Cutaneous Leishmaniasis
Conditions
Keywords
leishmaniasis, cutaneous leishmaniasis, Leishmania panamensis, L panamensis, Paromomycin, Paromomycin/Gentamicin
Brief summary
This study is a pivotal Phase 3, randomized, double-blind, 3-site, two-group trial assessing the efficacy and safety of WR 279,396 Topical Cream and Paromomycin Alone Topical Cream in subjects with CL in Panama. The primary objective of this study is to determine if WR 279,396 results in statistically superior final clinical cure rates of an index lesion when compared with Paromomycin Alone for the treatment of CL in Panama expected to be caused by L panamensis.
Detailed description
Subjects will be recruited from three regions in Panama known to be endemic for L panamensis CL. Subjects will be screened over a period up to 28 days for eligibility including medical history, physical examination, leishmaniasis history, vital signs, clinical chemistry, prior medications, and parasitology for confirmation of ulcerative CL. If eligible, subjects will be randomized in a targeted 1:1 ratio (200 subjects per group) using site as a stratification variable to receive either WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream) or Paromomycin Alone (15% paromomycin topical cream) by topical application to CL lesions once daily for 20 days. Efficacy will be assessed by measuring the size of the index lesion ulcer, non-index lesions ulcers, and overall size of other non-ulcerated lesions at baseline (before the start of treatment), and on Study Days 20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days. A notation will be made if clinical evidence of parasite persistence is observed at the Day 63 and beyond visits including significant erythema and induration when a lesion has otherwise completely re-epithelialized to document any subjects removed from the study early if the investigator judges them to be in need of rescue treatment. A photograph will be taken of all lesions at baseline, Day 20 and each of the follow-up visits. Safety will be assessed by monitoring adverse events (AEs) from the start of treatment until study completion, lesion site reactions during treatment, physical examination of the nasal and oral mucosa for appearance of mucosal leishmaniasis on Days 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days, concomitant medication use for the duration of the study, blood creatinine, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels on Study Day 20. After the sponsor's approval, biochemistry can be repeated in the case of abnormal results and if the causes of these results could not be determined. A repeat pregnancy test on Day 35. Recent infection with leishmaniasis prior to the start of the study may result in the development of lesions that were not present at the start of the study that did not receive treatment. New lesions may be treated at the discretion of the investigator with the topical cream to which the subject was assigned any time during the conduct of the study except that treatment must be completed by the Day 168 visit. If a new lesion is discovered at the final study visit, the subject will be referred to their primary physician for treatment. Subjects who fail therapy (see definition of failure below) will be taken off study and may be administered rescue therapy at the discretion of the subject's personal physician. If the subject met the criteria for therapy failure but was undergoing treatment for new lesions, the subject can continue in the study (by signing a consent addendum) if the investigator decides it is in the best interest of the subject to do so.
Interventions
DRUGWR 279,396
WR 279,396 is a topical cream of paromomycin 15% and gentamicin 0.5%
DRUGParomomycin
Paromomycin alone
Sponsors
U.S. Army Medical Research and Development Command
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female at least 2 years-of-age * Subject or legal guardian able to give written informed consent or assent, as appropriate * Diagnosis of CL in at least one lesion by at least one of the following methods: 1) positive culture for promastigotes or 2) microscopic identification of amastigotes in stained lesion tissue * At least one ulcerative lesion ≥ 1 cm and ≤ 5 cm that has a diagnosis of CL * Willing to forego other forms of treatments for CL including other investigational treatments during the study * In the opinion of the investigator, subject (or their legal guardian), subject is capable of understanding and complying with the protocol * If female and of child-bearing potential, must have a negative serum pregnancy test during screening and agree to use an acceptable method of birth control during the treatment phase and for 1 week after treatment is completed
Exclusion criteria
* Lesion due to leishmania that involves the nasal or oral mucosa or any signs of mucosal disease that might be due to Leishmania * Only a single lesion on the ear with erosive cartilage * Signs and symptoms of disseminated disease in the opinion of the investigator * More than 10 lesions * Female who is breast-feeding * Significant organ abnormality, chronic disease such as diabetes, severe hearing loss, evidence of renal or hepatic dysfunction, or creatinine, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) greater than 15% above the upper limit of normal (ULN) as defined by the clinical laboratory defined normal ranges * Received treatment for leishmaniasis including any medication with pentavalent antimony including sodium stibogluconate (Pentostam™), meglumine antimoniate (Glucantime™); amphotericin B (including liposomal amphotericin B and amphotericin B deoxycholate); or other medications containing paromomycin (administered parenterally or topically) or methylbenzethonium chloride (MBCL); gentamicin; fluconazole; ketoconazole; pentamidine; miltefosine, azithromycin or allopurinol that was completed within 56 days of starting study treatments * History of known or suspected hypersensitivity or idiosyncratic reactions to aminoglycosides
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Final Clinical Cure | baseline (before the start of treatment), and on Study Days 20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days | The primary efficacy endpoint is percent of subjects with final clinical cure. Final clinical cure is defined as follows: * Subject has initial clinical cure (100% re-epithelialization of index lesion by nominal Day 63); OR, * Subject has initial clinical improvement (\> 50% re-epithelialization of index lesion by nominal Day 63) followed by 100% re-epithelialization of the index lesion on or before nominal Day 100; AND, * Subject has no relapse of index lesion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With All Lesions Cured | 100 ± 14 days | • Percentage of subjects with all lesions cured, defined as: Final clinical cure as defined in primary objective (which is based solely on the index lesion); AND, Cure of all other lesions by nominal Day 100 (100% re-epithelialization of all ulcerated lesions and resolution of all other types of lesions) |
| Percentage of All Lesions Cured at Day 168 (Ignores Per Subject Cure Rate) | Day 168 | Percentage of all lesions meeting criteria for clinical cure during the study at 168 day mark for mITT subjects |
| Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | baseline (before the start of treatment), and on Study Days 20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days | Area of ulceration (mm\^2) of the index lesion at each measurement time point for mITT subjects |
| Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | baseline (before the start of treatment), and on Study Days 20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days | Area of ulceration (mm\^2) of all treated lesions from baseline (before the start of treatment), and on Study Days 20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days for mITT subjects. Data presented is as presented in the Final Clinical Study Report; any inconsistencies can't be changed. |
| Median Time to Initial Clinical Cure for Index Lesions | When 100% re-epithelialization of the index lesion is observed at any visit Study Days (20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days | Median time to initial clinical cure for index lesions (100% re-epithelialization of the index lesion) |
Countries
Panama
Participant flow
Recruitment details
Subjects were recruited from three regions in Panama. Subjects were screened over a 28 day period.
Participants by arm
| Arm | Count |
|---|---|
| WR 279,396 (Paromomycin and Gentamicin Topical Cream)
WR 279,396: WR 279,396 is a topical cream of paromomycin 15% and gentamicin 0.5% | 201 |
| Paromomycin Paromomycin alone
Paromomycin: Paromomycin alone | 198 |
| Total | 399 |
Baseline characteristics
| Characteristic | WR 279,396 | Paromomycin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 96 Participants | 88 Participants | 184 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 105 Participants | 110 Participants | 215 Participants |
| Age, Continuous | 22.9 years STANDARD_DEVIATION 16.8 | 23.6 years STANDARD_DEVIATION 15.1 | 23.2 years STANDARD_DEVIATION 16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 201 Participants | 196 Participants | 397 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Length of time between initial presence current lesions and treatment | 59.7 Days STANDARD_DEVIATION 53.6 | 62.1 Days STANDARD_DEVIATION 57.7 | 60.9 Days STANDARD_DEVIATION 55.6 |
| Lesion sizes | 120 mm STANDARD_DEVIATION 146 | 121 mm STANDARD_DEVIATION 152 | 120 mm STANDARD_DEVIATION 149 |
| Number of baseline lesions | 2.27 Lesions STANDARD_DEVIATION 1.71 | 2.13 Lesions STANDARD_DEVIATION 1.63 | 2.20 Lesions STANDARD_DEVIATION 1.67 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 198 Participants | 192 Participants | 390 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 6 Participants | 9 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 76 Participants | 73 Participants | 149 Participants |
| Sex: Female, Male Male | 125 Participants | 125 Participants | 250 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 201 | 0 / 198 |
| other Total, other adverse events | 201 / 201 | 198 / 198 |
| serious Total, serious adverse events | 2 / 201 | 1 / 198 |
Outcome results
Primary
Percent of Participants With Final Clinical Cure
The primary efficacy endpoint is percent of subjects with final clinical cure. Final clinical cure is defined as follows: * Subject has initial clinical cure (100% re-epithelialization of index lesion by nominal Day 63); OR, * Subject has initial clinical improvement (\> 50% re-epithelialization of index lesion by nominal Day 63) followed by 100% re-epithelialization of the index lesion on or before nominal Day 100; AND, * Subject has no relapse of index lesion.
Time frame: baseline (before the start of treatment), and on Study Days 20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days
Population: MITT subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| WR 279,396 | Percent of Participants With Final Clinical Cure | 78.6 percent of participants |
| Paromomycin | Percent of Participants With Final Clinical Cure | 77.8 percent of participants |
Secondary
Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point
Area of ulceration (mm\^2) of all treated lesions from baseline (before the start of treatment), and on Study Days 20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days for mITT subjects. Data presented is as presented in the Final Clinical Study Report; any inconsistencies can't be changed.
Time frame: baseline (before the start of treatment), and on Study Days 20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days
Population: All lesions for mITT Subjects
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WR 279,396 | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Change from baseline Day 100 | -113 mm^2 | Standard Deviation 166 |
| WR 279,396 | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Day 1 | 115 mm^2 | Standard Deviation 152 |
| WR 279,396 | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Day 20 | 656 mm^2 | Standard Deviation 683 |
| WR 279,396 | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Change from baseline Day 20 | 533 mm^2 | Standard Deviation 632 |
| WR 279,396 | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Day 35 | 53.0 mm^2 | Standard Deviation 132 |
| WR 279,396 | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Change from baseline Day 35 | -62.8 mm^2 | Standard Deviation 167 |
| WR 279,396 | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Day 49 | 21.4 mm^2 | Standard Deviation 76.8 |
| WR 279,396 | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Change from baseline Day 49 | -93.8 mm^2 | Standard Deviation 160 |
| WR 279,396 | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Day 63 | 19.9 mm^2 | Standard Deviation 94.6 |
| WR 279,396 | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Change from baseline Day 63 | -96.2 mm^2 | Standard Deviation 170 |
| WR 279,396 | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Day 100 | 7.49 mm^2 | Standard Deviation 58.8 |
| WR 279,396 | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Day 168 | 9.14 mm^2 | Standard Deviation 87.7 |
| WR 279,396 | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Change from baseline Day 168 | -118 mm^2 | Standard Deviation 182 |
| Paromomycin | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Day 100 | 4.64 mm^2 | Standard Deviation 42.8 |
| Paromomycin | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Change from baseline Day 49 | -92.1 mm^2 | Standard Deviation 132 |
| Paromomycin | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Day 1 | 115 mm^2 | Standard Deviation 149 |
| Paromomycin | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Change from baseline Day 100 | -109 mm^2 | Standard Deviation 143 |
| Paromomycin | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Day 20 | 699 mm^2 | Standard Deviation 897 |
| Paromomycin | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Day 63 | 15.8 mm^2 | Standard Deviation 82.3 |
| Paromomycin | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Change from baseline Day 20 | 577 mm^2 | Standard Deviation 829 |
| Paromomycin | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Change from baseline Day 168 | -114 mm^2 | Standard Deviation 147 |
| Paromomycin | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Day 35 | 66.1 mm^2 | Standard Deviation 159 |
| Paromomycin | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Change from baseline Day 63 | -98.7 mm^2 | Standard Deviation 142 |
| Paromomycin | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Change from baseline Day 35 | -51.9 mm^2 | Standard Deviation 146 |
| Paromomycin | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Day 168 | 0.83 mm^2 | Standard Deviation 7.23 |
| Paromomycin | Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point | Day 49 | 23.9 mm^2 | Standard Deviation 88.2 |
Secondary
Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point
Area of ulceration (mm\^2) of the index lesion at each measurement time point for mITT subjects
Time frame: baseline (before the start of treatment), and on Study Days 20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days
Population: mITT subjects
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| WR 279,396 | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Change from baseline Day 20 | 677 mm^2 | Standard Deviation 602 |
| WR 279,396 | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Day 63 | 29.9 mm^2 | Standard Deviation 119 |
| WR 279,396 | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Change from baseline Day 35 | -84.1 mm^2 | Standard Deviation 156 |
| WR 279,396 | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Change from baseline Day 63 | -123 mm^2 | Standard Deviation 167 |
| WR 279,396 | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Day 20 | 831 mm^2 | Standard Deviation 627 |
| WR 279,396 | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Day 100 | 12.5 mm^2 | Standard Deviation 85.9 |
| WR 279,396 | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Day 49 | 29.4 mm^2 | Standard Deviation 87.2 |
| WR 279,396 | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Change from baseline Day 100 | -144 mm^2 | Standard Deviation 163 |
| WR 279,396 | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Day 35 | 68.3 mm^2 | Standard Deviation 138 |
| WR 279,396 | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Day 168 | 13.3 mm^2 | Standard Deviation 111 |
| WR 279,396 | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Change from baseline Day 49 | -123 mm^2 | Standard Deviation 144 |
| WR 279,396 | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Change from baseline Day 168 | -147 mm^2 | Standard Deviation 171 |
| WR 279,396 | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Day 1 | 153 mm^2 | Standard Deviation 137 |
| Paromomycin | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Change from baseline Day 168 | -160 mm^2 | Standard Deviation 161 |
| Paromomycin | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Day 1 | 165 mm^2 | Standard Deviation 167 |
| Paromomycin | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Day 20 | 928 mm^2 | Standard Deviation 986 |
| Paromomycin | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Change from baseline Day 20 | 762 mm^2 | Standard Deviation 933 |
| Paromomycin | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Day 35 | 96.1 mm^2 | Standard Deviation 188 |
| Paromomycin | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Change from baseline Day 35 | -69.9 mm^2 | Standard Deviation 172 |
| Paromomycin | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Day 49 | 33.9 mm^2 | Standard Deviation 100 |
| Paromomycin | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Change from baseline Day 49 | -132 mm^2 | Standard Deviation 157 |
| Paromomycin | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Day 63 | 27.6 mm^2 | Standard Deviation 107 |
| Paromomycin | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Change from baseline Day 63 | -136 mm^2 | Standard Deviation 171 |
| Paromomycin | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Day 100 | 7.41 mm^2 | Standard Deviation 56.9 |
| Paromomycin | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Change from baseline Day 100 | -152 mm^2 | Standard Deviation 165 |
| Paromomycin | Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point | Day 168 | 1.37 mm^2 | Standard Deviation 9.89 |
Secondary
Median Time to Initial Clinical Cure for Index Lesions
Median time to initial clinical cure for index lesions (100% re-epithelialization of the index lesion)
Time frame: When 100% re-epithelialization of the index lesion is observed at any visit Study Days (20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days
Population: MITT subjects
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| WR 279,396 | Median Time to Initial Clinical Cure for Index Lesions | 36.000 Days |
| Paromomycin | Median Time to Initial Clinical Cure for Index Lesions | 48.000 Days |
Secondary
Percentage of All Lesions Cured at Day 168 (Ignores Per Subject Cure Rate)
Percentage of all lesions meeting criteria for clinical cure during the study at 168 day mark for mITT subjects
Time frame: Day 168
Population: Cure rates of all lesions over time without regard to subject for mITT subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| WR 279,396 | Percentage of All Lesions Cured at Day 168 (Ignores Per Subject Cure Rate) | 77.2 percentage of lesions |
| Paromomycin | Percentage of All Lesions Cured at Day 168 (Ignores Per Subject Cure Rate) | 83.3 percentage of lesions |
Secondary
Percentage of Subjects With All Lesions Cured
• Percentage of subjects with all lesions cured, defined as: Final clinical cure as defined in primary objective (which is based solely on the index lesion); AND, Cure of all other lesions by nominal Day 100 (100% re-epithelialization of all ulcerated lesions and resolution of all other types of lesions)
Time frame: 100 ± 14 days
Population: MITT subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| WR 279,396 | Percentage of Subjects With All Lesions Cured | 75.1 percentage of participants |
| Paromomycin | Percentage of Subjects With All Lesions Cured | 76.3 percentage of participants |