Study of Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy.

Официальное название

A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Study to Evaluate the Efficacy and Safety of Iptacopan (LNP023) in Complement 3 Glomerulopathy.

Обзор

The Primary Completion Date and Study Completion Date have been updated to reflect completion of the adolescent cohort, which has been added to the protocol. The study is designed as a multicenter, randomized, double-blind, parallel group, placebo-controlled study to evaluate the efficacy and safety of iptacopan (LNP023) in complement 3 glomerulopathy.

Подробное описание

The purpose of this study is to evaluate the efficacy and safety of iptacopan compared to placebo and standard of care in patients with native C3G. CLNP023B12301 is a Phase 3 pivotal trial for registration of iptacopan in C3G. The study aims to determine the reduction in UPCR and improvement in eGFR in participants treated with iptacopan compared to placebo, as well as the proportion of participants who achieve a composite renal endpoint consisting of eGFR and UPCR elements. These effects of iptacopan in conjunction with increases in serum C3 levels will provide support for an iptacopan profile that includes stabilization of eGFR, clinically meaningful reductions in proteinuria and inhibition of the complement AP. Kidney biopsies will be performed in adult participants to evaluate histopathological improvements in immunofluorescence and light microscopy that support these functional benefits of iptacopan.

Вмешательства

• Препарат Placebo
  Placebo to iptacopan 200mg b.i.d. (Adults 200mg b.i.d; Adolescents 2x 100mg b.i.d)
• Препарат iptacopan
  iptacopan 200 mg b.i.d. (Adults 200mg b.i.d; Adolescents 2x 100mg b.i.d)

Первичные конечные точки

• Adult cohort: Log-transformed ratio to baseline in UPCR (sampled from a 24-hour urine collection) [Срок оценки: 6 months (double-blind)]
• Adolescent cohort: Log-transformed ratio to baseline in UPCR (sampled from a 24-hour urine collection) [Срок оценки: 6 months (double-blind)]
• Change from baseline in log-transformed UPCR at the 12-month visit (both study treatment arms). [Срок оценки: 12 months (double-blind and open-label)]
• Change in log-transformed UPCR from the 6-month visit to the 12-month visit in the placebo arm [Срок оценки: From month 6 to month 12 (open-label)]

Вторичные конечные точки (12)

• Change from baseline in eGFR. [Срок оценки: 6 months (double-blind)]
• Proportion of participants who meet the criteria for achieving a composite renal endpoint [Срок оценки: 6 months (double-blind)]
• Adult cohort: Change from baseline in disease total activity score in a renal biopsy. [Срок оценки: 6 months (double-blind)]
• Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score. [Срок оценки: 6 months (double-blind)]
• Number of participants with abnormal clinically significant vital signs, ECGs and safety laboratory measurements [Срок оценки: 6 months (double-blind)]
• Number of participants with study drug discontinuation due to an AE [Срок оценки: 6 months (double-blind)]
• Proportion of participants who meet the criteria for achieving a composite renal endpoint [Срок оценки: 12 months (double-blind and open-label)]
• Proportion of patients achieving a composite renal endpoint from the 6-month visit to the 12-month visit of the placebo arm [Срок оценки: month 6, month 12 (open-label)]
• Change from baseline in the total activity score in a renal biopsy at 12 months [Срок оценки: Baseline, month 12 (double-blind and open-label)]
• Change in the total activity score in a renal biopsy from the 6-month visit to the 12-month visit of the placebo arm. [Срок оценки: month 6, month 12 (open-label)]
• Change from baseline in the FACIT-Fatigue score at 12 months [Срок оценки: Baseline, month 12 (double-blind and open-label)]
• Change in the FACIT-Fatigue score from the 6-month visit to the 12-month visit of the placebo arm [Срок оценки: month 6, month 12 (open-label)]

Критерии участия

Критерии включения

• Male and female participants age ≥ 12 and ≤ 60 years at screening.
• Diagnosis of C3G as confirmed by renal biopsy within 12 months prior to enrollment in adults and within 3 years in adolescents.
• Prior to randomization, all participants must have been on a maximally recommended or tolerated dose of an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) for at least 90 days. The doses of other antiproteinuric medications including mycophenolic acid, corticosteroids and mineralocorticoid receptor antagonists should be stable for at least 90 days prior to randomization.
• Reduced serum C3 (defined as less than 0.85 x lower limit of the central laboratory normal range) at Screening.
• UPCR ≥ 1.0 g/g sampled from the first morning void urine sample at Day -75 and Day -15.
• Estimated GFR (using the CKD-EPI formula for ages ≥ 18 years and modified Schwartz formula for ages 12 to 17 years) or measured GFR ≥ 30 ml/min/1.73m2 at screening and Day -15.
• Mandatory vaccination against Neisseria meningitidis and Streptococcus pneumoniae prior to the start of study treatment.
• If not previously vaccinated or if a booster is required, vaccination against Haemophilus influenzae infections should be given, if available and according to local regulations, at least 2 weeks prior to the first study treatment administration. If study treatment has to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment should be initiated.

Критерии исключения

• Participants who have received any cell or organ transplantation, including a kidney transplantation.
• Rapidly progressive crescentic glomerulonephritis defined as a 50% decline in the eGFR within 3 months with renal biopsy findings of glomerular crescent formation seen in at least 50% of glomeruli.
• Renal biopsy showing interstitial fibrosis/tubular atrophy (IF/TA) of more than 50%
• Monoclonal gammopathy of undetermined significance (MGUS) confirmed by the measurement of serum free light chains or other investigation as per local standard of care.
• Participants with an active systemic bacterial, viral or fungal infection within 14 days prior to study treatment administration
• The presence of fever ≥ 38°C (100.4°F) within 7 days prior to study treatment administration.
• A history of recurrent invasive infections caused by encapsulated organisms, e.g., N. meningitidis and S. pneumoniae.
• The use of inhibitors of complement factors (e.g., Factor B, Factor D, C3 inhibitors, anti C5 antibodies, C5a receptor antagonists) within 6 months prior to the Screening visit.
• The use of immunosuppressants (except mycophenolic acids), cyclophosphamide or systemic corticosteroids at a dose >7.5 mg/day (or equivalent for a similar medication) within 90 days of study drug administration.
• Acute post-infectious glomerulonephritis at screening based upon the opinion of the investigator.

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

Тройное слепое

Основная цель

Лечение

Центры проведения

США · 13 центров

• Childrens Hospital Colorado — Aurora
• Nicklaus Childrens Hospital — Miami
• Georgia Nephrology Research Inst — Lawrenceville
• IN University School of Med — Indianapolis
• University of Iowa Health Care — Iowa City
• University of Iowa Health Care — Iowa City
• Johns Hopkins Hospital — Baltimore
• Brigham and Womens Hosp Harvard Med School — Boston
• … и ещё 5 центров

Бразилия · 8 центров

• Novartis Investigative Site — Belo Horizonte
• Novartis Investigative Site — Recife
• Novartis Investigative Site — Passo Fundo
• Novartis Investigative Site — Joinville
• Novartis Investigative Site — Santo André
• Novartis Investigative Site — São Paulo
• Novartis Investigative Site — São Paulo
• Novartis Investigative Site — Salvador

Германия · 8 центров

• Novartis Investigative Site — Cologne
• Novartis Investigative Site — Aachen
• Novartis Investigative Site — Erlangen
• Novartis Investigative Site — Essen
• Novartis Investigative Site — Hamburg
• Novartis Investigative Site — Hanover
• Novartis Investigative Site — Heidelberg
• Novartis Investigative Site — Mainz

Япония · 6 центров

• Novartis Investigative Site — Nagoya
• Novartis Investigative Site — Asahikawa
• Novartis Investigative Site — Sapporo
• Novartis Investigative Site — Takatsuki
• Novartis Investigative Site — Ohtsu
• Novartis Investigative Site — Niigata

Испания · 6 центров

• Novartis Investigative Site — Barcelona
• Novartis Investigative Site — Port de Sagunt
• Novartis Investigative Site — Barcelona
• Novartis Investigative Site — Madrid
• Novartis Investigative Site — Málaga
• Novartis Investigative Site — Seville

Китай · 5 центров

• Novartis Investigative Site — Гуанчжоу
• Novartis Investigative Site — Ухань
• Novartis Investigative Site — Пекин
• Novartis Investigative Site — Пекин
• Novartis Investigative Site — Шанхай

Франция · 5 центров

• Novartis Investigative Site — Lille
• Novartis Investigative Site — Marseille
• Novartis Investigative Site — Montpellier
• Novartis Investigative Site — Paris
• Novartis Investigative Site — Paris

Индия · 5 центров

• Novartis Investigative Site — New Delhi
• Novartis Investigative Site — New Delhi
• Novartis Investigative Site — Hyderabad
• Novartis Investigative Site — Lucknow
• Novartis Investigative Site — Dehradun

Turkey (Türkiye) · 5 центров

• Novartis Investigative Site — Istanbul
• Novartis Investigative Site — Istanbul
• … и ещё 3 центра

Греция · 4 центра

• Novartis Investigative Site — Athens
• Novartis Investigative Site — Heraklion Crete.
• Novartis Investigative Site — Thessaloniki
• Novartis Investigative Site — Thessaloniki

Великобритания · 4 центра

Список центров уточняется — проверьте первичный протокол.

Аргентина · 3 центра

• Novartis Investigative Site — Córdoba
• Novartis Investigative Site — Buenos Aires
• Novartis Investigative Site — CABA

Канада · 3 центра

• Novartis Investigative Site — London
• Novartis Investigative Site — Toronto
• Novartis Investigative Site — Montreal

Италия · 3 центра

• Novartis Investigative Site — Ranica
• Novartis Investigative Site — Milan
• Novartis Investigative Site — Roma

Бельгия · 2 центра

• Novartis Investigative Site — Edegem
• Novartis Investigative Site — Leuven

Израиль · 2 центра

• Novartis Investigative Site — Petah Tikva
• Novartis Investigative Site — Petah Tikva

Нидерланды · 2 центра

• Novartis Investigative Site — Nijmegen
• Novartis Investigative Site — Leiden

Швейцария · 2 центра

• Novartis Investigative Site — Bern
• Novartis Investigative Site — Lausanne

Чехия · 1 центр

• Novartis Investigative Site — Prague

Публикации

• Kavanagh D, Bomback AS, Vivarelli M, Nester CM, Remuzzi G, Zhao MH, Wong EKS, Wang Y, Krishnan I, Schuhmann I, Trapani AJ, Webb NJA, Meier M, Israni RK, Smith RJH; APPEAR-C3G investigators. Oral iptacopan therapy in patients with C3 glomerulopathy: a randomised, double-blind, parallel group, multicentre, placebo-controlled, phase 3 study. Lancet. 2025 Oct 11;406(10512):1587-1598. doi: 10.1016/S014 PMID 41016405

Идентификаторы

NCT: NCT04817618 · CLNP023B12301 · 2020-004589-21

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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