A Study to Evaluate the Efficacy and Tolerance of WR279,396 for Old World Cutaneous Leishmaniasis

• Sponsor: U.S. Army Medical Research and Development Command (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT01536795
• Collaborator: (none)
• Enrollment: 48
• Location: 1
• Arms: 2
• Actual Duration (Months): 16
• Patients Per Site Per Month: 3

Study Details

Study Description

Brief Summary

This Phase 2 study is to determine whether WR279396 with occlusion (a polyurethane dressing) is more effective than WR279396 without occlusion for once daily treatment.

Extensive objective and subjective local tolerance data will also be captured during this trial, as well as surrogate markers (parasite loads and aminoglycosides concentration in the deep dermis) that may help to determine the optimal number and duration of treatments.

The results from this study will help determine the most practical treatment schedule and will answer questions that are crucial to improve the present treatment regimen with WR279396 which is twice a day for 20 days.

Condition or Disease	Intervention/Treatment	Phase
Old World Cutaneous Leishmaniasis	Drug: WR279,396 with Tegaderm Dressing; Drug: WR 279,396 with Gauze and Tape Dressing	Phase 2

Detailed Description

Forty-eight patients (48) with Old World cutaneous leishmaniasis will be randomly allocated to WR279396 treatment once a day for 20 days with an optimized polyurethane dressing (occlusion) (24 patients), or without occlusion (24 patients). All patients will be rescued with the standard of care accepted in Tunisia, if the patient is not cured. The active ingredients of WR279396 are two aminoglycosides - paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC).

Each subject will be followed for clinical cure for 90 days after the initiation of treatment. Cure is defined as 100% reepithelialization without relapse by 3 months.

Tolerance will be evaluated by local adverse reactions and by laboratory signs of systemic events.

In addition to the clinical evaluation of the CL lesions, the following parameters/clinical healing surrogates will be investigated:

1. parasite load will be determined in superficial and deep lesional dermis samples at D0 and D10. The mean parasite reduction ratio (parasite load at D10/parasite load at D0) in each group will be compared;

2. aminoglycoside concentrations in superficial and deep infiltrated dermis in each group will be compared.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Topical Treatment of Old World Cutaneous Leishmaniasis With WR279396 (Paromomycin/Gentamicin Ointment): Efficacy and Tolerance of a Regimen Using an Occlusive Polyurethane Dressing
• Actual Study Start Date: Oct 1, 2005
• Actual Primary Completion Date: Feb 1, 2007
• Actual Study Completion Date: Feb 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: WR279,396 with Tegaderm dressing 24 patients will be randomly allocated to WR279,396 treatment once-a-day for 20 days with using an occlusive polyurethane Tegaderm dressing	Drug: WR279,396 with Tegaderm Dressing; Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days with polyurethane dressing
Experimental: WR279,396 with Gauze and Tape Dressing 24 subjects will be randomly allocated to WR279,396 treatment once a day for 20 days without an optimized polyurethane dressing (gauze and tape only).	Drug: WR 279,396 with Gauze and Tape Dressing; Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days

Outcome Measures

Primary Outcome Measures

1. Safety: Overview of Adverse Events [During 20 day treatment period]

   Safety of WR279,396 through the tracking of local, systemic and spontaneous adverse reactions

Secondary Outcome Measures

1. Clinical Responses of Index Lesions (100% Re-epithelialization) [Day 50, 90]

   Efficacy will be evaluated in terms of the number of lesions cured at D50 (D1 is the first day of treatment) with no relapse by Day 90. Complete clinical respoonse is defined as 100% re-epithelialization of the index lesion by Day 50 or a > 50% re-epithelialization by Day 50 followed by complete re-epithelialization on or before Day 90, with no relapse ever having occurred from Day 50 through Day 90.

Other Outcome Measures

1. Area of the Index Lesion's Ulceration by Study Day [Days 1, 10, 20, 50 and 90]

   Area of the index lesion's ulceration over time in mm2

2. Area of the Index Lesion's Induration by Study Day [Days 1, 10, 20, 50 and 90]

   Area of the index lesion's induration over time in mm2

3. Percentage Change in Induration Area From Baseline and Days 10, 20, 50 and 90 [Days 10, 20, 50 and 90]

   Percentage of change of index lesion in induration area from baseline and days 10, 20, 50 and 90

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria: The study population will be selected from adults (18y) patients and children above 15y in Tunisia (Old World)

• Age: 15 - 75 years old

• Lesion character: each diameter (horizontal and vertical) of the lesion test must measure 7 mm, the lesion must be primarily ulcerative (i.e., not verrucous or nodular) and located in a biopsy friendly site of the body

• Parasitological diagnosis: have cutaneous leishmaniasis proven parasitologically in lesion selected for inclusion in study (lesion test).

• Informed consent: have given written informed consent to participate in the study: (i.e. patient or legal representative).

Exclusion Criteria:

• Drug intolerance: history of known or suspected hypersensitivity or idiosyncratic reactions to aminoglycosides in the patient or immediate family members.

• Previous use of antileishmanial drugs (within 2 months) or present use of routinely nephrotoxic or ototoxic drugs.

• Potential for follow up: Have less than 4 months time remaining in present address and/or plans to leave the area for more than 30 days.

• Extent of disease: More than 10 lesions or lesion ³ 5 cm or a lesion less than 2 cm from eye, in the ear, or a lesion in the face, that in the opinion of the attending dermatologist could potentially cause significant disfigurement.

• Location of disease: mucosal involvement.

• Disseminated disease: clinically significant lymphadenitis with nodules that are painful and > 1 cm in size in the lymphatic drainage of the ulcer.

• Concomitant medical problems: significant medical problems of the kidney or liver as determined by history and by the following laboratory studies:

• Kidney: clinically significant abnormalities of urine analysis, serum levels of Creatinine, BUN, total proteins > upper limit of normal for the laboratory.

• Liver: AST or ALT > upper limit of normal for the laboratory.

• General: glucose, Na, K, > upper limit of normal or < lower limit of normal for the laboratory. Volunteers in whom these normal laboratory values are exceeded by less than 25% will not be automatically excluded. These volunteers will be evaluated on the basis of history, physical, as well as laboratory values.

• Scheduled or ongoing pregnancy as determined clinical and biological criteria.

• Presence of signs or symptoms of peripheral neuropathy, myasthenia gravis or neuromuscular block

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Institut Pasteur	Tunis		Tunisia

Sponsors and Collaborators

• U.S. Army Medical Research and Development Command

Investigators

• Principal Investigator: Afif Ben Salah,, MD, PhD, Institut Pasteur, Tunisia

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: U.S. Army Medical Research and Development Command
• ClinicalTrials.gov Identifier: NCT01536795
• Other Study ID Numbers: A-9768.2; IND50,098
• First Posted: Feb 22, 2012
• Last Update Posted: Feb 12, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by U.S. Army Medical Research and Development Command: Ointment to treat leishmania skin lesions
• Additional relevant MeSH terms: Leishmaniasis; Leishmaniasis, Cutaneous

Study Results

Participant Flow

Recruitment Details	48 subjects were randomized and received treatment at the Institut Pasteur de Tunis and primary healthcare centers and schools of the study area in Sidi Bouzid and Elmmara, Tunisia.

Arm/Group Title	WR279,396 With Tegaderm Dressing	WR279,396 With Gauze and Tape Dressing
Arm/Group Description	24 patients will be randomly allocated to WR279,396 treatment once-a-day for 20 days with using an occlusive polyurethane Tegaderm dressing WR279,396 with Tegaderm Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days with polyurethane dressing	24 subjects will be randomly allocated to WR279,396 treatment once a day for 20 days without an optimized polyurethane dressing (gauze and tape only). WR 279,396 with Gauze and Tape Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days
Period Title: Overall Study
STARTED	24	24
COMPLETED	23	22
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	WR279,396 With Tegaderm Dressing	WR279,396 With Gauze and Tape Dressing	Total
Arm/Group Description	24 patients will be randomly allocated to WR279,396 treatment once-a-day for 20 days with using an occlusive polyurethane Tegaderm dressing WR279,396 with Tegaderm Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days with polyurethane dressing	24 subjects will be randomly allocated to WR279,396 treatment once a day for 20 days without an optimized polyurethane dressing (gauze and tape only). WR 279,396 with Gauze and Tape Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days	Total of all reporting groups
Overall Participants	24	24	48
Age (Count of Participants)
<=18 years	6 25%	5 20.8%	11 22.9%
Between 18 and 65 years	18 75%	19 79.2%	37 77.1%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	12 50%	13 54.2%	25 52.1%
Male	12 50%	11 45.8%	23 47.9%
Race/Ethnicity, Customized (Count of Participants)
Middle Eastern or North African	24 100%	23 95.8%	47 97.9%
Other (European/Arab)	0 0%	1 4.2%	1 2.1%
Region of Enrollment (participants) [Number]
Tunisia	24 100%	24 100%	48 100%
Subjects with a previous history of leishmaniasis (Count of Participants)
Yes	3 12.5%	2 8.3%	5 10.4%
No	21 87.5%	22 91.7%	43 89.6%

Outcome Measures

1. Primary Outcome

Title	Safety: Overview of Adverse Events
Description	Safety of WR279,396 through the tracking of local, systemic and spontaneous adverse reactions
Time Frame	During 20 day treatment period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	WR279,396 With Tegaderm Dressing	WR279,396 With Gauze and Tape Dressing
Arm/Group Description	24 patients will be randomly allocated to WR279,396 treatment once-a-day for 20 days with using an occlusive polyurethane Tegaderm dressing WR279,396 with Tegaderm Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days with polyurethane dressing	24 subjects will be randomly allocated to WR279,396 treatment once a day for 20 days without an optimized polyurethane dressing (gauze and tape only). WR 279,396 with Gauze and Tape Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days
Measure Participants	24	24
Subjects with atleast 1 AE	16 66.7%	7 29.2%
Subjects with an SAE	0 0%	0 0%
Withdrawals due to an AE	0 0%	0 0%
Not due to an AE	0 0%	1 4.2%
Deaths	0 0%	0 0%

2. Secondary Outcome

Title	Clinical Responses of Index Lesions (100% Re-epithelialization)
Description	Efficacy will be evaluated in terms of the number of lesions cured at D50 (D1 is the first day of treatment) with no relapse by Day 90. Complete clinical respoonse is defined as 100% re-epithelialization of the index lesion by Day 50 or a > 50% re-epithelialization by Day 50 followed by complete re-epithelialization on or before Day 90, with no relapse ever having occurred from Day 50 through Day 90.
Time Frame	Day 50, 90

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	WR279,396 With Tegaderm Dressing	WR279,396 With Gauze and Tape Dressing
Arm/Group Description	24 patients will be randomly allocated to WR279,396 treatment once-a-day for 20 days with using an occlusive polyurethane Tegaderm dressing WR279,396 with Tegaderm Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days with polyurethane dressing	24 subjects will be randomly allocated to WR279,396 treatment once a day for 20 days without an optimized polyurethane dressing (gauze and tape only). WR 279,396 with Gauze and Tape Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days
Measure Participants	24	24
Day 50 - Not Evaluable	1 4.2%	2 8.3%
Day 50 - Cured	19 79.2%	20 83.3%
Day 50 - Improved	2 8.3%	2 8.3%
Day 50 - Failure	2 8.3%	0 0%
Day 90 - Not Evaluable	1 4.2%	2 8.3%
Day 90 - Cured/Improved at D50 with no relapse	17 70.8%	20 83.3%
Day 90 - Improved	2 8.3%	2 8.3%
Day 90 - Failure	4 16.7%	0 0%

3. Other Pre-specified Outcome

Title	Area of the Index Lesion's Ulceration by Study Day
Description	Area of the index lesion's ulceration over time in mm2
Time Frame	Days 1, 10, 20, 50 and 90

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	WR279,396 With Tegaderm Dressing	WR279,396 With Gauze and Tape Dressing
Arm/Group Description	24 patients will be randomly allocated to WR279,396 treatment once-a-day for 20 days with using an occlusive polyurethane Tegaderm dressing WR279,396 with Tegaderm Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days with polyurethane dressing	24 subjects will be randomly allocated to WR279,396 treatment once a day for 20 days without an optimized polyurethane dressing (gauze and tape only). WR 279,396 with Gauze and Tape Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days
Measure Participants	24	24
Day 0/1	127.0 (147.39)	157.69 (179.52)
Day 10	118.87 (106.41)	140.64 (157.74)
Day 20	115.62 (101.45)	153.51 (176.37)
Day 50	20.0 (48.3)	1.3 (6.2)
Day 90	30.8 (117.9)	0.00 (0.0)

4. Other Pre-specified Outcome

Title	Area of the Index Lesion's Induration by Study Day
Description	Area of the index lesion's induration over time in mm2
Time Frame	Days 1, 10, 20, 50 and 90

Outcome Measure Data

Analysis Population Description

On D50 in the Gauze-Tape group no SD was given in the data table. All good cause efforts to locate the data for Day 50 SD value for gauze and tape dressing arm have been exhausted, data are missing and hence not available to be reported.

Arm/Group Title	WR279,396 With Tegaderm Dressing	WR279,396 With Gauze and Tape Dressing
Arm/Group Description	24 patients will be randomly allocated to WR279,396 treatment once-a-day for 20 days with using an occlusive polyurethane Tegaderm dressing WR279,396 with Tegaderm Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days with polyurethane dressing	24 subjects will be randomly allocated to WR279,396 treatment once a day for 20 days without an optimized polyurethane dressing (gauze and tape only). WR 279,396 with Gauze and Tape Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days
Measure Participants	24	24
Day 0/1	360.7 (262.5)	505.9 (431.6)
Day 10	405.14 (250.78)	495.25 (401.47)
Day 20	410.15 (269.62)	468.85 (344.01)
Day 50	122.7 (249.8)	148.05 (NA)
Day 90	74.6 (235.4)	0.00 (0.00)

5. Other Pre-specified Outcome

Title	Percentage Change in Induration Area From Baseline and Days 10, 20, 50 and 90
Description	Percentage of change of index lesion in induration area from baseline and days 10, 20, 50 and 90
Time Frame	Days 10, 20, 50 and 90

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	WR279,396 With Tegaderm Dressing	WR279,396 With Gauze and Tape Dressing
Arm/Group Description	24 patients will be randomly allocated to WR279,396 treatment once-a-day for 20 days with using an occlusive polyurethane Tegaderm dressing WR279,396 with Tegaderm Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days with polyurethane dressing	24 subjects will be randomly allocated to WR279,396 treatment once a day for 20 days without an optimized polyurethane dressing (gauze and tape only). WR 279,396 with Gauze and Tape Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days
Measure Participants	24	24
Day 10	28.3 (63.2)	45.0 (114.2)
Day 20	30.0 (62.0)	51.0 (116.2)
Day 50	-64.4 (78.5)	-83.9 (30.7)
Day 90	-65.1 (98.5)	-100.0 (0)

Adverse Events

Time Frame	90 Days
Arm/Group Title	WR279,396 With Tegaderm Dressing		WR279,396 With Gauze and Tape Dressing
Arm/Group Description	24 patients will be randomly allocated to WR279,396 treatment once-a-day for 20 days with using an occlusive polyurethane Tegaderm dressing WR279,396 with Tegaderm Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days with polyurethane dressing		24 subjects will be randomly allocated to WR279,396 treatment once a day for 20 days without an optimized polyurethane dressing (gauze and tape only). WR 279,396 with Gauze and Tape Dressing: Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days
All Cause Mortality
	WR279,396 With Tegaderm Dressing		WR279,396 With Gauze and Tape Dressing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)
Serious Adverse Events
	WR279,396 With Tegaderm Dressing		WR279,396 With Gauze and Tape Dressing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	WR279,396 With Tegaderm Dressing		WR279,396 With Gauze and Tape Dressing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/24 (66.7%)		7/24 (29.2%)
Ear and labyrinth disorders
Vertigo	2/24 (8.3%)	2	0/24 (0%)	0
General disorders
Local reaction (infection at biopsy site)	1/24 (4.2%)	1	0/24 (0%)	0
Edema	1/24 (4.2%)	1	5/24 (20.8%)	5
Pain	1/24 (4.2%)	1	4/24 (16.7%)	4
Pyrexia	0/24 (0%)	0	1/24 (4.2%)	1
Infections and infestations
Any infection and infestation	0/24 (0%)	0	1/24 (4.2%)	1
Erysipelas	0/24 (0%)	0	1/24 (4.2%)	1
Investigations
Any investigations	4/24 (16.7%)	4	1/24 (4.2%)	1
Blood creatinine increased	4/24 (16.7%)	4	1/24 (4.2%)	1
Skin and subcutaneous tissue disorders
Blister (vesicles)	10/24 (41.7%)	10	3/24 (12.5%)	3
Dermatitis contact (allergy to Tegaderm)	4/24 (16.7%)	4	0/24 (0%)	0
Erythema	7/24 (29.2%)	7	3/24 (12.5%)	3

Limitations/Caveats

[Not Specified]

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.