A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of NXT007 in Persons With Severe or Moderate Hemophilia A

Официальное название

A Phase I/II Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of NXT007 in Persons With Severe or Moderate Hemophilia A

Обзор

WP44714 is a Phase I/II, open-label, non-randomized, global, multicenter trial consisting of two parts: * Part 1 is a multiple-ascending dose (MAD) study in adult and adolescent male participants with severe or moderate hemophilia A with or without factor VIII (FVIII) inhibitors. * Part 2 is a multiple-dose study in pediatric male participants with severe or moderate hemophilia A with or without FVIII inhibitors. The overall aim of the study is to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy of NXT007.

Вмешательства

• Препарат NXT007
  Participants will receive NXT007 administered subcutaneously (SC), 2 loading doses once every two weeks (Q2W) followed by once every 4 weeks (Q4W) maintenance doses based on the schedule.

Первичные конечные точки

• Incidence and Severity of Adverse Events, with Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events Grading Scale [Срок оценки: From Baseline until study completion or discontinuation (up to 7.5 years)]
• Number of Participants with at Least One Clinical Laboratory Test Abnormality for Hematology Parameters [Срок оценки: From Baseline until study completion or discontinuation (up to 7.5 years)]
• Number of Participants with at Least One Clinical Laboratory Test Abnormality for Blood Chemistry Parameters [Срок оценки: From Baseline until study completion or discontinuation (up to 7.5 years)]
• Number of Participants with at Least One Vital Sign Abnormality [Срок оценки: From Baseline until study completion or discontinuation (up to 7.5 years)]
• Number of Participants with at Least One Abnormality on Electrocardiogram (ECG) Recordings [Срок оценки: From Baseline until study completion or discontinuation (up to 7.5 years)]

Вторичные конечные точки (12)

• Plasma Concentration of NXT007 at Specified Timepoints [Срок оценки: At prespecified timepoints from Week 1 to Week 23, every 28 days from Week 25 until Week 49, and every 12 weeks thereafter until study completion or discontinuation (up to 7.5 years)]
• Maximum Observed Plasma Concentration (Cmax) of NXT007 After the First Dose [Срок оценки: At prespecified timepoints from Day 1 to Day 15]
• Time to Maximum Observed Plasma Concentration (tmax) of NXT007 After the First Dose [Срок оценки: At prespecified timepoints from Day 1 to Day 15]
• Area Under the Plasma Concentration-Time Curve (AUC) of NXT007 After the First Dose [Срок оценки: At prespecified timepoints from Day 1 to Day 15]
• Number of Participants Testing Positive for Anti-Drug Antibodies Against NXT007 at Baseline and During Treatment with Study Drug [Срок оценки: Baseline (predose on Day 1) and from first dose of study drug until study completion or discontinuation (up to 7.5 years)]
• Number of Participants Testing Positive for Anti-Factor VIII Inhibitors at Baseline and During Treatment with Study Drug [Срок оценки: Baseline (predose on Day 1) and from first dose of study drug until study completion or discontinuation (up to 7.5 years)]
• Model-Based Annualized Bleeding Rate for Treated Bleeds [Срок оценки: From first dose of study drug until study completion or discontinuation (up to 7.5 years)]
• Mean Calculated Annualized Bleeding Rate for Treated Bleeds [Срок оценки: From first dose of study drug until study completion or discontinuation (up to 7.5 years)]
• Median Calculated Annualized Bleeding Rate for Treated Bleeds [Срок оценки: From first dose of study drug until study completion or discontinuation (up to 7.5 years)]
• Model-Based Annualized Bleeding Rate for All Bleeds [Срок оценки: From first dose of study drug until study completion or discontinuation (up to 7.5 years)]
• Mean Calculated Annualized Bleeding Rate for All Bleeds [Срок оценки: From first dose of study drug until study completion or discontinuation (up to 7.5 years)]
• Median Calculated Annualized Bleeding Rate for All Bleeds [Срок оценки: From first dose of study drug until study completion or discontinuation (up to 7.5 years)]

Критерии участия

Критерии включения

• Diagnosis of severe (Factor VIII \[FVIII\] coagulant activity <1 IU/dL) or moderate (FVIII coagulant activity ≥1 IU/dL and ≤5 IU/dL) congenital hemophilia A with or without inhibitors against FVIII
• Participants with FVIII inhibitors: participants using recombinant activated factor VII (rFVIIa) or willing to switch to rFVIIa as primary bypassing agent for the treatment of breakthrough bleeds, trauma, or procedures
• Historic local FVIII inhibitor test results being available during screening to confirm any previous inhibitor history and current status
• Participants who previously successfully completed immune tolerance induction (ITI) must have done so at least 5 years before screening and must have no evidence of inhibitor recurrence (permanent or temporary) since. FVIII tolerance defined as <0.6 Bethesda unit (BU)/mL (<1.0 BU/mL only for laboratories with an historical sensitivity cutoff for inhibitor detection of 1.0 BU/mL) and in vivo recovery >66%
• Documentation of number and type of bleeding episodes in the last 24 weeks prior to enrollment
• Adequate hematologic function, defined as platelet count ≥100,000 cells/μL and hemoglobin ≥11 g/dL at the time of screening
• Adequate hepatic function defined as total bilirubin ≤1.5× age-adapted upper limit of normal (ULN) (excluding Gilbert syndrome) and both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3× age-adapted ULN at the time of screening, and no clinical signs or known laboratory/radiographic evidence consistent with cirrhosis. For patients with Gilbert syndrome, bilirubin should be <4 mg/dL or 68.4 umol/L at the time of screening.
• For Part 1 only: Adequate renal function, defined as serum creatinine ≤2.5× age-adapted ULN and calculated creatinine clearance ≥30 mL/min by Cockroft-Gault formula
• For Part 2 only: Adequate renal function, defined as serum creatinine ≤1.5× age-adapted ULN. When the serum creatinine is ≥1.5× ULN, creatinine clearance by Bedside Schwartz formula must be >70 mL/min/1.73m\^2.
• Willingness and ability to comply with schedules visits, treatment plans, laboratory tests, and other study procedures

Критерии исключения

• Inherited or acquired bleeding disorders other than congenital hemophilia A
• Ongoing or planned ITI therapy
• Previous or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease
• At high risk for thrombotic microangiopathy (TMA), including past personal or family history of TMA, in the investigator's judgment
• For Part 1 only: Personal history of ischemic heart disease, cerebrovascular disease, or diabetes mellitus
• For Part 1 only: Strong family history of ischemic heart disease or cerebrovascular disease (i.e., first degree relatives such as parents, full siblings, or children): male relatives diagnosed under the age of 55 years and females under the age of 65 years
• For Part 1 only: Previous or concomitant malignancies or leukemia
• Other conditions (e.g., autoimmune conditions such as Systemic Lupus erythematosus and other systemic inflammatory disorders) that may currently increase the risk of bleeding or thrombosis
• History of clinically significant allergies
• Receipt of any of the following:

i) An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration or normalization of targeted parameters (e.g., anti-thrombin), whichever is longer; ii) A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, whichever is shorter; iii) Any other investigational drug currently being administered or planned to be administered; iv) Prior gene therapy or gene therapy planned to be administered; v) Use of systemic immunomodulators (e.g., interferon or rituximab) at enrollment or planned use during the study, with the exception of anti-retroviral therapy to treat HIV.

• Protein C activity, protein S free antigen, or anti-thrombin III activity levels below the lower limit of the reference range at screening
• Known HIV infection with CD4 counts <200 cells/μL
• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy and to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to excipient content
• History or presence of an abnormal ECG that is deemed clinically significant, (e.g., complete left bundle branch block, second- or third -degree atrioventricular heart block), including atrial fibrillation or evidence of prior myocardial infarction
• QT interval corrected through use of Fridericia's formula (QTcF) >450 ms demonstrated by at least two ECGs >30 minutes apart
• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome
• Current treatment with medications that are well known to prolong the QT interval

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 4 центра

• UC Davis Cancer Center — Sacramento
• Georgetown Uni Medical Center — Washington D.C.
• Indiana Hemophilia & Thrombosis center — Indianapolis
• University of Iowa Hospitals and Clnics Dept of Pediatrics — Iowa City

Испания · 3 центра

• Hospital Sant Joan de Deu — Esplugues de Llobregat
• Hospital Universitario la Paz — Madrid
• Hospital Regional Universitario Carlos Haya — Málaga

Канада · 2 центра

• British Columbia Children's Hospital — Vancouver
• Hamilton Health Sciences Corporation — Hamilton

Италия · 2 центра

• IRCCS Ca' Granda Ospedale Maggiore Policlinico — Milan
• Istituto Clinico Humanitas — Rozzano (MI)

Польша · 2 центра

• Uniwersyteckie Centrum Kliniczne — Gda?sk
• Instytut Hematologii i Transfuzjologii — Warsaw

Новая Зеландия · 1 центр

• Auckland Cancer Trial Centre — Auckland

Идентификаторы

NCT: NCT05987449 · WP44714 · 2023-503906-35-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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