Clinical Trials Register

Summary
EudraCT Number:	2019-001262-15
Sponsor's Protocol Code Number:	BiPhox-Trial
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-01-23
Trial 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

Austria - BASG

A.2

EudraCT number

2019-001262-15

A.3

Full title of the trial

Comparison of Biphozyl® and Phoxilium® as a replacement fluid during Continuous Veno-Venous Hemofiltration (CVVH) with Regional Citrate Anticoagulation (RCA) for Acute Kidney Injury (AKI) in adults and their effects on pH-, bicarbonate-levels and respiratory situation – A prospective, randomized, controlled, open, cross-over, Phase II, single-center pilot study

A.3.1

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

Comparison of two substitution fluids (Biphozyl® and Phoxilium® ) during continuous renal replacement therapy in adult critically ill patients with acute kidney injury and their effects on acid-base status and respiratory situation. – A prospective, randomized, controlled, open, cross-over, Phase II, single-center pilot study

A.3.2

Name or abbreviated title of the trial where available

BiPhox-Trial

A.4.1

Sponsor's protocol code number

BiPhox-Trial

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	Medical University Innsbruck
B.1.3.4	Country	Austria
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Baxter Healthcare Corporation
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	Medical University Innsbruck, Department of Internal Medicine, Division of Intensive Care and Emergency Medicine
B.5.2	Functional name of contact point	Head of Division
B.5.3	Address:
B.5.3.1	Street Address	Anichstraße 36
B.5.3.2	Town/ city	Innsbruck
B.5.3.3	Post code	6020
B.5.3.4	Country	Austria
B.5.6	E-mail	michael.joannidis@i-med.ac.at

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	Biphozyl®
D.2.1.1.2	Name of the Marketing Authorisation holder	Gambro Lundia AB, Magistratsvägen 16, 226 43 Lund, Schweden
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	Solution for haemodialysis/haemofiltration
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	Sodium
D.3.9.1	CAS number	N.A.
D.3.9.2	Current sponsor code	N.A.
D.3.9.3	Other descriptive name	SODIUM CHLORIDE
D.3.9.4	EV Substance Code	SUB20079
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/l millimole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	140
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Potassium
D.3.9.1	CAS number	N.A.
D.3.9.2	Current sponsor code	N.A.
D.3.9.3	Other descriptive name	POTASSIUM CHLORIDE
D.3.9.4	EV Substance Code	SUB12559MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/l millimole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Magnesium
D.3.9.1	CAS number	N.A.
D.3.9.2	Current sponsor code	N.A.
D.3.9.3	Other descriptive name	MAGNESIUM CHLORIDE
D.3.9.4	EV Substance Code	SUB20644
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/l millimole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.75
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Chloride
D.3.9.1	CAS number	N.A.
D.3.9.2	Current sponsor code	N.A.
D.3.9.3	Other descriptive name	SODIUM CHLORIDE
D.3.9.4	EV Substance Code	SUB12581MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/l millimole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	122
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Hydrogen phosphate
D.3.9.1	CAS number	N.A.
D.3.9.2	Current sponsor code	N.A.
D.3.9.3	Other descriptive name	HYDROGEN PHOSPHATE
D.3.9.4	EV Substance Code	SUB37052
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/l millimole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Hydrogen carbonate
D.3.9.1	CAS number	N.A.
D.3.9.2	Current sponsor code	N.A.
D.3.9.3	Other descriptive name	HYDROGEN CARBONATE
D.3.9.4	EV Substance Code	SUB37053
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/l millimole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	22
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	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	Phoxilium®
D.2.1.1.2	Name of the Marketing Authorisation holder	Gambro Lundia AB, Magistratsvägen 16, 226 43 Lund, Schweden
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	Solution for haemodialysis/haemofiltration
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	Sodium
D.3.9.1	CAS number	N.A.
D.3.9.2	Current sponsor code	N.A.
D.3.9.3	Other descriptive name	SODIUM CHLORIDE SOLUTION 0.9%
D.3.9.4	EV Substance Code	SUB20079
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/l millimole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	140.0
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Potassium
D.3.9.1	CAS number	N.A.
D.3.9.2	Current sponsor code	N.A.
D.3.9.3	Other descriptive name	POTASSIUM CHLORIDE
D.3.9.4	EV Substance Code	SUB12559MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/l millimole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4.00
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Magnesium
D.3.9.1	CAS number	N.A.
D.3.9.2	Current sponsor code	N.A.
D.3.9.3	Other descriptive name	MAGNESIUM CHLORIDE
D.3.9.4	EV Substance Code	SUB20644
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/l millimole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.60
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Chloride
D.3.9.1	CAS number	N.A.
D.3.9.2	Current sponsor code	N.A.
D.3.9.3	Other descriptive name	SODIUM CHLORIDE
D.3.9.4	EV Substance Code	SUB12581MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/l millimole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	115.9
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Hydrogen phosphate
D.3.9.1	CAS number	N.A.
D.3.9.2	Current sponsor code	N.A.
D.3.9.3	Other descriptive name	HYDROGEN PHOSPHATE
D.3.9.4	EV Substance Code	SUB37052
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/l millimole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.20
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Hydrogen carbonate
D.3.9.1	CAS number	N.A.
D.3.9.2	Current sponsor code	N.A.
D.3.9.3	Other descriptive name	HYDROGEN CARBONATE
D.3.9.4	EV Substance Code	SUB37053
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/l millimole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30.0
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Calcium
D.3.9.1	CAS number	N.A.
D.3.9.2	Current sponsor code	N.A.
D.3.9.3	Other descriptive name	CALCIUM CHLORIDE
D.3.9.4	EV Substance Code	SUB11767MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/l millimole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.25
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

Acute Kidney Injury (AKI). This is a A prospective, randomized, controlled, open, cross-over, Phase II, single-center pilot study to assess the effects of two different continuous veno-venous hemofiltration (CVVH) replacement fluids (Phoxilium® and Biphozyl®) in adult critically ill AKI patients treated with CVVH. Anticoagulation is delivered as pre-filter regional citrate anticoagulation with Regiocit® (Gambro Lundia AB, Sweden).

E.1.1.1

Medical condition in easily understood language

Acute kidney injury (AKI) is a clinical syndrome, where the kidney is not able to perform at its normal function. This is defined by an increased Serum Creatinine level and/or decreased Urine Volume.

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02]

MedDRA Classification

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 objectives of the BiPhox trial are to demonstrate, that the use of Biphozyl® as a replacement fluid in adult critically ill AKI patients, results in a lower rate of pH excursions and of HCO3- excursions compared to the use of Phoxilium® during the studied CVVH interval with regional citrate anticoagulation.

E.2.2

Secondary objectives of the trial

The secondary objectives of the BiPhox trial are to evaluate the time to pH level normalization and the HCO3- substitution rates after initiation of CVVH treatment. Further, to demonstrate that the use of Biphozyl® as a replacement fluid in adult critically ill AKI patients, results in a more stable acid-base-status as well as improved respiratory situation due to lower intracorporeal HCO3- and CO2 levels compared to the use of Phoxilium® during the studied CVVH interval with regional citrate anticoagulation.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

To be eligible for enrollment in the BiPhox-trial, a subject must fulfill all of the inclusion criteria and none of the exclusion criteria below:
1. Age ≥ 18 years (male & female & diverse)
2. Admission to Intensive Care Unit (ICU)
3. Indication for CVVH as determined by the attending physician
4. Planned CVVH treatment time ≥ 48 hours
5. Written informed consent or deferred consent or legally acceptable representative consent

E.4

Principal exclusion criteria

1. Lack of commitment to provide RRT as part of limitation of ongoing life support
2. Presence of a drug overdose that may result in acid-base-disorders and/or a shift of electrolytes
3. Receipt of RRT within the previous 72 hours
4. Dialysis dependent end-stage renal disease (ESRD)
5. Pregnancy
6. Combination of severely impaired liver function and shock with muscle hypoperfusion
7. Co-enrollment in another clinical trial
8. Subjects, who are legally exempted from participation in clinical trials (e.g. persons held in an institution by legal or official order)

E.5 End points

E.5.1

Primary end point(s)

The primary endpoints will be a) the rate of pH excursions from a set range of 7.35-7.45 and b) the rate of HCO3- excursions from a set range of 22-26 mmol/l

E.5.1.1

Timepoint(s) of evaluation of this end point

For each patient after cessation of the CVVH intervention or at least after 96h of the CVVH initiation.

E.5.2

Secondary end point(s)

• To compare the time to pH level normalization after initiation of CVVH treatment (Biphozyl® versus Phoxilium®)
• To compare the HCO3- substitution rates after initiation of CVVH treatment (Biphozyl® versus Phoxilium®)
• To compare the pH levels during CVVH treatment (Biphozyl® versus Phoxilium®)
• To compare the HCO3- levels during CVVH treatment (Biphozyl® versus Phoxilium®)
• To compare the base excess levels (BE) during CVVH treatment (Biphozyl® versus Phoxilium®)
• To compare the partial pressure of oxygen (pO2) and carbon dioxide (pCO2) levels during CVVH treatment (Biphozyl® versus Phoxilium®) in all patients and in the subset of subjects who are mechanically ventilated
• To compare phosphate levels during CVVH treatment (Biphozyl® versus Phoxilium®)
• To compare the substitution rate of Ca2+ and Mg2+ during CVVH treatment (Biphozyl® versus Phoxilium®)
• To compare the total-to-ionized Ca2+ ratio (T/I Ca2+ ratio) levels during CVVH treatment (Biphozyl® versus Phoxilium®)
• To compare the positive end-expiratory pressure (PEEP), tidal volume (Vt), respiratory minute volume (Ve), driving pressure (Δp), fraction of inspired oxygen (FiO2) and respiratory rate (RR) during CVVH treatment (Biphozyl® versus Phoxilium®) in mechanically ventilated patients
• All-cause mortality in ICU, in-hospital, at 28 days, and at 90 days
• Estimated glomerular filtration rate (eGFR) among patients alive at Day 90
• Major adverse kidney events, defined as death, RRT dependence or sustained reduction in kidney function (defined as eGFR < 75% baseline eGFR) at 28 and 90 days

E.5.2.1

Timepoint(s) of evaluation of this end point

For each patient after cessation of the CVVH intervention or at least after 96h of the CVVH initiation, if not differently defined for the specific endpoint (day 28 and day 90).

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

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)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

Yes

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

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

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

last visit of the last subject (LVLS)

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

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 2020-01-23.

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

Yes

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

The majority of patients have non-elective ICU stays and it is necessary to include intubated, sedated, and mechanically ventilated patents. Measures will be taken to protect this vulnerable population in accordance to local laws (e.g. § 43a AMG).

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

None

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

2020-03-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-01-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-03-11

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