Naproxen + Aspirin for Lynch Syndrome

Overseen By Eduardo Vilar-Sanchez, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: NSAIDs, Anticoagulants, Anticonvulsants, others

Disqualifiers: Total proctocolectomy, Active ulcer disease, Myocardial infarction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

40 Participants Needed

Trial Summary

What is the purpose of this trial?

To learn about the effects of naproxen and aspirin on the normal colon in people with Lynch Syndrome.

Do I need to stop taking my current medications for the trial?

Yes, you may need to stop taking certain medications. The trial requires participants to stop using aspirin, NSAIDs, COX-inhibitors, and several other specific drugs at least 7 days before starting the study. It's important to discuss with your doctor to see if you need to switch to alternative medications.

What data supports the effectiveness of the drug combination of Naproxen and Aspirin for Lynch Syndrome?

Research indicates that aspirin may reduce cancer risk in individuals with Lynch Syndrome, and it is recommended for colorectal cancer prevention. Additionally, naproxen has shown potential in promoting immune activation, which could be beneficial in preventing cancer in Lynch Syndrome patients. ^{1 2 3 4 5}

Is the combination of Naproxen and Aspirin generally safe for humans?

Naproxen has been shown to be effective and well-tolerated in long-term treatment for conditions like rheumatoid arthritis, with fewer side effects compared to aspirin. However, aspirin, especially in high doses, can increase the risk of serious gastrointestinal issues like bleeding and ulcers. Using a proton pump inhibitor (a type of medication that reduces stomach acid) can help reduce these risks when taking aspirin. ^{6 7 8 9 10}

How does the drug Naproxen + Aspirin for Lynch Syndrome differ from other treatments?

The combination of Naproxen and Aspirin may offer unique benefits due to Naproxen's antithrombotic effects, which could complement Aspirin's anti-platelet action, potentially providing enhanced protection against blood clots. However, like other NSAIDs, Naproxen poses a risk of gastrointestinal issues, which is a consideration when used with Aspirin. ^{6 11 12 13 14}

Research Team

Eduardo Vilar-Sanchez

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults over 18 with Lynch Syndrome, a condition predisposing them to colorectal cancer, can join this trial. They must have normal organ and marrow function, not be pregnant or breastfeeding, agree to use contraception if applicable, and refrain from NSAIDs during the trial. Those with recent cancers or major surgeries are excluded.

Inclusion Criteria

I agree to have two lower GI endoscopies with biopsies, one year apart.

I am mostly able to care for myself and carry out daily activities.

It's been over 6 months since my last cancer treatment.

Exclusion Criteria

I have not had an active stomach or upper small intestine ulcer in the last 5 years.

I have had a heart attack, stroke, or heart surgery in the last 5 years.

I do not have uncontrolled kidney problems.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either naproxen or aspirin daily to evaluate effects on immune cells and other parameters

12 weeks

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Aspirin
• Naproxen

Trial Overview The study is testing whether naproxen or aspirin could help prevent cancer in people with Lynch Syndrome by looking at their colon's response. Participants will randomly receive either drug and undergo regular colon examinations to track changes.

Participant Groups

Group I: Naproxen Experimental Treatment 1 Intervention

Participants will take two (2) naproxen matching capsules by mouth 1 time every day, at about the same time each day

Group II: Aspirin Active Control 1 Intervention

Participants will take two (2) aspirin matching capsules by mouth 1 time every day, at about the same time each day

Aspirin is already approved in European Union, United States, Canada, China for the following indications:

Approved in European Union as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in United States as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in Canada as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in China as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

A survey of 1007 UK general practitioners (GPs) revealed that while 70.8% had heard of Lynch Syndrome, only 46.7% were aware of aspirin's cancer preventive effects for carriers, indicating a need for better education on this topic.

Willingness to prescribe aspirin decreased with higher doses: 91.3% for 100 mg, 81.8% for 300 mg, and 62.3% for 600 mg, suggesting that GPs are more comfortable prescribing lower doses, which may impact the implementation of findings from the ongoing CaPP3 trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

General practitioner attitudes towards prescribing aspirin to carriers of Lynch Syndrome: findings from a national survey. Smith, SG., Foy, R., McGowan, J., et al.[2022]

A survey of 672 GPs in England and Wales found that 80.4% were willing to prescribe aspirin for colorectal cancer prevention in patients with Lynch syndrome, indicating a generally positive attitude towards the recommendation.

Providing additional information about NICE guidelines, trial results, and risk-benefit comparisons did not significantly influence GPs' willingness to prescribe aspirin, suggesting that other strategies may be needed to enhance prescribing practices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GPs' willingness to prescribe aspirin for cancer preventive therapy in Lynch syndrome: a factorial randomised trial investigating factors influencing decisions. Lloyd, KE., Hall, LH., Ziegler, L., et al.[2023]

A majority of clinicians (76%) believe that aspirin is an effective risk-reducing medication for patients with Lynch Syndrome, and those who feel confident discussing it are more likely to recommend it to their patients.

There is a significant need for patient educational materials about aspirin, as 87% of health professionals reported this necessity, which could help improve communication and consistency in care for Lynch Syndrome patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring clinicians' attitudes about using aspirin for risk reduction in people with Lynch Syndrome with no personal diagnosis of colorectal cancer. Chen, Y., Peate, M., Kaur, R., et al.[2018]

Carriers of Lynch syndrome mutations have a higher risk of certain cancers, but daily aspirin consumption may help reduce this risk, highlighting the importance of educating these individuals about potential preventive measures.

An educational leaflet developed for Lynch syndrome carriers was well-received, with over 70% of participants rating it positively, and 91% reporting improved understanding of aspirin's benefits and usage, indicating its potential to enhance patient-provider discussions on cancer risk reduction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Risk-Reducing Effect of Aspirin in Lynch Syndrome Carriers: Development and Evaluation of an Educational Leaflet. Kaur, R., McDonald, C., Meiser, B., et al.[2023]

In a Phase Ib clinical trial involving 80 participants with Lynch syndrome, naproxen was found to be safe and well-tolerated, with no significant difference in adverse events compared to placebo.

Naproxen significantly reduced levels of prostaglandin E2 in the colorectal mucosa and demonstrated robust chemopreventive activity in both human and mouse models, suggesting it may effectively target immune mechanisms involved in tumor development in Lynch syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa. Reyes-Uribe, L., Wu, W., Gelincik, O., et al.[2021]

In a study involving 47 healthy volunteers, low-dose enteric-coated aspirin (EC-ASA) maintained its strong anti-platelet effect (over 99% inhibition of thromboxane B2) even when taken with maximum over-the-counter doses of naproxen sodium or acetaminophen.

The results suggest that neither naproxen sodium nor acetaminophen interferes with the platelet inhibitory effects of EC-ASA, indicating that these medications can be safely co-administered without compromising aspirin's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of maximum OTC doses of naproxen sodium or acetaminophen on low-dose aspirin inhibition of serum thromboxane B2. Oldenhof, J., Hochberg, M., Schiff, M., et al.[2014]

In a study involving 42 patients, naproxen was found to be at least as effective as aspirin in treating rheumatoid arthritis, with fewer severe side effects reported.

Long-term follow-up over two years demonstrated that naproxen remains effective and well-tolerated, even when compared to placebo during short periods of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with naproxen in rheumatoid arthritis. Alexander, SJ.[2013]

Aspirin (ASA) therapy, particularly at high doses for treating ASA-exacerbated respiratory disease (AERD), carries a significant risk of serious gastrointestinal (GI) complications, including bleeding, ulcers, and perforation, especially in patients with certain risk factors.

To mitigate these GI risks, effective preventive strategies include the use of proton pump inhibitors (PPIs), misoprostol, or double dose H2-receptor antagonists (H2RAs) alongside ASA therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aspirin therapy in aspirin-exacerbated respiratory disease: a risk-benefit analysis for the practicing allergist. Baker, TW., Quinn, JM.[2016]

Low-dose acetylsalicylic acid (ASA) significantly reduces the risk of pre-eclampsia and other pregnancy complications, with a notable reduction in rates of preterm birth and fetal growth restriction, based on a review of multiple studies.

ASA is generally safe for use during pregnancy, with rare side effects, primarily related to bleeding, making it a beneficial option for women at high risk of pregnancy-associated morbidity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of Acetylsalicylic Acid in the Prevention of Pre-Eclampsia, Fetal Growth Restriction, and Preterm Birth. Stubert, J., Hinz, B., Berger, R.[2023]

A comprehensive list of acetylsalicylic acid (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) has been compiled to highlight the risk of serious side effects and drug interactions, especially in patients on anticoagulant therapy.

Physicians should be vigilant in preventing patients from inadvertently taking multiple ASA or NSAID products, and patients are advised to consult their doctor before starting any new medication, including over-the-counter options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetylsalicylic-acid-containing drugs and nonsteroidal anti-inflammatory drugs available in Canada. Brigden, M., Smith, RE.[2013]

Low-dose aspirin is commonly used for heart protection, but using it alongside NSAIDs like ibuprofen can increase the risk of gastrointestinal complications and may reduce aspirin's effectiveness due to competition at the COX-1 enzyme.

Acetaminophen is a safer alternative for managing mild-to-moderate pain in patients taking aspirin, as it does not cause gastrointestinal issues or interfere with aspirin's antithrombotic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential for drug-drug interactions in patients taking analgesics for mild-to-moderate pain and low-dose aspirin for cardioprotection. Gaziano, JM., Gibson, CM.[2013]

In a study of 11 patients experiencing heavy menstrual bleeding (menorrhagia) while using an IUD, treatment with naproxen significantly reduced menstrual blood loss from an average of 131 ml to 88 ml during three consecutive cycles (p < 0.001).

However, after stopping naproxen, menstrual blood loss returned to pre-treatment levels, indicating that while naproxen effectively managed bleeding during treatment, it did not provide a long-term solution for menorrhagia associated with IUD use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduction of menstrual blood loss by naproxen in intrauterine contraceptive device users. Davies, AJ.[2019]

Isoxicam, an anti-arthritic medication, maintains its effectiveness even when taken alongside aspirin or D-propoxyphene, unlike other similar drugs such as indomethacin and ibuprofen.

This suggests that isoxicam may have a unique mechanism of action that allows it to work effectively in the presence of these other medications, making it a potentially safer option for patients with arthritis who are also using these common pain relievers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-inflammatory activity of isoxicam in combination with aspirin or D-propoxyphene. DiPasquale, G., Rassaert, C., Welaj, P., et al.[2019]

PN400, a combination of esomeprazole and naproxen, significantly reduces the risk of gastric ulcers compared to enteric-coated naproxen, as shown in two Phase III trials involving patients with rheumatologic disorders.

Patients taking PN400 experienced fewer upper gastrointestinal adverse events and reported better tolerability, indicating it may be a safer alternative for managing pain and inflammation while minimizing gastrointestinal complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety aspects and rational use of a naproxen + esomeprazole combination in the treatment of rheumatoid disease. Roberts, DN., Miner, PB.[2021]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

General practitioner attitudes towards prescribing aspirin to carriers of Lynch Syndrome: findings from a national survey. [2022]

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

GPs' willingness to prescribe aspirin for cancer preventive therapy in Lynch syndrome: a factorial randomised trial investigating factors influencing decisions. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Exploring clinicians' attitudes about using aspirin for risk reduction in people with Lynch Syndrome with no personal diagnosis of colorectal cancer. [2018]

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

The Risk-Reducing Effect of Aspirin in Lynch Syndrome Carriers: Development and Evaluation of an Educational Leaflet. [2023]

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

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Effect of maximum OTC doses of naproxen sodium or acetaminophen on low-dose aspirin inhibition of serum thromboxane B2. [2014]

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

Clinical experience with naproxen in rheumatoid arthritis. [2013]

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

Aspirin therapy in aspirin-exacerbated respiratory disease: a risk-benefit analysis for the practicing allergist. [2016]

9. Germany pubmed.ncbi.nlm.nih.gov

The Role of Acetylsalicylic Acid in the Prevention of Pre-Eclampsia, Fetal Growth Restriction, and Preterm Birth. [2023]

10. Canada pubmed.ncbi.nlm.nih.gov

Acetylsalicylic-acid-containing drugs and nonsteroidal anti-inflammatory drugs available in Canada. [2013]

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

Potential for drug-drug interactions in patients taking analgesics for mild-to-moderate pain and low-dose aspirin for cardioprotection. [2013]

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

Reduction of menstrual blood loss by naproxen in intrauterine contraceptive device users. [2019]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Anti-inflammatory activity of isoxicam in combination with aspirin or D-propoxyphene. [2019]

14. New Zealand pubmed.ncbi.nlm.nih.gov

Safety aspects and rational use of a naproxen + esomeprazole combination in the treatment of rheumatoid disease. [2021]