Cutaneous Leishmaniasis
Conditions
Keywords
cutaneous leishmaniasis topical treatment safety efficacy
Brief summary
This study is to determine the effectiveness and safety of WR 279,396, a topical cream for the treatment of cutaneous leishmaniasis. This study is to be conducted with a placebo control under double-blind conditions in a local population group in Tunisia where leishmaniasis is endemic.
Detailed description
WR 279,396 is a paromomycin-based topical cream that has shown some suggestion of being effective for the treatment of non-serious, non-complicated cutaneous leishmaniasis in previous clinical studies. The goal of this study is to expand those observations in a larger, more rigorous study to clearly define the efficacy of this product and collect information about adverse effects. Subjects will be randomized to receive either WR 279,396 or vehicle placebo; applied twice a day for 20 days.
Interventions
DRUGWR 279,396
A topical cream containing 15% paromomycin and 0.5% gentamicin. Approximately 0.0005 mL per mm2 of skin lesion
DRUGPlacebo
Topical cream vehicle. Approximately 0.0005 mL per mm2 of skin lesion
Sponsors
Walter Reed Army Institute of Research (WRAIR)
U.S. Army Medical Research and Development Command
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
5 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age 5-75 years * Lesions must measure at least 1 cm and be primarily ulcerative * Have cutaneous leishmaniasis proven parasitologically in the lesion selected for study * Must have given written informed consent to participate in the study
Exclusion criteria
* Known drug intolerance to aminoglycosides in the patient or immediate family * Previous use of antileishmanial drugs (within 3 months) or present use of routinely nephrotoxic or ototoxic drugs * Patients with tuberculosis under treatment * Potential for follow-up: have less than 7 months time remaining in present address and/or plan to leave the area for more than 30 days * Extent of disease: more than 5 lesions or lesion equal to or greater than 5 cm or a lesion less than 5 cm from the eye, 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 greater than 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: * Hearing abnormality * Ongoing pregnancy or have plans to become pregnant * Females of child bearing age (Tunisia Only) * Signs or symptoms of peripheral neuropathy Kidney: clinically significant abnormalities of urine analysis, serum levels of creatinine, BUN, total proteins greater than the upper limit of normal for the laboratory. Liver: AST or ALT greater than the upper limit of normal for the laboratory General: glucose, Na+, or K+ greater than the upper limit of normal for the laboratory
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Clinical Response (CCR) of Lesion at Days 50, 100 and 180 (+7 Days) | 180 days | CCR is defined as at least 50% reduction, from baseline, in index lesion area of ulceration at study days 50, 100 and 180 (+ 7 days). Randomized subjects were compared using the uncorrected Fisher's exact test. Confidence intervals (95%) were constructed on the difference between the two group proportions. The log-rank test was used to compare the time to complete re-epithelialization of the index lesion without relapse. Cure of all subjects lesions was also compared using the Fisher's exact test. To adjust for baseline differences in the treatment groups, a linear model for the proportion of subjects achieving CCR was fit for each baseline variable of interest with covariates for treatment group and the baseline variable. The Breslow-Day test was used to examine whether the effect of WR 279,396 varied between subgroups |
| Safety of WR 279,396 (AEs and SAEs) | 180 days | Safety was evaluated on each day during daily administration of the topical products. Subjects were observed and questioned for the occurrence of solicited local side effects (eg, pain, erythema, edema) and solicited systemic side effects (eg, vertigo, tinnitus, diminished hearing). Non-solicited AE evaluations included spontaneous reports from subjects and clinical observations. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Complete Re-epithelialization of the Index Lesion Ulcer Without Relapse | 180 days | 100% re-epithelialization of the index lesion without having had a relapse. The log-rank test was used to compare the time to complete re-epithelialization. |
| Final Cure Rate by Subject of All Lesions | 180 days | Final cure rate by subject was determined using the Fisher's exact test. To adjust for baseline differences in the treatment groups, a linear model for the proportion of subjects achieving CCR was fit for each baseline variable of interest with covariates for treatment group and the baseline variable. |
| Rate of Relapse | 180 days | Relapse is defined as enlargement of the index lesion compared to previous measurement at any time after day 50 (+ 7 days) or not demonstrating CCR by study day 180. CCR was compared using uncorrected Fisher's exact test. Confidence intervals (95%) were constructed on the difference between the two group proportions. The log-rank test was used to compare the time to complete re-epithelialization of the index lesion without relapse. Cure of all subjects lesions was also compared using the Fisher's exact test. To adjust for baseline differences in the treatment groups, a linear model for the proportion of subjects achieving CCR was fit for each baseline variable of interest with covariates for treatment group and the baseline variable. |
Countries
France, Tunisia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| WR 279,396 WR 279,396 is a topical antibiotic cream containing paromomycin and gentamicin
WR 279,396: A topical cream containing 15% paromomycin and 0.5% gentamicin. Approximately 0.0005 mL per mm2 of skin lesion | 50 |
| Placebo Topical cream vehicle containing all of the components in WR 279,396 except the active ingredients.
Placebo: Topical cream vehicle. Approximately 0.0005 mL per mm2 of skin lesion | 42 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | WR 279,396 | Placebo | Total |
|---|---|---|---|
| Age, Customized <18 years | 47 years | 33 years | 80 years |
| Age, Customized >18 years | 3 years | 9 years | 12 years |
| Region of Enrollment France | 5 participants | 5 participants | 10 participants |
| Region of Enrollment Tunisia | 45 participants | 37 participants | 82 participants |
| Sex: Female, Male Female | 23 Participants | 15 Participants | 38 Participants |
| Sex: Female, Male Male | 27 Participants | 27 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 50 | 12 / 42 |
| serious Total, serious adverse events | 1 / 50 | 0 / 42 |
Outcome results
Primary
Complete Clinical Response (CCR) of Lesion at Days 50, 100 and 180 (+7 Days)
CCR is defined as at least 50% reduction, from baseline, in index lesion area of ulceration at study days 50, 100 and 180 (+ 7 days). Randomized subjects were compared using the uncorrected Fisher's exact test. Confidence intervals (95%) were constructed on the difference between the two group proportions. The log-rank test was used to compare the time to complete re-epithelialization of the index lesion without relapse. Cure of all subjects lesions was also compared using the Fisher's exact test. To adjust for baseline differences in the treatment groups, a linear model for the proportion of subjects achieving CCR was fit for each baseline variable of interest with covariates for treatment group and the baseline variable. The Breslow-Day test was used to examine whether the effect of WR 279,396 varied between subgroups
Time frame: 180 days
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| WR 279,396 | Complete Clinical Response (CCR) of Lesion at Days 50, 100 and 180 (+7 Days) | CCR | 47 Participants |
| WR 279,396 | Complete Clinical Response (CCR) of Lesion at Days 50, 100 and 180 (+7 Days) | CCR Failure | 3 Participants |
| Placebo | Complete Clinical Response (CCR) of Lesion at Days 50, 100 and 180 (+7 Days) | CCR | 30 Participants |
| Placebo | Complete Clinical Response (CCR) of Lesion at Days 50, 100 and 180 (+7 Days) | CCR Failure | 12 Participants |
Primary
Safety of WR 279,396 (AEs and SAEs)
Safety was evaluated on each day during daily administration of the topical products. Subjects were observed and questioned for the occurrence of solicited local side effects (eg, pain, erythema, edema) and solicited systemic side effects (eg, vertigo, tinnitus, diminished hearing). Non-solicited AE evaluations included spontaneous reports from subjects and clinical observations.
Time frame: 180 days
Population: All solicited local and systemic AEs and SAEs including immediate and delayed reactions that occurred during this study are summarized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| WR 279,396 | Safety of WR 279,396 (AEs and SAEs) | Solicited AEs- Severe | 2 Adverse Events |
| WR 279,396 | Safety of WR 279,396 (AEs and SAEs) | Non-Solicited AEs- Moderate | 10 Adverse Events |
| WR 279,396 | Safety of WR 279,396 (AEs and SAEs) | Solicited AEs- Moderate | 11 Adverse Events |
| WR 279,396 | Safety of WR 279,396 (AEs and SAEs) | Non-Soliciated AEs- Severe | 0 Adverse Events |
| WR 279,396 | Safety of WR 279,396 (AEs and SAEs) | Non-Solicited AEs- Mild | 13 Adverse Events |
| WR 279,396 | Safety of WR 279,396 (AEs and SAEs) | SAEs | 1 Adverse Events |
| WR 279,396 | Safety of WR 279,396 (AEs and SAEs) | Solicated AEs- Mild | 49 Adverse Events |
| Placebo | Safety of WR 279,396 (AEs and SAEs) | SAEs | 0 Adverse Events |
| Placebo | Safety of WR 279,396 (AEs and SAEs) | Solicated AEs- Mild | 40 Adverse Events |
| Placebo | Safety of WR 279,396 (AEs and SAEs) | Solicited AEs- Moderate | 5 Adverse Events |
| Placebo | Safety of WR 279,396 (AEs and SAEs) | Solicited AEs- Severe | 2 Adverse Events |
| Placebo | Safety of WR 279,396 (AEs and SAEs) | Non-Solicited AEs- Mild | 20 Adverse Events |
| Placebo | Safety of WR 279,396 (AEs and SAEs) | Non-Solicited AEs- Moderate | 10 Adverse Events |
| Placebo | Safety of WR 279,396 (AEs and SAEs) | Non-Soliciated AEs- Severe | 0 Adverse Events |
Secondary
Final Cure Rate by Subject of All Lesions
Final cure rate by subject was determined using the Fisher's exact test. To adjust for baseline differences in the treatment groups, a linear model for the proportion of subjects achieving CCR was fit for each baseline variable of interest with covariates for treatment group and the baseline variable.
Time frame: 180 days
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| WR 279,396 | Final Cure Rate by Subject of All Lesions | CCR | 46 Participants |
| WR 279,396 | Final Cure Rate by Subject of All Lesions | Treatment Failure | 4 Participants |
| Placebo | Final Cure Rate by Subject of All Lesions | CCR | 29 Participants |
| Placebo | Final Cure Rate by Subject of All Lesions | Treatment Failure | 13 Participants |
Secondary
Rate of Relapse
Relapse is defined as enlargement of the index lesion compared to previous measurement at any time after day 50 (+ 7 days) or not demonstrating CCR by study day 180. CCR was compared using uncorrected Fisher's exact test. Confidence intervals (95%) were constructed on the difference between the two group proportions. The log-rank test was used to compare the time to complete re-epithelialization of the index lesion without relapse. Cure of all subjects lesions was also compared using the Fisher's exact test. To adjust for baseline differences in the treatment groups, a linear model for the proportion of subjects achieving CCR was fit for each baseline variable of interest with covariates for treatment group and the baseline variable.
Time frame: 180 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| WR 279,396 | Rate of Relapse | 0 Participants |
| Placebo | Rate of Relapse | 3 Participants |
Secondary
Time to Complete Re-epithelialization of the Index Lesion Ulcer Without Relapse
100% re-epithelialization of the index lesion without having had a relapse. The log-rank test was used to compare the time to complete re-epithelialization.
Time frame: 180 days
Population: Days to 100% re-epithelialization of index lesion. Volunteer Identification Number (VIN). VINs 17, 72, and 109 failed to meet 100% re-epithelialization
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| WR 279,396 | Time to Complete Re-epithelialization of the Index Lesion Ulcer Without Relapse | WR 279,396 | 10 Participants |
| WR 279,396 | Time to Complete Re-epithelialization of the Index Lesion Ulcer Without Relapse | Placebo | 20 Participants |
| Placebo | Time to Complete Re-epithelialization of the Index Lesion Ulcer Without Relapse | Placebo | 10 Participants |
| Placebo | Time to Complete Re-epithelialization of the Index Lesion Ulcer Without Relapse | WR 279,396 | 34 Participants |
| Day 100 | Time to Complete Re-epithelialization of the Index Lesion Ulcer Without Relapse | WR 279,396 | 4 Participants |
| Day 100 | Time to Complete Re-epithelialization of the Index Lesion Ulcer Without Relapse | Placebo | 9 Participants |
| Day 180 (+7 Days) | Time to Complete Re-epithelialization of the Index Lesion Ulcer Without Relapse | WR 279,396 | 1 Participants |
| Day 180 (+7 Days) | Time to Complete Re-epithelialization of the Index Lesion Ulcer Without Relapse | Placebo | 1 Participants |