5-ASA Chronotherapy for Ulcerative Colitis

Recruiting in Chicago (>99 mi)

+1 other location

Overseen By Ali Keshavarzian, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Rush University Medical Center

Must be taking: 5-ASA

Must not be taking: Biologics, Immunomodulators, Prednisone, Antibiotics

Disqualifiers: Active UC, Major depression, Diabetes, others

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

Compensation: Varies

Number of Visits: 2

32 Participants Needed

Trial Summary

What is the purpose of this trial?

The hypothesis of this study is that appropriate time of day of administration of oral, once daily 5-ASA therapy in alignment with the host circadian rhythms will improve subclinical inflammation and microbial structure/function and increase mucosal 5-ASA levels. All subjects will be randomized to once daily 5-ASA medications at two different times of the day: between 06:00 - 10:00 h or 18:00 - 22:00 h. Three disease assessments will performed at: 1) enrollment just before randomization; 2) month 3, at the completion of first arm (Condition 1), and 3) month 6, after completion of the second arm (Condition 2). During these study time points, participants will be asked to complete questionnaires, track their 5-ASA medication usage, provide a stool sample, blood draw, urine test, collect saliva, wear a watch to measure sleep patterns, and complete a flexible sigmoidoscopy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those using certain medications like biologics, immunomodulatory drugs, and regular use of medications affecting intestinal function. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Chronotherapy for Ulcerative Colitis?

Chronotherapy, which involves timing medication to match the body's natural rhythms, has shown to be effective in reducing toxicity and improving outcomes in cancer treatments, such as colorectal cancer. This suggests that similar timing strategies could potentially enhance the effectiveness and safety of treatments for other conditions, like Ulcerative Colitis. ^{1 2 3 4 5}

Is 5-ASA safe for humans?

5-ASA is generally considered safe for humans, but it can have side effects, which vary and can sometimes be severe. In studies, side effects were reported in 14.2% of patients using 5-ASA. ^{6 7 8 9 10}

How does 5-ASA Chronotherapy differ from other treatments for ulcerative colitis?

5-ASA Chronotherapy is unique because it involves timing the administration of 5-aminosalicylic acid (5-ASA) to align with the body's natural rhythms, potentially improving effectiveness and tolerance compared to standard daily dosing. This approach may be more convenient for patients who work or attend school, as it can involve less frequent dosing, such as weekend-only treatments. ^{11 12 13 14 15}

Eligibility Criteria

Adults aged 18-65 with inactive Ulcerative Colitis and signs of subclinical inflammation can join this trial. They must have stable health, no recent flares or use of certain drugs, and a typical American diet. Excluded are those with significant heart, kidney, liver issues, drug abuse history, depression, sleep disorders or who've used specific ulcerative colitis treatments recently.

Inclusion Criteria

I am between 18 and 65 years old.

Normal psychological evaluation and negative drug screen

My ulcerative colitis is currently inactive.

Exclusion Criteria

I haven't taken drugs affecting my gut or NSAIDs in the last 4 weeks.

I have had surgery to remove part of my colon or to create an opening for waste to leave my body.

I do not have serious heart, kidney, or liver disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - Condition 1

Participants receive 5-ASA medication once daily between 06:00 - 10:00 h for 3 months

3 months

1 visit at month 3 (in-person)

Treatment - Condition 2

Participants receive 5-ASA medication once daily between 18:00 - 22:00 h for 3 months

3 months

1 visit at month 6 (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Chronotherapy

Trial Overview The study tests if taking the ulcerative colitis medication 5-ASA at different times (morning vs evening) affects inflammation and gut microbes. Participants will be randomly assigned to take the medicine in one time slot for three months then switch to the other. Assessments include questionnaires and medical tests.

Participant Groups

Group I: Night Medication Administration Experimental Treatment 1 Intervention

Subjects are directed to take their medication between 18:00 and 22:00.

Group II: Morning Medication Administration Experimental Treatment 1 Intervention

Subjects are directed to take their medication between 06:00 and 10:00.

Who Is Running the Clinical Trial?

Rush University Medical Center

Lead Sponsor

Trials

448

Recruited

247,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Findings from Research

Morning dosing of azathioprine/6-mercaptopurine (AZA/6-MP) significantly improved metabolite profiles, with higher levels of the beneficial metabolite 6-thioguanine and lower levels of the harmful metabolite 6-methylmercaptopurine, based on a 10-week study involving 26 participants with inactive inflammatory bowel disease (IBD).

The study suggests that individual chronotypes (sleep patterns) can help identify patients who may benefit from evening dosing, indicating that the timing of medication can be optimized based on biological rhythms to enhance efficacy and reduce toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial. Swanson, GR., Biglin, M., Raff, H., et al.[2023]

Chronotherapy, which involves timing chemotherapy delivery to align with the body's circadian rhythms, has been shown to significantly enhance tolerance to high doses of cancer drugs and improve their effectiveness in treating metastatic colorectal cancer, based on Phase I-III clinical trials.

This approach has led to successful surgical removal of previously unresectable liver and lung metastases, offering new hope for curing patients with advanced colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronotherapy of colorectal cancer. Giacchetti, S.[2019]

The suprachiasmatic nuclei (SCN) in mammals regulate biological rhythms, including sleep-wake cycles and hormone functions, and disruptions in these rhythms are linked to conditions like depression and diabetes.

Chronotherapy, which tailors treatment timing to align with biological rhythms, shows promise for improving outcomes in various diseases, and new drugs targeting molecular clocks are being developed to enhance therapeutic effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implications of biological clocks in pharmacology and pharmacokinetics of antitumor drugs. Ohdo, S., Koyanagi, S., Matsunaga, N.[2023]

Chronotherapy, which tailors chemotherapy delivery to the body's natural circadian rhythms, has been shown to be significantly less toxic and more effective than constant rate infusion in treating metastatic colorectal cancer, based on data from approximately 1500 patients across 15 trials.

This treatment approach not only improved tolerability but also allowed for secondary surgical resection of previously inoperable metastases, leading to a notable survival improvement, with over 20% of patients surviving for 3 years or more.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronotherapy of colorectal cancer metastases. Lévi, F., Giacchetti, S., Zidani, R., et al.[2018]

In a study involving 36 metastatic colorectal cancer patients, a combined chronotherapy regimen resulted in an impressive 81% response rate and 94% tumor control, indicating strong efficacy of the treatment.

The treatment was well-tolerated, with mild overall toxicity leading to dose reductions in only 11-13% of cases, and patients experienced prolonged survival times of 8.8 months progression-free and 15.6 months overall, especially in those who had not previously undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I - II study to assess the feasibility and activity of the triple combination of 5-fluorouracil/folinic acid, carboplatin and irinotecan (CPT-11) administered by chronomodulated infusion for the treatment of advanced colorectal cancer. Final report of the BE-1603 study. Focan, C., Kreutz, F., Graas, MP., et al.[2018]

Newer 5-ASA preparations are significantly more effective than placebo in inducing remission in active ulcerative colitis, with a pooled odds ratio of 0.51, indicating a lower failure rate for achieving clinical improvement.

While 5-ASA showed a trend towards better outcomes compared to sulfasalazine (SASP), the differences were not statistically significant, and SASP was found to be less well tolerated than 5-ASA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Sutherland, L., MacDonald, JK.[2020]

Newer 5-ASA preparations are significantly more effective than placebo in inducing remission in active ulcerative colitis, with a pooled odds ratio of 0.40, indicating a strong therapeutic benefit.

While 5-ASA showed a trend towards better outcomes compared to sulfasalazine (SASP), the differences were not statistically significant, and SASP was found to be less well tolerated than 5-ASA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Sutherland, L., Macdonald, JK.[2022]

In a multicenter trial involving 50 patients with moderately active distal ulcerative colitis, both 4-ASA and 5-ASA enemas showed significant clinical and endoscopic improvements, indicating their efficacy is comparable.

However, 4-ASA enemas were better tolerated than 5-ASA, with a significantly lower tolerance score, suggesting that patients may prefer 4-ASA for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Comparative randomized open study of the efficacy and tolerance of enemas with 2 gr of 4-amino-salicylic acid (4-ASA) and 1 gr of 5-amino-salicylic acid (5-ASA) in distal forms of hemorrhagic rectocolitis]. Marteau, P., Halphen, M.[2016]

In a study of 288 ulcerative colitis patients, 12.9% experienced adverse drug reactions (ADRs) related to 5-aminosalicylic acid (5-ASA), with lupus-like symptoms being the most common (56% of cases).

The study highlights that early recognition of ADRs can be improved by classifying them into four groups, as the time to ADR varied significantly, with symptoms mimicking IBD exacerbation appearing sooner than other types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Classification and clinical features of adverse drug reactions in patients with ulcerative colitis treated with 5-aminosalicylate acid: a single-center, observational study. Tsujii, Y., Nishida, T., Osugi, N., et al.[2022]

Both 5-ASA and SASP were effective in improving symptoms of active ulcerative colitis, with 71.4% of patients on 5-ASA and 70.3% on SASP showing improvement, although neither treatment led to complete remission.

The side effects were relatively low, occurring in 14.2% of patients taking 5-ASA and 21% taking SASP, indicating that both treatments are generally safe for managing the condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and tolerability of 5-aminosalicylic acid in the short-term treatment of ulcerative rectocolitis during the mild or moderate stage]. Bresci, G., Carrai, M., Venturini, G., et al.[2013]

Rectal 5-aminosalicylic acid (5-ASA) is effective for maintaining remission in patients with mild to moderately active distal ulcerative colitis, with 62% of patients maintaining symptomatic remission compared to 30% in the placebo group over 12 months.

The safety profile of rectal 5-ASA is comparable to placebo, with no significant difference in adverse events reported, indicating it is a safe option for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rectal 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Marshall, JK., Thabane, M., Steinhart, AH., et al.[2020]

Oral 5-aminosalicylic acid (5-ASA) is significantly more effective than placebo in inducing remission in ulcerative colitis, with a high-certainty evidence showing that 71% of 5-ASA participants failed to enter remission compared to 83% of placebo participants.

5-ASA shows similar efficacy to sulfasalazine (SASP) for treating ulcerative colitis, but with better tolerability, as only 15% of 5-ASA participants experienced adverse events compared to 29% for SASP, suggesting that 5-ASA may be a safer alternative.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Murray, A., Nguyen, TM., Parker, CE., et al.[2022]

The study found that using 5-ASA enemas twice a week as a maintenance therapy significantly reduced the relapse rate in patients with ulcerative colitis (UC), with only 18.2% of patients experiencing relapses compared to 76.9% in those taking oral 5-ASA alone.

The weekend enema regimen was well-tolerated and showed a multivariate hazard ratio of 0.19 for relapse, indicating a strong protective effect against UC relapse when combined with daily oral 5-ASA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of weekend 5-aminosalicylic acid (mesalazine) enema as maintenance therapy for ulcerative colitis: results from a randomized controlled study. Yokoyama, H., Takagi, S., Kuriyama, S., et al.[2018]

In a study of 34 patients with inactive distal ulcerative colitis, 5-ASA suppositories were found to be generally well tolerated and comfortable for long-term use, with 21 out of 28 patients remaining in clinical remission after 12 months.

Despite some initial intolerance leading to withdrawal in 4 patients, the majority of participants preferred suppositories over enemas, indicating a favorable acceptability for this treatment method.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practicality of 5-aminosalicylic suppositories for long-term treatment of inactive distal ulcerative colitis. Casellas, F., Vaquero, E., Armengol, JR., et al.[2013]

5-Aminosalicylic acid (5-ASA) significantly reduced disease activity in patients with ulcerative colitis, achieving an impressive remission rate of 86% after 4 to 6 weeks of treatment, while showing less effectiveness in Crohn's disease patients.

5-ASA is a safe treatment option with minimal side effects, making it a favorable choice for managing ulcerative colitis, as all patients in this group responded positively to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[5-Aminosalicylic acid in ulcerative colitis and Crohn's disease (author's transl)]. Maier, K., Fischer, C., Klotz, U., et al.[2013]

References

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

Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial. [2023]

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

Chronotherapy of colorectal cancer. [2019]

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

Implications of biological clocks in pharmacology and pharmacokinetics of antitumor drugs. [2023]

4. Greece pubmed.ncbi.nlm.nih.gov

Chronotherapy of colorectal cancer metastases. [2018]

5. France pubmed.ncbi.nlm.nih.gov

Phase I - II study to assess the feasibility and activity of the triple combination of 5-fluorouracil/folinic acid, carboplatin and irinotecan (CPT-11) administered by chronomodulated infusion for the treatment of advanced colorectal cancer. Final report of the BE-1603 study. [2018]

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

Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. [2022]

8. France pubmed.ncbi.nlm.nih.gov

[Comparative randomized open study of the efficacy and tolerance of enemas with 2 gr of 4-amino-salicylic acid (4-ASA) and 1 gr of 5-amino-salicylic acid (5-ASA) in distal forms of hemorrhagic rectocolitis]. [2016]

9. England pubmed.ncbi.nlm.nih.gov

Classification and clinical features of adverse drug reactions in patients with ulcerative colitis treated with 5-aminosalicylate acid: a single-center, observational study. [2022]

10. Italy pubmed.ncbi.nlm.nih.gov

[Efficacy and tolerability of 5-aminosalicylic acid in the short-term treatment of ulcerative rectocolitis during the mild or moderate stage]. [2013]

11. England pubmed.ncbi.nlm.nih.gov

Rectal 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. [2020]

12. England pubmed.ncbi.nlm.nih.gov

Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Effect of weekend 5-aminosalicylic acid (mesalazine) enema as maintenance therapy for ulcerative colitis: results from a randomized controlled study. [2018]

14. Greece pubmed.ncbi.nlm.nih.gov

Practicality of 5-aminosalicylic suppositories for long-term treatment of inactive distal ulcerative colitis. [2013]

15. Germany pubmed.ncbi.nlm.nih.gov

[5-Aminosalicylic acid in ulcerative colitis and Crohn's disease (author's transl)]. [2013]