Clinical Trials Register

Summary
EudraCT Number:	2019-004881-16
Sponsor's Protocol Code Number:	VX19-864-101
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-07-10
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

Germany - BfArM

A.2

EudraCT number

2019-004881-16

A.3

Full title of the trial

A Phase 2, Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of VX-864 in PiZZ Subjects

A.3.1

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

Evaluation of the Efficacy and Safety of VX-864 in Subjects With the PiZZ Genotype

A.4.1

Sponsor's protocol code number

VX19-864-101

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	001877 634 8789
B.5.5	Fax number	001510595 8183
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	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	VX864
D.3.2	Product code	VX864
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	VX864
D.3.9.2	Current sponsor code	VX-864
D.3.9.3	Other descriptive name	VX-864
D.3.9.4	EV Substance Code	SUB199437
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	250
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.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	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	VX864
D.3.2	Product code	VX864
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	VX864
D.3.9.2	Current sponsor code	VX-864
D.3.9.3	Other descriptive name	VX-864
D.3.9.4	EV Substance Code	SUB199437
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.3.11 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

Alpha 1 antitrypsin deficiency in Subjects With the PiZZ Genotype

E.1.1.1

Medical condition in easily understood language

Alpha 1 antitrypsin deficiency

E.1.1.2

Therapeutic area

Body processes [G] - Genetic Phenomena [G05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.1
E.1.2	Level	PT
E.1.2	Classification code	10083869
E.1.2	Term	Alpha-1 antitrypsin deficiency
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 efficacy of VX-864 in PiZZ subjects as measured by plasma functional AAT levels
• To evaluate the safety and tolerability of VX-864 in PiZZ subjects

E.2.2

Secondary objectives of the trial

• To evaluate the efficacy of VX-864 in PiZZ subjects as measured by plasma antigenic AAT levels
• To evaluate the pharmacokinetics (PK) of VX-864 in PiZZ subjects

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject will sign and date an informed consent form (ICF).
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions,
laboratory tests, highly effective methods of contraception (or
qualify for a waiver for highly effective methods of contraception; Section 11.5.6.1), and other study procedures.
3. Subjects will be 18 through 80 years of age, inclusive, at the time of signing of the ICF.
4. All female subjects must have a negative pregnancy test at screening (serum test). Premenopausal female subjects of child-bearing potential must also have a negative pregnancy test on Day 1 (urine test) and must not be breastfeeding or become pregnant during the study or within 90 days after the last study drug dose.
5. Body mass index (BMI) of 18.0 to 35.0 kg/m2, inclusive.
6. Subjects must have a PiZZ genotype confirmed at screening.
NOTE: PiZZ genotype must be tested at the central laboratory. Historical genotype results can be used to determine eligibility if they were obtained as part of a different Vertex study. In addition, if the screening PiZZ genotype result is not received before randomization, a previous non-Vertex PiZZ genotype laboratory report (approved by the medical monitor or designee) may be used to establish provisional eligibility. Subjects who have been randomized and whose screening genotype subsequently does not confirm study eligibility must be discontinued from the study.
7. Plasma antigenic AAT level <8 ìM during screening.
NOTE: For subjects who have been on augmentation therapy at any time, results used to
confirm eligibility must be drawn >42 days after the last dose of augmentation therapy.
Antigenic AAT levels must be obtained from the central laboratory and results confirmed
before randomization.
8. Willing to remain off of augmentation therapy from >42 days before antigenic AAT levels
are obtained for eligibility through the last Safety Follow-Up Visit.

E.4

Principal exclusion criteria

1. History or presence of any illness or clinical condition that, in the opinion of the investigator, might affect the subject's safety or compliance or confound the results of the study or pose an additional risk in administering study drug(s) to the subject. This includes, but is not limited to, the following:
• Solid organ, lung, or hematological transplantation or is currently on a transplant list
• Subjects who have undergone gastrectomy or other gastrointestinal tract surgery, except appendectomy, cholecystectomy, and hemorrhoid surgery.
• Cancer, except for squamous cell skin cancer, basal cell skin cancer, Stage 0 cervical carcinoma in situ, and Stage 0 or 1 melanoma (all 4 with no recurrence during the last 5 years)
2. History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year before screening, defined as more than 14 drinks/week for females or 21 drinks/week for males
3. Illegal drug use within 1 year before screening as deemed by the investigator, including but not limited to cocaine, heroin, and other opiates.
4. Ongoing or prior participation in a study of an investigational treatment within 28 days or
5 terminal half-lives (whichever is longer) before screening.
5. History of use of gene therapy or RNAi therapy at any time previously.
6. Use of oral corticosteroids (at any dose) for a duration of greater than 3 months at any time
within the 3 months before screening.
7. A post-bronchodilator forced expiratory volume in 1 second (FEV1) value <30% of predicted mean for age, sex, and height (equations of the Global Lung Function Initiative [GLI]) during screening. Post-bronchodilator spirometry measurements must meet American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria for acceptability and repeatability.
8. All clinically important pulmonary disease other than AATD-related pulmonary disease, including but not limited to interstitial lung disease, cystic fibrosis, pulmonary hypertension with or without cor pulmonale, history of pulmonary embolism, or malignant lung cancer.
9. Unstable AATD-related COPD as deemed by the investigator.
10. Documented chronic need for positive airway pressure therapy beyond nocturnal use.
11. Documented medical history or diagnosis of clinically evident liver disease including but not limited to a prior diagnosis of hepatitis of any etiology, cirrhosis, portal hypertension, or confirmed or suspected esophageal varices.
12. Any of the following abnormal laboratory values at screening:
. Platelet count <150 ~ 109/L.
. Albumin .3.5 g/dL
. International normalized ratio .1.2
. Hemoglobin <10 g/dL
. Total bilirubin > upper limit of normal (ULN)
. Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase
(GGT), or alkaline phosphatase (ALP) >2 ~ ULN
. Estimated glomerular filtration rate (eGFR) .30 mL/min/1.73 m2
13. Risk factors for Torsade de Pointes or concomitant medications that prolong the QT/QTc interval or any history of unstable cardiac disorder that, in the opinion of the investigator, might put the subject at risk or may confound the results of the study.
14. Any clinically significant ECG abnormality or median QTcF of triplicate standard 12-lead ECGs >450 msec at screening.
15. History of Gilbert's Syndrome.
16. Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) RNA, or HIV-1
and HIV-2 antibodies during screening.
17. Use of the substances, activities, or devices during the time periods indicated in Section 9.5.
18. Cigarette smoking during the past 6 months or a positive cotinine test at screening that is due
to smoking or an electronic nicotine delivery system. Positive cotinine test due to nicotine
replacement therapy for the purposes of smoking cessation, as attested by the investigator, is
permitted.
19. Male subjects who plan to donate sperm or who have a female partner who is pregnant,
breastfeeding, or planning to become pregnant during the study or within 90 days after the
last study drug dose.
20. The subject or a close relative of the subject is the investigator or a sub-investigator, research
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of
the study. An adult (18 years of age or older) who is a relative of a study staff member may
be enrolled in the study provided that
• the adult lives independently of and does not reside with the study staff member, and
• the adult participates in the study at a site other than the site at which the family member
is employed.
21. Hypersensitivity to any component of the investigational drug product or placebo (e.g., lactose).
22. Subjects for whom discontinuation of augmentation therapy is not considered to be in their best interest, based on the clinical judgement of the treating physician.

E.5 End points

E.5.1

Primary end point(s)

• Change from baseline in plasma functional AAT levels at Day 28
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, standard 12 lead ECGs, vital signs and pulse oximetry.

E.5.1.1

Timepoint(s) of evaluation of this end point

Plasma Functional AAT levels: From base line to day 28
Safety and tolerability assessment: From baseline to Safety follow up visit

E.5.2

Secondary end point(s)

• Change from baseline in plasma antigenic AAT levels at Day 28
• PK parameters of VX-864 derived from plasma concentration time data

E.5.2.1

Timepoint(s) of evaluation of this end point

Change in AAT Levels: From baseline to Day 28
PK Parameters: From baseline to safety follow up visit

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

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

Yes

E.6.13.1

Other scope of the trial description

Tolerability

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Canada

United States

Germany

Ireland

Sweden

United Kingdom

E.8.7

Trial has a data monitoring committee

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)

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

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

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

2020-09-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-07-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-05-04

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