Clinical Trials Register

Summary
EudraCT Number:	2021-004762-35
Sponsor's Protocol Code Number:	VX21-147-301
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:
Date on which this record was first entered in the EudraCT database:	2022-09-21
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2021-004762-35

A.3

Full title of the trial

A Phase 2/3 Adaptive, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of VX-147 in Adult and Pediatric Subjects With APOL1-mediated Proteinuric Kidney Disease

A.3.1

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

Phase 2/3 Study of VX 147 in Patients With APOL1-mediated Kidney Disease.

A.4.1

Sponsor's protocol code number

VX21-147-301

A.5.4

Other Identifiers

Name:

IND Number

Number:

141671

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/043/2023

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	02210-1862
B.5.3.4	Country	United States
B.5.4	Telephone number	001877634 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	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/0000090156
D.3 Description of the IMP
D.3.1	Product name	VX-147
D.3.2	Product code	VX-147
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	inaxaplin
D.3.9.1	CAS number	2446816-88-0
D.3.9.2	Current sponsor code	VX-147
D.3.9.3	Other descriptive name	VX-147
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	15
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	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/0000090156
D.3 Description of the IMP
D.3.1	Product name	VX-147
D.3.2	Product code	VX-147
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.3.11 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
D.8 Placebo: 2
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

APOL1-mediated Proteinuric Kidney Disease

E.1.1.1

Medical condition in easily understood language

Chronic Kidney Disease

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	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10038359
E.1.2	Term	Renal and urinary disorders
E.1.2	System Organ Class	10038359 - Renal and urinary 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-147 to reduce proteinuria
- To evaluate the efficacy of VX 147 on renal function as measured by eGFR slope

E.2.2

Secondary objectives of the trial

- To evaluate the efficacy of VX-147 to decrease the risk of the composite clinical outcome
- To evaluate the safety and tolerability of VX-147
- To identify the optimal dose from Phase 2 to carry forward to Phase 3
- To characterize the plasma pharmacokinetics (PK) of VX-147
- To evaluate the acceptability of VX-147 in pediatric subjects

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject (or their legally appointed representative) will sign and date 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. Subject has an APOL1 genotype of G1/G1, G2/G2, or G1/G2 obtained with a Vertex designated investigational clinical study assay.
4. For Phase 2, subjects must be between the ages of 18 and 65 years at
time of signing ICF, inclusive. For Phase 3, subjects must be between the
ages of 12 and 65 years at time of signing first ICF, inclusive. Subjects must be <66 years of age at time of randomization. Pediatric subjects may be enrolled only after IDMC review of Phase 2 data is
completed, the Phase 3 dose is selected, and a recommendation by the
IDMC on the inclusion of pediatric subjects is made. Up to approximately 15% of the total
number of subjects planned for enrollment may be >61 to ≤65 years of
age at time of signing first ICF, inclusive.
5. A BMI of 18.0 to 45.0 kg/m2, inclusive, and a total body weight ≥40 kg.
6. A UPCR of ≥0.7 g/g to <10 g/g in the first morning void based on the average of 3 measurements collected on 3 separate days within a 7-day period, during the Screening Period.
7. Estimated glomerular filtration rate (eGFR) ≥25 to <75 mL/min/1.73 m2 during the Screening Period, based on the Modified Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation without the race adjustment for subjects ≥18 years on Day 1 and the Chronic Kidney
Disease in Children Under 25 (CKiD-U25) equation for subjects <18 years on Day 1.
8. On a stable, maximum tolerated labeled dose (at least 4 weeks before screening) of an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), but not both concomitantly, unless documented to be intolerant to ACE inhibitor/ARB.
9. Subjects taking sodium glucose co transporter 2 (SGLT2) inhibitors, mineralocorticoid receptor antagonists (MRAs) or permitted immunosuppressants (prednisone ≤ 10 mg or steroid equivalent, mycophenolate, tacrolimus, cyclosporine or azathioprine) must have been on a stable dose for 4 weeks before screening.

E.4

Principal exclusion criteria

1. History of any illness or any clinical condition that, in the opinion of the investigator, might 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 or bone marrow transplantation
• Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical carcinoma in situ (each being disease-free for the last 5 years)
• Clinically significant and active bacterial, viral, fungal, or parasitic infection
• Clinically significant liver disease
• Ongoing alcohol abuse or illicit drug use
• Any condition possibly affecting drug absorption (e.g., gastrectomy, gastrointestinal tract surgery except appendectomy and cholecystectomy)
• Stroke or myocardial infarction within 6 months before screening
2. Evidence of FSGS with a known cause other that due to APOL1 mutations. This includes but is not limited to the following:
• FSGS occurring concomitantly to administration of drugs known to induce FSGS, including but not limited to lithium, interferon, and bisphosphonates (e.g., pamidronate), or FSGS occurring in a subject using intravenous illicit drugs at the time of diagnosis.
• FSGS occurring in a subject with known sickle cell disease.
• Known genetic mutation other than APOL1 G1 or G2 that is associated with FSGS.
• Positive serology for human immunodeficiency virus-1 (HIV-1) or human immunodeficiency virus-2 (HIV-2).
3. History of diabetes mellitus. A diagnosis of prediabetes is permitted.
4. Known underlying cause of kidney disease in the opinion of the investigator including but not limited to biopsy-confirmed or suspected cases of the following: lupus nephritis, myeloma kidney, glomerular basement membrane disease, membranoproliferative glomerulitis, polycystic kidney disease, sickle cell disease, diabetic nephropathy, HIV nephropathy, autoimmune-induced nephropathy, amyloidosis, anti phospholipase A2 receptor-mediated nephropathy, monoclonal gammopathy related kidney disease, complement related glomerulonephritis, thrombotic microangiopathy or hemolytic uremic syndrome, Alport syndrome, immunoglobulin A (IgA) nephropathy, post streptococcal glomerulonephritis, or acute kidney injury within the past 3 months if eGFR is not at pre-injury baseline.
5. Abnormal laboratory values at screening that present a risk to subject safety in the opinion of the investigator, or any of the following abnormal laboratory values at screening:
• Serum albumin <1 g/dL
• Total bilirubin ≥1.5 × upper limit of normal (ULN)
• Aspartate transaminase (AST) or alanine transaminase (ALT) ≥2 × ULN
• Hemoglobin < 9 g/dL.
6. Risk factors for Torsade de Pointes (e.g., familial long QT syndrome, chronic hypokalemia, heart failure) or concomitant medications that prolong the QT/QTc interval or any history of cardiac disorders that, in the opinion of the investigator, might put the subject at risk or may confound the results of the study.
7. Any clinically significant ECG abnormality (as determined by the investigator) or median QTcF of triplicate standard 12-lead ECGs >450 msec at screening.
8. Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) RNA, or positive HIV test during screening.
9. Screening blood pressure, based on the average of 3 measurements,
of ≥180 mm Hg (systolic) or ≥100 mm Hg (diastolic).
10. Pregnant or nursing female subjects. Females of childbearing potential must have a negative pregnancy test at screening (serum test) and Day 1 (urine test).
11. Participation in another interventional clinical study within 28 days or 5 half-lives, whichever is longer, before the first dose of study drug.
12. Inability to adhere to the study restrictions defined within the protocol Section 9.5, including restrictions before the first dose of study drug for strong CYP3A4 inhibitors or moderate and strong inducers, cyclophosphamide, rituximab, or high dose systemic corticosteroids (>10 mg/day of prednisone or prednisone equivalent).
13. Subject, or close relative or a caregiver of the subject, is the investigator or a subinvestigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study at that site. An adult (aged 18 years or older) who is a relative of a study staff member may be enrolled in the study provided the following:
• 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.
14. Known hypersensitivity to investigational medicinal product or to any of its excipients.

E.5 End points

E.5.1

Primary end point(s)

- Percent change in UPCR from baseline at Week 48 (assessed at the IA)
- eGFR slope (with ≥48 weeks of eGFR data assessed at the IA and at least 2 years of eGFR data assessed at the final analysis)

E.5.1.1

Timepoint(s) of evaluation of this end point

- From baseline to Week 48.
- From baseline to at least 2 years.

E.5.2

Secondary end point(s)

- Time to composite clinical outcome of a sustained decline of ≥30% from baseline in estimated glomerular filtration rate (eGFR), the onset of end-stage kidney disease (ESKD; i.e., maintenance dialysis for ≥28 days, kidney transplantation, or a sustained eGFR of <15 mL/min/1.73 m2) or death. (Sustained is defined as confirmation by a second measurement after ≥28 days) (assessed at the final analysis)
- Safety and tolerability based on adverse events (AEs), clinical laboratory values (i.e., hematology, serum chemistry, coagulation studies, urinalysis), standard 12-lead ECGs, and vital signs
- Plasma PK parameters of VX-147
- Acceptability of tablet formulation of VX-147 in pediatric subjects using
the convenience domain of the Treatment Satisfaction Questionnaire for
Medication (TSQM) Version 1.4

E.5.2.1

Timepoint(s) of evaluation of this end point

Study end

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

Yes

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)

Yes

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.8.5

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

Colombia

Ghana

Guadeloupe

Puerto Rico

Brazil

Canada

United Kingdom

United States

Belgium

France

Netherlands

Portugal

Spain

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

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:

444

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

466

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

2022-11-21

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status

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Orphan Designation Number:
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