Safety and Efficacy Study to Evaluate Different Combination Treatment Regimens for Visceral Leishmaniasis - Full Text View

Sponsor:	Drugs for Neglected Diseases
Information provided by:	Drugs for Neglected Diseases
ClinicalTrials.gov Identifier:	NCT00696969

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 III

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study
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:

MedlinePlus related topics: Leishmaniasis

Drug Information available for: Miltefosine Paromomycin sulfate Amphotericin B Paromomycin

U.S. FDA Resources

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 ]

Estimated Enrollment:	624
Study Start Date:	June 2008
Estimated Study Completion Date:	December 2009
Estimated Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

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

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

Contacts

Contact: Sally Ellis

sellis@dndi.org

Locations

India, Bihar
Kala-azar medical centre	Recruiting
Muzaffarpur, Bihar, India
Contact: Shyam Sundar, MD doctorshyamsundar@gmail.com
Principal Investigator: Shyam Sundar, MD
Rajendra Memorial research Institute	Recruiting
Patna, Bihar, India
Contact: P K Sinha, MD pksinha18@yahoo.com
Principal Investigator: P K, Sinha

Sponsors and Collaborators

Drugs for Neglected Diseases

Investigators

Study Director:

Farrokh Modabber

Drugs for Neglected Diseases

More Information

No publications provided

Responsible Party:	DNDi ( Clinical Project Coordinator )
Study ID Numbers:	VL Combo 07
Study First Received:	June 11, 2008
Last Updated:	June 12, 2008
ClinicalTrials.gov Identifier:	NCT00696969 History of Changes
Health Authority:	India: Drugs Controller General of India

Additional relevant MeSH terms:

Abelcet
Anti-Infective Agents
Antiprotozoal Agents
Skin Diseases, Parasitic
Antineoplastic Agents
Miltefosine
Mastigophora Infections
Liposomal amphotericin B
Paromomycin
Anti-Bacterial Agents
Antiparasitic Agents
Cholagogues and Choleretics
Therapeutic Uses
Antifungal Agents

Deoxycholic Acid
Antibiotics, Antifungal
Parasitic Diseases
Leishmaniasis, Visceral
Amphotericin B-deoxycholate
Amebicides
Leishmaniasis
Amphotericin B
Protozoan Infections
Skin Diseases
Gastrointestinal Agents
Pharmacologic Actions
Skin Diseases, Infectious
Sarcomastigophora Infections

ClinicalTrials.gov processed this record on February 08, 2010