Crohn's Disease Clinical Trial
Official title:
Pravastatin Therapy in Patients With Active Crohn's Disease: A Pilot Study
The primary objective of this study is to provide data regarding clinical and immunologic
activity of oral doses of pravastatin 80mg administered daily for 6 consecutive weeks, for
the treatment of active Crohn's disease as shown by the Harvey-Bradshaw Index (HBI) and/or
elevated C-reactive protein (CRP).
We hypothesize pravastatin will significantly reduce symptoms of Crohn's disease, as shown
by a decrease in HBI, by the end of the study period. Secondary outcomes of this study
include the effect of pravastatin on C-reactive protein, ESR, proinflammatory cytokines, and
fecal lactoferrin.
The HMG CoA (3-hydroxy-3-methylglutarylcoenzyme A) reductase inhibitors (statins) have been
found to significantly reduce cardiovascular morbidity and mortality (1,2). While these
clinical benefits are mediated in part by changes in lipids, particularly reductions in
low-density lipoproteins (LDL), recent studies have suggested broader anti-inflammatory
effects may also play a role by modifying various inflammatory pathways (3). Statins inhibit
the synthesis of several proinflammatory cytokines, including tumor necrosis factor-alpha
(TNF-alpha), IL-6, and IL-8 (4,5). Statins have also been shown to reduce inflammation by
down regulating expression of MHC II molecules (6). Statins inhibit the production of
chemokines and C-reactive protein (CRP), both molecules involved in inflammation (7-9).
On the basis of this data, several investigators have evaluated the effects of statin
therapy in several inflammatory diseases. Recent studies evaluating inflammatory arthritis
found that statins significantly decreased inflammation in an animal model (10). Statins
also appear to reduce the severity of chemically induced peritonitis in rats, primarily by
interfering with leukocyte adhesion and extravasation (11).
In humans, two small studies evaluating the use of statins in patients with rheumatoid
arthritis and several other autoimmune diseases found that short-term use of statins was
associated with significant decreases in disease activity and biochemical markers of
inflammation (12,13). A subsequent randomized, double-blinded study evaluating the role of
atorvastatin in 116 patients with rheumatoid arthritis found significant reductions in the
number of swollen joints and levels of several markers of inflammation, including ESR and
CRP, after 6 months of therapy compared with placebo (14). This animal and human data
confirm HMG CoA-reductase inhibitors play a role in modulating inflammatory pathways, and
suggest statins may have significant therapeutic potential in a range of chronic
inflammatory diseases.
The use of pravastatin has been shown to inhibit the development of colitis in a rat model
(15). Dextran sulfate (DSS) is a chemical that causes intestinal injury when given enterally
to animals, and DSS-induced colitis has been found to share many characteristics with
inflammatory bowel disease. Rats given DSS typically become cachectic, develop hematochezia,
and develop abnormalities of intestinal epithelial permeability. Rats do not develop
intestinal injury when DSS is given concomitantly with pravastatin. Pravastatin appears to
prevent intestinal injury at least in part by increased eNOS expression, which is typically
degraded by DSS administration (15). This animal model suggests that statins could
potentially play a role in reducing the inflammation associated with active inflammatory
bowel disease, and could potentially be a safe and well tolerated adjunctive therapy for the
treatment of inflammatory bowel disease.
This study is an open label pilot study designed to assess the safety and efficacy of
pravastatin on patients with active Crohn's disease. Patients enrolled in the study will be
given pravastatin 80mg daily for a total of six weeks. The primary endpoint will be
reduction in clinical disease activity, as measured by the Harvey-Bradshaw Index (HBI).
Patients will also be assessed for biochemical markers of inflammation before and at
completion of the study to assess the impact of pravastatin on these markers.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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