Real Life Evaluation of the Multi-organ Effects of Lumacaftor/Ivacaftor on F508del Homozygous Cystic Fibrosis Patients.
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 13
- 主要终点
- Pulmonary function tests
研究概览
简要总结
Background: Lumacaftor/Ivacaftor (LUM-IVA), a CFTR corrector-potentiator combination, was found to improve lung function and reduce pulmonary exacerbations (PEx). However, cystic fibrosis (CF) is a multi-organ disease and therefore there is a need for more information on the systemic effects of CFTR modulators.
Aim: To evaluate pancreatic function, bone metabolism and respiratory changes through a year of LUM-IVA treatment.
Methods: A prospective real world, one-year study on F508del homozygous adult CF patients who commenced treatment with LUM-IVA. Visits were scheduled on the first day of treatment and every 3 months evaluating: symptoms, Body Mass Index (BMI), spirometry, laboratory tests and Quality of life. At baseline and at 12 months, the patients underwent sweat test, oral glucose tolerance test (OGTT), chest CT and dual-energy X-ray absorptiometry (DEXA).
详细描述
Introduction Cystic fibrosis (CF) is a genetic multisystem disease that is characterized by pancreatic insufficiency (PI) and chronic airway infections associated with loss of lung function, repeated pulmonary exacerbations (PEx), and ultimately, respiratory failure. F508del, the deletion of a single amino acid, is the most common mutation that causes CF. In July 2015, the U.S. Food and Drug Administration approved the combination Lumacaftor/Ivacaftor (Orkambi®, Vertex pharmaceuticals) for use in patients with CF homozygous for the F508del mutation. Briefly, this combination of a corrector (Lumacaftor) and potentiator (Ivacaftor) partially restores the activity of the membranous CF transmembrane regulator (CFTR) protein. Lumacaftor improves the processing of F508del CFTR and its transport to the cell surface, while Ivacaftor increases the probability for the channel to be open and its transport of chloride. In clinical trials, treatment with Lumacaftor-Ivacaftor (LUM-IVA) in individuals homozygous for F508del led to an increase in lung function, weight, and a significant reduction in the frequency of PEx and CF-related hospitalizations.
Extra-pulmonary complications are common in CF. Of these, CF-related diabetes (CFRD) is one of the worst prognostic factors. In people with gating mutations responsive to Ivacaftor, treatment was associated with an improvement in insulin secretion after glucose challenge.
Another important extra-pulmonary complication is CF bone disease (CFBD), characterized by low bone mineral density. Osteopenia and fractures are noted among 50-75% of patients diagnosed with CF. The reasons for those pathologies are malabsorption of fat soluble vitamins, a complex abnormality of sex hormone composition, primary CFTR dysfunction, chronic infection and inflammation, and low levels of bone-building exercise resulting from advanced respiratory compromise. It is well known that growth and sexual development is delayed in CF patients, due in part to nutritional deficiencies and the severity of their chronic lung disease. These delays are accompanied by low levels of sex hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
The aim of the current study was to evaluate endocrine pancreatic function, bone metabolism and respiratory changes through the first year of LUM-IVA treatment in adult patients.
Materials and methods Study design and participants The study was a prospective, single center, observational real-world study on F508del homozygous adult CF patients, who commenced treatment with LUM-IVA and were followed for a year. Pregnant and nursing females; solid organ or hematological transplant recipients; alcohol or drug abusers; patients with an acute upper or lower respiratory infection, and those with PEx or changes in therapy for pulmonary disease within 28 days before Day 1 (first dose of study drug) were excluded.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects who meet all of the following inclusion criteria will be eligible for this study:
- •Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, and other study procedures.
- •Subjects (males and females), will be aged 18 years or older
- •Confirmed diagnosis of CF
- •Homozygous for the F508del-CFTR mutation.
- •Willing to remain on a stable CF medication regimen through 12 months.
排除标准
- •Subjects who meet any of the following exclusion criteria will not be eligible for this study:
- •History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject.
- •For example:
- •History of cirrhosis with portal hypertension, and/or history of risk factors for Torsade de Pointes (e.g., familial long QT syndrome, hypokalemia, heart failure, left ventricular hypertrophy, bradycardia, myocardial infarction, cardiomyopathy, history of arrhythmia [ventricular and atrial fibrillation]), obesity, acute neurologic events.
- •Any of the following abnormal laboratory values at Screening:
- •Abnormal liver function defined as any 2 or more of the following: ≥3 × upper limit of normal (ULN) aspartate aminotransferase (AST), ≥3 × ULN alanine aminotransferase (ALT), ≥3 × ULN gamma-glutamyl transpeptidase (GGT), ≥3 × ULN alkaline phosphatase (ALP), or ≥2 × ULN total bilirubin
- •Abnormal liver function defined as any increase of ≥5 × ULN AST or ALT
- •Abnormal renal function defined as glomerular filtration rate ≤50 mL/min/1.73 m2
- •An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug).
- •History of solid organ or hematological transplantation.
- •History or evidence of cataract, lens opacity, Y-suture, or lamellar rings determined to be clinically significant by the ophthalmologist during the ophthalmologic examination during the Screening Period.
- •History of alcohol or drug abuse in the past year, including but not limited to cannabis, cocaine, and opiates, as deemed by the investigator.
- •Pregnant or nursing females: Females of childbearing potential must have a negative pregnancy test at Screening and Day 1.
研究组 & 干预措施
F508del homozygous adult CF patients
F508del homozygous adult CF patients who commenced treatment with LUM-IVA
干预措施: Lumacaftor, Ivacaftor Drug Combination (Drug)
结局指标
主要结局
Pulmonary function tests
时间窗: 1 year
the absolute change from baseline through 12 months in the percentage of predicted Forced expiratory volume in 1 second (FEV1).
次要结局
- BMI(1 year)
- bone health factors(1 year)
- Additional Pulmonary function tests(1 year)
- Glucose metabolism(The change between 12 months (under treatment) to screening)
- bone parameters(1 year)
研究者
Karin Yaakobi Bianu
Senior physician, Pediatric Pulmonology Unit and CF Center
Carmel Medical Center