Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis.
We conducted a randomized, double-blind, ...placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1)).
The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire-revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient's quality of life) (P<0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was -48.1 mmol per liter (P<0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%).
Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride. (Funded by Vertex Pharmaceuticals and others; VX08-770-102 ClinicalTrials.gov number, NCT00909532.).
Background:
Confirmed Expanded Disability Status Scale (EDSS) progression occurring after a fixed-study entry baseline is a common measure of disability increase in relapsing-remitting multiple ...sclerosis (RRMS) studies but may not detect all disability progression events, especially those unrelated to overt relapses.
Objective:
To evaluate possible measures of disability progression unrelated to relapse using EDSS data over ≈5.5 years from the Tysabri® Observational Program (TOP).
Methods:
TOP is an ongoing, prospective, open-label study in RRMS patients receiving intravenous 300 mg natalizumab every 4 weeks. Measures of increasing disability were assessed using as a reference either study baseline score or a “roving” system that resets the reference score after ⩾24- or ⩾48-week confirmation of a new score.
Results:
This analysis included 5562 patients. Approximately 70% more EDSS progression events unrelated to relapse and 50% more EDSS worsening events overall were detected with a roving reference score (cumulative probability: 17.6% and 29.7%, respectively) than with a fixed reference baseline score (cumulative probability: 10.1% and 20.3%, respectively).
Conclusion:
In this long-term observational RRMS dataset, a roving EDSS reference value was more efficient than a study baseline EDSS reference in detecting progression/worsening events unrelated to relapses and thus the transition to secondary progressive disease.
A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to ...increase the activity of wild-type and defective cell-surface CFTR in vitro.
We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study).
At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was -3.5 mV (range, -8.3 to 0.5; P=0.02 for the within-subject comparison, P=0.13 vs. placebo), and the median change in the level of sweat chloride was -59.5 mmol per liter (range, -66.0 to -19.0; P=0.008 within-subject, P=0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P=0.008 for the within-subject comparison, P=0.56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770.
This study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis. (Funded by Vertex Pharmaceuticals and others; ClinicalTrials.gov number, NCT00457821.).
To characterize the reversibility of natalizumab-mediated changes in pharmacokinetics/pharmacodynamics in patients with multiple sclerosis (MS) following therapy interruption.
...Pharmacokinetic/pharmacodynamic data were collected in the Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis (AFFIRM) (every 12 weeks for 116 weeks) and Randomized Treatment Interruption of Natalizumab (RESTORE) (every 4 weeks for 28 weeks) studies. Serum natalizumab and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured using immunoassays. Lymphocyte subsets, α4-integrin expression/saturation, and vascular cell adhesion molecule-1 (VCAM-1) binding were assessed using flow cytometry.
Blood lymphocyte counts (cells/L) in natalizumab-treated patients increased from 2.1 × 10
to 3.5 × 10
. Starting 8 weeks post last natalizumab dose, lymphocyte counts became significantly lower in patients interrupting treatment than in those continuing treatment (3.1 × 10
vs 3.5 × 10
;
= 0.031), plateauing at prenatalizumab levels from week 16 onward. All measured cell subpopulation, α4-integrin expression/saturation, and sVCAM changes demonstrated similar reversibility. Lymphocyte counts remained within the normal range. Ex vivo VCAM-1 binding to lymphocytes increased until ≈16 weeks after the last natalizumab dose, then plateaued, suggesting reversibility of immune cell functionality. The temporal appearance of gadolinium-enhancing lesions was consistent with pharmacodynamic marker reversal.
Natalizumab's effects on peripheral immune cells and pharmacodynamic markers were reversible, with changes starting 8 weeks post last natalizumab dose; levels returned to those observed/expected in untreated patients ≈16 weeks post last dose. This reversibility differentiates natalizumab from MS treatments that require longer reconstitution times. Characterization of the time course of natalizumab's biological effects may help clinicians make treatment sequencing decisions.
This study provides Class III evidence that the pharmacodynamic markers of natalizumab are reversed ≈16 weeks after stopping natalizumab.
Abstract Background Oral naltrexone's effectiveness as an opioid antagonist has been limited due to poor patient adherence. A long-acting naltrexone formulation may be beneficial. This study ...evaluated the effects of extended-release injectable naltrexone (XR-NTX), targeted for a one-month duration of action, in blocking opioid agonist challenge effects in humans. Methods Outpatient non-dependent opioid abusers ( N = 27) were randomly assigned to a single double-blind IM administration of 75, 150, or 300 mg XR-NTX. To assess the extent of opioid blockade, hydromorphone challenges (0, 3, 4.5, 6 mg IM in ascending order at 1-h intervals up to 13.5 mg total) were given at pretreatment baseline and on days 7, 14, 21, 28, 42, and 56. Opioid blockade was assessed via (1) tolerability of the ascending hydromorphone doses; (2) visual analog scale (VAS) ratings of subjective opioid effects and (3) pupil diameter. Effects on the VAS and pupils were assessed via the slope of the time-action function over ascending hydromorphone doses, with zero slope indicating complete blockade. Results Blockade of the VAS “any drug effect” response to 3 mg hydromorphone was complete for 14, 21, and 28 days, respectively, for the XR-NTX doses of 75, 150, and 300 mg. Subjective effects were more readily blocked than was pupil constriction. Higher hydromorphone doses produced only modest increases in agonist effects. With the 300 mg XR-NTX dose the slope of VAS responses remained at or near zero for one month even with maximal cumulative hydromorphone dosing. Conclusions These data quantify the month-long opioid blockade underlying XR-NTX's efficacy in opioid dependence treatment.
Background:
No evidence of disease activity (NEDA) is a composite measurement, incorporating clinical and magnetic resonance imaging (MRI) elements of disease activity to sensitively evaluate the ...therapeutic efficacy of treatments for relapsing–remitting multiple sclerosis (RRMS).
Objective:
To assess the NEDA status of patients treated with peginterferon β-1a in the ADVANCE and ATTAIN studies and explore its predictive value on longer-term clinical outcomes.
Methods:
ATTAIN was a 2-year extension of the pivotal 2-year ADVANCE study of peginterferon β-1a for RRMS. Achievement of clinical NEDA, MRI NEDA, or overall NEDA was calculated cumulatively and by year over 4 years. Clinical outcomes during ATTAIN were analyzed based on NEDA status at the end of ADVANCE.
Results:
Significantly more patients treated with peginterferon β-1a every 2 weeks than every 4 weeks achieved clinical NEDA (60.6% versus 50.6%, p = 0.0063) and MRI NEDA (28.3% versus 15.8%, p = 0.0005) through year 4 and overall NEDA through year 3 (20.9% versus 13.9%, p = 0.0160). Over 4 years, 15.8% of patients in the every 2 weeks group and 10.7% of patients in the every 4 weeks group maintained overall NEDA (p = 0.0584). Achievement of clinical NEDA, MRI NEDA, or overall NEDA in ADVANCE was predictive of annualized relapse rate in ATTAIN; achievement of clinical NEDA in ADVANCE was also predictive of NEDA achievement and confirmed disability worsening in ATTAIN.
Conclusions:
Peginterferon β-1a every 2 weeks is associated with higher levels of NEDA compared with placebo in year 1 or peginterferon β-1a every 4 weeks in years 2–4. Overall NEDA within the first 2 years of treatment may be prognostic of long-term clinical outcomes.
Clinicaltrials.gov: NCT01332019
Nasal potential difference (NPD) is used as a biomarker of the cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) activity. We evaluated methods to detect ...changes in chloride and sodium transport by NPD based on a secondary analysis of a Phase II CFTR-modulator study. Thirty-nine subjects with CF who also had the G551D-CFTR mutation were randomized to receive ivacaftor (Kalydeco™; also known as VX-770) in four doses or placebo twice daily for at least 14 days. All data were analyzed by a single investigator who was blinded to treatment assignment. We compared three analysis methods to determine the best approach to quantify changes in chloride and sodium transport: (1) the average of both nostrils; (2) the most-polarized nostril at each visit; and (3) the most-polarized nostril at screening carried forward. Parameters of ion transport included the PD change with zero chloride plus isoproterenol (CFTR activity), the basal PD, Ringer's PD, and change in PD with amiloride (measurements of ENaC activity), and the delta NPD (measuring CFTR and ENaC activity). The average and most-polarized nostril at each visit were most sensitive to changes in chloride and sodium transport, whereas the most-polarized nostril at screening carried forward was less discriminatory. Based on our findings, NPD studies should assess both nostrils rather than a single nostril. We also found that changes in CFTR activity were more readily detected than changes in ENaC activity, and that rigorous standardization was associated with relatively good within-subject reproducibility in placebo-treated subjects (± 2.8 mV). Therefore, we have confirmed an assay of reasonable reproducibility for detecting chloride-transport improvements in response to CFTR modulation.
Extended-release naltrexone (XR-NTX) is a once-a-month injectable formulation that is Food and Drug Administration-approved for the treatment of alcohol dependence in patients able to abstain from ...alcohol before treatment initiation. This paper presents the results of an analysis of efficacy data from a subgroup of patients with 4 days or more of voluntary abstinence before treatment initiation (n = 82) on a wide range of drinking-related outcomes. In these patients, all of whom received counseling, the rate of abstinence was severalfold higher for XR-NTX 380 mg compared with placebo: median time to first drink was 41 days versus 12 days, respectively; rate of continuous abstinence at end of the study was 32% versus 11% (P = 0.02). Extended-release naltrexone 380 mg, compared with placebo, substantially increased time to first heavy drinking event (>180 days vs 20 days; P = 0.04) and decreased the median number of any drinking days per month by 90% (0.7 vs 7.2; P = 0.005) and heavy drinking days per month by 93% (0.2 days vs 2.9 days; P = 0.007). The XR-NTX 380 mg group also had more than twice as many responders compared with placebo (70% vs 30%; P = 0.006; responder defined as having no more than 2 heavy drinking days in any consecutive 28-day period) and experienced greater improvement in gamma-glutamyl transpeptidase levels (P = 0.03). Outcomes for XR-NTX 190 mg (n = 26) were generally intermediate, demonstrating a dose-response effect. In conclusion, XR-NTX 380 mg prolonged abstinence and reduced the number of heavy drinking days and drinking days in patients who were abstinent for as few as 4 days before treatment initiation.
Background: Oral naltrexone is effective in the treatment of alcohol dependence; however, a major limitation of its clinical utility is poor patient adherence to the daily dosing schedule. A ...biodegradable, long‐acting naltrexone microsphere formulation was developed to achieve continuous naltrexone exposure for 1 month in the treatment of alcohol dependence.
Methods: The single‐ and multiple‐dose safety and pharmacokinetics of a long‐acting naltrexone microsphere preparation were evaluated in healthy subjects. One group of subjects (n=28) received a single dose of oral naltrexone 50 mg followed by a single gluteal intramuscular (IM) injection of long‐acting naltrexone 190 or 380 mg or placebo. A different group of subjects (n=14) received oral naltrexone 50 mg daily for 5 days, followed by IM long‐acting naltrexone 380 mg or placebo every 28 days for a total of 4 doses. A 7‐day washout period separated oral and IM administrations. Blood samples were collected to determine plasma concentrations of naltrexone and the primary metabolite, 6β‐naltrexol.
Results: After a single IM injection of long‐acting naltrexone 380 mg, naltrexone plasma concentrations were measurable in all subjects for at least 31 days postdose. The pharmacokinetics were proportional to the dose and multiple dose observations were consistent with single dose observations. Mean apparent elimination half‐lives for naltrexone and 6β‐naltrexol ranged from 5 to 7 days. Exposure to 6β‐naltrexol was reduced with IM injection compared with that oral administration. No serious adverse events occurred.
Conclusions: This study demonstrated that the long‐acting naltrexone formulation was well tolerated, displayed predictable pharmacokinetics, and resulted in no meaningful drug accumulation upon multiple dosing. Intramuscular administration avoids first‐pass metabolism and changes the exposure ratio of 6β‐naltrexol to naltrexone compared with oral administration. By providing continuous exposure to naltrexone for several weeks following IM injection, this long‐acting naltrexone formulation may offer therapeutic benefit to those patients who experience difficulty adhering to the daily administration schedule necessitated by oral naltrexone therapy.
Background: Extended‐release naltrexone (XR‐NTX) is a once‐a‐month injectable formulation for the treatment of alcohol dependence previously shown to reduce drinking and heavy drinking relative to ...placebo (Garbutt et al., 2005). A 24‐week, randomized, double‐blind, placebo‐controlled study established the efficacy and safety of XR‐NTX in this patient population. In this report, the effect of XR‐NTX on quality of life (QOL) was examined.
Methods: Alcohol‐dependent patients were randomly assigned to receive XR‐NTX 380 mg (N = 205), XR‐NTX 190 mg (N = 210), or placebo (N = 209), combined with a standardized psychosocial intervention. QOL was assessed using the Medical Outcomes Study 36‐item short‐form health survey, administered at baseline and at 4‐week intervals during 24 weeks of treatment.
Results: Compared with U.S. population norms, patients showed initial impairment in the health‐related QOL domains of mental health, social functioning, and problems with work or other daily activities due to emotional problems. Adherence to all 6 injections was 65% for XR‐NTX 190 mg, 63% for XR‐NTX 380 mg, and 64% for placebo. Generalized estimating equations analyses using an intention‐to‐treat sample revealed that XR‐NTX 380 mg was associated with significantly greater improvements from baseline in mental health (p = 0.0496), social functioning (p = 0.010), general health (p = 0.048), and physical functioning (p = 0.028), compared with placebo. Linear regression analyses revealed that reductions from baseline in drinking (percentage of drinking days and percentage of heavy drinking days in the last 30 days) were significantly (p < 0.05) correlated with improvements in quality of life.
Conclusion: Extended‐release naltrexone 380 mg in combination with psychosocial intervention was associated with improvements in QOL, specifically in the domains of mental health, social functioning, general health, and physical functioning.
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