Multicenter Study to Evaluate the Efficacy and Safety of Metoclopramide Nasal Spray in Women With Diabetic Gastroparesis

• Sponsor: Evoke Pharma (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02025725
• Collaborator: (none)
• Enrollment: 205
• Locations: 50
• Arms: 2
• Duration (Months): 27
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is provide confirmation of the safety and efficacy of Metoclopramide Nasal Spray compared to placebo in reducing the symptoms of diabetic gastroparesis in adult women.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Gastroparesis	Drug: Metoclopramide Nasal Spray; Drug: Placebo Nasal Spray	Phase 3

Detailed Description

Diabetic women with clinical symptoms attributed to diabetic gastroparesis and documentation of delayed gastric emptying who meet the protocol-specified entry criteria will be randomized to Metoclopramide Nasal Spray 10 mg or placebo administered as a single intranasal spray four (4) times daily; 30 minutes before meals and at bedtime for a total of four (4) weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 205 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase 3 Study of Intranasal Metoclopramide in Women With Symptomatic Diabetic Gastroparesis
• Study Start Date: Mar 27, 2014
• Actual Primary Completion Date: May 27, 2016
• Actual Study Completion Date: Jun 27, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 10 mg Metoclopramide Nasal Spray Metoclopramide Nasal Spray 10 mg, 30 minutes before meals and at bedtime (QID) for 4 weeks	Drug: Metoclopramide Nasal Spray; nasal spray formulation of metoclopramide; Other Names: EVK-001
Placebo Comparator: Placebo Nasal Spray Placebo Nasal Spray 30 minutes before meals and at bedtime (QID) for 4 weeks	Drug: Placebo Nasal Spray; nasal spray formulation with vehicle only; Other Names: EVK-001 Placebo

Outcome Measures

Primary Outcome Measures

1. Gastroparesis Symptom Assessment (GSA), a Patient Reported Outcome Measure [Baseline Period to Week 4 of the Treatment Period]

   Change from the Baseline Period to Week 4 of the Treatment Period in the mean daily Gastroparesis Symptom Assessment (GSA) total score for subjects receiving Metoclopramide Nasal Spray 10 mg versus subjects receiving placebo. The GSA minimum value is 0 (no symptoms) and the maximum value is 4 (very severe symptoms). A higher score is a worse outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Non pregnant, non lactating female subjects between the ages of 18 and 75 years

• Willingness and ability to give written informed consent

• The ability to read, understand and speak English

• Prior diagnosis of Type 1 or Type 2 diabetes

• Diagnosis of diabetic gastroparesis with confirmation of delayed gastric emptying

• A mean daily gastroparesis symptom score of ≥1.4 and ≤3.5 prior to randomization

• Subjects of childbearing potential must agree to use contraception

• Willingness to discontinue current treatment for diabetic gastroparesis and to avoid all proscribed (excluded) medications, as specified by the protocol, for the duration of the study

Exclusion Criteria:

• Gastric bypass, gastric banding, gastric pacemaker, post surgical causes of gastroparesis and disorders known to be associated with abnormal gastrointestinal motility

• A history of allergic or adverse responses, including, but not limited to, acute dystonic reactions and tardive dyskinesia, to metoclopramide or any comparable or similar product

• A history of, or physical findings suggestive of, tardive dyskinesia

• A history of epilepsy or currently using and unwilling or unable stop other drugs known to be associated with extrapyramidal reactions at screening

• A history of allergy to any of the ingredients in the study drug formulation

• A history of organ transplant, chronic pancreatitis, gross malabsorptive syndromes, celiac disease, active inflammatory bowel disease (IBD), or symptomatic irritable bowel syndrome (IBS)

• Malignancy (with the exception of treated squamous cell or basal cell carcinoma of the skin) currently present, initially diagnosed or recurring within five (5) years of screening

• Renal dysfunction calculated as creatinine clearance (CrCl) <40 mL/min at screening

• Hemoglobin A1c >11.5% at screening

• Subjects who are trying to conceive, are pregnant, or are lactating

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Birmingham Gasteroenterology Associates, P.C.	Birmingham	Alabama	United States	35209
2	Digestive Specialists of the Southeast	Dothan	Alabama	United States	36305
3	Clinical Research Associates	Huntsville	Alabama	United States	35801
4	Central Arizone Medical Associates/Clinical Research Advantage	Mesa	Arizona	United States	85206
5	Preferred Research Partners	Little Rock	Arkansas	United States	72211
6	Arkansas Gastroenterology	Sherwood	Arkansas	United States	72120
7	Precision Research Institute, LLC	Chula Vista	California	United States	91910
8	John Muir Physician Network Clinical Research Center	Concord	California	United States	94520
9	Precision Research Institute, LLC	San Diego	California	United States	92114
10	The Center for Gastrointestinal Disorders	Hollywood	Florida	United States	33021
11	Nature Coast Clinical Research	Inverness	Florida	United States	34452
12	International Research Associates, LLC	Miami	Florida	United States	33183
13	Advanced Medical Research	Port Orange	Florida	United States	32127
14	Tri-County Research	Athens	Georgia	United States	30606
15	Digestive Healthcare of Georgia	Atlanta	Georgia	United States	30309
16	Newton Medical Center	Conyers	Georgia	United States	30013
17	Gastrointestinal Specialists of Georgia, PC	Marietta	Georgia	United States	30060
18	Atlanta Gastroenterology Associates	Marietta	Georgia	United States	30067
19	Southwest Gastroenterology	Oak Lawn	Illinois	United States	60453
20	Indiana University Health UH 1634	Indianapolis	Indiana	United States	46202
21	Professional Research Network of Kansas	Wichita	Kansas	United States	67203
22	Gastroenterology Associates, LLC	Baton Rouge	Louisiana	United States	70809
23	Delta Research Partners, LLC	Monroe	Louisiana	United States	71201
24	Clinical Research Institute of Michigan	Chesterfield	Michigan	United States	48047
25	Center for Digestive Health	Troy	Michigan	United States	48098
26	Gastroenterology Associates of Western Michigan	Wyoming	Michigan	United States	49519
27	Gastrointestional Associates	Jackson	Mississippi	United States	39202
28	Kansas City Gastroenterology & Hepatology	Kansas City	Missouri	United States	64131
29	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
30	The Gastroenterology Group of South Jersey	Vineland	New Jersey	United States	08360
31	Lovelace Scientific Resources, Inc.	Albuquerque	New Mexico	United States	87108
32	Premier Medical Group of the Hudson, PC	Poughkeepsie	New York	United States	12601
33	Cumberland Research Associates	Fayetteville	North Carolina	United States	28304
34	LeBauer Research Associates	Greensboro	North Carolina	United States	27406
35	Kinston Medical Specialist Clinical Research Office	Kinston	North Carolina	United States	28501
36	Wake Research Associates	Raleigh	North Carolina	United States	27612
37	PMG Research of Salisbury	Salisbury	North Carolina	United States	28144
38	Piedmont Medical Research	Winston-Salem	North Carolina	United States	27103
39	Dayton Gastroenterology	Beavercreek	Ohio	United States	45440
40	Temple University	Philadelphia	Pennsylvania	United States	19140
41	HCCA Clinical Research Solutions	Jackson	Tennessee	United States	37805
42	Gastroenterology Associates	Kingsport	Tennessee	United States	37660
43	Quality Medical Research	Nashville	Tennessee	United States	37211
44	Texas Clinical Research Institute	Arlington	Texas	United States	76012
45	Lovelace Scientific Resources	Austin	Texas	United States	78758
46	Texas Tech University Health Sciences Center	El Paso	Texas	United States	79905
47	Burke Internal Medicine	Burke	Virginia	United States	22015
48	Manassas Clinical Research	Manassas	Virginia	United States	20110
49	National Clinical Research	Norfolk	Virginia	United States	23502
50	Wisconsin Center for Advanced Research	Milwaukee	Wisconsin	United States	53215

Sponsors and Collaborators

• Evoke Pharma

Investigators

• Study Director: Marilyn R. Carlson, DMD, MD, Evoke Pharma, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Evoke Pharma
• ClinicalTrials.gov Identifier: NCT02025725
• Other Study ID Numbers: METO-IN-003
• First Posted: Jan 1, 2014
• Last Update Posted: Jul 7, 2020
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Evoke Pharma: Gastroparesis; Diabetic; Delayed gastric emptying; Gastric stasis; Nausea; Vomiting; Bloating; Abdominal pain; Early satiety; Gastropathy
• Additional relevant MeSH terms: Gastroparesis; Metoclopramide

Study Results

Participant Flow

Recruitment Details	Recruitment Period: 27 March 2014 to 27 May 2016 Types of Location: Medical Clinics, University-Based Practices Screening Period consisted of Washout Period, Qualification Period and Baseline Period. Mean daily Gastroparesis Symptom Assessment (GSA) total score ≥ 1.4 and ≤ 3.5 was required during Qualification and Baseline periods
Pre-assignment Detail	613 participants Screened, 205 participants completed and randomized to treatment. Negative Gastric Emptying Scintigraphy 129 Inclusion/Exclusion Failed 213 Withdrawal by participant 25 Other Reasons 41

Arm/Group Title	10 mg Metoclopramide Nasal Spray	Placebo Nasal Spray
Arm/Group Description	Metoclopramide Nasal Spray 10 mg, 30 minutes before meals and at bedtime (QID) for 4 weeks Metoclopramide Nasal Spray: nasal spray formulation of metoclopramide	Placebo Nasal Spray 30 minutes before meals and at bedtime (QID) for 4 weeks Placebo Nasal Spray: nasal spray formulation with vehicle only
Period Title: Overall Study
STARTED	102	103
COMPLETED	91	99
NOT COMPLETED	11	4

Baseline Characteristics

Arm/Group Title	10 mg Metoclopramide Nasal Spray	Placebo Nasal Spray	Total
Arm/Group Description	Metoclopramide Nasal Spray 10 mg, 30 minutes before meals and at bedtime (QID) for 4 weeks Metoclopramide Nasal Spray: nasal spray formulation of metoclopramide	Placebo Nasal Spray 30 minutes before meals and at bedtime (QID) for 4 weeks Placebo Nasal Spray: nasal spray formulation with vehicle only	Total of all reporting groups
Overall Participants	102	103	205
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	87 85.3%	90 87.4%	177 86.3%
>=65 years	15 14.7%	13 12.6%	28 13.7%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	52.9 (11.6)	52.5 (10.9)	52.7 (11.2)
Sex: Female, Male (Count of Participants)
Female	102 100%	103 100%	205 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	11 10.8%	14 13.6%	25 12.2%
Not Hispanic or Latino	91 89.2%	89 86.4%	180 87.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 2%	3 2.9%	5 2.4%
Asian	2 2%	0 0%	2 1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	20 19.6%	37 35.9%	57 27.8%
White	78 76.5%	63 61.2%	141 68.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	102 100%	103 100%	205 100%
Qualification Mean Daily GSA Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.259 (0.481)	2.242 (0.487)	2.251 (0.483)
Baseline Mean Daily GSA Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.28 (0.518)	2.30 (0.552)	2.29 (0.53)
Diabetes Mellitus Type (Count of Participants)
Type 1	13 12.7%	11 10.7%	24 11.7%
Type 2	89 87.3%	92 89.3%	181 88.3%
Diabetes Mellitus Duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.4 (10.51)	13.4 (10.9)	12.9 (10.7)
Current Diabetes Mellitus Treatment (Count of Participants)
Diet	30 29.4%	33 32%	63 30.7%
Oral Diabetic Medications	69 67.6%	74 71.8%	143 69.8%
Insulin	51 50%	54 52.4%	105 51.2%
Other	11 10.8%	17 16.5%	28 13.7%
None	0 0%	1 1%	1 0.5%
Co-Existing Complications of Diabetes (Count of Participants)
No Complications	64 62.7%	60 58.3%	124 60.5%
Any Complication	38 37.3%	41 39.8%	79 38.5%
Diabetic Retinopathy	7 6.9%	2 1.9%	9 4.4%
Neuropathy	35 34.3%	39 37.9%	74 36.1%
Nephropathy	2 2%	1 1%	3 1.5%
Peripheral Vascular Disease/Amputation	2 2%	3 2.9%	5 2.4%

Outcome Measures

1. Primary Outcome

Title	Gastroparesis Symptom Assessment (GSA), a Patient Reported Outcome Measure
Description	Change from the Baseline Period to Week 4 of the Treatment Period in the mean daily Gastroparesis Symptom Assessment (GSA) total score for subjects receiving Metoclopramide Nasal Spray 10 mg versus subjects receiving placebo. The GSA minimum value is 0 (no symptoms) and the maximum value is 4 (very severe symptoms). A higher score is a worse outcome.
Time Frame	Baseline Period to Week 4 of the Treatment Period

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population

Arm/Group Title	10 mg Metoclopramide Nasal Spray	Placebo Nasal Spray
Arm/Group Description	Metoclopramide Nasal Spray 10 mg, 30 minutes before meals and at bedtime for 4 weeks Metoclopramide Nasal Spray: nasal spray formulation of metoclopramide	Placebo Nasal Spray 30 minutes before meals and at bedtime for 4 weeks Placebo Nasal Spray: nasal spray formulation with vehicle only
Measure Participants	102	103
Mean (Standard Deviation) [score on a scale]	-0.925 (0.935)	-0.896 (0.947)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	10 mg Metoclopramide Nasal Spray, Placebo Nasal Spray
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.881
	Comments
	Method	ANCOVA
	Comments

2. Post-Hoc Outcome

Title	Gastroparesis Symptom Assessment (GSA)
Description	Change from the Baseline Period to Weeks 1, 2, 3 and 4 of the Treatment Period in the mean daily Gastroparesis Symptom Assessment (GSA) total score in subjects with moderate to severe symptoms at Baseline (GSA score greater than 2.7) receiving Metoclopramide Nasal Spray 10 mg versus subjects receiving placebo. The GSA minimum value is 0 (no symptoms) and the maximum value is 4 (very severe symptoms). A higher score is a worse outcome.
Time Frame	Baseline Period to Weeks 1, 2, 3 and 4 of the Treatment Period

Outcome Measure Data

Analysis Population Description

Subjects in the intent-to-treat population with moderate to severe disease (symptoms) at Baseline (i.e., baseline GSA scores higher than 2.7 on the 0-4 scale). Results presented are Weeks 1, 2, 3 and 4 compared to the Baseline Period.

Arm/Group Title	10 mg Metoclopramide Nasal Spray	Placebo Nasal Spray
Arm/Group Description	Metoclopramide Nasal Spray 10 mg, 30 minutes before meals and at bedtime (QID) for 4 weeks Metoclopramide Nasal Spray: nasal spray formulation of metoclopramide	Placebo Nasal Spray 30 minutes before meals and at bedtime (QID) for 4 weeks Placebo Nasal Spray: nasal spray formulation with vehicle only
Measure Participants	52	53
Week 1 of Treatment compared to Baseline Period	-0.587 (0.520)	-0.388 (0.444)
Week 2 of Treatment compared to Baseline Period	-0.949 (0.864)	-0.616 (0.635)
Week 3 of Treatment compared to Baseline Period	-1.095 (0.912)	-0.750 (0.785)
Week 4 of Treatment compared to Baseline Period	-1.218 (0.991)	-0.857 (0.938)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	10 mg Metoclopramide Nasal Spray, Placebo Nasal Spray
	Comments	Change in mean daily GSA total score from Baseline to Week 1: metoclopramide nasal spray minus placebo.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.201
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	10 mg Metoclopramide Nasal Spray, Placebo Nasal Spray
	Comments	Change in mean daily GSA total score from Baseline to Week 2: metoclopramide nasal spray minus placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.336
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	10 mg Metoclopramide Nasal Spray, Placebo Nasal Spray
	Comments	Change in mean daily GSA total score from Baseline to Week 3: metoclopramide nasal spray minus placebo.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.039
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.347
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	10 mg Metoclopramide Nasal Spray, Placebo Nasal Spray
	Comments	Change in mean daily GSA total score from Baseline to Week 4: metoclopramide nasal spray minus placebo.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.085
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.364
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse Event (AE) data were collected through the last study visit (Day 28). Serious AEs (SAEs) were collected for up to 30 days after the final dose of study drug.
Adverse Event Reporting Description	Adverse event (AE) collection began after subjects signed the Informed Consent Form and continued until the subject was discharged from the study due to completion or Early Termination. All AEs observed by the Investigator, reported by the subject, from laboratory findings, or other means, were collected. AEs after the first dose of study drug were classified as treatment-emergent AEs.
Arm/Group Title	10 mg Metoclopramide Nasal Spray		Placebo Nasal Spray
Arm/Group Description	Metoclopramide Nasal Spray 10 mg, 30 minutes before meals and at bedtime for 4 weeks Metoclopramide Nasal Spray: nasal spray formulation of metoclopramide		Placebo Nasal Spray 30 minutes before meals and at bedtime for 4 weeks Placebo Nasal Spray: nasal spray formulation with vehicle only
All Cause Mortality
	10 mg Metoclopramide Nasal Spray		Placebo Nasal Spray
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/102 (0%)		0/103 (0%)
Serious Adverse Events
	10 mg Metoclopramide Nasal Spray		Placebo Nasal Spray
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/102 (2.9%)		2/103 (1.9%)
Eye disorders
chalazion	1/102 (1%)	1	0/103 (0%)	0
General disorders
non-cardiac chest pain	0/102 (0%)	0	1/103 (1%)	1
Infections and infestations
cellulitis	1/102 (1%)	1	0/103 (0%)	0
Psychiatric disorders
anxiety disorder	0/102 (0%)	0	1/103 (1%)	1
Vascular disorders
orthostatic hypotension	1/102 (1%)	1	0/103 (0%)	0
Other (Not Including Serious) Adverse Events
	10 mg Metoclopramide Nasal Spray		Placebo Nasal Spray
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/102 (20.6%)		36/103 (35%)
Ear and labyrinth disorders
Ear pain	2/102 (2%)	2	0/103 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/102 (1%)	1	5/103 (4.9%)	5
Abdominal tenderness	1/102 (1%)	1	2/103 (1.9%)	2
Constipation	1/102 (1%)	1	2/103 (1.9%)	2
Diarrhoea	3/102 (2.9%)	3	0/103 (0%)	0
General disorders
Fatigue	2/102 (2%)	2	1/103 (1%)	1
Non-cardiac chest pain	0/102 (0%)	0	2/103 (1.9%)	2
Infections and infestations
Pharyngitis	0/102 (0%)	0	2/103 (1.9%)	2
Upper respiratory tract infection	0/102 (0%)	0	2/103 (1.9%)	2
Musculoskeletal and connective tissue disorders
Muscle twitching	2/102 (2%)	3	1/103 (1%)	1
Nervous system disorders
Headache	5/102 (4.9%)	6	7/103 (6.8%)	9
Respiratory, thoracic and mediastinal disorders
Cough	1/102 (1%)	1	4/103 (3.9%)	4
Nasal discomfort	1/102 (1%)	1	4/103 (3.9%)	4
Epistaxis	1/102 (1%)	1	2/103 (1.9%)	2
Oropharyngeal pain	2/102 (2%)	2	0/103 (0%)	0
Skin and subcutaneous tissue disorders
Skin exfoliation	0/102 (0%)	0	2/103 (1.9%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.