Gabexate mesilate in human acute pancreatitis

1993: 104: 1165-l

GASTROENTEROLOGY

170

Gabexate Mesilate in Human Acute Pancreatitis MARKUS BijCHLER,* PETER MALFERTHEINER,* WALDEMAR UHL,* JijRGEN SCHijLMERICH,§ FRITZ STijCKMANN,” GUIDO ADLER,” WILHELM GAUS,# KLAUS ROLLE,** HANS G. BEGER,* and the GERMAN PANCREATITIS STUDY GROUP** *Departments of Surgery and *Internal Medicine, University of Ulm; “Department of Internal Medicine, University of Freiburg; “Department Internal Medicine, University of GiXtingen; “Department of Internal Medicine, University of Marburg; ‘Department of Medical Statistics, University of Ulm; and **Sanol Schwarz G.m.b.H., Clinical Research and Medical Statistics, Monheim, Germany

Bat&round: A multicenter controlled study was performed to evaluate the effect of high doses of the low molecular weight protease inhibitor gabexate mesilate on mortality and complications associated with moderate and severe acute pancreatitis. Methods: Two hundred twenty-three patients from 29 hospitals were entered in the randomized, double-blind trial. Admission to the study was based on strict criteria excluding mild acute pancreatitis. The patients received placebo or 4 g gabexate mesilate per day intravenously for 7 days. All patients were followed up for 90 days after randomization. The analysis was based on 14 complications, including death. Results: There was no statistical difference in either mortality or complications associated with acute pancreatitis between the placebo and gabexate mesilate groups. Conclusions: The results show that gabexate mesilate was not effective in preventing complications and mortality in acute pancreatitis.

of

tiproteases such as gabexate mesilate (GM; 417 dalton) have been synthesized. ” Animal studies using GM in experimental open

acute pancreatitis’8-20

as well as the first

clinical

trials using this compound provided results. 2’-25 In addition, a multicenter con-

promising

trolled trial in Germany,

in which 900 mg GM was

applied daily for 7 days, showed a reduction of pancreatitis-related operations in the verum group.26 This finding

was encouraging

and prompted

us to use a

higher dosage of GM, which in addition to having a stronger antiprotease

effect, would have also an inhibi-

tory effect on phospholipase

A2.27-30 Phospholipase

A,

is suggested to be a key enzyme in the pathogenesis acute pancreatitis.3’ dose treatment

protocol of GM, we performed

ticenter controlled

of

In an attempt to evaluate a highrandomized

a mul-

and double-blind

trial

using 4 g of GM per day for 7 days in patients with moderate and severe acute pancreatitis.

Materials and Methods

T

here is still no causal therapy for human acute

pancreatltis.’ ‘* Protease inhibition, however, is a prevailing concept in the treatment of patients with acute pancreatitis.9-1’ Just recently, several experimental studies have shown intracellular activation of serine proteases in vivo in acute cerulein-induced atitis and in vitro following of cholecystokinin.

stimulation

pancre-

by high doses

12-‘6 That means that intracellular

activation of proteolytic enzymes could represent a trigger mechanism for the start of acute pancreatitis. Consequently, protease inhibitors that enter pancreatic acinar cells have been suggested as being beneficial drugs for acute pancreatitis. Aprotinin was the first antiprotease drug to enter clinical trials, and apart from the first study, which produced positive results ,9 further attempts using this compound were disappointing.“,” The molecular weight of 6500 dalton of aprotinin was considered too high to enter pancreatic acinar cells to inhibit intracellular proteases. Meanwhile, low molecular weight an-

Following approval of the study protocol by the Ulm University

Ethics

Committee,

tals (28 in Germany,

223 patients

1 in Austria)

1988 to 1990 and were randomized

from

entered either

29 hospi-

the trial from

to GM or placebo

groups. Inclusion

(Table

1) was based on 4 obligatory

well as 10 facultative These

criteria

patients

with

exclusion

criteria,

4 of which

were established moderate

criteria

to ensure

and severe

are given

criteria

inclusion

of only

acute pancreatitis.

in Table

as

had to be fulfilled. The

2.

Randomization The drug packages sequentially

for each hospital

and the package

number.

A randomization

sequence

of GM and placebos

bers.

After

6 packages,

number

were numbered

was used as patient

list was applied

to get a random

for increasing

the numbers

of GM

package

num-

and placebo

Abbreviation used in this paper: GM, gabexate mesilate. 0 1993 by the American Gastroenterologkal Association 0016-5065/93/$3.00

1166

BUCHLER ET AL.

GASTROENTEROLOGY Vol. 104, No. 4

Table 1. Inclusion Criteria

Table 3. Monitoring

Obligatory criteria First symptoms of acute pancreatitis 5 168 hours until enrollment of patients Threefold enzyme elevations of total amylase or lipase within 96 hours after onset of acute pancreatitis Upper abdominal pain Written informed consent of the patient Facultative criteria (4 had to be fulfilled) Upper abdominal guarding Subileus/ileus Arterial p0, ~65 mm Hg Shock: pulse rate rlOO/min; systolic RR 280 mm Hg for longer 110 minutes Anuria Leukocyte count 2 12 G/L Blood glucose (fasting) 28.4 mmol/L (this criterion was excluded in case of pre-existing diabetes mellitus) Characteristic findings of moderate to severe acute pancreatitis by ultrasound and/or CT scan Hypocalcemia ~2.0 mmol/L Serum creatinine >240 pmol/L

Clinical parameters (daily) Presence of pain, abdominal guarding, ileus, nausea, vomiting, bloating, or diarrhea; systolic and diastolic blood pressure, pulse rate, rectal temperature Biochemical parameters (days 1, 2, 3, 5, 7, 11, 14, 2 1, and weekly thereafter) Arterial blood gas analysis; levels of total serum protein, albumin, lactatedehydrogenase, glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, y-glutamyl transpeptidase, alkaline phosphatase, triglycerides, cholesterol, serum creatinine, and total bilirubin; leukocyte count; differential blood count; red blood cell count; hemoglobin concentration; hematocrit; platelet count; prothrombin time; partial thromboplastin time; levels of fibrinogen, blood glucose, potassium, sodium, chloride, calcium, total amylase, and lipase; phospholipase A, catalytic activity; and a,-antitrypsin, %macroglobulin, and C-reactive protein levels

plications

to check the severity

each of the 21 days after hospital

Statistical were balanced. The packages patients

were admitted

were used sequentially

randomization

in two parallel by the hospitals,

groups

(GM, placebo),

and double

during

admission.

Analysis

as the At the design

to the study. Thus, there was a strict

were stratified

of acute pancreatitis

which

blindness

rate of 40% of patients

stage of the study, we had expected with one or more complications

a in

was

guaranteed.

Table 4.

Standard Treatment Following nothing apy (3-5

Complication

hospitalization,

by mouth;

a gastric

L cristalloid

all

patients

received

tube and intravenous

solution

per day) via a trilumen

cen-

line was used. For 7 days after the randomiza-

tion, either

placebo venous

or GM was given via a separate catheter

continuously

a dosage of 53 mg . kg-’ * day-’ (4 g/day Clinical monitored

and

biochemical

during

hospitalization,

(infusion

Sepsis

line of

pump)

at

in a 75-kg subject).

parameters

(Table

3) were

and all patients

were fol-

lowed up for 90 days after randomization. ters were monitored

Shock

(IV) ther-

tral venous the central

Definition of Complications

daily, biochemical

Clinical

parame-

Pulmonary failure

data were checked

on days 1, 2, 3, 5, 7, 11, 14, 21, and weekly

thereafter.

Renal failure Peritonitis

Outcome Variable We defined atitis,

including

system

(Table

14 typical complications death

within

5) was established

of acute pancre-

90 days (Table

4). A score

Hemorrhage Ileus/subileus

on the basis of these comHypocalcemia Coagulation disorders

Table 2. Exclusion Criteria Pre-existing chronic renal insufficiency Age ~18 yr Pregnancy Psychosis (not alcoholic delirium) Pretreatment with aprotinin, glucagon, calcitonin, or somatostatin Previous participation in the study

Jaundice Hyperglycemia Encephalopathy

Metabolic acidosis Death within 90 days

Definition Pulse rate > lOO/min, systolic blood pressure ~80 mm Hg (longer than IO min) Leukocytes 212 G/L or (4 G/L, platelets 5 100 G/L rectal temperature >38.5”C positive blood culture metabolic acidosis: base excess >-4 mmol/L (4 of 5 had to be fulfilled) Arterial p0, ~65 mm Hg (in spite of 4 L Odmin via nose) or need of mechanical ventilation Serum creatinine >240 umol/L lntraoperative finding of diffuse suppurative intra-abdominal inflammation >4 units of blood Clinical/radiological signs of intestinal paralysis/obstruction Calcium 12.0 mmol/L Prothrombin time ~70% partial thromboplastin time >45 seconds Total serum bilirubin >20 umol/L Blood glucose >8.4 mmol/L Neuropsychiatric symptoms, abnormal electroencephalogram (alcoholic delirium excluded) Base excess >-4.0 mmol/L

Table 6. Randomization

Table 5. Score System: Complications Points

Points

4 4 3 3 3 3

Shock Sepsis Pulmonary insufficiency Renal insufficiency Peritonitis Hemorrhage

Hypocalcemia Clotting disorders Jaundice Hyperglycemia Encephalopathy Metabolic acidosis

2 2

1 1 1 1

1 3oa

Ileus/subileus Death

NOTE. Individual scoring parameters were weighed according to clinical relevance in acute pancreatitis. aSum of all complications + 1.

the placebo

group.

significance

level

reasonable

to recruit

ber of patients

A power

calculation

of P < 0.05 indicated 85 patients

made it possible

complication

for a two-tailed that

it would

for each group. to detect

This num-

a reduction

rate from 40% in the placebo

be

group

violation

Analysis

223 patients,

115 were occurred

group.

in the treatment treatment

A protocol

of five patients: with aprotinin;

one

(placebo) who had only fulfilled 3 of the facultative criteria; one (placebo) who died before the drug infusion was started;

and two patients

out of the study

Comparability

(1 GM,

1 placebo)

on day 3 after enroll-

ment. These five patients were evaluation as an intention-to-treat

retained in the final analysis.

of Groups

The groups were highly to sex, etiology

42 66

45 70

50 (46%) 26 (24%) 11 (10%) 21 (19%) 3.7 (l-9)

43 (37%) 31 (27%) 17 (15%) 24 (21%) 3.7 (l-9)

5.1 k 3.4

5.8 rtr 4.2

21 (8-51)

21 (9-39)

Mortality and Complications Mortality (90 days) was 16% (18 of 115) in the GM group and 15% (16 of 108) in the placebo group. Pancreatitis-related debridement,

operations,

whereas

e.g., necrosectomy

elective

gallbladder

and

surgery

was

of acute

comparable

pancreatitis,

with regard

Ranson’s

age was 47 years in the placebo

52 years in the GM group

group.

Median (quartiles) duration in the hospital was 26 (20-43) days for the patients taking GM and 23 (2834) days for the patients Following of newly

developed

two groups ences

prog-

group

and

(P < 0.05).

taking

placebo.

the start of drug infusion, complications

(Table

(Tables

7). There

the occurrence

was similar

in the

were no statistical

differ-

7 and 8) between

the GM and the pla-

cebo groups with regard to the number of patients with newly developed complications, the number and type of each complication, at each day following only exception

nostic signs,32 our own complication score (Table 5), and duration of symptoms until hospitalization (Table 6). Median

52 (39-67)

aMedian (lower and upper quartile). bMean (range). ‘Mean * SD.

placebo

108 were in the placebo

in the GM

one (GM) with previous

who dropped

47 (33-65)

excluded, were necessary in 25 of 115 patients (22%) in the GM group and in 23 of 108 patients (21%) in the

Intention-to-Treat and

GM(n = 115)

of the

Results Of the

Placebo (r-i = 108) Age” Sex Female Male Etiology Alcohol Biliary Idiopathic Others Ranson scoreb Complication score at hospitalization” Hours since start of pair?

to 20% in

the GM group with a power of 90%. To check differences between the two groups, Fisher’s Exact Test was used for qualitative variables, the Mann-Whitney U test for quantitative variables, and the exact U test with correction for ties (Uleman’s test) for rating variables. In addition, confidence intervals were computed.

group

1167

GABEXATE IN ACUTE PANCREATITIS

April 1993

or the complication

randomization

was the criterion

scores

up to day 21. The

“jaundice,”

which

de-

veloped significantly (P < 0.05) more frequently in the GM group. There were no remarkable differences in the biochemical The mortality pating hospitals confidence

parameters assessed (Table 3). and complication rates in the particiwith at least 6 patients and their 95%

intervals

given

in Figure

1 show

that the

Side Effects Table 7. Number of Patients With Newly Developed Undesired

events

occurred

in 3 patients,

con-

sisting of severe diarrhea in 2 (1 GM, 1 placebo) and diffuse skin exanthema in 1 (placebo). All 3 responded to medical treatment, and in no case was discontinuation of the study necessary.

Complications

Placebo (n = 108) GM (n = 115)

None

1

2

r3 complications

40 41

32 30

17 21

19 patients 23 patients

1168

BUCHLER

Table 8.

ET AL.

Number

GASTROENTEROLOGY

and Type of Newly

or severe acute pancreatitis

Developed

Vol. 104,

No. 4

by defining strict inclusion

criteria.

Complications

Our success in excluding patients with mild pancre-

Placebo (n = 108) Shock Sepsis Pulmonary failure Renal failure Peritonitis Hemorrhage Ileus/subileus Hypocalcemia Clotting disorders Jaundicea Hyperglycemia Encephalopathy Metabolic acidosis Death Pancreatitis-related operations

atitis is illustrated

(n Yl5)

9 18 15 10 6 2 6 24 4 10 10 2 23 16 (15%)

7 17 18 11 5 2 3 26 7 19 15 2 28 18 (16%)

23 (21%)

25 (22%)

by a mean Ranson

score of 3.7

points within 48 hours after hospital admission.

Fur-

ther evidence is the 60% rate of newly developed complications

in both groups and by the high mortality of

15%-l 6% in both groups. Therefore,

this study popula-

tion seemed to be adequate3* to prove whether

GM

might be helpful in human acute pancreatitis. In several experimental

models including

dogs, GM was shown to be of considerable

A 100

rats and

value, par-

Pe mmt

Gabexate m&late

Placebo

“P < 0.05 (placebo vs. GM). 80

in treatment

variation

significant

influence

in the various hospitals had no on the outcome of the study.

Discussion The present protease inhibitor complications

!

study showed that the synthetic GM is not effective

in preventing

and mortality in acute pancreatitis.

result is based on a sufficiently

This

large study population.

In the first open human trials using dosages of 100900 mg/day, GM was shown to improve the clinical course of acute pancreatitis, hyperamylasemia

to shorten the duration of

and to reduce

newly developed complications.21-24

the prevalence

of

In two controlled

clinical studies using GM at a dosage of 600-900

mg/

day for up to 14 days, the results were not conclusive because the number of patients was too small to achieve sufficient statistical power.33,34 In a recent German

randomized

multicenter

pla-

cebo-controlled and double-blind trial using 900 mg of GM per day for 7 days,26 the number of pancreatitisrelated operations could be reduced in the GM group as the single positive finding, whereas all other factors including mortality, complications, serum pancreatic enzymes levels, and length of hospitalization were the same in both groups. Previous clinical trials in acute pancreatitis had been limited by the fact that the study population consisted mainly of patients with mild interstitial-edematous acute pancreatitis with low morbidity and almost no mortality.2’-25~33-38 Therefore, we restricted the recruitment of patients to those suffering from moderate

20

1 1 2 3 4 5 9 7 9 9 10 II12

total

lot., 1 2 3 4 5 6 7 9 9 10 1112

centero Figure 1. Mortality (A) and complication (B) rates in the participating hospitals with at least 6 patients, the entire patient groups, and their 95% confidence intervals. A confidence interval gives the precision of the observed mortalities and complications. The interval is large for each hospital because of small patient numbers in a single hospital. All confidence intervals overlap, hence a common mortality can be assumed. Furthermore, the confidence intervals for GM and placebo for the entire groups also overlap, indicating that there is no significant influence. Centers (placebo vs. GM): 1 (28 vs. 30); 2 (9 vs. 10); 3 (10 vs. 9); 4 (7 vs. 6); 5 (6 vs. 6); 6 (5 vs. 5); 7 (3 vs. 5); 8 (4 vs. 4); 9 (3 vs. 4); 10 (3 vs. 3); 11 (3 vs. 3); 12 (3 vs. 3).

GABEXATE IN ACUTE PANCREATITIS

April 1993

titularly

1169

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Received May 11, 1992. Accepted October 20, 1992. Address requests for reprints to: Hans G. Beger, M.D., Department of Surgery, University of Ulm, Steinhoevelstrasse 9, D-7900 Ulm, Germany. $$ German Pancreatitis Study Group: H. G. Beger, M. Bbchler, and W. Uhl, Department of Surgery, University of Ulm; H. Ditschuneit and P. Malfertheiner, Department of Gastroenterology, University of Ulm; J. Scholmerich, M. Lausen, H. G. Leser, and V. GroD, University of Freiburg; W. Creutzfeldt, F. Stockmann, University of Gottlngen; G. Adler, University of Marburg; F. Tympner, Kreiskrankenhaus Neumarkt; H. Leonhardt, Krankenanstalten Duren; J. Frelse, Medizinische Hochschule, Hannover; U. Marsch-Ziegler, St. Gertrauden-Hospital, Berlin; W. Rosch, Krankenhaus Nordwest, Frankfurt; K.-P. Littmann, Stadtisches Klinikum Braunschweig; H. Schmidt, Medizinische Klinik, Wiesbaden; J. Schoenemann, St. Elisabeth-Hospital, Koln; M. Otte, Medlzlnische Hochschule, Lubeck; G. Junge-Hulsing, Stadtische Kliniken, Osnabruck; P. G. Lankisch, Stadtisches Krankenhaus, Luneburg; Th. Scholten, Allgemeines Krankenhaus Hagen, Germany; G. Schwab, 2nd University of Surgery, Innsbruck, Austria; M. Kahle, Stadtisches Krankenhaus, Landshut; B. Lamberts, Knappschaftskrankenhaus, Dortmund; S. Matern, and M. M. Lerch, Klinikum der RWTH, Aachen; W. Stier, Evangelisch Krankenhaus Bethesda, Duisburg; E. Seifert, Stadtisches Krankenhaus Kemperhof, Koblenz; G. E. Feurle, Stadt-Krankenhaus, Neuwied; G. K.-H. Durr, Kreiskrankenhaus, Lahr; E. Muhe, Kreiskrankenhaus, Boblingen; P. Czygan, Krankenanstalten “Lukaskrankenhaus”, Neuss; H. Goebell, M. V. Singer, University of Essen; and E. Huegl, Krankenhaus, Andernach, Germany.