Atorvastatin for Ulcerative Colitis

Recruiting at 4 trial locations

Overseen By Guang-Yu Yang, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Northwestern University

Must be taking: Mesalamine, Thiopurines, Biologics

Must not be taking: Corticosteroids, Statins, Cyclosporine, others

Disqualifiers: Ulcerative proctitis, HIV, Pregnancy, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 12 months

42 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial studies atorvastatin, a cholesterol-lowering drug, in patients with ulcerative colitis who are at risk of colon cancer. The goal is to see if atorvastatin can reduce cancer risk by lowering cholesterol and affecting certain proteins and genes linked to cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you must not have used statins in the last 12 months or corticosteroids in the past 3 months. You also cannot use certain medications like cyclosporine, fibrates, or strong CYP3A4 inhibitors or inducers.

What data supports the effectiveness of the drug atorvastatin for treating ulcerative colitis?

Research shows that atorvastatin, when combined with another drug called mesalazine, can reduce inflammation and symptoms in a rat model of ulcerative colitis. This combination therapy was more effective than using either drug alone, suggesting atorvastatin may help manage ulcerative colitis by reducing inflammation. ^{1 2 3 4 5}

Is atorvastatin generally safe for humans?

Atorvastatin is generally considered safe for humans, but there is a case report of severe stomach ulcers in a person taking atorvastatin, which resolved after stopping the drug. This suggests that while rare, serious side effects can occur, and any new abdominal pain should be reported to a doctor. ^{2 3 5 6 7}

How does atorvastatin differ from other drugs for ulcerative colitis?

Atorvastatin is unique for ulcerative colitis because it has anti-inflammatory effects that are not directly related to its cholesterol-lowering activity, and it can enhance anti-inflammatory effects when combined with mesalazine, potentially improving outcomes by targeting specific inflammatory pathways. ^{1 2 3 5 8}

Research Team

Guang-Yu Yang

Principal Investigator

Northwestern University

Eligibility Criteria

Adults aged 18-70 with longstanding ulcerative colitis and a specific P53 mutation, in clinical remission for at least 8 years. They must not have used statins or had chemotherapy within the last year or two respectively, no recent corticosteroid use, and cannot be pregnant. Participants should have stable cholesterol levels and agree to contraception during the study.

Inclusion Criteria

Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (SGPT) =< 1.5 X institutional upper limit of normal (ULN)

I am between 18 and 70 years old.

I have had ulcerative colitis for over 8 years and am in remission, confirmed by yearly endoscopy.

Exclusion Criteria

Pregnant or lactating participants are excluded

I have used corticosteroids in the last 3 months due to a high risk of my disease returning.

I have not had chemotherapy in the last 2 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive atorvastatin or placebo orally once daily for 12 months, with colonoscopy and blood collection

12 months

Monthly visits for monitoring and sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

2 weeks

1 visit (in-person)

Treatment Details

Interventions

• Atorvastatin Calcium
• Placebo Administration

Trial Overview The trial is testing if Atorvastatin can lower colon cancer risk in patients with ulcerative colitis who are at increased risk of large intestinal cancer. It involves taking Atorvastatin versus a placebo while monitoring health through biopsies, blood tests, questionnaires, and biospecimen collection.

Participant Groups

Group I: Arm I (atorvastatin, biospecimen collection) Experimental Treatment 4 Interventions

Patients receive atorvastatin PO QD for 12 months. Patients also undergo colonoscopy with biopsy, and collection of blood on the trial.

Group II: Arm II (placebo, biospecimen collection) Placebo Group 4 Interventions

Patients receive placebo PO QD for 12 months. Patients also undergo colonoscopy with biopsy, and collection of blood on the trial.

Atorvastatin Calcium is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease

Approved in United States as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease
• Reduction of risk of myocardial infarction, stroke, angina, and revascularization procedures

Approved in Canada as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease

Approved in Japan as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease

Approved in China as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease

Approved in Switzerland as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular disease

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study involving 30 female mice with colitis induced by DSS, both simvastatin and atorvastatin significantly reduced disease activity, with reductions of 64% and 76% respectively, compared to a 41% reduction in the control group.

The effectiveness of statins in modifying disease activity in this colitis model was found to be comparable to that of an anti-TNFalpha treatment, suggesting a potential therapeutic role for statins in inflammatory bowel disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disease modifying effect of statins in dextran sulfate sodium model of mouse colitis. Kanagarajan, N., Nam, JH., Noah, ZA., et al.[2018]

In a long-term study involving 1124 patients with ulcerative colitis treated with tofacitinib, lipid levels remained stable over time, indicating that the medication does not significantly alter cholesterol or triglyceride levels.

The incidence of major adverse cardiovascular events was very low at 0.26 per 100 patient-years, suggesting that tofacitinib is safe in terms of cardiovascular risk for patients with ulcerative colitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipid Profiles in Patients With Ulcerative Colitis Receiving Tofacitinib-Implications for Cardiovascular Risk and Patient Management. Sands, BE., Colombel, JF., Ha, C., et al.[2022]

Statins and omega-3 polyunsaturated fatty acids were found to positively influence lipid levels and acute phase proteins in patients with ulcerative colitis, suggesting potential benefits for managing this condition.

The study highlights the importance of these interventions in addressing subclinical atherosclerosis, indicating a dual role in both inflammatory bowel disease and cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment optimization of subclinical atherosclerosis in patients with ulcerative colitis]. Chopeĭ, IV., Ternushchak, TM., Chubirko, KI., et al.[2015]

In a study of 497 ulcerative colitis patients, those with dyslipidaemia exhibited more severe disease activity, particularly with low levels of high-density lipoprotein (HDL) cholesterol, which was linked to increased risks of severe disease (p < 0.05).

Patients with persistent dyslipidaemia faced significantly higher risks of needing surgery (HR: 3.27) and developing tumors (HR: 7.92), along with shorter surgery- and tumor-free survival, highlighting the importance of monitoring lipid levels for better management of ulcerative colitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dyslipidaemia Is Associated with Severe Disease Activity and Poor Prognosis in Ulcerative Colitis: A Retrospective Cohort Study in China. Liu, Z., Tang, H., Liang, H., et al.[2023]

The combination of mesalazine and atorvastatin significantly improved symptoms of ulcerative colitis in rats, reducing diarrhea, rectal bleeding, and weight loss while enhancing colon health compared to single drug treatments.

This combination therapy worked by decreasing inflammatory markers like IL-6 and TNF-α and increasing protective factors such as IL-10 and ZO-1, suggesting a mechanism that restores balance in the colon's inflammatory response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting IL-10, ZO-1 gene expression and IL-6/STAT-3 trans-signaling by a combination of atorvastatin and mesalazine to enhance anti-inflammatory effects and attenuates progression of oxazolone-induced colitis. El-Mahdy, NA., El-Sayad, ME., El-Kadem, AH., et al.[2021]

A 41-year-old man developed severe gastric ulceration after 3 months of taking atorvastatin for high cholesterol, marking the first reported case of this side effect.

Switching from atorvastatin to simvastatin and starting proton pump inhibitors led to complete resolution of the patient's gastrointestinal symptoms, highlighting the need for awareness of potential gastric issues in patients on atorvastatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atorvastatin-induced severe gastric ulceration: a case report. El-Hajj, II., Mourad, FH., Shabb, NS., et al.[2019]

In a study of 64 patients with mild to moderately severe acute exacerbation of ulcerative colitis (UC), atorvastatin did not show significant clinical improvement compared to placebo, with only 25% of patients in the atorvastatin group meeting the primary outcome criteria for improvement.

Interestingly, atorvastatin was associated with a paradoxical increase in disease activity in some patients, highlighting the need for caution and further research in larger studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized clinical trial: atorvastatin versus placebo in patients with acute exacerbation of mild to moderate ulcerative colitis. Dhamija, P., Hota, D., Kochhar, R., et al.[2021]

In a study on rats with TNBS-induced ulcerative colitis, both simvastatin and rosuvastatin significantly reduced colonic mucosal damage and inflammation, as indicated by lower disease activity index scores and reduced neutrophil accumulation.

The beneficial effects of simvastatin and rosuvastatin were attributed to their anti-inflammatory and antioxidant properties, suggesting they may be effective treatments for ulcerative colitis beyond their cholesterol-lowering effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protective effect of simvastatin and rosuvastatin on trinitrobenzene sulfonic acid-induced colitis in rats. Maheshwari, RA., Balaraman, R., Sailor, GU., et al.[2018]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Disease modifying effect of statins in dextran sulfate sodium model of mouse colitis. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Lipid Profiles in Patients With Ulcerative Colitis Receiving Tofacitinib-Implications for Cardiovascular Risk and Patient Management. [2022]

3. Poland pubmed.ncbi.nlm.nih.gov

[Treatment optimization of subclinical atherosclerosis in patients with ulcerative colitis]. [2015]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Dyslipidaemia Is Associated with Severe Disease Activity and Poor Prognosis in Ulcerative Colitis: A Retrospective Cohort Study in China. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Targeting IL-10, ZO-1 gene expression and IL-6/STAT-3 trans-signaling by a combination of atorvastatin and mesalazine to enhance anti-inflammatory effects and attenuates progression of oxazolone-induced colitis. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Atorvastatin-induced severe gastric ulceration: a case report. [2019]

7. India pubmed.ncbi.nlm.nih.gov

Randomized clinical trial: atorvastatin versus placebo in patients with acute exacerbation of mild to moderate ulcerative colitis. [2021]

8. India pubmed.ncbi.nlm.nih.gov

Protective effect of simvastatin and rosuvastatin on trinitrobenzene sulfonic acid-induced colitis in rats. [2018]