A Study to Evaluate BMS-986470 in Healthy Volunteers and Participants With Sickle Cell Disease

Официальное название

A Phase 1/2a, First-in-human, Randomized, Double-blinded, Placebo-controlled, Dose-finding Study in Healthy Volunteers and Participants With Sickle Cell Disease to Evaluate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics, pH and Food Effect, and Preliminary Efficacy of BMS-986470

Обзор

The purpose of this study is to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics, pH and food effect, and preliminary efficacy of BMS-986470 in healthy volunteers and participants with sickle cell disease.

Вмешательства

• Препарат BMS-986470
  Specified dose on specified days
• Препарат Placebo
  Specified dose on specified days
• Препарат Famotidine
  Specified dose on specified days
• Препарат Pantoprazole
  Specified dose on specified days

Первичные конечные точки

• Number of participants with adverse events (AEs) [Срок оценки: Up to 26 months]
• Number of participants with serious adverse events (SAEs) [Срок оценки: Up to 26 months]
• Number of participants with AEs meeting protocol-defined Dose Limiting Toxicity (DLT) criteria [Срок оценки: Up to 26 months]
• Number of participants with AEs leading to discontinuation [Срок оценки: Up to 26 months]
• Number of deaths [Срок оценки: Up to 26 months]
• Proportion of participants achieving HbF ≥ 10% [Срок оценки: Up to 28 days after last dose]
• Proportion of participants achieving HbF ≥ 20% [Срок оценки: Up to 28 days after last dose]
• Proportion of participants achieving HbF ≥ 30% [Срок оценки: Up to 28 days after last dose]

Вторичные конечные точки (12)

• Maximum observed plasma concentration (Cmax) [Срок оценки: Up to Day 28]
• Area under the concentration-time curve (AUC) [Срок оценки: Up to Day 28]
• Time of maximum observed plasma concentration (Tmax) [Срок оценки: Up to Day 28]
• Dose proportionality of BMS-986470 for Cmax and AUC [Срок оценки: Up to Day 28]
• Change from baseline in total hemoglobin (Hb) [Срок оценки: Up to 26 months]
• Change from baseline in total Hb fractions: adult Hb (HbA) [Срок оценки: Up to Day 28]
• Change from baseline in total Hb fractions: fetal Hb (HbF) [Срок оценки: Up to 26 months]
• Change from baseline in total Hb fractions: sickle Hb (HbS) [Срок оценки: Up to 26 months]
• Change from baseline in markers of red blood cell (RBC) lysis: total Hb [Срок оценки: Up to 26 months]
• Change from baseline in markers of RBC lysis: aspartate aminotransferase (AST) [Срок оценки: Up to 26 months]
• Change from baseline in markers of RBC lysis: lactate dehydrogenase (LDH) [Срок оценки: Up to 26 months]
• Change from baseline in markers of RBC lysis: total bilirubin [Срок оценки: Up to 26 months]

Критерии участия

Критерии включения

Cohort A:

• Healthy male and female (who are not of childbearing potential) participants, as determined by the investigator based on medical history and other determinations. Females not of childbearing potential must have been amenorrhoeic for at least 12 months without an alternative medical cause and have follicle-stimulating hormone (FSH) levels of at least 40 IU/L or have undergone a hysterectomy, bilateral oophorectomy, or bilateral salpingectomy.
• Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive. BMI = weight (kg)/\[height (m)\]2 as measured at screening.
• No evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG, or clinical laboratory assessments beyond what is consistent with the target population.

Cohort B:

• Participants with a documented diagnosis of sickle cell disease (SCD) with genotype HbSS, HbSβ0-thal, or HbSβ+-thal.
• For Cohort B Part 1 only: Participants with ≥ 4 vaso-occlusive crises (VOCs) within the previous 12 months or ≥ 2 VOCs within the previous 6 months. For Cohort B Part 2 only: Participants with ≥ 2 VOCs and ≤ 15 VOCs within the previous 12 months.
• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Participants must have the following laboratory values:

i) Hemoglobin ≥ 5.5 and ≤ 12 g/dL (males) or ≥ 5.5 and ≤ 10.6 g/dL (females). ii) Absolute neutrophil count ≥ 1500/μL. iii) Platelet count ≥ 100 × 10\^3/μL. iv) Absolute reticulocyte count > 100 × 10\^3/μL or > 50 × 10\^3/μL if taking hydroxyurea.

Критерии исключения

Cohort A:

• Any significant medical condition or any condition that confounds the ability to interpret data from the study.
• Participant has any condition, including the presence of laboratory abnormalities, that places the participant at unacceptable risk if the participant was to participate in the study.
• Any major surgery or planned surgery (except GI surgery) within 12 weeks of the first study intervention administration.

Cohort B:

• Participants with any condition, including significant acute or chronic medical illness, active or uncontrolled infection, or the presence of laboratory abnormalities, that places participants at unacceptable risk if participating in this study.
• For Cohort B Part 1 only: participants with more than 6 severe VOCs defined as VOCs requiring ≥ 24 hours of hospital admission within 12 months prior to the first dose of study intervention.
• For Cohort B Part 1 only: participants with any episode of acute chest syndrome within the last 6 months prior to the first dose of study intervention.
• Creatinine clearance (CrCl) < 60 mL/min/1.72m2 using Chronic Kidney Disease Epidemiology (CKD-EPI) equation.

Cohort A and B:

• Participant is receiving regularly scheduled RBC or platelet transfusions or has received a RBC transfusion within 28 days and a platelet transfusion within 14 days prior to starting treatment with BMS-986470.
• Other protocol-defined Inclusion/Exclusion criteria apply.

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

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

США · 19 центров

• University of Alabama at Birmingham — Birmingham
• University of California San Diego - La Jolla — La Jolla
• UCSF Benioff Children's Hospital Oakland — Oakland
• Yale-New Haven Hospital — New Haven
• Winship Cancer Institute of Emory University — Atlanta
• Local Institution - 0034 — Chicago
• Local Institution - 0001 — Lenexa
• Local Institution - 0064 — Baltimore
• … и ещё 11 центров

Великобритания · 5 центров

• University Hospitals Sussex NHS Foundation Trust — East Sussex
• Local Institution - 0044 — London
• King's College Hospital — London
• Local Institution - 0005 — Leeds
• Local Institution - 0047 — London

Франция · 4 центра

• Local Institution - 0061 — Créteil
• Assistance Publique Hôpitaux de Marseille - Hôpital de la Timone — Marseille
• Hôpital Universitaire Necker Enfants Malades — Paris
• CHU Strasbourg-Hautepierre — Strasbourg

Италия · 3 центра

• Local Institution - 0011 — Milan
• Local Institution - 0037 — Padua
• Local Institution - 0009 — Verona

Канада · 2 центра

• Local Institution - 0050 — Vancouver
• Local Institution - 0051 — Toronto

Идентификаторы

NCT: NCT06481306 · CA230-1019 · 2023-510283-12 · U1111-1301-6753

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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