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

This study has been completed.
Sponsor:
Information provided by:
Drugs for Neglected Diseases
ClinicalTrials.gov Identifier:
NCT00696969
First received: June 11, 2008
Last updated: February 10, 2010
Last verified: February 2010
  Purpose

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.


Condition Intervention Phase
Visceral Leishmaniasis
Drug: Amphotericin B Deoxycholate
Drug: Ambisome + Miltefosine
Drug: Ambisome and Paromomycin
Drug: Miltefosine and Paromomycin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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).

Resource links provided by NLM:


Further study details as provided by Drugs for Neglected Diseases:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

Enrollment: 634
Study Start Date: June 2008
Study Completion Date: January 2010
Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1 Drug: Amphotericin B Deoxycholate
1 mg/kg e.o.d for 30 days
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

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.
  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00696969

Locations
India
Kala-azar medical centre
Muzaffarpur, Bihar, India
Rajendra Memorial research Institute
Patna, Bihar, India
Sponsors and Collaborators
Drugs for Neglected Diseases
Investigators
Study Director: Farrokh Modabber Drugs for Neglected Diseases
  More Information

No publications provided by Drugs for Neglected Diseases

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Clinical Project Coordinator, DNDi
ClinicalTrials.gov Identifier: NCT00696969     History of Changes
Other Study ID Numbers: VL Combo 07
Study First Received: June 11, 2008
Last Updated: February 10, 2010
Health Authority: India: Drugs Controller General of India

Additional relevant MeSH terms:
Leishmaniasis
Leishmaniasis, Visceral
Euglenozoa Infections
Protozoan Infections
Parasitic Diseases
Skin Diseases, Parasitic
Skin Diseases, Infectious
Skin Diseases
Amphotericin B
Paromomycin
Liposomal amphotericin B
Amphotericin B, deoxycholate drug combination
Miltefosine
Deoxycholic Acid
Amebicides
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Anti-Bacterial Agents
Antifungal Agents
Cholagogues and Choleretics
Gastrointestinal Agents
Antineoplastic Agents

ClinicalTrials.gov processed this record on August 28, 2014