Efficacy Trial of Ambisome Given Alone and Ambisome Given in Combination With Miltefosine for the Treatment of VL HIV Positive Ethiopian Patients.
Condition: Visceral Leishmaniasis
MeSH terms: HIV Seropositivity; Leishmaniasis; Leishmaniasis, Visceral
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

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.
    

Intervention name(s): Liposomal Amphotericin B; Miltefosine
Intervention type(s): Drug; Drug
Intervention description(s): 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); 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 intervention name(s): Ambisome; Impavido
Intervention MeSH terms: Amphotericin B; Liposomal amphotericin B; Miltefosine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Visceral Leishmaniasis; HIV positive patients; Phase III trial; Randomised; Liposomal amphotericin B; Ambisome; Miltefosine; Pentamidine; Efficacy; Safety