A Phase 3 Study of Zodasiran in Adolescent and Adult Subjects With Homozygous Familial Hypercholesterolemia (YOSEMITE)

Официальное название

Phase 3 Study to Evaluate the Efficacy and Safety of Zodasiran in Adolescent and Adult Subjects With Homozygous Familial Hypercholesterolemia (YOSEMITE)

Обзор

This multicenter, randomized, placebo-controlled study will evaluate the efficacy and safety of zodasiran subcutaneous (SC) injection in subjects 12 years of age and older with genetically or clinically diagnosed Homozygous familial hypercholesterolemia (HoFH). After completion of the double blind (DB) treatment period subjects will be eligible to continue in the optional open-label extension (OLE) period of the study. All placebo subjects who opt to continue will transition to active drug during the OLE Period.

Вмешательства

• Препарат zodasiran Injection
  ARO-ANG3 Injection
• Препарат Placebo
  sterile normal saline (0.9% NaCl)

Первичные конечные точки

• Percent Change from Baseline to Month 12 in Fasting Low Density Lipoprotein Cholesterol (LDL-C) (Randomized period) [Срок оценки: Baseline, Month 12]

Вторичные конечные точки (12)

• Change and Percent Change from Baseline to Month 12 in Fasting Apolipoprotein B (ApoB) (Randomized Period) [Срок оценки: Baseline, Month 12]
• Change and Percent Change from Baseline to Month 12 in Fasting Non-High Density Lipoprotein Cholesterol (non-HDL-C) (Randomized Period) [Срок оценки: Baseline, Month 12]
• Change from Baseline to Month 12 in Fasting LDL-C (Randomized Period) [Срок оценки: Baseline, Month 12]
• Area Under the Plasma Concentration Versus the Time Curve (AUC) from Baseline to Month 12 for Fasting LDL-C (Randomized Period) [Срок оценки: Baseline, Month 12]
• Change and Percent Change from Baseline to Month 12 in Fasting Triglycerides (TGs) (Randomized Period) [Срок оценки: Baseline, Month 12]
• Change and Percent Change from Baseline to Month 12 in Fasting Angiopoietin-like Protein 3 (ANGPTL3) (Randomized Period) [Срок оценки: Baseline, Month 12]
• Change and Percent Change from Baseline to Month 12 in Fasting Total Cholesterol (Randomized Period) [Срок оценки: Baseline, Month 12]
• Change and Percent Change from Baseline to Month 12 in Fasting High-Density Lipoprotein Cholesterol (HDL-C) (Randomized Period) [Срок оценки: Baseline, Month 12]
• Proportion of Participants who Meet European Union (EU) LDL-C Apheresis Eligibility Criteria (per German Apheresis Working Group) at Month 12 (Randomized Period) [Срок оценки: Month 12]
• Proportion of Participants who Meet United States (US) Apheresis Eligibility Criteria (per National Lipid Association) at Month 12 (Randomized Period) [Срок оценки: Month 12]
• Proportion of Participants with Fasting LDL-C <100 mg/dL (2.6 mmol/L) at Month 12 (Randomized Period) [Срок оценки: Month 12]
• Change from Baseline in Fasting LDL-C Over Time (Randomized Period) [Срок оценки: Baseline, Day 1, Months 1, 2, 3, 4.5, 6, 7.5, 9, 10.5, and 12]

Критерии участия

Критерии включения

• Age ≥12 years, non pregnant, non lactating, do not plan to become pregnant during the study
• Body weight ≥35 kg at Screening as patients could theoretically be <35 kg as the study continues.
• HoFH based on a supportive genetic test or a clinical diagnosis (total cholesterol >500 mg/dL\[13 mmol/L\] OR treated LDL-C concentration of ≥300 mg/dL \[≥8 mmol/L\] either accompanied by TGs <300 mg/dL \[3.4 mmol/L\] AND both parents with documented total cholesterol >250 mg/dL \[6.5 mmol/L\] OR cutaneous or tendinous xanthoma before 10 years of age)
• LDL-C ≥70 mg/dL (1.8 mmol/L). For adolescents 12 to <18 years of age, screening LDL-C ≥116 mg/dL (3 mmol/L).
• Hemoglobin A1c (HbA1c) ≤9.5%
• Total bilirubin <2xULN, unless in previously confirmed cases of Gilbert's syndrome
• Alanine aminotransferase or aspartate aminotransferase <3×ULN
• On standard of care, maximally tolerated lipid-lowering therapy to include a maximally tolerated statin, ezetimibe, and a PCSK9 inhibitor

Критерии исключения

• Use of a hepatocyte-targeted siRNA within 365 days before Day 1 (except inclisiran, which is permitted; administration of inclisiran and study drug must be separated by at least 4 weeks)
• Use of an antisense oligonucleotide molecule within 3 months before Day 1 (except inclisiran, which is permitted; administration of inclisiran and study drug must be separated by at least 4 weeks)
• Use of evinacumab within 3 months before Day 1. Evinacumab use is prohibited during the study.
• Non-response to evinacumab, defined as LDL-C reduction <15% from baseline after 2 doses
• Use of any other investigational agent or device within 30 days or 5 half-lives (whichever is longer) before Day 1
• Use of systemic corticosteroids (unless used as replacement therapy for pituitary/adrenal disease with a stable regimen)
• Estimated glomerular filtration rate <30 mL/min

NOTE: Additional Inclusion/exclusion criteria may apply per protocol

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Япония · 6 центров

• Research Site 26 — Kanazawa
• Research Site 27 — Suita
• Research Site 20 — Fukushima
• Research Site 16 — Okayama
• Research Site 22 — Saitama
• Research Site 25 — Tokyo

США · 4 центра

• Research Site 7 — Park Ridge
• Research Site 2 — New York
• Research Site 1 — Cincinnati
• Research Site 14 — Pittsburgh

Австралия · 4 центра

• Research Site 13 — Camperdown
• Research Site 9 — Saint Leonards
• Research Site 21 — Heidelberg
• Research Site 3 — Nedlands

Австрия · 4 центра

• Research Site 40 — Innsbruck
• Research Site 39 — Linz
• Research Site 42 — Vienna
• Research Site 37 — Vienna

Канада · 3 центра

• Research Site 5 — Vancouver
• Research Site 6 — Chicoutimi
• Research Site 4 — Québec

Грузия · 3 центра

• Research Site 17 — Tbilisi
• Research Site 18 — Tbilisi
• Research Site 19 — Tbilisi

Испания · 3 центра

• Research Site 43 — Barcelona
• Research Site 28 — Córdoba
• Research Site 29 — Madrid

Turkey (Türkiye) · 3 центра

• Research Site 36 — Afyonkarahisar
• Research Site 41 — Bornova/Izmir
• Research Site 38 — Melikgazi/Kayseri

Бельгия · 2 центра

• Research Site 33 — La Louvière
• Research Site 34 — Leuven

Израиль · 2 центра

• Research Site 10 — Jerusalem
• Research Site 15 — Tel Litwinsky

ЮАР · 2 центра

• Research Site 11 — Parktown
• Research Site 8 — Cape Town

Бразилия · 1 центр

• Research Site 24 — Cerqueira César

Чехия · 1 центр

• Research Site 30 — Hradec Králové

Франция · 1 центр

• Research Site 23 — Paris

Германия · 1 центр

• Research Site 35 — Berlin

Новая Зеландия · 1 центр

• Research Site 12 — Christchurch

Саудовская Аравия · 1 центр

• Research Site 31 — Riyadh

Швеция · 1 центр

• Research Site 32 — Gothenburg

Идентификаторы

NCT: NCT07037771 · AROANG3-3001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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