Old World Cutaneous Leishmaniasis
Conditions
Keywords
Ointment to treat leishmania skin lesions
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.
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.
Interventions
DRUGWR279,396 with Tegaderm Dressing
Ointment containing paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC)applied for 20 days with polyurethane dressing
DRUGWR 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
Sponsors
U.S. Army Medical Research and Development Command
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
Countries
Tunisia
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.
Participants by arm
| Arm | Count |
|---|---|
| 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
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 |
| 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).
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 | 24 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 2 |
Baseline characteristics
| Characteristic | WR279,396 With Tegaderm Dressing | WR279,396 With Gauze and Tape Dressing | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 5 Participants | 11 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 19 Participants | 37 Participants |
| Race/Ethnicity, Customized Race Middle Eastern or North African | 24 Participants | 23 Participants | 47 Participants |
| Race/Ethnicity, Customized Race Other (European/Arab) | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Tunisia | 24 participants | 24 participants | 48 participants |
| Sex: Female, Male Female | 12 Participants | 13 Participants | 25 Participants |
| Sex: Female, Male Male | 12 Participants | 11 Participants | 23 Participants |
| Subjects with a previous history of leishmaniasis No | 21 Participants | 22 Participants | 43 Participants |
| Subjects with a previous history of leishmaniasis Yes | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 16 / 24 | 7 / 24 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 |
Outcome results
Primary
Safety: Overview of Adverse Events
Safety of WR279,396 through the tracking of local, systemic and spontaneous adverse reactions
Time frame: During 20 day treatment period
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| WR279,396 With Tegaderm Dressing | Safety: Overview of Adverse Events | Subjects with an SAE | 0 Participants |
| WR279,396 With Tegaderm Dressing | Safety: Overview of Adverse Events | Not due to an AE | 0 Participants |
| WR279,396 With Tegaderm Dressing | Safety: Overview of Adverse Events | Withdrawals due to an AE | 0 Participants |
| WR279,396 With Tegaderm Dressing | Safety: Overview of Adverse Events | Deaths | 0 Participants |
| WR279,396 With Tegaderm Dressing | Safety: Overview of Adverse Events | Subjects with atleast 1 AE | 16 Participants |
| WR279,396 With Gauze and Tape Dressing | Safety: Overview of Adverse Events | Deaths | 0 Participants |
| WR279,396 With Gauze and Tape Dressing | Safety: Overview of Adverse Events | Subjects with atleast 1 AE | 7 Participants |
| WR279,396 With Gauze and Tape Dressing | Safety: Overview of Adverse Events | Subjects with an SAE | 0 Participants |
| WR279,396 With Gauze and Tape Dressing | Safety: Overview of Adverse Events | Withdrawals due to an AE | 0 Participants |
| WR279,396 With Gauze and Tape Dressing | Safety: Overview of Adverse Events | Not due to an AE | 1 Participants |
Secondary
Clinical Responses of Index Lesions (100% Re-epithelialization)
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
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| WR279,396 With Tegaderm Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 50 - Not Evaluable | 1 Participants |
| WR279,396 With Tegaderm Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 90 - Not Evaluable | 1 Participants |
| WR279,396 With Tegaderm Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 50 - Improved | 2 Participants |
| WR279,396 With Tegaderm Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 50 - Cured | 19 Participants |
| WR279,396 With Tegaderm Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 90 - Improved | 2 Participants |
| WR279,396 With Tegaderm Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 50 - Failure | 2 Participants |
| WR279,396 With Tegaderm Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 90 - Failure | 4 Participants |
| WR279,396 With Tegaderm Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 90 - Cured/Improved at D50 with no relapse | 17 Participants |
| WR279,396 With Gauze and Tape Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 90 - Failure | 0 Participants |
| WR279,396 With Gauze and Tape Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 50 - Not Evaluable | 2 Participants |
| WR279,396 With Gauze and Tape Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 50 - Cured | 20 Participants |
| WR279,396 With Gauze and Tape Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 50 - Improved | 2 Participants |
| WR279,396 With Gauze and Tape Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 50 - Failure | 0 Participants |
| WR279,396 With Gauze and Tape Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 90 - Not Evaluable | 2 Participants |
| WR279,396 With Gauze and Tape Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 90 - Cured/Improved at D50 with no relapse | 20 Participants |
| WR279,396 With Gauze and Tape Dressing | Clinical Responses of Index Lesions (100% Re-epithelialization) | Day 90 - Improved | 2 Participants |
Other Pre-specified
Area of the Index Lesion's Induration by Study Day
Area of the index lesion's induration over time in mm2
Time frame: Days 1, 10, 20, 50 and 90
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WR279,396 With Tegaderm Dressing | Area of the Index Lesion's Induration by Study Day | Day 10 | 405.14 mm^2 | Standard Deviation 250.78 |
| WR279,396 With Tegaderm Dressing | Area of the Index Lesion's Induration by Study Day | Day 50 | 122.7 mm^2 | Standard Deviation 249.8 |
| WR279,396 With Tegaderm Dressing | Area of the Index Lesion's Induration by Study Day | Day 20 | 410.15 mm^2 | Standard Deviation 269.62 |
| WR279,396 With Tegaderm Dressing | Area of the Index Lesion's Induration by Study Day | Day 90 | 74.6 mm^2 | Standard Deviation 235.4 |
| WR279,396 With Tegaderm Dressing | Area of the Index Lesion's Induration by Study Day | Day 0/1 | 360.7 mm^2 | Standard Deviation 262.5 |
| WR279,396 With Gauze and Tape Dressing | Area of the Index Lesion's Induration by Study Day | Day 90 | 0.00 mm^2 | Standard Deviation 0 |
| WR279,396 With Gauze and Tape Dressing | Area of the Index Lesion's Induration by Study Day | Day 0/1 | 505.9 mm^2 | Standard Deviation 431.6 |
| WR279,396 With Gauze and Tape Dressing | Area of the Index Lesion's Induration by Study Day | Day 10 | 495.25 mm^2 | Standard Deviation 401.47 |
| WR279,396 With Gauze and Tape Dressing | Area of the Index Lesion's Induration by Study Day | Day 20 | 468.85 mm^2 | Standard Deviation 344.01 |
| WR279,396 With Gauze and Tape Dressing | Area of the Index Lesion's Induration by Study Day | Day 50 | 148.05 mm^2 | — |
Other Pre-specified
Area of the Index Lesion's Ulceration by Study Day
Area of the index lesion's ulceration over time in mm2
Time frame: Days 1, 10, 20, 50 and 90
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WR279,396 With Tegaderm Dressing | Area of the Index Lesion's Ulceration by Study Day | Day 10 | 118.87 mm^2 | Standard Deviation 106.41 |
| WR279,396 With Tegaderm Dressing | Area of the Index Lesion's Ulceration by Study Day | Day 50 | 20.0 mm^2 | Standard Deviation 48.3 |
| WR279,396 With Tegaderm Dressing | Area of the Index Lesion's Ulceration by Study Day | Day 20 | 115.62 mm^2 | Standard Deviation 101.45 |
| WR279,396 With Tegaderm Dressing | Area of the Index Lesion's Ulceration by Study Day | Day 90 | 30.8 mm^2 | Standard Deviation 117.9 |
| WR279,396 With Tegaderm Dressing | Area of the Index Lesion's Ulceration by Study Day | Day 0/1 | 127.0 mm^2 | Standard Deviation 147.39 |
| WR279,396 With Gauze and Tape Dressing | Area of the Index Lesion's Ulceration by Study Day | Day 90 | 0.00 mm^2 | Standard Deviation 0 |
| WR279,396 With Gauze and Tape Dressing | Area of the Index Lesion's Ulceration by Study Day | Day 0/1 | 157.69 mm^2 | Standard Deviation 179.52 |
| WR279,396 With Gauze and Tape Dressing | Area of the Index Lesion's Ulceration by Study Day | Day 10 | 140.64 mm^2 | Standard Deviation 157.74 |
| WR279,396 With Gauze and Tape Dressing | Area of the Index Lesion's Ulceration by Study Day | Day 20 | 153.51 mm^2 | Standard Deviation 176.37 |
| WR279,396 With Gauze and Tape Dressing | Area of the Index Lesion's Ulceration by Study Day | Day 50 | 1.3 mm^2 | Standard Deviation 6.2 |
Other Pre-specified
Percentage Change in Induration Area From Baseline and Days 10, 20, 50 and 90
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WR279,396 With Tegaderm Dressing | Percentage Change in Induration Area From Baseline and Days 10, 20, 50 and 90 | Day 10 | 28.3 % change in induration | Standard Deviation 63.2 |
| WR279,396 With Tegaderm Dressing | Percentage Change in Induration Area From Baseline and Days 10, 20, 50 and 90 | Day 20 | 30.0 % change in induration | Standard Deviation 62 |
| WR279,396 With Tegaderm Dressing | Percentage Change in Induration Area From Baseline and Days 10, 20, 50 and 90 | Day 50 | -64.4 % change in induration | Standard Deviation 78.5 |
| WR279,396 With Tegaderm Dressing | Percentage Change in Induration Area From Baseline and Days 10, 20, 50 and 90 | Day 90 | -65.1 % change in induration | Standard Deviation 98.5 |
| WR279,396 With Gauze and Tape Dressing | Percentage Change in Induration Area From Baseline and Days 10, 20, 50 and 90 | Day 90 | -100.0 % change in induration | Standard Deviation 0 |
| WR279,396 With Gauze and Tape Dressing | Percentage Change in Induration Area From Baseline and Days 10, 20, 50 and 90 | Day 10 | 45.0 % change in induration | Standard Deviation 114.2 |
| WR279,396 With Gauze and Tape Dressing | Percentage Change in Induration Area From Baseline and Days 10, 20, 50 and 90 | Day 50 | -83.9 % change in induration | Standard Deviation 30.7 |
| WR279,396 With Gauze and Tape Dressing | Percentage Change in Induration Area From Baseline and Days 10, 20, 50 and 90 | Day 20 | 51.0 % change in induration | Standard Deviation 116.2 |