Constipation Treatment for Chronic Kidney Disease

Overseen By Csaba P. Kovesdy, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Tennessee

Must not be taking: Antibiotics, Immunosuppressants, Prebiotics, Probiotics

Disqualifiers: Drug abuse, IBS, Liver cirrhosis, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 4 weeks

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how treating constipation affects people with chronic kidney disease (CKD), focusing on changes in health and specific biological markers. Participants will receive either a 4-week treatment with lactulose, a common constipation remedy, or no treatment, except for a backup laxative if needed. Eligible participants should have CKD and experience constipation, either from opioid use or other functional causes, without regular laxative use.

As an unphased trial, this study provides a unique opportunity to contribute to understanding constipation treatment in CKD patients.

Will I have to stop taking my current medications?

The trial requires that you stop taking any laxatives for at least one week before screening, but you can use one bisacodyl 5 mg tablet if you don't have a bowel movement for 3 days or if symptoms become intolerable. Also, you must not have used antibiotics, immunosuppressants, prebiotics, or probiotics within 30 days before joining the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that lactulose is safe for treating constipation and is generally well-tolerated by patients. Side effects are usually mild, including stomach bloating and gas. Lactulose's current use in treating constipation further supports its safety for this condition.

Research also shows that lactulose, like other treatments such as linaclotide, is minimally absorbed into the body. This suggests it is likely safe for people with chronic kidney disease (CKD). No specific dose changes are needed for patients with kidney issues, indicating lactulose's safety for those with CKD, a key group in this trial.

Overall, evidence suggests that the constipation treatment being tested, which includes lactulose, is safe and well-tolerated, especially for those with CKD. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this constipation treatment for chronic kidney disease because it uses lactulose, a non-digestible sugar that helps draw water into the bowel, softening stools and promoting easier bowel movements. Unlike standard treatments like fiber supplements or stimulant laxatives, lactulose acts as an osmotic agent, making it particularly beneficial for patients with kidney issues who need gentler options. Additionally, lactulose may improve gut health by promoting beneficial bacteria, providing a dual benefit beyond just relieving constipation.

What evidence suggests that this treatment might be an effective treatment for constipation in CKD?

In this trial, one group of participants will receive a 4-week intervention of constipation treatment with lactulose. Research shows that lactulose can relieve constipation by increasing bowel movements. It draws water into the bowel, softening stools and making them easier to pass. Studies have found that lactulose is generally well-tolerated and can improve constipation symptoms in people with chronic kidney disease (CKD). Its long history of safe use supports its role in managing constipation. Although specific data on lactulose for CKD patients is limited, its overall effectiveness in treating constipation is well-documented. ^{3 5 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults over 18 with chronic kidney disease stages G3-G5 who are not on dialysis, have an eGFR under 60 mL/min/1.73m2, and suffer from functional or opioid-induced constipation. Participants must stop taking laxatives a week before the study but can use a rescue tablet if needed. Women must test negative for pregnancy unless postmenopausal or surgically sterile.

Inclusion Criteria

Patients able and willing to provide written informed consent and HIPAA authorization

I am not pregnant, or I am postmenopausal, or I have had a tubal ligation or hysterectomy.

I have constipation as defined by specific medical criteria.

Exclusion Criteria

I have galactosemia.

I have liver cirrhosis or chronic active hepatitis, but treated hepatitis is okay.

I have had surgery on my digestive system, but not for appendicitis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

Treatment

Participants receive a 4-week intervention of constipation treatment with lactulose

4 weeks

Weekly visits for monitoring and assessment

Follow-up

Participants are monitored for changes in clinical, biochemical, and microbiological parameters

2 weeks

1-2 visits for follow-up assessments

What Are the Treatments Tested in This Trial?

Interventions

• Constipation treatment

Trial Overview The trial is exploring how treating constipation affects people with chronic kidney disease (CKD). It will look at whether this treatment can improve clinical outcomes and influence biochemical and microbiological parameters in patients with CKD who also experience constipation.

How Is the Trial Designed?

Group I: Constipation treatment Experimental Treatment 1 Intervention

A 4-week intervention of constipation treatment with lactulose

Group II: Control Active Control 1 Intervention

No constipation treatment except bisacodyl rescue therapy

Constipation treatment is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Linzess for:

• Irritable bowel syndrome with constipation
• Chronic idiopathic constipation
• Functional constipation

Approved in European Union as Constella for:

• Irritable bowel syndrome with constipation
• Chronic idiopathic constipation

Approved in Canada as Constella for:

• Irritable bowel syndrome with constipation
• Chronic idiopathic constipation

Who Is Running the Clinical Trial?

University of Tennessee

Lead Sponsor

Trials

202

Recruited

146,000+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

University of Florida

Collaborator

Trials

1,428

Recruited

987,000+

Published Research Related to This Trial

Lubiprostone, a drug known for treating chronic constipation, was effective in alleviating symptoms in two patients with IgA nephropathy, indicating its potential use in this population.

In addition to improving constipation, lubiprostone treatment unexpectedly reduced urinary protein excretion and other markers, suggesting it may help slow the progression of IgA nephropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Lubiprostone on Urinary Protein Excretion: A Report of Two IgA Nephropathy Patients with Chronic Constipation. Takeshita, M., Tanaka, A., Nakamura, T., et al.[2020]

Linaclotide has been shown to provide more frequent relief from constipation-related symptoms compared to a placebo in two clinical trials involving about 1600 patients, lasting 3 to 6 months.

However, it can cause significant gastrointestinal side effects, particularly diarrhea, which affected 20% of patients and led to discontinuation in about 10%, raising concerns about its safety and the lack of evidence showing it is more effective than other laxatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Linaclotide. A bacterial enterotoxin derivative with a laxative action, nothing more. [2017]

In a study involving 22 patients with pre-dialysis chronic kidney disease (CKD), both lactulose and senna plus ispaghula husk significantly improved bowel movements, with no serious adverse events reported, indicating their safety and efficacy for treating constipation.

The effectiveness of lactulose and senna plus ispaghula husk was similar, as both treatments led to significant increases in complete spontaneous bowel movements and improved stool appearance, with no significant differences between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Lactulose versus Senna Plus Ispaghula Husk Among Patients with Pre-Dialysis Chronic Kidney Disease and Constipation: A Randomized Controlled Trial. Nata, N., Suebsiripong, S., Satirapoj, B., et al.[2022]

Constipation is common in patients with chronic kidney disease (CKD) and can worsen kidney function, making its management crucial for overall health; lifestyle changes are recommended despite practical challenges.

Lactulose, lubiprostone, and prucalopride have shown efficacy and safety in treating constipation in CKD patients, with prucalopride requiring a reduced dose, while other laxatives may have limited effectiveness and potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Constipation in Patients With Chronic Kidney Disease. Cha, RR., Park, SY., Camilleri, M.[2023]

A study involving 6 normal subjects showed that mesalamine, when ingested, is effectively released throughout the small intestine, with significant concentrations measured in the duodenum, jejunum, and ileum, indicating its potential therapeutic efficacy for Crohn's disease affecting the small bowel.

The majority of mesalamine is delivered to the colon, with 82% of the dose reaching this area, which supports its effectiveness in treating inflammatory bowel disease while also providing high concentrations in the small intestine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delivery and fate of oral mesalamine microgranules within the human small intestine. Layer, PH., Goebell, H., Keller, J., et al.[2019]

A new Chinese medicine intestine formula (CIF) significantly enhances the effectiveness of mesalazine in treating ulcerative colitis (UC), as shown in a study of 60 patients.

The combination of mesalazine and CIF not only improved clinical symptoms and colon health but also positively affected inflammatory markers, suggesting that CIF may help regulate inflammation in UC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A New Chinese Medicine Intestine Formula Greatly Improves the Effect of Aminosalicylate on Ulcerative Colitis. Liu, B., Piao, X., Guo, L., et al.[2022]

In a study of 127 patients with extensive mild/moderate ulcerative colitis, adding a mesalazine enema to oral mesalazine significantly improved remission rates at eight weeks (64% vs. 43% for placebo).

The combination therapy was found to be safe and well-accepted, suggesting it could be considered a first-line treatment option for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study. Marteau, P., Probert, CS., Lindgren, S., et al.[2018]

Linaclotide (Linzess) is an effective treatment for patients suffering from irritable bowel syndrome with constipation and chronic idiopathic constipation, helping to relieve symptoms.

The medication works by increasing fluid secretion in the intestines and accelerating bowel movements, which can significantly improve the quality of life for those affected.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Linaclotide (Linzess) for Irritable Bowel syndrome With Constipation and For Chronic Idiopathic Constipation. Thomas, RH., Allmond, K.[2022]

Oral Pentasa (mesalazine) is effective in inducing and maintaining remission in patients with mild-to-moderate ulcerative colitis, showing significant superiority over placebo in a meta-analysis of 12 studies involving 3674 patients.

Pentasa has a similar safety profile to placebo and is better tolerated than sulfasalazine, making it a viable option for long-term management of ulcerative colitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of oral Pentasa (prolonged-release mesalazine) in mild-to-moderate ulcerative colitis: a systematic review and meta-analysis. Paridaens, K., Fullarton, JR., Travis, SPL.[2021]

Polyethylene glycol is the first-line treatment for chronic idiopathic constipation (CIC), while stimulant laxatives are recommended as a second-line option, highlighting the importance of effective pharmacological management.

Emerging treatments like prucalopride, linaclotide, and plecanatide offer additional options for patients who do not respond to standard therapies, although availability may vary by region.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Idiopathic Constipation in Adults: A Review on Current Guidelines and Emerging Treatment Options. Bassotti, G., Usai Satta, P., Bellini, M.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10577456/

Constipation in Patients With Chronic Kidney Disease Linaclotide and plecanatide have very limited systemic absorption and appear safe in patients with CKD. Tenapanor reduces paracellular ...

2. jnmjournal.org jnmjournal.org/journal/view.html?spage=428&volume=29&number=4

Constipation in Patients With Chronic Kidney Disease Prucalopride leads to improvements in bowel function and constipation-related symptoms in cases in which response to conventional laxatives are inadequate.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4040778/

Linaclotide: A new drug for the treatment of chronic ... Linaclotide 100 µg was significantly more effective than placebo in increasing bowel frequency, while linaclotide 1000 µg significantly decreased stool ...

4. mayoclinic.org mayoclinic.org/drugs-supplements/linaclotide-oral-route/description/drg-20075770

Linaclotide (oral route) - Side effects & dosage It works by increasing intestinal fluid secretion, which helps ease the passage of stools and relieve the symptoms of constipation.

5. nature.com nature.com/articles/s41598-024-83855-w

Association between constipation and incident chronic ... Overall, no significant protective effect against incident CKD was found with the use of any type of laxative, except for unspecified laxative ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2016/202811s011lbl.pdf

LINZESS (linaclotide) capsules, for oral use Avoid use of. LINZESS in pediatric patients 6 through 17 years of age. The safety and efficacy of LINZESS has not been established in pediatric patients ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9189524/

Linaclotide utilization and potential for off-label use ... There were 9.6%, 19.0%, and 3.4% of patients with hepatic or renal impairment at the start of linaclotide treatment in the United Kingdom, Spain ...

8. linzesshcp.com linzesshcp.com/linzess-dosing

Dosing and Administration | LINZESS® (linaclotide) | For HCPs Duration of use is not limited ; Dosing adjustments for patients with renal or hepatic impairment are not required ; No drug-drug interactions are anticipated ...