Nutritional Adequacy Therapeutic Enhancement in the Critically Ill. The NUTRIATE Study
Condition: Gastroparesis
MeSH terms: Gastroparesis; Critical Illness
Intervention: GSK962040 50 mg; Metoclopramide 10 mg; Placebo NG; Placebo IV
Intervention description: GSK962040 50 mg will be administered once daily enteral dose through NG tube up to 7 days.; Metoclopramide will be administered IV every 6 h; Matching placebo once daily enteral dose will be administered through NG tube up to 7 days; Placebo will be administered IV every 6 hours
Intervention MeSH terms: Metoclopramide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 91.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: tolerability; camicinal; single dose; acetaminophen; gastric emptying; critically ill; GSK962040; pharmacokinetics; pharmacodynamics; gut motility

Summary:

      This is a multi-center, parallel group, placebo-controlled and active-compared, randomized
      study to assess the ability of GSK962040 to enhance the delivery of enteral feed to
      critically ill subjects that are predisposed to developing feeding intolerance (e.g.,
      percentage of goal volume); enhance gastric emptying in this population; and provide
      preliminary evidence of the drug's effect on outcomes of therapy (length of stay in the
      Intensive Care Unit [ICU], time on ventilator, ICU acquired infections, and 60-day
      mortality). Other aims are evaluation of GSK962040 safety, tolerability and pharmacokinetics
      upon repeat dosing in a critically ill population.

      After meeting eligibility criteria, male and female subjects will be randomized to either
      receive GSK962040 (50 milligram [mg]) once daily (OD) via naso-gastric (NG) or orogastric
      (OG) feeding tube (oral solution), or placebo by the same route. If subjects develop
      intolerance to enteral feeding at any point up to Dose 5 of study medication (inclusive),
      study treatments will switch such that those originally receiving GSK962040 will receive
      metoclopramide (10 mg, intravenous [iv], every 6 hours) and those subjects originally
      randomized to receive placebo will receive GSK962040 (50 mg, via NG, OD). Additionally, if
      subjects develop intolerance prior to any treatment, they will be randomized to receive
      either GSK962040 (50 mg, via NG, OD) or metoclopramide (10 mg, iv, every 6 hours).

      The study will consist of a screening/baseline assessment, a treatment period (up to 7 days
      in duration), and a 4-day post treatment safety follow-up assessment. The duration of each
      subject's participation in the study from screening to follow-up safety assessment will be up
      to approximately 2 weeks. In addition, mortality will be assessed 60 days after admission to
      the ICU.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age & Gender: Male or female between 18 and 85 years of age inclusive, at the time of
             obtaining the informed consent.

          -  First admitted to participating ICU within the previous 48 hours.

          -  Intubated and invasively mechanically ventilated

          -  Indicated to receive early EN or are already receiving EN (subject must be on EN prior
             to receiving study treatment)

          -  Have at least one of the following

          -  Clinical evidence of cardiovascular dysfunction defined as the need for vasopressor
             agents (e.g. norepinephrine, epinephrine, vasopressin), >5 microgram/kg/min of
             dopamine, or >/= 50 microgram/min phenylephrine) for greater than or equal to 2 hours;

          -  Poly-trauma with an injury severity score (ISS) >=15 points

          -  Acute traumatic or non-traumatic brain injury Glasgow Coma Scale (GCS) <=12, prior to
             the initiation of sedation.

        Exclusion Criteria:

          -  Subjects who are not expected to be in the ICU and alive for at least 48 hrs from
             point of screening.

          -  Subjects with acute hepatitis (e.g. acute hepatitis B or C) or severe chronic liver
             disease (e.g. Child Pugh class C cirrhosis) will be excluded

          -  Liver function tests: If Alanine aminotransferase (ALT) >=8x upper limit of normal
             (ULN); OR If ALT >5-8x ULN and bilirubin >2<=3 ULN or bilirubin >3x ULN (Include only
             if bilirubin <1.5xULN); OR If ALT <=5xULN and Bilirubin >3xULN (Include only if ALT
             <=3xULN and Bilirubin >2 <=3xULN)

          -  Subjects who have received a gastric prokinetic agent in the previous 12 hours (e.g.,
             erythromycin, azithromycin, metoclopramide, domperidone).

          -  QT duration corrected for heart rate (QTc) >480 ms. QTcF is the recommended correction
             factor for all sites. If QT duration corrected for heart rate by Fridericia's formula
             (QTcF) is not possible to obtain or calculate, QT duration corrected for heart rate by
             Bazett's formula (QTcB) or machine or manual over read, may be obtained after
             consultation with the medical monitor. The QT correction formula used to determine
             inclusion and discontinuation should be the same throughout the study.

          -  Use of strong Cyp3A4 inhibitors

          -  Subjects who require renal replacement therapy or with an estimated glomerular
             filtration rate (GFR) of <30 mL/min byCockroft-Gault calculation).

          -  Subjects who have a history of or who have undergone major esophageal or gastric
             surgery on this admission (major lower abdominal surgery will not result in exclusion
             unless this carries a contraindication to enteral feeding).

          -  Subjects with an absolute contraindication to enteral nutrition e.g. subjects with
             ongoing bowel obstruction or perforation.

          -  Subject has a gastric pacemaker

          -  Pregnant or lactating females

          -  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.

          -  Concurrent enrollment in other interventional study involving a novel (i.e.unapproved
             or experimental) chemical or biopharmaceutical entity.

          -  Previous randomization in this study

          -  Subjects for whom the reason for admission to ICU was an overdose (deliberate or
             accidental; medicinal product or not).

          -  Exclusion to re-randomization:

          -  Subjects with an untreated pheochromocytoma.

          -  Subjects with a past history of a seizure disorder (e.g., epilepsy) and is currently
             receiving anti-epileptic treatment for their seizure disorder, ongoing refractory, or
             sustained seizure disorder (prophylactic use for head injury/isolated new seizure
             maintained on anti-seizure meds in ICU acceptable).

          -  Subjects taking drugs likely to cause extrapyramidal reactions.