Study on Acute blood poisoning due to infection and toxins resulting into bleeding tendency

Phase 3

Completed

• Conditions: Other specified diseases of bloodand blood-forming organs,

• Registration Number: CTRI/2013/09/003995
• Lead Sponsor: Asahi Kasei Pharma America Corporation

Brief Summary

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|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.

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|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 

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|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 Xigris which showed evidence of efficacy in early clinical trials, was withdrawn from the market by the manufacturer (Eli Lilly and Co.) on October 25, 2011.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

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|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 

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|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.

Detailed Description

Not available

Study Timeline

• Study Start: 2013-12-26
• Last Update Posted: 2019-01-04
• Study Completion: 2019-02-21

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 800

Inclusion Criteria

• Subjects must be receiving treatment in an ICU or in an acute care setting (e.g., Emergency Room, Recovery Room).
• Subjects with a.
• Clinical objective evidence of bacterial infection and a known site of infection.
• 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.
• 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.
• 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.
• 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.
• 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.

Exclusion Criteria

• 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.
• 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.
• Confirmed or suspected endocarditis.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
•28 day all-cause mortality	•long term survival status at the 3 month, 6 month and 12 month time points

Secondary Outcome Measures

Name	Time	Method
•Follow-up of all-cause mortality at 3 months	•Resolution of Organ Dysfunction through Day 28 as measured by

Trial Locations

Locations (10)

Artemis Hospital; 🇮🇳 Gurgaon, HARYANA, India

Bharati Vidyapeeth Deemed University Medical College Bharti Hospital and Research Centre; 🇮🇳 Pune, MAHARASHTRA, India

J.S.S.Hospital; 🇮🇳 Mysore, KARNATAKA, India

KLES Dr.Prabhakar Kore Hospital & Medical Research centre; 🇮🇳 Belgaum, KARNATAKA, India

Maulana Azad Medical College and Associated L N Hospitals; 🇮🇳 Delhi, DELHI, India

Mazumdar Shaw Medical centre (Unit of Narayana Health); 🇮🇳 Bangalore, KARNATAKA, India

Noble Hospital; 🇮🇳 Pune, MAHARASHTRA, India

Ruby Hall Clinic; 🇮🇳 Pune, MAHARASHTRA, India

Shalby Hospital; 🇮🇳 Ahmadabad, GUJARAT, India

St. Theresa Hospital; 🇮🇳 Hyderabad, ANDHRA PRADESH, India

Artemis Hospital

🇮🇳Gurgaon, HARYANA, India

Dr Reshma Tewari

Principal investigator

91-1246767708

reshma@artemishospitals.com