Study Design and Participants
The study was a prospective, single center, observational study on F508del homozygous adults with CF who commenced treatment with LUM-IVA and were followed for a year. Pregnant or nursing females, solid organ or hematological transplant recipients, alcohol or drug abusers, patients with an acute upper or lower respiratory infection, and patients with PEx or changes in therapy within 28 days before Day 1 (first dose of LUM-IVA) were excluded.
All subjects received 400 mg Lumacaftor and 250 mg Ivacaftor (LUM-IVA) fixed-dose combination film coated tablets for oral administration every 12 hours. All participants remained on their pre-study stable CF medication regimen throughout the year. They were followed in the CF Center at Carmel Medical Center, Haifa, Israel between November 2016 and June 2019. The institutional board reviewed and approved the study protocol. All patients provided written informed consent. The ClinicalTrials.gov identifier of the study is NCT04623879.
In Israel, F508del allele frequency accounts for only around 23%, and therefore 13 adults with the F508del homozygous genotype attend our center.
Study Assessments
The primary endpoint assessed pancreatic function by the absolute and relative change from baseline in oral glucose tolerance (OGTT) test through 12 months. Secondary endpoints included absolute and relative changes from baseline through 12 months in bone metabolism parameters, nutritional factors, fertility hormones, sweat chloride, pulmonary status, and CFQR score.
Pancreatic function evaluation: At screening visit, 3 months, and 12 months, an OGTT was performed in patients without CF-related diabetes: 75g of glucose were ingested, and glucose, insulin, and c-peptide were examined at three time points: 0, 1 hour, and 2 hours. In addition, HbA1C levels were evaluated in all patients at each study visit.
Bone indices: At screening and at 12 months, bone density was measured, using a dual-energy x-ray absorptiometry (DEXA) scan test. In addition, during every visit, bone metabolism factors, including parathyroid hormone (PTH), alkaline-phosphatase, phosphor, calcium, vitamin D levels, and urine Ca/Cr ratio were assessed.
Nutritional status: Body mass index (BMI) and levels of vitamin A, E (absolute), and albumin were assessed at each visit.
Fertility evaluation: Reproductive hormones including LH, FSH, testosterone, and estradiol were assessed at each visit in individuals of both sexes.
Additional parameters: Vital signs, physical examination, sputum cultures, laboratory tests (e.g. complete blood count [CBC] and chemistry tests including electrolytes, liver and kidney function, and coagulation function) were assessed in every visit.
Pulmonary: Pulmonary and lung morphology evaluations were carried out by
(1) The absolute change from baseline in the percentage of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and forced expiratory flow between 25–75 (FEF25-75), all were assessed every visit. To obtain these parameters, spirometry was performed in accordance with the American Thoracic Society/European Respiratory Society (ATS/ERS) Task Force, using a KoKo® spirometer (n-Spire Healthcare, Inc., Longmont CO, USA)[12]. Absolute values of spirometry were transferred to percent predicted (pp) using Global Lung Function Initiative (GLI) reference data. (2) Chest computed tomography (CT) scans were performed at baseline and after one year, scored using the Bhalla scoring method[13] by a radiologist-investigator (the total score ranges from 9 to 25, with a higher score indicating more severe structural lung changes). (3) Quality of life was measured using the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score every visit (scores range from 0 to 100, with higher scores indicating a better quality of life and four points considered to be a minimal clinically important difference)[14]. (4) PEx was defined as deteriorations in respiratory symptoms that led to changes in treatment[15]. Each PEx was counted as a separate event, and the number of PEx during one year prior to commencing treatment with LUM-IVA was compared to PEx through the first year of treatment. We documented the number of exacerbations, oral vs. intravenous (IV) antibiotic treatments, hospitalizations, presence of fever > 38°C, laboratory parameters (white blood cells count [WBC], absolute neutrophil count [ANC], and C-reactive protein [CRP] at PEx start in hospitalized patients), sputum culture results, and time to next PEx.
CFTR function: Evaluation was measured through testing the concentration of sweat chloride that was performed at screening and after a year of treatment by Macroduct ® sweat collection system[16].
Statistical Analysis
Statistical analyses were performed using the SAS version 9.4 (SAS Institute, Cary North Carolina, USA). All measured variables and derived parameters were tabulated by descriptive statistics. For categorical variables, summary tables are provided presenting sample size and absolute and relative frequency. For continuous variables, summary tables are provided presenting sample size, arithmetic mean, standard deviation, median, minimum, and maximum for means of variables. A paired t-test for two means (repeated observations) was applied for testing the statistical significance of the change from baseline for each continuous variable. A logistic regression model was applied for testing the statistical significance of the difference in several exacerbation parameters between before and after LUM-IVA treatment. All tests were two-tailed, and a p-value of 5% or less was considered statistically significant.