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CTRI Number  CTRI/2015/05/005807 [Registered on: 25/05/2015] Trial Registered Prospectively
Last Modified On: 01/10/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group Trial 
Public Title of Study   A randomized trial of AmBisome® single therapy and combination of AmBisome® and miltefosine for the treatment of Kala Azar in HIV positive patients in India 
Scientific Title of Study   A randomized trial of AmBisome® monotherapy and combination of AmBisome® and miltefosine for the treatment of Visceral Leishmanaisis in HIV positive patients in India 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Modification(s)  
Name  Dr Krishna Pandey 
Designation  Principal Investigator 
Affiliation  Rajendra Memorial Research Institute of Medical Sciences 
Address  Rajendra Memorial Research Institute of Medical Sceinces, (Indian Council of Medical Research), Agam Kuan, Patna
Rajendra Memorial Research Institute of Medical Sciences, (Indian Council of Medical Research) Agam Kuan, Patna
Patna
BIHAR
800007
India 
Phone  06122636651  
Fax  06122634379  
Email  drkrishnapandey@yahoo.com  
 
Details of Contact Person
Scientific Query
Modification(s)  
Name  Dr Sakib Burza 
Designation  Coordinating Investigator 
Affiliation  Medecins Sans Frontieres 
Address  Medecins Sans Frontieres C384 Defence Colony New Delhi

New Delhi
DELHI
110024
India 
Phone  9871258886  
Fax    
Email  sakib.burza@barcelona.msf.org  
 
Details of Contact Person
Public Query  
Name  Dr Sakib Burza 
Designation  Coordinating Investigator 
Affiliation  Medecins Sans Frontieres 
Address  Medecins Sans Frontieres C203 Defence Colony New Delhi

New Delhi
DELHI
110024
India 
Phone  9871258886  
Fax    
Email  sakibburza@gmail.com  
 
Source of Monetary or Material Support  
Medecins Sans Frontieres 
 
Primary Sponsor  
Name  Medecins Sans Frontieres 
Address  Nou de la Rambla 26 08001 Barcelona Spain 
Type of Sponsor  Other [Not for Profit Organisation] 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study
Modification(s)  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Krishna Pandey  Rajendra Memorial Research Institute of Medical Sciences  Rajendra Memorial Research Institute of Medical Sciences, (Indian Council of Medical Research) Agam Kuan
Patna
BIHAR 		 9431042119
06122634379
drkrishnapandey@yahoo.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 3  
Name of Committee  Approval Status 
London School of Hygiene and Tropical Medicine  Approved 
Medecins Sans Frontieres Institutional Review Board  Approved 
RMRIMS Ethics Review Board  Approved 
 
Regulatory Clearance Status from DCGI
Modification(s)  
Status 
No Objection Certificate 
 
Health Condition / Problems Studied
Modification(s)  
Health Type  Condition 
Patients  (1) ICD-10 Condition: B550||Visceral leishmaniasis, Visceral Leishmaniasis (VL), also known as Kala Azar, in patients with HIV infection,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Liposomal Amphotericin B (AmBisome)  AmBisome mono therapy infusion of 40mg/kg liposomal amphotericin B (5mg/kg on day 1-4, 8, 10, 17, 24) 
Intervention  Liposomal Amphotericin B (AmBisome), Miltefosine   AmBisome infusion 30mg/kg liposomal amphotericin B (5mg/kg on day 1,3,5,7,9,11) given in combination with oral miltefosine 100mg in two divided doses (i.e. 2.50mg capsules) every day during 14 days 
Comparator Agent  Not Applicable  Not Applicable 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  80.00 Year(s)
Gender  Both 
Details  Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:

Confirmed HIV positive test (2 rapid diagnostics tests (RDTs) as per National Programme guidelines, WB for any discrepancy

Diagnosis of VL confirmed by bone marrow or spleen aspirate.

Male and female age ≥ 18 years

Written informed consent from the patient. 
 
ExclusionCriteria 
Details  Women of child-bearing potential 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 three months after.

Pregnant women or breast-feeding mothers.

Clinical or biological evidence of severe cardiac, renal or hepatic impairment.

Known hypersensitivity to AmBisome® and/or miltefosine.

Concomitant severe infection such as TB or other serious underlying disease that would preclude evaluation of patients response to study medication

Hb <5mg/dl, WBC <1x103/mm3, platelets <40,000/mm3

Abnormal liver function tests (ALT/AST) more than 3 times the upper limit of normal

Creatinine >1.2 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Sequentially numbered, sealed, opaque envelopes 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
The primary endpoint is cure at day 210 and is defined as survival and being symptom free of VL at day 210.  Day 210 
 
Secondary Outcome
Modification(s)  
Outcome  TimePoints 
Relapse-free survival at 12 months as defined as:
- The patient being alive and symptom-free from day 210 (if initially cured) and remains symptom-free until the last follow up assessment (i.e. day 390).
 		 Day 390 
Initial cure at Day 29 as defined as:
Patient presents clinical improvement, defined as cessation of fever and reduction in any initial splenomegaly and a negative parasitological assessment by tissue aspirate. 		 Day 29 
Relapse-free survival of patients with no concurrent TB infection at 6 and 12 months defined as:
The patient has no diagnosis of TB prior to day 58 and is alive and disease-free (defined as absence of signs and symptoms of VL or if symptomatic, a negative parasitological assessment by tissue aspirate) at day 210 and remains disease free and alive from day 210 (if initially cured) until the last follow up assessment (i.e. day 390). 		 Day 210 and Day 390 
Safety
Assessment of safety during treatment and follow-up based on clinical adverse events, laboratory parameters during treatment and 1 month follow up. 		 Up to day 58 
 
Target Sample Size
Modification(s)  		 Total Sample Size="150"
Sample Size from India="150" 
Final Enrollment numbers achieved (Total)= "0"
Final Enrollment numbers achieved (India)="150" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)
Modification(s)  		 01/11/2016 
Date of Study Completion (India) 28/05/2019 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Date Missing 
Estimated Duration of Trial   Years="2"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Completed 
Recruitment Status of Trial (India)  Completed 
Publication Details    
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Brief Summary
Modification(s)  

One third ofall HIV patients worldwide live in regions where leishmaniasis is endemic [1]. Visceral leishmaniasis (VL) caused by the parasite L.donovani is endemic to Bihar, a populous state of 110 million people in East India, which carries an estimated 40% of the world’s VL burden [2]. Although Bihar has a relatively low prevalence of HIV (between 0.22 - 0.33%), its high population density means that in absolute numbers an estimated 300,000 people in the state live with HIV/AIDS [3]. 

 

The evidence base regarding best treatment practices for co-infected patients worldwide is limited, due to a lack of randomized trials and to the fact that most available data comes from observational studies with relatively short follow-up periods, and often with high rates of loss to follow-up [15]. Nevertheless, worse outcomes in almost every respect have consistently been reported in this patient group when compared to patients not known to be HIV-positive—for example, in terms of higher relapse rates, mortality, and VL drug toxicity and treatment failure [15].

 

Considering the lack of quality evidence surrounding treatment for co-infected patients in the Indian context, we suggest that a study examining the effectiveness of 40mg/kg AmBisome® — as recommended by the WHO for VL-HIV co-infection [17] but never tested in India or on L. donovani in the Indian subcontinent â€” and a lower dose combination of AmBisome®  and miltefosine be formally evaluated in order to provide the Indian policy makers with evidence to develop specific guidelines for the treatment of co-infected patients. Note that this evidence gap is also being currently addressed in Ethiopia, where a clinical trial in co-infected patients comparing two arms (AmBisome monotherapy and AmBisome – miltefosine combination therapy) is currently underway [31]. However, the very different behavior of the parasite between the two regions means that results cannot be extrapolated from one region to another.

 

This protocol will evaluate the efficacy and safety of the combination of AmBisome® 30 mg/kg with miltefosine (100 mg daily for 14 days) and AmBisome® monotherapy (high dose: 40 mg/kg) in Bihar, India.

 
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