Clinical Trials Register

Summary
EudraCT Number:	2017-003206-41
Sponsor's Protocol Code Number:	TAK-954-2002
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-03-07
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2017-003206-41

A.3

Full title of the trial

A Phase 2b, Randomized, Multi-Center, Double-Blind, Dose-Ranging Study to Assess the Efficacy, Safety and Pharmacokinetics of Intravenous TAK-954 in Critically Ill Patients With Enteral Feeding Intolerance

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

This study is to understand if TAK-954 can improve the daily nutritional intake of enteral feed that can be administered in patients who have become intolerant to enteral feeding.

A.4.1

Sponsor's protocol code number

TAK-954-2002

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Millennium Pharmaceuticals, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Millennium Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Takeda Development Centre Europe Ltd.
B.5.2	Functional name of contact point	Study Manager
B.5.3	Address:
B.5.3.1	Street Address	61 Aldwych
B.5.3.2	Town/ city	London
B.5.3.3	Post code	WC2B 4AE
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+442031168000
B.5.5	Fax number	+442031168199
B.5.6	E-mail	clinicaloperations@tgrd.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TAK-954
D.3.2	Product code	TAK-954
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TAK-954
D.3.9.1	CAS number	916075-84-8
D.3.9.3	Other descriptive name	TAK-954
D.3.9.4	EV Substance Code	SUB188136
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Metoclopromide
D.2.1.1.2	Name of the Marketing Authorisation holder	Hameln pharmaceuticals ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Metoclopramide
D.3.4	Pharmaceutical form	Concentrate for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METOCLOPRAMIDE
D.3.9.1	CAS number	7232-21-5
D.3.9.4	EV Substance Code	SUB03271MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

E.1.1.1

Medical condition in easily understood language

Enteral feeding intolerance is when a person has difficulty receiving food though a tube down their throat into their stomach.

E.1.1.2

Therapeutic area

Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10074293
E.1.2	Term	Enteral feeding intolerance
E.1.2	System Organ Class	100000004861

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to assess the treatment effect of IV TAK-954 in improving the average daily protein adequacy received through enteral nutrition.

E.2.2

Secondary objectives of the trial

• Assess the treatment effect of TAK-954 on GRV.
• Assess the safety and tolerability of multiple IV doses of TAK-954.
• Assess the treatment effect of TAK-954 on the ability to meet average target daily nutritional goals.
• Assess the treatment effect of TAK-954 on clinical outcomes.
• Evaluate the PK of TAK-954.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. In the opinion of the investigator, the participant, or the participant’s legally acceptable representative (LAR), is capable of understanding and complying with protocol requirements.
2. The participant or, when applicable, the participant’s LAR, signs and dates a written, informed consent form and any required privacy authorisation before the initiation of any study procedures.
3. The participant is male or female (and not pregnant) and is at least 18 years old.
4. The participant has at least a size 12-Fr nasogastric or orogastric tube with its tip at least 10 cm below the oesophagogastric junction confirmed radiologically (the tip of the tube must be in the body or the antrum of the stomach and not in the fundus).
5. The participant is intubated and mechanically ventilated in the ICU.
6. The participant is expected to remain alive, mechanically ventilated, and receive continuous enteral feeding for ≥48 hours following randomisation.
7. Have EFI, defined as a single GRV measurement of ≥250 mL with vomiting/retching within the last 24 hours, or a single GRV measurement of ≥500 mL with or without vomiting/retching within the last 24 hours.
8. A female participant of childbearing potential willing and agreeable to use highly effective contraception or sexual abstinence during the course of the study and up to 30 days post treatment.

E.4

Principal exclusion criteria

1. Has received any investigational compound within 30 days before Screening.
2. Has received TAK-954 in a previous clinical study or as a therapeutic agent.
3. Has an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
4. Is under consideration for withdrawal of life-sustaining treatments within the next 72 hours.
5. Has had major esophageal or gastric surgery or direct luminal trauma on this admission (participants with lower abdominal surgery are not excluded unless enteral feeding is contraindicated).
6. Has mechanical bowel obstruction, short bowel syndrome, or the presence of an active gastric pacemaker.
7. Have pre-existing hepatic disease that meets Child-Pugh Class B (moderate; total score 7 to 9 points) or C (severe; total score 10 to 15 points).
8. Has alanine aminotransferase (ALT) >8×upper limit of normal (ULN).
9. Has an estimated glomerular filtration rate (GFR) <30 mL/min.
10. Is required to take excluded medications listed in the Protocol, Section 7.3.
11. Has been admitted primarily for treatment of a drug overdose.
12. Has a presence of a post-pyloric tube in place at Randomisation that may be used for EN.
13. Is receiving PN at Screening.
14. Is in diabetic ketoacidosis or non-ketotic hyperosmolar coma.
15. Has clinically significant ECG abnormalities indicative of acute cardiac instability, as determined by the investigator at Screening; more than first degree AV block; >5 beats of non-sustained ventricular tachycardia (VT) at a rate >120 bpm; ECG changes consistent with acute myocardial ischemia or infarction.
Note: Controlled atrial fibrillation (AF) or supraventricular tachycardia (SVT) is allowed with heart rate under 100 bpm at baseline.
16. Has QTcF interval ≥450 msec or other factors that increase the risk of QT prolongation or arrhythmic events at Screening. Participants with bundle branch block and a prolonged QTcF should be reviewed by a cardiologist for potential inclusion.
17. Has a different nutrient requirement than allowed in feeding protocol.(outside a range of 1.2 to 2 g/kg/day of proteins and up to 1.5 kcal/mL)
18. Have received erythromycin or metoclopramide in the previous 24 hours before Screening; domperidone or azythromycin in the previous 72 hours, or need ongoing macrolide antibiotics. Patients on chronic treatment with metoclopramide or that have received continuous treatment (≥7 days) with metoclopramide during this hospital stay should be excluded.
19. Is in the opinion of the treating physician not eligible for treatment with metoclopramide.
20. Has received agents known to directly influence the 5-HT4/acetylcholine prokinetic mechanism (eg, serotonin-specific reuptake inhibitors, anticholinergic agents, or acetylcholinesterase inhibitors) within the 72 hours before Randomisation.
21. Has a history of hypersensitivity or allergies to TAK-954 or metoclopramide.
22. Is female and lactating or pregnant or intending to become pregnant within 30 days after last dose of the study medication; or intending to donate ova during such time period.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint will be the average daily protein adequacy received through enteral nutrition (defined by % of goal protein delivered per day [% protein goal delivered = actual protein achievement / total patient-specific target protein]) over the first 5 days of study treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

5 days.

E.5.2

Secondary end point(s)

• Average daily protein adequacy received through enteral nutrition received through enteral nutrition (defined by % of goal protein delivered per day [% protein goal delivered = actual protein achievement / total patient-specific target protein]) over the study treatment period.
• Average daily change in 24-hour GRV over the first 5 days of study treatment.
• Average daily caloric adequacy received through enteral nutrition (defined by % of goal calories achieved per day [% calorie goal achieved = actual calorie achievement / total patient-specific target calories]) over the first 5 days of study treatment and over the study treatment period.
• Time to resolution of EFI defined as GRV <250 mL in the absence of symptoms.
• Proportion of participants achieving at least 80% of daily goal calories through enteral nutrition and maintaining it for at least 2 consecutive days and/or the rest of the Treatment Period.
• Proportion of participants achieving at least 80% of daily goal protein through enteral nutrition and maintain it for at least 2 consecutive days and/or the rest of the Treatment Period.
• PK parameters of TAK-954: Ctrough on Day 5.

E.5.2.1

Timepoint(s) of evaluation of this end point

5 days.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Metoclopramide

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Canada

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

End of trial is defined as last patient last follow-up call.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

190

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Participants of this study may be ventilated and unconscious at the time of recruitment and unable to provide their own consent until they regain consciousness.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

200

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Study drug will not be available upon completion of the subject’s participation in the study. The subject should be returned to the care of a physician and standard therapies as required.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-05-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-29

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2018-11-02

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