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

NCT ID: NCT00696969

Last Updated: 2010-02-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 634 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-06-30
• Study Completion Date: 2010-01-31

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.

Conditions

Visceral Leishmaniasis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

Group Type: ACTIVE_COMPARATOR

Amphotericin B Deoxycholate

Intervention Type: DRUG

1 mg/kg e.o.d for 30 days

2

Group Type: EXPERIMENTAL

Ambisome + Miltefosine

Intervention Type: DRUG

Ambisome (i.v. single dose 5 mg/kg)+ Miltefosine 7 days

3

Group Type: EXPERIMENTAL

Ambisome and Paromomycin

Intervention Type: DRUG

Ambisome 5 mg/kg single dose + Paromomycin Sulphate 15mg/kg/day for 10 days

4

Group Type: EXPERIMENTAL

Miltefosine and Paromomycin

Intervention Type: DRUG

Miltefosine (standard dose) and Paromomycin Sulphate 15mg/kg/day for 10 days

Interventions

Amphotericin B Deoxycholate

1 mg/kg e.o.d for 30 days

Intervention Type: DRUG

Ambisome + Miltefosine

Ambisome (i.v. single dose 5 mg/kg)+ Miltefosine 7 days

Intervention Type: DRUG

Ambisome and Paromomycin

Ambisome 5 mg/kg single dose + Paromomycin Sulphate 15mg/kg/day for 10 days

Intervention Type: DRUG

Miltefosine and Paromomycin

Miltefosine (standard dose) and Paromomycin Sulphate 15mg/kg/day for 10 days

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Drugs for Neglected Diseases

OTHER

Sponsor Role: lead

Responsible Party

DNDi

Principal Investigators

Farrokh Modabber

Role: STUDY_DIRECTOR

Drugs for Neglected Diseases

Locations

Kala-azar medical centre

Muzaffarpur, Bihar, India

Rajendra Memorial research Institute

Patna, Bihar, India

Countries

India

References

Sundar S, Sinha PK, Rai M, Verma DK, Nawin K, Alam S, Chakravarty J, Vaillant M, Verma N, Pandey K, Kumari P, Lal CS, Arora R, Sharma B, Ellis S, Strub-Wourgaft N, Balasegaram M, Olliaro P, Das P, Modabber F. Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. Lancet. 2011 Feb 5;377(9764):477-86. doi: 10.1016/S0140-6736(10)62050-8. Epub 2011 Jan 20.

Reference Type: DERIVED

PMID: 21255828 (View on PubMed)

Other Identifiers

VL Combo 07

Identifier Type: -

Identifier Source: org_study_id