NUTRItional Adequacy Therapeutic Enhancement in the Critically Ill: A Randomized Double Blind, Placebo-controlled Trial of the Motilin Receptor Agonist GSK962040. The NUTRIATE Study
Overview
- Phase
- Phase 2
- Intervention
- GSK962040 50 mg
- Conditions
- Gastroparesis
- Sponsor
- GlaxoSmithKline
- Enrollment
- 91
- Locations
- 1
- Primary Endpoint
- Average Percentage Goal Volume Delivered Prior to Development of Intolerance for ITT Population
- Status
- Terminated
- Last Updated
- 8 years ago
Overview
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.
Investigators
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
Arms & Interventions
Initial randomization: GSK962040 Arm
Subjects in the GSK962040 Arm will receive 50 mg once daily enteral dose administered through NG tube up to 7 days.
Intervention: GSK962040 50 mg
Initial randomization: Placebo Arm
Subjects in the placebo arm will receive once daily dose enteral dose administered through NG tube up to 7 days.
Intervention: Placebo NG
Treatment change due to intolerance: GSK962040 Arm
Subjects that develop intolerance and that originally received Placebo will receive 50 mg once daily enteral dose administered through NG tube + placebo IV
Intervention: GSK962040 50 mg
Treatment change due to intolerance: GSK962040 Arm
Subjects that develop intolerance and that originally received Placebo will receive 50 mg once daily enteral dose administered through NG tube + placebo IV
Intervention: Placebo IV
Treatment change due to intolerance: Metoclopramide Arm
Subjects that develop intolerance and that originally received GSK962040 will receive metoclopramide 10 mg IV every 6 h + placebo NG
Intervention: Metoclopramide 10 mg
Treatment change due to intolerance: Metoclopramide Arm
Subjects that develop intolerance and that originally received GSK962040 will receive metoclopramide 10 mg IV every 6 h + placebo NG
Intervention: Placebo NG
Outcomes
Primary Outcomes
Average Percentage Goal Volume Delivered Prior to Development of Intolerance for ITT Population
Time Frame: Up to Day 7
The average percentage goal volume received via EN was defined as the percent of goal volume received via EN from the first study dose up to permanent discontinuation of EN. It is calculated as 100 multiplied by total volume received via EN during the on treatment period prior to intolerance divided by total prescribed volume. 'Prior to intolerance' means 'prior to start of intolerance treatment. One participant was missing for prior to start of intolerance treatment. The average percentage goal volume received via EN was assessed and comparison between Camicinal 50mg and placebo arm was performed. Adjusted mean and its 95% confidence interval (CI) were estimated and Analysis of Covariance (ANCOVA) model was used for analysis.
Average Percentage Goal Volume Delivered Prior to Development of Intolerance for PP Population
Time Frame: Up to Day 7
The average percentage goal volume received via EN was defined as the percent of goal volume received via EN from the first study dose up to permanent discontinuation of EN. It is calculated as 100 multiplied by total volume received via EN during the on treatment period prior to intolerance divided by total prescribed volume. 'Prior to intolerance' means 'prior to start of intolerance treatment. One participant was missing for prior to start of intolerance treatment. The average percentage goal volume received via EN was assessed and comparison between Camicinal 50mg and placebo arm was performed. Adjusted mean and its 95% CI were estimated and ANCOVA model was used for analysis.
Secondary Outcomes
- Average Percentage Goal Calories Delivered Prior to Development of Intolerance(Up to Day 7)
- Average Percentage Goal Protein Delivered Prior to Development of Intolerance(Up to Day 7)
- Time to Delivery of 80 Percent Prescribed Calories Prior to Intolerance(Up to Day 7)
- Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)(up to 23 days)
- Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)(Up to 23 days)
- Change From Baseline in Heart Rate (HR)(Up to 23 days)
- Number of Participants With Maximum Increase From Baseline in Electrocardiogram (ECG) Values(Up to 23 days)
- Change From Baseline in Albumin and Total Protein Levels(Up to 23 days)
- Change From Baseline in Alkaline Phosphatase (Alk. Phosph.), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Levels(Up to 23 days)
- Change From Baseline in Total and Direct Bilirubin, Creatinine and Uric Acid Levels(Up to 23 days)
- Change From Baseline in Calcium, Chloride, Carbon Dioxide, Glucose, Potassium, Sodium, Blood Urea Nitrogen (BUN) Values(Up to 23 days)
- Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet and White Blood Cell (WBC) Levels(Up to 23 days)
- Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Levels(Up to 23 days)
- Change From Baseline in Hematocrit Level(Up to 23 days)
- Change From Baseline in Mean Corpuscle Volume (MCV) Levels(Up to 23 days)
- Change From Baseline in Red Blood Cell (RBC) and Reticulocyte Count(Up to 23 days)
- Change From Baseline in Mean Corpuscle Hemoglobin (MCH) Levels(Up to 23 days)
- Log Transformed Concentration at 60 Minutes (Min) (C60) and Maximum Observed Concentration (Cmax) of Acetaminophen (Prior to Intolerance)(At Day 2)
- Log Transformed AUC[0-60] of Acetaminophen(At Day 2)
- Log Transformed AUC[0-60] of 3-O-methylglucose (3- OMG)(At Day 2)
- Log Transformed C60 of 3-OMG(At Day 2)
- Derived Tmax of 3-OMG Post Intolerance(At Day 2)
- Percentage of Participants That Became Intolerant(Up to Day 7)
- Time to Development of Feeding Intolerance(Up to Day 7)
- GE Assessment as AUC (0-60) Within 24 Hrs of Developing Intolerance and Prior to Change of Treatment Using Acetaminophen(Day 2)
- GE Assessment as Cmax Within 24 Hrs of Developing Intolerance and Prior to Change of Treatment Using Acetaminophen(Baseline, Day 2, Day 3, Day 4)
- 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(Baseline, Day 2, Day 3, Day 4)
- GE Assessment as C60 Within 24 Hrs of Developing Intolerance and Prior to Change of Treatment Using 3-OMG(Baseline, Day 2, Day 3, Day 4)
- Derived Tmax of GSK962040 Post Intolerance(Day 2 and Day 4)
- Derived Accumulation Ratio (RO) of GSK962040 Post Intolerance(Baseline, Day 2, Day 3, Day 4)
- Number of Participants With Occurrences of Vomiting, Regurgitation and Macroaspiration Episodes(up to 23 days)
- Total GRV for 24 hr Period(Up to Day 7)
- Log Transformed Derived Plasma Cmax of GSK962040 Prior to Intolerance(Day 2, Day 3, Day 4, Day 7)
- Log Transformed Derived Plasma Cmax of GSK962040 Post Intolerance(Day 2 and Day 4)
- Derived AUC Over the Dosing Period [AUC(0-tau)] of GSK962040 Post Intolerance(Day 2 and Day 4)