Linaclotide for Pediatric Constipation

Recruiting in Palo Alto (17 mi)

+55 other locations

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Waitlist Available

Sponsor: AbbVie

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

Functional constipation (FC) is a common healthcare problem in children of all ages, potentially due to genetic predisposition, inadequate fiber and fluid intake, and immobility. Currently, there are no pharmacological therapies approved for the treatment of FC. This study will assess adverse events and change in disease activity with linaclotide therapy in participants with FC. Linaclotide is an approved drug being developed for the treatment of FC in pediatric patients, ages 2 to 5, who meet modified Rome IV criteria for childhood FC. In Part 1 of this study, participants are placed in 1 of 2 groups, called treatment arms. Each group receives a different treatment. There is a 1 in 2 chance that participants will be assigned to placebo. All participants in Part 2 will receive linaclotide. Approximately 116 participants aged 2 to 5 years with FC will be enrolled in this study at around 45 sites worldwide. Participants will receive daily doses of oral Linaclotide capsules or matching placebo for 12 weeks in Part 1 of the study. In Part 2, the open label long-term safety extension, participants with FC who completed study intervention in Part 1 of Study M21-572 or the Phase 2 Study LIN-MD-67 will receive linaclotide for 24 weeks. There may be higher treatment burden for participants in this trial compared to their standard of care (due to study procedures). Participants will attend visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

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

The trial protocol does not specify if you need to stop taking your current medications. However, if you are using laxatives, suppositories, or enemas, you should not use them within 24 hours before a bowel movement for at least one month before screening. Please consult with the trial team for more details.

What data supports the idea that Linaclotide for Pediatric Constipation is an effective drug?

The available research shows that Linaclotide is effective in treating constipation in adults with irritable bowel syndrome and chronic idiopathic constipation. In studies, Linaclotide provided more relief from constipation symptoms compared to a placebo, with improvements in pain and bowel movements. However, it is important to note that there are no direct comparisons with other laxatives, and some patients experienced side effects like diarrhea. While these findings are promising for adults, there is no specific data provided for its effectiveness in children with constipation. ^{1 2 3 4 5}

What safety data exists for Linaclotide in treating constipation?

Linaclotide has been evaluated in several studies primarily for adults with irritable bowel syndrome with constipation and chronic idiopathic constipation. It is generally well tolerated, with the most common adverse effect being diarrhea, which can be severe or prolonged in some cases. About 10% of patients discontinued due to gastrointestinal adverse effects. There is no safety data for use during pregnancy, and it should be avoided in such cases. Linaclotide has low oral bioavailability and acts locally in the gastrointestinal tract. It has been shown to improve bowel function and abdominal symptoms compared to placebo in clinical trials. ^{1 2 3 4 6}

Is the drug Linaclotide a promising treatment for pediatric constipation?

Linaclotide is a promising drug because it helps increase bowel movements and reduces abdominal pain, improving the quality of life for people with constipation. It has been shown to be effective in treating constipation-related symptoms and is generally well tolerated. ^{1 6 7 8 9}

Research Team

ABBVIE INC.

Principal Investigator

AbbVie

Eligibility Criteria

This trial is for children aged 2 to 5 with functional constipation, meeting specific criteria like having fewer than two bowel movements per week without laxatives. They must not have certain conditions like cystic fibrosis or untreated hypothyroidism, and their caregiver must be able to use an eDiary.

Inclusion Criteria

Participant meets modified Rome IV criteria for FC: For at least 1 month before Screening (Visit 1), the participant has had 2 or fewer defecations (with each defecation occurring in the absence of any laxative, suppository, or enema use during the preceding 24 hours) per week. In addition, at least once per week, participant must meet 1 or more of the following:

You have a history of holding in your bowel movements or intentionally not going to the bathroom when you need to.

I have a significant blockage in my rectum.

Exclusion Criteria

You have a mental health condition that is not well managed or controlled and could affect your ability to take part in the study.

I have a birth defect affecting my anus.

I have had symptoms of an active anal fissure within the last 2 weeks.

Treatment Details

Interventions

• Linaclotide (Guanylate Cyclase-C Agonist)
• Placebo for Linaclotide (Other)

Trial Overview The study tests Linaclotide against a placebo in young children with functional constipation. It's split into two parts: the first part randomly assigns participants to either the drug or placebo for 12 weeks; the second part gives all participants Linaclotide for another 24 weeks.

Participant Groups

Group I: Part 2 Linaclotide Experimental Treatment 1 Intervention

Participants who completed study intervention in Part 1 of this study or the Phase 2 Study LIN-MD-67 will receive 24 weeks of linaclotide exposure.

Group II: Part 1 Placebo Experimental Treatment 1 Intervention

Participants will receive placebo for 12 weeks.

Group III: Part 1 Linaclotide Experimental Treatment 1 Intervention

Participants will receive linaclotide for 12 weeks.

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

🇺🇸 Approved in United States as Linzess for:

• Chronic idiopathic constipation
• Irritable bowel syndrome with constipation (IBS-C)
• Functional constipation in pediatric patients 6 to 17 years of age

🇪🇺 Approved in European Union as Constella for:

• Chronic idiopathic constipation
• Irritable bowel syndrome with constipation (IBS-C)

🇨🇦 Approved in Canada as Linzess for:

• Chronic idiopathic constipation
• Irritable bowel syndrome with constipation (IBS-C)
• Functional constipation in pediatric patients 6 to 17 years of age

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Detroit Clinical Research Center /ID# 251088 Farmington Hills, MI

Meridian Clinical Research - Hastings /ID# 252132 Hastings, NE

Meridian Clinical Research- Charleston /ID# 252133 Charleston, SC

Velocity Clinical Research Phoenix /ID# 266280 Phoenix, AZ

More Trial Locations

Who Is Running the Clinical Trial?

AbbVie

Lead Sponsor

Trials

1079

Patients Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Ironwood Pharmaceuticals, Inc.

Industry Sponsor

Trials

42

Patients Recruited

17,100+

References

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

Linaclotide (Linzess) for Irritable Bowel syndrome With Constipation and For Chronic Idiopathic Constipation. [2022] Linaclotide (Linzess) for irritable bowel syndrome with constipation and for chronic idiopathic constipation.

2. Spain pubmed.ncbi.nlm.nih.gov

Linaclotide in the treatment of patients with irritable bowel syndrome and constipation - analysis of an opportunity. [2019] Linaclotide is a secretagogue that provides a combined effect on visceral pain. The European Medicines Agency has authorized its indication for the symptomatic treatment of moderate to severe irritable bowel syndrome with constipation in adults. The purpose of this review is to discuss the clinical framework for linaclotide use in our setting, the drug´s characteristics and pre-clinical development, and the clinical studies supporting its use in order to establish relevant views regarding its validity and clinical applicability. The results suggest that the only -non-severe- adverse effect associated with this drug is diarrhea. As regards effectiveness, linaclotide consistently shows favorable, significant differences in absolute risk versus placebo for all objective outcome variables described by regulatory agencies, with a combined pain and constipation response between 12.6% and 22.8% according to the variable and trial under consideration. This response is sustained and drug-related, as it goes away upon discontinuation. To conclude, linaclotide has a safety and efficacy profile that, from a clinical perspective, warrants its use for patients meeting irritable bowel syndrome and constipation criteria, with significant symptoms that cannot be relieved with other less specific measures. In the absence of predictive rules for response, it is recommended that, should the patient fail to respond, he or she should be considered not eligible for linaclotide therapy, and both indication and treatment continuity should be reserved for objective responders alone.

3. France pubmed.ncbi.nlm.nih.gov

Linaclotide. A bacterial enterotoxin derivative with a laxative action, nothing more. [2017] When patients complain of recurrent functional bowel disorders consisting of alterations in intestinal transit with abdominal pain or discomfort, treatment is purely symptomatic. Increased intake of dietary fibre or use of a bulk-forming or osmotic laxative is used when constipation is the main complaint. Linaclotide, a small peptide closely related to certain toxins secreted by diarrhoea-causing strains of Escherichia coli, has been authorised in the European Union for the treatment of adults with recurrent functional bowel disorders consisting mainly of constipation. Clinical evaluation of linaclotide includes no trials versus other laxatives. It is based on two placebo-controlled trials including a total of about 1600 patients, lasting 3 and 6 months. A pooled analysis of the results obtained at 3 months showed more frequent "relief" with linaclotide than with placebo. Adverse effects included gastrointestinal disorders, with diarrhoea occurring in one in five patients. Diarrhoea was sometimes severe or prolonged. About 10% of patients discontinued linaclotide because of gastrointestinal adverse effects (diarrhoea in half of these cases). The consequences of diarrhoea can be severe, particularly in patients predisposed to fluid and electrolyte imbalances. Co-administration of other laxative substances enhances the laxative effect of linaclotide. The laxative action is likely to reduce the gastrointestinal absorption of co-administered medications. Linaclotide should be avoided during pregnancy, as there are no relevant safety data. In practice, given the absence of head-to-head comparisons with other laxatives, linaclotide is currently just another laxative with no proven advantages over existing first-line options.

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

Effect of 5 days linaclotide on transit and bowel function in females with constipation-predominant irritable bowel syndrome. [2022] Oral linaclotide, a novel agonist of guanylate cylase-C, stimulates intestinal fluid secretion and transit, and decreases visceral hypersensitivity in animal studies. In healthy volunteers, linaclotide was safe, well tolerated, increased stool frequency, and decreased stool consistency and time to first bowel movement. This randomized, double-blind, placebo-controlled study evaluated the effects of oral linaclotide, 100 and 1000 microg once daily, in 36 women with constipation-predominant irritable bowel syndrome; colonic transit was normal in >50% patients.

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

Economic Evaluation of Linaclotide for the Treatment of Adult Patients With Chronic Idiopathic Constipation in the United States. [2017] To evaluate the effectiveness and costs of linaclotide (Linzess) versus lubiprostone (Amitiza) in the treatment of adult patients with chronic idiopathic constipation (CIC).

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

Linaclotide: a review of its use in the treatment of irritable bowel syndrome with constipation. [2022] Linaclotide (Constella®) is a synthetic 14-amino acid peptide, structurally related to guanylin and uroguanylin, that acts as a potent guanylate cyclase C receptor agonist. It is a first-in-class agent recently approved in the EU for the treatment of adult patients with moderate to severe irritable bowel syndrome with constipation (IBS-C). Linaclotide has very low oral bioavailability and acts locally in the gastrointestinal tract to stimulate fluid secretion, increase colonic transit, and reduce abdominal pain. In phase III trials, once-daily, oral linaclotide significantly increased compared with placebo the proportions of 12-week abdominal pain/discomfort responders and 12-week degree-of-relief responders (co-primary endpoints recommended by the European Medicines Agency). Linaclotide also significantly increased the proportions of responders at 26 weeks compared with placebo, and significantly improved all abdominal symptoms and measures of bowel function at 12 weeks compared with placebo. In addition, linaclotide generally improved health-related quality of life compared with placebo. Linaclotide was generally well tolerated; the most common adverse event was diarrhoea. Thus, linaclotide is a novel and effective single agent for the treatment of IBS-C in adults.

7. Japan pubmed.ncbi.nlm.nih.gov

[Pharmacological and clinical profile of linaclotide (Linzess&#174;), a novel therapeutic agent for irritable bowel syndrome with constipation and chronic constipation]. [2019] Linaclotide (Linzess&#174; tablets 0.25&#8197;mg) is a guanylate cyclase-C (GC-C) agonist with high selectivity and binding affinity to GC-C. In Japan, linaclotide was approved for &#12317;irritable bowel syndrome with constipation (IBS-C)&#12319; in December 2016 and &#12317;chronic constipation (CC) (excluding constipation due to organic disease)&#12319; in August 2018. Non-clinical studies demonstrated that linaclotide binding to GC-C increases intracellular cyclic guanosine monophosphate (cGMP), resulting in increased fluid secretion and gastrointestinal transit. In rats with colonic hyperalgesia, but not in normal rats, linaclotide suppressed the visceral nociceptive response, mediated by increased submucosal cGMP. In clinical studies in Japan, improvements were observed in the responder rates for global assessment of IBS symptom relief, complete spontaneous bowel movements in patients with IBS-C, and the frequency of spontaneous bowel movement in patients with CC, which were maintained during long-term treatment. Additionally, abdominal bloating, which has been associated with lower quality of life (QOL) and lower satisfaction with other approved therapies, and IBS QOL were improved throughout treatment with linaclotide. Diarrhea, a consequence of linaclotide's mechanism of action, was observed during the clinical studies, but was generally controllable by decreasing the linaclotide dose. No drug resistance was observed during the clinical studies, unlike some other approved agents. These results of non-clinical and clinical studies demonstrate that linaclotide can improve constipation, various abdominal symptoms, and QOL with a favorable safety profile in patients with IBS-C and CC.

8. England pubmed.ncbi.nlm.nih.gov

The pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of linaclotide. [2017] Linaclotide is a novel intestinal secretagogue that is in the advanced stages of development for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic constipation. These functional gastrointestinal disorders are highly prevalent in adults and children and often do not respond satisfactorily to available treatments. Linaclotide appears to be a promising new agent for patients who are not satisfied with currently available agents.

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

Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: a meta-analysis. [2018] Linaclotide is a minimally absorbed, 14-amino acid peptide used to treat patients with irritable bowel syndrome with constipation (IBS-C) or chronic constipation (CC). We performed a meta-analysis to determine the efficacy of linaclotide, compared with placebo, for patients with IBS-C or CC.