Cognitive and Psychiatric Effects of Linaclotide on Patients With Irritable Bowel Syndrome-Constipation Predominant and Chronic Idiopathic Constipation

Cognitive and Psychiatric Effects of Linaclotide on Patients With Constipation



Sponsors

Lead Sponsor



Source

McMaster University

Oversight Info

Has Dmc

No


Brief Summary

Irritable Bowel syndrome - constipation predominant (IBS-C) is a chronic and
disabling,disorder of the gut that is characterized by abdominal pain or discomfort.
Approximately 50% of patients with IBS-C will also meet criteria for anxiety or depression.

Anti depressant medication is widely used in the treatment of IBS. Linaclotide is a novel
medication for IBS that is also effective at relieving pain associated with IBS, which may be
in part to signalling between the gut and the brain. However, the impact of Linaclotide on
the psychiatric symptoms of anxiety and depression on IBS has not been investigated.

Detailed Description

Irritable bowel syndrome (IBS) is a chronic, disabling functional gastrointestinal disorder
that is characterized by abdominal pain or discomfort and a disturbance in bowel habit. It
has long been recognized that psychological factors can be important in IBS, and that
bi-directional signaling between the gut and the brain is likely involved in the
pathophysiology of the syndrome. Approximately 50% of patients with IBS at a tertiary center
will also meet criteria for anxiety or depression. Anti-depressant medications are widely
used in the treatment of IBS, even without psychiatric comorbidity, with good evidence for
both tricyclic antidepressants and selective serotonin reuptake inhibitors. Unfortunately
both classes of anti-depressants have significant gastrointestinal side effects and a large
number of patients cannot tolerate the medications.

Linaclotide, a guanylate cyclase agonist, has emerged as an important, novel treatment for
patients with constipation-predominant IBS (IBS-C) and Chronic Idiopathic Constipation (CIC).
Linaclotide is effective at relieving pain associated with IBS, which may be in part mediated
by modulation of signaling between the gut and the brain. In this study the investigators
will study the effect of Linaclotide on anxiety, depression and cognitive functioning in
patients with IBS-C and CIC. If Linaclotide is also effective in treating anxiety and
depression and improving cognitive functioning in patients with IBS-C and CIC, this will be
an important therapeutic advance for the 50% of IBS patients with psychiatric comorbidity.

The investigators also propose to investigate the mechanisms by which Linaclotide may effect
psychiatric symptoms and neuropsychological functioning by measuring changes in the gut
microbiome and inflammatory biomarkers. The gut and the brain are intimately connected by
several, bidirectional, signaling pathways including neural, humoral and immune mechanisms.
The concept of the "gut-brain axis" has recently been supplanted by the "microbiota-gut-brain
axis," emphasizing the important role the gut microbiota plays in mediating brain responses.
The gut microbiota communicate with the brain through immune and neuronal pathways and some
microbiota can directly secrete neurotransmitters such as serotonin, dopamine and
gamma-aminobutyric acid (GABA) . In true bidirectional fashion, the brain can also influence
the microbiota through the secretion of cortisol and sympathetic neurotransmission, changing
gut motility, secretion and mucin production, which can affect the habitat of the resident
microbiota and thereby alter the composition of the microbiota. Alterations in gut microbiota
have been associated with irritable bowel syndrome in multiple studies.

Given the importance of the gut microbiota in mediating gut-brain responses, the
investigators propose that the gut microbiota may play a direct role in the pathophysiology
of anxiety and depression in patients with IBS. If Linaclotide is effective in reducing
psychiatric and neuropsychological symptoms in patients with IBS, this may occur through
changes in the gut microbiota, perhaps as a result of altered colonic motility and altered
habitat of resident microbiota.

Overall Status

Recruiting

Start Date

2016-03-01

Completion Date

2018-12-01

Primary Completion Date

2018-12-01

Phase

N/A

Study Type

Observational

Primary Outcome

Measure

Time Frame

To measure anxiety and depression using the Depression, Anxiety and Stress Scale (DASS) in patients with IBS-C and CIC before and after treatment with Linaclotide
Change from baseline to week 8

Secondary Outcome

Measure

Time Frame

To measure neuropsychological performance in Patients with IBS-C and CIC using a standardized neuropsychological assessment in patients (CNS vital signs) before and after treatment with Linaclotide
Change from baseline to week 8
To determine changes in fecal microbiome profile and inflammatory biomarkers before and after treatment with Linaclotide and whether these changes correlate with changes in psychiatric symptoms and cognition.
Change from baseline to week 8

Number Of Groups

1

Enrollment

100

Conditions


Intervention

Intervention Type

Other

Intervention Name


Description

Questionnaires rating IBS symptoms, constipation, anxiety and depression


Intervention Type

Other

Intervention Name


Description

Administration of online cognitive battery


Intervention Type

Other

Intervention Name


Description

Measurement of cytokines/inflammatory biomarkers


Intervention Type

Other

Intervention Name


Description

Measurement of the gut microbiome



Eligibility

Study Pop

Patients with IBS-C or CIC starting on Linaclotide

Sampling Method

Probability Sample

Criteria

Inclusion Criteria:

- IBS-C or CIC as defined by Rome III criteria

- able to provide and sign informed consent

- age 18-65 years

Exclusion Criteria:

- Previous diagnosis of bipolar, schizophrenia, or schizoaffective disorder

- psychosis

- active suicidal thoughts

- presence of a major neurocognitive disorder, delirium or other cognitive disorder

- active substance dependence ( including the use of cannabis more than 3 times per week

- active eating disorder

- pregnant or breastfeeding

Gender

All

Minimum Age

18 Years

Maximum Age

65 Years

Healthy Volunteers

No


Overall Official

Last Name

Role

Affiliation

Rebecca Anglin, MD, PhD
Principal Investigator
McMaster University

Overall Contact

Last Name

Rebecca Anglin, MD, PhD

Phone

905-521-2100

Phone Ext

76380

Email



Location

Facility

Status

Contact

McMaster University Health Centre
Hamilton Ontario L8N 3Z5 Canada
Recruiting
Last Name: Rebecca Anglin, MD PhD
Phone: 905-521-2100
Phone Ext: 76380
Email: [email protected]

Location Countries

Country

Canada


Verification Date

2017-11-01

Lastchanged Date

2017-11-09

Firstreceived Date

2016-03-01

Responsible Party

Responsible Party Type

Principal Investigator

Investigator Affiliation

McMaster University

Investigator Full Name

Rebecca Anglin

Investigator Title

Assistant Professor


Keywords


Has Expanded Access

No

Condition Browse


Firstreceived Results Date

N/A

Firstreceived Results Disposition Date

N/A

Study Design Info

Observational Model

Cohort

Time Perspective

Prospective


Study First Submitted

March 1, 2016

Study First Submitted Qc

November 9, 2017

Study First Posted

November 14, 2017

Last Update Submitted

November 9, 2017

Last Update Submitted Qc

November 9, 2017

Last Update Posted

November 14, 2017


ClinicalTrials.gov processed this data on November 14, 2017

Conditions

Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov, conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions

Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied. Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase

Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions that study is seeking to answer:

In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.



© 2017 ICH GCP