Ulinastatin final

Septic Shock.. Evidence based role of ulinastatin

1. ULINASTATIN DR ANKIT GAJJAR MD, IDCCM INTENSIVIST MISSION HOSPITAL, SURAT

2. Goals of Talk Sepsis definition & Pathophysiology Treatment Modalities Gaps in Current Therapies Need for the specific drug Ulinastatin Pharmacology Ulinastatin Uses Evidence

3. Developing new definitions European Society of Intensive Care Medicine Society of Critical Care Medicine “ Shift of focus from Inflammation to Organ Dysfunction”

4. New definitions Sepsis: A life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock: Sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Terms like severe sepsis/ septicemia removed

5. Therapeutic Strategies Sepsis Management

6. The principles in the management of sepsis include the following components: Early recognition Fluid therapy Blood and other body fluids for culture Early and adequate antibiotic therapy Source control Early hemodynamic resuscitation and continued support Tight glycemic control Corticosteroids Proper ventilator management 8

7. Scope of Sepsis Sepsis affects over 18 million people worldwide and has an expected 1% increase in incidence per year. It is the most common cause of death in hospitalized patients Indian Scenario * Incidence of sepsis is 16.45% of ICU admissions (~ 1 Mn cases annually) Mortality rate (28 day mortality) has been reported at 65%- which is higher than reported in western literature (35% to 40%) Incidence / 100000 * Todi S et al, Epidemiology of severe sepsis in India: an update. Critical Care 2010; 14( Suppl 1): P382

8. Epidemiology of severe sepsis in India: an update S Todi , 1 S Chatterjee, 1 S Sahu, 2 and M Bhattacharyya 1 1 AMRI Hospitals, Kolkata, India 2 Kalinga Hospital, Bhubaneswar, India Conference abstract 30th International Symposium on Intensive Care and Emergency Medicine. 9–12 March 2010, Brussels, Belgium Results Multicentre, prospective study in 4 ICUs over 3 years period All ICU admissions screened daily for SIRS, organ dysfunction and severe sepsis 5,478 ICU admissions, SIRS with organ dysfunction in 1,385 (25%) Sepsis in 731 (52.77%) Severe sepsis = 16.45% of all admissions. Median APACHE II score =13 (IQR 13 to 14) Mortality: All ICU patients 12.08% Sepsis: ICU - 59.26%., Hospital – 65.2%, 28-day mortality – 64.6% Median ICU stay = 13 days (IQR 11 to 17). Conclusions Severe sepsis is common in Indian ITUs. ITU mortality is higher compared with western literature..

9. Severe Sepsis: Comparative Incidence and Mortality

10. Am J Respir Crit Care Med 2006;173:256-263

11. Lack of Treatment Options

12. The eritoran trial began in June 2005 and was in the last stage of patient studies generally required to seek regulatory approval. It studied patients and compared their mortality rate after 28 days of hospitalization Lack of Treatment Options TLR4 antagonist Structurally similar to Lipid A of bacterial lipopolysaccharide

13. Gaps in Existing Therapies Sepsis - leading cause of morbidity and mortality throughout the world. Although bacteria cause sepsis, death in patients not merely due to bacteria Rather death due to paralysis of immune system and uncontrolled systemic inflammatory response. Antibiotics & supportive ICU care are the only available treatment for Sepsis. Mortality remains high despite current standard of care Need for new drugs to reduce inflammation, reverse SIRS, shorten duration of illness, decrease mortality 16

14. Launching India's 1 st Ulinastatin Bharat Serums and Vaccines Limited

15. INTRODUCTION Sepsis is caused by the interaction between pathogen-associated molecular patterns and pattern recognition receptors on host immune cells . Many of the intermediaries in the systemic inflammatory processes are serine proteases. To counter-regulate the effect of these proteases, several protease inhibitors are produced by the liver in the presence of inflammation .

16. What is Ulinastatin ? IMMUNOMODULATORY AGENT First developed in 1970s- 1980s in JAPAN Ulinastatin ( Urinary Trypsin Inhibitor) is a kind of protease inhibitor extracted from human blood and urine. It is an acidic glycoprotein (molecular weight 30  kDa ) and composed of 143 amino acid residues and includes two Kunitz -type domains Produced from hepatocyte in presence of inflammation .

17. INTRODUCTION It is cleaved from the larger inter-α-trypsin inhibitor molecule by neutrophil elastase in the presence of inflammation, It reduces pro inflammatory response and inflammatory cytokines. Decrease in serum level in sepsis and septic shock.* *Lim YP et al J Infect Dis 188:919-926

18. ULINASTATIN : MOA Ulinastatin inhibits various enzymes such as α- chymotrypsin, thrombin, kallikrein , plasmin, cathepsin , lipase, amylase, neutrophil elastase , pancreatic elastase , polymorphonuclear leukocyte elastase , carboxylase, and the endotoxin-stimulated production of tumour necrosis factor (TNF)- α, IL-1, IL-8 and IL-6.  It reduces LPS-elicited circulatory failure through modulating TNF-α production, via the inhibition of early growth response factor (EGFR)-1 in monocytes and pulmonary induction of inducible nitric oxide synthase ( iNOS ). This causes a significant reduction in mortality by sepsis . Ulinastatin increases the serum level of fibrinogen and fibrinogen degradation products, thereby improving the coagulatory disturbance caused by sepsis

19. ULINASTATIN PHARMACODYNAMICS: Ulinastatin inhibits inflammatory markers: trypsin , pancreatic elastase , polymorphonuclear leukocyte elastase and the endotoxin-stimulated production of TNF alpha and interleukin 1, 8 and 6. It inhibits coagulation and fibrinolysis and promotes microperfusion . Ulinastatin is an effective agent for immune modulation to prevent organ dysfunction and promote homeostasis PHARMACOKINETICS : After intravenous injection of 200,000 I.U./10ml into healthy man, its concentration in blood decreases linearly . The half life of Ulinastatin is about 40 minutes. 6 hours after the administration, 24% of Ulinastatin is discharged in urine

20. ULINASTATIN PHYSICAL INFORMATION Clear colourless liquid 50000 – 100,000 I.U./ml Vial Dosage: 200,000 I.U. iv BD for 3-5 days (can be vary) Administration: Reconstituted in 100 ml of Dextrose 5% or 100 ml of 0.9% Normal Saline) by intravenous infusion over 1 hour each time Special Populations: Pregnancy – No Data Lactation – Contraindicated Children – No Data No Renal or Hepatic adjustment

21. ULINASTATIN WARNINGS: 1 . Not to be used for patients who are hypersensitive. 2 . Not to used in lactating women . PRECAUTIONS : Ulinastatin can NOT replace the traditional therapeutic methods for shocks DRUG INTERACTION: No drug interactions have been reported or noted .

22. ULINASTATIN OVERDOSE: No specific antidote is recommended in case of accidental overdose . UNDESIRABLE EFFECTS OR ADVERSE REACTION: 1. Rare cases of rash, itching and pain at the site of injection. 2. Rare cases of allergy. 3. Rare cases of elevation of SGOT and SGPT. 4. Rare cases of nausea, vomiting and diarrhea .

23. INDICATIONS Sepsis and Septic Shock Acute Pancreatitis Px of Post ERCP Pancreatitis ARDS TBI Post surgery Stevens–Johnson syndrome , Toxic epidermal necrolysis Severe Burns Post operative cognitive disorder Prevention of Renal failure ……. ……………………..

24. Usage Rationale: Clinical Studies

25. Anti-inflammatory role J Inflamm ( Lond ) 2010;7:45 Decrease in serum levels of ulinastatin in sepsis, with the lowest levels being found in patients with severe sepsis and septic shock . (J Infect Dis. 2003;188:919–926 ) Mortality due to experimental sepsis is higher in genetically modified knockout mice that lack the genes for synthesis of urinary trypsin inhibitor . ( Inflamm Res. 2010;59:679–687 ) Reduction in the systemic inflammatory response and organ dysfunction due to sepsis in animals treated with ulinastatin . ( Exp Toxicol Pathol . 2012;64:543–547 ) Ulinastatin may have a role as a novel therapy in severe sepsis . ( Immunotherapy. 2011;3:117–128 )

26. SEPSIS

27. A prospective, multicentric , double-blind, randomized, phase III clinical study to compare the efficacy and safety of I.V. Ulinastatin vs. placebo along with standard supportive care in subjects of severe sepsis n=114 32 D.R. Karnad et.al, Intensive Care Medicine; April 2014 Indian Experience

28. Study Design Multicenter Seven sites at various locations in India Medical or Surgical ICUs Site City ICU B Y L Nair Hospital & T N Medical College Mumbai Medical Lokmanya Tilak Muncipal General Hospital & Medical College Mumbai Medical Maulana Azad Medical College New Delhi Medical Vardhaman Mahavir Medical College and Safdarjung Hospita l  New Delhi Surgical Jehangir Hospital & Research Center Pune Medical/Surgical NDMVP Samaj Medical College & Hospital Nashik Medical/Surgical Bhatia Hospital Mumbai Medical/Surgical

29. Study design Randomization Block randomization Subjects were randomised in a 1:1 ratio Double blind Opaque sealed envelope for each subject Treatment Ulinastatin 200,000 IU dissolved in 250 ml normal saline within 48 hours IV infusion over one hour - twice a day (10 – 14 hours apart) x 5 days. Placebo Dissolved in 250 ml normal saline IV infusion over one hour - twice a day (10 – 14 hours apart) x 5 days.

30. Inclusion criteria Age between 18-60 years and Weight <135kg Evidence of infection Presence of systemic inflammatory response syndrome (SIRS) At least one organ system failure All four criteria must be present at enrollment

31. Absolute mortality reduction 13% Relative reduction in mortality 66% Number needed to treat 7.2 patients Primary end-point: 28 day all cause mortality

32. There was a significant reduction in the onset of new organ dysfunction, 26% Absolute reduction Secondary end points: onset of new organ dysfunction New onset organ dysfunction or worsening from baseline Placebo Ulinastatin P value (n=59) (n=55) Cardiovascular 9 4 0.18 Respiratory 8 4 0.27 Hematological 7 4 0.41 Hepatic 3 2 1 Renal 4 2 0.68 Central Nervous System 3 2 1 Total No. of patients with New Onset of organ dysfunction 26 10 0.003 

33. Decrease in duration of ventilation is highly suggestive of efficacy of Ulinastatin Reduces cost of care – important end point from pharmaco -economic perspective Decrease in Hospital stay is highly suggestive of better efficacy in UTI group Secondary end points: ventilator-free days & Duration of Hospitalisation

34. Limitations Less no. of patients… 114 Patients > 60 years were excluded

35. Journal of Evolution of Medical & Dental Sciences Observational Study First Author: Farhana Bashir n = 50 patients with Severe Sepsis 25 patients were administered 2 lac IU of ulinastatin twice a day for 7 days (Group A) , 25 patients formed the control group ( GroupB ) U- Tryp : Indian Evidences

36. Significant improvement was observed in APACHE II , MOF & GCS score J of Evolution of Med and Dent Sci / eISSN - 2278-4802, pISSN - 2278-4748/ Vol. 3/ Issue 53/Oct 16, 2014

37. European Society of Intensive Care Medicine Retrospective Cohort Study 1 st Author: Y. Mehta, 2014 n= 134 Severe Sepsis Patients 67 Patients received U- Tryp 200000 units, twice a day for 5 days along with antibiotics & standard care 67 patients received antibiotics and standard care Key Observations: 1. 24% reduction in mortality in the U- Tryp group 2. Significant reduction in the duration of Vassopressor Requirement & ICU Stay 2. Significant improvement in SOFA Score (14%, p 0.003) 3.Significant improvement in Serum Creatinine levels U-Tryp Indian Experiences

38. Ulinastatin in Sepsis Inhibition of the cytokines, reduction in the levels of TNF- α and Interleukin-6 Suppresses the activity of neutrophil Elastase and prevents the incidence of DIC Prevents progression to MOD’s in Sepsis Reduces New onset organ-dysfunction. Reduces overall mortality in sepsis

39. Ulinastatin in other indications Acute Pancreatitis

40. Efficacy and safety of intravenous ulinastatin versus placebo along with standard supportive care in subjects with mild or severe acute pancreatitis. Abraham P ,  Rodriques J ,  Moulick N ,  Dharap S ,  Chafekar N ,  Verma PK ,  Agrawal A ,  Prabhakar B ,  Basavaraj A ,  Shah A ,  Chaphekar AP ,  Biswal UC ,  Malhan ST ,  Bakshi G . CONCLUSIONS: Ulinastatin prevents new organ dysfunction and reduces mortality in subjects with severe pancreatitis. J Assoc Physicians India.  2013 Aug;61(8):535-8.

41. Ulinastatin in other indications Acute Lung injury and acute respiratory distress syndrome

42. Ulinastatin seems to be effective for ALI and ARDS though most trials included were of poor quality and no information on safety was provided

43. ARDS Twenty-nine RCTs with 1726 participants No studies discussed adverse effect. Oxygenation index was reported in twenty-six studies (1552 patients). Ulinastatin had a significant effect in improving oxygenation [standard mean difference (SMD) = 1.85, 95%CI: 1.42-2.29, P < 0.00001, I 2 = 92%]. ICU mortality and 28-d mortality were respectively reported in eighteen studies (987 patients) and three studies (196 patients).

44. Ulinastatin significantly de- creased the ICU mortality [I2 = 0%, RR = 0.48, 95%CI: 0.38-0.59, number needed to treat (NNT) = 5.06, P < 0.00001], while the 28-d mortality was not significantly affected (I2 = 0%, RR = 0.78, 95%CI: 0.51-1.19, NNT = 12.66, P = 0.24). The length of ICU stay (six studies, 364 patients) in the ulinastatin group was significantly lower than that in the control group (SMD = -0.97, 95%CI: -1.20--0.75, P < 0.00001, I 2 = 86%).

45. Ulinastatin in other indications Severe traumatic brain injury

46. Ulinastatin in other indications Trauma with hemorrhagic shock

47. Ulinastatin in other indications Acute traumatic craniocerebral injury

48. Ulinastatin in other indications Gastrectomy

49. Ulinastatin in other indications Liver Resection

50. Ulinastatin in other indications Acute circulatory insufficiency after surgical operation

51. Ulinastatin in other indications Major orthopedic surgery

52. Take Home Message Ulinastatin is Novel drug (IMMUNOMODULATION) No documented ADR Reduction in Cytokine Surge in Sepsis and other inflammatory conditions Animal datas and pilot studies shown benefits in mortality, organ dysfunction and ICU stay Can be used in Septic shock, Acute Pancreatitis, Px of Post ERCP Pancreatitis based on previous RCTs Needs further RCT trials with larger study samples

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54. Launching India's 1 st Ulinastatin Bharat Serums and Vaccines Limited