Miltefosine Combined With Intralesional Pentamidine for Leishmania Braziliensis Cutaneous Leishmaniasis in Bolivia
Phase: PHASE2
Conditions: Leishmaniasis, Cutaneous
Sponsor: Jonathan Berman

ORAL MILETOSINE plus INTRALESIONAL PENTAMIDINE 
FOR BOLIVIAN CUTANEOUS LEISHMANIASIS 
 
 
1. Introduction  
 
1.1 
Background 
 
Cutaneous leishmaniasis (CL) is endemic in the New World from approximately 
the US-Mexican border through Central America and the Northern part of South America 
down to the level of Rio de Janeiro.  
The cure rate for New World CL is only approximately 70% for all recognized 
therapies.  For systemic therapy with the classic agent pentavalent antimony, recent cure 
rates of New World CL are 50% to 75% [1-5]. For the new oral agent miltefosine in 3 of 
these studies, the cure rate was 57-75% [2-4]. CL can also be treated locally. For 
intralesional (IL) antimony, cure rates are reported as 56-75% for Iranian CL [6-7], 80-
83% for L braziliensis in Brazil [8-9], and most recently 70% for L braziliensis in Bolivia 
when the concomitant placebo cure rate was 18% [10].  
A novel approach was to evaluate intralesional pentamidine for Bolivian CL. The 
rationale for IL pentamidine is that little drug is administered via intralesional injection, 
thus the toxicity of systemic pentamidine would be unlikely to be seen. For Bolivian CL, 
3-injections of IL Pentamidine over 5 days cured 72% of patients whereas 3-injections of 
IL antimony over 5 days cured 57% [manuscript submitted].  Adverse effects were local 
irritation and injection site pain: IL pentamidine (30 patients)—mild (4 patients), 
moderate (3); IL antimony (60 patients)—mild (25 patients), moderate (4). No 
pentamidine patient experienced the side effects of systemic pentamidine administration: 
sterile abscess, hypotension, or hypoglycemia. We concluded that IL pentamidine is an 
attractive alternative to standard intralesional antimony for Bolivian Leishmania 
braziliensis on the basis of efficacy, the threat of antimony-resistant parasites, tolerance, 
and patient convenience of 3 visits over 5 days.   
 
1.2 
Rationale  
 
Although patients can be treated with one of these agent with the anticipation of 
an approximately 70% cure rate, and failures of the first treatment could then be treated 
with another agent, an initial cure rate > 70% would be desirable.  
We propose to evaluate oral miltefosine plus intralesional pentamidine for 
Bolivian CL. Efficacy should be additive, since the postulated mechanisms of the drugs is 
different. The structure of miltefosine is similar to that of  phosphotidylcholine, and may 
interfere with phosphatidylcholine biosynthesis or function[11]. In contrast, it is thought 
that pentamidine interferes with polyamine biosynthesis [12]. The advantage of the 
combination of oral miltefosine and IL pentamidine vs other possible drug combinations 
is that the systemic partner is oral rather than parenteral, and that the intralesional partner 
is the most active of the IL agents that we have found in Bolivia.The combination should 
be well tolerated, since the local side effects of pentamidine would not interact with the 
systemic gastrointestinal side effects of miltefosine. Finally, this combination would be 

convenient, since intralesional injections of pentamidine would occur on days 1, 3, and 5 
of the standard 28-day miltefosine treatment course when patients are already under 
medical care. 
 
 
 

2.0 Study Aims and design 
 
2.1 Aim:  
 
The primary purpose of this study is to evaluate the cure rate of a standard course 
of oral miltefosine in combination with intralesional pentamidine for single lesions 
predominately due to L braziliensis in Bolivia. 
 
A secondary purpose is to determine the tolerance of this regimen. 
 
2.2 Design: 
 
 
Open label evaluation of miltefosine (28 days) plus intralesional pentamidine 
(days 1, 3, 5).  
 
After treatment, all patients will be followed for 1, 3, and 6 months. 
 
The initial number of patients will be 30.  
 
 
3.0 Experimental Plan 
 
3.1 Site 
 
Catchment area: Nor Yungas, Departamento de La Paz  Bolivia 
Treatment site: Hospital Local Palos Blancos Bolivia. The patients will be in 
residence at the treatment site during treatment.  
 
3.2 Study Population (inclusion and exclusion criteria) 
 
Gender: 
Male or female 
Age: 
 
>12 yrs of age 
Presentation: 1 ulcerative lesion, < 30 mm in largest diameter, and with a total 
lesion area <900 mm2.  
Parasitology:  Parasitological confirmation of the lesion will be made by 
visualization or culture of leishmania from the biopsy or aspirate of 
the lesion.   
Previous treatment for leishmaniasis:  
No specific or putatively specific therapy (Sb, pentamidine, 
amphotericin B, miltefosine, imidazoles, allopurinol) in the last 3 
months 
Other diseases: No concomitant diseases by history that would be likely in the 
PI’s opinion to interact, either positively or negatively, with 
treatment. 

 
3.3 Study treatments 
 
 
3.3.1 Miltefosine 
 
Miltefosine will be administered daily for 28 days as per the US Product Label: 
 
“Administer with food to ameliorate gastrointestinal adverse reactions. 
• 30 to 44 kg: one 50 mg capsule twice daily for 28 consecutive days. 
• 45 kg or greater: one 50 mg capsule three times daily for 28 consecutive 
days.” 
 
 
3.3.2 IL pentamidine 
 
  
IL pentamidine [Pentacarinat® Sanofi-Aventis: 30 mg/ml] will administered at a 
dose of 120 ug (4 ul) per mm2 of lesion area 3 times (on days 1, 3, and 5) as per our 
previous experience. 
A small button of Xylocaine® will be applied by means of a thin needle at the 
four cardinal points of the lesion and then a small gauge (23g) needle will introduce the 
drug in each cardinal point. The needle will be moved in all directions to infiltrate of 
whole lesion and surrounding infiltrated area.  
 
 
3.3.3 Pretreatment 
If bacterial superinfection appears to be present, the lesions will receive topical 
fusidic acid and/or oral dicloxacillin during 7 days previous to the first day of leishmania 
treatment. Initial size will be measured after the antibacterial treatment. 
 
3.4 Efficacy evaluation 
 
 
For each lesion, the size of its ulcer will be measured at 1 month, 3 months, and 6 
months after the end of therapy.  
 
3.5 Adverse events recording 
 
Re Miltefosine: Adverse events especially gastrointestinal will be recorded. 
 
 
Re IL pentamidine: Patients will be evaluated for local side effects (pain, itching, 
irritation (erythema/edema), vesicles/bullae, sterile abscesses)  and the possibility of 
bacterial superinfection both local and disseminated to the draining lymph nodes on each 
day that therapy is applied.  Any other subjective complaint spontaneously referred by the 
patient will be registered and evaluated. 
 
In addition, pentamidine patients will be evaluated for hypoglycemia. 
 
 
 
 

 
 
 
 
3.6 Procedural Timetable  
 
Action 
Day 0 
Day 1 
Day28 
1 M 
3 M 
6M 
 
 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
Hx /PE 
X 
 
   X 
X 
  X 
  X 
Parasitology 
X  
 
 
 
 
 
   (aspirate:smear/cult) 
 
 
 
 
 
 
Evaluate lesion 
X 
    X 
   X 
X 
  X 
  X 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
Oral Miltefosine 
     
    day 1 to day 28 
 
 
 
IL pentamidine 
     
days 1, 3, 5 
 
 
 
 
 
 
 
 
 
 
Adverse events (esp. GI)  
X 
day 1  
to day 28 
 
 
 
Blood Glucose 
X 
weeks 2 
and 4 
 
 
 
AST 
X 
weeks 2 and 4 
 
 
 
Creatinine 
X 
weeks 2 and 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Day 0” includes the screening period. 
 
 
 
 
 
 
 3.7 Efficacy response criteria (cure and failure) 
 
  
A lesion will be defined as a treatment failure if: 
- enlarges by 50% by 1 month after therapy 
-does not diminish by 50% at 3 months after therapy 
-does not completely reepithelialize by 6 months after the end of therapy.   
-relapses (enlarges substantially---approximately 25%) after previously 
diminishing in size  
-new lesion from which Leishmania can be demonstrated  
 
Cure will be defined as complete healing of all lesions by 6 months after the end of 
therapy.  
Thus for a patient to be cured: no lesion could enlarge by 50%, relapse, or heal 
incompletely; and no new Leishmania-positive lesion can have appeared.   
 
 
3.8  
Early withdrawal from study 
 

 
- If a lesion fails.  
 
- If the physician or patient otherwise thinks it advisable. 
 
3.8.1 Treatment of withdrawn patients 
 
 
Withdrawn patients will be treated off-protocol with best available measures as 
determined by the patient’s personal physician. 
 
3.9 Additional patients 
 
 
After 30 patients have been evaluated, the cure rate and tolerance of the regimen 
will be analyzed. If the cure rate is close to 90%, further patients may be enrolled to 
better ascertain the cure rate of this regimen. 
 
 
4.0 Data analysis 
 
4.1  Primary outcome variable (cure) 
       
Cure vs failure will be computed using the chi-square test or Fischer’s exact test. 
 
4.2 Tolerance 
Side effects will be described by descriptive statistics and analyzed by T-test. 
 
 
5.0 Investigators and Study controls 
 
5.1 
PI 
 
Dr Jaime Soto.  Dr Soto is overall in charge of the investigation. 
 
5.2  
Co-PIs  
Dr. ANA VARGAS (MD, responsible of clinical control and follow up and 
pentamidine administration) 
DR. ROLO PARRA (DO, responsible of clinical control and follow up) 
LIC. RUTH ESCOVAR (RN, responsible of daily administration of miltefosine 
and follow up during treatment period and during f-u visits. She will also be responsible 
to maintain contact with patients to avoid losses).  
5.3  
Associate Investigators 
Dr Jonathan Berman will provide consultative advice on cutaneous leishmaniasis 
 
5.4 
Data handling 
Dr Soto will devise CRFs, and check CRF data vs source data. Given the 
relatively low numbers of patients and relatively small numbers of data points, each entry 
in the CRF can be checked against the source data (2-person method). 
 
5.5  
 Ethical review 

 
The protocol will be approved by the responsible ethical committee as an 
extension of the IL pentostam/ IL pentamidine protocol. 
 
The protocol will be listed on www.ClinicalTrials. Gov.  
 

6.0 References 
 
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