Phase III, Study of Three Short Course Combo (Ambisome®, Miltefosine, Paromomycin) Compared With AmBisome for the Treatment of VL in Bangladesh

This protocol will evaluate the efficacy and safety of various combinations of the three drugs; AmBisome, Paromomycin and Miltefosine at reduced total dosage against the standard treatment with a total dose of 15mg/kg of AmBisome.

Visceral leishmaniasis (VL) is the most severe form of leishmaniasis. The causative parasite in Bangladesh is almost exclusively L. donovani.

• The current treatment options in Bangladesh are not satisfactory as they are either toxic and long, or are of limited use in women of childbearing age due to possible teratogenicity, long treatment duration which leads to non-compliance and possible emergence of resistance or expensive.

In collaboration with Indian Medical Research Council and investigators in India, DNDi initiated a combination trial for treatment of VL in Bihar, India in 2008 including 624 patients from age 5 - 60. The same combinations will be used in the present study. An interim safety review was conducted on the first 120 patients included in the Indian VL Combination study and revealed no safety issues with combination treatment. The enrolment is complete and the final results for 624 patients are expected in Q1 2010.

This is a randomized, controlled, open-label, parallel group study to compare the safety and efficacy of different combination regimens with AmBisome for the treatment of VL in Bangladesh.

This trial is designed in two steps:

Step 1: First 120 patients will be recruited in a hospital setting in a study including parasitology and laboratory assessments at Community Based Medical College, Bangladesh (CBMC,B), primarily for the purpose of reconfirming the safety of combination treatments in Bangladesh. Pending the review and approval of an independent DSMB of the Day 45 data, step 2 will commence.

Step 2: Approximately 554 Patients will then be recruited and treated in Upazilla Health Centre's (UZHC), situated in endemic regions of Bangladesh. We will use rapid diagnostic test (RDT) and the limited laboratory assessments that are available in the centres.

Female patients will be stratified according to marital status, such that unmarried women of child-bearing age will be stratified to receive treatments that do not contain Miltefosine, and married women will be stratified to receive one of the four treatment regimens and must consent to use an approved method of contraception and undergo pregnancy test at the start of the study. Child-bearing age is defined as achieving menarche.

There will be one planned safety review assessing safety and initial cure at Day 45 following completion of Step 1.

Eligibility Criteria:
Inclusion Criteria:

* VL proven by parasitological examination of splenic or bone marrow aspirate. Parasite burden to be graded according to Chulay and Bryceson 1983 and subsequently adopted by WHO. (Step 1 only)
* History of fever, for at least 2 weeks with one or more of the followings criteria: Anaemia (5\<Hb\<10g/dl), Loss of weight, Splenomegaly
* rk39 positive at baseline assessments
* willing and able to attend follow-up visits
* Male or Female age: 5-60 yrs
* Written informed consent from the patient or from patient's parent or guardian if the patient is under 18 yrs, in addition written assent from patients of 11 - 17 yrs of age. If the patient or parent/guardian are illiterate an impartial witness should be present during the consenting procedure and should also sign.

Exclusion Criteria:

* Married women of child-bearing potential (defined as women who have achieved menarche) who are not using an assured method of contraception or are unwilling to use an assured method of contraception for the duration of treatment and three months after. Assured methods of contraception include i.e. IUCD or depot hormone injection of medroxyprogesterone acetate MPA (DepoProvera®)
* Platelet count less than 40,000/mm3 (Step 1 only)
* Prothrombin time 5 seconds or greater than normal range (Step 1 only)
* Known hepatitis B, C or known HIV positive
* Patients who present with Para Kala-azar Dermal Leishmaniasis
* Signs/symptoms indicative of severe VL (Hb \< 5gm/dl, etc)
* Patients with a previous history of VL
* Patients who have received any investigational (unlicensed) drugs within the last 3 months
* Severe malnutrition BMI\<15 in adults, weight for height less than 60% in children
* Clinical symptoms of chronic underlying disease such as severe cardiac, renal or hepatic impairment
* Positive HRP2/pLDH Combo test for malaria
* Pregnant woman or breast-feeding mother
* Known alcohol or other drug abuse
* Concomitant chronic drug treatment eg. TB, HIV etc.
* Known hypersensitivity to AmBisome, Paromomycin and other aminoglycosides and/or Miltefosine