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CTRI Number  CTRI/2013/09/003995 [Registered on: 18/09/2013] Trial Registered Prospectively
Last Modified On: 01/04/2019
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Biological 
Study Design  Randomized, Parallel Group, Placebo Controlled Trial 
Public Title of Study   Study on Acute blood poisoning due to infection and toxins resulting into bleeding tendency 
Scientific Title of Study   A randomized double blind, placebo controlled phase 3 study to assess the safety and efficacy of ART-123 in subjects with severe sepsis and coagulopathy 
Trial Acronym  NA 
Secondary IDs if Any
Modification(s)  
Secondary ID  Identifier 
3-001 Ver 4.1 dated 28 Apr 2017  Protocol Number 
NCT01598831  ClinicalTrials.gov 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Modification(s)  
Name  Dr Veena Ramanna 
Designation  Project Director 
Affiliation  Asiatic Clinical Research Pvt. Ltd. 
Address  169/53, 14 th Main road, 1st block east, Jayanagar, BANGALORE

Bangalore
KARNATAKA
560 011
India 
Phone  91-80-41681122  
Fax  91-80-41213841  
Email  sepsis-associates@asiaticlinical.com  
 
Details of Contact Person
Scientific Query
Modification(s)  
Name  Dr Veena Ramanna 
Designation  Project Director 
Affiliation  Asiatic Clinical Research Pvt. Ltd. 
Address  169/53, 14 th Main road, 1st block east, Jayanagar, BANGALORE

Bangalore
KARNATAKA
560 011
India 
Phone  91-80-41681122  
Fax  91-80-41213841  
Email  sepsis-associates@asiaticlinical.com  
 
Details of Contact Person
Public Query
Modification(s)  
Name  Dr Veena Ramanna 
Designation  Project Director 
Affiliation  Asiatic Clinical Reasearch Pvt. Ltd. 
Address  169/53, 14 th Main road, 1st block east, Jayanagar, BANGALORE

Bangalore
KARNATAKA
560 011
India 
Phone  91-80-41681122  
Fax  91-80-41213841  
Email  sepsis-associates@asiaticlinical.com  
 
Source of Monetary or Material Support  
Asahi Kasei Pharma America Corporation 
 
Primary Sponsor  
Name  Asahi Kasei Pharma America Corporation 
Address  200 Fifth avenue, Waltham, MA 02451 USA 
Type of Sponsor  Other [Biopharmaceutical company] 
 
Details of Secondary Sponsor  
Name  Address 
Asiatic clinical research pvt ltd  169/53, 14 main road, 1st block east, Jayanagar Bangalore- 560 011 
 
Countries of Recruitment
Modification(s)  		   United States of America
Argentina
Australia
Belgium
Brazil
Bulgaria
Canada
Colombia
Croatia
Czech Republic
Finland
France
Germany
Greece
Hungary
India
Israel
Netherlands
New Zealand
Peru
Republic of Korea
Russian Federation
Serbia
Spain
Taiwan
Turkey
United Kingdom  
Sites of Study
Modification(s)  
No of Sites = 10  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Reshma Tewari  Artemis Hospital  Sector 51, Wazirabad Village, Gurgaon, Haryana 122001
Gurgaon
HARYANA 		 91-1246767708
91-1246767708
reshma@artemishospitals.com 
Dr Shivakumar Iyer  Bharati Vidyapeeth Deemed University Medical College Bharti Hospital and Research Centre  Pune-Satara Road Katraj Dhanakwadi, Pune 411043
Pune
MAHARASHTRA 		 91-9822051719
020-24375541
suchetashiva@gmail.com 
Dr Sudharshana Murthy KA  J.S.S.Hospital   M.G.Road Mysore-570004
Mysore
KARNATAKA 		 91-9448457077
91-8212548368
drsurthy@gmail.com 
Dr Jayaprakash Appajigol  KLES Dr.Prabhakar Kore Hospital & Medical Research centre  Nehru nagar, Belgaum-590010
Belgaum
KARNATAKA 		 91-9844595659
091-8312493099
jayaprakashappajigol@gmail.com 
Dr Mradul Kumar Daga  Maulana Azad Medical College and Associated L N Hospitals  129, B. L. Taneja Block, Bahadur Shah Zafar Marg New Delhi Delhi 110002
New Delhi
DELHI 		 91-9968604273
01191-23222964
drmraduldaga@gmail.com 
Dr Shivprasad Chandrasekhar  Mazumdar Shaw Medical centre (Unit of Narayana Health)  258/A Bommasandra Industrial Area Hosur Road, Anekal taluk Bangalore 560099
Bangalore
KARNATAKA 		 91-9845017485
91-08027832648
prasad_905@yahoo.com 
Dr Zafer A Khan  Noble Hospital   Magarpatta City Road, Hadapsar, Pune 411013
Pune
MAHARASHTRA 		 91-020-43285136
91-020-26890157
zafer_a_khan@yahoo.com 
Dr Sanmay Chowdhury  Ruby Hall Clinic  Grant Medical Foundation, Ruby Hall Clinic #40 Sassoon Road Pune 411011
Pune
MAHARASHTRA 		 91-02066455495
91-0206645628
drsanmay@gmail.com 
Dr Minesh Mehta  Shalby Hospital  S.G. Highway Ahmadabad 380015
Ahmadabad
GUJARAT 		 919904403751
917940203115
minesh.mehta@shalby.in 
Dr Sambit Sahu  St. Theresa Hospital  Opposite Rythu bazaar, Sanathnagar Hyderabad 500 018
Hyderabad
ANDHRA PRADESH 		 91-04023814556
91-04423814556
sambit2k@yahoo.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 10  
Name of Committee  Approval Status 
Artemis Health Sciences Institutional Ethics Committee  Approved 
Ethics Committee - Shalby Limited  Approved 
Ethics Committee KLE University   Approved 
Ethics committee St Theresas hospital  Approved 
Institutional Ethics Committee Bharati Vidyapeeth Deemed University  Approved 
Institutional Ethics Committee Maulana Azad Medical College and Associated Hospital  Approved 
Institutional Ethics Committee JSS Medical College  Approved 
Institutional ethics committee Poona medical research foundation  Approved 
Narayana Hrudayalaya Medical Ethics Committee (NHMEC)  Approved 
Noble Hospital institutional ethics committee  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied
Modification(s)  
Health Type  Condition 
Patients  (1) ICD-10 Condition: D758||Other specified diseases of bloodand blood-forming organs,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  ART-123 and standard of care  ART-123 , are administered at the equivalent dose of 0.06 mg/kg/day up to a maximum dose of 6.0 mg/day for six days. ART-123 is given by intravenous bolus or rapid IV infusion, in which case 0.06 mg/kg/day up to a maximum dose of 6.0 mg/day is diluted in 50 mL of Normal Saline (NS) and given over the period of 15 minutes.  
Comparator Agent  Placebo and standard of care  Placebo, are administered at the equivalent dose of 0.06 mg/kg/day up to a maximum dose of 6.0 mg/day for six days. It is given by intravenous bolus or rapid IV infusion, in which case 0.06 mg/kg/day up to a maximum dose of 6.0 mg/day is diluted in 50 mL of Normal Saline (NS) and given over the period of 15 minutes. 
 
Inclusion Criteria
Modification(s)  
Age From  18.00 Year(s)
Age To  65.00 Year(s)
Gender  Both 
Details  1. Subjects must be receiving treatment in an ICU or in an acute care setting (e.g., Emergency Room, Recovery Room).
2. Subjects with a. Clinical objective evidence of bacterial infection and a known site of infection. b. Current treatment with intravenous antibiotics.c. White Blood Cell (WBC) count greater than 12,000 per mm3 or less than 4,000 per mm3 or Bandemia greater than 10percent. d. Temperature of less than 36 degree centrigrade or fever greater than 38 degree centigrade. For hypothermia, a core reading is preferred. Note 1 If a subject has a Gram stain consistent with bacterial infection, positive culture from blood or an otherwise sterile body fluid, observed peritonitis, positive urinary antigen, clinical presentation of meningococcemia, or otherwise compelling evidence of infection as determined by the CCC, only one of the two inclusion criteria 2c (WBC) or 2d (temperature) is required. Note 2 The presence of concurrent fungal or viral infection is allowed for the study entry, provided that the primary reason for treatment is bacterial infection.
3. Subjects with sepsis-associated organ dysfunction defined by at least one of the following:
a. Cardiovascular Dysfunction defined as requiring both adequate fluid resuscitation and vasopressors to maintain Mean Arterial Pressure (MAP) greater than or equal to 65 mmHg (implies fluid resuscitation alone does not raise MAP to greater than 65 mmHg). Adequate fluid resuscitation is defined as:
o Intravenous administration of at least 20 mL perkg crystalloid or 10 mL perkg colloid infusion within 6 hours.
OR
o Central Venous Pressure (CVP) of greater than 8 mmHg or Pulmonary Artery Wedge Pressure (PAWP) of greater than 12 mmHg.
If dopamine is the only vasopressor used, the infusion rate must be greater than 5 μg perkg permin (i.e., must be prescribed to support cardio-pulmonary perfusion). If vasopressin is used, it must be given in conjunction with another vasopressor.
b. Respiratory Dysfunction is defined as the acute need for mechanical ventilation and PaO2-FiO2 ratio of less than 250 (or less than 200 when lung is the site of infection). For the purposes of this protocol, mechanical ventilation is defined as any type of ventilation administered via an endotracheal tube or nasotracheal intubation. A simple administration of supplemental oxygen is NOT considered to be mechanical ventilation for the purposes of this study.
4. Subjects with coagulopathy characterized by an INR greater than1.40 without other known etiology (e.g., anticoagulant therapy, chronic liver disease)
5. Subjects with coagulopathy characterized by platelet count in the range of greater than 30,000 permm3 to less than 150,000 per mm3 OR a greater than 30 percent decrease in platelets in 24 hours
 
 
ExclusionCriteria 
Details  Candidates for the study will be excluded if ANY of the following criteria are present:

1. Subject or Authorized Representative is unable or unwilling to provide initial or ongoing informed consent (as applicable per local and country regulations)
2. Subject is pregnant or breastfeeding or intends to get pregnant within 28 days of enrolling into the study
3. Subject is of childbearing potential and has a positive pregnancy test since admission to the hospital
4. Subject is less than 18 years of age
5. Subject has a known allergy to ART-123 or any components of the drug product
6. Subject is unwilling to allow transfusion of blood or blood products
7. Presence of an advance directive to withhold life-sustaining treatment (patients not wishing to receive Cardiopulmonary Resuscitation (CPR) may qualify provided they receive all other resuscitative measures e.g. mechanical ventilation, vasoactive agents, cardioversion).
8. Subject has had previous treatment with ART-123
9. Body weight equal to or greater than 175 kg
10. PT prolongation or thrombocytopenia that is not due to sepsis (e.g. AML or ALL in induction therapy, acute leukemia of the M3 type, myeloablative therapy within 4 weeks prior to enrollment, AIDS with persistent thrombocytopenia and/or bleeding disorder, ongoing pre-existing thrombocytopenia or coagulopathy),Platlets ≤ 30,000 / mm3 for any reason.
11. Any surgery that is potentially hemorrhagic (e.g. intra-thoracic, intra-abdominal or non-traumatic orthopedic surgery of the femur or pelvis) within 12 hours prior to the first dose of study drug, or ongoing impairment of hemostasis as a result of one of these procedures.
12. A history of head trauma, spinal trauma, or other acute trauma with an increased risk of bleeding within 3 months prior to consent (subjects with minor head trauma may be enrolled if there is a normal neurological examination and a normal CT scan of the head/spine post injury documented in the medical record).
13. Cerebral Vascular Accident (CVA) within 3 months prior to consent.
14. Any history of Intracerebral Arteriovenous Malformation (AVM), cerebral aneurysm, or mass lesions of the central nervous system.
15. A history of congenital bleeding diatheses (e.g. hemophilia).
16. Significant gastrointestinal bleeding (e.g., melena, hematemesis) within 6 weeks prior to consent unless a corrective interventional procedure has been performed (i.e. endoscopy).
17. Subject is diagnosed with a known medical condition associated with a hypercoagulable state, including:
a. Resistance to activated protein C or known Factor V Leiden
b. Hereditary deficiency of protein C or protein S
c. Presence of anticardiolipin antibody, antiphospholipid antibody, or prothrombin gene mutation
d. Deep-vein thrombosis or pulmonary embolism within 3 months prior to consent (if evaluation is in progress, this should be completed before consideration for this trial)
e. Any disorder with a requirement for full anticoagulation.
18. History of cirrhosis or current Class C liver disease (Child-Pugh score of 10-15)
19. Portosystemic hypertension or known history of bleeding esophageal varices.
20. History of solid organ, allogeneic bone marrow, or stem cell transplantation within the 6 months prior to consent (uncomplicated kidney and autologous stem cell/bone marrow transplant subjects may be enrolled at any time after they have recovered from their transplant procedure).
21. Acute pancreatitis where infection has not been documented by a positive blood or abdominal fluid culture. Also, in the opinion of the treating physician the subject is at an increased risk for developing hemorrhagic pancreatitis over the duration of the study.
22. Subjects with renal dysfunction defined as:
a. Chronic renal failure requiring renal replacement therapy (RRT), or
b. Subjects with sepsis induced renal dysfunction (average urine output < 0.3ml/kg/hr) for greater than 48 hours prior to first dose of study drug whether receiving RRT or not
Note: Except for 22a and 22b, subjects with renal dysfunction are eligible for this study regardless of whether they are or are not receiving RRT.
23. Use of anticoagulants, antiplatelet agents, antithrombotics and thrombolytics within the 72 hours prior to first dose of study drug with the exception of:
a. Heparin locks or flushes
b. DVT prophylaxis per prophylactic dosing on the package insert as approved in your country
c. Up to 325mg of aspirin daily for cardiac prophylaxis only
d. Anticoagulants for RRT: Regional citrate is preferred. It is recommended that if unfractionated heparin or LMWH is used, that the systemic exposure be less than or equal to the DVT prophylaxis dose allowed.
24. Life expectancy less than 90 days due to underlying conditions such as, but not limited to, the following:
a. Poorly controlled neoplasms
b. New York Heart Association class IV or pulmonary vascular disease resulting in severe exercise restriction (i.e., unable to climb stairs or perform household duties), or chronic restrictive or obstructive pulmonary disease that also results in severe exercise restriction, or documented chronic hypoxia (needs continuous home oxygen treatment), hypercapnia, secondary polycythemia, severe pulmonary hypertension (Mean Arterial Pulmonary pressure level of greater than 40 mmHg) or respiratory dependency
c. Prior cardiac arrest requiring CPR without fully demonstrated neurological recovery, or subject with imminent death.
d. End-stage neurological disorders (e.g., amyotrophic lateral sclerosis-Lou Gehrig’s disease)
25. Current use of any chemotherapy agent likely to cause myeloablation
26. Participation in another research study involving an investigational agent within 30 days prior to consent.
27. Confirmed or suspected endocarditis
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Centralized 
Blinding/Masking   Participant and Outcome Assessor Blinded 
Primary Outcome  
Outcome  TimePoints 
• 28 day all-cause mortality  •long term survival status at the 3 month, 6 month and 12 month time points 
 
Secondary Outcome
Modification(s)  
Outcome  TimePoints 
• Follow-up of all-cause mortality at 3 months
• Resolution of Organ Dysfunction through Day 28 as measured by
o Shock free and alive days
o Ventilator free and alive days
o Dialysis free and alive days 		 long term survival status at the 3 month, 6 month and 12 month time points 
 
Target Sample Size   Total Sample Size="800"
Sample Size from India="120" 
Final Enrollment numbers achieved (Total)= "816"
Final Enrollment numbers achieved (India)="86" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)
Modification(s)  		 26/12/2013 
Date of Study Completion (India) 21/02/2019 
Date of First Enrollment (Global)  31/10/2012 
Date of Study Completion (Global) 28/02/2019 
Estimated Duration of Trial
Modification(s)  		 Years="5"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Completed 
Recruitment Status of Trial (India)  Completed 
Publication Details   Not Applicable 
Individual Participant Data (IPD) Sharing Statement

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

Brief Summary  

i.Severe Sepsis is a life threatening condition which is defined by the presence of severe infection and systemic inflammatory response to the infection, leading to one or more organ failures.

ii.Mortality remains very high, about 25-50%, in severe sepsis patients in spite of advanced antibiotics therapy and supportive care in the form of vasopressors, and fluid infusions.

iii.Sepsis is the most common cause of death in the ICU.

  Rationale for ART-123 in Sepsis with Coagulopathy

i.Coagulopathy is associated with increased mortality in sepsis.

 ii.Coagulation and inflammatory pathways are intricately linked and Thrombomodulin appears to play a key role both as a scavenger and modulator of 

thrombin activity, and its role as an endothelial cell surface protein.

iii.Modulation of coagulation is a likely method to impact the prognosis of patients with sepsis and coagulopathy. iv.ART-123 treated subjects with infection and coagulopathy have shown reducedmortality in a Phase III clinical trial conducted in Japan and a positive trend of reduced mortality in a Phase II b clinical trial conducted globally. v.Numerous therapies intended to target the various biological pathways of sepsis like Drotrecogin alfa (recombinant human activated protein C, Xigris®), have failed to show evidence of efficacy. Xigris which showed evidence of efficacy in early clinical trials, was withdrawn from the market by the manufacturer (Eli Lilly and Co.) on October 25, 2011.  Global Phase 2 b trial (INDIA was part of the trial): Rationale for ART-123 The post-hoc analysis of the global phase 2b study suggested that ART-123 was beneficial to sepsis patients with coagulopathy (INR > 1.4), and elevated inflammation (at least one organ dysfunction). It is therefore proposed that ART-123 will be indicated for reduction of mortality in patients with coagulopathy as a result of severe sepsis based on both its mode of action, and results from the previous clinical trials.

In the safety pharmacology studies of ART-123, no effects were noted on,

•General Behaviour,

•Central and Autonomic Nervous System,

•Respiratory,

•Cardiovascular,

•Gastro-intestinal, or

•Urinary systems

Mild and transient salivation events have been documented and there was no dose-dependence.
Since direct and excessive inhibition of thrombin is thought to cause bleeding, this 
absence of direct inhibitory effect from clinically recommended dose of ART-123 would present a lower risk of bleeding. This makes ART-123 much safer in terms of bleeding risk than direct thrombin inhibitors like Heparin.
The animal studies substantiating the wider safety margin to haemorrhage compared with Heparin is given in several reports, like IB, non-clinical data, and scientific advice from EMEA.
  
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