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CompletedNCT01032382Updated Jul 16, 2015Results posted

Safety, Efficacy and Pharmacokinetics (PK) Study of WR 279,396 Versus Paromomycin for Treatment of Cutaneous Leishmaniasis (Peru-PK)

A Phase 2 interventional study of WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream) and Paromomycin Alone Cream (15% paromomycin topical cream) in Leishmaniasis, Cutaneous, sponsored by U.S. Army Medical Research and Development Command. Completed at 1 site in Peru. Open to participants aged 5 Years and older. Per ClinicalTrials.gov, last updated 2015-07-16.

Sponsored by U.S. Army Medical Research and Development Command · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
30
Allocation
Randomized
Ages
5 Years and older
Sex
All
01

Study summary

The objectives of the study are to evaluate the pharmacokinetics (PK), safety, and efficacy of WR 279,396 (Paromomycin + Gentamicin Topical Cream) and Paromomycin Topical Cream in subjects with cutaneous leishmaniasis (CL).

Read the detailed description

This study is a single-site, randomized, double-blind, two group trial assessing the PK, safety and efficacy of WR 279,396 Topical Cream and Paromomycin Topical Cream in subjects with CL. Subjects will be screened over a period up to 28 days for eligibility including parasitology for confirmation of ulcerative CL. Subjects will be randomized in a targeted 1:1 ratio to receive either WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream) (target n=15) or Paromomycin Topical Cream (15% paromomycin topical cream) (target n=15) by topical application to CL lesions once daily for 20 days. Because the primary objective of this trial is to determine PK in all age groups, subjects will be stratified by age: 5-11 yrs, 12-17 yrs, and ≥ 18 yrs with at least 6 PK subjects in each age stratum and no more than 18 total subjects will be randomized in any age range. A target of 30 subjects who complete the PK part of the study is the goal. Any subject who does not complete the PK portion of the study will be replaced with another subject from the same age group that will be given the same treatment assignment to maintain the balance. Safety will be assessed by monitoring adverse events (AEs), lesion site reactions, vital signs, and blood creatinine levels. The primary efficacy analysis will be by evaluation of an index lesion with secondary efficacy analyses including all lesions. Lesions will also be examined for parasite negativity by classical means (positive culture for promastigotes or microscopic identification of amastigotes in stained lesion tissue) on Day 21.

In adult subjects, on Days 1 and 20, blood will be collected prior to topical cream application and at 0.5h, 1h, 2h, 3h, and 4h ± 5 minutes and 8h, 12h, and 24h ± 15 minutes after completion of cream application to determine plasma levels of paromomycin and gentamicin to calculate PK parameters. Thus, the last blood draw in this series will occur on Day 21. In addition, blood will be collected on Days 4, 7, 12, and 17 ± 1 day before study drug application to examine trough plasma levels of paromomycin and gentamicin. A follow-up plasma sample for PK analysis will also be obtained on Day 28 ± 2 days.

Subjects under the age of 18 years will have a total of four blood samples drawn. The first will be drawn at pre-application and the second will be drawn at 4 hours ± 5 minutes after completion of application of the topical cream on Study Day 1. The third will be drawn pre-application and the fourth at 4 hours ± 5 minutes after completion of application of the topical cream on Study Day 20. Subjects who receive Paromomycin Topical Cream are not expected to have blood levels of gentamicin, but as the study is blinded, plasma specimens will be tested for both paromomycin and gentamicin.

The index lesion (primary ulcerated) and all other ulcerated lesions will be assessed for clinical response by measurement of the length and width of area of ulceration. A lesion will be considered to be completely cured if 100% re-epithelialization is observed (i.e., this is a measurement of ulceration of 0 x 0 mm). Non-ulcerated lesions will also be measured to monitor the total area of exposure of lesions to study drug and will be evaluated for cure (i.e., absence of signs of an active lesion).

Subjects will have an in-clinic follow-up weekly (Days 28, 35, 42, 49, 56, and 63 ± 2 days) after completion of treatment for safety assessments, lesion measurements, and lesion photographs. On Day 21, index lesions in adult subjects that have not completely re-epithelialized will be assessed for parasites by classical means (positive culture for promastigotes or microscopic identification of amastigotes in stained lesion tissue). An interim analysis of all of the data collected on all subjects who were randomized and completed the nominal Day 63 follow-up will be performed to make decisions about the final design of a Phase 3 trial. Subjects will continue to be followed for outcomes at Day 100 and 168 ± 14 days. A final analysis of outcomes after the longer term followup period has been completed for all subjects will be performed when the trial is closed. Follow-up evaluations include AEs, medication use, lesion measurements, and lesion photographs.

Patients who fail therapy (see definition of failure below) may be administered rescue therapy at the discretion of the patient's personal physician.

02

Conditions studied

  • Leishmaniasis, Cutaneous

Keywords

  • leishmaniasis
  • cutaneous
  • WR 279,396
  • paromomycin
  • gentamicin
  • pharmacokinetics
  • safety
  • efficacy
03

In context

Leishmaniasis

185 studies on the registry are indexed under Leishmaniasis; 15 are open to participants now.

This study's enrollment of 30 is below the median of 80 across 133 interventional studies indexed under Leishmaniasis.

Browse Leishmaniasis studies →

Lead sponsor

U.S. Army Medical Research and Development Command is the lead sponsor of 151 studies on the registry; 8 are open to participants now.

Of its 23 completed or terminated interventional studies of FDA-regulated products, 16 (70%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
5 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • To be eligible for the study, the following must be answered "YES" or not applicable, as appropriate for the study subject:

    1. Is the subject a male or female at least 5 years-of-age?
    2. Is the subject or legal guardian able to give written informed consent or assent, as appropriate?
    3. Does the subject have a 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.
    4. Does the subject have at least one ulcerative lesion ≥ 1 cm and ≤ 5 cm, that meets the criteria for an index lesion?
    5. Is the subject willing to forego other forms of treatments for CL including other investigational treatments during the study?
    6. In the opinion of the investigator, is the subject (or their legal guardian) capable of understanding and complying with the protocol?
    7. If female and of child-bearing potential, did the subject have a negative pregnancy test during screening and agree to use an acceptable method of birth control during the treatment phase and for 1 month after treatment is completed?
    8. Does the subject have adequate venous access for blood draws?

Exclusion criteria

Exclusion Criteria:

To be eligible for the study, the following must be answered "NO" or not applicable as appropriate for the study subject:

  1. Does the subject have only a single lesion whose characteristics include any of the following: verrucous or nodular lesion (non-ulcerative), lesion \<1 cm in its greatest diameter, lesion in a location that in the opinion of the Investigator is difficult to maintain application of study drugs topically?
  2. Does the subject have a lesion due to leishmania that involves the mucosa or palate or any signs of mucosal disease that might be due to leishmania?
  3. Does the subject have signs and symptoms of disseminated disease in the opinion of the Principal Investigator?
  4. Does the subject have > 10 lesions?
  5. Is the subject a female who is breast-feeding?
  6. Does the subject have an active malignancy or history of solid, metastatic or hematologic malignancy with the exception of basal or squamous cell carcinoma of the skin that has been removed?
  7. Does the subject have significant organ abnormality, chronic disease such as diabetes, severe hearing loss, evidence of renal or hepatic dysfunction, or creatinine greater than 15%, or aspartate aminotransferase (AST), or alanine aminotransferase (ALT) greater than 1.5 times the above the upper limit of normal (ULN) as defined by the clinical laboratory defined normal ranges?
  8. Has the subject 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 8 weeks of starting study treatments?
  9. Does the subject have a history of known or suspected hypersensitivity or idiosyncratic reactions to aminoglycosides?
  10. Does the subject have any other topical disease/condition which would interfere with the objectives of this study?
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Triple (Participant, Care provider, Investigator)
Enrollment
30 participants (actual)

Study arms

  • Active comparator
    Paromomycin Alone Treatment

    Drug: Paromomycin Alone Cream (15% paromomycin topical cream)

  • Active comparator
    WR 279,396

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

Interventions

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

    topical application to CL lesions once daily for 20 days

    Also known as: Topical paromomycin/gentimicin cream

  • DrugParomomycin Alone Cream (15% paromomycin topical cream)

    topical application to CL lesions once daily for 20 days

06

What researchers measure

Primary outcomes

  1. Final Clinical Cure for Index Lesions

    Final clinical cure was defined as follows: 1. Subject has initial clinical cure (100% re-epithelialization of index lesion by nominal Day 63); OR, 2. 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, 3. Subject has no relapse of index lesion by Day 168. Relapse was defined as an index lesion meeting the criteria for initial clinical cure that had any new ulceration/nodule (\> 0 x 0 mm measurement) by nominal day 168, or an index lesion meeting the criteria for initial clinical improvement that subsequently enlarged by nominal Day 168.

    Time frame: Initial clinical cure by day 63 and no relapse by day 168

Secondary outcomes

  1. Detectable Paromomycin Plasma Levels

    Paromomycin plasma concentrations following administration of paromomycin alone or WR 279,396 in adults

    Time frame: Day 4, 7, 12, 17, 20, 28

  2. Paromomycin Plasma Concentrations in Children

    Paromomycin plasma concentrations 4 hours following administration of paromomycin alone or WR 279,396 in children

    Time frame: 0 and 4 hours on days 1 and 20

  3. Pharmacokinetic Parameter: Cmax

    Cmax of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

    Time frame: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20

  4. Pharmacokinetic Parameter: Tmax

    Pharmacokinetic Parameter: Tmax

    Time frame: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20

  5. Pharmacokinetic Parameter: Area Under the Curve (AUC)

    Area under the curve (AUC) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

    Time frame: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20

  6. Pharmacokinetic Parameter: t(1/2)

    t(1/2) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

    Time frame: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20

  7. Pharmacokinetic Parameter: Cmax/D

    Maximum observed plasma concentration divide by topical dose (Cmax/D) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

    Time frame: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20

  8. Pharmacokinetic Parameter: AUC/D

    Area under the plasma concentration-time curve over 24 hrs divided by topical dose (AUC/D) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

    Time frame: Days 1 and 20

  9. Final Clinical Cure on All Lesions Independent of Subjects

    Final clinical cure was defined as follows: 1. Subject has initial clinical cure (100% re-epithelialization of lesion by nominal Day 63); OR, 2. Subject has initial clinical improvement (\> 50% re-epithelialization of lesion by nominal Day 63 followed by 100% re-epithelialization of the lesion on or before nominal Day 100; AND, 3. Subject has no relapse of lesion by Day 168. Relapse was defined as a lesion meeting the criteria for initial clinical cure that had any new ulceration/nodule (\> 0 x 0 mm measurement) by nominal day 168, or a lesion meeting the criteria for initial clinical improvement that subsequently enlarged by nominal Day 168.

    Time frame: Initial clinical cure by day 63 and no relapse by day 168

  10. Number of Index Lesions Meeting Criteria for Clinical Cure During the Study

    Number of study participants who meet the criteria for clinical cure (100% re-epithelialization) at specified timepoints during the study.

    Time frame: Day 1, 4, 7, 12, 17, 20, 28, 35, 42, 49, 56, 63, 100, 168

07

Results

Posted Aug 22, 2014
Limitations and caveats
All randomized subjects were included in the mITT analysis. All subjects also met the criteria for the evaluable subset; therefore, no separate analysis of an evaluable subset of subjects was performed.

Participant flow

Participant flow — Overall Study
MilestoneParomomycin Alone TreatmentWR 279,396
Started1614
Completed119
Not completed55
Withdrew: Disease dissemination11
Withdrew: Treatment failure31
Withdrew: Index lesion relapse13

Outcome measures

PrimaryFinal Clinical Cure for Index Lesions

Final clinical cure was defined as follows: 1. Subject has initial clinical cure (100% re-epithelialization of index lesion by nominal Day 63); OR, 2. 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, 3. Subject has no relapse of index lesion by Day 168. Relapse was defined as an index lesion meeting the criteria for initial clinical cure that had any new ulceration/nodule (\> 0 x 0 mm measurement) by nominal day 168, or an index lesion meeting the criteria for initial clinical improvement that subsequently enlarged by nominal Day 168.

Time frame:
Initial clinical cure by day 63 and no relapse by day 168
Reported as:
Number · participants
Final Clinical Cure for Index Lesions
participantsParomomycin Alone TreatmentWR 279,396
Final Clinical Cure for Index Lesions119
SecondaryDetectable Paromomycin Plasma Levels

Paromomycin plasma concentrations following administration of paromomycin alone or WR 279,396 in adults

Time frame:
Day 4, 7, 12, 17, 20, 28
Reported as:
Mean · ng/mL
Detectable Paromomycin Plasma Levels
ng/mLParomomycin Alone TreatmentWR 279,396
Day 412.1 ± 27.037.3 ± 74.5
Day 710.3 ± 23.117.9 ± 35.8
Day 1236.2 ± 33.278.9 ± 81.6
Day 17210.0 ± 327.0162.0 ± 123.0
Day 2087.3 ± 109.0128.0 ± 58.7
Day 280 ± 00 ± 0
SecondaryParomomycin Plasma Concentrations in Children

Paromomycin plasma concentrations 4 hours following administration of paromomycin alone or WR 279,396 in children

Time frame:
0 and 4 hours on days 1 and 20
Reported as:
Mean · ng/mL
Paromomycin Plasma Concentrations in Children
ng/mLParomomycin Alone TreatmentWR 279,396
Day 1 hour 06.2 ± 20.522.1 ± 69.9
Day 1 hour 471.2 ± 88.0322.0 ± 757.0
Day 20 hour 093.8 ± 59.989.2 ± 132.0
Day 20 hour 4744.0 ± 503.01030.0 ± 1460.0
SecondaryPharmacokinetic Parameter: Cmax

Cmax of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

Time frame:
0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20
Reported as:
Mean · ng/mL
Pharmacokinetic Parameter: Cmax
ng/mLParomomycin Alone TreatmentWR 279,396
Day 1511 ± 445155.0 ± 139.0
Day 201400 ± 842882 ± 124
SecondaryPharmacokinetic Parameter: Tmax

Pharmacokinetic Parameter: Tmax

Time frame:
0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20
Reported as:
Mean · hr
Pharmacokinetic Parameter: Tmax
hrParomomycin Alone TreatmentWR 279,396
Day 12.25 ± 0.53 ± 1.73
Day 204.6 ± 3.133 ± 1.15
SecondaryPharmacokinetic Parameter: Area Under the Curve (AUC)

Area under the curve (AUC) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

Time frame:
0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20
Reported as:
Mean · ng*hr/mL
Pharmacokinetic Parameter: Area Under the Curve (AUC)
ng*hr/mLParomomycin Alone TreatmentWR 279,396
Day 13154 ± 35621228 ± 1413
Day 2013331 ± 91568955 ± 1955
SecondaryPharmacokinetic Parameter: t(1/2)

t(1/2) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

Time frame:
0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20
Reported as:
Mean · hr
Pharmacokinetic Parameter: t(1/2)
hrParomomycin Alone TreatmentWR 279,396
Day 12.55 ± 1.234.51 ± 0.06
Day 207.17 ± 3.296.81 ± 3.2
SecondaryPharmacokinetic Parameter: Cmax/D

Maximum observed plasma concentration divide by topical dose (Cmax/D) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

Time frame:
0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20
Reported as:
Mean · 1/ML
Pharmacokinetic Parameter: Cmax/D
1/MLParomomycin Alone TreatmentWR 279,396
Day 1185 ± 14445.9 ± 35.8
Day 20368 ± 196283 ± 118
SecondaryPharmacokinetic Parameter: AUC/D

Area under the plasma concentration-time curve over 24 hrs divided by topical dose (AUC/D) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama

Time frame:
Days 1 and 20
Reported as:
Mean · hr/ML
Pharmacokinetic Parameter: AUC/D
hr/MLParomomycin Alone TreatmentWR 279,396
Day 1996.7 ± 976.1340.5 ± 368.9
Day 203335 ± 14823155 ± 2151
SecondaryFinal Clinical Cure on All Lesions Independent of Subjects

Final clinical cure was defined as follows: 1. Subject has initial clinical cure (100% re-epithelialization of lesion by nominal Day 63); OR, 2. Subject has initial clinical improvement (\> 50% re-epithelialization of lesion by nominal Day 63 followed by 100% re-epithelialization of the lesion on or before nominal Day 100; AND, 3. Subject has no relapse of lesion by Day 168. Relapse was defined as a lesion meeting the criteria for initial clinical cure that had any new ulceration/nodule (\> 0 x 0 mm measurement) by nominal day 168, or a lesion meeting the criteria for initial clinical improvement that subsequently enlarged by nominal Day 168.

Time frame:
Initial clinical cure by day 63 and no relapse by day 168
Reported as:
Number · Cured ulcerated lesions
Final Clinical Cure on All Lesions Independent of Subjects
Cured ulcerated lesionsParomomycin Alone TreatmentWR 279,396
Final Clinical Cure on All Lesions Independent of Subjects1214
SecondaryNumber of Index Lesions Meeting Criteria for Clinical Cure During the Study

Number of study participants who meet the criteria for clinical cure (100% re-epithelialization) at specified timepoints during the study.

Time frame:
Day 1, 4, 7, 12, 17, 20, 28, 35, 42, 49, 56, 63, 100, 168
Reported as:
Number · Lesions meeting clinical cure criteria
Number of Index Lesions Meeting Criteria for Clinical Cure During the Study
Lesions meeting clinical cure criteriaParomomycin Alone TreatmentWR 279,396
Day 100
Day 400
Day 700
Day 1200
Day 1700
Day 2010
Day 2856
Day 35811
Day 421011
Day 491012
Day 561110
Day 631110
Day 1001210
Day 168119

Adverse events

Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Paromomycin Alone Treatment—0/16 (0%)16/16 (100%)
WR 279,396—0/14 (0%)14/14 (100%)
Most frequent other events
Showing 10 of 53
Most frequent other events
EventParomomycin Alone TreatmentWR 279,396
Application site pruritusGeneral disorders16/1614/14
Application site painGeneral disorders13/163/14
HypersensitivityImmune system disorders12/1611/14
Application site erythemaGeneral disorders12/169/14
Upper respiratory tract infectionInfections and infestations12/169/14
Application site vesiclesGeneral disorders2/166/14
Application site oedemaGeneral disorders6/165/14
HeadacheInvestigations6/164/14
NasopharyngitisInfections and infestations1/164/14
Cutaneous leishmaniasis relapseInfections and infestations2/163/14

Baseline characteristics

Age, Continuous
Age, Continuous(years)Paromomycin Alone TreatmentWR 279,396Total
Mean20.7 ± 16.218.2 ± 15.119.5 ± 15.5
Age, Customized
Age, Customized(participants)Paromomycin Alone TreatmentWR 279,396Total
Adults (18+ years)549
Children (12 to 17 years)538
Children (5 to 11 years)6713
Sex: Female, Male
Sex: Female, Male(Participants)Paromomycin Alone TreatmentWR 279,396Total
Female549
Male111021
08

Study locations

1 site
  • Universidad Peruana Cayetano Heredia (UPCH)
    Lima, Peru
09

References and documents

Publications

  • Ravis WR, Llanos-Cuentas A, Sosa N, Kreishman-Deitrick M, Kopydlowski KM, Nielsen C, Smith KS, Smith PL, Ransom JH, Lin YJ, Grogl M. Pharmacokinetics and absorption of paromomycin and gentamicin from topical creams used to treat cutaneous leishmaniasis. Antimicrob Agents Chemother. 2013 Oct;57(10):4809-15. doi: 10.1128/AAC.00628-13. Epub 2013 Jul 22. PubMed 23877689 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jul 16, 2015, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01032382
Lead sponsor
U.S. Army Medical Research and Development Command
Responsible party
Sponsor
First posted
Dec 15, 2009
Start date
Jan 2010
Primary completion
Mar 2011
Completion
Jul 2011
Results posted
Aug 22, 2014
Last update
Jul 16, 2015

Study contacts

Alejandro Llanos-Cuentas, M.D.
principal investigator · Universidad Peruana Cayetano Heredia (UPCH)

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

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