Phase III, Study of Three Short Course Combination Regimens (Ambisome®, Miltefosine, Paromomycin) Compared With AmBisome® Alone for the Treatment of Visceral Leishmaniasis in Bangladesh

• Definitive cure [ Time Frame: 6 month post treatment ] [ Designated as safety issue: No ]

  The primary endpoint variable is definitive cure at month 6, and is defined as no significant clinical signs or symptoms of VL at Day 45 including lack of fever [axiliary temperature < 99.5°F] and at least one of the following:

  • improved Hb if the patient was anaemic at baseline (Hb< 8g/dl)
  • spleen regression if the spleen was palpable on admission and absence of clinical signs and symptoms of VL (fever, weight loss, splenomegaly) at any time during 6 months post treatment period.
  
  

• Initial Cure [ Time Frame: Day 45 ] [ Designated as safety issue: No ]

  Initial Cure is defined as no significant clinical signs or symptoms of VL at Day 45 ie lack of fever [axiliary temp < 99.5°F and at least one of the following:

  • improved Hb if the patient was anaemic at baseline (Hb< 8g/dl)
  • spleen regression if the spleen was palpable on admission
  
  
• Adverse events [ Time Frame: Treatment ] [ Designated as safety issue: Yes ]

  Assess safety during treatment and follow-up in different healthcare settings

  • in hospital setting based on clinical adverse events, laboratory parameters during treatment and 6 months follow-up
  • In UZHC setting based on clinical adverse events, limited laboratory parameters during treatment and 6 months follow-up
  
  

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.