-
1.
First clinical trials of novel ENaC targeting therapy, SPX-101, in healthy volunteers and adults with cystic fibrosis.
Couroux, P, Farias, P, Rizvi, L, Griffin, K, Hudson, C, Crowder, T, Tarran, R, Tullis, E
Pulmonary pharmacology & therapeutics. 2019;:101819
Abstract
BACKGROUND ENaC inhibition has been investigated as a CF treatment; however, small molecule inhibitors of ENaC lack efficacy and/or have shown dose-limiting hyperkalemia. SPX-101 is a novel, investigational small peptide (SPLUNC1 mimetic) that regulates ENaC density with the potential for efficacy without systemic effects. METHODS Two trials are presented: The first was a Phase 1, 2-part, randomized, double-blind, placebo-controlled, ascending-dose study of nebulized SPX-101 in healthy adults. Part 1 evaluated 4 single doses of SPX-101 ranging from 20 to 240 mg. Part 2 evaluated a 14-day regimen of SPX-101 at 4 doses of SPX-101 ranging from 10 to 120 mg BID. Pharmacokinetics, adverse events, spirometry, vital signs, electrocardiograms, pulse oximetry, and clinical laboratory values were assessed. The second trial was a tolerability-confirming, Phase 1b, open-label study conducted in 5 adult subjects with CF. Ascending doses of SPX-101 inhalation solution (10 mg-120 mg BID) were administered for 7 days. Safety was assessed as described above. RESULTS All 64 healthy volunteers (32 in each Part) completed the single and multiple dose study. SPX-101 was well tolerated with little/no systemic exposure and with no hyperkalemia. Adverse events were generally mild with reported respiratory events associated with the purported pharmacological activity of SPX-101. Tolerability of SPX-101 was similarly observed in adults with CF; all 5 subjects treated with SPX-101 completed the study. CONCLUSIONS SPX-101 was well-tolerated across a range of doses and had little/no systemic exposure in healthy adults and adults with CF, thus supporting further study in patients with CF. CLINICALTRIAL. GOV REGISTRATION NCT03056989.
-
2.
High-dose Cholecalciferol Supplementation in Adults with Cystic Fibrosis.
Janzen, KM, Sakon, C, Lehman, A, Sommer, B, Brown, C
Pharmacotherapy. 2019;(9):874-880
-
-
Free full text
-
Abstract
INTRODUCTION Despite the availability of consensus guidelines for the treatment of vitamin D deficiency, prospective trials are lacking to examine alternative dosing strategies for adult patients with cystic fibrosis (CF) who do not meet therapeutic goals with standard regimens. OBJECTIVES The primary objective of this study was to determine the efficacy of high-dose cholecalciferol supplementation in increasing serum vitamin D (25-OHD) levels in adult patients with CF. METHODS Patients were eligible for inclusion if they were 18 years or older, had baseline 25-OHD levels lower than 30 ng/ml, and were diagnosed with CF and pancreatic insufficiency. Patients were given a single dose of cholecalciferol 300,000 or 500,000 IU based on baseline 25-OHD levels. Response was defined by 25-OHD and ionized calcium levels at 3 months. At 6 months, responders received a second dose of the same strength, and nonresponders were given a weekly supplement of cholecalciferol 50,000 IU in addition to cholecalciferol 500,000 IU. A second 25-OHD level was obtained at 9 months. RESULTS Of the 46 patients enrolled, 32 patients (70%) completed the study. Baseline levels of 25-OHD significantly increased over time in the per protocol population at 3 and 9 months. A total of 16 patients (50%) were considered nonresponders and required weekly supplementation. CONCLUSION A protocol using high-dose cholecalciferol or high-dose plus weekly cholecalciferol is safe and effective in treating adult patients with CF and pancreatic insufficiency.
-
3.
Red blood cell distribution width is not a reliable biomarker for low iron stores in children with cystic fibrosis.
Akkermans, MD, Uijterschout, L, Nuijsink, M, Hendriks, DM, van Goudoever, JB, Brus, F
Pediatric hematology and oncology. 2017;(1):10-16
Abstract
Low iron stores in children, absolute iron deficiency (AID), can lead to impaired neurodevelopment and requires iron therapy. In the presence of infection/inflammation, like in cystic fibrosis (CF), serum ferritin (SF) is not a reliable biomarker for AID. Red blood cell distribution width (RDW) is a promising alternative reported not to be influenced by infection in healthy children. Currently, there are no data on the diagnostic capacity of RDW to detect AID in pediatric CF patients. This was a prospective observational study that investigated iron status biomarkers in 53 Dutch pediatric CF patients. AID was defined using World Health Organization criteria for SF in stable patients (no recent pulmonary exacerbation) and C-reactive protein (CRP) ≤10 mg/l. Patients with AID had higher RDW levels than patients without AID (p = 0.019). An RDW ≥13.2% showed the following test statistics: sensitivity 100%; specificity 39.4%; positive predictive value 20%; and negative predictive value 100%. Furthermore, we found a correlation between RDW and CRP in the total group that originated from the stable patients (r = 0.308; p = 0.042). In conclusion, the diagnostic capacity of RDW for detecting AID in pediatric CF patients seems limited because RDW levels might also be influenced by chronic infection/inflammation in these patients.
-
4.
Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR.
Milla, CE, Ratjen, F, Marigowda, G, Liu, F, Waltz, D, Rosenfeld, M, ,
American journal of respiratory and critical care medicine. 2017;(7):912-920
-
-
Free full text
-
Abstract
RATIONALE Combination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged 12 years and older with cystic fibrosis and homozygous for F508del-CFTR, but it has not been assessed in younger patients. OBJECTIVES In this open-label phase III trial, we evaluated the safety, tolerability, pharmacodynamics, and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6-11 years with cystic fibrosis who were homozygous for F508del-CFTR. METHODS Patients (N = 58) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications. MEASUREMENTS AND MAIN RESULTS Lumacaftor/ivacaftor was well tolerated; the safety profile was generally similar to that observed in larger lumacaftor/ivacaftor trials with older patients. Four patients discontinued (two because of drug-related adverse events: elevated liver transaminases, n = 1; rash, n = 1). No safety concerns were associated with spirometry. No significant changes in percent predicted FEV1 were observed (change from baseline at Week 24, +2.5 percentage points; 95% confidence interval [CI], -0.2 to 5.2; P = 0.0671). At Week 24, significant improvements from baseline were observed in sweat chloride (-24.8 mmol/L; 95% CI, -29.1 to -20.5; P < 0.0001), body mass index z score (+0.15; 95% CI, 0.08 to 0.22; P < 0.0001), Cystic Fibrosis Questionnaire-Revised respiratory domain score (+5.4; 95% CI, 1.4 to 9.4; P = 0.0085), and lung clearance index based on lung volume turnover required to reach 2.5% of starting N2 concentration (-0.88; 95% CI, -1.40 to -0.37; P = 0.0018). CONCLUSIONS Lumacaftor/ivacaftor was well tolerated in this young population; no new safety concerns were identified. Improvements in lung clearance index, sweat chloride, nutritional status, and health-related quality of life were observed after 24 weeks of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT01897233).
-
5.
Safety and efficacy of Creon® micro in children with exocrine pancreatic insufficiency due to cystic fibrosis.
Kashirskaya, NY, Kapranov, NI, Sander-Struckmeier, S, Kovalev, V
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2015;(2):275-81
Abstract
BACKGROUND Pancreatic enzyme replacement therapy is the foundation of nutritional management for exocrine pancreatic insufficiency (EPI). METHODS A 3-month, open-label, multicentre study in Russia assessing safety, efficacy, and ease-of-use of Creon(®) Micro (5000 lipase units/spoon) in children aged 1 month to <4 years with EPI due to cystic fibrosis. Efficacy assessments included growth parameters. RESULTS All 40 subjects (mean age 26.5 months) completed treatment. Adverse events occurred in 40% of the subjects (most commonly respiratory tract infection [15%], frequent bowel movements [8%], rhinitis, stomatitis, nasopharyngitis, and diarrhoea [all 5%]), none were serious or led to discontinuation. After 3 months, mean±SD increases from baseline z-scores were height/length-for-age 0.13±0.48, weight-for-age 0.20±0.39, and BMI-for-age 0.29±0.65. Treatment was rated 'easy' to administer by 95% caregivers and acceptance 'good'/'very good' by 90%. CONCLUSIONS Creon Micro was well tolerated. Growth development parameters increased over the 3-month treatment period. Treatment was considered easy to use and acceptance was good.
-
6.
[Nebulized colistin versus tobramycin in the treatment of chronic Pseudomonas colonization in cystic fibrosis patients].
Quintana-Gallego, E, Lopez-Campos, JL, Calero, C, Dapena, FJ
Medicina clinica. 2014;(2):59-63
Abstract
BACKGROUND AND OBJECTIVE To compare the efficacy, safety and treatment satisfaction with inhaled colistin versus tobramycin in the cure of chronic Pseudomonas colonization in cystic fibrosis patients. PATIENTS AND METHOD A quasi-experimental open paired data trial in which patients with cystic fibrosis and chronic colonization by Pseudomonas aeruginosa were included. Patients performed 2 periods of 6 consecutive months of nebulized antibiotics: inhaled tobramycin at a dose of 300 mg/12 h (Pari LC Plus(®)) and colistimethate (I-neb(®)) at a dose of 1 MIU twice a day. Visits were made monthly and at the beginning and the end of each period; we evaluated the body mass index, lung function, number of exacerbations and sputum microbiology. Patient satisfaction was assessed with 2 questionnaires of satisfaction on the treatment and the inhalation devices. RESULTS A group of 25 patients (8 men and 6 under 14 years) with a mean age of 21.4 (7.2) years and 59.8 (21.1) % of forced expiratory volume in one second (FEV1) were included. During the second period, clinical benefits were obtained in terms of lung function with an FEV1 gain of 5% at 6 months of treatment and reducing the number of exacerbations (1.84 [1.2] vs 0.8 [0.8]; P=.001). The questionnaire score was higher in period 2. CONCLUSIONS Colistimethate sodium administered through the misting system I-neb(®) provides clinical benefits in terms of exacerbations and improvement of lung function and patient satisfaction for the nebulized antibiotic treatment.
-
7.
Induced sputum compared to bronchoalveolar lavage in young, non-expectorating cystic fibrosis children.
Blau, H, Linnane, B, Carzino, R, Tannenbaum, EL, Skoric, B, Robinson, PJ, Robertson, C, Ranganathan, SC
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2014;(1):106-10
Abstract
BACKGROUND Induced sputum (IS) is feasible and safe in young CF children and is a readily accessible, non-invasive technique. However, it has not been compared to bronchoalveolar lavage (BAL), the gold standard for diagnosing lower airway infection. METHODS We compared bacterial yield from IS and BAL in 11 non-expectorating CF children, aged 3 to 7.4 years. IS samples were obtained in 10/11 cases. RESULTS Eight out of ten had the same predominant bacteria cultured from IS and BAL: Pseudomonas aeruginosa and Stenotrophomonas maltophilia[1], Staphylococcus aureus[3], and upper respiratory tract flora [4]. In one, Serratia marcescens and Haemophilus parainfluenzae were cultured from IS alone, whereas in one, non-group B Haemophilus influenzae was cultured from BAL alone. CONCLUSIONS As proof of principle, IS samples showed good bacteriologic correlation with BAL. Larger studies are recommended to confirm IS as a clinically valuable tool and measure for early intervention studies in young CF children.
-
8.
A first-year dornase alfa treatment impact on clinical parameters of patients with cystic fibrosis: the Brazilian cystic fibrosis multicenter study.
Rozov, T, Silva, FA, Santana, MA, Adde, FV, Mendes, RH, ,
Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo. 2013;(4):420-30
Abstract
OBJECTIVE To describe the clinical impact of the first year treatment with dornase alfa, according to age groups, in a cohort of Brazilian Cystic Fibrosis (CF) patients. METHODS The data on 152 eligible patients, from 16 CF reference centers, that answered the medical questionnaires and performed laboratory tests at baseline (T0), and at six (T2) and 12 (T4) months after dornase alfa initiation, were analyzed. Three age groups were assessed: six to 11, 12 to 13, and >14 years. Pulmonary tests, airway microbiology, emergency room visits, hospitalizations, emergency and routine treatments were evaluated. Student's t-test, chi-square test and analysis of variance were used when appropriated. RESULTS Routine treatments were based on respiratory physical therapy, regular exercises, pancreatic enzymes, vitamins, bronchodilators, corticosteroids, and antibiotics. In the six months prior the study (T0 phase), hospitalizations for pulmonary exacerbations occurred in 38.0, 10.0 and 61.4% in the three age groups, respectively. After one year of intervention, there was a significant reduction in the number of emergency room visits in the six to 11 years group. There were no significant changes in forced expiratory volume in one second (VEF(1)), in forced vital capacity (FVC), in oxygen saturation (SpO(2)), and in Tiffenau index for all age groups. A significant improvement in Shwachman-Kulczychi score was observed in the older group. In the last six months of therapy, chronic or intermittent colonization by P. aeruginosa was detected in 75.0, 71.4 and 62.5% of the studied groups, respectively, while S. aureus colonization was identified in 68.6, 66.6 and 41.9% of the cases. CONCLUSIONS The treatment with dornase alfa promoted the maintenance of pulmonary function parameters and was associated with a significant reduction of emergency room visits due to pulmonary exacerbations in the six to 11 years age group, with better clinical scores in the >14 age group, one year after the intervention.
-
9.
Can Burkholderia cepacia complex be eradicated with nebulised amiloride and TOBI?
Ball, R, Brownlee, KG, Duff, AJ, Denton, M, Conway, SP, Lee, TW
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2010;(1):73-4
-
10.
Safety and tolerability of a new formulation of pancrelipase delayed-release capsules (CREON) in children under seven years of age with exocrine pancreatic insufficiency due to cystic fibrosis: an open-label, multicentre, single-treatment-arm study.
Graff, GR, McNamara, J, Royall, J, Caras, S, Forssmann, K
Clinical drug investigation. 2010;(6):351-64
Abstract
Exocrine pancreatic insufficiency (EPI) is a deficiency of digestive enzymes caused by diseases such as cystic fibrosis (CF). Patients with EPI due to CF require pancreatic enzyme replacement therapy (PERT) in order to maintain adequate nutrition. A new formulation of pancrelipase delayed-release capsules (CREON) recently received US FDA approval and has demonstrated efficacy and safety in patients with CF aged > or =7 years. The objectives of this study were to observe the safety and tolerability of new formulation pancrelipase delayed-release capsules (study drug) versus the standard of care PERT (standard therapy) in children aged <7 years with CF and EPI. Secondary objectives were to assess the ease of accurate dosing of study drug, monitor clinical symptoms and compare the efficacy of both treatments. This was an open-label, multicentre, single-treatment-arm study in children aged <7 years with a confirmed diagnosis of CF and EPI. After the screening period (approximately 14 days), all patients entered a 3-day assessment period on their usual PERT (standard therapy), followed by the study drug treatment phase (10-14 days; target dose 8000 lipase units/kg bodyweight/day), which included a second 3-day assessment period. The safety and tolerability of both treatments were documented by recording adverse events (AEs). Clinical symptoms (mean daily stool frequency, abdominal pain, stool consistency and flatulence) were monitored and ease of accurate dosing, as judged by caregivers, was reported. Efficacy was determined by comparison of percent stool fat in spot stool samples collected during both 3-day assessment periods. Of the 19 patients who had informed consent from their parent/legally acceptable representative, one was withdrawn as a screen failure and was excluded from the safety and efficacy analyses; thus, 18 patients completed the study. The median age (range) was 23 (4-71) months and 13 (72%) were male. During study drug treatment, patients received a mean +/- SD dose in lipase units/kg bodyweight/day of 7542 +/- 1335 versus 6966 +/- 3392 on standard therapy. Overall, nine (50%) patients had at least one treatment-emergent AE (TEAE) whilst receiving either treatment. All TEAEs in this study were reported as mild and none resulted in patient discontinuation. The caregivers had a slight preference for study drug over standard therapy in terms of ease of accurate dosing: six (33.3%) caregivers thought the study drug was easier to dose while only one (5.6%) thought the study drug was harder to dose than standard therapy. Clinical symptom assessment results were similar between treatments. There was no clinically meaningful difference (significance not tested) between study drug and standard therapy in the mean +/- SD percent of stool fat: 28.1 +/- 9.9 and 27.9 +/- 8.9, respectively. In this study in children aged <7 years with EPI due to CF, the new formulation pancrelipase delayed-release capsules (CREON) were clinically comparable with standard therapy in terms of safety, tolerability and efficacy.