Normal Non-fluencyPhase 1NCT02447835
Effect of Short Term Atypical Antipsychotic Administration Compared to Placebo on Hepatic Insulin Extraction
A Phase 1 study testing Olanzapine in people with Normal Non-fluency, run by Michael Rickels at 1 site in United States.
Trial summary
Within the past 20 years, there has been a striking increase in the incidence of obesity 1;2, type 2 diabetes mellitus (T2DM) 3-5, and cardiovascular diseases (CVD) in the schizophrenic population 6-8 . Read more about this study
- Who is it for?
- Ages 18 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Normal Non-fluency
- What is being tested?
- Olanzapine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 15 participants
- Where
- 1 siteUnited States
- Study dates
- Aug 2012to Dec 2014
- Phase
- Phase 1
- 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 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Men and women ages 18-40
- BMI 19-24.5kg/m2
- Systolic BP <130mm Hg
- Diastolic BP <85mm Hg
- Subjects capable of giving informed consent, with no past or present psychiatric history
- Only women on oral contraceptives with constant dosing regimens or Depo-Provera for >3 months, to ensure uniform hormonal delivery throughout the study duration
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- No medications except as above noted
- Weight stable
- Minimal exercise regime that includes walking, running or biking
Who cannot join
- History of heart disease, colitis, autonomic neuropathy, hepatic or renal disease
- DSM-IV diagnosis of past or present psychiatric history, including clinically significant depression
- Drug/Alcohol dependence, homelessness, or inability to give informed consent
- History of asthma, congenital obstructive bladder, peptic ulcer, vasomotor instability, epilepsy, Parkinsonism, elevated thyroid hormone levels
- Diagnosis of diabetes
- BMI>25 kg/m2
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- Prescription medication (excluding the contraceptive methods described above)
- Hemoglobin <11
- Abnormal laboratory tests which are clinically significant per the investigator
- Females pregnant or lactating
- Females: not taking hormonal contraceptives; taking hormonal contraceptives of varying dosage throughout the month
- Currently on a weight loss diet
- Moderate to significant exercise regime that includes swimming, weight lifting or other form of exercise not reproducible within CTRC.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
About this study
Official title: The Effect of Short Term Atypical Antipsychotic Administration Compared to Placebo on Hepatic Insulin Extraction and Muscarinic Mediation of B-Cell Function: A Small Mechanistic, Single-Site Study
Within the past 20 years, there has been a striking increase in the incidence of obesity 1;2, type 2 diabetes mellitus (T2DM) 3-5, and cardiovascular diseases (CVD) in the schizophrenic population 6-8 . Large NIH-funded trials indicate that the prevalence of metabolic syndrome is twice to three times greater in schizophrenic patients on a specific class of drug termed the "atypical antipsychotics" (AAPs), of which olanzapine is an example, as compared to matched controls 8. Identification of the pathophysiological mechanisms contributing to metabolic disease in schizophrenic patients on AAPs has been hampered by the inability to differentiate underlying disease from treatment-emergent complications. In addition, despite falling within the same drug class, different AAPs exhibit differential associations with metabolic disease. Olanzapine is one of the AAPs associated with the greatest weight gain and degree of metabolic impairments.
Read the detailed description
The increased incidence of T2DM and CVD with the AAPs has been assumed a consequence of weight gain. However, accumulating evidence of weight-independent effects derived from in vitro and rodent studies suggests a direct effect of some AAPs on the pancreatic B-cell and the liver. We have recently completed the first of two studies supported by an NIH grant which provides evidence for a direct effect of olanzapine on metabolism, independent of weight gain or psychiatric disease. Findings from the first study indicate that short-term administration (9-days) of olanzapine compared to aripiprazole, another AAP as well as placebo dramatically increases post-prandial insulin levels in healthy control subjects independent of weight gain; providing evidence of tissue specific effects of the drug in humans. We also found that the increase in insulin was not accompanied by an increase in plasma C-peptide concentrations suggesting that olanzapine may decrease hepatic insulin extraction. Decreases in hepatic insulin extraction can be mediated through muscarinic blockade and in fact, data from our laboratory demonstrates that atropine (the muscarinic antagonist) inhibits hepatic insulin extraction in humans. Blockade of muscarinic receptors is consistent with the receptor binding profile of olanzapine which shows a higher receptor antagonism for muscarinic receptors compared to other AAPs. In addition, we also found significant increases in glucagon-like peptide 1 (GLP-1) and decreases in insulin sensitivity following olanzapine administration compared to aripiprazole and placebo. The proposed study follows up on these findings with a study designed to investigate the mechanisms contributing to the olanzapine-induced post-prandial hyperinsulinemia and GLP-1. The overall hypothesis of this study is that olanzapine blocks peripheral muscarinic receptors, leading to a compensatory increase in vagal efferent activation which contributes to an increase in insulin secretion.
- Conditions
- Normal Non-fluency
- Being tested
- Olanzapine
- Keywords
- Metabolic Disorders
- Medical subject headings
- Metabolic Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OlanzapineDrug
Also called Zyprexa
Olanzapine is approved for the treatment of schizophrenia and mania associated with bipolar disorder. Olanzapine is a psychotropic agent that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-4methyl-1 piperazinyl-10H-thienol (2,3-b)[1,5]benzodiazepine. The molecular formula is C17H20N4S which corresponds to a molecular weight of 312.44.Olanzpine is a yellow crystalline solid which is practically insoluble in water. Olanzapine is a selective monoaminergic antagonist with high affinity binding to the following receptors:5HT2A2C, 5HT6, dopamine 2-4, histamine H1, and adrenergic α-1. In addition olanzapine is an antagonist with moderate affinity for muscarinic M1-5 and 5HT3. The mechanism of action of olanzapine is unknown although it may be mediated through a combination of dopamine and serotonergic type 2 receptors.
| Study group | Role | What they receive |
|---|---|---|
| Olanzapine | Active comparator | Olanzapine administration Receives: Drug: Olanzapine |
| Placebo | Placebo comparator | Placebo administration Receives: Drug: Olanzapine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Determine the vagal contribution to the olanzapine-induced increase in circulating insulin levels.
Measured: 12 days
Secondary outcomes (1)
Determine if olanzapine increases meal-related/satiety peptides
Measured: 12 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 May 2015 (estimated)
- Study startAug 2012
- Primary completionDec 2014
- Study completionDec 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Normal Non-fluencyStudies of the same condition, open and under way.
- 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 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- Michael Rickels
- Sponsor type
- University, hospital or other
- Collaborators
- University of Pennsylvania
- Responsible party
- Sponsor-investigator, Michael Rickels, Monell Chemical Senses Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02447835
- Sponsor's protocol ID
- 815905
- Status last verified
- May 2015
- First submitted
- 25 Oct 2012
- Last updated
- 19 May 2015
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 19 May 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Short Term Atypical Antipsychotic Administration Compared to Placebo on Hepatic Insulin Extraction and Muscarinic Mediation of B-Cell Function: A Small Mechanistic, Single-Site Study
- ClinicalTrials.gov ID
- NCT02447835
- Acronym / sponsor ID
- 815905
- Conditions
- Normal Non-fluency
- Keywords
- Metabolic Disorders
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- Michael RickelsUniversity, hospital or other
- Collaborators
- University of Pennsylvania
- Study start
- Aug 2012
- Primary completion
- Dec 2014 (actual)
- Study completion
- Dec 2014 (actual)
- First posted
- 19 May 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.
Within the past 20 years, there has been a striking increase in the incidence of obesity 1;2, type 2 diabetes mellitus (T2DM) 3-5, and cardiovascular diseases (CVD) in the schizophrenic population 6-8 . Large NIH-funded trials indicate that the prevalence of metabolic syndrome is twice to three times greater in schizophrenic patients on a specific class of drug termed the "atypical antipsychotics" (AAPs), of which olanzapine is an example, as compared to matched controls 8. Identification of the pathophysiological mechanisms contributing to metabolic disease in schizophrenic patients on AAPs has been hampered by the inability to differentiate underlying disease from treatment-emergent complications. In addition, despite falling within the same drug class, different AAPs exhibit differential associations with metabolic disease. Olanzapine is one of the AAPs associated with the greatest weight gain and degree of metabolic impairments.
Detailed description
The increased incidence of T2DM and CVD with the AAPs has been assumed a consequence of weight gain. However, accumulating evidence of weight-independent effects derived from in vitro and rodent studies suggests a direct effect of some AAPs on the pancreatic B-cell and the liver. We have recently completed the first of two studies supported by an NIH grant which provides evidence for a direct effect of olanzapine on metabolism, independent of weight gain or psychiatric disease. Findings from the first study indicate that short-term administration (9-days) of olanzapine compared to aripiprazole, another AAP as well as placebo dramatically increases post-prandial insulin levels in healthy control subjects independent of weight gain; providing evidence of tissue specific effects of the drug in humans. We also found that the increase in insulin was not accompanied by an increase in plasma C-peptide concentrations suggesting that olanzapine may decrease hepatic insulin extraction. Decreases in hepatic insulin extraction can be mediated through muscarinic blockade and in fact, data from our laboratory demonstrates that atropine (the muscarinic antagonist) inhibits hepatic insulin extraction in humans. Blockade of muscarinic receptors is consistent with the receptor binding profile of olanzapine which shows a higher receptor antagonism for muscarinic receptors compared to other AAPs. In addition, we also found significant increases in glucagon-like peptide 1 (GLP-1) and decreases in insulin sensitivity following olanzapine administration compared to aripiprazole and placebo. The proposed study follows up on these findings with a study designed to investigate the mechanisms contributing to the olanzapine-induced post-prandial hyperinsulinemia and GLP-1. The overall hypothesis of this study is that olanzapine blocks peripheral muscarinic receptors, leading to a compensatory increase in vagal efferent activation which contributes to an increase in insulin secretion.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Olanzapine | Active comparator | Drug: OlanzapineOlanzapine administration |
| Placebo | Placebo comparator | Drug: OlanzapinePlacebo administration |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (9 listed)
- Men and women ages 18-40
- BMI 19-24.5kg/m2
- Systolic BP <130mm Hg
- Diastolic BP <85mm Hg
- Subjects capable of giving informed consent, with no past or present psychiatric history
Key exclusion criteria (13 listed)
- History of heart disease, colitis, autonomic neuropathy, hepatic or renal disease
- DSM-IV diagnosis of past or present psychiatric history, including clinically significant depression
- Drug/Alcohol dependence, homelessness, or inability to give informed consent
- History of asthma, congenital obstructive bladder, peptic ulcer, vasomotor instability, epilepsy, Parkinsonism, elevated thyroid hormone levels
- Diagnosis of diabetes
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 |
|---|---|---|
| OlanzapineAlso: ZyprexaOlanzapine is approved for the treatment of schizophrenia and mania associated with bipolar disorder. Olanzapine is a psychotropic agent that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-4methyl-1 piperazinyl-10H-thienol (2,3-b)[1,5]benzodiazepine. The molecular formula is C17H20N4S which corresponds to a molecular weight of 312.44.Olanzpine is a yellow crystalline solid which is practically insoluble in water. Olanzapine is a selective monoaminergic antagonist with high affinity binding to the following receptors:5HT2A2C, 5HT6, dopamine 2-4, histamine H1, and adrenergic α-1. In addition olanzapine is an antagonist with moderate affinity for muscarinic M1-5 and 5HT3. The mechanism of action of olanzapine is unknown although it may be mediated through a combination of dopamine and serotonergic type 2 receptors. | Drug | Olanzapine, Placebo |
Primary outcome
Determine the vagal contribution to the olanzapine-induced increase in circulating insulin levels.
Time frame: 12 days
1 secondary outcome
Determine if olanzapine increases meal-related/satiety peptides
Time frame: 12 days
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 19 May 2015.
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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Olanzapine in people with Normal Non-fluency, run by Michael Rickels at 1 site in United States.
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 9 inclusion and 13 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 19 May 2015. 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 United States. 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. Some participants in this study may receive a placebo. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
Determine the vagal contribution to the olanzapine-induced increase in circulating insulin levels. (time frame: 12 days). 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 19 May 2015.