Clinical Trials Register

Summary
EudraCT Number:	2019-001698-10
Sponsor's Protocol Code Number:	ION-682884-CS3
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:	2019-12-02
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

Spain - AEMPS

A.2

EudraCT number

2019-001698-10

A.3

Full title of the trial

A Phase 3 Global, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of ION-682884 in Patients with Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

Estudio en fase III, global, abierto y aleatorizado para evaluar la eficacia y la seguridad de ION-682884 en pacientes con polineuropatía amiloidótica familiar por transtiretina

A.3.1

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

Study to determine the effectiveness and safety of ION-682884 in patients with Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

Estudio para determinar la efectividad y seguridad de ION-682884 en pacientes con polineuropatía amiloidótica familiar por transtiretina

A.3.2

Name or abbreviated title of the trial where available

NEURO – TTRANSFORM

A.4.1

Sponsor's protocol code number

ION-682884-CS3

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	Ionis Pharmaceuticals, 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	Ionis Pharmaceuticals, Inc.
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	Ionis Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Ionis Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	2855 Gazelle Court
B.5.3.2	Town/ city	Carlsbad
B.5.3.3	Post code	CA 92010
B.5.3.4	Country	United States
B.5.4	Telephone number	+1760931 9200
B.5.5	Fax number	+1760603 2504
B.5.6	E-mail	ClinicalTrials@ionisph.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	ION-682884
D.3.2	Product code	ION-682884
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ION-682884
D.3.9.1	CAS number	1637600-16-8
D.3.9.2	Current sponsor code	ION-682884
D.3.9.3	Other descriptive name	ION-682884
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
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	Yes
D.3.11.13.1	Other medicinal product type	Antisense Oligonucleotide
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.2.5	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/3/14/1250
D.3 Description of the IMP
D.3.1	Product name	Inoserten
D.3.2	Product code	ISIS 420915
D.3.4	Pharmaceutical form	Solution for infusion in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INOTERSEN
D.3.9.1	CAS number	1432726-13-0
D.3.9.2	Current sponsor code	ISIS 420915
D.3.9.4	EV Substance Code	SUB188590
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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

Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

Polineuropatía amiloidótica familiar por transtiretina

E.1.1.1

Medical condition in easily understood language

An inherited condition that causes damage to peripheral nerves

Una condición hereditaria que causa daño a los nervios periféricos

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

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	10057949
E.1.2	Term	Familial amyloid polyneuropathy
E.1.2	System Organ Class	100000004850

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 efficacy of ION-682884 after administration for 65 weeks, as compared to the historical control of the placebo cohort (inotersen) in the NEURO-TTR trial, based on the change from Baseline in serum TTR concentration, mNIS+7 and in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN) in patients with hATTR.

Evaluar la eficacia de ION-698884 tras administración durante 65 semanas, en comaración con el control histórico de la cohorte del placebo (inotersen), basándose en el cambio desde el inicio en la concentración sérica de TTR, mNIS+7 y el cuestionario sobre la calidad de vida con neuropatía diabética de Norfolk (Norfolk QOL-DN) en pacientes con PAF-TTR

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of ION-682884, as compared to the placebo cohort in the NEURO-TTR trial, based on the change from Baseline in the following measures:
- Neuropathy Symptom and Change Score (NSC)
- Physical component summary (PCS) score of 36-Item Short Form Survey (SF-36)
- Polyneuropathy disability (PND) score
- Modified body mass index (mBMI)

Evaluar la eficacia de ION-682884, en comparación con la cohorte de placebo del ensayo NEURO-TTR, basándose en el cambio desde el inicio en lo siguiente:
•Puntuación en el cuestionario de síntomas y cambios de la neuropatía (NSC)
•Puntuación en el resumen del componente físico (PCS) del cuestionario breve de salud de 36 ítems (SF-36)
•Puntuación de discapacidad por polineuropatía (PND)
•Índice de masa corporal modificado (IMCm)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Aged 18 to 82 years at the time of informed consent
2. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal
3. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject's non-pregnant female partner must be using a highly effective contraceptive method
4. Diagnosis of hereditary transthyretin-mediated polyneuropathy as defined by meeting all 3 of the following:
• Stage 1 or Stage 2 FAP
• Documented genetic mutation in the TTR gene
• Symptoms and signs consistent with polyneuropathy as measured by NIS score ≥ 10 and ≤ 130

1. Edad de entre 18 y 82 años en el momento del consentimiento informado
2. Las mujeres deberan no estar embarazadas ni en periodo de lactacia y con esterilización quirúrgica o posmenopáusicas
3. Los varones deberan ser estériles quirúrgicamente o, abstenentes o, si mantienen relaciones sexuales con mujeres con posibilidad de embarazo, el paciente o su pareja no embarazada deben utilizar un método anticonceptivo muy eficaz
4. Diagnostico de Polineuropatía amiloidótica familiar por transtiretina según se define mediante los 3 criterios siguientes;
- Estado 1 o 2 PAF
- Mutación genética documentada en el gen TTR
- Signos y síntomas indicativos de neuropatía asociada con ploneuropatía includa una putuación >_10 y <_130

E.4

Principal exclusion criteria

1. Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion, including but not limited to abnormal safety labs
2. Karnofsky performance status ≤ 50
3. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease), including uncontrolled diabetes
4. Prior liver transplant or anticipated liver transplant within 1-yr of Screening
5. New York Heart Association (NYHA) functional classification of ≥ 3
6. Acute coronary syndrome or major surgery within 3 months of Screening
7. Other types of amyloidosis
8. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the Study
9. Current treatment with any approved drug for hereditary TTR amyloidosis such as Vyndaqel® / Vyndamax™ (tafamidis), Tegsedi™ (inotersen), Onpattro™ (patisiran),off-label use of diflunisal or doxycycline, and tauroursodeoxycholic acid (TUDCA).If previously treated with Vyndaqel® / Vyndamax™, diflunisal or doxycycline, and TUDCA, must have discontinued treatment for 2 weeks prior to Study Day 1
10. Previous treatment with TegsediTM (Inotersen) or OnpattroTM (patisiran), or other oligonucleotide or RNA therapeutic (including siRNA)

1. Anomalías de importancia clínica en el historial médico, en los resultados de laboratorio de la selección, o en el examen físico que haría que un sujeto no sea apto para la inclusión, incluído pero no limitado alos de seguridad de laboratorio
2. Estado funcional de Karnofsky <_50
3. Otras causas de neuropatía autónoma o sensitivomotora (p. ej., enfermedad autoinmunitaria), incluída diabetes no controlada
4. Trasplante de hígado previo o previsto en el plazo de 1 año de la selección
5. Clasificación funcional de la Asociación de Cardiología de Nueva York (New York Heart Association, NYHA) >_3
6. Síndrome coronario agudo o cirugía mayor dentro de los 3 meses posteriores a la detección.
7. Otros tipos de amiloidosis
8. Otros trastornos que, en opinión del investigador, hagan que el paciente no sea apto para la inclusión o que puedan interferir en su participación o su capacidad de completar el estudio.
9. Tratamiento en curso con algún fármaco autorizado para la amiloidosis hereditaria por TTR, como Vyndaqel®/Vyndamax™ (tafamidis), Tegsedi™ (inotersén), Onpattro™ (patisirán) o uso para una indicación no recogida en la ficha técnica de diflunisal, doxiciclina o ácido tauroursodeoxicólico (tauroursodeoxycholic acid, TUDCA). En caso de tratamiento previo con Vyndaqel®/Vyndamax™, diflunisal o doxiciclina y TUDCA, este debe haberse interrumpido al menos 2 semanas antes del día 1 del estudio
10. Tratamiento previo con Tegsedi™ (inotersén) u Onpattro™ (patisirán) u otros oligonucleótidos o ARN terapéuticos (incluido el ARNip)

E.5 End points

E.5.1

Primary end point(s)

Interim Analysis Co-Primary Efficacy Endpoints at Week 35
- Percent change from Baseline in serum TTR concentration
- Change from Baseline in mNIS+7

Final Analysis Co-Primary Efficacy Endpoints at Week 66
- Percent change from Baseline in serum TTR concentration
- Change from Baseline in mNIS+7
- Change from Baseline in Norfolk QOL-DN

Análisis intermedio de los criterios de valoración principales en la semana 35:
- Porcentaje de cambio desde el inicio en la concentración sérica de TTR
- Cambio desde el inicio en mNIS+37

Análisis final de los criterios de valoración principales en la semana 66:
- Porcentaje de cambio desde el inicio en la concentración sérica de TTR
- Cambio desde el inicio en mNIS+37

E.5.1.1

Timepoint(s) of evaluation of this end point

Interim Analysis Co-Primary Efficacy Endpoints at Week 35
Final Analysis Co-Primary Efficacy Endpoints at Week 66

Análisis intermedio de los criterios de valoración principales en la semana 35
Análisis final de los criterios de valoración principales en la semana 66

E.5.2

Secondary end point(s)

Interim Analysis Key Secondary Efficacy Endpoint at Week 35
- Change from Baseline in Norfolk QOL-DN

Final Analysis Secondary Endpoint
- Change from Baseline in Norfolk QOL-DN
- Change from Baseline in the PCS score of SF-36
- Change from Baseline in PND score
- Change from Baseline in mBMI

Análisis intermedio de los criterios de valoración secundarios en la semana 35
- Cambios desde el inicio en Norfolk QOL-DN

Analisis final de los criterios de valoración secundarios:
- Cambios desde el inicio en Norfolk QOL-DN
- Cambios desde el inicio en la puntuación PCS y en el cuestionario SF-36
- Cambios desde el inicio en la puntuación PND

E.5.2.1

Timepoint(s) of evaluation of this end point

Interim Analysis Key Secondary Efficacy Endpoint at Week 35

Change from Baseline in NSC at Weeks 35 and 66
Change from Baseline in the PCS score of SF-36 at Week 65
Change from Baseline in PND score at Week 65
Change from Baseline in mBMI at Week 65

Análisis intermedio de los criterios de valoración secundarios claves en la semana 35:
- Cambio desde el inicio en la puntuación del NSC en las semanas 35 y 66
- Cambio desde el inicio en la puntuación del PCS del cuestionario SF-36 en la semana 65
- Cambio desde el inicio en la puntuación de PND en la semana 65
- Cambio desde el inicio en el IMCm en la semana 65

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

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

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

Argentina

Australia

Austria

Belgium

Brazil

Canada

Chile

China

Colombia

Cyprus

Estonia

France

Germany

Greece

Ireland

Israel

Italy

Japan

Korea, Democratic People's Republic of

Latvia

Malaysia

Mexico

Netherlands

New Zealand

Portugal

Spain

Switzerland

Taiwan

Turkey

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

The End-of-Study is last subject, last visit.

El fin de Estudio es la última visita del último paciente

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:

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

F.4.2.2

In the whole clinical trial

140

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)

Eligible patients (including patients that initially received inotersen) may elect to enroll in an open-label extension study where they will receive ION-682884 once every 4 weeks, pending study approval by the IRB/IEC and appropriate regulatory authority. In this case, patients will not participate in the Post-Treatment Evaluation Period.

Los pacientes elegibles (incluidos los pacientes que inicialmente hayan recibido inotersen) puede ser elegidos para participar en un estudio de extensión abierto donde recibirán ION-682884 una vez cada 4 semans, a la espera de la aprobación del estudio por parte del IRB/IEC y de las autoridades regulatorias que correspondan. En este caso, los pacientes no participarán en el periodo de evaluación post-tratamiento

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

2020-02-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-02-14

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

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