Clinical trial NCT01934192: Nutritional Adequacy Therapeutic Enhancement in the Critically Ill. The NUTRIATE Study
Official title: NUTRItional Adequacy Therapeutic Enhancement in the Critically Ill: A Randomized Double Blind, Placebo-controlled Trial of the Motilin Receptor Agonist GSK962040. The NUTRIATE Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Gastroparesis
Keywords: tolerability
camicinal
single dose
acetaminophen
gastric emptying
critically ill
GSK962040
pharmacokinetics
pharmacodynamics
gut motility
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-09-04
Enrollment: 91
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Average Percentage Goal Volume Delivered Prior to Development of Intolerance for ITT Population
timeFrame: Up to Day 7
measure: Average Percentage Goal Volume Delivered Prior to Development of Intolerance for PP Population
timeFrame: Up to Day 7
Secondary outcomes:
measure: Average Percentage Goal Calories Delivered Prior to Development of Intolerance
timeFrame: Up to Day 7
measure: Average Percentage Goal Protein Delivered Prior to Development of Intolerance
timeFrame: Up to Day 7
measure: Time to Delivery of 80 Percent Prescribed Calories Prior to Intolerance
timeFrame: Up to Day 7
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: up to 23 days
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Up to 23 days
measure: Change From Baseline in Heart Rate (HR)
timeFrame: Up to 23 days
measure: Number of Participants With Maximum Increase From Baseline in Electrocardiogram (ECG) Values
timeFrame: Up to 23 days
measure: Change From Baseline in Albumin and Total Protein Levels
timeFrame: Up to 23 days
measure: Change From Baseline in Alkaline Phosphatase (Alk. Phosph.), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Levels
timeFrame: Up to 23 days
measure: Change From Baseline in Total and Direct Bilirubin, Creatinine and Uric Acid Levels
timeFrame: Up to 23 days
measure: Change From Baseline in Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium, Blood Urea Nitrogen (BUN) Values
timeFrame: Up to 23 days
measure: Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet and White Blood Cell (WBC) Levels
timeFrame: Up to 23 days
measure: Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Levels
timeFrame: Up to 23 days
measure: Change From Baseline in Hematocrit Level
timeFrame: Up to 23 days
measure: Change From Baseline in Mean Corpuscle Volume (MCV) Levels
timeFrame: Up to 23 days
measure: Change From Baseline in Red Blood Cell (RBC) and Reticulocyte Count
timeFrame: Up to 23 days
measure: Change From Baseline in Mean Corpuscle Hemoglobin (MCH) Levels
timeFrame: Up to 23 days
measure: Log Transformed Concentration at 60 Minutes (Min) (C60) and Maximum Observed Concentration (Cmax) of Acetaminophen (Prior to Intolerance)
timeFrame: At Day 2
measure: Log Transformed AUC[0-60] of Acetaminophen
timeFrame: At Day 2
measure: Log Transformed AUC[0-60] of 3-O-methylglucose (3- OMG)
timeFrame: At Day 2
measure: Log Transformed C60 of 3-OMG
timeFrame: At Day 2
measure: Derived Tmax of 3-OMG Post Intolerance
timeFrame: At Day 2
measure: Percentage of Participants That Became Intolerant
timeFrame: Up to Day 7
measure: Time to Development of Feeding Intolerance
timeFrame: Up to Day 7
measure: GE Assessment as AUC (0-60) Within 24 Hrs of Developing Intolerance and Prior to Change of Treatment Using Acetaminophen
timeFrame: Day 2
measure: GE Assessment as Cmax Within 24 Hrs of Developing Intolerance and Prior to Change of Treatment Using Acetaminophen
timeFrame: Baseline, Day 2, Day 3, Day 4
measure: GE Assessment as AUC (0-60) and AUC (0-240) Within 24 Hrs of Developing Intolerance and Prior to Change of Treatment Using 3-OMG
timeFrame: Baseline, Day 2, Day 3, Day 4
measure: GE Assessment as C60 Within 24 Hrs of Developing Intolerance and Prior to Change of Treatment Using 3-OMG
timeFrame: Baseline, Day 2, Day 3, Day 4
measure: Number of Participants With Occurrences of Vomiting, Regurgitation and Macroaspiration Episodes
timeFrame: up to 23 days
measure: Total GRV for 24 hr Period
timeFrame: Up to Day 7
measure: Log Transformed Derived Plasma Cmax of GSK962040 Prior to Intolerance
timeFrame: Day 2, Day 3, Day 4, Day 7
measure: Log Transformed Derived Plasma Cmax of GSK962040 Post Intolerance
timeFrame: Day 2 and Day 4
measure: Derived Tmax of GSK962040 Post Intolerance
timeFrame: Day 2 and Day 4
measure: Derived AUC Over the Dosing Period [AUC(0-tau)] of GSK962040 Post Intolerance
timeFrame: Day 2 and Day 4
measure: Derived Accumulation Ratio (RO) of GSK962040 Post Intolerance
timeFrame: Baseline, Day 2, Day 3, Day 4
Other outcomes:
Locations:
city: Aurora
country: United States
facility: GSK Investigational Site
state: Colorado
city: Augusta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Louisville
country: United States
facility: GSK Investigational Site
state: Kentucky
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Randwick
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Southport
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Adelaide
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Woodville
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Calgary
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Calgary
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Hamilton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Kingston
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Sainte-Foy
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Sherbrooke
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Quebec
country: Canada
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: