Clinical Trials Register

Summary
EudraCT Number:	2011-001483-21
Sponsor's Protocol Code Number:	KBT009
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-01-24
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

Spain - AEMPS

A.2

EudraCT number

2011-001483-21

A.3

Full title of the trial

A Placebo-controlled, Double-blind, Randomised, Parallel-group, Long-term Phase III Trial Assessing the Safety and Efficacy of 50 µg and 100 µg/day of eprotirome in Patients with Heterozygous Familial Hypercholesterolaemia who are on Optimal Standard of Care

Ensayo en Fase III de largo plazo, randomizado, en grupos paralelos, doble ciego, controlado con placebo, para evaluar la seguridad y eficacia de 50 µg y 100 µg/día de eprotirome en pacientes con hipercolesterolemia familiar heterocigótica que están bajo un tratamiento de referencia habitual adecuado

A.3.1

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

N/A

A.3.2

Name or abbreviated title of the trial where available

AKKA

A.4.1

Sponsor's protocol code number

KBT009

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	Karo Bio AB
B.1.3.4	Country	Sweden
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	Karo Bio
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Karo Bio AB
B.5.2	Functional name of contact point	Regulatory Affairs Director
B.5.3	Address:
B.5.3.1	Street Address	Novum, Halsovagen 7
B.5.3.2	Town/ city	Huddinge
B.5.3.3	Post code	SE-141 57
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+468608 6007
B.5.5	Fax number	+468608 6188
B.5.6	E-mail	elisabeth.augustsson@karobio.se

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	eprotirome
D.3.2	Product code	KB2115
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	eprotirome
D.3.9.1	CAS number	CAS355129-15
D.3.9.2	Current sponsor code	KB2115
D.3.9.3	Other descriptive name	BMS356384
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hipercolesterolemia Heterocigotica Familiar
Heterozygous Familial Hypercholesterolaemia

E.1.1.1

Medical condition in easily understood language

Hipercolesterolemia Heterocigotica Familiar

E.1.1.2

Therapeutic area

Body processes [G] - Metabolic Phenomena [G03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10057099
E.1.2	Term	Heterozygous familial hypercholesterolaemia
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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 compare the efficacy of eprotirome 50 µg and eprotirome 100 µg versus placebo in terms of the percent change in LDL-C from baseline to Week 12 in HeFH patients with CAD, or who are at high risk for CAD, and who are on optimal standard of care consisting of a statin with or without ezetimibe

El objetivo principal de este estudio es comparar la eficacia de eprotirome 50 µg y eprotirome 100 µg frente a placebo, en cuanto a cambio porcentual en el cLDL, desde el valor inicial hasta la Semana12,
en pacientes de HFHe con APC o con alto riesgo de APC, y que estén en tratamiento de referencia adecuado, constituido por una estatina, con o sin ezetimiba.

E.2.2

Secondary objectives of the trial

Comparar la eficacia de eprotirome 50 µg y 100 µg frente al placebo, en cuanto al cambio porcentual en cLDL, desde el valor de referencia inicial hasta la Semana28, Semana52, Semana76 y
Semana100; en cuanto al cambio porcentual de triglicéridos (TG), colesterol de lipoproteínas de alta densidad (cHDL), colesterol no-cHDL , colesterol total (CT), apolipoproteína (apo) A-I, apo B,
lipoproteína (a) (Lp[a]) y marcadores de inflamación, en cuanto a la proporción de pacientes que presentan una reducción del cLDL de > 15 % desde el valor inicial a la Semana 12; Monitorizar la exposición sistémica al producto de reacción nitrado KB42899 en la población, a través del muestreo disperso y explorar la farmacocinética (FC) de KB42899 y eprotirome a través del muestreo exhaustivo en los casos seleccionados; Evaluar los efectos de eprotirome en el esqueleto con la densidad mineral ósea (DMOMO), usando la absorciometría de rayos X

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

1) DXA Scan and Echocardiography- In subsets of patients, safety assessments will also include echocardiography and DXA scans of the lumbar spine for BMD. The DXA scan substudy will be composed of the first 300 patients who qualify and are able to undergo a screening/baseline DXA scan (ie, no presence of osteoporosis and no orthopaedic hardware in the lumbar region). The echocardiogram substudy will be composed of the first 300 patients who qualify and undergo a screening/baseline echocardiogram. This substudy is included in the main protocol.

2)24-Hour PK Sampling- At least 20 patients who have consented to full PK sampling, and who have the highest values of KB42899, will have a full 24 hour PK sampling which includes the collection of 17 samples for analysis of both eprotirome and KB42899 in plasma.

3)Genetic-substudy- There will be one optional deoxyribonucleic acid (DNA) sample collected in this study that may be used to confirm the diagnosis of HeFH, to explore possible genetic factors that may explain the effect of eprotirome on the liver, as well as identifying/exploring genetic variations that may affect PK, PD, safety, and tolerability related to eprotirome treatment.

1) DXA y ecocardiografía en subgrupos de pacientes- El subestudio DEXA estará formado por los primeros 300 pacientes que sean incluidos y sean capaces de someterse a un examen DXA (es decir,
sin presencia de osteoporosis y sin necesidad de hardware ortopédica en la región lumbar). El subestudio de ecocardiogramas estará formado por los primeros 300 pacientes que reúnan los
requisitos y puedan someterse a un examen / ecocardiograma basal.

2) Sub-estudio Farmacocinético- Se realizará al menos a un subgrupo de 20 pacientes que tengan los valores más altos de KB42899 que hayan dado su consentimiento para que regresen a la clínica para un muestreo completo de farmacocinética de 24 horas, que incluya la recogida de 17 muestras para el análisis, tanto de eprotirome como de KB42899 en plasma.

3) Sub-estudio Genético- Habrá una recogida de muestra opcional de ácido desoxirribonucleico (ADN) en este estudio que puede usarse para confirmar el diagnóstico de HFHe, estudiar los factores genéticos que puedan explicar el efecto de eprotirome en el hígado, así como también identificar/estudiar las variaciones genéticas que puedan afectar la FC, PD, la seguridad y la tolerabilidad relacionadas con el tratamiento de eprotirome.

E.3

Principal inclusion criteria

1)Patients with confirmed HeFH who are 18 years of age or older, understand the study procedures and agree to participate in the study by giving written informed consent at Visit 1 and must have:
a) Presence of clinical atherosclerotic disease that confers high risk for CAD events together with an LDL-C >2 mmol/L (>80 mg/dL) at Visit 2, based on one or more of the following; or
b) Presence of at least 2 risk factors for CVD (other than the HeFH diagnosis) together with an LDL-C >2.5 mmol/L (>100 mg/dL) at Visit 2:
2) Patients should be on an optimal standard of care, defined as being on a stable dose of statin (at least half of the maximum dose of either rosuvastatin, atorvastatin, or simvastatin) with or without ezetimibe for at least 8 weeks prior to randomisation. If lower doses of rosuvastatin, atorvastatin, or simvastatin or any dose of fluvastatin or pravastatin are used the reasons must be clearly documented.
3) Women must not be pregnant or lactating. Women of childbearing potential must use a medically acceptable form of contraception at least 4 weeks prior to the start of the study and for at least 4 weeks after the patient?s last study visit. Subjects who are on systemic hormonal contraceptives must agree to use an additional method of contraception (barrier method).

1) Pacientes con HFHe confirmada que tengan una edad de 18 años en el screening. 2) Los pacientes también deben tener: a) Presencia de ateroesclerosis clínica que confiere alto riesgo de casos de APC
junto con cLDL 2 mmol/l ( 80 mg/dl) en la Visita 2, basándose en uno o más casos de los siguientes; o b) Presencia de 2 factores de riesgo de la ECV (aparte del diagnóstico HFHe) junto con cLDL 2,5
mmol/l ( 100 mg/dl) en la Visita 2. 3) Los pacientes deberán estar en tratamiento de referencia adecuado, definido éste como una dosis estable de estatina (al menos la mitad de la dosis máxima de
rosuvastatina, atorvastatina, o simvastatina) con o sin ezetimiba durante 8 semanas antes de la randomización. Si se usan dosis inferiores de rosuvastatina, atorvastatina o simvastatina, o bien
cualquier dosis de fluvastatina o pravastatina, las razones deben estar claramente justificadas. 4) Los pacientes deben entender los procedimientos del estudio y estar de acuerdo en participar en el estudio dando el consentimiento informado por escrito en la Visita 1; y 5) Las mujeres no deben estar embarazadas o en período de lactancia. Las mujeres en edad fértil deben usar una forma aceptable de anticoncepción al menos 4 semanas antes del inicio del estudio y durante al menos 4 semanas tras la última visita del estudio del paciente. Las pacientes que estén tomando anticonceptivos hormonales sistémicos deben estar de acuerdo en usar un método anticonceptivo adicional (método de barrera).

E.4

Principal exclusion criteria

1) Other dyslipidaemic or metabolic disorders that could affect the evaluation of eprotirome in HeFH, such as increased serum TG >4.5 mmol/L, HbA1c >8.5%, secondary dyslipidaemia or ongoing or planned apharesis
2) cardiac diseases that may interfere with the safety evaluation of eprotirome, such as congestive heart failure (NYHA III and IV), planned percutaneous coronary intervention, coronary
artery bypass surgery, uncontrolled hypertension (defined as systolic blood pressure equal to or more than 160 mmHg or diastolic blood pressure equal to or more than 100 mmHg) or evidence of cardiac electrophysiologic instability including uncontrolled sick sinus syndrome, sino-atrial or atrioventricular block, ventricular arrhythmias, uncontrolled atrial fibrillation/flutter or uncontrolled supraventricular tachycardia with a ventricular response heart rate (>100 bpm) or a QTcF >450 ms
3) No other lipid-lowering medication with the exception of statins and ezetimibe are allowed
4) Patients with disturbed thyroid function, thyrotoxicosis, taking thyroid hormone or anti-thyroid medication are excluded
5) Drugs known to affect thyroid function tests are also prohibited
6) Patients with liver dysfunction such as: AST or ALT or ALP >1.5 x ULN, total bilirubin >ULN, active hepatobiliary disease, cholestasis, or serologic evidence of past or active hepatitis B or hepatitis C, acquired immune deficiency syndrome, positive HIV, substantial consumption of alcohol or drug abuse
7) Patients with serum creatinine >160 mmol/L or unexplained serum creatine kinase >3 x ULN
8) Patients on oral anticoagulant therapy other than vitamin K antagonists and anti-platelets agents
9) Rheumatoid arthritis; history of cancer, history of or current primary or secondary adrenal insufficiency or any other condition that in the opinion of the investigator confound the evaluation and interpretation of efficacy and or safety data.

Los pacientes no deberán presentar trastornos metabólicos que pudieran afectar a la evaluación de eprotirome en HFHe, tales como el aumento de TG en suero > 4,5 mmol/l, HbA1c > 8,5 %, dislipidemia
secundaria o aféresis planificada o continuada. Enfermedades cardíacas que pudieran interferir con la evaluación de seguridad de eprotirome, como la insuficiencia cardíaca congestiva (NYHA III y IV),
intervención coronaria percutánea planificada, derivación de las arterias coronarias, hipertensión incontrolada (definida como presión arterial sistólica ³160mmHg o tensión arterial diastólica
³100mmHg) o evidencia de inestabilidad electrofisiológica cardíaca, incluyendo el síndrome del seno enfermo no controlado, el bloqueo auriculoventricular o sinoauricular, arritmias ventriculares,
fibrilación/aleteo auricular no controlado, taquicardia supraventricular no controlada con frecuencia cardíaca de respuesta ventricular (>100lpm) o una QTcF >450 ms anterior a la randomización. No se
permite ninguna otra medicación hipolipemiante, a excepción de las estatinas y la ezetimiba. También se excluye a los pacientes con cualquier patología médica o quirúrgica que pudiera alterar
significativamente la absorción, la distribución, el metabolismo o la excreción de la medicación del estudio. Se excluyen a los pacientes con alteración de la función tiroidea, tirotoxicosis, que tomen
hormona tiroidea o medicación antitiroidea. Los pacientes con disfunción hepática deberán ser excluidos antes de la randomización, como por ejemplo: AST o ALT o ALP >1,5 ´ LSN, bilirrubina
total >LSN, enfermedad hepatobiliar activa, colestasis o evidencia serológica de hepatitis B o hepatitis
C activas o anteriores, síndrome de inmunodeficiencia adquirida, prueba serológica positiva para la infección por el virus de inmunodeficiencia humana, consumo sustancial de alcohol o drogadicción.
Quedan excluidos los pacientes con creatinina sérica >160mmol/l o creatina quinasa sérica idiopática >3
´ LSN. Están excluidos los pacientes sometidos a tratamiento anticoagulante oral que no sean
antagonistas de la vitamina K y los antiagregantes plaquetarios. Están excluidos los pacientes con las
siguientes enfermedades: artritis reumatoide; antecedentes oncológicos, antecedentes de o insuficiencia
suprarrenal primaria o secundaria actual o cualquier otra patología que en opinión del investigador confunda la evaluación e interpretación de la eficacia y/o los datos de seguridad.

E.5 End points

E.5.1

Primary end point(s)

Efficacy:
The percent change in LDL-C from baseline to Week 12.

Efficacia: El cambio porcentual de LDL desde la visita basal a la semana 12

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 12

Semana 12

E.5.2

Secondary end point(s)

Efficacy:
Percent change in LDL-C from baseline to Week 28, Week 52, Week 76, and Week 100;
Percent change in TG, HDL-C, non-HDL-C, TC, apo A-I, apo B, Lp(a), and hsCRP from baseline to Week 12, Week 28, Week 52, Week 76, and Week 100; and
Proportion of patients with an LDL-C reduction from baseline of more than 15% at Week 12.

E.5.2.1

Timepoint(s) of evaluation of this end point

Week, 12, Week 28, Week 52, Week 76 and Week 100

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

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

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

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

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

Austria

Czech Republic

Denmark

India

Israel

Netherlands

Norway

Russian Federation

South Africa

Spain

Sweden

United Kingdom

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

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

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)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

1050

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1050

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

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

626

F.4.2.2

In the whole clinical trial

1050

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)

No treatment planned.

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

2011-08-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-07-04

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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