A Study to Assess the Effect of Repeat Doses of GSK962040 on the Pharmacokinetics of L-DOPA in Subjects With Parkinson's Disease Exhibiting Delayed Gastric Emptying

NCT01602549 | Completed Phase 2 Results

• 1 other identifier: 115816
• Study Type: interventional
• Target: 58
• Locations: 4 countries
• Sites: 11

Brief Summary

Gastric emptying is the end-result of a complex and carefully regulated series of events which follow the ingestion of a meal, each of which is dependent on the other and subject to neurohormonal control. Motilin is an endogenous peptide, produced mainly in the duodenum, whose physiological action is mediated by motilin receptors located on enteric neurons, peripheral terminals of the vagus, and on the smooth muscle of the gut. Motilin and non-peptide agonists at motilin receptors increases the gastric emptying rate and therefore provide a potential approach to the treatment of a range of clinical conditions in which delayed gastric emptying is thought to be part of the physiopathology and may be contributory to symptoms. Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by degeneration of nigrostriatal dopaminergic neurones. It affects 1.5% of the global population over 65 years of age. Cardinal symptoms comprise bradykinesia, rigidity, resting tremors and postural instability. Gastrointestinal dysfunction, including gastroparesis, is a frequent feature of PD affecting approximately 90% of patients, and is caused by autonomic dysfunction as well as an adverse effect of antiparkinsonian drug therapy. The therapeutic mainstay for PD treatment is the neutral amino acid L-3,4-dihydroxyphenylalanine (L-DOPA), a dopamine prodrug, as it provides the most rapid and effective symptomatic control of motor impairment in PD. The primary determinant of L-DOPA bioavailability is gastric emptying (GE); delays in GE slow delivery of L-DOPA to its proximal small intestinal absorption sites, increasing the extent of presystemic metabolism, and leading to slowed and diminished absorption.

Conditions

Gastroparesis

Outcome Measures

Primary Outcomes (6)

• Dose-normalized Levodopa (L-DOPA) Area Under the Plasma Concentration-time Curve From Zero to 4 Hours AUC(0-4) at Baseline

  Dose-normalized L-DOPA AUC(0-4) was derived from L-DOPA plasma concentration-time data. AUC is a measure of levodopa exposure.

  Baseline

• Dose-normalized L-DOPA AUC(0-4) at Day 1 and Day 8

  Dose-normalized L-DOPA AUC(0-4) was derived from L-DOPA plasma concentration-time data. The adjusted means and ratios (GSK962040 50 mg: Placebo) were estimated using a mixed model fitting treatment, visit, treatment\*visit, Baseline L-dopa pharmacokinetic (PK) parameter, and Baseline gastric emptying half-time as fixed effects, and participant as a random effect. AUC is a measure of levodopa exposure

  Day 1 and Day 8

• Dose-normalized L-DOPA Maximum Observed Concentration (Cmax) at Baseline

  Dose-normalized L-DOPA Cmax was derived from L-DOPA plasma concentration-time data.

  Baseline

• Dose-normalized L-DOPA Cmax at Day 1 and Day 8

  Dose-normalized L-DOPA Cmax was derived from L-DOPA plasma concentration-time data. The adjusted means and ratios were estimated using a mixed model fitting treatment, visit, treatment\*visit, Baseline L-dopa PK parameter, and Baseline gastric emptying half-time as fixed effects, and participant as a random effect.

  Day 1 and Day 8

• L-DOPA Time of Occurrence of Cmax (Tmax) at Baseline, Day 1,and Day 8

  L-DOPA Tmax was derived from L-DOPA plasma concentration-time data.

  Baseline, Day 1, and Day 8

• L-DOPA Terminal Phase Half-life (t1/2) at Baseline, Day 1, and Day 8

  L-DOPA t1/2 was derived from L-DOPA plasma concentration-time data. This endpoint was not assessed because there were insufficient L-DOPA data/profiles to calculate this parameter.

  Baseline, Day 1, and Day 8

Secondary Outcomes (24)

• Gastric Half Emptying Time (GE t1/2) at Baseline (BL), Day 1, and Day 8

  Baseline, Day 1, and Day 8

• Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Scores at Baseline, Day 1, and Day 8 (Pre-levodopa Dose)

  Baseline, Day 1, and Day 8 at pre-levodopa dose

• Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III Scores at Baseline, Day 1, and Day 8 (Pre-dose; 120, 180, and 240 Minutes Post-dose)

  Baseline, Day 1, and Day 8 at pre-dose and 120, 180, and 240 minutes (min) post-dose (PD); Follow-up visit (up to Day 25)

• Period Mean Amount of Hours Spent "ON," "ON" Without Dyskinesia, "ON" With Non-troublesome Dyskinesia, "ON" With Troublesome Dyskinesia, and "OFF" at Baseline and During the Treatment Period (Days 1-8), Week 1 of Follow-up, and Week 2 of Follow-up

  Baseline, Days 1-8, Week 1 of Follow-up (Days 6 and 7 of Follow-up; up to Day 16), and Week 2 of Follow-up (Days 13 and 14 of Follow-up; up to Day 23)

• Number of Times a Participant Could Alternatively Tap Two Counter Keys 30 Centimeters Apart in 1 Minute (Min) at Baseline, Day1, Day 8, and Follow-up

  Baseline, Day 1, and Day 8 at pre-dose and 0, 30, 60, 90, 120, 180, and 240 minutes post-dose; Follow-up visit (up to Day 25)

Study Arms (1)

Cohort

EXPERIMENTAL

1:2 ratio, placebo, 50 mg administered orally once daily for 7-9 days

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

Interventions

GSK962040 (25 mg tablet) DRUG

25 mg tablet

Cohort

Placebo DRUG

matching placebo tablet

Cohort

Eligibility Criteria

• Age: 40 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of idiopathic Parkinson's Disease (according to modified Hoehn \& Yahr criteria Stages II-IV) and with suboptimal motor control on L-DOPA or L-DOPA combination therapy (i.e. wearing off, peak dose dyskinesias, delayed on or no-on effects)
• Subjects receiving a stable regimen of L-DOPA for at least four weeks prior to screening
• Patient has gastric half-time of emptying \> or = 70 min as determined by 13C oral breath test
• Between 40 and 80 years of age, 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 4 weeks
• A female subject 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 \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/ml and estradiol \< 40 pg/ml (\<147 pmol/L) is confirmatory\]. Child-bearing potential and is abstinent or 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 subjects must agree to use contraception until at least 5 days post-last dose.
• ALT \< 2xULN; alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Single or Average QTc, QTcB or QTcF\< 450 msec; or QTc \< 480 msec in subjects with Bundle Branch Block.

You may not qualify if:

• Late stage advanced subjects with incapacitating peak dose or biphasic dyskinesia ona stable L-DOPA regime.
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
• Patient has a gastric pacemaker
• Patient is on chronic enteral (e.g., feeding tube) or parenteral feeding
• Patient has evidence of severe cardiovascular autonomic neuropathy (e.g. history of recurrent syncope in the last 6 months)
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.
• Lactating females.
• Unable to refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication until followup.
• 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)
• Unable to refrain from use of prohibited medications listed in Section 9 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (11)

GSK Investigational Site

Randwick, New South Wales, 2031, Australia

Location

GSK Investigational Site

Ulm, Baden-Wurttemberg, 89081, Germany

Location

GSK Investigational Site

Bochum, North Rhine-Westphalia, 44791, Germany

Location

GSK Investigational Site

Bonn, North Rhine-Westphalia, 53105, Germany

Location

GSK Investigational Site

Cologne, North Rhine-Westphalia, 50937, Germany

Location

GSK Investigational Site

Berlin, State of Berlin, 13088, Germany

Location

GSK Investigational Site

Jena, Thuringia, 07747, Germany

Location

GSK Investigational Site

Uppsala, SE-751 85, Sweden

Location

GSK Investigational Site

Cambridge, C2B 2PY, United Kingdom

Location

GSK Investigational Site

Newcastle upon Tyne, NE4 5PL, United Kingdom

Location

GSK Investigational Site

Norwich, NR4 7UY, United Kingdom

Location

Related Publications (1)

• Marrinan SL, Otiker T, Vasist LS, Gibson RA, Sarai BK, Barton ME, Richards DB, Hellstrom PM, Nyholm D, Dukes GE, Burn DJ. A randomized, double-blind, placebo-controlled trial of camicinal in Parkinson's disease. Mov Disord. 2018 Feb;33(2):329-332. doi: 10.1002/mds.27259. Epub 2017 Dec 26.

  PMID: 29278279 DERIVED

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: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 17, 2012
• First Posted: May 21, 2012
• Study Start: July 1, 2012
• Primary Completion: May 1, 2014
• Study Completion: May 1, 2014
• Last Updated: February 6, 2017
• Results First Posted: February 6, 2017

Record last verified: 2015-02

Locations

AU (1); DE (6); SE (1); GB (3)