Clinical Trials Register

Summary
EudraCT Number:	2016-002663-33
Sponsor's Protocol Code Number:	NUH-ALS-2015-04
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-09-19
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

2016-002663-33

A.3

Full title of the trial

Preventing Oxidative stress-induced Ischemic Injury and Systemic Inflammation complications during and after invasive Cardiac surgery with Alkaline Phosphatase (APPIRED III)

A.3.1

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

Preventing Systemic Inflammation after Cardiac surgery with Alkaline Phosphatase (APPIRED III)

Alkalische Phosphatase um immunologische Nebenwirkungen der Herz-Lungen-Maschine bei Herzoperationen zu verhindern (APPIRED III)

A.3.2

Name or abbreviated title of the trial where available

APPIRED III

A.4.1

Sponsor's protocol code number

NUH-ALS-2015-04

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03050476

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	Alloksys Life Sciences BV
B.1.3.4	Country	Netherlands
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	Alloksys Life Sciences BV
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Aix Scientifics
B.5.2	Functional name of contact point	Contract Research Organisation
B.5.3	Address:
B.5.3.1	Street Address	Theaterstr. 7
B.5.3.2	Town/ city	Aachen
B.5.3.3	Post code	52062
B.5.3.4	Country	Germany
B.5.4	Telephone number	+492414500 358
B.5.5	Fax number	+492414500 357
B.5.6	E-mail	eike@aix-scientifics.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	Alkaline Phosphatase (RESCAP®)
D.3.2	Product code	EC 3.1.3.1 , CAS-Nummer: 9001-78-9
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	bovine alkaline phosphatase
D.3.9.1	CAS number	9001-78-9
D.3.9.2	Current sponsor code	RESCAP®
D.3.9.3	Other descriptive name	BOVINE INTESTINAL ALKALINE PHOSPHATASE
D.3.9.4	EV Substance Code	SUB27380
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	1000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate for solution for injection/infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

systemic inflammation as side-effect of heart-lung machine during cardiac surgery

E.1.1.1

Medical condition in easily understood language

side-effects of heart-lung machine during cardiac surgery

E.1.1.2

Therapeutic area

Body processes [G] - Immune system processes [G12]

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	10017501
E.1.2	Term	Functional disturbances following cardiac surgery
E.1.2	System Organ Class	10022117 - Injury, poisoning and procedural complications

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

First primary endpoint
Demonstrate that RESCAP® intervention reduces the time to reach stability, while at ICU.
Severity of illness is assessed using the SOFA (Sequential Organ Failure Assessment) score
over 12 days while the patient remains in the ICU. Outcome will be compared after 72
hours in the ICU.

Second primary composite endpoint
Demonstrate that alkaline phosphatase reduces the incidence and extent of acute kidney injury after cardiopulmonary bypass as defined by the AKIN criteria.
• Rise in serum creatinine of by 0.3 mg/dl or 26 µmol/L in 48 hours/ a percentage increase in the serum creatinine concentration of ≥50 percent 10 or
• A drop in urine output to 0.5 ml/kg/hour for 6 hours
Occurrence of acute kidney injury will be checked within 30 days and additionally after 90 after surgery.

E.2.2

Secondary objectives of the trial

1. Measure cost-related outcomes associated to CPB and AP intervention including
a) the incidence and duration of renal replacement therapy,
b) Influence of the prolonged time of treatment (24 vs. 96 hours) on the primary endpoints
(study outcome).
c) days spent in the ICU and hospital, and
d) the incidence of arrhythmias in the two groups
2. Compare plasma levels of a set of inflammatory markers (IL-6, IL-8, IL-10, IL-17, IL-18, TNF-alpha) and increase endogenous alkaline phosphatase levels and kidney function markers (IL18, NGAL, TIMP-1, GFR) in the control and AP treated groups.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

A potential subject must meet all of the following criteria to participate in the study:
1. > 21 years of age (legal adult in Singapore)
2. Undergoing cardiac surgery with planned cardiopulmonary bypass
3. EuroSCORE II >= 3
4. Ability to provide informed consent (not incapacitated)
5. Patient has given written informed consent prior to participation in the trial and
undertakes to comply with the protocol.

E.4

Principal exclusion criteria

Any subjects meeting the following criteria at baseline will be excluded:
1. Already on renal replacement therapy
2. Patients with chronic kidney disease defined as urinary albumin excretion of ≥30 mg/day, or equivalent or estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 for > 3 months.
3. Patients who are pregnant or lactating.
4. Concurrent enrolment in another clinical trial
5. Known allergic reaction to bovine alkaline phosphatase
6. Patient with ongoing infections or current use of steroids
7. Patient with high-risk emergency surgery or with follow-up procedures already
planned at admission (like e.g., TEVAR)

E.5 End points

E.5.1

Primary end point(s)

Efficacy
We will have two efficacy endpoints that will be independently monitored by the data-safety monitoring board:

• Stop administering placebo but continue with experimental drug if AKI (defined by AKIN) is significantly lower in the experimental group
• Stop administering placebo but continue with experimental drug if mortality is significantly lower in the experimental group.

Given the results of previous studies in sepsis patients, we anticipate that the greatest benefits will be seen in the prevention of AKI in the experimental group. If these benefits reach a level of statistical significance and are considered clinically relevant at any of the yearly reviews, the DSMB will recommend that the placebo arm be stopped and all patients receive the experimental drug.

Safety
We will have two safety endpoints that will be independently monitored by the data-safety monitoring board.

• Stop if all cause mortality, cardiac mortality, acute kidney injury, or the primary compound outcome is significantly higher in the experimental group
• Stop if more than 5% of patients have a serious adverse/allergic reaction to the administration of the drug.

The safety committee will review the safety endpoints once at the 30-day mark to ensure there are no immediate safety concerns with the trial and then proceed with a yearly review of the outcomes

E.5.1.1

Timepoint(s) of evaluation of this end point

30 days

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

Yes

E.6.3

Therapy

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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)

E.8.2.2

Placebo

Yes

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

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

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

Malaysia

Singapore

Russian Federation

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

• Stop after 2 years after enrollment of the first patient if the current enrollment rate will not allow the study to be finished in ultimately 5 years and likely less than 4 years.
• Stop after 2 years if the event rate is significantly lower than anticipated and will not allow the study to be adequately powered with the estimated sample size

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

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:

625

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

625

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 2017-09-19.

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

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

150

F.4.2

For a multinational trial

F.4.2.1

In the EEA

850

F.4.2.2

In the whole clinical trial

1250

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 - no study-special treatment

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

2017-10-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-10-10

P. End of Trial
P.	End of Trial Status	Ongoing

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