Avaliação do Maralixibat no Prurido Associado à Doença Hepática Colestática Geral (EXPAND)
Estudo randomizado duplo-cego controlado por placebo de fase 3 para avaliar a eficácia e segurança do maralixibat no tratamento de participantes com prurido colestático
The purpose of this study is to determine whether the investigational treatment (maralixibat) is safe and effective in pediatric and adult participants who have cholestatic liver disease with pruritus that has been refractory to other therapies, and who have no other treatment options.
Visão geral do estudo
Status
Intervenção / Tratamento
Descrição detalhada
This study will be conducted in multiple sites in North America, Europe, Middle East and South America.
Tipo de estudo
Inscrição (Estimado)
Estágio
- Fase 3
Contactos e Locais
Locais de estudo
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Hamburg, Alemanha
- Universitätsklinikum Hamburg Eppendorf - Klinik für Kinder- und Jugendmedizin
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Brasília, Brasil
- Hospital de Criança de Brasília (HCB)
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Porto Alegre, Brasil
- Hospital da Criança Santo Antonio
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São Paulo, Brasil
- Hospital Sírio-Libanês
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Alberta
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Edmonton, Alberta, Canadá, T6G 2B7
- Stollery Children's Hospital
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Barcelona, Espanha
- Hospital Universitario Vall d'Hebron
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Madrid, Espanha
- Hospital Universitario La Paz
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California
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Los Angeles, California, Estados Unidos, 90027
- Children's Hospital Los Angeles (CHLA)
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Palo Alto, California, Estados Unidos, 94304
- Stanford Children's Health in Palo Alto
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Illinois
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Chicago, Illinois, Estados Unidos, 60611
- Lurie Children's Hospital
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New York
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New York, New York, Estados Unidos, 10016
- NYU Langone Health
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New York, New York, Estados Unidos, 10032
- Morgan Stanley Children's Hospital - NewYork Presbyterian
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Ohio
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Cincinnati, Ohio, Estados Unidos, 45229
- Cincinnati Children's Hospital Medical Center
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Texas
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Houston, Texas, Estados Unidos, 77030
- Baylor College of Medicine
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Utah
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Salt Lake City, Utah, Estados Unidos, 84112
- University of Utah
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Marseille, França, 13005
- Hôpitaux Universitaires de Marseille Timone
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Paris, França
- Hôpital Kremlin Bicêtre
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Bergamo, Itália, 24127
- Azienda Ospedaliera Papa Giovanni XXIII
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Palermo, Itália, 90127
- ISMETT - Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione
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Rome, Itália, 00165
- Ospedale Pediatrico Bambino Gesu
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Beirut, Líbano
- Hotel Dieu de France
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Warsaw, Polônia
- Instytut Pomnik Centrum Zdrowia Dziecka
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London, Reino Unido
- King's College Hospital NHS Foundation Trust
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
Inclusion Criteria:
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Informed consent and assent (as applicable)
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Age ≥6 months at time of baseline visit
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Diagnosis of a rare cholestatic liver disease with cholestatic pruritus based on the following:
- Chronic liver biochemical abnormalities (>90 days) and/or pathological evidence of progressive liver disease. Total sBA >2× ULN is required.
- Persistent pruritus (>90 days). An average worst-daily (morning and evening) ItchRO(Obs)/ItchRO(Pt) score ≥1.5 during the 2 consecutive weeks of the screening period leading to the baseline visit. If both instruments are administered, a score ≥1.5 is required only for ItchRO(Obs).
Participants with the following rare diseases will be enrolled in the study:
Any rare cholestatic liver disease associated with persistent cholestatic pruritus, including but not limited to the following: alpha-1 antitrypsin deficiency, ARC syndrome, BA, Caroli's disease, ciliopathies, hepatic sarcoidosis, idiopathic amyloidosis, IgG4-related sclerosing cholangitis, ischemic cholangiopathy, metabolic or genetic cholestatic liver diseases (e.g., bile acid synthesis defects, defects of bile acid transport or disorders such as transaldolase deficiency, where chronic cholestasis and pruritus are present), secondary sclerosing cholangitis.
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Completion of at least 10 valid daily (morning and evening) ItchRO(Obs)/ItchRO(Pt) entries during 2 consecutive weeks of the screening period, leading to the baseline visit. Each week should have at least 4 valid daily (morning and evening) entries. If both instruments are administered, the completion criterion is required only for ItchRO(Obs).
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If taking antipruritics or ursodeoxycholic acid, the participant has to be on a stable dosing regimen (i.e., same dose and frequency in the 30 days prior to the screening visit and will continue this dosing regimen up to Week 40 [adjustment for body weight is allowed]).
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Non-pregnant, non-lactating females of childbearing potential who are sexually active must agree to use at least an acceptable effective method of contraception during the study. Females of childbearing potential must have a negative pregnancy test result.
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Access to email or telephone for scheduled participant contacts and access to smart phone or tablet for PROs (Exception: Participants who do not use a smart phone or tablet because of cultural restrictions will complete the PROs on paper.)
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Ability to read and/or understand the questionnaires (both caregivers and participants ≥9 years of age)
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For participants ≤18 years of age: Access to consistent caregiver(s) during the study
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Willingness (participant or caregiver) to comply with all study visits and requirements through the end of the study
Exclusion Criteria:
Those who meet any of the following criteria are NOT eligible to participate in the study:
Patient Characteristics
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Diagnosis of ALGS, ICP, PBC, PFIC, or PSC
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Active atopic dermatitis or other non-cholestatic diseases associated with pruritus that are not controlled by standard treatment and that may interfere with the severity assessment of cholestasis-associated pruritus
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Decompensated cirrhosis or complications of cirrhosis (e.g., esophageal or gastric variceal bleeding in the last 6 months, high-risk esophageal or gastric varices [e.g., large, coiled, occupying >1/3 of the esophageal lumen, red varices or red signs], ascites, hepatic encephalopathy, hepatorenal syndrome). Patients with compensated cirrhosis with preserved hepatic synthetic function (see Exclusion Criterion #6) and absence of complications are eligible.
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Suspected or proven cholangiocarcinoma or hepatocellular carcinoma
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Unstable and/or serious medical disease that is likely to impair the ability to participate in all aspects of the study, confound efficacy and/or safety assessments, or result in substantially shortened life expectancy (e.g., any active malignancy including hematological malignancy, end-stage heart failure, active infection, acute and chronic diarrhea). Exceptionally, previous history of malignancy, adequately treated/in remission, that in opinion of investigator and medical monitor does not impact participant safety and participation in the study, may be allowed. The investigator should contact the medical monitor to discuss these cases and seek approval before the screening period.
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Laboratory results during the screening visit as follows:
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Platelet count <70,000/mm3
. Patients with any condition that further increases bleeding risk (e.g., recent clinically relevant bleeding event [6 months], recent major surgery [12 weeks], anticoagulant use, platelet function disorders) are excluded.
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Albumin <30 g/L
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INR ≥1.5 (after intravenous or subcutaneous supplementation of vitamin K)
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Total bilirubin: For participants <18 years of age: total bilirubin >10 mg/dL For participants ≥18 years of age: total bilirubin ≥3× ULN
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ALT: For participants <18 years of age: ALT >10× ULN For participants ≥18 years of age: ALT >5× ULN
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Presence of any other disease or condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs, including bile salt metabolism in the intestine (e.g., clinically relevant inflammatory bowel disease involving the terminal ileum), per investigator discretion
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History of liver transplant Prior/Concomitant Therapy
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Use of an IBAT inhibitor within 8 weeks prior to the screening visit
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Use of any other investigational medication within 30 days or 5 times the half-life, whichever is greater, prior to the screening visit Other Exclusions
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Pregnant or nursing
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Known intolerance/hypersensitivity to maralixibat or its excipients
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History of nonadherence to medical regimens, unreliability, medical condition, mental instability, or cognitive impairment that, in the opinion of the investigator, could compromise the validity of informed consent, compromise the safety of the participant, or lead to nonadherence with the study protocol or inability to conduct the study procedures
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Clinically relevant alcohol use disorder or drug abuse within 12 weeks of screening:
- Moderate alcohol consumption as defined for this study by >1 and >2 standard drinks on average per day for women and men, respectively, within 12 weeks prior to the screening visit. A standard drink is defined as 44 mL (1.5 oz, one shot) of liquor, 148 mL (5 oz) of nonfortified wine, or 355 mL (12 oz) of beer (1 oz=29.57 mL; NIAAA)
- Drug abuse within the 12 weeks prior to, or a positive drug screening result at, the screening visit unless it can be explained by a drug prescription. A positive drug screen will exclude participants if the investigator deems the result to be reflective of a pattern of behavior that might impair the participant's ability to participate in the study.
- Use of cannabinoids (legal, prescribed, or otherwise) is allowed, provided use is stable (including as-needed use without need for increased frequency of use) for ≥12 weeks prior to the screening visit and throughout the entire study duration.
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Randomizado
- Modelo Intervencional: Atribuição Paralela
- Mascaramento: Quadruplicar
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
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Experimental: Maralixibat
Participants will receive maralixibat oral solution 300 μg/kg orally once daily for 1 week and then twice daily for 39 weeks. |
Maralixibat will be provided as an oral solution along with 0.5-, 1.0-, and 3.0-mL sized dosing dispensers. During the double-blind dose escalation period (4 weeks), the study drug (maralixibat) will be administered once daily for 1 week and then twice daily (BID; morning and evening). During the double-blind stable dosing period (16 weeks), participants will be treated with 300 μg/kg BID or the maximum tolerated dose (determined during the double-blind dose-escalation period) of maralixibat. During the open-label dose escalation period (4 weeks), all participants will receive maralixibat treatment once daily for 1 week and then twice daily (BID; morning and evening). During the open-label stable dosing period (at least 16 weeks), participants will be treated with 300 μg/kg BID or the maximum tolerated dose (determined during the open-label dose-escalation period) of maralixibat.
Outros nomes:
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Comparador de Placebo: Placebo
Participants will receive placebo matched to maralixibat oral solution orally once daily for 1 week and then twice daily for 19 weeks. After 20 weeks, participants will receive maralixibat oral solution 300 μg/kg orally once daily for 1 week and then twice daily for 19 weeks. |
Placebo matched to maralixibat will be provided as an oral solution along with 0.5-, 1.0-, and 3.0-mL sized dosing dispensers. During the double-blind dose escalation period (4 weeks), study drug will be administered once daily for 1 week and then twice daily (BID; morning and evening). During the double-blind stable dosing period (16 weeks), participants will be treated with 300 μg/kg BID or the maximum tolerated dose (determined during the double-blind dose-escalation period) of study drug. During the open-label dose escalation period (4 weeks), all participants will receive maralixibat treatment once daily for 1 week and then twice daily (BID; morning and evening). During the open-label stable dosing period (16 weeks), participants will be treated with 300 μg/kg BID or the maximum tolerated dose (determined during the open-label dose-escalation period) of maralixibat. |
O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
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Mean change in the ItchRO(Obs) severity score
Prazo: From baseline to average of week 13 to week 20
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ItchRO(Obs) severity score = Itch Reported Outcome Observer assessment severity score; scale between 0 (not itchy at all) and 4 (extremely itchy); the lower the score the better. |
From baseline to average of week 13 to week 20
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Medidas de resultados secundários
Medida de resultado |
Prazo |
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Alteração média no nível total de sBA (ácido biliar sérico)
Prazo: Da linha de base até a média da semana 12 e semana 20
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Da linha de base até a média da semana 12 e semana 20
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Colaboradores e Investigadores
Patrocinador
Publicações e links úteis
Links úteis
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo (Real)
Conclusão Primária (Estimado)
Conclusão do estudo (Estimado)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Real)
Atualizações de registro de estudo
Última Atualização Postada (Real)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Palavras-chave
Termos MeSH relevantes adicionais
- Doenças do aparelho digestivo
- Manifestações de pele
- Doenças das vias biliares
- Doenças de pele
- Anomalias congénitas
- Doenças das vias biliares
- Anormalidades do sistema digestivo
- Doenças e Anormalidades Congênitas, Hereditárias e Neonatais
- Condições Patológicas, Sinais e Sintomas
- Doenças da Pele e do Tecido Conjuntivo
- Sinais e sintomas
- Colangite
- Colangite Esclerosante
- Prurido
- Atresia Biliar
- maralixibat
Outros números de identificação do estudo
- MRX-802
- 2024-511287-85-00 (Ctis)
Plano para dados de participantes individuais (IPD)
Planeja compartilhar dados de participantes individuais (IPD)?
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