| Conditions: |
|
Crohn's Disease |
| Purpose: |
|
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.
|
| Study Summary: |
|
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.
|
| Criteria: |
|
Inclusion Criteria:
- Males and non-pregnant females on an adequate contraceptive regimen aged 18-65
- Active Crohn's disease (HBI >5 or serum CRP concentration above the upper limits of
normal on initial labs.
- Stable regimen of medications for treatment of Crohn's disease for at least 4 weeks
and will continue the current regimen for the 6 weeks of drug administration.
Patients taking azathioprine/6-MP and methotrexate will need to be on a stable dose
of these medications for a minimum of 8 weeks prior to study enrollment.
- Medications for the treatment of Crohn's disease meeting inclusion criteria are
azathioprine/6-MP, methotrexate, mesalamine, ciprofloxacin, metronidazole,
budesonide, and/or less than or equal to 20mg prednisone or an equivalent steroid per
day
Exclusion Criteria:
- Patients less than 18 or greater than 65
- Current therapy with a statin or alternative medication for hyperlipidemia
- Hypersensitivity or known adverse reaction to statin therapy in the past
- Pregnancy
- Use of cyclosporin, erythromycin, and/or greater than 20mg of prednisone or its
equivalent per day during the 4 weeks prior to study entry and/or during the 6 week
study drug administration period.
- Use of infliximab during 8 weeks prior to study entry and/or during the 6 week study
drug administration period.
- AST, ALT or CK more than twice the upper limits of normal on baseline laboratory data
- Serum creatinine greater than 1.5 or estimated creatinine clearance less than
40mL/min on baseline laboratory data.
- Clinically significant perianal fistulae
- Patients with diverting or end ostomy.
- Experimental therapy for Crohn's disease in the 4 weeks prior to study entry
- Presence of medical condition or disease that, in the opinion of the investigators,
may place the patient at unacceptable risk for study participation, including, but
not limited to, pregnancy, lactation, and/or inability/unwillingness to adhere to a
contraceptive regimen.
|
| NCT ID: |
|
NCT00599625 |
| Primary Contact: |
|
Principal Investigator
Brian Behm, MD
University of Virginia
Brian Behm, MD
Phone: 434-924-2959
Email: bwb2c@virginia.edu
|
| Backup Contact: |
|
Email: slo2n@virginia.edu
Sandra Oliphant
Phone: 434-982-0871
|
| Location Contact: |
|
Charlottesville, Virginia 22908
United States
Brian Behm, MD
Phone: 434-924-2959
Email: bwb2c@virginia.edu
Site Status: Recruiting |