Safety and Efficacy Study to Evaluate Different Combination Treatment Regimens for Visceral Leishmaniasis

Study Overview
=================
Brief Summary
-----------------
The overall objective of this trial is to identify a safe and effective combination, (coadministration) short course treatment for the treatment of visceral leishmaniasis which could be easily deployed in a control programme and will reduce the risk of parasite resistance occurring. Safety and tolerability should be such that the combination can be easily deployed.

Detailed Description
-----------------
New, effective, less toxic and simplified treatments are urgently needed to replace or complement the few currently available drugs to treat visceral Leishmaniasis. An interim strategy and one which will slow the emergence of resistant parasite strains is to use coadministration of currently available drugs. In India, first line treatment is now amphotericin B which is administered as an intravenous infusion, on alternate days over a 4 week period. A liposomal formulation of amphotericin B, AmBisome, is also available, and is substantially less nephrotoxic than amphotericin B, but is expensive. It is acknowledged that AmBisome is the most effective therapy for visceral leishmaniasis, but it's high cost has hampered implementation. Use as part of a combination treatment, potentially as a single, lower dose, could reduce treatment costs considerably and thereby increase access for patients. Two new treatments have recently been licensed in India for the treatment of patients with VL, Paromomycin administered as an intramuscular injection, once daily for 21 days Miltefosine administered as an oral tablet, once daily for 28 days. These drugs are now being used as monotherapy with high risk of emergence of resistant parasites. With price reduction for AmBisome, preferential pricing for Miltefosine and the concern for emergence of resistant parasites due to monotherapy, it is time to move rapidly toward obtaining definitive data for making recommendations on combination therapy as soon as possible, before these valuable drugs become useless. The present protocol will be a definitive Phase-III trial with the aim that at the end of this trial, strong evidence-based recommendations on combination therapy with available drugs can be made to Authorities in the Indian sub-continent. This protocol will evaluate various combinations of the three drugs; AmBisome, Paromomycin and Miltefosine at reduced total dosage and in shorter courses, against the present standard treatment with amphotericin B deoxycholate.

Official Title
-----------------
Randomized, Open-label, Parallel-group, Safety & Efficacy Study to Evaluate Different Combination Treatment Regimens, of Either AmBisome and Paromomycin, AmBisome and Miltefosine, or Paromomycin and Miltefosine Compared With Amphotericin B Deoxycholate (the Standard) Therapy for the Treatment of Acute, Symptomatic Visceral Leishmaniasis (VL).

Conditions
-----------------
Visceral Leishmaniasis

Intervention / Treatment
-----------------
* Drug: Amphotericin B Deoxycholate
* Drug: Ambisome + Miltefosine
* Drug: Ambisome and Paromomycin
* Drug: Miltefosine and Paromomycin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults ( male or female) 18-60 years of age Acute, symptomatic, non-severe (minimum Hb.5 gm/dL) VL proven by parasitological examination of splenic or bone marrow aspirate. History of fever. Living within reachable distance of the trial site to enable attendance for follow-up visits Written informed consent to participate Proven HIV negative status Women of child-bearing potential who are using an assured method of contraception Exclusion Criteria: Signs/symptoms indicative of severe VL ( Hb.< 5gm/dl, evidence of cardiac failure, etc) Patients who have received anti-leishmanial or anti-fungal treatment within the last 45 days Patients who have received any investigational (unlicensed) drugs within the last 6 months Severe malnutrition BMI<15 in adults, weight for height less than 60% in children. Chronic underlying disease such as severe cardiac, renal, or hepatic impairment. Renal function tests (serum creatinine) outside the normal range Liver function tests (transaminases) more than three times the upper limit of the normal range at study entry Jaundice (bilirubin >2.0mg/dL) Known hepatitis B or C positive Platelet count less than 40,000/mm3 Prothrombin time 5 seconds or greater than normal range TotalWBC < 1,000/mm3 Known alcohol or other drug abuse HIV positive status Pregnancy and/or lactation Females having unprotected sexual intercourse, or using a non-assured method of contraception (e.g. condom) Concomitant chronic drug treatment eg for diabetes, hypertension, TB, HIV etc Concomitant drug usage for acute infection, eg malaria, pneumonia etc within the last 7 days Any other condition which may invalidate the trial Known hypersensitivity to AmBisome, Paromomycin, amphotericin B and/or Miltefosine

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br> | Drug: Amphotericin B Deoxycholate<br>* 1 mg/kg e.o.d for 30 days<br>|
| Experimental: 2<br> | Drug: Ambisome + Miltefosine<br>* Ambisome (i.v. single dose 5 mg/kg)+ Miltefosine 7 days<br>|
| Experimental: 3<br> | Drug: Ambisome and Paromomycin<br>* Ambisome 5 mg/kg single dose + Paromomycin Sulphate 15mg/kg/day for 10 days<br>|
| Experimental: 4<br> | Drug: Miltefosine and Paromomycin<br>* Miltefosine (standard dose) and Paromomycin Sulphate 15mg/kg/day for 10 days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Definitive cure based on parasitological clearance at Day 15 after start of combination therapy (Day 31 for standard therapy), no evidence of parasites at day 45 and no clinical signs or symptoms of VL at 6 months post treatment. |  | 6 months post treatment |