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 Modification(s)	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  Registry  VL PV 2011  Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)	Name  Dr Pradeep Das  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 Contact Person Scientific Query	Name  Dr Bhawna Sharma  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 Contact Person Public Query	Name  Dr Bhawna Sharma  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 Modification(s)	No of Sites = 15   Contact Person  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   09470003720 dhssaran@gmail.com  Dr Satyendra Kumar Gupta  Goraul PHC  Goraul Primary Health Center Vaishali   09470003818 Vl_goraul.rks@rediffmail.com  Dr Gaurav Mitra  Hajipur Hospital  Hajipur Sadar Hospital Vaishali   09835261010 gaurabmitra12@yahoo.co.in  Dr Vibesh Prasad Singh Civil Surgeon  Hajipur Hospital  Hajipur Hospital, District-Vaishali Bihar Vaishali   09470003807 bhs_vaishali@rediffmail.com  Dr Anil Kumar  Manhar  MOIC, Manhar Primary Health Center Vaishali   09939134910 Vl_mahnar.rks@rediffmail.com  Dr Akhileshwar Kumar  Primary Health Centre (PHC) Dariyapur  MOIC,Primary Health Centre (PHC) Dariyapur Saran   09470003723 phcdariyapur@gmail.com  Dr Birendra Kumar  Primary Health Centre (PHC) Mahua  Primary Health Centre (PHC) Mahua Vaishali   09934903501 Vl_mahua.rks@rediffmail.com  Dr Narendra Kumar  Primary Health Centre (PHC) Parsa  MOIC,Primary Health Centre (PHC) Parsa Saran   09470003709 phcparsa@gmail.com  Dr Sunil Keshri  Primary Health Centre (PHC) Raghopur  Primary Health Centre (PHC) Raghopur Vaishali   09470003825 Vl_raghopur.rks@rediffmail.com  Dr Anil Kumar Sinha  Primary Health Centre (PHC) Vaishali  Primary Health Centre (PHC) Vaishali Vaishali   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   0612-2636651 0612-2634379 drpradeep.das@gmail.com  Dr Harish Chandra Prasad  Referral Hospital, Baniyapur  MOIC,Referral Hospital, Baniyapur Saran   09470003712 phcbaniyapur@gmail.com  Dr R N Tiwary  Referral Hospital, Marhourah  MOIC,Referral Hospital, Marhourah Saran   09470003708 phcmarhoarh@gmail.com  Dr Ravi Shankar Singh   Sadar Hospital Chhapra  Pediatrician,Sadar Hospital Chhapra Saran   06152-233965 sadarhospital.cpr@gmail.com  Dr Shambu Nath Singh  Sadar Hospital Chhapra  Deputy Superintendent (Kala Azar Incharge),Sadar Hospital Chhapra Saran   09470003711 sadarhospital.cpr@gmail.com
Details of Ethics Committee Modification(s)	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 Modification(s)	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"
Phase of Trial	Phase 4
Date of First Enrollment (India) Modification(s)	16/08/2012
Date of First Enrollment (Global)	No Date Specified
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.