Clinical Trials Register

Summary
EudraCT Number:	2018-000185-11
Sponsor's Protocol Code Number:	VX17-445-105
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-01-22
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-000185-11

A.3

Full title of the trial

A Phase 3, Open-label Study Evaluating the Long-term Safety and Efficacy of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous or Heterozygous for the F508del Mutation

Studio in aperto di fase 3 per la valutazione della sicurezza e dell’efficacia a lungo termine della terapia combinata VX-445 in soggetti con fibrosi cistica omozigoti o eterozigoti per la mutazione F508del

A.3.1

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

A Study Evaluating the Long-term Safety and Efficacy of VX-445 Combination Therapy

Uno studio per la valutazione della sicurezza e dell’efficacia a lungo termine della terapia combinata VX-445

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

VX17-445-105

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	VERTEX PHARMACEUTICALS INCORPORATED
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	Vertex Pharmaceuticals Incorporated
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	Vertex Pharmaceuticals Incorporated
B.5.2	Functional name of contact point	Clinical Trials and Medical Info
B.5.3	Address:
B.5.3.1	Street Address	50 Northern Avenue
B.5.3.2	Town/ city	Boston
B.5.3.3	Post code	MA 02210-1862
B.5.3.4	Country	United States
B.5.4	Telephone number	0018776348789
B.5.5	Fax number	0015105958183
B.5.6	E-mail	medicalinfo@vrtx.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	Trikafta
D.2.1.1.2	Name of the Marketing Authorisation holder	Vertex Pharmaceuticals Incorporated (MA n.: US NDA 212,273)
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	100 mg ELX/50 mg TEZ /75 mg IVA FDC
D.3.2	Product code	[ELX/TEZ/IVA]
D.3.4	Pharmaceutical form	Film-coated 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	Elexacaftor
D.3.9.1	CAS number	2216712-66-0
D.3.9.2	Current sponsor code	VX-445
D.3.9.3	Other descriptive name	VX-445
D.3.9.4	EV Substance Code	SUB185183
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	100
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tezacaftor
D.3.9.1	CAS number	1152311-62-0
D.3.9.2	Current sponsor code	VX-661
D.3.9.3	Other descriptive name	VX-661
D.3.9.4	EV Substance Code	SUB33135
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	50
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ivacaftor
D.3.9.1	CAS number	873054-44-5
D.3.9.2	Current sponsor code	VX-770
D.3.9.4	EV Substance Code	SUB33103
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	75
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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.IMP: 2
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	Kalydeco 150 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Vertex Pharmaceuticals (Europe) Limited (MA n.:EU/1/12/782/001-002)
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/3/08/556
D.3 Description of the IMP
D.3.1	Product name	Ivacaftor
D.3.2	Product code	[VX-770]
D.3.4	Pharmaceutical form	Film-coated 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	IVACAFTOR
D.3.9.1	CAS number	873054-44-5
D.3.9.2	Current sponsor code	VX-770
D.3.9.4	EV Substance Code	SUB33103
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	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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Cystic Fibrosis

Fibrosi Cistica

E.1.1.1

Medical condition in easily understood language

Cystic Fibrosis

Fibrosi Cistica

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10011762
E.1.2	Term	Cystic fibrosis
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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 evaluate the long-term safety and tolerability of VX-445 in TC with TEZ and IVA in subjects with CF who are homozygous or heterozygous for the F508del mutation

Valutare la sicurezza e la tollerabilità a lungo termine di VX-445 in tripla combinazione (TC) con tezacaftor (TEZ) e ivacaftor (IVA) in soggetti con fibrosi cistica (FC) omozigoti o eterozigoti per la mutazione F508del

E.2.2

Secondary objectives of the trial

To evaluate the long-term efficacy of VX-445 in TC with TEZ and IVA
To evaluate the pharmacodynamics (PD) of VX-445 in TC with TEZ and IVA

• Valutare l’efficacia a lungo termine di VX-445 in TC con TEZ e IVA
• Valutare la farmacodinamica (PD) di VX-445 in TC con TEZ e IVA

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject (or his or her legally appointed and authorized representative) will sign and date an informed consent form (ICF), and, when appropriate, an assent form.
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
3. Did not withdraw consent from a parent study.
4. Meets at least 1 of the following criteria:
Completed study drug treatment in a parent study.
Had study drug interruption(s) in a parent study, but completed study visits up to the last scheduled visit of the Treatment Period of a parent study.
5. Willing to remain on a stable CF treatment regimen (as defined in Section 9.5) through completion of study participation.

1. Il soggetto (o il suo rappresentante legalmente nominato e autorizzato) firmerà e la daterà un modulo di consenso informato (MCI) e, ove opportuno, un modulo di assenso.
2. Il soggetto è disposto e in grado di presentarsi alle visite programmate, di osservare il piano terapeutico e le restrizioni previste per lo studio, di sottoporsi a test di laboratorio, di osservare le linee guida in materia di contraccezione e le altre procedure dello studio.
3. Il soggetto non ha ritirato il proprio consenso a partecipare a uno studio iniziale.
4. Il soggetto soddisfa almeno uno dei seguenti criteri:
• Ha completato il trattamento con il farmaco dello studio nell'ambito di uno studio iniziale.
• Ha interrotto, una o più volte, il trattamento con il farmaco dello studio nell'ambito di uno studio iniziale, ma ha completato le visite dello studio fino all'ultima visita programmata del periodo di trattamento in uno studio iniziale.
5. Il soggetto deve essere disposto a seguire un regime terapeutico stabile per la fibrosi cistica (come definito nella Sezione 9.5) fino al completamento della sua partecipazione allo studio.

E.4

Principal exclusion criteria

1. History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject.
2. Pregnant and nursing females. Females of childbearing potential must have a negative pregnancy test at the Day 1 Visit before receiving the first dose of study drug.
3. History of drug intolerance in a parent study that would pose an additional risk to the subject in the opinion of the investigator. (e.g., subjects with a history of allergy or hypersensitivity to the study drug.)
4. Current participation in an investigational drug trial (other than a parent study). Participation in a non-interventional study (including observational studies, registry studies, and studies requiring blood collections without administration of study drug) and screening for another Vertex study is permitted.

1. Storia di qualsiasi comorbilità che, secondo lo sperimentatore, potrebbe confondere i risultati dello studio o rappresentare un ulteriore rischio per la somministrazione del farmaco dello studio al soggetto.
2. Donne in gravidanza e in allattamento. Le donne in età fertile devono risultare negative al test di gravidanza alla visita del Giorno 1 prima di ricevere la prima dose di farmaco dello studio.
3. Storia di intolleranza al farmaco nell'ambito di uno studio iniziale che, secondo lo sperimentatore, potrebbe rappresentare un ulteriore rischio per il soggetto. (Es. soggetti con una storia di allergia o ipersensibilità al farmaco dello studio.)
4. Partecipazione in corso a uno studio su un farmaco sperimentale (fatta eccezione per uno studio iniziale). E' consentita la partecipazione a uno studio non interventistico (inclusi studi osservazionali, studi di registro e studi che richiedono la raccolta di sangue senza la somministrazione del farmaco dello studio) e allo screening per un altro studio di Vertex.

E.5 End points

E.5.1

Primary end point(s)

Safety and tolerability of long-term treatment with VX-445 in TC with
TEZ and IVA based on adverse events (AEs), clinical laboratory values,
ECGs, vital signs, and pulse oximetry.

Sicurezza e tollerabilità del trattamento a lungo termine con VX-445 in TC con TEZ e IVA basate su eventi avversi (AE), valori clinici di laboratorio, ECG, segni vitali e pulsossimetria

E.5.1.1

Timepoint(s) of evaluation of this end point

from baseline through safety follow-up (up to 100 weeks)

dal basale fino al follow-up di sicurezza ( fino a 100 settimane)

E.5.2

Secondary end point(s)

Secondary Endpoints
Absolute change from baseline in ppFEV1
Absolute change in sweat chloride (SwCl)
Number of pulmonary exacerbations (PEx)
Time-to-first PEx
Absolute change in body mass index (BMI)
Absolute change in BMI z-score
Absolute change in body weight
Absolute change from baseline in CFQ-R respiratory domain score
Additional Endpoints
Absolute change in CFQ-R non-respiratory domain scores
Changes in inflammatory mediators
Changes in microbiology analysis

• Cambiamento assoluto dal basale della percentuale del valore previsto di volume espiratorio forzato in 1 secondo (ppFEV1)
• Cambiamento assoluto del cloruro nel sudore (SwCl)
• Numero di riacutizzazioni polmonari (PEx)
• Tempo alla prima PEx
• Cambiamento assoluto dell’indice di massa corporea (BMI)
• Cambiamento assoluto del punteggio z del BMI
• Cambiamento assoluto del peso corporeo
• Cambiamento assoluto dal basale del punteggio relativo al dominio respiratorio del questionario revisionato per la fibrosi cistica (CFQ-R)
Endpoint aggiuntivi
• Cambiamento assoluto dei punteggi relativi ai domini non respiratori del CFQ-R
• Cambiamenti nei mediatori infiammatori
• Cambiamenti nelle analisi microbiologiche

E.5.2.1

Timepoint(s) of evaluation of this end point

from baseline through last dose of study drug (up to 96 weeks)

dal basale fino all'ultima dose di farmaco dello studio ( fino a 96 settimane)

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

Yes

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

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

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

In aperto

Open

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

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

Information not present in EudraCT

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

Australia

Canada

United States

Austria

Belgium

Czechia

France

Germany

Greece

Italy

Netherlands

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

LSLV

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

Yes

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

370

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.7.1

Details of other specific vulnerable populations

minors 12-17 years

minori 12-17 anni

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

166

F.4.2.2

In the whole clinical trial

460

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

nessuno

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

2018-10-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-09-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-12-28

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IMP with orphan designation in the indication
Orphan Designation Number:
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