the same topical cream used in arm 1 will be applied to lesions daily and covered with a protective sterile gauze and tape dressing.

Vehicle Placebo Cream

The cream base without the addition of paromomycin or gentamicin

Vehicle placebo cream: Applied daily to cutaneous leishmaniasis lesions, primarily ulcerative, and covered with a protective, sterile gauze and tape dressing.

Participant Flow: Overall Study

	WR 279,396 Topical Treament	Paromomycin Alone Topical Treatment	Vehicle Placebo Cream
STARTED	125	125	125
COMPLETED	123	122	103
NOT COMPLETED	2	3	22
Lost to Follow-up	1	1	4
Clinical failures	1	0	12
Withdrawal by investigator	0	1	6
Withdrawal by Subject	0	1	0

Baseline Characteristics

Hide Baseline Characteristics

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups

	Description
WR 279,396 Topical Treament	WR 279,396 topical cream (15% paromomycin + 0.5% gentamicin topical cream) WR 279,396 topical cream: WR 279,396 is a topical antibiotic cream containing 15% paromomycin and 0.5% gentamicin that will be applied to each lesion once a day and covered with a sterile gauze and tape dressing.
Paromomycin Alone Topical Treatment	Paromomycin Alone topical cream (15% paromomycin topical cream) Paromomycin Alone topical cream: The antibiotic paromomycin 15% in the same topical cream used in arm 1 will be applied to lesions daily and covered with a protective sterile gauze and tape dressing.
Vehicle Placebo Cream	The cream base without the addition of paromomycin or gentamicin Vehicle placebo cream: Applied daily to cutaneous leishmaniasis lesions, primarily ulcerative, and covered with a protective, sterile gauze and tape dressing.
Total	Total of all reporting groups

Baseline Measures

WR 279,396 Topical Treament

Paromomycin Alone Topical Treatment

Vehicle Placebo Cream

Total

Overall Participants Analyzed
[Units: Participants]

125

375

Age
[Units: Years]
Mean (Standard Deviation)

23.4 (15.9)

24.6 (15.7)

23.2 (15.2)

23.7 (15.6)

Age, Customized
[Units: Participants]

Adults

190

Children (12 to 17)

Children (5 to 11)

Gender
[Units: Participants]

Female

182

Male

193

Race/Ethnicity, Customized
[Units: Participants]

North African

125

375

Total Number of lesions per subject
[Units: Participants]

1 lesion

158

More than 1 lesions

217

All lesion characteristics
[Units: Lesions]

Number of

243

272

282

797

Flat-like

Nodule

Other

Papule

Ulcerative

240

262

279

781

Index lesion ulceration area ^[1]
[Units: Mm^2]
Mean (Standard Deviation)

126 (121)

90.2 (74.5)

97.7 (112)

105 (105)

^[1]	Index lesion ulceration area per participant

Index lesion
[Units: Participants]

Area of ulceration ≤ 100 m^2

245

Area of ulceration > 100 mm^2

130

All lesion ulceration area ^[1]
[Units: Mm^2]
Mean (Standard Deviation)

86.8 (107)

65.6 (91.1)

70.3 (91.4)

73.8 (96.5)

^[1]	Lesion ulceration area per lesion independent of participant

All ulcerated lesions
[Units: Lesions]

Area of ulceration ≤ 100 m^2

175

210

222

607

Area of ulceration > 100 mm^2

174

Days before treatment that index lesion was first noticed
[Units: Days]
Mean (Standard Deviation)

39.3 (25.7)

39.5 (20.0)

38.9 (20.5)

39.2 (22.2)

Days before treatment that index lesion was first noticed (categorical)
[Units: Participants]

≤ 60 days

110

109

328

> 60 days

Outcome Measures

Hide All Outcome Measures

1. Primary:

Final Clinical Cure Rate [ Time Frame: Day 42, 98, and 168 ]

Measure Type	Primary
Measure Title	Final Clinical Cure Rate
Measure Description	Final clinical cure was defined as an index lesion that met the criteria for initial clinical cure without relapse. Definitions for index lesion outcomes were as follows: Initial Clinical Improvement: At least 50% to 99% reduction in the size of the measured lesion from the baseline measurement by the Day 42 evaluation. Initial Clinical Cure: 100% re-epithelialization (ie, a 0 x 0 length x width measurement) of the lesion at the nominal Day 42 evaluation, or initial clinical improvement followed by 100% re-epithelialization by Day 98. Relapse: Initial clinical cure followed by re-ulceration by Day 168, or initial clinical improvement followed by lesion enlargement by Day 168. Final Clinical Cure: Initial clinical cure without relapse through study Day 168.Clinical Failure: Lack of at least initial clinical improvement by Day 42, or relapse.
Time Frame	Day 42, 98, and 168

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Modified intention-to-treat (mITT) – all subjects randomized who received at least one treatment of study drug.

Reporting Groups

Description

WR 279,396 Topical Treament

WR 279,396 topical cream (15% paromomycin + 0.5% gentamicin topical cream)

Paromomycin Alone Topical Treatment

Paromomycin Alone topical cream (15% paromomycin topical cream)

Paromomycin Alone topical cream: The antibiotic paromomycin 15% in the same topical cream used in arm 1 will be applied to lesions daily and covered with a protective sterile gauze and tape dressing.

Vehicle Placebo Cream

The cream base without the addition of paromomycin or gentamicin

Vehicle placebo cream: Applied daily to cutaneous leishmaniasis lesions, primarily ulcerative, and covered with a protective, sterile gauze and tape dressing.

Measured Values

	WR 279,396 Topical Treament	Paromomycin Alone Topical Treatment	Vehicle Placebo Cream
Participants Analyzed [Units: Participants]	125	125	125
Final Clinical Cure Rate [Units: Participants]	101	102	73

Statistical Analysis 1 for Final Clinical Cure Rate

Groups ^[1]	WR 279,396 Topical Treament vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.0001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	H01: There is no difference in the final clinical cure rate between WR 279,396 and Vehicle AND there is no difference in the final clinical cure rate between Paromomycin Alone and Vehicle.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Final Clinical Cure Rate

Groups ^[1]	Paromomycin Alone Topical Treatment vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Chi-squared
P Value ^[4]	<0.0001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	H01: There is no difference in the final clinical cure rate between WR 279,396 and Vehicle AND there is no difference in the final clinical cure rate between Paromomycin Alone and Vehicle.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Final Clinical Cure Rate

Groups ^[1]	WR 279,396 Topical Treament vs. Paromomycin Alone Topical Treatment
Statistical Test Type ^[2]	Non-Inferiority or Equivalence
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.871

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	H02: There is no difference in clinical cure between WR 279,396 and Paromomycin Alone. Test of H02: If H01 was rejected, then H02 would be tested. The comparison of WR 279,396 versus Paromomycin Alone would be considered statistically significant if p < .05.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	Test of H02: If H01 was rejected, then H02 would be tested. The comparison of WR 279,396 versus Paromomycin Alone would be considered statistically significant if p < .05.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

2. Secondary:

Final Clinical Cure Rate (Per Protocol Dataset) [ Time Frame: Day 42, 98, and 168 ]

Measure Type	Secondary
Measure Title	Final Clinical Cure Rate (Per Protocol Dataset)
Measure Description	Final clinical cure was defined as an index lesion that met the criteria for initial clinical cure without relapse. Definitions for index lesion outcomes as described in the primary outcome measure.
Time Frame	Day 42, 98, and 168

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Per protocol – all randomized subjects who received at least one treatment of study drug and whose outcomes at Day 42, Day 98 (if applicable) and Day 168 could be assessed. However, a subject was still considered per-protocol if withdrawn early for treatment failure.

Reporting Groups

Description

WR 279,396 Topical Treament

WR 279,396 topical cream (15% paromomycin + 0.5% gentamicin topical cream)

Paromomycin Alone Topical Treatment

Paromomycin Alone topical cream (15% paromomycin topical cream)

Paromomycin Alone topical cream: The antibiotic paromomycin 15% in the same topical cream used in arm 1 will be applied to lesions daily and covered with a protective sterile gauze and tape dressing.

Vehicle Placebo Cream

The cream base without the addition of paromomycin or gentamicin

Vehicle placebo cream: Applied daily to cutaneous leishmaniasis lesions, primarily ulcerative, and covered with a protective, sterile gauze and tape dressing.

Measured Values

	WR 279,396 Topical Treament	Paromomycin Alone Topical Treatment	Vehicle Placebo Cream
Participants Analyzed [Units: Participants]	125	124	120
Final Clinical Cure Rate (Per Protocol Dataset) [Units: Participants]	101	102	73

Statistical Analysis 1 for Final Clinical Cure Rate (Per Protocol Dataset)

Groups ^[1]	WR 279,396 Topical Treament vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.0006

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Final Clinical Cure Rate (Per Protocol Dataset)

Groups ^[1]	Paromomycin Alone Topical Treatment vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.0002

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Final Clinical Cure Rate (Per Protocol Dataset)

Groups ^[1]	WR 279,396 Topical Treament vs. Paromomycin Alone Topical Treatment
Statistical Test Type ^[2]	Non-Inferiority or Equivalence
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.767

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	Test of H02: If H01 was rejected, then H02 would be tested. The comparison of WR 279,396 versus Paromomycin Alone would be considered statistically significant if p < .05.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

3. Secondary:

Estimated Percentage Subjects With Re-epithelialization of the Index Lesion Without Relapse [ Time Frame: Day 42 ]

Measure Type	Secondary
Measure Title	Estimated Percentage Subjects With Re-epithelialization of the Index Lesion Without Relapse
Measure Description	For the first of the above analyses, subjects were considered to have endpoint events at the first assessment on or before Day 42 where complete re-epithelialization occurred at the index lesion that was not followed by a later assessment where ulceration was present. Subjects who did not have complete re-epithelialization by Day 42 or who relapsed after Day 42 were censored in the analysis at the Day 42 assessment. This analysis was only to be conducted through Day 42.
Time Frame	Day 42

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
mITT dataset

Reporting Groups

Description

WR 279,396 Topical Treament

WR 279,396 topical cream (15% paromomycin + 0.5% gentamicin topical cream)

Paromomycin Alone Topical Treatment

Paromomycin Alone topical cream (15% paromomycin topical cream)

Paromomycin Alone topical cream: The antibiotic paromomycin 15% in the same topical cream used in arm 1 will be applied to lesions daily and covered with a protective sterile gauze and tape dressing.

Vehicle Placebo Cream

The cream base without the addition of paromomycin or gentamicin

Vehicle placebo cream: Applied daily to cutaneous leishmaniasis lesions, primarily ulcerative, and covered with a protective, sterile gauze and tape dressing.

Measured Values

	WR 279,396 Topical Treament	Paromomycin Alone Topical Treatment	Vehicle Placebo Cream
Participants Analyzed [Units: Participants]	125	125	125
Estimated Percentage Subjects With Re-epithelialization of the Index Lesion Without Relapse [Units: Percentage of participants] Number (95% Confidence Interval)	67.2 (58.5 to 74.8)	68.8 (60.2 to 76.3)	48.8 (40.2 to 57.5)

Statistical Analysis 1 for Estimated Percentage Subjects With Re-epithelialization of the Index Lesion Without Relapse

Groups ^[1]	WR 279,396 Topical Treament vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Log Rank
P Value ^[4]	0.330

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	Mantel-Cox (log-rank) grouped failure time test using proportion re-epithelialized at each of the scheduled assessments through Day 42 without relapse
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Estimated Percentage Subjects With Re-epithelialization of the Index Lesion Without Relapse

Groups ^[1]	Paromomycin Alone Topical Treatment vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Log Rank
P Value ^[4]	0.275

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Estimated Percentage Subjects With Re-epithelialization of the Index Lesion Without Relapse

Groups ^[1]	WR 279,396 Topical Treament vs. Paromomycin Alone Topical Treatment
Statistical Test Type ^[2]	Non-Inferiority or Equivalence
Statistical Method ^[3]	Log Rank
P Value ^[4]	0.830

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	The comparison of WR 279,396 versus Paromomycin Alone would be considered statistically significant if p < .05.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

4. Secondary:

Estimated Percentage of Subjects With Re-epithelialization of the Index Lesion Without Relapse at Various Times of Follow-up [ Time Frame: Days 42, 49, and 98 ]

Measure Type	Secondary
Measure Title	Estimated Percentage of Subjects With Re-epithelialization of the Index Lesion Without Relapse at Various Times of Follow-up
Measure Description	No text entered.
Time Frame	Days 42, 49, and 98

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
mITT dataset. The data show that 95.8% of the Vehicle-treated subjects remaining in the study at Day 168 (the percentage excludes the 17.6% of subjects who dropped out or were withdrawn early due to treatment failure) had re-epithelialization of the index lesion.

Reporting Groups

Description

WR 279,396 Topical Treament

WR 279,396 topical cream (15% paromomycin + 0.5% gentamicin topical cream)

Paromomycin Alone Topical Treatment

Paromomycin Alone topical cream (15% paromomycin topical cream)

Paromomycin Alone topical cream: The antibiotic paromomycin 15% in the same topical cream used in arm 1 will be applied to lesions daily and covered with a protective sterile gauze and tape dressing.

Vehicle Placebo Cream

The cream base without the addition of paromomycin or gentamicin

Vehicle placebo cream: Applied daily to cutaneous leishmaniasis lesions, primarily ulcerative, and covered with a protective, sterile gauze and tape dressing.

Measured Values

	WR 279,396 Topical Treament	Paromomycin Alone Topical Treatment	Vehicle Placebo Cream
Participants Analyzed [Units: Participants]	125	125	125
Estimated Percentage of Subjects With Re-epithelialization of the Index Lesion Without Relapse at Various Times of Follow-up [Units: Percentage of participants] Number (95% Confidence Interval)
Day 42	67.2 (59.5 to 76.0)	68.5 (60.8 to 77.2)	49.4 (41.1 to 59.3)
Day 49	72.9 (65.5 to 81.2)	81.5 (74.9 to 88.6)	57.1 (48.7 to 67.0)
Day 98	94.3 (90.3 to 98.5)	99.2 (97.6 to 100.0)	90.9 (85.3 to 96.8)

No statistical analysis provided for Estimated Percentage of Subjects With Re-epithelialization of the Index Lesion Without Relapse at Various Times of Follow-up

5. Secondary:

Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 42 [ Time Frame: Days 42 ]

Measure Type	Secondary
Measure Title	Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 42
Measure Description	No text entered.
Time Frame	Days 42

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
mITT dataset

Reporting Groups

Description

WR 279,396 Topical Treament

WR 279,396 topical cream (15% paromomycin + 0.5% gentamicin topical cream)

Paromomycin Alone Topical Treatment

Paromomycin Alone topical cream (15% paromomycin topical cream)

Paromomycin Alone topical cream: The antibiotic paromomycin 15% in the same topical cream used in arm 1 will be applied to lesions daily and covered with a protective sterile gauze and tape dressing.

Vehicle Placebo Cream

The cream base without the addition of paromomycin or gentamicin

Vehicle placebo cream: Applied daily to cutaneous leishmaniasis lesions, primarily ulcerative, and covered with a protective, sterile gauze and tape dressing.

Measured Values

	WR 279,396 Topical Treament	Paromomycin Alone Topical Treatment	Vehicle Placebo Cream
Participants Analyzed [Units: Participants]	125	125	125
Units Analyzed (Lesions) [Units: Lesions]	157	134	115
Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 42 [Units: Percentage of lesions] Number (95% Confidence Interval)	51.7 (45.7 to 58.4)	81.6 (77.0 to 86.4)	58.1 (52.4 to 64.4)

No statistical analysis provided for Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 42

6. Secondary:

Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 49 [ Time Frame: Days 49 ]

Measure Type	Secondary
Measure Title	Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 49
Measure Description	No text entered.
Time Frame	Days 49

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
mITT dataset

Reporting Groups

Description

WR 279,396 Topical Treament

WR 279,396 topical cream (15% paromomycin + 0.5% gentamicin topical cream)

Paromomycin Alone Topical Treatment

Paromomycin Alone topical cream (15% paromomycin topical cream)

Paromomycin Alone topical cream: The antibiotic paromomycin 15% in the same topical cream used in arm 1 will be applied to lesions daily and covered with a protective sterile gauze and tape dressing.

Vehicle Placebo Cream

The cream base without the addition of paromomycin or gentamicin

Vehicle placebo cream: Applied daily to cutaneous leishmaniasis lesions, primarily ulcerative, and covered with a protective, sterile gauze and tape dressing.

Measured Values

	WR 279,396 Topical Treament	Paromomycin Alone Topical Treatment	Vehicle Placebo Cream
Participants Analyzed [Units: Participants]	125	125	125
Units Analyzed (Lesions) [Units: Lesions]	56	42	67
Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 49 [Units: Percentage of lesions] Number (95% Confidence Interval)	81.4 (76.6 to 86.5)	90.4 (86.9 to 94.1)	64.9 (59.2 to 71.1)

No statistical analysis provided for Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 49

7. Secondary:

Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 98 [ Time Frame: Days 98 ]

Measure Type	Secondary
Measure Title	Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 98
Measure Description	No text entered.
Time Frame	Days 98

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
mITT dataset

Reporting Groups

Description

WR 279,396 Topical Treament

WR 279,396 topical cream (15% paromomycin + 0.5% gentamicin topical cream)

Paromomycin Alone Topical Treatment

Paromomycin Alone topical cream (15% paromomycin topical cream)

Paromomycin Alone topical cream: The antibiotic paromomycin 15% in the same topical cream used in arm 1 will be applied to lesions daily and covered with a protective sterile gauze and tape dressing.

Vehicle Placebo Cream

The cream base without the addition of paromomycin or gentamicin

Vehicle placebo cream: Applied daily to cutaneous leishmaniasis lesions, primarily ulcerative, and covered with a protective, sterile gauze and tape dressing.

Measured Values

	WR 279,396 Topical Treament	Paromomycin Alone Topical Treatment	Vehicle Placebo Cream
Participants Analyzed [Units: Participants]	125	125	125
Units Analyzed (Lesions) [Units: Lesions]	23	10	36
Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 98 [Units: Percentage of lesions] Number (95% Confidence Interval)	91.5 (88.1 to 95.1)	98.9 (97.6 to 100.0)	92.2 (88.6 to 96.0)

No statistical analysis provided for Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 98

8. Secondary:

Number of Subjects Achieving Initial Clinical Improvement of the Index Lesion [ Time Frame: Day 42 ]

Measure Type	Secondary
Measure Title	Number of Subjects Achieving Initial Clinical Improvement of the Index Lesion
Measure Description	No text entered.
Time Frame	Day 42

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups

Description

WR 279,396 Topical Treament

WR 279,396 topical cream (15% paromomycin + 0.5% gentamicin topical cream)

Paromomycin Alone Topical Treatment

Paromomycin Alone topical cream (15% paromomycin topical cream)

Paromomycin Alone topical cream: The antibiotic paromomycin 15% in the same topical cream used in arm 1 will be applied to lesions daily and covered with a protective sterile gauze and tape dressing.

Vehicle Placebo Cream

The cream base without the addition of paromomycin or gentamicin

Vehicle placebo cream: Applied daily to cutaneous leishmaniasis lesions, primarily ulcerative, and covered with a protective, sterile gauze and tape dressing.

Measured Values

	WR 279,396 Topical Treament	Paromomycin Alone Topical Treatment	Vehicle Placebo Cream
Participants Analyzed [Units: Participants]	125	125	125
Number of Subjects Achieving Initial Clinical Improvement of the Index Lesion [Units: Participants]	105	107	77

Statistical Analysis 1 for Number of Subjects Achieving Initial Clinical Improvement of the Index Lesion

Groups ^[1]	WR 279,396 Topical Treament vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.0001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Number of Subjects Achieving Initial Clinical Improvement of the Index Lesion

Groups ^[1]	Paromomycin Alone Topical Treatment vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Chi-squared
P Value ^[4]	<0.0001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Number of Subjects Achieving Initial Clinical Improvement of the Index Lesion

Groups ^[1]	WR 279,396 Topical Treament vs. Paromomycin Alone Topical Treatment
Statistical Test Type ^[2]	Non-Inferiority or Equivalence
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.725

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	Test of H02: If H01 was rejected, then H02 would be tested. The comparison of WR 279,396 versus Paromomycin Alone would be considered statistically significant if p < .05.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

9. Secondary:

Number of Subjects Achieving Re-epithelialization of the Index Lesion Without Relapse [ Time Frame: Day 168 ]

Measure Type	Secondary
Measure Title	Number of Subjects Achieving Re-epithelialization of the Index Lesion Without Relapse
Measure Description	Number of Subjects Achieving Re-epithelialization of the Index Lesion by Day 42 without Relapse from Day 42 Onward, Imputing Relapse for any Subject with a Missing Visit after Day 42
Time Frame	Day 168

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
mITT population

Reporting Groups

Description

WR 279,396 Topical Treament

WR 279,396 topical cream (15% paromomycin + 0.5% gentamicin topical cream)

Paromomycin Alone Topical Treatment

Paromomycin Alone topical cream (15% paromomycin topical cream)

Paromomycin Alone topical cream: The antibiotic paromomycin 15% in the same topical cream used in arm 1 will be applied to lesions daily and covered with a protective sterile gauze and tape dressing.

Vehicle Placebo Cream

The cream base without the addition of paromomycin or gentamicin

Vehicle placebo cream: Applied daily to cutaneous leishmaniasis lesions, primarily ulcerative, and covered with a protective, sterile gauze and tape dressing.

Measured Values

	WR 279,396 Topical Treament	Paromomycin Alone Topical Treatment	Vehicle Placebo Cream
Participants Analyzed [Units: Participants]	125	125	125
Number of Subjects Achieving Re-epithelialization of the Index Lesion Without Relapse [Units: Participants]	84	84	62

Statistical Analysis 1 for Number of Subjects Achieving Re-epithelialization of the Index Lesion Without Relapse

Groups ^[1]	WR 279,396 Topical Treament vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.005

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Number of Subjects Achieving Re-epithelialization of the Index Lesion Without Relapse

Groups ^[1]	Paromomycin Alone Topical Treatment vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.005

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Number of Subjects Achieving Re-epithelialization of the Index Lesion Without Relapse

Groups ^[1]	WR 279,396 Topical Treament vs. Paromomycin Alone Topical Treatment
Statistical Test Type ^[2]	Non-Inferiority or Equivalence
Statistical Method ^[3]	Chi-squared
P Value ^[4]	1.000

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	Test of H02: If H01 was rejected, then H02 would be tested. The comparison of WR 279,396 versus Paromomycin Alone would be considered statistically significant if p < .05.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

10. Secondary:

Number of Subjects Achieving Re-epithelialization of All Treated Ulcerated Lesions Without Subsequent Relapse [ Time Frame: Day 168 ]

Measure Type	Secondary
Measure Title	Number of Subjects Achieving Re-epithelialization of All Treated Ulcerated Lesions Without Subsequent Relapse
Measure Description	Number of Subjects Achieving Re-epithelialization of All Treated Ulcerated Lesions at Day 42 without Subsequent Relapse from Day 42 Onward,
Time Frame	Day 168

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
mITT dataset

Reporting Groups

Description

WR 279,396 Topical Treament

WR 279,396 topical cream (15% paromomycin + 0.5% gentamicin topical cream)

Paromomycin Alone Topical Treatment

Paromomycin Alone topical cream (15% paromomycin topical cream)

Paromomycin Alone topical cream: The antibiotic paromomycin 15% in the same topical cream used in arm 1 will be applied to lesions daily and covered with a protective sterile gauze and tape dressing.

Vehicle Placebo Cream

The cream base without the addition of paromomycin or gentamicin

Vehicle placebo cream: Applied daily to cutaneous leishmaniasis lesions, primarily ulcerative, and covered with a protective, sterile gauze and tape dressing.

Measured Values

	WR 279,396 Topical Treament	Paromomycin Alone Topical Treatment	Vehicle Placebo Cream
Participants Analyzed [Units: Participants]	125	125	125
Number of Subjects Achieving Re-epithelialization of All Treated Ulcerated Lesions Without Subsequent Relapse [Units: Participants]	83	84	60

Statistical Analysis 1 for Number of Subjects Achieving Re-epithelialization of All Treated Ulcerated Lesions Without Subsequent Relapse

Groups ^[1]	WR 279,396 Topical Treament vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.003

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Number of Subjects Achieving Re-epithelialization of All Treated Ulcerated Lesions Without Subsequent Relapse

Groups ^[1]	Paromomycin Alone Topical Treatment vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.002

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Number of Subjects Achieving Re-epithelialization of All Treated Ulcerated Lesions Without Subsequent Relapse

Groups ^[1]	WR 279,396 Topical Treament vs. Paromomycin Alone Topical Treatment
Statistical Test Type ^[2]	Non-Inferiority or Equivalence
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.893

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	Test of H02: If H01 was rejected, then H02 would be tested. The comparison of WR 279,396 versus Paromomycin Alone would be considered statistically significant if p < .05.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

11. Secondary:

Number of All Ulcerated Lesions Achieving 100% Re-epithelialization by Day 42 [ Time Frame: Day 42 ]

Measure Type	Secondary
Measure Title	Number of All Ulcerated Lesions Achieving 100% Re-epithelialization by Day 42
Measure Description	No text entered.
Time Frame	Day 42

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
mITT dataset

Reporting Groups

Description

WR 279,396 Topical Treament

WR 279,396 topical cream (15% paromomycin + 0.5% gentamicin topical cream)

Paromomycin Alone Topical Treatment

Paromomycin Alone topical cream (15% paromomycin topical cream)

Paromomycin Alone topical cream: The antibiotic paromomycin 15% in the same topical cream used in arm 1 will be applied to lesions daily and covered with a protective sterile gauze and tape dressing.

Vehicle Placebo Cream

The cream base without the addition of paromomycin or gentamicin

Vehicle placebo cream: Applied daily to cutaneous leishmaniasis lesions, primarily ulcerative, and covered with a protective, sterile gauze and tape dressing.

Measured Values

	WR 279,396 Topical Treament	Paromomycin Alone Topical Treatment	Vehicle Placebo Cream
Participants Analyzed [Units: Participants]	125	125	125
Units Analyzed (Ulcerated lesions) [Units: Ulcerated lesions]	240	262	279
Number of All Ulcerated Lesions Achieving 100% Re-epithelialization by Day 42 [Units: Ulcerated lesions]	190	218	160

Statistical Analysis 1 for Number of All Ulcerated Lesions Achieving 100% Re-epithelialization by Day 42

Groups ^[1]	WR 279,396 Topical Treament vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Chi-squared
P Value ^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Number of All Ulcerated Lesions Achieving 100% Re-epithelialization by Day 42

Groups ^[1]	Paromomycin Alone Topical Treatment vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Chi-squared
P Value ^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Number of All Ulcerated Lesions Achieving 100% Re-epithelialization by Day 42

Groups ^[1]	WR 279,396 Topical Treament vs. Paromomycin Alone Topical Treatment
Statistical Test Type ^[2]	Non-Inferiority or Equivalence
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.247

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	The comparison of WR 279,396 versus Paromomycin Alone would be considered statistically significant if p < .05.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

12. Secondary:

Number of Subjects With a Relapse on or After Day 42 [ Time Frame: Day 168 ]

Measure Type	Secondary
Measure Title	Number of Subjects With a Relapse on or After Day 42
Measure Description	No text entered.
Time Frame	Day 168

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups

Description

WR 279,396 Topical Treament

WR 279,396 topical cream (15% paromomycin + 0.5% gentamicin topical cream)

Paromomycin Alone Topical Treatment

Paromomycin Alone topical cream (15% paromomycin topical cream)

Paromomycin Alone topical cream: The antibiotic paromomycin 15% in the same topical cream used in arm 1 will be applied to lesions daily and covered with a protective sterile gauze and tape dressing.

Vehicle Placebo Cream

The cream base without the addition of paromomycin or gentamicin

Vehicle placebo cream: Applied daily to cutaneous leishmaniasis lesions, primarily ulcerative, and covered with a protective, sterile gauze and tape dressing.

Measured Values

	WR 279,396 Topical Treament	Paromomycin Alone Topical Treatment	Vehicle Placebo Cream
Participants Analyzed [Units: Participants]	125	125	125
Number of Subjects With a Relapse on or After Day 42 [Units: Participants]	4	3	2

Statistical Analysis 1 for Number of Subjects With a Relapse on or After Day 42

Groups ^[1]	WR 279,396 Topical Treament vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.409

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 2 for Number of Subjects With a Relapse on or After Day 42

Groups ^[1]	Paromomycin Alone Topical Treatment vs. Vehicle Placebo Cream
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.651

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Number of Subjects With a Relapse on or After Day 42

Groups ^[1]	WR 279,396 Topical Treament
Statistical Test Type ^[2]	Non-Inferiority or Equivalence
Statistical Method ^[3]	Chi-squared
P Value ^[4]	0.701

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	The comparison of WR 279,396 versus Paromomycin Alone would be considered statistically significant if p < .05.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Serious Adverse Events

Show Serious Adverse Events

Other Adverse Events

Show Other Adverse Events

Limitations and Caveats

Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

More Information

Hide More Information

Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact:

Name/Title: Division of Regulated Activies and Compliance
Organization: US Army Medical Materiel Development Activity (USAMMDA)
phone: 301-619-0317
e-mail: usarmy.detrick.medcom-usammda.mbx.usamrmc-regulatory-affairs@mail.mil

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ben Salah A, Ben Messaoud N, Guedri E, Zaatour A, Ben Alaya N, Bettaieb J, Gharbi A, Belhadj Hamida N, Boukthir A, Chlif S, Abdelhamid K, El Ahmadi Z, Louzir H, Mokni M, Morizot G, Buffet P, Smith PL, Kopydlowski KM, Kreishman-Deitrick M, Smith KS, Nielsen CJ, Ullman DR, Norwood JA, Thorne GD, McCarthy WF, Adams RC, Rice RM, Tang D, Berman J, Ransom J, Magill AJ, Grogl M. Topical paromomycin with or without gentamicin for cutaneous leishmaniasis. N Engl J Med. 2013 Feb 7;368(6):524-32. doi: 10.1056/NEJMoa1202657.

Responsible Party:	U.S. Army Medical Research and Materiel Command
ClinicalTrials.gov Identifier:	NCT00606580 History of Changes
Other Study ID Numbers:	A-14134
Study First Received:	January 21, 2008
Results First Received:	May 12, 2014
Last Updated:	June 11, 2014

To Top