Combination Therapy in Indian Visceral Leishmaniasis

Study Overview
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Brief Summary
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Rationale The overall objective of this trial is to identify a safe and effective combination, (co-administration) short course treatment for the treatment of VL which could be easily deployed in a control programme. The hypothesis is that the combination treatment is as effective or better than the 5 mg/kg single dose of AmBisome and will reduce the risk of parasite resistance occurring. Safety and tolerability should be such that the combination can be easily deployed. Objective The specific primary and secondary objectives are as follows: Primary objective: To identify a short course combination treatment regimen which is at least as effective as a single dose of AmBisome 5mg/kg Secondary objective: To compare safety and tolerability of the various treatments measured by vital signs, blood biochemistry, (renal and liver function tests) haematology, spontaneous and elicited adverse event reporting Primary Endpoint: The primary efficacy endpoint variable is parasitological clearance 2 weeks after start of treatment with no relapse during follow up and no clinical signs or symptoms of VL at 6 months post treatment. Parasitology is only carried out at any time during follow-up or at six months post treatment if there are signs or symptoms of VL infection.

Official Title
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A Randomised, Open-label, Parallel-group, Safety and Efficacy Study to Evaluate Different Combination Treatment Regimens (Co-administration), of AmBisome, Paromomycin and Miltefosine in Visceral Leishmaniasis (VL)

Conditions
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Leishmaniasis, Visceral

Intervention / Treatment
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* Drug: amphotericin B deoxycholate
* Drug: Liposomal Amphotericin B with Miltefosine
* Drug: Liposomal Amphotericin B and Paromomycin Sulfate
* Drug: miltefosine + Paromomycin sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients > 5 years old with symptoms and signs of kala-azar (fever, weight loss, splenomegaly) and parasites demonstrated by microscopy in splenic aspirate smear Exclusion Criteria: Pregnant or breast-feeding women Individuals seropositive to HIV or individuals with a serious concurrent infection such as tuberculosis or bacterial pneumonia. Women of child-bearing age will be counseled about adequate birth control during and for three months after miltefosine treatment and provided with a satisfactory method of contra-ception. Granulocyte count < 1,000/mm3, hemoglobin < 5 g/dL or platelet count < 40,000/mm3 Hepatic transaminases or total bilirubin greater than three times normal Serum creatinine > 2.0 mg/dL Prothrombin time > 5 seconds above control Inability of subject or guardian to provide written informed consent

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>AmBisome 5 mg/kg iv infusion over 2 h x 1 day (single dose) + oral miltefosine 50mg once daily (< 25 kg body weight) or twice daily ( > 25 kg body weight) or 2.5 mg/kg for children under 12 years, for 7 days on day 2-8 | Drug: Liposomal Amphotericin B with Miltefosine<br>* Liposomal Amphotericin B 5 mg Miltefosine 50 mg twice daily if patient weighs equal to or > 25 kg Miltefosine 50 mg once daily if patient weighs <25 mg<br>|
| Experimental: B<br>AmBisome 5mg/kg iv infusion over 2 h x 1 day (single dose) + paromomycin sulfate 15 mg/kg/day i.m for 10 days, on day 2-11 | Drug: Liposomal Amphotericin B and Paromomycin Sulfate<br>* AmBisome 5mg/kg iv infusion over 2 h x 1 day (single dose) + paromomycin sulfate 15 mg/kg/day i.m for 10 days, on day 2-11<br>|
| Experimental: C<br>oral miltefosine 50mg once daily (< 25 kg body weight) or twice daily ( > 25 kg body weight) or 2.5 mg/kg for children under 12 years, for 10 days + Paromomycin sulfate 15 mg/kg/day im. for 10 days | Drug: miltefosine + Paromomycin sulfate<br>* oral miltefosine 50mg once daily (< 25 kg body weight) or twice daily ( > 25 kg body weight) or 2.5 mg/kg for children under 12 years, for 10 days + Paromomycin sulfate 15 mg/kg/day im. for 10 days<br>|
| Active Comparator: D<br>amphotericin B deoxycholate at 1 mg/kg every other day for 15 infusions | Drug: amphotericin B deoxycholate<br>* Amphotericin B deoxycholate 1 mg/kg on alternate days for 15 infusions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Final cure at six month follow up |  | 18 months | 
| Cure at six month follow up |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Initial cure at the end of treatment |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kala-azar, miltefosine, liposomal amphotericin B