Why Clinical Trials Might Succeed in Acute

Jean-Louis Frossard, Philippe Morel, Catherine M Pastor
Division d'Hépatologie et de Gastro-entérologie and Département de Chirurgie Digestive, Hôpital
Universitaire de Genève. Genève, Switzerland
Sepsis and acute pancreatitis, which bear a
significant morbidity and mortality, are two
diseases frequently encountered in intensive
care units. Twenty percent of patients with
acute pancreatitis have a severe form of the
disease and 15-20% of them will die [1]. The
mortality in septic shock varies from 40 to
60% [2]. Interestingly, both diseases have
several features in common: the occurrence of
multiple organ dysfunction over time and the
involvement of mediators such as cytokines in
the pathogenesis of the disease [3, 4, 5].
While numerous therapeutic clinical trials
have been carried out in patients suffering
from septic shock, only a small number of
trials were done in patients with acute
pancreatitis. In septic shock, the results of
such trials have been disappointing for several
reasons, all of which have been emphasized in
recent literature. However, such treatments,
which failed during septic shock, might be of
interest in patients with severe acute
pancreatitis. This hypothesis will be the focus
of our article.
Clinical Trials in Septic Shock
Many pro-inflammatory mediators have been
involved in the physiopathology of sepsis [3].
Tumor necrosis factor-α (TNF-α) and
interleukin-1 (IL-1) are two major mediators
of the early host response to bacteria
proliferation. In experimental septic shock,
concentrations of TNF-α and IL-1 increase,
thus promoting the release of IL-6 which is
responsible for the acute phase response [6, 7,
8]. IL-8, IL-12 and products released by
activated leukocytes such as O2-derived free
radicals and platelet-activating factor (PAF)
are also involved at the beginning of the
systemic inflammation. A concomitant anti-
inflammatory response is also evidenced by
the increased synthesis of IL-10, soluble
TNF-α receptors and the IL-1 receptor
antagonist (IL-1ra) which counteract the
effects of the pro-inflammatory mediators.
Interestingly, the survival rate during sepsis is
increased when animals are treated either by
the inhibition of these pro-inflammatory
cytokines or by IL-10, soluble TNF-α
receptors and IL-1ra.
Following these promising experimental
findings, large clinical trials have been
initiated. Early clinical trials demonstrated
that the inhibition of pro-inflammatory
mediators was able to reduce the mortality of
septic patients by 10%. However, many
subsequent clinical trials failed to improve the
outcome of septic shock and the reasons for
such failure are numerous [9, 10, 11, 12].
Most clinical trials were unable to evidence a
10% improvement of the overall mortality in
septic patients because they were not large
enough [13]. To enroll patients in clinical
trials, positive microbiological cultures were
not required and only a limited number of
patients had positive cultures. The criteria of
inclusion did not consider the length of the
infection before enrollment nor the anatomic
site of the infection. Most of the criteria used
in these trials included clinical features which
defined the multiple organ dysfunction.

Page 2
JOP. J Pancreas (Online) 2003; 4(1):11-16.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 4, No. 1 – January 2003
12
Moreover, although various immuno-
modulatory treatments were beneficial in
experimental models of sepsis, the
extrapolation of these findings to patients
might be questionable. Indeed, most
experimental models of sepsis used a single
injection of endotoxin and this experimental
model greatly differs from clinical sepsis.
Moreover, treatments have been injected in
animals before the septic challenge. Cecal
ligation and puncture which create
polymicrobial peritonitis mimicking a
perforated appendix and diverticulitis
observed in human sepsis might be a more
appropriate model. In this experimental model
of sepsis, cytokine blockade has, for the most
part, been unsuccessful. Moreover, animals
are healthy and do not suffer from underlying
diseases as is frequently observed in humans.
Another reason for the failure of clinical trials
might be that septic patients were
heterogeneous with many co-morbidities
associated with sepsis [14]. Consequently, the
mediators of inflammation greatly differ from
one patient to another. For example, most of
the patients included in anti-TNF-α trials had
normal plasma concentrations of TNF-α
when the treatment began. In contrast, anti-
TNF-α antibodies are effective in
homogeneous groups of patients suffering
from well-characterized chronic pathologies
such as Crohn’s disease [15] or rheumatoid
arthritis [16]. Additionally, the onset of sepsis
is difficult to determine precisely. Thus, it is
difficult to treat each patient at the same time-
point of the disease. Finally, the classic
endpoint of all clinical trials is the 28-day
overall mortality [2, 3]. Due to the various
events which occur in intensive care units and
the severe underlying diseases of these
patients, a single therapy might be insufficient
to significantly modify the outcome of the
disease.
Similarities between Sepsis and Acute
Pancreatitis
Acute pancreatitis is also a severe
inflammatory disease frequently encountered
in intensive care units [1] (Table 1). It is
diagnosed mainly by acute abdominal pain
associated with a concomitant rise of serum
amylase and lipase concentrations. Gallstone
migration into the common bile duct and
alcohol abuse account for most of the
etiologies of the disease. Usually the injury is
mild, but 20% of the patients have a severe
injury and, among them, 15 to 25% will die.
In recent years, treatment of these patients has
greatly improved following a better
understanding of the pathophysiology of the
disease [17, 18]. This pathophysiology
includes the activation and release of
pancreatic enzymes in the interstitium, the
autodigestion of the pancreas and a multiple
organ dysfunction following their release into
the systemic circulation. In 1988,
Rinderknecht [19] first hypothesized that
cytokines may also play an important role and
suggested that inappropriate activation of the
immune system might increase the severity of
the local disease and the systemic
complications. Over the past few years,
significant evidence has been accumulated
indicating that the synthesis and release of
pro-inflammatory cytokines and chemokines
were responsible for the local injury and the
systemic dispersion of the inflammation [20,
Table 1. Similarities between septic shock and acute pancreatitis.
Septic shock
Acute pancreatitis
Severe inflammatory disease
Yes
Yes
Pro-inflammatory mediators involved in the disease
Yes
Yes
Anti-inflammatory response
Yes
Yes
Multiple organ dysfunction in the evolution of the disease
Yes
Yes
Benefit of immunomodulatory treatments in experimental models
Yes
Yes

Page 3
JOP. J Pancreas (Online) 2003; 4(1):11-16.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 4, No. 1 – January 2003
13
21, 22]. Thus, inflammatory mediators
produced within the gland increase the
pancreatic injury and spread to distant organs,
transforming a local inflammation into a
severe systemic disease. Interestingly, the
mediators involved in this systemic
inflammation are similar to those encountered
during sepsis. Moreover, an anti-
inflammatory response is also initiated which
includes the synthesis of IL-10 and IL1ra [23,
24, 25].
Because it is important to predict the severity
of the disease as early as possible in order to
optimize the therapy and to prevent organ
dysfunction and local complications, several
scores such as Ranson [26], Glasgow [27] and
the Acute Physiology And Chronic Health
Evaluation (APACHE II) [28] scores have
been used. Recently, new serum markers have
emerged and their ability to provide
additional information on the severity of the
disease has been evaluated [29]. Interestingly,
because the serum concentration of some of
these markers is correlated to the severity of
the disease and because they are detected
before the occurrence of multiple organ
dysfunction, it is then conceivable that the
therapeutic antagonism of these mediators
might prevent or attenuate the severity of the
multiple organ dysfunction, and consequently
the outcome of the disease.
Thus, common mediators are involved in the
pathogenesis of both diseases and
interestingly most of the reasons why clinical
trials failed in septic shock can be avoided in
acute pancreatitis.
Why Clinical Trials Might Succeed in
Acute Pancreatitis when They Failed in
Septic Shock
Criteria for the diagnosis and the
classification of the severity of acute
pancreatitis are better defined than those of
sepsis (Table 2). The routine availability of
early markers of severity, such as trypsinogen
activated peptide [30, 31], IL-6 [32, 33, 34],
and IL-8 [35, 36] should improve the
selection of severe patients before the
development of multiple organ dysfunction.
Consequently, the early administration of
antagonists targeting these factors should
improve the outcome of the disease and
prevent the development of multiple organ
dysfunction. Patients included in clinical trials
are more homogeneous in acute pancreatitis
than in sepsis. Underlying diseases are less
common than in sepsis. Additionally, the
cause of acute pancreatitis moderately
influences the evolution of the disease [37].
During acute pancreatitis, the time of onset is
easy to determine because the first abdominal
pain is usually well-described by the patient.
For that reason, it is possible to standardize
the timing of treatment administration.
Provided that the patient is admitted soon
after the onset of abdominal pain, the
therapeutic window is between 24 and 48
hours [22].
The early clinical trials for severe pancreatitis
have been disappointing. Administration of
proteolytic enzyme inhibitors, steroids and
inhibitors of pancreatic exocrine secretion did
Table 2. Why clinical trials might succeed in acute pancreatitis when they failed in septic shock.
Septic shock
Acute pancreatitis
Precise diagnostic of the disease
No
Yes
Specific biological criteria for the diagnosis
No
Yes
Onset of the disease easy to determine
No
Yes*
Heterogenous population
Yes
No
Frequent underlying diseases
Yes
No
Early treatment at the onset of the disease
No
Yes
* Abdominal pain

Page 4
JOP. J Pancreas (Online) 2003; 4(1):11-16.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 4, No. 1 – January 2003
14
not alter the course of severe pancreatitis [38,
39, 40]. In recent years, the only trials
targeting an inflammatory mediator in acute
pancreatitis used the inhibitor of PAF
receptor, lexipafant [41, 42, 43]. PAF is a low
molecular weight phospholipid which acts via
specific cell surface receptors on platelets,
leukocytes and endothelial cells. Normal acini
synthesize PAF but, during acute pancreatitis,
pancreatic and pulmonary tissue as well as
blood concentrations rise, indicating that PAF
is a key mediator of the systemic
inflammatory syndrome. When patients with
severe acute pancreatitis were treated with
lexipafant at admission for up to 3 [41] or 7
[42] days, the severity score for organ
dysfunction was lower in the treated group
than in the group of patients treated with
saline. However, a recent study showed the
absence of the efficacy of the inhibition of
PAF in improving the severity of the disease
more definitely [43]. Interestingly, when
severe septic patients were treated with
lexipafant for up to 3 or 7 days, the 28-day
mortality was similar in the treated and
control groups [44].
Nevertheless, other agents, such as PAF
acetylhydrolase, might be tested during acute
pancreatitis. This enzyme which degrades
PAF might represent another way to
inactivate PAF [45]. Its efficacy has been
proven in opossum, and clinical trials have
started in the USA. The development of
additional immunomodulatory clinical trials
might also be helpful. Thus, similarly to
clinical trials in sepsis shock [46, 47],
antibodies to TNF-α, soluble TNF-α
receptors, IL1-ra, and soluble IL-1 receptors
might be tested. IL-10, which reduces the
incidence of acute pancreatitis after
therapeutic
endoscopic
retrograde
cholangiopancreatography might be another
candidate [48].
Conclusion
In conclusion, although anti-inflammatory
drugs have failed to improve the outcome in
septic shock, a reassessment of the potential
benefits of such treatments in acute
pancreatitis might be interesting. Considering
the lessons learned from the clinical trials in
septic shock and the reasons for which these
trials failed, patients suffering from acute
pancreatitis might benefit from these anti-
inflammatory treatments.
Received September 3rd, 2002 – Accepted
October 14th, 2002
Keywords Bacterial Infections; Clinical
Trials; Cytokines; Inflammation
Abbreviations IL-1ra: interleukin-1 receptor
antagonist; PAF: platelet-activating factor
Correspondence
Catherine M Pastor
Division d'Hépatologie et de Gastro-entérologie
Hôpital Universitaire de Genève
24 Rue Micheli-du-Crest
CH 1211 Geneva 14
Switzerland
 
References
1. Steinberg W, Tenner S. Acute pancreatitis. N Engl
J Med 1994; 330:1198-210. [AN 94187814]
2. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein
AM, Knaus WA, et al. Definitions for sepsis and organ
failure and guidelines for the use of innovative
therapies in sepsis. Chest 1992; 101:1644-55. [AN
92289319]
3. Bone RC, Grodzin CJ, Balk RA. Sepsis:a new
hypothesis for pathogenesis of the disease process.
Chest 1997; 112:235-43. [AN 97372118]
4. Rangel-Frausto MS, Pittet D, Costigan M, Hwang
T, Davis CS,Wenzel RP. The natural history of the
systemic inflammatory response syndroms (SIRS).
JAMA 1995; 273:117- 23. [AN 95097446]
5. Saluja AK, Steer ML. Pathophysiology of
pancreatitis. Role of cytokines and other mediators of
inflammation. Digestion 1999; 60:(Suppl 1):27-33.
6. Michie HR, Manogue KR, Priggs DR, Revhaug A,
O'Dwyer S, Dinarello CA, et al. Detection of

Page 5
JOP. J Pancreas (Online) 2003; 4(1):11-16.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 4, No. 1 – January 2003
15
circulating TNF after endotoxin administration. N Engl
J Med 1988; 318:1481-6. [AN 88216750]
7. Dinarello CA. Biologic basis for interleukin-1 in
disease. Blood 1996; 87:2095-147. [AN 96203776]
8. Gabay C, Kushner I. Acute-phase proteins and
other systemic response to inflammation. N Engl J
Med 1999; 340:448-54. [AN 99122626]
9. Abraham E, Raffin TA. Sepsis therapy trials.
Continued disappointment or reason for hope? JAMA
1994; 271:1876-8. [AN 94254202]
10. Natanson C, Esposito CJ, Banks SM. The sirens'
songs of confirmatory sepsis trials:selection bias and
sampling error. Crit Care Med 1998; 26:1927-31. [AN
99091115]
11. Vincent
JL.
Search
for
effective
immunomodulating strategies against sepsis. Lancet
1998; 351:922-3. [AN 98404000]
12. Abraham E. Why immunomodulatory therapies
have not worked in sepsis. Intensive Care Med 1999;
25:556-66. [AN 99343314]
13. Zeni F, Freeman B, Natanson C. Anti-
inflammatory therapies to treat sepsis and septic
shock:a reassessment. Crit Care Med 1997; 25:1095-
1100. [AN 97376955]
14. Sprung CL, Finch RG, Thijs LG, Glauser MP.
International sepsis trial (INTERSEPT):role and
impact of a clinical evaluation committee. Crit Care
Med 1996; 24:1441-7. [AN 96390627]
15. van Deventer SJ. Anti-TNF antibody treatment of
Crohn's disease. Ann Rheum Dis 1999; 58:Suppl
1:I114-20. [AN 20046944]
16. Maini RN, Taylor PC, Paleolog E, Charles P,
Ballara S, Brennan FM, et al. Anti-tumor necrosis
factor specific antibody (infliximab) treatment provides
insights into the pathophysiology of rheumatoid
arthritis. Ann Rheum Dis 1999; 58:Suppl 1:I56-60.
[AN 20046931]
17. Steer ML, Meldolesi J. The cell biology of
experimental pancreatitis. N Engl J Med 1987;
316:144-50. [AN 87090173]
18. Pastor CM, Frossard JL. Are genetically modified
mice useful for the understanding of acute pancreatitis?
FASEB J 2001; 15:893-7. [AN 21189144]
19. Rinderknecht H. Fatal pancreatitis, a consequence
of excessive leukocyte stimulation? Int J Pancreatol
1988; 3:105-12. [AN 88199203]
20. Kaufmann P, Tilz GP, Lueger A, Demel U.
Elevated plasma levels of soluble tumor necrosis factor
receptor (sTNFRp60) reflect severity of acute
pancreatitis. Intensive Care Med 1997; 23:841-8. [AN
97456845]
21. Bhatia M, Brady M, Shokuhi S, Christmas S,
Neoptolemos JP, Slavin J. Inflammatory mediators in
acute pancreatitis. J Pathol 2000; 190:117-25. [AN
20124017]
22. Norman JG. New approaches to acute
pancreatitis:role of inflammatory mediators. Digestion
1999; 60 (Suppl 1):57-60. [AN 99152100]
23. Pezzilli R, Billi P, Miniero R, Barakat B. Serum
interleukin-10 in human acute pancreatitis. Dig Dis Sci
1997; 42:1469-72. [AN 97388815]
24. Chen CC, Wang SS, Lu RH, Chang FY, Lee SD.
Serum interleukin 10 and interleukin 11 in patients
with acute pancreatitis. Gut 1999; 45:895-9. [AN
20031703]
25. Simovic MO, Bonham MJ, Abu-Zidan FM,
Windsor JA. Anti-inflammatory cytokine response and
clinical outcome in acute pancreatitis. Crit Care Med
1999; 27:2662-5. [AN 20092187]
26. Ranson JH, Pasternack BS. Statistical methods for
quantifying the severity of clinical pancreatitis. J Surg
Res 1977; 22:79-91. [AN 77122330]
27. Blamey SL, Imrie CW, O'Neil J, Gilmour WH,
Carter DC. Prognostic factors in acute pancreatitis. Gut
1984; 25:1340-6. [AN 85077717]
28. Wilson C, Heath DI, Imrie CW. Prediction of
outcome in acute pancreatitis: a comparative study of
APACHE II, clinical assessment and multiple factor
scoring systems. Br J Surg 1990; 77:1260-4. [AN
91070206]
29. Frossard JL, Hadengue A, Pastor CM. New serum
markers for the detection of severe acute pancreatitis in
humans. Am J Resp Crit Care Med 2001; 164:162-70.
[AN 21328541]
30. Gudgeon AM, Heath DI, Hurley P, Jehanli A,
Patel G, Wilson C, et al. Trypsinogen activation
peptides assay in the early prediction of severity of
acute pancreatitis. Lancet 1990; 335:4-8. [AN
90113538]
31. Neoptolemos JP, Kemppainen EA, Mayer JM,
Fitzpatrick JM, Raraty MG, Slavin J, et al. Early
prediction of severity in acute pancreatitis by urinary
trypsinogen activation peptide:a multicentre study.
Lancet 2000; 355:1955-60. [AN 20315573]
32. Leser HG, Gross V, Scheibenbogen C, Heinisch
A, Salm R, Lausen M, et al. Elevation of serum
interleukin-6 concentration precedes acute-phase
response and reflects severity in acute pancreatitis.
Gastroenterology 1991; 101:782-5. [AN 91317425]
33. Heath DI, Cruickshank A, Gudgeon M, Jehanli A,
Shenkin A, Imrie CW. Role of interleukin-6 in
mediating the acute phase protein response and
potential as an early means of severity assessment in
acute pancreatitis. Gut 1993; 34:41-5. [AN 93162506]

Page 6
JOP. J Pancreas (Online) 2003; 4(1):11-16.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 4, No. 1 – January 2003
16
34. Pezzilli R, Billi P, Miniero R, Fiocchi M,
Cappelletti O, Morselli-Labate AM, et al. Serum
interleukin-6, interleukin-8, and β2-microglobulin in
early assessment of severity of acute pancreatitis.
Comparison with serum C-reactive protein. Dig Dis Sci
1995; 40:2341- 8. [AN 96083453]
35. Chen CC, Wang SS, Lee FY, Chang FY, Lee SD.
Proinflammatory cytokines in the early assessment of
the prognosis of acute pancreatitis. Am J Gastroenterol
1999; 94:213-8. [AN 99131457]
36. Gross V, Andreesen R, Leser HG, Ceska M, Liehl
E, Lausen M, et al. Interleukin-8 and neutrophil
activation in acute pancreatitis. Eur J Clin Invest 1992;
22:200-3. [AN 92258463]
37. Uhl W, Isenmann R, Curti G, Vogel R, Beger HG,
Büchler MW. Influence of etiology on the course and
outcome of acute pancreatitis. Pancreas 1996; 13:335-
43. [AN 97055506]
38. Trapnell JE, Rigby CC, Talbot CH, Duncan EH. A
controlled trial of Trasylol in the treatment of acute
pancreatitis. Br J Surg 1974; 61:177-82. [AN
74137980]
39. Bachrach WH, Schild PD. A double-blind study of
Trasylol in the treatment of pancreatitis. Ann N Y
Acad Sci 1968; 146:580-92. [AN 69205705]
40. Valderrama R, Perez-Mateo M, Navarro S,
Vazquez N, Sanjose L, Adrian MJ, et al. Multicentre
double blind trial of gabexate mesilate (FOY) in
unselected patients with acute pancreatitis. Digestion
1992; 51:65-70. [AN 92363079]
41. Kingsnorth AN, Galloway SW, Formela LJ.
Randomized, double-blind phase II trial of Lexipafant,
a platelet-activating factor antagonist, in human acute
pancreatitis. Br J Surg 1995; 82:1414-20. [AN
96097842]
42. McKay CJ, Curran F, Sharples C, Baxter JN, Imrie
CW. Prospective placebo-controlled randomized trial
of lexipafant in predicted severe acute pancreatitis. Br J
Surg 1997; 84:1239-43. [AN 97458927]
43. Johnson CD, Kingsnorth AN, Imrie CW,
McMahon MJ, Neoptolemos JP, McKay C, et al.
Double blind, randomized, placebo controlled study of
a platelet activating factor antagonist, lexipafant, in the
treatment and prevention of organ failure in predicted
severe acute pancreatitis. Gut 2001; 48:62-9. [AN
20567661]
44. Suputtamongolkol Y, Intaranongpai S, Smith MD,
Angus B, Chaowagul W, Permpikul C, et al. A double-
blind placebo-controlled study of a infusion of
Lexipafant (platelet- activating factor receptor
antagonist) in patients with severe sepsis. Antimicrob
Agents Chemother 2000; 44:693-6. [AN 20145391]
45. Hofbauer B, Saluja AK, Bhatia M, Frossard JL,
Lee HS, Bhagat L, et al. Effect of recombinant platelet-
activating factor acetylhydrolase on two models of
experimental acute pancreatitis. Gastroenterology
1998; 115:1238-47. [AN 99014212]
46. Cain BS, Meldrum DR, Harken AH, McIntyre RC.
The physiological basis of anticytokine clinical trials in
the treatment of sepsis. J Am Coll Surg 1998; 186:337-
50. [AN 98169085]
47. Marshall JC. Clinical trials of mediators-directed
therapy in sepsis:what have we learned? Intensive Care
Med 2000; 26:S75-83. [AN 20246643]
48. Deviere J, Le Moine O, Van Laethem JL,
Eisendrath P, Ghilain A, Severs N, et al. Interleukin-10
reduces the incidence of pancreatitis after therapeutic
endoscopic retrograde cholangiopancreatography.
Gastroenterology 2001; 120:498-505. [AN 21100083]

There are no products listed under this category.