| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| APOL1-mediated Proteinuric Kidney Disease |
| Enfermedad renal proteinúrica mediada por APOL1 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Kidney Disease |
| Enfermedad renal crónica |
|
| 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 |
• Evaluar la eficacia de VX-147 para reducir la proteinuria
• Evaluar la eficacia de VX‐147 sobre la función renal medida por la pendiente de la TFGe |
|
| 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 |
• Evaluar la eficacia de VX-147 para reducir el riesgo del resultado clínico compuesto
• Evaluar la seguridad y tolerabilidad de VX-147
• Identificar la dosis óptima de la fase II para continuar a la fase III
• Caracterizar la farmacocinética (FC) plasmática de VX-147 |
|
| 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. Subjects must be between the ages of 18 and 60 years, inclusive.
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.
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 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. |
1. El sujeto (o su representante legal) firmará y fechará el formulario de consentimiento informado y cuando sea necesario, un formulario de asentimiento.
2. Capaz y dispuesto a cumplir con las visitas programadas, el plan de tratamiento, las restricciones del estudio, evaluaciones de laboratorio, guías sobre anticoncepción y demás procedimientos del estudio.
3. El sujeto tien genopo APOL1 de G1/G1, G2/G2 o G1/G2 según test clínico designado por Vertex
4. Los sujetos deben tener entre 18 y 60 años incluídos
5. IMC entre 18.0 y 40.0 Kg/m2 incluidos y peso corporal total ≥40 kg
6. UPCR de entre ≥0.7 g/g y <10 g/g a primera hora de la mañana en base a una media de 3 mediciones tomadas en 3 días distintos durante un periodo de 7 días, durante el periodo de selección.
7. Tasa de filtración glomerular (eGFR) de entre ≥25 y <75 mL/min/1.73 m2 en base a la ecuaciuón CKD-EPI sin el ajuste por raza
8. Con dosis estable de un inhibidor de la encima conversora de la angiotensina (ACE) máxima tolerada (durante al menos las 4 semanas anteriores a la selección) o un bloqueador del receptor de la angiotensina (ARB), a menos que esté documentada la intolerancia a los inhibidores ACE/ARB.
9. Los sujetos que toman un inhibidor del co-transportador de la glucosa de sodio 2 (SGLT2) o inmunosupresores permitidos (prednisona ≤ 10 mg o esteroide equivalente, micofenolato, tacrolimus o ciclosporina) deben permanecer en dosis estable durante las 4 semanas anteriores a la selección. |
|
| 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. Diagnosis 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 ≥150 mm Hg (systolic) or ≥90 mm Hg (diastolic), based on the average of 3 measurements.
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 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. |
1. Cualquier antecedente de enfermedad o condición que en opinion del investigador pueda confundir los resultados del estudio o suponer un riesgo adicional para administrar al sujeto la medicación en estudio. Incluyendo pero sin limitarse a:
• Trasplante de órgano sólido o médula ósea
• Cáncer, excepto cáncer de células epiteliales escamosas, basales o carcinoma cervical in situ grado 0 (todos superados durante al menos 5 años)
• Infección bacterial, viral o por hongos o parásitos activa y clínicamente significante
• Enfermedad hepática clinicamente significativa
• Abuso de alcohol o uso de drogas ilegales
• Cualquier condición que pueda afectar la absorción de la medicación (p.ej.: gastrectomía, cirugía del tracto gastrointestinal excepto apendicetomia y colicestomía)
• Ictus o infarto de miocardio los 6 meses anteriores a la selección
2. Evidencia de FSGS con causa conocida distinta a las mutaciones en APOL1. Esto incluye pero no se limita a:
• FSGS concomitante a la administración de inductores de la FSGS incluyendo pero no limitados a litio, interferón y bifosfonatos (p.ej.: pamidronato) o FSGS que ocurra mientras el sujeto se inyecta drogas ilegales en vena en el momento del diagnóstico.
• FSGS con enfermedad de células falciformes conocida
• Mutación genética conocida distinta a APL1 G1 o G2 asociada a FSGS
• Positivo en serología para VIH1 o VIH2
3. Diagnóstico de diabetes mellitus
4. Causas subyacentes para padecer enfermedad renal en opinión del investigador, incluyendo sin limitarse casos confirmados mediante biopsia o bien casos sospechados de: nefritis lúpica, melanoma de riñón, enfermedad glomerular de la membrana basal, glomerulitis membranoproliferativa, enfermedad del riñón poliquística, enfermedad de células falciformes, nefropatía diabética, nefropatía por VIH, nefropatía autoinmune, amiloidosis, nefropatía mediada por el receptor fosfolipasa A2, enfermedad renal por gamopatía monoclonal, glomerulonefritis asociadas a alteraciones del complemento, microangiopatía trombótica o síndrome hemolítico urémico, síndrome de Alport, nefropatía de la inmunoglobulina A (IgA), glomerulonefritis post-estreptocócica o daño renal agudo los últimos 3 meses si la eGFR no es una pre-enfermedad de base.
5. Resultados de laboratorio anormales durante la selección que indican riesgo para la seguridad del paciente en opinión del investigador o cualquiera de los siguientes:
• Albúmina en suero <1 g/dL
• Bilirrubina total ≥1.5 del límite normal superior
• Transaminasa aspartato (AST) o tranaminasa alanina (ALT) ≥2 del límite normal superior
• Hemoglobina <10 mg/dL
6. Factores de riesgo para Torsa de Pointes (p.ej.: síndrome familiar de QC prolongado, hipocalemia crónica, fallo cardíaco) o medicación concomitante que prolongue el intervalo QT/QCc o antecedentes de desórdenes cardíacos que en opinión del investigador pudieran poner en riesgo al sujeto o confundir los resultados del estudio.
7. Cualquier anormalidad clínica significativa en el ECG (según determine el investigador) o mediana de QTcF que triplique los 450 mseg estándar de un ECG de 12 derivaciones en la selección.
8. Positivo para antígeno de superficie de hepatitis B (HBsAg), ARN de virus de hepatitis C o VIH durante la selección.
9. Presión sanguínea sistólica ≥150 mm Hg o diastólica ≥90 mm Hg en selección, en base a la media de 3 mediciones.
10. Mujeres embarazadas o lactantes. Las mujeres fértiles deben tener un test de embarazo negativo en suero durante la selección y en orina en el día 1.
11. Participar en otro estudio clínico intervencionista los 28 días o 5 semividas anteriores a la primera dosis de la medicación en estudio, lo que sea más largo.
12. Imposibilidad de cumplir con las restricciones del estudio definidas en la sección 9.5 del protocolo incluyendo las restricciones necesarias antes de la primera dosis para inhibidores potentes de CYP3A4 o inductores moderados o fuertes, ciclofosfamida, rituximab o conticoesteroides en dosis altas (<10 mg/día de prednisona o equivalente).
13. El sujeto o un familiar cercano del mismo es el investigador u un miembro del equipo investigador directamente implicado en el estudio en el centro. Los adultos parientes de un miembro de estudio pueden incluirse siempre que:
• Vive de manera independiente y no con el miembro del equipo y
• Participa en el estudio en un centro distinto en el que trabaja su familiar
14. Hipersensibilidad conocida al producto en investigación o cualquiera de sus excipientes. |
|
| 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) |
• Cambio porcentual en el CPCO con respecto al inicio hasta la semana 48 (evaluado en el AP)
• Pendiente del TFGe (con ≥48 semanas de datos del TFGe evaluados en el AP y al menos 2 años de datos de TFGe evaluados en el análisis final) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- From baseline to Week 48.
- From baseline to at least 2 years. |
- Desde la selección a la semana 48
- Desde la selección hasta al menos 2 años |
|
| 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 |
• Tiempo hasta el resultado clínico compuesto de una disminución mantenida de ≥30% desde el inicio en el índice de filtración glomerular estimado (TFGe), la aparición de enfermedad renal terminal (ERT; es decir, diálisis de mantenimiento durante ≥28 días, trasplante renal o un TFGe mantenido de <15 ml/min/1,73 m2) o muerte. (El mantenimiento se define como la confirmación mediante una segunda medición después de ≥28 días) (evaluado en el análisis final)
• Seguridad y tolerabilidad basadas en los acontecimientos adversos (AA), valores analíticos clínicos (es decir, hematología, bioquímica sérica, estudios de coagulación, análisis de orina), ECG de 12 derivaciones estándar y constantes vitales
• Parámetros FC plasmáticos de VX-147 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Study end |
| Fin del estudio |
|
| 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
| No |
| 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 | 4 |
| 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 |
| Brazil |
| Canada |
| Martinique |
| Puerto Rico |
| United States |
| France |
| Netherlands |
| Spain |
| Belgium |
| Portugal |
| 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
|
| LVLS |
| Última visita del último sujeto |
|
| 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 |
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