Atorvastatin ± Aspirin for Lynch Syndrome
Recruiting in Palo Alto (17 mi)
Overseen ByMichael J Hall, MD, MS
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase < 1
Recruiting
Sponsor: Fox Chase Cancer Center
Disqualifiers: Active cancer, Statin intolerance, others
No Placebo Group
Approved in 6 jurisdictions
Trial Summary
What is the purpose of this trial?This trial is testing whether a cholesterol-lowering drug (atorvastatin) alone or with a pain reliever (aspirin) can reduce colon cancer risk in people with Lynch syndrome. These individuals are at high risk for colon cancer. The study will look at how these drugs affect cell growth, death, and gene changes in the colon. Statins have anticancer activity in various cell types, including colon cancer cells.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. However, if you have a statin intolerance or cannot take aspirin or atorvastatin, you may not be eligible to participate.
What data supports the effectiveness of the drug for Lynch Syndrome?
Research shows that taking aspirin regularly can reduce the risk of colorectal cancer in people with Lynch syndrome, as seen in the CAPP2 study, which found a significant reduction in cancer risk after extended follow-up.
12345Is it safe to use aspirin for Lynch Syndrome?
Aspirin is generally considered safe for people with Lynch Syndrome, as it has been shown to reduce the risk of colorectal cancer in this group. However, there is some uncertainty about the best dosage and treatment duration, and potential side effects should be discussed with a healthcare provider.
24567How does the drug Atorvastatin differ from other treatments for Lynch Syndrome?
Atorvastatin is unique in its potential use for Lynch Syndrome as it is primarily a cholesterol-lowering drug, known for its ability to significantly reduce LDL cholesterol levels, which is not a standard treatment approach for this genetic condition. Its novel application in this context may involve its anti-inflammatory and other non-lipid-lowering effects, which are not typically targeted by existing treatments for Lynch Syndrome.
89101112Eligibility Criteria
This trial is for adults over 18 with Lynch Syndrome, a genetic condition raising colorectal cancer risk. Participants must understand English to give informed consent and have no active cancer or recent hormonal therapy. Those with statin intolerance, aspirin contraindications, or who are pregnant/breastfeeding cannot join.Inclusion Criteria
Able to read and sign an informed consent document in English
Eligible subjects will have molecular evidence of Lynch Syndrome (mutation in MLH1, MSH2, MSH6, EPCAM or PMS2)
Subjects who are 18 years of age or older
+1 more
Exclusion Criteria
Are <18 years of age
Unable to read and sign an informed consent document in English
Have active cancer or are less than 3 years post hormonal maintenance therapy for cancer
+2 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive atorvastatin alone or with aspirin for 6 weeks. Blood and colon biopsies are obtained at Day 0 and at 6 weeks.
6 weeks
2 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, including adverse event assessments and medication adherence.
4 weeks
2 visits (virtual)
Participant Groups
The study tests if Atorvastatin (a cholesterol-lowering drug), alone or combined with Aspirin (an anti-inflammatory drug), can lower the risk of colorectal cancer in individuals at high risk due to Lynch Syndrome.
2Treatment groups
Active Control
Group I: Atorvastatin and AspirinActive Control1 Intervention
Atorvastatin (LIPITOR) 20 milligram tablet and Aspirin 325 mg tablet daily for 6 weeks
Group II: AtorvastatinActive Control1 Intervention
Atorvastatin (LIPITOR) 20 milligram tablet daily for 6 weeks
Atorvastatin 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
- Homozygous familial hypercholesterolemia
🇺🇸 Approved in United States as Lipitor for:
- Hypercholesterolemia
- Mixed dyslipidemia
- Homozygous familial hypercholesterolemia
- Prevention of cardiovascular disease
🇨🇦 Approved in Canada as Lipitor for:
- Hypercholesterolemia
- Mixed dyslipidemia
- Homozygous familial hypercholesterolemia
- Prevention of cardiovascular disease
🇯🇵 Approved in Japan as Lipitor for:
- Hypercholesterolemia
- Mixed dyslipidemia
- Homozygous familial hypercholesterolemia
🇨🇳 Approved in China as Lipitor for:
- Hypercholesterolemia
- Mixed dyslipidemia
- Homozygous familial hypercholesterolemia
🇨🇭 Approved in Switzerland as Lipitor for:
- Hypercholesterolemia
- Mixed dyslipidemia
- Homozygous familial hypercholesterolemia
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Fox Chase Cancer CenterPhiladelphia, PA
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Who Is Running the Clinical Trial?
Fox Chase Cancer CenterLead Sponsor
References
Effect of chemoprevention by low-dose aspirin of new or recurrent colorectal adenomas in patients with Lynch syndrome (AAS-Lynch): study protocol for a multicenter, double-blind, placebo-controlled randomized controlled trial. [2021]Lynch syndrome (LS) is the most common cause of inherited colorectal cancer (CRC) and confers a high lifetime risk of CRC estimated to be up to 60%. Colonoscopy is recommended every 2 years in LS patients above the 20-25-year-old age bracket, and every year when colonic neoplasia has been detected. Efficient chemoprevention has the potential to represent a cost-effective intervention in these high-risk patients and could allow a delay in colonoscopy surveillance. Several epidemiological studies have shown that regular use of low dose aspirin is associated with a 20 to 30% reduction in the risk of sporadic colonic adenomas and colorectal cancer regardless of family risk. However, in recent large randomized trials in specific populations, aspirin use showed no protection for colorectal cancer. A prospective randomized CAPP-2 trial evaluated the effect of aspirin use in LS patients. The primary analysis of this trial showed no significant decrease in CRC in LS patients under daily aspirin. However, a preplanned secondary analysis after an extended follow-up showed a significant reduced risk of CRC in the aspirin group in the per-protocol analysis. The real effect and clinical benefit of aspirin are still to be consolidated in this population. The AAS-Lynch trial-a prospective, multicentric, double-blind, placebo-controlled, randomized clinical trial-was designed to investigate if daily aspirin therapy, at a dose of 100 or 300 mg, would decrease the occurrence or recurrence of colorectal adenomas in patients under 75 years of age, compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov NCT02813824 . Registered on 27 June 2016. The trial was prospectively registered.
Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. [2023]Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population.
GPs' willingness to prescribe aspirin for cancer preventive therapy in Lynch syndrome: a factorial randomised trial investigating factors influencing decisions. [2023]The National Institute for Health and Care Excellence (NICE) 2020 guidelines recommends aspirin for colorectal cancer prevention for people with Lynch syndrome. Strategies to change practice should be informed by understanding the factors influencing prescribing.
Barriers and facilitators to using aspirin for preventive therapy: a qualitative study exploring the views and experiences of people with Lynch syndrome and healthcare providers. [2022]The National Institute for Health and Care Excellence (NG151) recommends considering daily aspirin for people with Lynch syndrome to reduce colorectal cancer risk. However, deciding whether to initiate aspirin could be a complex decision for patients and their healthcare providers, as both the potential benefits and harms need to be considered.
Aspirin Colorectal Cancer Prevention in Lynch Syndrome: Recommendations in the Era of Precision Medicine. [2023]Cancer prevention in the era of precision medicine has to consider integrated therapeutic approaches. Therapeutic cancer prevention should be offered to selected cohorts with increased cancer risk. Undoubtedly, carriers of hereditary cancer syndromes have a well-defined high cancer risk. Lynch Syndrome is one of the most frequent hereditary syndromes; it is mainly associated with colorectal cancer (CRC). Nonsteroidal anti-inflammatory drugs and, in particular, aspirin use, has been associated with reduced CRC risk in several studies, initially with contradictory results; however, longer follow-up confirmed a reduced CRC incidence and mortality. The CAPP2 study recruited 861 Lynch syndrome participants randomly assigned to 600 mg of aspirin versus placebo. Like sporadic CRCs, a significant CRC risk reduction was seen after an extended follow-up, with a median treatment time that was relatively short (2 years). The ongoing CAPP3 will address whether lower doses are equally effective. Based on pharmacology and clinical data on sporadic CRCs, the preventive effect should also be obtained with low-dose aspirin. The leading international guidelines suggest discussing with Lynch syndrome carriers the possibility of using low-dose aspirin for CRC prevention. We aim systematically promote this intervention with all Lynch syndrome carriers.
The Risk-Reducing Effect of Aspirin in Lynch Syndrome Carriers: Development and Evaluation of an Educational Leaflet. [2023]Carriers of germline mutations in genes associated with Lynch syndrome are at increased risk for colorectal, endometrial, ovarian, and other cancers. There is evidence that daily consumption of aspirin may reduce cancer risk in these individuals. There is a need for educational resources to inform carriers of the risk-reducing effects of aspirin or to support decision-making. An educational leaflet describing the risks and benefits of using aspirin as risk-reducing medicine in carriers of Lynch-syndrome-related mutations is developed and pilot tested in 2017. Carriers are ascertained through a familial cancer clinic and surveyed using a mailed, self-administered questionnaire. The leaflet is highly rated for its content, clarity, length, relevance, and visual appeal by more than 70% of the participants. Most participants (91%) report "a lot" or "quite a bit" of improvement in perceived understanding in knowledge about who might benefit from taking aspirin, its benefits, how long to take it, the reduction in bowel cancer risk, and the optimal dosage. A few (14%) participants seek more information on the dosage of aspirin. This leaflet will be useful as an aid to facilitate discussion between patients and their health care professionals about the use of aspirin as a risk-reducing medication.
Exploring clinicians' attitudes about using aspirin for risk reduction in people with Lynch Syndrome with no personal diagnosis of colorectal cancer. [2018]Recent research has shown that aspirin reduces the risk of cancers associated with Lynch Syndrome. However, uncertainty exists around the optimal dosage, treatment duration and whether the benefits of aspirin as a risk-reducing medication (RRM) outweigh adverse medication related side-effects. Little is known about clinicians' attitudes, current practice, and perceived barriers to recommending aspirin as a RRM. To explore the attitudes of clinicians who discuss risk management options with patients with Lynch Syndrome towards using aspirin as a RRM. Clinicians were invited through professional organisations to complete an online survey. Topics included their clinical experience with Lynch Syndrome, views and practice of recommending aspirin as a RRM, and knowledge about clinical risk management guidelines for Lynch Syndrome. Comparison of attitudes was made between three professional groups. 181 respondents were included in the analysis: 59 genetics professionals (genetic counsellors and clinical geneticists, medical oncologists with specialist training in familial cancer), 49 gastroenterologists and 73 colorectal surgeons. Most clinicians (76 %) considered aspirin to be an effective RRM and most (72 %) were confident about discussing it. In all professional categories, those who were confident about discussing aspirin with patients perceived it to be an effective RRM (OR = 2.8 [95 % CI = 1.8-4.2], p
Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia. [2018]Atorvastatin is a synthetic hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. In dosages of 10 to 80 mg/day, atorvastatin reduces levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride and very low-density lipoprotein (VLDL)-cholesterol and increases high-density lipoprotein (HDL)-cholesterol in patients with a wide variety of dyslipidaemias. In large long-term trials in patients with primary hypercholesterolaemia. atorvastatin produced greater reductions in total cholesterol. LDL-cholesterol and triglyceride levels than other HMG-CoA reductase inhibitors. In patients with coronary heart disease (CHD), atorvastatin was more efficacious than lovastatin, pravastatin. fluvastatin and simvastatin in achieving target LDL-cholesterol levels and, in high doses, produced very low LDL-cholesterol levels. Aggressive reduction of serum LDL-cholesterol to 1.9 mmol/L with atorvastatin 80 mg/day for 16 weeks in patients with acute coronary syndromes significantly reduced the incidence of the combined primary end-point events and the secondary end-point of recurrent ischaemic events requiring rehospitalisation in the large. well-designed MIRACL trial. In the AVERT trial, aggressive lipid-lowering therapy with atorvastatin 80 mg/ day for 18 months was at least as effective as coronary angioplasty and usual care in reducing the incidence of ischaemic events in low-risk patients with stable CHD. Long-term studies are currently investigating the effects of atorvastatin on serious cardiac events and mortality in patients with CHD. Pharmacoeconomic studies have shown lipid-lowering with atorvastatin to be cost effective in patients with CHD, men with at least one risk factor for CHD and women with multiple risk factors for CHD. In available studies atorvastatin was more cost effective than most other HMG-CoA reductase inhibitors in achieving target LDL-cholesterol levels. Atorvastatin is well tolerated and adverse events are usually mild and transient. The tolerability profile of atorvastatin is similar to that of other available HMG-CoA reductase inhibitors and to placebo. Elevations of liver transaminases and creatine phosphokinase are infrequent. There have been rare case reports of rhabdomyolysis occurring with concomitant use of atorvastatin and other drugs.
Atorvastatin. [2019]Atorvastatin (Lipitor, Pfizer) is a safe and effective 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (statin). It is the most potent currently available statin in terms of lowering low-density lipoprotein (LDL) and total cholesterol levels. It was the first statin shown to lower triglycerides in patients with isolated hypertriglyceridaemia. It has a good safety profile. In common with other statins, it has non-lipid-lowering effects including improving endothelial function, antiproliferative actions on smooth muscle and reducing platelet aggregation. It also has anti-inflammatory effects and may reduce plasma glucose levels. Clinical trial evidence with this statin is currently limited. It did slightly reduce events in the AVERT trial comparing patients receiving coronary angioplasty with those receiving high-dose atorvastatin therapy and in the MIRACL study reduced ischemia in patients with acute coronary syndromes. Other end point trials are in progress.
Atorvastatin: a hydroxymethylglutaryl-coenzyme A reductase inhibitor. [2022]The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, interactions, and formulary considerations of atorvastatin relative to other hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are discussed. Atorvastatin calcium, a synthetic stereoisomer of a pentasubstituted pyrrole, prevents the conversion of HMG-CoA by competitive and selective inhibition of HMG-CoA reductase. This limits cholesterol formation. Atorvastatin undergoes extensive first-pass metabolism; the first-pass effect is saturable at higher doses. Time to maximum plasma concentration ranges from one to four hours. The plasma elimination half-life is considerably longer than for other statins. Like other statins, atorvastatin reduces low-density-lipoprotein cholesterol (LDL-C) and total cholesterol in patients with hypercholesterolemia. However, the reductions achieved with atorvastatin exceed those for other statins. Atorvastatin recipients are more likely to achieve LDL-C goals and to do so more quickly. Atorvastatin also moderately reduces triglyceride levels in patients with hypertriglyceridemia and may play a role in the management of familial hypercholesterolemia. Adequate lipid control with atorvastatin monotherapy may preclude the need for combination drug therapy in some patients. The adverse effects of atorvastatin include mild gastrointestinal disturbances, increased liver enzyme levels, and myalgia. Drug interactions involving atorvastatin can be expected to parallel those of other statins metabolized via CYP3A4. Atorvastatin has become a popular addition to hospital formularies, even though formal pharmacoeconomic analyses are lacking. Atorvastatin effectively reduces blood lipids and may offer some advantages over other statins, but more studies are needed to clarify its optimal role in pharmacotherapy.
Atorvastatin. A review of its pharmacology and therapeutic potential in the management of hyperlipidaemias. [2018]Atorvastatin is a synthetic HMG-CoA reductase inhibitor which lowers plasma cholesterol levels by inhibiting endogenous cholesterol synthesis. It also reduces triglyceride levels through an as yet unproven mechanism. Dose-dependent reductions in total cholesterol, low density lipoprotein (LDL)-cholesterol and triglyceride levels have been observed with atorvastatin in patients with hypercholesterolaemia and in patients with hypertriglyceridaemia. In large trials involving patients with hypercholesterolaemia, atorvastatin produced greater reductions in total cholesterol, LDL-cholesterol, apolipoprotein B and triglyceride levels than lovastatin, pravastatin and simvastatin. In patients with primary hypercholesterolaemia, the combination of atorvastatin and colestipol tended to produce larger reductions in LDL-cholesterol levels and smaller reductions in triglyceride levels than atorvastatin monotherapy. Although atorvastatin induced smaller reductions in triglyceride levels and more modest increases in high density lipoprotein (HDL)-cholesterol levels than either fenofibrate or nicotinic acid in patients with combined hyperlipidaemia, it produced larger reductions in total cholesterol and LDL-cholesterol. As with other HMG-CoA reductase inhibitors, the most frequently reported adverse events associated with atorvastatin are gastrointestinal effects. In comparative trials, atorvastatin had a similar adverse event profile to that of other HMG-CoA reductase inhibitors. Clinical data with atorvastatin are limited at present. However, with its ability to markedly reduce LDL-cholesterol levels, atorvastatin is likely to join other members of its class as a first-line agent for the treatment of patients with hypercholesterolaemia, if changes in lipid levels with atorvastatin convert to reductions in CHD mortality and morbidity. Atorvastatin may be particularly suitable for patients with heterozygous or homozygous familial hypercholesterolaemia because of the marked reductions in LDL-cholesterol experienced with the drug. Additionally, because of its triglyceride-lowering properties, atorvastatin appears to have the potential to become an appropriate treatment for patients with combined hyperlipidaemia or hypertriglyceridaemia.
[Atorvastatin (Lipitor)]. [2018]Atorvastatin is a second generation synthetic statin, introduced in Belgium in May 1998. Its mechanism of action is similar to that of the other statins, i.e. the inhibition of HMG Co-A reductase, the key enzyme in cholesterol synthesis, which leads to the increase of LDL receptors. The prolonged half-life (20-30 H) of atorvastatin and its active metabolites, induces a prolonged inhibition of HMG Co-A reductase and a reduction of hepatitic apo B production. The biological efficacy of atorvastatin is high: 41 to 61% lowering of LDL depending of the dose. Atorvastatin is indicated in primary hypercholesterolemia, mixed hyperlipidemia and homozygous familial hypercholesterolemia. If necessary, a resin or even a fibrate may be added. The safety profile is good. The most common adverse effects are gastro-intestinal and transient. Liver tests or muscle enzymes are rarely modified. If clinical proof of reduction of CV morbidity and mortality in primary and secondary prevention is obtained, atorvastatin shall represent a major step forward in the treatment of hypercholesterolemia.