E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
APOL1-mediated Proteinuric Kidney Disease |
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E.1.1.1 | Medical condition in easily understood language |
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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 |
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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
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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
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E.2.3 | Trial contains a sub-study | No |
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 years at time of signing ICF and 65 years at Screening, inclusive. For Phase 3, subjects must be between the ages of 12 years at time of signing ICF and 65 years at Screening, inclusive. Up to approximately 15% of the total number of subjects planned for enrollment may be >61 to ≤65 years of age. 5. A BMI of 18.0 to 40.0 kg/m2, inclusive, and a total body weight ≥40 kg. 6. A UPCR of ≥0.7 g/g and <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 based on the Modified Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation without the race adjustment for subjects ≥18 years on Day 1 and CKD-EPI40 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), 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 immunosuppression (prednisone ≤ 10 mg or steroid equivalent, mycophenolate, tacrolimus or cyclosporine) must have been on a stable dose for 4 weeks before screening. |
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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. 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 < 10 mg/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 ≥150 mm Hg (systolic) or ≥90 mm Hg (diastolic), for subjects ≥18 years old and ≥140 mm Hg systolic and ≥90 mm Hg diastolic for subjects <18 years old. 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. |
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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)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- From baseline to Week 48. - From baseline to at least 2 years. |
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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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
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 | No |
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 |
Martinique |
Puerto Rico |
Brazil |
Canada |
United Kingdom |
United States |
Belgium |
France |
Netherlands |
Portugal |
Spain |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |