Genetics in medicine : official journal of the American College of Medical Genetics · 2025
Efficacy, safety, and tolerability of chenodeoxycholic acid (CDCA) in adult patients with cerebrotendinous xanthomatosis (RESTORE): A randomized withdrawal, double-blind, placebo-controlled, crossover phase-3 study.
СтатьяРандомизированное исследованиеКлиническое исследование III фазыПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Kisanuki Yaz Y, Nobrega Paulo R, Himes Ryan, Jayadev Suman, Bernat John A, Prakash Vikram, Gibson James B, Larson Austin, Sgobbi Paulo, DeBarber Andrea E, Murphy Edward, Fedor Brian, Wong Po Foo Cheryl, Dutta Rana, Imperiale Michael, Garner Will, Quan Joanne, Vig Pamela, Duell P Barton, Perez Sarah, Ramdhani Ritesh A, Saute Jonas Alex, RESTORE Study Group Collaborators
Аннотация
PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by pathogenic variants in CYP27A1, resulting in sterol 27-hydroxylase deficiency and accumulation of cholestanol and bile alcohols. Clinical features include cholestasis, diarrhea, cataracts, tendon xanthomas, and neurological deterioration. Chenodeoxycholic acid (CDCA) is the standard treatment for CTX. The effects of CDCA withdrawal on CTX biomarkers and safety in adult patients were evaluated.
METHODS: Patients (≥16 years) received CDCA 750-mg/day for 2 8-week open-label periods followed by double-blinded (DB) CDCA or placebo for 2 4-week periods. Key endpoints included changes from baseline in CTX biomarkers (23S-pentol, cholestanol, 7αC4, 7α12αC4) and the proportion of patients requiring CDCA rescue during DB periods.
RESULTS: CDCA withdrawal resulted in a 20-fold increase in 23S-pentol and increases in cholestanol (2.8-fold), 7αC4 (50-fold), and 7α12αC4 (14-fold). During the DB withdrawal periods, 61% of participants on placebo required rescue medication. CDCA treatment was well tolerated; the most common treatment-emergent adverse events were diarrhea and headache, most of them mild/moderate in severity and not considered treatment related.
CONCLUSION: CDCA withdrawal caused statistically significant increases in CTX biomarkers and necessitated rescue therapy in most participants. CDCA treatment is critical for control of biochemical abnormalities and helps avoid disease progression.
METHODS: Patients (≥16 years) received CDCA 750-mg/day for 2 8-week open-label periods followed by double-blinded (DB) CDCA or placebo for 2 4-week periods. Key endpoints included changes from baseline in CTX biomarkers (23S-pentol, cholestanol, 7αC4, 7α12αC4) and the proportion of patients requiring CDCA rescue during DB periods.
RESULTS: CDCA withdrawal resulted in a 20-fold increase in 23S-pentol and increases in cholestanol (2.8-fold), 7αC4 (50-fold), and 7α12αC4 (14-fold). During the DB withdrawal periods, 61% of participants on placebo required rescue medication. CDCA treatment was well tolerated; the most common treatment-emergent adverse events were diarrhea and headache, most of them mild/moderate in severity and not considered treatment related.
CONCLUSION: CDCA withdrawal caused statistically significant increases in CTX biomarkers and necessitated rescue therapy in most participants. CDCA treatment is critical for control of biochemical abnormalities and helps avoid disease progression.