A Randomized, Double-Blind Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of a Single Dose of Intravenous TD-8954 Compared With Metoclopramide in Critically Ill Patients With Enteral Feeding Intolerance

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01953081
• Collaborator: Theravance Biopharma (Industry)
• Enrollment: 13
• Location: 1
• Arms: 2
• Duration (Months): 9
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

This study is being conducted to evaluate the safety, tolerability and early efficacy of IV TD 8954 compared to metoclopramide in critically ill subjects, aged 18 to 85 years, who are admitted to the intensive care require mechanical ventilation, and are intolerant to enteral feeding.

Condition or Disease	Intervention/Treatment	Phase
Enteral Feeding Intolerance	Drug: TD-8954; Drug: Metoclopramide	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of a Single Dose of Intravenous TD-8954 Compared With Metoclopramide in Critically Ill Patients With Enteral Feeding Intolerance
• Study Start Date: Jan 1, 2014
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TD-8954 TD-8954 single infusion for 1 hour and 4 injections of saline every 6 hours	Drug: TD-8954
Active Comparator: Metoclopramide Metoclopramide 4 doses every 6 hours for 24 hours and 1 hour infusion of saline	Drug: Metoclopramide

Outcome Measures

Primary Outcome Measures

1. Adverse Events [6 Days]

   the number of subjects reporting adverse events by treatment group

2. Gastric Retention by Scintigraphy [180 minutes]

   Number of subjects with retention less than 13% at 180 minutes after dosing.

Secondary Outcome Measures

1. Tmax [72 hours]

   Time to maximal concentration in plasma

2. AUC [72 hours]

   Area under the plasma concentration time curve from 0 to 72 hours after dosing.

3. Cmax [72 hours]

   Maximum plasma concentration

4. Gastric Emptying by Breath Test [180 minutes]

   Time to 1/2 gastric emptying by breath test

5. Percentage Gastric Retention by Scintigraphy at 60 Minutes Postdose [60 minutes]

   Mean gastric retention percentage after dosing.

6. Percentage Gastric Retention by Scintigraphy at 120 Minutes Postdose [120 minutes]

   Mean gastric retention percentage after dosing.

7. Percentage of Gastric Retention by Scintigraphy at 240 Minutes Postdose [240 minutes]

   Mean gastric retention percentage after dosing.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Intubated, on mechanical ventilation, and anticipated to remain on mechanical ventilation for 2 days after enrollment into the study

• Receiving enteral feeding and assessed to have developed EFI, as defined by a GRV measurement ≥250 mL within the 24 hours before randomization

Exclusion Criteria:

• History of diabetic or idiopathic gastroparesis

• Screening blood glucose >15 mmol/L (270 mg/dL) while receiving insulin

• Impaired renal function, as defined by estimated glomerular filtration rate (eGFR) <30 mL/min, as determined by the Cockcroft-Gault formula -Bilirubin concentration in blood

2 times the upper limit of normal

• ALT or AST >3 times upper limit of normal

• Alkaline phosphatase >2 times upper limit of normal

• Contraindication to enteral feeding

• Opioid or other drug overdose as the primary reason for admission to Intensive Care Unit (ICU)

• Receipt of a drug that can be used as a gastric prokinetic agent

• Receipt of agents known to directly influence the 5 HT4/acetylcholine prokinetic mechanism

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Royal Adelaide Hospital	Adelaide	South Australia	Australia

Sponsors and Collaborators

• Takeda
• Theravance Biopharma

Investigators

• Study Director: Daniel Canafax, PharmD, FCCP, Theravance Biopharma, US, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01953081
• Other Study ID Numbers: 0082
• First Posted: Sep 30, 2013
• Last Update Posted: Feb 18, 2020
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Takeda: Enteral feeding
• Additional relevant MeSH terms: Critical Illness; Metoclopramide

Study Results

Participant Flow

Arm/Group Title	TD-8954	Metoclopramide
Arm/Group Description	TD-8954 single infusion for 1 hour and 4 injections of saline every 6 hours	Metoclopramide 4 doses every 6 hours for 24 hours and 1 hour infusion of saline
Period Title: Overall Study
STARTED	7	6
COMPLETED	5	3
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	TD-8954	Metoclopramide	Total
Arm/Group Description	TD-8954 single infusion for 1 hour and 4 injections of saline every 6 hours	Metoclopramide 4 doses every 6 hours for 24 hours and 1 hour infusion of saline	Total of all reporting groups
Overall Participants	7	6	13
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.0 (25.29)	55.5 (13.37)	54.7 (19.9)
Sex: Female, Male (Count of Participants)
Female	1 14.3%	2 33.3%	3 23.1%
Male	6 85.7%	4 66.7%	10 76.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	7 100%	6 100%	13 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
Australia	7 100%	6 100%	13 100%

Outcome Measures

1. Primary Outcome

Title	Adverse Events
Description	the number of subjects reporting adverse events by treatment group
Time Frame	6 Days

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	TD-8954	Metoclopramide
Arm/Group Description	TD-8954 single infusion for 1 hour and 4 injections of saline every 6 hours	Metoclopramide 4 doses every 6 hours for 24 hours and 1 hour infusion of saline
Measure Participants	7	6
Number [participants]	5 71.4%	4 66.7%

2. Primary Outcome

Title	Gastric Retention by Scintigraphy
Description	Number of subjects with retention less than 13% at 180 minutes after dosing.
Time Frame	180 minutes

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	TD-8954	Metoclopramide
Arm/Group Description	TD-8954 single infusion for 1 hour and 4 injections of saline every 6 hours	Metoclopramide 4 doses every 6 hours for 24 hours and 1 hour infusion of saline
Measure Participants	7	6
Number [participants]	6 85.7%	3 50%

3. Secondary Outcome

Title	Tmax
Description	Time to maximal concentration in plasma
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

PK Analysis set for subjects receiving TD-8954, metoclopramide concentrations were not measured in the metoclopramide group.

Arm/Group Title	TD-8954	Metoclopramide
Arm/Group Description	TD-8954 single infusion for 1 hour and 4 injections of saline every 6 hours	Metoclopramide 4 doses every 6 hours for 24 hours and 1 hour infusion of saline
Measure Participants	6	0
Median (Full Range) [hours]	0.500

4. Secondary Outcome

Title	AUC
Description	Area under the plasma concentration time curve from 0 to 72 hours after dosing.
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

One subject did not receive the full dose of TD-8954 and was excluded from PK analysis for the TD-8954 group; Metoclopramide concentrations were not measured in the Metoclopramide group.

Arm/Group Title	TD-8954	Metoclopramide
Arm/Group Description	TD-8954 single infusion for 1 hour and 4 injections of saline every 6 hours	Metoclopramide 4 doses every 6 hours for 24 hours and 1 hour infusion of saline
Measure Participants	6	0
Mean (Standard Deviation) [pg*hr/mL]	23200 (9240)

5. Secondary Outcome

Title	Cmax
Description	Maximum plasma concentration
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

One subject did not receive the full dose of TD-8954 and was excluded from PK analysis for the TD-8954 group; Metoclopramide concentrations were not measured in the Metoclopramide group.

Arm/Group Title	TD-8954	Metoclopramide
Arm/Group Description	TD-8954 single infusion for 1 hour and 4 injections of saline every 6 hours	Metoclopramide 4 doses every 6 hours for 24 hours and 1 hour infusion of saline
Measure Participants	6	0
Mean (Standard Deviation) [pg/mL]	5040 (1780)

6. Secondary Outcome

Title	Gastric Emptying by Breath Test
Description	Time to 1/2 gastric emptying by breath test
Time Frame	180 minutes

Outcome Measure Data

Analysis Population Description

One subject in the TD-8954 group did not receive the full dose of TD-8954 and was excluded from the TD-8954 analysis.

Arm/Group Title	TD-8954	Metoclopramide
Arm/Group Description	TD-8954 single infusion for 1 hour and 4 injections of saline every 6 hours	Metoclopramide 4 doses every 6 hours for 24 hours and 1 hour infusion of saline
Measure Participants	6	6
Mean (Standard Deviation) [minutes]	135.7 (41.61)	132.5 (53.87)

7. Secondary Outcome

Title	Percentage Gastric Retention by Scintigraphy at 60 Minutes Postdose
Description	Mean gastric retention percentage after dosing.
Time Frame	60 minutes

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	TD-8954	Metoclopramide
Arm/Group Description	TD-8954 single infusion for 1 hour and 4 injections of saline every 6 hours	Metoclopramide 4 doses every 6 hours for 24 hours and 1 hour infusion of saline
Measure Participants	7	8
Mean (Standard Deviation) [percentage of retention]	29.6 (36.28)	43.3 (30.14)

8. Secondary Outcome

Title	Percentage Gastric Retention by Scintigraphy at 120 Minutes Postdose
Description	Mean gastric retention percentage after dosing.
Time Frame	120 minutes

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	TD-8954	Metoclopramide
Arm/Group Description	TD-8954 single infusion for 1 hour and 4 injections of saline every 6 hours	Metoclopramide 4 doses every 6 hours for 24 hours and 1 hour infusion of saline
Measure Participants	7	8
Mean (Standard Deviation) [percentage of retention]	19.6 (36.10)	32.3 (28.32)

9. Secondary Outcome

Title	Percentage of Gastric Retention by Scintigraphy at 240 Minutes Postdose
Description	Mean gastric retention percentage after dosing.
Time Frame	240 minutes

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	TD-8954	Metoclopramide
Arm/Group Description	TD-8954 single infusion for 1 hour and 4 injections of saline every 6 hours	Metoclopramide 4 doses every 6 hours for 24 hours and 1 hour infusion of saline
Measure Participants	7	8
Mean (Standard Deviation) [percentage of retention]	11.1 (24.85)	16.3 (25.64)

Adverse Events

Time Frame	6 Days
Arm/Group Title	TD-8954		Metoclopramide
Arm/Group Description	TD-8954 single infusion for 1 hour and 4 injections of saline every 6 hours TD-8954		Metoclopramide 4 doses every 6 hours for 24 hours and 1 hour infusion of saline Metoclopramide
All Cause Mortality
	TD-8954		Metoclopramide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	TD-8954		Metoclopramide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/7 (28.6%)		3/6 (50%)
General disorders
Disease progression	0/7 (0%)	0	1/6 (16.7%)	1
Nervous system disorders
Cerebral Hemorrhage	1/7 (14.3%)	1	0/6 (0%)	0
Hemorrhage intracranial	0/7 (0%)	0	1/6 (16.7%)	1
Subarachnoid hemorrhage	0/7 (0%)	0	1/6 (16.7%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/7 (14.3%)	1	0/6 (0%)	0
Other (Not Including Serious) Adverse Events
	TD-8954		Metoclopramide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/7 (71.4%)		2/6 (33.3%)
Gastrointestinal disorders
Diarrhea	0/7 (0%)	0	1/6 (16.7%)	1
Vomiting	1/7 (14.3%)	1	0/6 (0%)	0
Infections and infestations
Pneumonia	1/7 (14.3%)	1	0/6 (0%)	0
Metabolism and nutrition disorders
Hyperkalemia	1/7 (14.3%)	1	0/6 (0%)	0
Psychiatric disorders
Agitation	1/7 (14.3%)	1	0/6 (0%)	0
Skin and subcutaneous tissue disorders
Decubitus ulcer	1/7 (14.3%)	1	0/6 (0%)	0
Vascular disorders
Hypertension	0/7 (0%)	0	1/6 (16.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The PI may communicate the trial results generated by the PI, but only after the first publication or presentation of the combined study results generated by all participating sites. The Sponsor can then review trial results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The Sponsor cannot require changes to the communication and cannot extend the embargo.