Clinical Trials Register

Summary
EudraCT Number:	2016-000868-42
Sponsor's Protocol Code Number:	B3461045
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-07-15
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2016-000868-42

A.3

Full title of the trial

A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE-BLIND, EXTENSION STUDY TO EVALUATE THE SAFETY OF DAILY ORAL DOSING OF TAFAMIDIS MEGLUMINE (PF-06291826) 20 MG OR 80 MG IN SUBJECTS DIAGNOSED WITH TRANSTHYRETIN CARDIOMYOPATHY (TTR-CM)

ESTUDIO DE EXTENSIÓN DE FASE 3, MULTICÉNTRICO, ALEATORIZADO Y DOBLE CIEGO PARA EVALUAR LA SEGURIDAD DE LA ADMINISTRACIÓN DIARIA POR VÍA ORAL DE 20 MG U 80 MG DE TAFAMIDIS MEGLUMINA (PF 06291826) EN PACIENTES CON UN DIAGNÓSTICO DE MIOCARDIOPATÍA POR TRANSTIRETINA (MC TTR)

A.3.1

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

Phase 3, double-blind randomized, long-term extension safety study designed to obtain additional safety data for 20 mg and 80 mg tafamidis and to continue to provide subjects who have completed 30 months of blinded treatment on Protocol B3461028 with tafamidis for up to 60 additional months, or until subject has access to tafamidis for TTR-CM via prescription, whichever occurs first.

Estudio de seguridad de extensión a largo plazo de fase 3, doble ciego, aleatorizado diseñado para obtener datos adicionales de seguridad para tafamidis 20 mg y 80 mg y para continuar proporcionando a los sujetos que han completado 30 meses de tratamiento enmascarado en el protocolo B3461028 con tafamidis hasta un máximo de 60 meses más, o hasta que el sujeto tenga acceso a tafamidis para MC TTR mediante prescripción, lo que ocurra antes.

A.4.1

Sponsor's protocol code number

B3461045

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	Pfizer Inc.
B.1.3.4	Country	United States
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	Pfizer Inc, 235 42nd Street, New York, NY 10017
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	Pfizer Inc
B.5.2	Functional name of contact point	Clinicaltrials.gov Call Center
B.5.3	Address:
B.5.3.1	Street Address	235 East 42nd Street
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	NY 10017
B.5.3.4	Country	United States
B.5.4	Telephone number	+3491 490 99 00
B.5.5	Fax number	0013037391119
B.5.6	E-mail	clinicaltrials.govcallcenter@pfizer.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	Yes
D.2.1.1.1	Trade name	Vyndaqel 20 mg soft capsule
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/06/401
D.3 Description of the IMP
D.3.1	Product name	Tafamidis meglumine
D.3.2	Product code	PF-06291826-83
D.3.4	Pharmaceutical form	Capsule, soft
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	Tafamidis meglumine
D.3.9.1	CAS number	951395-08-7
D.3.9.2	Current sponsor code	PF-06291826
D.3.9.3	Other descriptive name	TAFAMIDIS MEGLUMINE
D.3.9.4	EV Substance Code	SUB31457
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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	Capsule, soft
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

Transthyretin amyloid cardiomyopathy (TTR-CM)

Miocardiopatía amiloidea por transtiretina (MC TTR)

E.1.1.1

Medical condition in easily understood language

A condition characterized by the buildup of abnormal deposits of a protein called amyloid in the body's organs and tissues that include the heart, which can result in worsening of its function

Una enfermedad caracterizada por la acumulación de depósitos anormales de una proteína llamada amiloide en órganos y tejidos inluido el corazón, que puede resultar en un empeoramiento de su función.

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10002020
E.1.2	Term	Amyloid cardiomyopathy
E.1.2	System Organ Class	100000004849

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

- To obtain additional, long-term, safety data for tafamidis in subjects with transthyretin amyloid cardiomyopathy (TTR-CM).
- To provide investigational product, tafamidis, to TTR-CM subjects who complete 30 months of blinded treatment on protocol B3461028.

- Obtener más datos de seguridad a largo plazo de tafamidis en sujetos con miocardiopatía amiloidea por transtiretina (MC TTR).
- Proporcionar el producto en investigación, tafamidis, a sujetos con MC TTR que completen 30 meses de tratamiento enmascarado en el protocolo B3461028.

E.2.2

Secondary objectives of the trial

Not Applicable

No Aplica.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male and female subjects with TTR amyloid cardiomyopathy who have completed 30 months of study treatment on Protocol B3461028.
2. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
3. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
4. Male subjects able to father children and female subjects of childbearing potential and at risk for pregnancy must agree to use 2 highly effective methods of contraception throughout the study and for at least 28 days after the last dose of assigned treatment.
Female subjects who are not of childbearing potential (ie, meet at least 1 of the following criteria):
- Have undergone a documented hysterectomy and/or bilateral oophorectomy;
- Have medically confirmed ovarian failure; or
- Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum folliclestimulating hormone (FSH) level confirming the post-menopausal state.
All other female subjects (including females with tubal ligations) will be considered o be of childbearing potential.

1. Sujetos de uno u otro sexo con miocardiopatía amiloidea por TTR que hayan completado 30 meses de tratamiento del estudio en el protocolo B3461028.
2. Existencia de un documento de consentimiento informado, firmado y fechado personalmente, que indique que se ha informado al sujeto de todos los aspectos pertinentes del estudio.
3. Disposición del sujeto a cumplir las visitas programadas, el plan de tratamiento, las pruebas analíticas y otros procedimientos del estudio y capacidad de hacerlo.
4. Los varones con capacidad de engendrar hijos y las mujeres en edad fértil y con riesgo de embarazo deberán comprometerse a utilizar dos métodos anticonceptivos muy eficaces durante todo el estudio y hasta, como mínimo, 28 días después de la última dosis del tratamiento asignado.
Se considerará que no están en edad fértil a las mujeres que cumplan al menos uno de los criterios siguientes:
• Se han sometido a una histerectomía u ovariectomía bilateral documentada.
• Presentan insuficiencia ovárica confirmada médicamente.
• Han llegado al estado posmenopáusico, definido de la manera siguiente: cese de la menstruación regular durante al menos 12 meses consecutivos sin otra causa patológica o fisiológica; dicho estado puede confirmarse con una determinación de la concentración sérica de folitropina (FSH) que confirme el estado posmenopáusico.
Se considerará que todas las demás mujeres (incluso las que se hayan sometido a una ligadura de trompas) están en edad fértil.

E.4

Principal exclusion criteria

1. Chronic use of diflunisal, TTR stabilizer, tauroursodeoxycholate, doxycycline, digitalis, calcium channel blockers, investigational drug(s) or other experimental interventions, other than tafamidis, independently or as part of a study within 30 months prior to enrollment.
2. Use of certain non-steroidal anti-inflammatory drugs (NSAIDs)
3. Liver and/or heart transplant, or implanted cardiac mechanical assist device.
4. Pregnant females (or planning to become pregnant during the study interval); breastfeeding females; male subjects with partners currently pregnant.
5. Require initiation of treatment with calcium channel blockers.
6. Urinary retention requiring chronic self-catheterization.
7. Breach of compliance with treatment/significant protocol violations during conduct of B3461028 for which the subject was accountable.
8. Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees directly involved in the conduct of he study.
9. Other severe acute or chronic medical or psychiatric condition or laboratory bnormality that may increase the risk associated with study participation or investigational product administration, or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject an appropriate for entry into this study.

1. Uso crónico de diflunisal, estabilizadores de TTR, tauroursodesoxicolato, doxiciclina, digitálicos, antagonistas del calcio, fármaco en investigación u otras intervenciones experimentales, diferente de tafamidis, independientemente o como parte de un estudio en los 30 meses previos al reclutamiento.
2. Uso de determinados antiinflamatorios no esteroideos (AINE).
3. Trasplante de hígado o corazón o implantación de un dispositivo de asistencia mecánica cardíaca.
4. Mujeres embarazadas (o que tengan previsto quedarse embarazadas durante el intervalo del estudio) o lactantes y varones cuyas parejas estén embarazadas.
5. Necesidad de iniciar un tratamiento con antagonistas del calcio.
6. Retención urinaria con necesidad de autosondaje a largo plazo.
7. Incumplimiento del tratamiento o transgresiones importantes del protocolo durante la realización del estudio B3461028 de las que fue responsable el sujeto.
8. Sujetos que sean miembros del personal del centro de investigación con intervención directa en la realización del estudio y sus familiares, miembros del personal del centro supervisado por el investigador o empleados de Pfizer que intervengan directamente en la realización del estudio.
9. Otro trastorno médico o psiquiátrico grave, agudo o crónico, o cualquier alteración analítica que pueda aumentar el riesgo asociado a la participación en el estudio o a la administración del producto en investigación o que pueda interferir en la interpretación de los resultados del estudio y que, en opinión del investigador, impida la participación del sujeto.

E.5 End points

E.5.1

Primary end point(s)

Safety as measured by:
 All-cause mortality.
 Incidence of treatment-emergent adverse events.

Seguridad determinada mediante.
• Mortalidad global.
• Incidencia de acontecimientos adversos surgidos durante el tratamiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

Both primary end points will be assessed throughout the study.

Ambos criterios de valoración se valorarán a lo largo de todo el estudio.

E.5.2

Secondary end point(s)

Cardiovascular-related mortality.

Frequency of all-cause hospitalization.

Frequency of cardiovascular-related hospitalization (including heart failure, arrhythmia, myocardial infarction, stroke and other cardiovascular-related events).

Change from baseline at each visit in Kansas City Cardiomyopathy Questionnaire. Overall Score and domain scores (Physical limitation, Symptom stability, Symptoms, Self-efficacy, Social limitation, and Quality of life) and domain summary scores (Functional summary and Clinical summary).
New York Heart Association classification at each visit.

Change from baseline in Body Mass Index/modified Body Mass Index at each visit.

Assessment of physical examinations, use of concomitant medications,
electrocardiograms (ECGs), clinical laboratory testing, vital signs at each visit.

- Mortalidad de origen cardiovascular.
- Frecuencia de hospitalizaciones por cualquier causa.
- Frecuencia de hospitalizaciones por motivos cardiovasculares (como insuficiencia cardíaca, arritmia, infarto de miocardio, ictus y otros episodios cardiovasculares).
- Variación entre el momento basal y cada visita de la puntuación global en el Cuestionario de miocardiopatía de Kansas City, así como de las puntuaciones de dominios (limitación física, estabilidad de síntomas, síntomas, eficacia valorada por el propio sujeto, limitación social y calidad de vida) y las puntuaciones resumen de dominios (resumen funcional y resumen clínico).
- Clasificación de la New York Heart Association en cada visita.
- Variación entre el momento basal y cada visita del índice de masa corporal/índice de masa corporal modificado.
- Evaluación de la exploración física, uso de medicamentos concomitantes, electrocardiogramas (ECG), pruebas analíticas y constantes vitales en cada visita.

E.5.2.1

Timepoint(s) of evaluation of this end point

- 12-lead ECG: An annual basis (every 12 months) at clinic visits Months 12, 24, 36, 48 and 6at 0 month or early study termination
- NYHA Classification: At day 0, evry 6 months, at 60 month or early study termination
- KCCQ: At day 0, evry 6 months, at 60 month or early study termination

- ECG de 12 derivaciones: anualmente (cada 12 meses) en las visitas de los meses 12, 24, 36, 48 y 6 en el mes 0 o en la finalización prematura del estudio.
- Clasificacion NYHA: el día 0, cada 6 meses, en el mes 60 o en la finalización prematura del estudio.
- KCCQ: El día 0, cada 6 meses, en el mes 60 o en la finalización prematura del estudio

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

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

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

Belgium

Brazil

Canada

Czech Republic

France

Germany

Italy

Japan

Netherlands

Spain

Sweden

United Kingdom

United States

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

The time at which it is deemed that a sufficient number of subjects have been recruited and completed the study as stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application in the Member State. Poor recruitment (recruiting less than the anticipated number in the CTA) by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State.

El momento en el que se considere que se ha reclutado un número suficiente de sujetos y se ha completado el estudio como se establece en la solicitud regulatoria (esto es, la solicitud de ensayo clínico) y la solicitud del comité en el Estado Miembro. Un bajo reclutamiento (reclutar menos del número previsto en la solicitud de ensayo clínico) por un Estado Miembro no es un motivo para la finalizacion prematura, pero se considera como un final normal del estudio en el Estado Miembro.

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)

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:

300

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

123

F.4.2.2

In the whole clinical trial

330

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

ninguno

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

2016-09-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-07-26

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials