ULINASTATIN IN THE MANAGEMENT OF SEPSIS & ACUTE PANCREATITIS

DR PUNIT D. GHETIA

MD , IDCCM (MUMBAI)

CONSULTANT INTENSIVIST , BANKERS HEART INSTITUTE

Ulinastatin is a kind of glycoprotein extracted from human urinewhich acts as a Urinary Trypsin Inhibitor (UTI).

Physical Information:Ulinastatin for Injection is available as a clear, colourless liquid. Itcontains UTI of not less than 45,000 units per ml and not less than2500 units per mg protein.

Chemical Information:Molecular Weight: Ranges from 62 kDa to 72 kDa

ULINASTATIN

Pharmaceutical Information:

Appearance: White or light yellow lyophilized powder or clear colourless liquidpH: 6-8Sterility: SterileAssay: 90% to 110% of label claimShelf life: 2 years under the storage conditions at 2°C-8°C

MOLECULAR BASIS OF SEPSIS

Complement systemC3, C4, C9Factor BC1 inhibitorC4b - binding proteinMannose - binding protein

Coagulation and fibrinolyticsystemFibrinogen, PlasminogenTissue plasminogen activatorUrokinase, Protein S, VitronectinPlasminogen-activator inhibitor-1

TNF-alpha

NeutrophilElastase

UTI

UTIUTI

UlinastatininhibitsNeutrophil

elastasePlasminThrombinCathepsinKallikreinTrypsinTryptaseChymotrypsinSIRS

USAGE RATIONALEPRE-CLINICAL STUDIES

URINARY TRYPSIN INHIBITOR REDUCES INFLAMMATORY RESPONSE IN KIDNEY INDUCED BY LIPOPOLYSACHHARIDE

ROLE OF ULINASTATIN IN DOWNREGULATION OF TNF-α

Masaaki, U et al. Journal of Bioscience andBioengineering, 2007, Vol. 104, No. 4, 315-320

Absence of Ulinastatin gene increases organ injury induced by bacterial endotoxin

WT LPS

UTI (-/-) LPS

p<0.01KIDNEY

WT LPS

UTI (-/-) LPS

p<0.01LIVER

Ken-Ichiro I, et al. Mol Pharmacol67:673–680, 2005

WT LPS

UTI (-/-) LPS

p<0.01LUNG

WT : Wild type miceUTI (-/-) : Knock out mice without UTI gene

URINARY TRYPSIN INHIBITOR PROTECTS AGAINST SYSTEMIC INFLAMMATION INDUCED BY LIPOPOLYSACCHARIDE

Hiroshi Kobayashi et al. The Journal of Infectious Diseases 2005; 191:930–8

ULINASTATIN IMPROVES SURVIVAL LPS

LPS + UTI 25

LPS + UTI 50

ULINASTATIN SUPPRESSES LIPOPOLYSACCHARIDE-INDUCED LETHALITY THROUGH DOWN-REGULATION OF TUMOR NECROSIS FACTOR–Α AND INTERLEUKIN-1Β IN MACROPHAGES.

0 6 12

8

18 24 0

50

100

Kaplan Meier survival curve

SU

RV

IVA

L

USAGE RATIONALE: CLINICAL STUDIES

A prospective, multicentric, double-blind, randomized, phase III clinical study to comparethe efficacy and safety of I.V. Ulinastatin vs. placebo along with standard supportive care in subjects of severe sepsis

n=114

10

D.R. Karnad et.al, Intensive Care Medicine; April 2014

Indian Experience

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 Hospital

New Delhi Surgical

Jehangir Hospital & Research Center Pune Medical/Surgical

NDMVP Samaj Medical College & Hospital Nashik Medical/Surgical

Bhatia Hospital Mumbai Medical/Surgical

STUDY DESIGN

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

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.

STUDY DESIGN

1. Age between 18-60 years and Weight <135kg

2. Evidence of infection

3. Presence of systemic inflammatory response syndrome (SIRS)

4. At least one organ system failure

All four criteria must be present at enrollment

INCLUSION CRITERIA

Absolute mortality reduction 13%Relative reduction in mortality 66%

PRIMARY END-POINT: 28 DAY ALL CAUSE MORTALITY

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

There was a significant reduction in the onset of new organ dysfunction, 26% Absolute reduction

SECONDARY END POINTS:VENTILATOR-FREE DAYS & DURATION OF HOSPITALISATION

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

ULINASTATIN IN SEPSIS

Inhibition of the cytokines, reduction in the levels of TNF-α and Interleukin-6

Suppresses the activity of neutrophil elastaseand prevents the incidence of DIC

Prevents progression to MOD’s in Sepsis

Reduces New onset organ-dysfunction.

Reduces overall mortality in sepsis

CLINICAL STUDIES

N= 50 Group A: Received 2 lac IU of UlinastatinGroup B: Placebo

J of Evolution of Med and Dent Sci/ eISSN- 2278-4802, pISSN- 2278-4748/ Vol. 3/ Issue 53/Oct 16, 2014

CONCLUSION OF STUDY :Prevents progression to MOD’s in Sepsis Reduces New onset organ-dysfunction.Reduces overall mortality in sepsis

Ulinastatin in the treatment acute pancreatitis

ULINASTATIN IN THE TREATMENT ACUTE PANCREATITIS: A MULTICENTRIC CLINICAL TRIAL

A multicenter randomized controlled clinical trial, N = 94

Stratified by AHNP(=ACUTE HEMORRAGIC NECROTISING PANCREATITIS) or AEP(= ACUTE EDEMATOUS PANCREATITIS)

patients were randomly allocated into either the treatment group (with ulinastatin) or the control group

Ulinastatin was shown to be effective in treating AEP and AHNP with few adverse effects.

in cases of AEP, the cured rates for ulinastatin were 83.3%.

Global effective rate for ulinastatin in the treatment of AHNP 78.6%

Ulinastatin is a broad-spectrum enzyme inhibitor

ULINASTATIN FOR PANCREATITIS AFTER ERCP: A RANDOMIZED CONTROLLED TRIAL

N = 406 Patients

2.9% of subjects on ulinastatin and 7.4% on placebo developed pancreatitis (p=0.041).

Incidence of hyperenzymemia was significantly lower in the ulinastatin group than in the placebo group

Clin Gastroenterol Hepatol. 2005;3:376.

A PROSPECTIVE, MULTICENTER, DOUBLE-BLIND, RANDOMIZED, PHASE III CLINICAL STUDY TO COMPARE THE EFFICACY AND SAFETY

OF INTRAVENOUS ULINASTATIN VERSUS PLACEBO ALONG WITH STANDARD SUPPORTIVE CARE IN SUBJECTS WITH MILD OR SEVERE

ACUTE PANCREATITIS

P. Abraham et.al;JAPI 2013;Aug(61)

DEFINITIONS

Mild acute pancreatitis

APACHE II score <8, with no extrapancreatic manifestation or

complication

Severe acute pancreatitis

APACHE II score ≥8, with or without any organ failure or local

complication

STUDY DESIGN

Randomization

1:1 ratio

Double blind

Opaque sealed envelopes

Treatment

Ulinastatin

200,000 IU dissolved in 100 mL 5% dextrose or 0.9% saline IV injection over one hour every 12 hours for 5 days

Placebo

Dissolved in 100 mL 5% dextrose or 0.9% saline IV injection over one hour every 12 hours for 5 days

INCLUSION CRITERIA

I. Age 18-70 years (both inclusive)

II. Any two of the following three:

1. Abdominal pain characteristic of acute pancreatitis

2. Serum amylase and/or lipase ≥3 times upper limit of normal

3. Characteristic findings of acute pancreatitis on USG, contrast-

enhanced CT or MRI

III. Elevated serum CRP level

EXCLUSION CRITERIA

1. Pregnancy or breast-feeding

2. Evidence of chronic pancreatitis on imaging (calcification,

ductal irregularity or dilatation)

3. Subjects requiring immediate surgery (within 7 days)

4. Moribund state in which death was perceived to be

imminent (≤24 hours)

5. Participation in another investigational study within 30

days before current study

EFFICACY END POINTS

Primary end-points

Reduction in serum CRP on Day 7 from commencement of IP

administration

Secondary end-points

Mortality

Prevention of new-onset organ failure

Hospital stay (days) till discharge in survivors

CONSORT DIAGRAM

Mild pancreatitis Severe pancreatitis

Group Ulinastatin(n=30)

Placebo (n=32)

p value

Ulinastatin(n=35)

Placebo(n=32)

p value

CRP Day 7Median (IQR)

22.6(0.1 - 144.8)

11.17(0.3 -

145.3)

.942 12 (1 - 430) 10 (0.3 -165)

.71

CRP changeD0 - D7 Median (IQR)

15.52(-12.17 -

135.4)

8.46(-70 - 112)

.344 7.15(-100 -

126)

9.9(-24 -168)

.71

RESULTS: PRIMARY END-POINT

Mild pancreatitis Severe pancreatitis

Group Ulinastatin

(n=30)Placebo (n=32)

p value

Ulinastatin(n=35)

Placebo(n=32)

p value

MortalityNo. (%)

1 (3.3%) 0 .48 1 (2.8%) 6 (18.7%) .048

New-onset organ dysfunction No. (%)

5 (16.7%) 4 (12.5%) .74 12 (34.3%)29

(90.6%).0026

Hospital stay (days) Median (IQR)

7 (5 - 22) 8 (5 - 15) .0749

(6 - 22)10

(6 - 22).207

Adverse events

33 35 0.62 23 45 .000013

RESULTS: SECONDARY END-POINTS

CONCLUSIONS

The 22-day all-cause mortality was reduced significantly from 18.8% in the placebo group to 2.8% in the Ulinastatin group in the severe pancreatitis subjects.

CONCLUSIONS

New-onset organ failure decreased from 90% in the placebo group to 34% in the Ulinastatin group; this was statistically significant.

CONCLUSIONS

Hospital stay was shorter in the Ulinastatin group.

The reduction of Serum CRP was comparable in the two treatment groups.

No infusion-related toxicity was seen in any of the study subjects in either group.

Incidence of adverse events were significantly less in the Ulinastatin group compared to the Placebo group.

THANK YOU