Clinical Trials Register

Summary
EudraCT Number:	2017-005097-19
Sponsor's Protocol Code Number:	EVOLVD
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-07-16
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

Sweden - MPA

A.2

EudraCT number

2017-005097-19

A.3

Full title of the trial

Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients (EVOLVD)

Kolesterolsänkning med evolocumab för att förebygga kranskärlssjukdom efter hjärttransplantation (EVOLVD)

A.3.1

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

Cholesterol lowering in heart transplant recipients

Kolesterolsänkning hos patienter som har genomgått hjärttransplantation

A.3.2

Name or abbreviated title of the trial where available

EVOLVD

EVOVLD

A.4.1

Sponsor's protocol code number

EVOLVD

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03734211

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	Oslo University Hospital
B.1.3.4	Country	Norway
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	Amgen Europe B.V
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	Oslo University Hospital
B.5.2	Functional name of contact point	Department of Cardiology
B.5.3	Address:
B.5.3.1	Street Address	Sognsvannsveien 20
B.5.3.2	Town/ city	Oslo
B.5.3.3	Post code	4950
B.5.3.4	Country	Norway
B.5.4	Telephone number	+4723070000
B.5.5	Fax number	+4723070650
B.5.6	E-mail	lars.gullestad@medisin.uio.no

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	Repatha®
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen®
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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	Evolocumab
D.3.4	Pharmaceutical form	Solution for injection in pre-filled injector
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
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	Yes
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	No
D.2.1.1.1	Trade name	Placebo to Repatha
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen®
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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	placebo to Repatha®
D.3.4	Pharmaceutical form	Concentrate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
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)	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection in pre-filled injector
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

De novo heart transplantation

Personer som nyligen har genomgått hjärttransplantation

E.1.1.1

Medical condition in easily understood language

Patients who have recently undergone heart transplantation

Personer som nyligen har genomgått hjärttransplantation

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

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	10066521
E.1.2	Term	Coronary artery disease progression
E.1.2	System Organ Class	100000004849

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 evaluate the effect of the PCSK9 inhibitor evolocumab on cardiac allograft vasculopathy in de novo heart transplant recipients

Att undersöka om evolocumab kan minska utvecklingen av kranskärlssjukdom hos patienter som nyligen genomgått hjärttranpsplantation

E.2.2

Secondary objectives of the trial

• Cardiac allograft vasculopathy (defined as mean a maximal intimal thickness ≥0.5 mm over the entire matched segment)
• Total atheroma volume
• The Index of Microvascular Resistance
• LDL cholesterol
• Estimated glomerular filtration rate (eGFR) assessed with the MDRD formula
• Quality of life as assessed by the SF36 and the EQ 5D questionnaires
• N-terminal pro-B-type natriuretic peptide (NT-proBNP)
• Cardiac troponin T (TnT)
• Number of rejections
• The number of adverse events
• The number of major clinical adverse events, defined as death, myocardial infarction, percutaneous coronary intervention/coronary bypass surgery, cerebral stroke, cancer, end stage renal disease (exploratory endpoint)

• Kranskärlssjukdom definierat som medelvärde av maximal intima-media tjocklek ≥ 0,5 mm mätt över hela kärlsegmentet.
• Total ateromatös volym
• Index av mikrovaskulär resistens (IMR)
• LDL kolesterol
• Estimerad glomerular filtrationshastighet (eGFR) mätt med MDRD formeln
• Livskvalitet (SF36 och EQ 5D frågeformulär)
• N-terminalt pro-B-typ natriuretiskt peptid (NT-proBNP)
• Troponin T (TnT)
• Antal avstötningar
• Antal biverkningar ("adverse events")
• Antal ogynnsamma kliniska händelser inklusive död, hjärtinfarkt, PCI, CABG, stroke, cancer och terminal njursvikt (explorativt utfallsmått)

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

EVOLVD SUBSTUDY: Biomarkers for Diagnosis, Prognosis, and Targeted Therapy After Heart Transplantation (EMBIO) (Prof. Karl Lemström, University of Henlsinki, Finland)
The aim of the sub-study is:
A. To develop liquid biopsies for diagnosis, prognosis, and treatment for acute rejection, late graft loss, and to monitor rejections after heart transplantation
B. to study the effect of genetic diversity between the donor and recipient on the response to immunosuppressive drugs and the development of complications after heart transplantation

I en sub-studie till EVOLD studien, EMBIO (Prof. Karl Lemström, Helsingfors Universitet) planerar man att undersöka DNA, RNA, proteomics och metabolomics i blodprover från både donator och recipient för att utvärdera om det går att hitta cirkulerande biomarkörer som är användbara för att monitorera förekomst av avstötning. På så sätt kunde patienter i framtiden slippa invasiva undersökningar med hjärtbiopsier. Forskningen riktar sig framför allt mot genetiska markörer från donatorvävnad som jämförs med DNA profilen hos recipienten.

E.3

Principal inclusion criteria

• Heart transplant recipient within the last 4 – 8 weeks.
• Age between 18 and 70 years.
• Informed consent obtained and documented according to Good Clinical Practice (GCP), and national/regional regulations.
• No contraindications to coronary angiography with intravascular ultrasound

• Genomgått hjärttransplantation inom 4–8 veckor
• Ålder mellan 18 och 70 år
• Skriftligt informerat samtycke efter muntlig och skriftlig studieinformation enligt GCP
• Inga hinder för kranskärlsröntgen med intravaskulärt ultraljud
• Estimerad glomerulär filtrationshastighet över 20ml/min/1,73 m2 beräknad enligt MDRD formeln

E.4

Principal exclusion criteria

• Decompensated liver disease (Child-Pugh class C)
• Severe renal failure, i.e. eGFR < 20 ml/min/1.73 m2 or on renal replacement therapy
• Ongoing rejections or infections
• Known sensitivity or intolerance to evolocumab or any of the excipients of Repatha®
• Prior use of PCSK9 inhibition treatment
• Alcohol or drug abuse within 3 months of informed consent that would interfere with trial participation or any ongoing condition leading to decreased compliance with study procedures or study drug intake
• Participation in another clinical trial involving an investigational drug and/or follow-up within 30 days prior to enrolment.
• Pregnancy.
• Female subject who has either (1) not used at least one highly effective method of birth control* for at least 1 month prior to screening or (2) is not willing to use such a method during treatment and for an additional 15 weeks after the end of treatment, unless the subject is sterilised or postmenopausal

• Sviktande leverfunktion enligt prövarens bedömning
• Svår njursvikt (eGFR <20 ml/min/1,73m2) eller dialys
• Pågående avstötning eller infektion
• Känd intolerans mot evolocumab
• Tidigare behandling med PCSK9 hämmare
• Alkohol eller drog-missbruk inom 3 månader före studiestart
• Deltagande i en annan kliniskstudie
• Graviditet
• Fertil kvinna som inte accepterar att använda preventivmedel

E.5 End points

E.5.1

Primary end point(s)

Baseline-adjusted maximal intima-media thickness as measured by coronary intravascular ultrasound (IVUS)

Maximal intima-media tjocklek mätt med intravaskulärt ultraljud (IVUS) justerat för baseline värde

E.5.1.1

Timepoint(s) of evaluation of this end point

After 12 months treatment with study drug

Efter 12 månaders behandling med studiedrog

E.5.2

Secondary end point(s)

• Cardiac allograft vasculopathy (defined as mean a maximal intimal thickness ≥0.5 mm over the entire matched segment)
• Total atheroma volume as measured by IVUS
• Index of Microvascular Resistance
• LDL cholesterol
• Estimated GFR
• Quality of life as assessed by the SF-36 and 5D EuroQoL questionnaires
• N-terminal pro-B-type natriuretic peptide (NT-proBNP)
• Cardiac troponin T (TnT)
• The number of allograft rejections
• The number of adverse events
• The number of major clinical adverse events, defined as death, myocardial infarction, percutaneous coronary intervention/coronary bypass surgery, cerebral stroke, cancer, end stage renal disease (exploratory endpoint)

• Kranskärlssjukdom definierat som medelvärde av maximal intima-media tjocklek ≥ 0,5 mm mätt över hela kärlsegmentet.
• Total ateromatös volym
• Index av mikrovaskulär resistens (IMR)
• LDL kolesterol
• Estimerad glomerulär filtrationshastighet (eGFR) mätt med MDRD formeln
• Livskvalitet (SF36 och EQ 5D frågeformulär)
• N-terminalt pro-B-typ natriuretiskt peptid (NT-proBNP)
• Troponin T (TnT)
• Antal avstötningar
• Antal biverkningar ("adverse events")
• Antal ogynnsamma kliniska händelser inklusive död, hjärtinfarkt, PCI, CABG, stroke, cancer och terminal njursvikt (explorativt utfallsmått)

E.5.2.1

Timepoint(s) of evaluation of this end point

After 12 months treatment with study drug

Efter tolv månaders behandling med studieläkemedel

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

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

Yes

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

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

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

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

30 November 2021

30 november 2021

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

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:

100

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

130

F.4.2.2

In the whole clinical trial

130

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)

After the study the patients will continue to be followed according to rutin procedures at the heart transplantation outpatient clinic.

Efterstudien kommer patenterna att följas enligt rutin vid hjärttransplantationsmottagningen.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Oslo University Hospital
G.4.3.4	Network Country	Norway
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Copenhagen Univerity Hospital
G.4.3.4	Network Country	Denmark
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	Aarhus University Hospital
G.4.3.4	Network Country	Denmark
G.4 Investigator Network to be involved in the Trial: 4
G.4.1	Name of Organisation	Helsinki University Hospital
G.4.3.4	Network Country	Finland

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-09-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-08-19

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

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