NORIG: Nortriptyline for Idiopathic Gastroparesis

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00765895
• Collaborator: (none)
• Enrollment: 130
• Locations: 7
• Arms: 2
• Actual Duration (Months): 45
• Patients Per Site: 18.6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The principal objective of this multicenter, randomized, placebo-controlled trial is to evaluate whether treatment with nortriptyline will improve gastroparesis symptoms compared with placebo.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Gastroparesis	Drug: Nortriptyline Hydrochloride; Drug: Placebo (for nortriptyline)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 130 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Nortriptyline for Idiopathic Gastroparesis: A Multicenter, Randomized, Double-Masked, Placebo-Controlled Trial (NORIG)
• Actual Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Nortriptyline Nortriptyline Hydrochloride dose escalation from 10 mg to 75 mg	Drug: Nortriptyline Hydrochloride; Nortriptyline; 10 mg, one capsule, po qhs (by mouth at bedtime each night) x 3 weeks, f03 visit, 25 mg, one capsule, po qhs x 3 weeks, f06 visit, 50 mg, two capsules, po qhs x 3 weeks, f09 visit, 75 mg, three capsules, po qhs x 6 weeks, f15 visit: taper study drug by one capsule a week, off study drug for the last week; Other Names: Nortriptyline HCl Pamelor
Placebo Comparator: Placebo (for nortriptyline) No treatment	Drug: Placebo (for nortriptyline); Placebo (for nortriptyline), 10 mg, one capsule, po qhs x 3 weeks, f03 visit, 25 mg, one capsule, po qhs x 3 weeks;

Outcome Measures

Primary Outcome Measures

1. Decrease From the Baseline GCSI of at Least 50% on Any Two Consecutive Follow-up Visits [at end of treatment, 15 weeks from baseline assessment]

   A decrease from the baseline Gastroparesis Cardinal Symptom Index (GCSI) score (sum of the 9 individual symptom scores) of at least 50% on any two consecutive follow-up visits during the 15 week treatment period with maximum tolerated study drug dose. The total score ranges from 0-45 with higher scores indicating greater symptom severity.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 21 through 65 years old at registration

• Documentation of delayed gastric emptying on gastric emptying scintigraphy within 2 years of registration, defined as greater than 60% retention at 2 hours or greater than 10% retention at 4 hours

• Symptoms of gastroparesis for at least 6 months (does not have to be contiguous) prior to registration with Gastroparesis Cardinal Symptom Index (GCSI) score of 21 or greater

• Negative upper endoscopy or upper GI series within 2 years of registration

Exclusion Criteria:

• Normal gastric emptying confirmed with scintigraphy

• Diabetic gastroparesis or post-surgical gastroparesis including fundoplication

• Another active disorder which could explain symptoms in the opinion of the investigator

• History of significant cardiac arrhythmias and/or prolonged QTc

• History of seizures

• Use of narcotics more than 3 days per week

• Use of tricyclic antidepressants for refractory symptoms of gastroparesis within 6 weeks prior to randomization

• Use of strongly anticholinergic medications

• Use of calcium channel blockers

• Use of erythromycin

• Clear history of failed trial of nortriptyline use for gastroparetic symptoms

• Symptoms of primary depression or suicidal ideation

• Contraindications to nortriptyline:

1. hypersensitivity or allergy to any tricyclic antidepressant drug

2. concomitant therapy with a monoamine oxidase inhibitor (MAOI)

3. recent myocardial infarction

4. glaucoma

• Pregnancy or nursing

• Any other condition, which in the opinion of the investigator would impede compliance or hinder completion of the study

• Use of a G tube, J tube,or a central catheter for nutrition

• Use of a gastric electrical stimulator

• Failure to give informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	California Pacific Medical Center	San Francisco	California	United States	94115
2	Stanford University	Stanford	California	United States	94305-5187
3	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
4	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
5	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
6	Temple University Hospital	Philadelphia	Pennsylvania	United States	19140
7	Texas Tech University Health Sciences Center	El Paso	Texas	United States	79905

Sponsors and Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Study Director: Frank Hamilton, MD, MPH, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for information on gastroparesis research

Publications

None provided.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT00765895
• Other Study ID Numbers: U01DK074008 NORIG; 1U01DK073983; 1U01DK073975; 1U01DK073985; 1U01DK074007; 1U01DK073974; 1U01DK074008
• First Posted: Oct 3, 2008
• Last Update Posted: May 14, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): idiopathic gastroparesis
• Additional relevant MeSH terms: Gastroparesis; Nortriptyline

Study Results

Participant Flow

Arm/Group Title	Nortriptyline	Placebo
Arm/Group Description	Nortriptyline Hydrochloride dose escalation from 10 mg to 75 mg Nortriptyline Hydrochloride: Nortriptyline; 10 mg, one capsule, po qhs (by mouth at bedtime each night) x 3 weeks, f03 visit, 25 mg, one capsule, po qhs x 3 weeks, f06 visit, 50 mg, two capsules, po qhs x 3 weeks, f09 visit, 75 mg, three capsules, po qhs x 6 weeks, f15 visit: taper study drug by one capsule a week, off study drug for the last week	No treatment Nortriptyline-Placebo: Nortriptyline-placebo, 10 mg, one capsule, po qhs x 3 weeks, f03 visit, 25 mg, one capsule, po qhs x 3 weeks; f06 visit, 50 mg, two capsules, po qhs x 3 weeks; f09 visit, 75 mg, three capsules, po qhs x 6 weeks, po qhs x 15 wks f15 visit: taper study drug by one capsule a week, off study drug for the last week
Period Title: Overall Study
STARTED	65	65
COMPLETED	65	65
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Nortriptyline	Placebo	Total
Arm/Group Description	Nortriptyline Hydrochloride dose escalation from 10 mg to 75 mg Nortriptyline Hydrochloride: Nortriptyline; 10 mg, one capsule, po qhs (by mouth at bedtime each night) x 3 weeks, f03 visit, 25 mg, one capsule, po qhs x 3 weeks, f06 visit, 50 mg, two capsules, po qhs x 3 weeks, f09 visit, 75 mg, three capsules, po qhs x 6 weeks, f15 visit: taper study drug by one capsule a week, off study drug for the last week	No treatment Nortriptyline-Placebo: Nortriptyline-placebo, 10 mg, one capsule, po qhs x 3 weeks, f03 visit, 25 mg, one capsule, po qhs x 3 weeks; f06 visit, 50 mg, two capsules, po qhs x 3 weeks; f09 visit, 75 mg, three capsules, po qhs x 6 weeks, po qhs x 15 wks f15 visit: taper study drug by one capsule a week, off study drug for the last week	Total of all reporting groups
Overall Participants	65	65	130
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42 (12)	40 (12)	41 (12)
Sex: Female, Male (Count of Participants)
Female	60 92.3%	56 86.2%	116 89.2%
Male	5 7.7%	9 13.8%	14 10.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.5%	0 0%	1 0.8%
Asian	0 0%	1 1.5%	1 0.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	10 15.4%	9 13.8%	19 14.6%
White	54 83.1%	54 83.1%	108 83.1%
More than one race	0 0%	1 1.5%	1 0.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 10.8%	8 12.3%	15 11.5%
Not Hispanic or Latino	58 89.2%	57 87.7%	115 88.5%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	65 100%	65 100%	130 100%
Body mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27 (5)	28 (7)	27 (6)
proton-pump inhibitor taken in last month (participants) [Number]
Number [participants]	48 73.8%	49 75.4%	97 74.6%
benzodiazepine taken in last month (participants) [Number]
Number [participants]	26 40%	14 21.5%	40 30.8%
prokinetic taken in last month (participants) [Number]
Number [participants]	23 35.4%	25 38.5%	48 36.9%
antiemetics taken in last month (participants) [Number]
Number [participants]	39 60%	33 50.8%	72 55.4%
selective serotonin reuptake inhibitor taken in last month (participants) [Number]
Number [participants]	7 10.8%	11 16.9%	18 13.8%
GSCI total score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	30.9 (6.1)	30.3 (6.5)	30.6 (6.3)
GSCI- nausea sub score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	8.2 (3.6)	8.2 (4.2)	8.2 (3.9)
GSCI- satiety sub score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	15.4 (3.4)	15.1 (4.1)	15.3 (3.7)
GSCI- bloating sub score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	7.2 (2.9)	7.0 (2.7)	7.1 (2.8)
PAGI-SYM- upper abdominal pain sub score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.8 (2.9)	6.5 (2.9)	6.6 (2.9)
PAGI-SYM- lower abdominal pain sub score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.7 (3.3)	4.3 (3.3)	4.5 (3.3)
PAGI-SYM- GERD sub score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	15.4 (9.4)	17.9 (10.5)	16.7 (10.7)
GI symptoms constipation sub score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.8 (1.9)	2.4 (1.7)	2.6 (1.8)
GI symptom diarrhea sub score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	1.8 (1.7)	2.0 (1.8)	1.9 (1.8)
PAGI-SYM nausea/vomiting predominant symptom (participants) [Number]
Number [participants]	27 41.5%	22 33.8%	49 37.7%
clinical global patient impression score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	-0.7 (0.9)	-0.7 (1.2)	-0.7 (1.0)
Gastroparesis Symptom Rating Scale score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.6 (1.1)	3.7 (1.2)	3.6 (1.2)
SF-36 Quality of Life - Physical component (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	35 (10)	36 (10)	35 (10)
SF-36 Quality of Life -Mental component (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	41 (13)	40 (13)	40 (13)
Beck Depression Inventory- total score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	17 (11)	18 (12)	17 (12)
Beck Depression Inventory- severe depression score (participants) [Number]
Number [participants]	12 18.5%	15 23.1%	27 20.8%
Brief Pain Inventory- severity score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.0 (2.5)	4.1 (2.7)	4.0 (2.6)
Brief Pain Inventory- interference score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.2 (3.0)	4.1 (3.3)	4.1 (3.1)
State Trait Anxiety Inventory- State Anxiety score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	42 (13)	41 (12)	42 (12)
State Trait Anxiety Inventory- Trait Anxiety score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	43 (12)	43 (13)	43 (12)
Patient Health Questionnaire-15 (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	14 (5)	14 (5)	14 (5)

Outcome Measures

1. Primary Outcome

Title	Decrease From the Baseline GCSI of at Least 50% on Any Two Consecutive Follow-up Visits
Description	A decrease from the baseline Gastroparesis Cardinal Symptom Index (GCSI) score (sum of the 9 individual symptom scores) of at least 50% on any two consecutive follow-up visits during the 15 week treatment period with maximum tolerated study drug dose. The total score ranges from 0-45 with higher scores indicating greater symptom severity.
Time Frame	at end of treatment, 15 weeks from baseline assessment

Outcome Measure Data

Analysis Population Description

intention to treat

Arm/Group Title	Nortriptyline	Placebo
Arm/Group Description	Nortriptyline Hydrochloride dose escalation from 10 mg to 75 mg Nortriptyline Hydrochloride: Nortriptyline; 10 mg, one capsule, po qhs (by mouth at bedtime each night) x 3 weeks, f03 visit, 25 mg, one capsule, po qhs x 3 weeks, f06 visit, 50 mg, two capsules, po qhs x 3 weeks, f09 visit, 75 mg, three capsules, po qhs x 6 weeks, f15 visit: taper study drug by one capsule a week, off study drug for the last week	No treatment Nortriptyline-Placebo: Nortriptyline-placebo, 10 mg, one capsule, po qhs x 3 weeks, f03 visit, 25 mg, one capsule, po qhs x 3 weeks; f06 visit, 50 mg, two capsules, po qhs x 3 weeks; f09 visit, 75 mg, three capsules, po qhs x 6 weeks, po qhs x 15 wks f15 visit: taper study drug by one capsule a week, off study drug for the last week
Measure Participants	65	65
Number (95% Confidence Interval) [participants]	15 23.1%	14 21.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nortriptyline, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.86
	Comments
	Method	Mantel Haenszel
	Comments	Stratified by clinic

Adverse Events

Time Frame	Duration of treatment. 15 weeks and for 3 weeks after treatment ended ( 18 weeks total)
Arm/Group Title	Nortriptyline		Placebo
Arm/Group Description	Nortriptyline Hydrochloride dose escalation from 10 mg to 75 mg Nortriptyline Hydrochloride: Nortriptyline; 10 mg, one capsule, po qhs (by mouth at bedtime each night) x 3 weeks, f03 visit, 25 mg, one capsule, po qhs x 3 weeks, f06 visit, 50 mg, two capsules, po qhs x 3 weeks, f09 visit, 75 mg, three capsules, po qhs x 6 weeks, f15 visit: taper study drug by one capsule a week, off study drug for the last week		No treatment Nortriptyline-Placebo: Nortriptyline-placebo, 10 mg, one capsule, po qhs x 3 weeks, f03 visit, 25 mg, one capsule, po qhs x 3 weeks; f06 visit, 50 mg, two capsules, po qhs x 3 weeks; f09 visit, 75 mg, three capsules, po qhs x 6 weeks, po qhs x 15 wks f15 visit: taper study drug by one capsule a week, off study drug for the last week
All Cause Mortality
	Nortriptyline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nortriptyline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/65 (7.7%)		1/65 (1.5%)
Cardiac disorders
cardiac event	1/65 (1.5%)	1	0/65 (0%)	0
Gastrointestinal disorders
vomiting	2/65 (3.1%)	2	0/65 (0%)	0
Nausea and vomiting	1/65 (1.5%)	1	0/65 (0%)	0
abdominal pain	0/65 (0%)	0	1/65 (1.5%)	1
General disorders
allergic reaction	1/65 (1.5%)	1	0/65 (0%)	0
Other (Not Including Serious) Adverse Events
	Nortriptyline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/65 (27.7%)		23/65 (35.4%)
Cardiac disorders
cardiac	5/65 (7.7%)	6	5/65 (7.7%)	5
Endocrine disorders
endocrine	0/65 (0%)	0	1/65 (1.5%)	1
Eye disorders
ocular events	1/65 (1.5%)	1	0/65 (0%)	0
Gastrointestinal disorders
gastrointestinal events	3/65 (4.6%)	5	5/65 (7.7%)	6
General disorders
swelling of hands and feet	1/65 (1.5%)	1	0/65 (0%)	0
general disorders	0/65 (0%)	0	3/65 (4.6%)	3
pain	0/65 (0%)	0	2/65 (3.1%)	2
Metabolism and nutrition disorders
weight gain/loss	0/65 (0%)	0	3/65 (4.6%)	3
Nervous system disorders
Nervous system	4/65 (6.2%)	5	2/65 (3.1%)	2
Psychiatric disorders
psychiatric	0/65 (0%)	0	3/65 (4.6%)	5
Renal and urinary disorders
renal and urinary events	3/65 (4.6%)	3	0/65 (0%)	0
Skin and subcutaneous tissue disorders
rash	1/65 (1.5%)	1	0/65 (0%)	0

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.