Dose Response of 28 Days of Dosing of GSK962040 in Type I and II Diabetic Male and Female Subjects With Gastroparesis

NCT01262898 | Completed Phase 2 Results

• 2 other identifiers: 1144792010-023186-21
• Study Type: interventional
• Target: 79
• Locations: 6 countries
• Sites: 22

Brief Summary

GSK962040 is a novel small molecule motilin agonist. The Phase I studies (MOT107043 and MOT109681) demonstrated that single doses of GSK962040 up to 150 mg and repeat dosing of up to 125 mg/day for 14 days were well tolerated with adverse events not occurring in greater prevalence than placebo, and no significant abnormal vital sign, ECG, or clinical laboratory findings. Pharmacokinetic parameters were linear and approximately dose proportional over the range of doses administered. Single doses of 50 mg - 150 mg GSK962040 significantly increased the rate of gastric emptying up to 40% as measured by the 13C octanoic acid stable isotope breath test. A similar effect of 50 mg and 125 mg on gastric emptying was observed throughout repeated dosing to healthy volunteers for 14-days. The aims of the present investigation (MOT114479) are to assess the pharmacodynamic effects (gastric emptying and symptoms), safety, tolerability, and pharmacokinetics of GSK962040 after 28 days of once-daily dosing in Type I and Type II diabetic subjects with gastroparesis. An additional aim is to characterize the dose/exposure - pharmacodynamic effect relationship.

Conditions

Gastroparesis

Keywords

tolerability; pharmacokinetics; 13 C oral breath test; Type I and II Diabetes mellitus; gastroparesis; gut motility; phase II; pharmacodynamics; repeat dose; gastric emptying; symptoms; GSK962040

Outcome Measures

Primary Outcomes (1)

• Gastric Half Emptying Time (GEt1/2)

  Gastric half emptying time is the time taken for half the contents of the stomach to empty. Gastric emptying was measured using the 13C-oral breath test, which is a tracer method that utilizes 13C, a non-radioactive isotope. Basal breath samples were obtained after an overnight fast or otherwise after 4 hours of fasting following a light meal. On Day 1 and Day 28, participants were then dosed with GSK962040 and additional breath test samples were taken prior to administration of a 13C-labelled test meal. The test meal was consumed approximately 80 minutes(min) later. After consumption of the test meal, breath samples were collected at pre-specified time points over an approximately 4 hour period following the test meal. For the duration of the breath test, no food or drink were allowed. The 13C breath content was determined by isotope ratio mass spectrometry. GE t1/2 was determined by using the cumulative percentage of the administered dose of 13C excreted in breath over 4 hours.

  Screening2/Baseline (Day -30 to -1) , Day 1, and Day 28

Secondary Outcomes (29)

• Number of Participants With On-treatment Adverse Events (AES) and Serious Adverse Events(SAEs)

  Up to follow-up (5-10 days post last dose)

• Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure(DBP) at Specified Time Points in Semi-supine Position

  Baseline, Day 1, and Day 8

• Change From Baseline in Heart Rate at Specified Time Points in Semi-supine Position

  Baseline, Day 1, and Day 8

• Change From Baseline in Electrocardiography Parameters (12-lead ECG)

  Baseline, Day 1 and Day 28

• Number of Participants Outside the Normal Range for SBP and DBP

  Screening2/Baseline (Day -30 to -1), Day 1 and 28

Study Arms (4)

GSK962040 (10 mg)

EXPERIMENTAL

GSK962040 10 mg

Drug: GSK962040 (5 mg tablet)

GSK962040 (50 mg)

EXPERIMENTAL

GSK962040 50 mg

Drug: GSK962040 (25 mg tablet)

GSK962040 (125 mg)

EXPERIMENTAL

GSK962040 125 mg

Drug: GSK962040 (125 mg tablet)

Placebo

EXPERIMENTAL

Placebo

Drug: GSK962040 (5 mg tablet); Drug: GSK962040 (25 mg tablet); Drug: GSK962040 (125 mg tablet); Drug: Placebo

Interventions

GSK962040 (5 mg tablet) DRUG

5 mg tablet

GSK962040 (10 mg); Placebo

GSK962040 (25 mg tablet) DRUG

25 mg tablet

GSK962040 (50 mg); Placebo

GSK962040 (125 mg tablet) DRUG

125 mg tablet

GSK962040 (125 mg); Placebo

Placebo DRUG

matching placebo tablet

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Type I or II Diabetes Mellitus (HbA1C \< 10%)
• Male or female between 18 and 80 years of age, inclusive.
• Patient has gastroparesis at screening (gastric half-time of emptying \> upper limit of normal as determined by 13C-oral breath test)
• Patient must have a \> or = 3 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.
• A female patient is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/mL, or a value consistent with the local laboratory standard value, is confirmatory. OR Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female patients must agree to use contraception for at least 5 days following the last dose of study medication.
• Male patients must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication through at least 5 days after the last dose of study medication.
• BMI \>18 and \< or = 35.0 kg/m2 (inclusive).
• Patient 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, except for routine adjustments in daily insulin treatments.
• Estimated (or measured) glomerular filtration rate \> or = 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 \< or = 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).

You may not qualify if:

• Patient has acute severe gastroenteritis
• Patient has a gastric pacemaker
• Patient is on chronic parenteral feeding
• Patient has pronounced dehydration
• Recent (last 6 weeks) history of poor control of diabetes e.g. hypoglycaemia requiring medical intervention, diabetic ketoacidosis, admission for control diabetes or complications of diabetes
• Patient has evidence of severe cardiovascular autonomic neuropathy (e.g. history of recurrent syncope in the last 6 months)
• Patient has a history of eating disorders (anorexia nervosa, binge eating, bulimia)
• 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
• Use of prohibited medications listed in Section 9.2 within the restricted timeframe relative to the first dose of study medication.
• The patient 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 or GSK Medical Monitor, contraindicates their participation.
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (22)

GSK Investigational Site

Concord, California, 94520, United States

Location

GSK Investigational Site

Indianapolis, Indiana, 46202, United States

Location

GSK Investigational Site

Chevy Chase, Maryland, 20815, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02114, United States

Location

GSK Investigational Site

Great Neck, New York, 11023, United States

Location

GSK Investigational Site

Chattanooga, Tennessee, 37421, United States

Location

GSK Investigational Site

San Antonio, Texas, 78258, United States

Location

GSK Investigational Site

Richmond, Virginia, 23294, United States

Location

GSK Investigational Site

Milwaukee, Wisconsin, 53215, United States

Location

GSK Investigational Site

Randwick, New South Wales, 2031, Australia

Location

GSK Investigational Site

Brussels, 1090, Belgium

Location

GSK Investigational Site

Leuven, 3000, Belgium

Location

GSK Investigational Site

Calgary, Alberta, T2N 4N1, Canada

Location

GSK Investigational Site

Edmonton, Alberta, T6G 2E1, Canada

Location

GSK Investigational Site

Thornhill, Ontario, L4J 8L7, Canada

Location

GSK Investigational Site

Toronto, Ontario, M4G 3E8, Canada

Location

GSK Investigational Site

Uppsala, SE-751 85, Sweden

Location

GSK Investigational Site

Cambridge, CB2 2GG, United Kingdom

Location

GSK Investigational Site

Dundee, DD1 9SY, United Kingdom

Location

GSK Investigational Site

London, W12 0HS, United Kingdom

Location

GSK Investigational Site

London, W1G 6AD, United Kingdom

Location

GSK Investigational Site

Salford, M6 8HD, United Kingdom

Location

MeSH Terms

Conditions

Gastroparesis

Interventions

N-(3-fluorophenyl)-1-((4-(((3S)-3-methyl-1-piperazinyl)methyl)phenyl)acetyl)-4-piperidinamine; Tablets

Condition Hierarchy (Ancestors)

Stomach Diseases; Gastrointestinal Diseases; Digestive System Diseases; Paralysis; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 16, 2010
• First Posted: December 17, 2010
• Study Start: May 3, 2011
• Primary Completion: February 26, 2013
• Study Completion: February 26, 2013
• Last Updated: July 15, 2021
• Results First Posted: October 13, 2017

Record last verified: 2021-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (copy the URL below to your browser)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

CA (4); AU (1); BE (2); SE (1); GB (5); US (9)