A Pilot Study on the Efficacy and Safety of Olanzapine in Gastroparesis

• Sponsor: University of Michigan (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01625923
• Collaborator: Massachusetts General Hospital (Other)
• Enrollment: 3
• Locations: 2
• Arm: 1
• Duration (Months): 76.9
• Patients Per Site: 1.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Gastroparesis is a disorder characterized by impaired gastric emptying in the absence of obstruction in the proximal GI tract. It is a common condition affecting up to 5 million persons in the United States alone. Despite this, metoclopramide is currently the only FDA approved medication for the treatment of gastroparesis. However, the evidence supporting metoclopramide in gastroparesis is fairly weak and was recently issued a black box warning because of potential irreversible side effects. There is clearly an urgent need for newer therapeutic options with better efficacy and tolerability. Olanzapine is a second generation anti-psychotic that is currently FDA approved for the treatment of schizophrenia and bipolar disorder. Because of actions at several receptors throughout the body, including dopamine and serotonin receptors, Olanzapine may provide anti-nausea and pro-motility effects in the stomach. Long-term use of olanzapine may also increase plasma levels of ghrelin. Ghrelin is a hormone produced by the gut that stimulates appetite and has also been shown to have beneficial effects on gastroparesis. The investigators hypothesize that olanzapine will be effective and safe in controlling symptoms as well as stimulate appetite and weight gain in gastroparesis. The investigators also hypothesize that olanzapine will stimulate gastric motility. Finally, the investigators hypothesize that olanzapine will modulate the secretion of ghrelin in gastroparesis. This pilot study may provide further information on the efficacy and safety of olanzapine in gastroparesis which could be utilized in a larger randomized, prospective study in the future.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Gastroparesis	Drug: Olanzapine	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study on the Efficacy and Safety of Olanzapine in Improving Symptoms and Gastric Motility in Gastroparesis
• Study Start Date: Jan 1, 2013
• Actual Primary Completion Date: Jun 1, 2019
• Actual Study Completion Date: Jun 1, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Olanzapine An open-label pilot study of 20 consecutive subjects ages 18 - 70 with documented delayed gastric emptying within the past 2 years and history of nausea, vomiting, bloating, anorexia, early satiation, post-prandial fullness, and weight loss for at least 6 months without structural or organic cause will be enrolled.

Drug: Olanzapine; Subjects will initially start on olanzapine 2.5 mg per mouth daily. Subjects will return on days 7 and 14 to determine response to medication and medication dose can be increased to 5 mg and 10 mg, respectively, based on incomplete symptom response (mean change GCSI-DD < 0.5). The total dose of olanzapine will not exceed 10 mg daily during this study and subjects will continue on treatment for a total of 8 weeks.; Other Names: Zyprexa

Outcome Measures

Primary Outcome Measures

1. Change in Mean BMI [8 weeks]

   Subjects will undergo regular testing of blood glucose, insulin, hemoglobin (Hgb) A1c, body mass index (BMI), liver enzymes, thyroid stimulating hormone (TSH), and prolactin levels during the study as well as after treatment completion to determine the safety of the medication. All adverse events will be compiled to investigate the tolerability of the medication.

2. Mean GCSI-DD Before/After Treatment With Olanzapine [8 weeks]

   The investigators will utilize the gastroparesis cardinal symptom index daily diary (GCSI-DD) to compare severity of symptoms before and after treatment with olanzapine. The total GCSI-DD is a validated questionnaire that measures the daily relevant symptoms of gastroparesis and ranges from 0 (no symptoms) to 5 (severe symptoms).

3. Change in Mean Serum Glucose [8 weeks]

   Subjects will undergo regular testing of blood glucose, insulin, hemoglobin (Hgb) A1c, body mass index (BMI), liver enzymes, thyroid stimulating hormone (TSH), and prolactin levels during the study as well as after treatment completion to determine the safety of the medication. All adverse events will be compiled to investigate the tolerability of the medication.

Secondary Outcome Measures

1. Change in Mean Gastric Emptying Time [8 weeks]

   The investigators aim to test gastric motility, including gastric emptying and antroduodenal contractility parameters, by wireless motility capsule (WMC) before and at the completion of the study to determine if olanzapine has any pro-motility effects in gastroparesis.

2. Change in Mean Ghrelin Levels Over Time [8 weeks]

   The investigators seek to determine whether olanzapine promotes secretion of ghrelin in gastroparesis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female between 18 and 70 years of age

• Must have a > or = 6 month history of relevant symptoms of gastroparesis, (e.g., chronic post-prandial fullness, early satiety, postprandial nausea), patients will have a mean of the daily scores over a minimum of 7 days indicating > or = mild (2) and < or = severe (4) post-prandial fullness assessed using the GCSI-DD during the screening period prior to randomization

• Documented abnormal gastric emptying within the past 2 years

• Has gastroparesis at screening (gastric half-time of emptying > upper limit of normal as determined by wireless motility capsule)

• BMI between 18 - 30 kg/m2

• A female subject is eligible to participate if she is of non-childbearing potential or child-bearing potential and agrees to use one of the approved contraception methods. Female patients must agree to use contraception for at least 5 days following the last dose of study medication

• Subject has never had a gastrectomy, nor major gastric surgical procedure or any evidence of bowel obstruction or strictures within the previous 12 months

• Dosage of any concomitant medications has been stable for at least 3 weeks.

• Estimated (or measured) glomerular filtration rate ≥ 30 mL/min

• QTcB or QTcF < 450 msec or QTc < 480 msec in patients with Bundle Branch. Block based on single or average QTc value of triplicate values obtained over a brief recording period

• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

• AST and ALT < 2xULN; alkaline phosphatase and bilirubin ≤ 1.5xULN; normal CBC, TSH, and prolactin levels

Exclusion Criteria:

• History of diabetes mellitus or hyperglycemia

• History of cardiovascular or cerebrovascular disease

• History of hyperlipidemia

• History of cardiac arrhythmia or long QT syndrome

• History of seizure disorder

• History of hyperprolactinemia

• History of renal dysfunction

• History of hepatic impairment

• History of schizophrenia, bipolar disorder, or previous use of olanzapine

• History of Parkinson's disease, dementia or severe cognitive impairment

• History of GI surgery or placement of gastric pacemaker

• History of cardiac pacemaker or implantable cardiac defibrillator

• History of eating disorder

• History of intrapyloric botulinum toxin injections

• Subject is on chronic enteral or parenteral feeding

• Subject has pronounced dehydration

• Subject has evidence of severe cardiovascular autonomic neuropathy (e.g. history of recurrent syncope in the last 6 months)

• Use of medications potentially influencing upper gastrointestinal motility or appetite within one week of the study (e.g., prokinetic drugs, macrolide antibiotics (erythromycin), GLP-1 mimetics)

• Regular opiate use

• Subjects who are taking drugs that potentially interact with olanzapine including diazepam, lorazepam, alcohol, carbamazepine, fluvoxamine, olanzapine and fluoxetine in combination, CNS acting drugs, levodopa and dopamine agonist, and olanzapine when used in combination with lithium or valproate

• History or presence of clinically significant gastro-intestinal, hepatic or renal disease or other condition that would in the opinion of the investigator or medical monitor make the subject unsuitable for inclusion in this clinical study

• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer)

• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator would make the subject unsuitable for inclusion in this clinical study

• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day time-period

• Pregnant females as determined by positive serum or urine hCG test (from the first urine of the day) at screening or prior to dosing

• Lactating females

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)

• Subject is unable to swallow pills

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	University of Michigan	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• University of Michigan
• Massachusetts General Hospital

Investigators

• Principal Investigator: Allen Lee, MD, University of Michigan
• Principal Investigator: Braden Kuo, MD, Massachusetts General Hospital
• Principal Investigator: William Hasler, MD, University of Michigan

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 29, 2016

More Information

Publications

None provided.

• Responsible Party: Allen Lee, Clinical Lecturer, University of Michigan
• ClinicalTrials.gov Identifier: NCT01625923
• Other Study ID Numbers: ACG-SP-002-2012
• First Posted: Jun 22, 2012
• Last Update Posted: Sep 10, 2019
• Last Verified: Aug 1, 2019

• Keywords provided by Allen Lee, Clinical Lecturer, University of Michigan: Gastroparesis; Idiopathic; Olanzapine
• Additional relevant MeSH terms: Gastroparesis; Olanzapine

Study Results

Participant Flow

Arm/Group Title	Olanzapine
Arm/Group Description	Subjects were enrolled to receive olanzapine open-label for 8 weeks. Subjects were initially started on olanzapine 2.5 mg by mouth daily at bedtime. Subjects returned on days 7 and 14 to determine response to medication. Medication dose was increased to 5 mg on day 7 and 10 mg on day 14, respectively, if there was incomplete symptom response, which was defined as a mean change in GCSI-DD score < 0.5 from baseline.
Period Title: Overall Study
STARTED	3
COMPLETED	3
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Olanzapine
Arm/Group Description	Olanzapine
Overall Participants	3
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	40.3
Sex: Female, Male (Count of Participants)
Female	3 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	3 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%

Outcome Measures

1. Primary Outcome

Title	Change in Mean BMI
Description	Subjects will undergo regular testing of blood glucose, insulin, hemoglobin (Hgb) A1c, body mass index (BMI), liver enzymes, thyroid stimulating hormone (TSH), and prolactin levels during the study as well as after treatment completion to determine the safety of the medication. All adverse events will be compiled to investigate the tolerability of the medication.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Change in mean BMI

Arm/Group Title	Olanzapine
Arm/Group Description	Subjects were enrolled to receive olanzapine open-label for 8 weeks. Subjects were initially started on olanzapine 2.5 mg by mouth daily at bedtime. Subjects returned on days 7 and 14 to determine response to medication. Medication dose was increased to 5 mg on day 7 and 10 mg on day 14, respectively, if there was incomplete symptom response, which was defined as a mean change in GCSI-DD score < 0.5 from baseline.
Measure Participants	3
Baseline BMI	23.5 (3.4)
BMI at Week 8	24.9 (3.6)

2. Primary Outcome

Title	Mean GCSI-DD Before/After Treatment With Olanzapine
Description	The investigators will utilize the gastroparesis cardinal symptom index daily diary (GCSI-DD) to compare severity of symptoms before and after treatment with olanzapine. The total GCSI-DD is a validated questionnaire that measures the daily relevant symptoms of gastroparesis and ranges from 0 (no symptoms) to 5 (severe symptoms).
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Olanzapine
Arm/Group Description	An open-label pilot study of 20 consecutive subjects ages 18 - 70 with documented delayed gastric emptying within the past 2 years and history of nausea, vomiting, bloating, anorexia, early satiation, post-prandial fullness, and weight loss for at least 6 months without structural or organic cause will be enrolled. Olanzapine: Subjects will initially start on olanzapine 2.5 mg per mouth daily. Subjects will return on days 7 and 14 to determine response to medication and medication dose can be increased to 5 mg and 10 mg, respectively, based on incomplete symptom response (mean change GCSI-DD < 0.5). The total dose of olanzapine will not exceed 10 mg daily during this study and subjects will continue on treatment for a total of 8 weeks.
Measure Participants	3
Baseline GCSI-DD Score	3.11 (0.42)
GCSI-DD Score After Intervention	2.17 (0.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olanzapine
	Comments
	Type of Statistical Test	Other
	Comments	T-test comparing GCSI-DD scores before/after intervention
Statistical Test of Hypothesis	p-Value	.06
	Comments
	Method	t-test, 2 sided
	Comments

3. Primary Outcome

Title	Change in Mean Serum Glucose
Description	Subjects will undergo regular testing of blood glucose, insulin, hemoglobin (Hgb) A1c, body mass index (BMI), liver enzymes, thyroid stimulating hormone (TSH), and prolactin levels during the study as well as after treatment completion to determine the safety of the medication. All adverse events will be compiled to investigate the tolerability of the medication.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Change in mean serum glucose

Arm/Group Title	Olanzapine
Arm/Group Description	Subjects were enrolled to receive olanzapine open-label for 8 weeks. Subjects were initially started on olanzapine 2.5 mg by mouth daily at bedtime. Subjects returned on days 7 and 14 to determine response to medication. Medication dose was increased to 5 mg on day 7 and 10 mg on day 14, respectively, if there was incomplete symptom response, which was defined as a mean change in GCSI-DD score < 0.5 from baseline.
Measure Participants	3
Baseline Serum Glucose	90.5 (0.7)
Serum Glucose at Week 8	90.5 (0.7)

4. Secondary Outcome

Title	Change in Mean Gastric Emptying Time
Description	The investigators aim to test gastric motility, including gastric emptying and antroduodenal contractility parameters, by wireless motility capsule (WMC) before and at the completion of the study to determine if olanzapine has any pro-motility effects in gastroparesis.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Change in mean gastric emptying time by WMC

Arm/Group Title	Olanzapine
Arm/Group Description	Subjects were enrolled to receive olanzapine open-label for 8 weeks. Subjects were initially started on olanzapine 2.5 mg by mouth daily at bedtime. Subjects returned on days 7 and 14 to determine response to medication. Medication dose was increased to 5 mg on day 7 and 10 mg on day 14, respectively, if there was incomplete symptom response, which was defined as a mean change in GCSI-DD score < 0.5 from baseline.
Measure Participants	3
Baseline GET (minutes)	468.3 (233.4)
GET at Week 8 (minutes)	563.3 (582.6)

5. Secondary Outcome

Title	Change in Mean Ghrelin Levels Over Time
Description	The investigators seek to determine whether olanzapine promotes secretion of ghrelin in gastroparesis.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Change in mean ghrelin levels over time

Arm/Group Title	Olanzapine
Arm/Group Description	Subjects were enrolled to receive olanzapine open-label for 8 weeks. Subjects were initially started on olanzapine 2.5 mg by mouth daily at bedtime. Subjects returned on days 7 and 14 to determine response to medication. Medication dose was increased to 5 mg on day 7 and 10 mg on day 14, respectively, if there was incomplete symptom response, which was defined as a mean change in GCSI-DD score < 0.5 from baseline.
Measure Participants	3
Baseline plasma ghrelin (pg/ml)	615.7 (339.1)
Plasma ghrelin at week 8 (pg/ml)	577.0 (253.4)

Adverse Events

Time Frame	8 weeks
Arm/Group Title	Olanzapine
Arm/Group Description	Olanzapine
All Cause Mortality
	Olanzapine
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Serious Adverse Events
	Olanzapine
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Other (Not Including Serious) Adverse Events
	Olanzapine
	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)
General disorders
Fatigue	2/3 (66.7%)
Weight gain	2/3 (66.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.