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
Condition: Gastroparesis
MeSH terms: Gastroparesis; Parkinson Disease
Intervention: GSK962040 (25 mg tablet); Placebo
Intervention description: 25 mg tablet; matching placebo tablet
Phase: Phase 2
Study type: Interventional
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 58.0
Sex: All
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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.

        Exclusion Criteria:

          -  Late stage advanced subjects with incapacitating peak dose or biphasic dyskinesia ona
             stable L-DOPA regime.

          -  Presence, or history within the previous 3 months, of significant and/or uncontrolled
             psychiatric, neurological (other than Parkinson's disease), gastro-intestinal,
             hematological, endocrinologic, neurological (other than Parkinson's disease),
             cardiovascular disease, active malignancy (other than basal cell cancer) or other
             condition that would in the opinion of the investigator or medical monitor make the
             subject unsuitable for inclusion in this clinical study.

          -  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.