Bipolar DisorderPhase 3COGDYS-GLP1NCT02423824
Cognitive Dysfunction and Glucagon-like Peptide-1 Agonists
A Phase 3 study testing Liraglutide in people with Bipolar Disorder and Major Depressive Disorder, run by University Health Network, Toronto at 1 site in Canada.
Trial summary
Cognitive deficits are a core feature across disparate brain disorders, being highly prevalent and pervasive. Impairments in executive function are one of the most consistent findings in clinical and meta-analytical studies and were reported to be a principal mediator of psychosocial impairment and disability. Read more about this study
- Who is it for?
- Ages 18 to 45 years
- Conditions the study is for
- Bipolar Disorder, Major Depressive Disorder
- What is being tested?
- Liraglutide
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 1 siteCanada
- Study dates
- May 2015to May 2016
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Informed consent before study-related activity
- Individuals between the ages of 18 and 45 who meet DSM-5 criteria for bipolar disorders or depressive disorders
- Below-average (i.e. 1 standard deviation below norm) performance in the TMTB.
- Individuals must be receiving guideline concordant pharmacotherapy, in stable doses, without withdrawal or addition of medication in the last month.
Who cannot join
- Diagnosis of possible or probable AD, MCI, or any other dementia
- History of neurological disorder (ischemic attacks, carotid bruits, or lacunes upon MRI scan), or evidence of neurologic or other physical illness that could produce cognitive deterioration
- Individuals in a severe mood episode, defined as a Hamilton Depression Rating scale 17- item (HAMD-17) total score of >23 or a Young Mania Rating Scale (YMRS) total score of >20.
- Actively suicidal or evaluated as being a suicide risk (operationalized as a score of ≥3 on HAMD-17 suicide item and/or by clinical assessment).
- Substance use disorder within 3 months before screening or a positive baseline toxicology screen.
- Currently being treated for diabetes, with oral hypoglycemic agents and/or insulin, as these medications affect glucose and insulin levels, as well as the HOMA-IR calculation.
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- Presence of absolute or relative contraindication to liraglutide (e.g. hepatic impairment, renal impairment with CKD stage 3 and above, personal or familial history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2)
- History of alcoholism; history of pancreatitis or pancreatic cancer
- Presence of clinically unstable general medical illness.
- Pregnancy or breastfeeding women.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Exploring the Neural Substrates of Cognitive Dysfunction With Glucagon-like Peptide-1 Agonists
Cognitive deficits are a core feature across disparate brain disorders, being highly prevalent and pervasive. Impairments in executive function are one of the most consistent findings in clinical and meta-analytical studies and were reported to be a principal mediator of psychosocial impairment and disability. Cognitive dysfunction is thought to be underlied by abnormalities in distributed brain circuits, at the cellular and molecular levels. Nonetheless, the neural mechanisms underlying the dysregulation in these circuits are poorly understood. Emerging evidence indicates that metabolic abnormalities are highly relevant for the domain of cognitive function and indicate that alterations in metabolic pathways may be relevant to neurocognitive decline across different populations. The incretin glucagon-like peptide-1 (GLP-1) is a hormone secreted by intestinal epithelial cells. GLP-1 receptors are widely expressed in the central nervous systems. Pre-clinical trials have demonstrated significant neuroprotective effects of GLP-1. Ongoing clinical trials measuring cognition and mood in populations with various psychiatric disorders lend further impetus to explore the effects of GLP-1R agonists on brain structure and cognitive function. We hypothesize that GLP-1 and the GLP-1R are relevant for molecular and cellular processes that are thought to underlie the formation and maintenance of brain circuits. A derivative of this hypothesis is that the administration of GLP-1 agonists may result in enhanced neuronal survival and consequential increase in gray matter volume. We therefore propose to explore the cellular and molecular abnormalities within and between neural circuits subserving cognition using the GLP-1R agonist liraglutide.
The overall goal of this study is to explore the relationship between a metabolic molecular target (i.e. the GLP1 system), the neural circuits of interest and the behavioral phenotype cognitive function.
Read the detailed description
We propose to explore the effects of GLP-1 agonism on brain structure and function. We hypothesize that the administration of GLP-1 agonists may result in increased connectivity in the executive control network. Multiple clinical trials with pharmacological agents, as well as cognitive therapy, have reported that measurements of brain structure and function are correlated with cognitive performance, indicating that they are a valid biological correlate of cognitive function. To assess this hypothesis we will recruit a clinical population, represented by individuals with a measurable impairment in executive function, wherein the target of our proposed intervention was shown to be altered.
We are currently not in a position to sufficiently homogenize subgroups of adults with mood disorder on the basis of any single or combinatorial biomarkers. It is also unlikely that alterations in GLP-1 receptor function, and the proposed model herein, is sufficiently explanatory to all sub-populations of adults with mood disorders. Instead, we propose that adults with mood disorders, who have co-existing metabolic disorders (e.g. type 2 diabetes mellitus), would be more likely to have a brain illness that is influenced by (i.e. cause, consequence or both) alterations in cellular bioenergetics. Moreover, convergent evidence suggest that GLP-1 receptor function may be, at least partially, dependent on glucose levels and/or insulin sensibility. It is a separate, yet testable, hypothesis that subpopulations enriched on the basis of having metabolic comorbidity (i.e. insulin resistance) may be more responsive to an intervention that targets a metabolic pathway.
We plan to test the effects of adjunctive liraglutide on executive function. We will select a subpopulation of patients, with a mood disorder and impairment in executive function, as defined by a below-average (i.e. 1 standard deviation below norm) performance in the Trail Making Test-B (TMTB). Furthermore, we plan to recruit two groups of patients, with and without insulin resistance, as defined by a homeostatic model assessment for insulin resistance (HOMA-IR) above 2.5, which will allow a comparison of the effects of liraglutide in a metabolically heterogeneous population.
- Conditions
- Bipolar Disorder, Major Depressive Disorder
- Being tested
- Liraglutide
- Medical subject headings
- Bipolar Disorder, Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LiraglutideBiological
Study participants will received the following study intervention in addition to 'standard of care' treatment: Adjunctive liraglutide will be initiated at 0.6 mg for the first 1 week, then increased to 1.2 mg with the option of increasing to 1.8 mg thereafter based on efficacy/tolerability (n=15 in each group). Liraglutide will be adjunctively administered to a conventional antidepressant, antipsychotic and mood stabilizing agent at guideline-concordant therapeutic plasma levels. Subjects will be randomized to receive liraglutide for a 4 week period. No major change in the pharmacological regimen will be permitted during the 4 week trial unless required for medical reasons.
| Study group | Role | What they receive |
|---|---|---|
| Insulin Resistance | Active comparator | Adjunctive Liraglutide 1.2-1.8mg/day Receives: Biological: Liraglutide |
| Non-Insulin Resistance | Active comparator | Adjunctive Liraglutide 1.2-1.8mg/day Receives: Biological: Liraglutide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Executive function
The primary efficacy variable will be mean change from baseline to week 4 on executive function performance, as measured by Trail Making Test B.
Measured: 4 weeks
Secondary outcomes (1)
Resting-state functional network connectivity
We will evaluate the effects of liraglutide on functional connectivity (i.e. the degree of correlation of the time series of activation between distributed neuronal areas) within and between key components of the executive control network, including the dorsolateral prefrontal cortex (dlPFC), ventromedial prefrontal cortex and parietal cortex, as well as other regions of interest, such as the hippocampus.
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Apr 2015 (estimated)
- Study startMay 2015
- Primary completionApr 2016
- Study completionMay 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Bipolar DisorderStudies of the same condition, open and under way.
- More trials run by University Health Network, TorontoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Health Network, Toronto
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Roger S McIntyre, M.D., Principal investigator, Professor of Psychiatry and Pharmacology, University of Toronto
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02423824
- Sponsor's protocol ID
- 14-8561-A
- Acronym
- COGDYS-GLP1
- Status last verified
- May 2016
- First submitted
- 17 Apr 2015
- Last updated
- 13 May 2016
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 May 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Exploring the Neural Substrates of Cognitive Dysfunction With Glucagon-like Peptide-1 Agonists
- ClinicalTrials.gov ID
- NCT02423824
- Acronym / sponsor ID
- COGDYS-GLP1 / 14-8561-A
- Conditions
- Bipolar Disorder, Major Depressive Disorder
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 21 participants (actual)
- Lead sponsor
- University Health Network, TorontoUniversity, hospital or other
- Study start
- May 2015
- Primary completion
- Apr 2016 (actual)
- Study completion
- May 2016 (actual)
- First posted
- 22 Apr 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Cognitive deficits are a core feature across disparate brain disorders, being highly prevalent and pervasive. Impairments in executive function are one of the most consistent findings in clinical and meta-analytical studies and were reported to be a principal mediator of psychosocial impairment and disability. Cognitive dysfunction is thought to be underlied by abnormalities in distributed brain circuits, at the cellular and molecular levels. Nonetheless, the neural mechanisms underlying the dysregulation in these circuits are poorly understood. Emerging evidence indicates that metabolic abnormalities are highly relevant for the domain of cognitive function and indicate that alterations in metabolic pathways may be relevant to neurocognitive decline across different populations. The incretin glucagon-like peptide-1 (GLP-1) is a hormone secreted by intestinal epithelial cells. GLP-1 receptors are widely expressed in the central nervous systems. Pre-clinical trials have demonstrated significant neuroprotective effects of GLP-1. Ongoing clinical trials measuring cognition and mood in populations with various psychiatric disorders lend further impetus to explore the effects of GLP-1R agonists on brain structure and cognitive function. We hypothesize that GLP-1 and the GLP-1R are relevant for molecular and cellular processes that are thought to underlie the formation and maintenance of brain circuits. A derivative of this hypothesis is that the administration of GLP-1 agonists may result in enhanced neuronal survival and consequential increase in gray matter volume. We therefore propose to explore the cellular and molecular abnormalities within and between neural circuits subserving cognition using the GLP-1R agonist liraglutide.
The overall goal of this study is to explore the relationship between a metabolic molecular target (i.e. the GLP1 system), the neural circuits of interest and the behavioral phenotype cognitive function.
Detailed description
We propose to explore the effects of GLP-1 agonism on brain structure and function. We hypothesize that the administration of GLP-1 agonists may result in increased connectivity in the executive control network. Multiple clinical trials with pharmacological agents, as well as cognitive therapy, have reported that measurements of brain structure and function are correlated with cognitive performance, indicating that they are a valid biological correlate of cognitive function. To assess this hypothesis we will recruit a clinical population, represented by individuals with a measurable impairment in executive function, wherein the target of our proposed intervention was shown to be altered.
We are currently not in a position to sufficiently homogenize subgroups of adults with mood disorder on the basis of any single or combinatorial biomarkers. It is also unlikely that alterations in GLP-1 receptor function, and the proposed model herein, is sufficiently explanatory to all sub-populations of adults with mood disorders. Instead, we propose that adults with mood disorders, who have co-existing metabolic disorders (e.g. type 2 diabetes mellitus), would be more likely to have a brain illness that is influenced by (i.e. cause, consequence or both) alterations in cellular bioenergetics. Moreover, convergent evidence suggest that GLP-1 receptor function may be, at least partially, dependent on glucose levels and/or insulin sensibility. It is a separate, yet testable, hypothesis that subpopulations enriched on the basis of having metabolic comorbidity (i.e. insulin resistance) may be more responsive to an intervention that targets a metabolic pathway.
We plan to test the effects of adjunctive liraglutide on executive function. We will select a subpopulation of patients, with a mood disorder and impairment in executive function, as defined by a below-average (i.e. 1 standard deviation below norm) performance in the Trail Making Test-B (TMTB). Furthermore, we plan to recruit two groups of patients, with and without insulin resistance, as defined by a homeostatic model assessment for insulin resistance (HOMA-IR) above 2.5, which will allow a comparison of the effects of liraglutide in a metabolically heterogeneous population.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Insulin Resistance | Active comparator | Biological: LiraglutideAdjunctive Liraglutide 1.2-1.8mg/day |
| Non-Insulin Resistance | Active comparator | Biological: LiraglutideAdjunctive Liraglutide 1.2-1.8mg/day |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Informed consent before study-related activity
- Individuals between the ages of 18 and 45 who meet DSM-5 criteria for bipolar disorders or depressive disorders
- Below-average (i.e. 1 standard deviation below norm) performance in the TMTB.
- Individuals must be receiving guideline concordant pharmacotherapy, in stable doses, without withdrawal or addition of medication in the last month.
Key exclusion criteria (10 listed)
- Diagnosis of possible or probable AD, MCI, or any other dementia
- History of neurological disorder (ischemic attacks, carotid bruits, or lacunes upon MRI scan), or evidence of neurologic or other physical illness that could produce cognitive deterioration
- Individuals in a severe mood episode, defined as a Hamilton Depression Rating scale 17- item (HAMD-17) total score of >23 or a Young Mania Rating Scale (YMRS) total score of >20.
- Actively suicidal or evaluated as being a suicide risk (operationalized as a score of ≥3 on HAMD-17 suicide item and/or by clinical assessment).
- Substance use disorder within 3 months before screening or a positive baseline toxicology screen.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LiraglutideStudy participants will received the following study intervention in addition to 'standard of care' treatment: Adjunctive liraglutide will be initiated at 0.6 mg for the first 1 week, then increased to 1.2 mg with the option of increasing to 1.8 mg thereafter based on efficacy/tolerability (n=15 in each group). Liraglutide will be adjunctively administered to a conventional antidepressant, antipsychotic and mood stabilizing agent at guideline-concordant therapeutic plasma levels. Subjects will be randomized to receive liraglutide for a 4 week period. No major change in the pharmacological regimen will be permitted during the 4 week trial unless required for medical reasons. | Biological | Insulin Resistance, Non-Insulin Resistance |
Primary outcome
Executive function
Time frame: 4 weeks
The primary efficacy variable will be mean change from baseline to week 4 on executive function performance, as measured by Trail Making Test B.
1 secondary outcome
Resting-state functional network connectivity
Time frame: 4 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 May 2016.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Roger S McIntyre, M.D. principal investigator
Professor of Psychiatry and Pharmacology, University of Toronto
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Liraglutide in people with Bipolar Disorder and Major Depressive Disorder, run by University Health Network, Toronto at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 May 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Executive function (time frame: 4 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 May 2016.