Clinical Trials Register

Summary
EudraCT Number:	2017-001972-46
Sponsor's Protocol Code Number:	SKNt-001-CP4
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-11-08
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

France - ANSM

A.2

EudraCT number

2017-001972-46

A.3

Full title of the trial

Reaching Protein Target with SmofKabiven® extra Nitrogen Versus Olimel N9E: A Prospective, Randomised, Active-controlled, Patient-blinded, Multicentre Clinical Trial During the Early Phase of Acute Critical Illness

A.4.1

Sponsor's protocol code number

SKNt-001-CP4

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	Fresenius Kabi Deutschland GmbH
B.1.3.4	Country	Germany
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	Fresenius Kabi Deutschland GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fresenius Kabi Deutschland GmbH
B.5.2	Functional name of contact point	Divisional Medical Clinical Affairs
B.5.3	Address:
B.5.3.1	Street Address	Else-Kröner-Str. 1
B.5.3.2	Town/ city	Bad Homburg
B.5.3.3	Post code	61352
B.5.3.4	Country	Germany
B.5.4	Telephone number	4961726864598

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	Yes
D.2.1.1.1	Trade name	SmofKabiven extra Nitrogen
D.2.1.1.2	Name of the Marketing Authorisation holder	Fresenius Kabi s.r.o
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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.3.4	Pharmaceutical form	Emulsion for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Parenteral use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	amino acids
D.3.9.3	Other descriptive name	AMINO ACIDS
D.3.9.4	EV Substance Code	SUB23205
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	64,5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Glucose
D.3.9.3	Other descriptive name	GLUCOSE
D.3.9.4	EV Substance Code	SUB13981MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	84,7
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lipid emulsion
D.3.9.1	CAS number	8100001-14-9
D.3.9.3	Other descriptive name	LIPIDS NOS
D.3.9.4	EV Substance Code	SUB14363MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	28,9
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	Yes
D.3.11.13.1	Other medicinal product type	parenteral nutrition solution for infusion containing glucose, lipids and amino acids with electrolytes
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	Olimel N9E
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter SAS
D.2.1.2	Country which granted the Marketing Authorisation	France
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.3.4	Pharmaceutical form	Emulsion for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Parenteral use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	amino acids
D.3.9.3	Other descriptive name	AMINO ACIDS
D.3.9.4	EV Substance Code	SUB23205
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	56,9
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Glucose
D.3.9.3	Other descriptive name	GLUCOSE
D.3.9.4	EV Substance Code	SUB13981MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	110
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Lipid emulsion
D.3.9.1	CAS number	8100001-14-9
D.3.9.3	Other descriptive name	LIPIDS NOS
D.3.9.4	EV Substance Code	SUB14363MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/l gram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
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	Yes
D.3.11.13.1	Other medicinal product type	parenteral nutrition solution for infusion containing glucose, lipids and amino acids with electrolytes

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

Parenteral nutrition (PN) when oral or enteral nutrition (ON or EN) is impossible, insufficient, or contraindicated in the early phase of critical illness

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10051284
E.1.2	Term	Parenteral nutrition
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To explore the efficacy of SmofKabiven® extra Nitrogen compared with Olimel N9E in reducing the cumulative protein deficit with the same caloric target during the early phase of acute critical illness in haemodynamically stable adult patients who require PN

E.2.2

Secondary objectives of the trial

N/A

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients must fulfil all of the following criteria to be eligible for enrolment into the study:
1. Age ≥18 years and <90 years, male and female
2. Critically ill, medical or surgical ICU patient
3. Admitted to the ICU during the previous 24 hours with a minimum expected ICU stay of ≥3 days
4. Central venous access is available for continuous infusion of the study drugs
5. SOFA score ≥2
6. Contraindication against EN or limited tolerance to EN and it is planned that patient receives ≥80% of the total target caloric intake from PN during the first 3 nutritional treatment days
7. Written informed consent from the patient or the patient’s legal representative or deferred written consent from the patient or patient’s legal representative (deferred proxy consent)

E.4

Principal exclusion criteria

Medical Exclusions
1. Contraindication against PN or inability to receive PN via central venous access
2. Received PN within 7 days before randomisation
3. It is planned that patient receives ≥20% of the total target caloric intake via EN and/or non-nutritional sources (e.g. glucose solution for drug dilution or lipids from propofol) during the first 3 nutritional treatment days
4. BMI <18.5 kg/m2 or >35 kg/m2 5. Burn injury
6. Any severe, persistent blood coagulation disorder with uncontrolled bleeding
7. Any congenital errors of amino acid metabolism
8. Uncontrolled hyperglycaemia despite insulin treatment
9. Known hypersensitivity to fish, egg, soybean proteins, peanut protein, or to any of the active substances or excipients contained in SmofKabiven® extra Nitrogen or Olimel N9E
10. Known hypersensitivity to milk protein or to any other substance contained in
Fresubin® Original Fibre
11. Treatment-refractory cardiopulmonary or metabolic instability showing persistent or progressive worsening despite increased interventions, including severe pulmonary oedema, severe cardiac insufficiency, myocardial infarction, acute phase of circulatory shock, severe sepsis, embolism, haemodynamic instability, metabolic or respiratory acidosis, hypotonic dehydration, or hyperosmolar coma
12. Severe renal dysfunction, defined as serum creatinine ≥2.0 times baseline or urine output <0.5 mL/kg/h/ for ≥12 hours (Acute Kidney Injury stage ≥2; (KDIGO 2012)), and BUN exceeding 2 x ULN
13. Severe liver failure with encephalopathy, including intoxication (e.g. paracetamol, death cap, golden chain) and/or liver enzymes (AST, ALT, GGT) or bilirubin exceeding 5 x ULN
14. Oncologic disease under current anticancer treatment
15. Preceding transplantation causal for acute critical illness
16. Hemophagocytic syndrome
17. Pregnancy or lactation
18. Receiving end-of-life care
Laboratory Exclusions (assessed by local laboratory at study site):
19. Pathologically altered blood pH (arterial pH <7.0), oxygen saturation (SpO2 <80%), or carbon dioxide concentration (PaCO2 ≥80 mm Hg)
20. Hyperlipidaemia or any disorder of lipid metabolism characterised by
hypertriglyceridemia (serum triglyceride levels >4 mmol/L [>350 mg/dL])
21. Treatment-refractory, clinically significant major abnormality in the serum
concentration of any electrolyte (sodium, potassium, magnesium, total calcium,
chloride, inorganic phosphorous)
Concomitant Therapy Exclusions:
22. Administration of growth hormone including teduglutide within the previous 4 weeks before randomisation
Other Exclusions:
23. Participation in another interventional clinical trial within the previous 4 weeks
24. Previous inclusion in the present study

E.5 End points

E.5.1

Primary end point(s)

Protein intake during the 5-day treatment period:
• Proportion of patients reaching ≥70% of the cumulative target for protein delivery from Study Day 2 through Study Day 6
- The cumulative target for protein delivery is 6.75 g/kg/5d (based on a daily target of 0.75 g/kg on Study Day 2 and 1.5 g/kg/d on Study Days 3 through 6); 70% of the cumulative target for protein delivery = 4.73 g/kg/5d
- The cumulative protein delivery is calculated as the cumulative intake of amino acids from study drug and protein from EN on Study Day 2 through 6
• Percentage of the cumulative target for protein delivery reached from Study Day 2 through Study Day 6
- Actual cumulative protein delivery (g/kg/5d) divided by 6.75 (g/kg/5d) multiplied by 100
• Mean cumulative protein delivery by PN and EN from Study Day 2 through Study Day 6
• Calculated mean cumulative protein deficit during the period from Study Day 2 through Study Day 6
- The cumulative protein deficit is calculated as the cumulative target for protein delivery (6.75 g/kg/5d) minus the actual administered dose (g/kg/5d amino acids from study drug + g/kg/5d protein from EN)

Energy intake during the 5-day treatment period:
• Mean total cumulative energy intake from PN during the 5-day treatment period (calculated for each day from Study Day 2 through Study Day 6)
• Mean total cumulative energy intake from EN during the 5-day treatment period (calculated for each day from Study Day 2 through Study Day 6)
• Time to increase of daily EN intake above 20% of total energy target of 20 kcal/kg/d during the 5-day treatment period

Insulin dose during the 5-day treatment period:
• Mean daily insulin dose during the 5-day treatment period
• Mean cumulative insulin dose for the 5-day treatment period
• Mean change from baseline in daily insulin dose (Study Day 2 through Study Day 6)
• Maximum single insulin dose during the 5-day treatment period

Blood glucose profile during the 5-day treatment period:
• Mean maximum daily blood glucose value during the 5-day treatment period
• Mean minimum daily blood glucose value during the 5-day treatment period
• Mean blood glucose value during the 5-day treatment period
• Mean change from baseline in mean daily blood glucose value (Study Day 2 through Study Day 6)

Clinical outcome parameters (up to Study Day 28):
• Change from baseline in SOFA score, calculated daily from Study Day 3 through Study Day 7
• Overall survival time up to Study Day 28
• All-cause mortality up to Study Day 28
• Length of stay in the ICU up to Study Day 28
• Re-admission to ICU up to Study Day 28
• ICU mortality up to Study Day 28
• Length of stay in the hospital up to Study Day 28
• Re-admission to hospital up to Study Day 28
• Hospital mortality up to Study Day 28
• Therapeutic Intervention Scoring System (TISS)-28 score (including individual item score, category score, and total score) on Study Day 7

Functional Outcome Parameters (up to Study Day 28):
• Duration of mechanical ventilation up to Study Day 28
• Change from baseline in Medical Research Council (MRC) sum score on Study Day 7, and either at discharge from ICU or on Study Day 28, whatever occurs first
• Change from baseline ofin Functional Independence Measure (FIM™) scoreICU Mobility Scale on Study Days 7, 14, and 28

E.5.1.1

Timepoint(s) of evaluation of this end point

Protein intake during the 5-day treatment period: from Study Day 2 to Day 6

Energy intake during the 5-day treatment period: from Study Day 2 to Day 6

Insulin dose during the 5-day treatment period: from Study Day 2 to Day 6

Blood glucose profile during the 5-day treatment period: from Study Day 2 to Day 6

Clinical outcome parameters (up to Study Day 28)

Functional Outcome Parameters (up to Study Day 28)

E.5.2

Secondary end point(s)

N/A

E.5.2.1

Timepoint(s) of evaluation of this end point

N/A

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

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

multicentre

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

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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 the last visit of the last patient.

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 months

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:

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2018-11-08.

Yes

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

Informed consent from patient or legal rep. prior inclusion in the study. For incapacitated patients, if not possible to collect the consent of the patient´s legal rep. prior inclusion, deferred consent must be given from a legal representative.

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

120

F.4.2.2

In the whole clinical trial

120

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)

if nutritional support is still required after the study treatment period, this will be at the investigator´s discretion.

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

2019-01-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-05-14

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-09-07

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