Assessment and Comparison of Metabolic Changes in Non-psychotic Adults Taking Iloperidone or Olanzapine or Placebo

• ClinicalTrials.gov Identifier: NCT01920802
• Recruitment Status: Completed
• First Posted: August 12, 2013
• Results First Posted: March 20, 2017
• Last Update Posted: March 20, 2017
• Sponsor: New York State Psychiatric Institute
• Collaborator: Novartis Pharmaceuticals
• Information provided by (Responsible Party): New York State Psychiatric Institute

Study Description

Brief Summary:

The purpose of this pilot randomized clinical trial is to begin to delineate the pathophysiological changes associated with antipsychotic associated metabolic side effects. The study will be performed in 36 healthy people between the ages of 18 and 30, who have never taken an antipsychotic, will undergo baseline laboratory tests before being randomized to 5mg BID of olanzapine or 6mg BID of iloperidone or placebo to take for up to 4 weeks. The primary outcome measure will be a correlation of early changes in leptin with weight gain. We will also record changes in food intake, resting metabolic rate, oral glucose tolerance and fasting insulin and glucose levels, lipids and inflammation markers. Subjects will be followed closely to monitor for safety throughout the 4-week study and will be discontinued if there is a medically significant change in metabolic status or other antipsychotic side effects. Metabolic assessments will be performed again at the time of discontinuation or at the end of an 4-week period, and change from baseline in the two treatment groups will be compared.

Condition or disease	Intervention/treatment	Phase
Healthy	Drug: olanzapine; Drug: iloperidone; Drug: Placebo	Phase 4

Detailed Description:

Study hypotheses:

1. Early changes (baseline vs day 3) in leptin will correlate with later changes in weight (at study termination.)

   1. Olanzapine will cause the greatest increase in calorie consumption from baseline on the multi-item meal compared with iloperidone or placebo.
   2. Olanzapine subjects will report the greatest frequency/quantity of eating in food diaries, and report increased preference for calorically dense foods (ie, higher fat content) compared to iloperidone or placebo.
   3. Early markers of endocrine changes caused by olanzapine will be greater than those caused by iloperidone or placebo, and these early changes will correlate with weight gain.

2. Olanzapine will have greater effects on glucose homeostasis than iloperidone or placebo, and these effects will be separate from effects on body weight and composition.

   1. Early signs of metabolic disturbance, including glucose intolerance (greater excursion on OGTT) and insulin resistance (higher plasma insulin) will precede any significant weight gain.
   2. Early evidence of glucose intolerance and/or insulin resistance will predict greater metabolic derangements with further dosing of olanzapine, as evidenced by exacerbated glucose intolerance on OGTT or higher plasma glucose/insulin levels. These effects may not necessarily parallel weight gain.
   3. Olanzapine will be associated with greater markers of inflammation than iloperidone or placebo.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Quantitative Assessment and Comparison of Metabolic Changes in Non-psychotic Adults Taking the Antipsychotic Medications Fanapt (Iloperidone) or Zyprexa (Olanzapine) or Placebo
• Study Start Date: November 2012
• Actual Primary Completion Date: August 2014
• Actual Study Completion Date: September 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: olanzapine; 5mg BID olanzapine for up to 4 weeks	Drug: olanzapine; 5mg BID up to 4 weeks; Other Name: Zyprexa
Experimental: iloperidone; 6mg BID iloperidone up to 4 weeks	Drug: iloperidone; 6 mg BID up to 4 weeks; Other Name: Fanapt
Placebo Comparator: placebo; BID placebo up to 4 weeks	Drug: Placebo; BID up to 4 weeks

Outcome Measures

Primary Outcome Measures :

1. Change in Body Weight [ Time Frame: baseline and 6 week visit ]
   Delineate a pathophysiological mechanism of antipsychotic induced weight gain
2. Change in Adiposity [ Time Frame: Baseline to Day 28 ]
   Total fat mass (excluding head) from baseline to Day 28

Secondary Outcome Measures :

1. Change in Leptin [ Time Frame: change in baseline to Day 3 ]
   Leptin levels measured at Day 3 compared to baseline

Other Outcome Measures:

1. Change Glucose in People Taking Olanzapine or Iloperidone [ Time Frame: Baseline to study termination (about 12 weeks) ]
   To quantify, prospectively, change in glucose from baseline to Day 28
2. Change in Insulin [ Time Frame: Baseline to Day 28 ]
   Change in Insulin levels from baseline to Day 28
3. Insulin Resistance [ Time Frame: Baseline to Day 28 ]
   Homeostatic model assessment for Insulin Resistance (HOMA-IR) is a method for assessing β-cell function and insulin resistance (IR) from basal (fasting) glucose and insulin.
4. Change in Food Intake [ Time Frame: Baseline to Day 28 ]
   Total grams of food consumed
5. Change in Lipid Metabolism [ Time Frame: Baseline to Day 28 ]
   Change in lipid metabolism as measured by cholesterol/HDL ratio

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 35 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Male or female between the ages of 18-35 with no history of any Axis-I diagnosis
• Does not meet criteria for substance abuse or dependence in the past six months
• Female subjects will use barrier-method, non-hormonal contraception
• Capacity to understand all the relevant risks and potential benefits of the study (informed consent)
• Must be able to speak and read English

Exclusion Criteria:

• Current or past Axis I psychiatric diagnosis, including alcohol or substance abuse or dependence (except nicotine or caffeine), but not including minor Axis I disorders (e.g. simple phobia)
• Lifetime use of psychotropic medications, including antipsychotics, antidepressants, mood stabilizers, and anxiolytics
• Presence or history of medical or neurological illness that, in the judgment of the investigator, could influence the results of the study
• Diagnosis of diabetes, hemoglobin A1C > 6.5, hypertension, or dyslipidemias, or elevated random or fasting glucose, abnormal lipid levels, BP 130/85
• BMI 25 or < 19, history of BMI >35, and/or waist circumference >35 inches for females, 40 inches for males
• Subjects who are pregnant or breast-feeding or planning to become pregnant during the study
• Acute suicidality
• Meets criteria for a Diagnostic and Statistical Manual, Version 4 (DSM-IV) defined eating disorder
• Use of, or clinical indication for, one or more of the following medications: lithium, anti-epileptic medication, steroids (oral or inhaled), stimulants, serotonin reuptake inhibitors, mirtazapine, tricyclic antidepressants, thyroid supplementation, sibutramine, metformin, thiazolidinediones, beta-blockers, clonidine, niacin
• Subjects who have had >10% change in their body weight within the three months prior to enrollment
• HIV positive subjects
• Presence of mental retardation or pervasive developmental disorder
• History of recent (within 6 months) significant self-injurious behavior or violence
• Daily multivitamin or B-complex vitamin use
• A known history of dieting and difficulty with weight loss
• A strong family history of diabetes and/or heart disease
• History of congenital long QT syndrome or prolonged corrected QT interval (QTc) on screening EKG (>450ms)
• Concomitant use of any medication that inhibits 2D6 or 3A4 metabolism
• Low serum potassium or magnesium

Contacts and Locations

Locations

United States, New York

New York State Psychiatric Institute

New York, New York, United States, 10032

Sponsors and Collaborators

New York State Psychiatric Institute

Novartis Pharmaceuticals

Investigators

• Principal Investigator: Jeffrey Lieberman, MD; New York State Psychiatric Institute

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ballon JS, Pajvani UB, Mayer LE, Freyberg Z, Freyberg R, Contreras I, Rosenbaum M, Leibel RL, Lieberman JA. Pathophysiology of drug induced weight and metabolic effects: findings from an RCT in healthy volunteers treated with olanzapine, iloperidone, or placebo. J Psychopharmacol. 2018 May;32(5):533-540. doi: 10.1177/0269881118754708. Epub 2018 Feb 15.

• Responsible Party: New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT01920802
• Other Study ID Numbers: 6525
• First Posted: August 12, 2013
• Results First Posted: March 20, 2017
• Last Update Posted: March 20, 2017
• Last Verified: January 2017

Additional relevant MeSH terms:

Olanzapine; Iloperidone; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Antipsychotic Agents; Tranquilizing Agents; Central Nervous System Depressants; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Serotonin Agents