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CTRI Number  CTRI/2012/08/002891 [Registered on: 16/08/2012] Trial Registered Prospectively
Last Modified On: 02/06/2016
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Non-randomized, Multiple Arm Trial 
Public Title of Study   An open-label, prospective, non randomised, non comparative, multicenter, observational pharmacovigilence study of the safety and effectiveness of new treatment modalities to treat VL in public sector of India. 
Scientific Title of Study   A Pilot Project To Evaluate The Safety And Effectiveness Of New Treatment Modalities For The Management Of Visceral Leishmaniasis (VL) In The Endemic Regions Of India 
Secondary IDs if Any  
Secondary ID  Identifier 
VL PV 2011  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Pradeep Das 
Designation  Director 
Affiliation  Rajendra Memorial Research Institute of Medical Sciences 
Address  Rajendra Memorial Research Institute of Medical Sciences, (Indian Council of Medical Research) Agam Kuan, Patna

Patna
BIHAR
800 007
India 
Phone  0612-2636651  
Fax  0612-2634379  
Email  drpradeep.das@gmail.com  
 
Details of Contact Person
Scientific Query
 
Name  Dr Bhawna Sharma 
Designation  Head, Regional Office 
Affiliation  Drugs for Neglected Diseases initiative 
Address  Drugs for Neglected Diseases initiative ICMR, 2nd Campus, Room no.3, 1st Floor TB Association Building, 3 Red Cross Road, New Delhi

New Delhi
DELHI
110001
India 
Phone  91-11-23731635  
Fax  91-11-23731635  
Email  bsharma@dndi.org  
 
Details of Contact Person
Public Query
 
Name  Dr Bhawna Sharma 
Designation  Head, Regional Office 
Affiliation  Drugs for Neglected Diseases initiative 
Address  Drugs for Neglected Diseases initiative ICMR, 2nd Campus, Room no.3, 1st Floor TB Association Building, 3 Red Cross Road, New Delhi

New Delhi
DELHI
110001
India 
Phone  91-11-23731635  
Fax  91-11-23731635  
Email  bsharma@dndi.org  
 
Source of Monetary or Material Support  
Drugs for Neglected Diseases initiative (DNDi) 
 
Primary Sponsor  
Name  Drugs for Neglected Diseases initiative DNDi 
Address  15, Chemin Louis-Dunant, 1202, Geneva-Switzerland Tel: +41(0) 22 906 92 30/34 Fax: +41 (0) 22 906 92 31  
Type of Sponsor  Other [Not for Profit Organozation] 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 15  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Vinay Kumar Yadav  Civil Surgeon Office, Sadar Hospital Chhapra  Civil Surgeon Office, Sadar Hospital Chhapra
Saran
BIHAR 
09470003720

dhssaran@gmail.com 
Dr Satyendra Kumar Gupta  Goraul PHC  Goraul Primary Health Center
Vaishali
BIHAR 
09470003818

Vl_goraul.rks@rediffmail.com 
Dr Gaurav Mitra  Hajipur Hospital  Hajipur Sadar Hospital
Vaishali
BIHAR 
09835261010

gaurabmitra12@yahoo.co.in 
Dr Vibesh Prasad Singh Civil Surgeon  Hajipur Hospital  Hajipur Hospital, District-Vaishali Bihar
Vaishali
BIHAR 
09470003807

bhs_vaishali@rediffmail.com 
Dr Anil Kumar  Manhar  MOIC, Manhar Primary Health Center
Vaishali
BIHAR 
09939134910

Vl_mahnar.rks@rediffmail.com 
Dr Akhileshwar Kumar  Primary Health Centre (PHC) Dariyapur  MOIC,Primary Health Centre (PHC) Dariyapur
Saran
BIHAR 
09470003723

phcdariyapur@gmail.com 
Dr Birendra Kumar  Primary Health Centre (PHC) Mahua  Primary Health Centre (PHC) Mahua
Vaishali
BIHAR 
09934903501

Vl_mahua.rks@rediffmail.com 
Dr Narendra Kumar  Primary Health Centre (PHC) Parsa  MOIC,Primary Health Centre (PHC) Parsa
Saran
BIHAR 
09470003709

phcparsa@gmail.com 
Dr Sunil Keshri  Primary Health Centre (PHC) Raghopur  Primary Health Centre (PHC) Raghopur
Vaishali
BIHAR 
09470003825

Vl_raghopur.rks@rediffmail.com 
Dr Anil Kumar Sinha  Primary Health Centre (PHC) Vaishali  Primary Health Centre (PHC) Vaishali
Vaishali
BIHAR 
09470003823

Vl_vaishali.rks@rediffmail.com 
Dr Pradeep Das  Rajendra Memorial Research Institute of Medical Sciences  Rajendra Memorial Research Institute of Medical Sciences, (Indian Council of Medical Research) Agam Kuan, Patna
Patna
BIHAR 
0612-2636651
0612-2634379
drpradeep.das@gmail.com 
Dr Harish Chandra Prasad  Referral Hospital, Baniyapur  MOIC,Referral Hospital, Baniyapur
Saran
BIHAR 
09470003712

phcbaniyapur@gmail.com 
Dr R N Tiwary  Referral Hospital, Marhourah  MOIC,Referral Hospital, Marhourah
Saran
BIHAR 
09470003708

phcmarhoarh@gmail.com 
Dr Ravi Shankar Singh   Sadar Hospital Chhapra  Pediatrician,Sadar Hospital Chhapra
Saran
BIHAR 
06152-233965

sadarhospital.cpr@gmail.com 
Dr Shambu Nath Singh  Sadar Hospital Chhapra  Deputy Superintendent (Kala Azar Incharge),Sadar Hospital Chhapra
Saran
BIHAR 
09470003711

sadarhospital.cpr@gmail.com 
 
Details of Ethics Committee  
No of Ethics Committees= 3  
Name of Committee  Approval Status 
London School of Hygiene & Tropical Medicine Ethics Committee   Approved 
RMRI Ethics Committee   Approved 
RMRI Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Notified 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  Visceral Leishmaniasis (VL), also known as Kala Azar,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Treatment-1: Miltefosine Capsule and Paromomycin injection  Treatment 1: Miltefosine Capsules (50 mg and 10 mg) & Paromomycin Injections combination treatment given as follows: • Miltefosine given orally for 10 days (day 1-10) at 100mg daily for adults over 25kg , 50mg daily for adults under 25kg, and 2.5mg/kg daily for children plus paromomycin 11mg/kg base given intramuscularly for 10 days (day 1-10): this treatment will be used in at least 5 PHCs.  
Intervention  Treatment-2:Ambisome infusion and Miltefosine Capsule  Treatment 2: • AmBisome® 5mg/kg infusion on day 1 plus Miltefosine capsules given orally at 100mg daily for adults over 25kg , 50mg daily for adults under 25kg, and 2.5mg/kg daily for children for 7 days (days 2-8): this treatment will be used in at least 5PHCs.  
Intervention  Treatment-3:Ambisome infusion  Treatment 3: • Single dose AmBisome® 10mg/kg infusion on day 1: this treatment will be used at hospital and referral level in the district(s) involved. 
 
Inclusion Criteria  
Age From  2.00 Year(s)
Age To  80.00 Year(s)
Gender  Both 
Details  Primary cases: all ‘new cases’ with clinical features of VL (fever for 2 weeks and splenomegaly) and are rk39 or parasitology positive.
Relapse cases: all cases that have previously been treated for VL (but not involving any one of the drugs that are part of the new treatment modality used at that treatment centre), have fever, splenomegaly and are confirmed by parasitology.
Written consent to receive one of the new treatment modalities and allow information to be collected as part of a pilot project.
 
 
ExclusionCriteria 
Details  Pregnant women and women of child bearing age who cannot be assured contraceptive cover will be excluded from all miltefosine containing regimens. These cases may be referred and managed with non-miltefosine new treatment modalities in the nearest district hospital/ designated referral centre. Their exclusion will be recorded within the surveillance register.
All patients who have previously been treated with one of the drugs that are part of the new treatment modality in use at that centre will be excluded (e.g. any patient treated with miltefosine monotherapy will not be retreated with a miltefosine combination treatment; any patient treated with high dose AmBisome® will not be given single dose AmBisome® or an AmBisome® combination). Their admission will however be recorded within the surveillance register.
All known HIV+ patients (see special cases below) patients will be treated with alternative regimens. Their admission will however be recorded within the surveillance register.
All PKDL patients will be treated with alternative regimens. Their admission will however be recorded within the surveillance register.
All patients with a history of allergy or hypersensitivity to the relevant drug
Special cases
A category of special cases will be defined on entry based on the classifications below. These cases will either be managed by specific treatments (e.g. one particular new treatment modality) and/ or in specialist referral centres.
All pregnant women can be included and will be treated with AmBisome® 10mg/kg single dose. All pregnant cases treated, or patients given a new treatment modality and who become pregnant within one month of end of treatment will be entered into a special pregnancy follow up register.
All women of child bearing age who cannot be assured contraceptive cover will be treated with either AmBisome® & paromomycin or AmBisome® single dose.
All patients with signs and symptoms of severe diseases: defined as severe anaemia (i.e. haemoglobin 4 and/ or signs of cardiac failure), renal failure or hepatic failure (e.g. jaundice), serious concomitant infection (e.g. severe pneumonia), severe malnutrition, will be referred to the nearest district hospital or RMRIMS for further specialist management. These patients may be treated with one of the new treatment modalities according to the physician’s decision.
All patients with proven TB/VL co-infection will be referred to the nearest district hospital or RMRIMS for further specialist management. These patients may be treated with one of the new treatment modalities according to the physician’s decision.
All children under 2 will be referred to the nearest district hospital or RMRIMS for further specialist management. These patients may be treated with one of the new treatment modalities according to the physician’s decision.
Note: All patients with proven HIV/ VL co-infection will also be referred to the nearest district hospital or RMRIMS for further specialist management. However, as defined in the exclusion criteria, these patients will not be treated with one of the new treatment modalities. Compassionate high dose therapy with AmBisome® or a high dose combination of drugs may be used according to the physician’s decision.
All consenting patients entering a centre where one of the new treatment modalities is being piloted will be entered in to a register. All patients treated with one of the new treatment modalities will also be entered in the PV programme and compliance survey (step 1 only). 
 
Method of Generating Random Sequence   Not Applicable 
Method of Concealment   Not Applicable 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
The effectiveness or final proportion cured (success) of the treatments proposed will reach a target of 95%. Therefore the proportion of observed failures will be 5% for each of the proposed treatments.
The level of expedited safety events reported (Deaths, Serious and Unexpected Adverse Drug reactions) will be ≤ 2% for each of the proposed treatments.
 
Initial Cure is 10 days and the final cure is 06 months 
 
Secondary Outcome  
Outcome  TimePoints 
Initial outcome: Initial cured, died, defaulted, treatment stopped, treatment failure, referred to another centre  Initial Cure is 10 days 
 
Target Sample Size   Total Sample Size="7000"
Sample Size from India="7000" 
Final Enrollment numbers achieved (Total)= ""
Final Enrollment numbers achieved (India)="" 
Phase of Trial   Phase 4 
Date of First Enrollment (India)   16/08/2012 
Date of Study Completion (India) Date Missing 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Date Missing 
Estimated Duration of Trial   Years="5"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  
Not Applicable 
Recruitment Status of Trial (India)  Completed 
Publication Details    
Brief Summary  

This is an open-label, prospective, non randomised, non comparative, multicenter, observational pharmacovigilence study of the safety and effectiveness of new treatment modalities to treat VL in public sector of India.

The objectives stated above will be achieved through:

1) The implementation of a PV network to evaluate safety across all the participating VL treatment sites. This will also involve the development of a reporting system for individual Serious and unexpected ADRs to a steering committee and the relevant authorities.

2) The development of a VL treatment and follow up surveillance register (referred to hence as the ‘surveillance register’) listing all patients that receive one of the new treatment modalities in the participating sites and the periodic reporting of aggregated outcome data to the national authorities.

Sites:

In order to reflect the current situation of health care provision for VL in endemic areas, the project will be implemented in the following structures:

-          Ministry of health structures from PHC level upwards: most centres and patients to be included in this project will be in this category.

-          A few key health providers with experience managing VL (e.g. RMRIMS).

-          In 5 PHCs and 1 district hospital in Vaishalli District, Bihar State, where Médecins Sans Frontières-Spain/OCBA is currently working within the government structures.

 

Treatments to be implemented (new treatment modalities)

i) NON AmBisome® Based treatment: targeted for first line administration at the primary health care (PHC) level in a district

Treatment 1: MF&PM combination treatment given as follows:

·         Miltefosine given orally for 10 days (day 1-10) at 100mg daily for adults over 25kg , 50mg daily for adults under 25kg, and 2.5mg/kg daily for children plus paromomycin 11mg/kg base given intramuscularly for 10 days (day 1-10): this treatment will be used in at least 5 PHCs.

ii) AmBisome® Based treatment: targeted for administration where AmBisome® is feasible in a district (i.e. PHCs able to maintain cold chain, familiar with amphotericin B administration, or district hospitals).  AmBisome® based treatment modalities that will be evaluated consist of the following:

Treatment 2:

·         AmBisome® 5mg/kg on day 1 plus miltefosine given orally at 100mg daily for adults over 25kg , 50mg daily for adults under 25kg, and 2.5mg/kg daily for children for 7 days (days 2-8): this treatment will be used in at least 5PHCs.

Treatment 3:

Single dose AmBisome® 10mg/kg on day 1: this treatment will be used at hospital and referral level in the district(s) involved. 
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