Efficacy Trial of Ambisome Given Alone and Ambisome Given in Combination With Miltefosine for the Treatment of VL HIV Positive Ethiopian Patients.

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified July 2014 by Drugs for Neglected Diseases
Sponsor:
Collaborators:
Medecins Sans Frontieres
London School of Hygiene and Tropical Medicine
Amhara region Regional Laboratory Bahir
Addis Ababa University
Institute of Tropical Medicine, Belgium
Slotervaart Hospital
Information provided by (Responsible Party):
Drugs for Neglected Diseases
ClinicalTrials.gov Identifier:
NCT02011958
First received: November 18, 2013
Last updated: July 10, 2014
Last verified: July 2014
  Purpose

The overall objective of this trial is to identify a safe and effective treatment for visceral leishmaniasis (VL) in HIV co-infected Ethiopian patients.

Patients will receive either Ambisome alone or Ambisome in combination with Miltefosine.

Patients who do not undergo treatment failure will be given a VL prophylactic treatment with Pentamidine one month after the end of the study treatment.


Condition Intervention Phase
Visceral Leishmaniasis
Drug: Liposomal Amphotericin B
Drug: Miltefosine
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Trial of Ambisome Monotherapy and Combination of Ambisome and Miltefosine for the Treatment of VL in HIV Positive Patients in Ethiopia Followed by Secondary VL Prophylactic Treatment With Pentamidine.

Resource links provided by NLM:


Further study details as provided by Drugs for Neglected Diseases:

Primary Outcome Measures:
  • Initial parasitological cure at day 29 [ Time Frame: Day 29 ] [ Designated as safety issue: No ]
    Absence of parasites in tissue aspirate at day 29; hence no rescue medication provided up to this time-point.


Secondary Outcome Measures:
  • Relapse-free survival at day 390 [ Time Frame: Day 390 ] [ Designated as safety issue: No ]
    The patient being alive and disease free from day 29 (if initially cured) or day 58 in case of extended treatment (absence of signs and symptoms of visceral leishmaniasis or if symptomatic, a negative parasitological assessment by tissue aspirate)


Other Outcome Measures:
  • Safety endpoint [ Time Frame: From the first dose of study medication up to 1 month after the stop of treatment ] [ Designated as safety issue: Yes ]
    Adverse Events and Serious Adverse Events

  • Response to antiretroviral treatment [ Time Frame: Screening , Day 29, Day 58, Day 210 and Day 390 ] [ Designated as safety issue: No ]
    Measurement of CD4 (cluster of differentiation 4) count and HIV viral load

  • Pharmacokinetics: drug-drug interaction between VL treatment and antiretroviral drugs (Arm 1: PK AmphoB (Amphotericin B) and PK/EFV (Efavirenz)/NVP (Nevirapine)/LPV (Lopinavir)/RTV, Arm 2: PK AmphoB, PK Miltefosine and PK EFV/NVP/LPV/RTV) [ Time Frame: Arm1:PK AmphoB, Day 1 and 24 post-dose / PK EFV/NVP/LPV/RTV: Day 1,24,58,210 and 390 post-dose. Arm 2: PK AmphoB, Day 1 and 11 post-dose/PK Miltefosine: Pre-dose, day 11,29,58,210 post-dose / PK EFV/NVP/LPV/RTV: Day 1,29,58,210 and 390 post-dose ] [ Designated as safety issue: No ]
    In a subgroup of patients, blood concentrations of Ambisome (EDTA plasma), Miltefosine (DBS) and Anti Retroviral Drugs (DBS)


Estimated Enrollment: 132
Study Start Date: July 2014
Estimated Study Completion Date: April 2017
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Liposomal Amphotericin B / Miltefosine

Liposomal Amphotericin B : 30mg/kg total dose: IV infusion 5mg/kg per day on day 1, 3, 5, 7, 9, 11

Miltefosine: orally taken every day during 28 days

  • 1 x 50 mg capsule per day if patient weights less or equal to 25 kg
  • 2 x 50 mg capsules per day if the patient weights more than 25 kg
Drug: Liposomal Amphotericin B

40 mg/kg total dose: IV infusion of 5mg/kg per day on day 1 to 5, 10,17,24 (when administered as a monotherapy)

30 mg/kg total dose: IV infusion 5 mg/kg per day on day 1, 3, 5, 7, 9, 11 (when administered in combination with Miltefosine)

Other Name: Ambisome
Drug: Miltefosine

Orally taken every day during 28 days

  • 1 x 50 mg capsule per day if the patient weights less or equal to 25 kg
  • 2 x 50 mg capsules per day if the patient weights more than 25 kg (1 capsule in the morning / 1 capsule in the evening)
Other Name: Impavido
Experimental: Liposomal Amphotericin B
Liposomal Amphotericin B: 40 mg/kg total dose : IV infusion of 5mg/kg per day on day 1 to 5, 10, 17, 24
Drug: Liposomal Amphotericin B

40 mg/kg total dose: IV infusion of 5mg/kg per day on day 1 to 5, 10,17,24 (when administered as a monotherapy)

30 mg/kg total dose: IV infusion 5 mg/kg per day on day 1, 3, 5, 7, 9, 11 (when administered in combination with Miltefosine)

Other Name: Ambisome

Detailed Description:

Visceral Leishmaniasis (VL) is a neglected disease which is fatal if left untreated. Ethiopia is one of the countries where the majority of cases occur. With spread of HIV in VL endemic areas an increase in co-infected cases has been reported in Ethiopia.

HIV and VL mutually influence each other as they both affect cellular immunity. The most important features of co-infection include poor outcome, increased drug toxicity and relapse of treatment with the need for maintenance therapy.

There are few studies in co-infected patients. There are no specific recommendations for HIV-VL co-infected patients in Ethiopia.

This protocol will evaluate the efficacy and safety of the combination of Ambisome with Miltefosine and Ambisome monotherapy (high dose) in Ethiopia.

It is designed as a randomised, parallel arm, open-label trial. No comparator will be included.

The randomization will be stratified according to centre as well as wether VL is a primary case or a relapse. The study will be analysed according to group-sequential methods, specifically the triangular test. Data from each arm will be analysed after every 10 patients reach the primary endpoint of final cure at day 29. The data will be analysed as proportions according to an intention to treat and per protocol analysis for each arm.In order to address potential heterogeneity of the population, a test will be performed when a treatment is stopped. Depending on the outcome of this test for heterogeneity, recruitment may be continued into one stratum.

The treatment duration will be 28 days or 56 days in case of extended treatment.

  • If at Day 29 assessment, tissue aspirate is parasite negative, the patient will be eligible for secondary prophylaxis (Pentamidine 4mg/kg IM (intramuscular) once a month up to a maximum of 18 months) and enter the 1 year follow up phase.
  • If at day 29 assessment, tissue aspirate is positive but the patient is well, he/she will receive another complete course of treatment (but classified as treatment failure). The patient will be evaluated again on day 58. Those who still have a parasite positive tissue aspirate will be offered a rescue treatment. Those who are negative will be offered secondary prophylaxis if eligible (Pentamidine 4mg/kg IM once a month up to a maximum of 18 months).
  • If at day 29 assessment, tissue aspirate is positive and the patient is unwell, he/she will be treated with rescue treatment (and considered as treatment failure)
  • All patients, independently of their outcome at day 29 and/or day 58 will enter the follow-up assessments at day 210 and day 390.

Rescue treatment will also be given in case of relapse during the follow-up period and in case of occurence of severe grade 2 or grade 3 PKDL or PKDL with mucosal and/or eye involvement after treatment period.

All patients who are not yet on antiretroviral treatment (ART) at inclusion will commence ART once they have completed routine voluntary counselling and testing procedures. Patients who are already on ART at diagnosis of VL will continue ART throughout the study.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed HIV positive test (2 rapid diagnostics tests (RDTs) followed by a confirmatory ELISA test).
  • Diagnosis of VL (first episode or relapse) confirmed by bone marrow or spleen aspirate.
  • Male and female age: 18-60 years.
  • Written informed consent from the patient.

Exclusion Criteria:

  • Women of child-bearing potential (defined as women who have achieved menarche) who are not using an assured method of contraception or are unwilling to use an assured method of contraception for the duration of treatment and four months after.
  • Pregnant women or breast-feeding mothers.
  • Patients with grade 2 or 3 post kala-azar dermal leishmaniasis (PKDL) lesions.
  • Clinical or biological evidence of severe cardiac, renal or hepatic impairment.
  • Known hypersensitivity to AmBisome® and/or miltefosine.
  • Patients receiving allopurinol treatment
  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: NCT02011958

Contacts
Contact: Nathalie Strub-Wourgaft +41 22 906 92 46 nstrub@dndi.org
Contact: Séverine Blesson +41 22 906 92 57 sblesson@dndi.org

Locations
Ethiopia
Abdurafi, Ethiopia
Gondar, Ethiopia
Sponsors and Collaborators
Drugs for Neglected Diseases
Medecins Sans Frontieres
London School of Hygiene and Tropical Medicine
Amhara region Regional Laboratory Bahir
Addis Ababa University
Institute of Tropical Medicine, Belgium
Slotervaart Hospital
Investigators
Principal Investigator: Ermias Diro, Dr. MD University of Gondar
  More Information

No publications provided

Responsible Party: Drugs for Neglected Diseases
ClinicalTrials.gov Identifier: NCT02011958     History of Changes
Other Study ID Numbers: HIV/VL 0511
Study First Received: November 18, 2013
Last Updated: July 10, 2014
Health Authority: Ethiopia: Ethical Review Committee
Ethiopia: Food, Medicine and Health Care Administration and Control Authority of Ethiopia

Keywords provided by Drugs for Neglected Diseases:
Visceral Leishmaniasis
HIV positive patients
Phase III trial
Randomised
Liposomal amphotericin B
Ambisome
Miltefosine
Pentamidine
Efficacy
Safety

Additional relevant MeSH terms:
HIV Seropositivity
Leishmaniasis
Leishmaniasis, Visceral
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Euglenozoa Infections
Protozoan Infections
Parasitic Diseases
Skin Diseases, Parasitic
Skin Diseases, Infectious
Skin Diseases
Amphotericin B
Liposomal amphotericin B
Pentamidine
Miltefosine
Amebicides
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Anti-Bacterial Agents
Antifungal Agents

ClinicalTrials.gov processed this record on August 20, 2014