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

February 10, 2010 updated by: Drugs for Neglected Diseases

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).

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

634

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • India
    • Bihar
      • Muzaffarpur, Bihar, India
        • Kala-azar medical centre
      • Patna, Bihar, India
        • Rajendra Memorial research Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 56 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
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.
Time Frame: 6 months post treatment
6 months post treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Drugs for Neglected Diseases

Investigators

  • Study Director: Farrokh Modabber, Drugs for Neglected Diseases

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2008

Primary Completion (Actual)

January 1, 2010

Study Completion (Actual)

January 1, 2010

Study Registration Dates

First Submitted

June 11, 2008

First Submitted That Met QC Criteria

June 12, 2008

First Posted (Estimate)

June 13, 2008

Study Record Updates

Last Update Posted (Estimate)

February 11, 2010

Last Update Submitted That Met QC Criteria

February 10, 2010

Last Verified

February 1, 2010

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • VL Combo 07

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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