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CTRI Number  CTRI/2024/01/061915 [Registered on: 29/01/2024] Trial Registered Prospectively
Last Modified On: 01/08/2025
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Multiple Arm Trial 
Public Title of Study   Safety and Effectiveness Study in Patients with Liver and Kidney Related Severe Complications using Ambrisentan (N-003) in Micro Doses  
Scientific Title of Study   A Multi-Centre, Randomised, Open-Label, Phase II Study of Ambrisentan in Patients with Hepatorenal Syndrome 
Trial Acronym  NIL 
Secondary IDs if Any  
Secondary ID  Identifier 
N-003-CRD005 Version 1.0 Dated 28.06.2023  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Shalimar 
Designation  Additional Professor 
Affiliation  All India Institute of Medical Sciences 
Address  Department of Gastroenterology and Human Nutrition Unit, Room No. 3111, 3rd floor, Teaching Block, All India Institute of Medical Sciences, Ansari Nagar

New Delhi
DELHI
110029
India 
Phone  9868397211  
Fax    
Email  drshalimar@yahoo.com  
 
Details of Contact Person
Scientific Query  
Name  Mala Srivastava  
Designation  Co-founder & Managing Partner 
Affiliation  Nextvel Consulting LLP 
Address  Nextvel Consulting LLP Novel Business Park, # 57, Salarpuria Triton, 13th Cross, Anepalya

Bangalore
KARNATAKA
560030
India 
Phone  9845238384  
Fax    
Email  malas@nextvel.com  
 
Details of Contact Person
Public Query  
Name  Mala Srivastava  
Designation  Co-founder & Managing Partner 
Affiliation  Nextvel Consulting LLP 
Address  Nextvel Consulting LLP Novel Business Park, # 57, Salarpuria Triton, 13th Cross, Anepalya

Bangalore
KARNATAKA
560030
India 
Phone  9845238384  
Fax    
Email  malas@nextvel.com  
 
Source of Monetary or Material Support  
Noorik Biopharmaceuticals AG 
 
Primary Sponsor  
Name  Noorik Biopharmaceuticals AG 
Address  Lange Gasse 15, 4052 Basel, Switzerland  
Type of Sponsor  Other [Privately owned Drug Development Company] 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study
Modification(s)  
No of Sites = 11  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Manas Kumar Panigrahi  All India Institute of Medical Science (AIIMS)  Sijua, Patrapada, Bhubaneswar - 751019.
Khordha
ORISSA 		 9438884267

manaskumarpanigrahi@gmail.com 
Dr Shalimar  All India Institute of Medical Sciences (AIIMS)  All India Institute of Medical Sciences, Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India – 110029.
New Delhi
DELHI 		 9868397211

drshalimar@yahoo.com 
Dr Raghu D K   Apollo Hospitals  Apollo Health City, Jubilee Hills, Hyderabad, Telangana-500096.
Hyderabad
TELANGANA 		 91 9121712121

rdk757@yahoo.com 
Dr Anand V Kulkarni  Asian Institute of Gastroenterology (AIG) Hospital  Asian Institute of Gastroenterology (AIG) Hospital, 1-66/AIG/2 to 5, Mindspace Road, Gachibowli, Hyderabad, Telangana - 500032
Hyderabad
TELANGANA 		 8553322434

anandvk90@gmail.com 
Dr Vinay Kumar  Ganesh Shankar Vidyarthi Memorial Medical College (GSVM)  Ganesh Shankar Vidyarthi Memorial Medical College (GSVM), Post Graduate Department of Medicine, GSVM Medical College, Kanpur, U.P., India – 208002
Kanpur Nagar
UTTAR PRADESH 		 8004877113

dr.vinaysachan@gmail.com 
Dr Sangitanjan Dutta  Gauhati Medical College and Hospital  Internal Medicine, Department of Medicine, Nanakasur Hiltop, Bhangagarh, Guwahati
Kamrup
ASSAM 		 8011933188

sangitanjandutta@gmail.com 
Dr Chitranshu Vashishtha  Institute of Liver and Biliary Sciences (ILBS)  Institute of Liver and Biliary Sciences, ILBS, D-1, Vasant Kunj, New Delhi, India – 110070
New Delhi
DELHI 		 9540951042

chitranshuv@gmail.com 
Dr SK Mahiuddin Ahammed  Institute of Post Graduate Medical Education and Research (IPGMER) and SSKM Hospital  Department of Hepatology, 244 AJC Bose Road, Kolkata, 700020
Kolkata
WEST BENGAL 		 9051157404

skmahiuddinahammed@gmail.com 
Dr B V Tantry  Kasturba Medical College (KMC)  Department of Gastroenterology, Dr B R Ambedkar Circle, Mangalore - 575001
Dakshina Kannada
KARNATAKA 		 9845789100

tantrybv@gmail.com 
Dr Ajay Kumar Duseja  Post Graduate Institute of Medical Education and Research  Nehru Hospital Extension Block (NHEB), Department of Hepatology, Room No.36, Ground Floor, PGIMER Chandigarh- 160012
Chandigarh
CHANDIGARH 		 9417007416

ajayduseja@yahoo.co.in 
Dr Akash Shukla  Sir H N Reliance Hospital Foundation and Research Center  Sir. H.N. Reliance Foundation Hospital and Research Centre, Prarthana Samaj, Raja Rammohan Roy Rd, Girgaon, Mumbai, Maharashtra, India – 400004.
Mumbai
MAHARASHTRA 		 9137009394

drakashshukla@yahoo.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 11  
Name of Committee  Approval Status 
Ethics Committee Gsvm Medical College Kanpur  Approved 
IEC of Sir H N Reliance Foundation Hospital and RC  Submittted/Under Review 
Institute Ethics Committee All India Institute of Medical Sciences  Submittted/Under Review 
Institutional Ethics Committee Asian Institute of Gastroenterology  Approved 
Institutional Ethics Committee Gauhati Medical College and Hospital  Submittted/Under Review 
Institutional Ethics Committee Institute of Liver and Biliary Sciences  Submittted/Under Review 
Institutional Ethics Committee(Faculty Research), AIIMS,Bhubaneswar  Approved 
Institutional Ethics Committee, PGIMER Chandigarh  Approved 
Institutional Ethics Committee-Clinical Studies Apollo Hospitals Hyderabad  Approved 
IPGMEandR Research Oversight Committee  Submittted/Under Review 
MAHE Ethics Committee   Submittted/Under Review 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: K767||Hepatorenal syndrome,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  N-003 (ambrisentan)  Ambrisentan is an endothelin receptor antagonist (ATC code: C02KX02, Antihypertensives for Pulmonary Arterial Hypertension (PAH)), preferentially selective to the endothelin type A receptor (ETA). At steady-state, ex vivo studies have shown that ambrisentan is more than 4000-fold selective for the ETA receptor than the ETB receptor. Ambrisentan is currently authorized for marketing in the European Union and approved in the US as Volibris® and Letairis® tablets, respectively and for the treatment of PAH. Ambrisentan is administered to patients with PAH at doses of 5 mg or 10 mg once per day. Ambrisentan is also available in India and commercialized since 2010. Subjects assigned to either of the ambrisentan arms (Group AMB1 – Low Dose – LD and Group AMB2 – High Dose – HD) will receive the study medication once a day, from Day 1 to Day 60.  
Comparator Agent  Terlipressin  Terlipressin is a vasopressor which is used as a standard of care in patients with Hepatorenal syndrome. Subjects assigned to terlipressin group [Group T] will receive the treatment from Day 1 to Day 14. 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  60.00 Year(s)
Gender  Both 
Details  1. Written Informed consent prior to any study-related procedures.2. Age greater than or equal to 18 years and less than or equal to 60 years.3. Male or non-pregnant, non-lactating female. Women of child-bearing potential must have a confirmed negative serum pregnancy test at the time of screening and must use a highly effective contraceptive method throughout the study. Men must use an effective contraception method, and should not donate semen during the study. Men are considered to be fertile from the time of puberty, except for those men with permanent sterility secondary to bilateral orchiectomy. 4. Cirrhosis of the liver by laboratory examination, clinical history or biopsy. 5. History of ascites. 6. Increase in serum creatinine greater than or equal to 0.3 mg/dl (26.5 micro mol/L) from a value obtained in the 7 days prior to admission, OR a serum creatinine greater than or equal to 1.5 mg/dl (132.6 micro mol/L) and is greater than or equal to 1.5-fold above the most recent and lowest value obtained in the last 3 months. 7. Subject has completed 48 hours of diuretic withdrawal and plasma volume expansion with albumin prior to study inclusion (e.g., 1 g/kg for first 24 hours and not to exceed 100 g, followed by 20-40 g in second 24 hours). 8. No sustained improvement in renal function during 48 hours of both diuretic withdrawal and plasma volume expansion with albumin, defined as a decrease in serum creatinine of less than 20% from initial value. 
 
ExclusionCriteria 
Details  1. Serum creatinine > 5 mg/dL at the end of the 48-hour diuretic withdrawal and plasma volume expansion with albumin period.
2. Mean arterial pressure (MAP) < 60 mmHg, Large Volume Paracentesis in the 3 days prior to screening.
3. Sepsis, uncontrolled bacterial infection or less than 2 days anti-infective therapy for documented or suspected bacterial infection.
4. Total bilirubin > 8 mg/dL (137 micro mol/L).
5. Serum sodium < 130 mmol/L.
6. International Normalised Ratio (INR) greater than or equal to 3.5.
7. Proteinuria greater than or equal to 500 mg/dL.
8. Microhaematuria > 50 red blood cells per high power field.
9. Clinically significant casts on urinalysis, including granular casts.
10. History or evidence of obstructive uropathy or parenchymal renal disease on ultrasound or other imaging.
11. Subject with a recent history of circulatory shock defined as MAP < 60 mmHg within 5 days prior to screening requiring vasopressors or subjects requires circulatory support with vasopressors during screening.
12. Subject requiring oxygen supplementation or mechanical ventilation.
13. Recent exposure to nephrotoxic agents or exposure to radiographic contrast agents within 72 hrs prior to screening.
14. Superimposed acute liver failure/injury due to factors other than alcohol, including acute viral hepatitis, drugs, medications (e.g., acetaminophen), or other toxins (e.g., mushroom [Amanita] poisoning).
15. Severe cardiovascular disease, including, but not limited to, unstable angina, pulmonary oedema, congestive heart failure (NYHA ≥ II), or persisting symptomatic peripheral vascular disease, myocardial infarction or stable chronic angina within the past 12 months, or any other cardiovascular disease judged by the Investigator to be severe.
16. Subject has a history of Transjugular Intrahepatic Portosystemic shunt (TIPS).
17. Subject with acute variceal bleeding at the time of screening who may undergo pre-emptive TIPS or is anticipated to be treated with terlipressin.
18. Current or recent Renal Replacement Therapy (RRT) within 30 days of enrolment, or anticipation of RRT in the next 3 days after screening.
19. Hepatocellular Carcinoma (HCC) beyond the Milan criteria or other malignancy affecting survival beyond 6 months.
20. Participation in a study of an investigational medical product or device within the last 30 days preceding screening.
21. Hepatic Encephalopathy with West Haven Grade III or IV.
22. Current or recent (30 days prior to enrolment) treatment with endothelin receptor antagonists, including ambrisentan. Subjects receiving midodrine and/or octreotide may be enrolled. Midodrine and octreotide treatment must be stopped prior to enrolment.
23. Estimated life expectancy of less than 3 days. Known allergy or sensitivity to ambrisentan or propylene glycol. History of Idiopathic Pulmonary Fibrosis.
24. Subject is unable or unwilling to follow instructions or comply with study procedures.
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Centralized 
Blinding/Masking   Not Applicable 
Primary Outcome  
Outcome  TimePoints 
The primary efficacy endpoint is defined as the change in eGFR from baseline to Day 4  From baseline to Day 4 
 
Secondary Outcome  
Outcome  TimePoints 
Proportion of subjects achieving HRS Reversal up to Day 14  Up to Day 14 
Proportion of subjects experiencing HRS Recurrence up to Day 60
 		 Up to Day 60 
Overall survival up to Day 60  Up to Day 60 
 
Target Sample Size   Total Sample Size="45"
Sample Size from India="45" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 2 
Date of First Enrollment (India)   20/02/2024 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="1"
Months="3"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Not Applicable 
Recruitment Status of Trial (India)  Open to Recruitment 
Publication Details   N/A 
Individual Participant Data (IPD) Sharing Statement

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

Response - NO
Brief Summary  

The study is multi-center, randomised, open-label, interventional, proof-of-concept trial of parallel groups. For repurposing of Ambrisentan which is already approved in India since 2010 for Pulmonary Arterial Hypertension (PAH) at 5 and 10 mg strengths. In this trial, the microdose of Ambrisentan which is 80 folds less than the approved dose to be used in Hepatorenal Syndrome (HRS) subjects. Prior clinical studies have reported encouraging results with the microdose of Ambrisentan developed by Noorik Biopharmaceuticals. Therefore, this trial is being proposed in Indian subjects to potentially treat the HRS subjects.

Ambrisentan has a well-studied and understood safety and pharmacokinetic profile. It has been proven to be safe based on the various toxicity studies performed with Ambrisentan in various animal species. Phase I Clinical Trial with N-003 in healthy subjects to determine the pharmacokinetic profile. Two Phase II studies in liver cirrhosis and ascites patients shows that Ambrisentan is pharmacologically active at micro-doses and a reversal of the effects of endothelin in the liver and kidney have been observed.

This Phase II, Multi-Centre, Randomised, Open-Label, with N-003 in Patients with HRS is planned to be performed at 9 leading institutions in India. 45 subjects enrolled will be randomly assigned equally to one of three arms - Group AMB1: Low dose and Group AMB2 – High Dose, and Group T: Terlipressin. For AMB1 and AMB2 subjects will receive 60 days treatment and followed up 10 days post cessation of treatment. Group T treatment will be for 14 days as per standard practice.

 
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