Validation of the post sleep questionnaire for assessing subjects with restless legs syndrome: results from two double-blind, multicenter, placebo-controlled clinical trials.

BACKGROUND: Because of the subjective nature of Restless Legs Syndrome (RLS) symptoms and the impact of these symptoms on sleep, patient-reported outcomes (PROs) play a prominent role as study endpoints in clinical trials investigating RLS treatments. The objective of this study was to validate a new measure, the Post Sleep Questionnaire (PSQ), to assess sleep dysfunction in subjects with moderate-to-severe RLS symptoms. METHODS: Pooled data were analyzed from two 12-week, randomized, placebo-controlled trials of gabapentin enacarbil (N = 540). At baseline and Week 12, subjects completed the PSQ and other validated health surveys: IRLS Rating Scale, Clinical Global Impression of Improvement (CGI-I), Profile of Mood States (POMS), Medical Outcomes Study Scale-Sleep (MOS-Sleep), and RLS-Quality of Life (RLSQoL). Pooled data were used post hoc to examine the convergent, divergent, known-group validity and the responsiveness of the PSQ. RESULTS: Convergent validity was demonstrated by significant correlations between baseline PSQ items and total scores of IRLS, POMS, RLSQoL, and the MOS-Sleep Scale (p ≤ 0.007 each). Divergent validity was demonstrated through the lack of significant correlations between PSQ items and demographic characteristics. Correlations (p < 0.0001) between RLS severity groups and PSQ items demonstrated known-group validity. Mean changes in investigator- and subject-rated CGI-I scores for each PSQ item (p < 0.0001) demonstrated the PSQ's responsiveness to patient change as reported by their care provider. CONCLUSIONS: Although these analyses were potentially limited by the use of clinical trial data and not prospective data from a study conducted solely for validation purposes, the PSQ demonstrated robust psychometric properties and is a valid instrument for assessing sleep and sleep improvements in subjects with moderate-to-severe RLS symptoms. TRIAL REGISTRATION: This study analyzed data from two registered trials, NCT00298623 and NCT00365352.

Efficacy of gabapentin enacarbil vs placebo in patients with postherpetic neuralgia and a pharmacokinetic comparison with oral gabapentin.

BACKGROUND: The efficacy of gabapentin in some patients with postherpetic neuralgia (PHN) may be limited by suboptimal drug exposure from unpredictable and saturable absorption. Gabapentin enacarbil (GEn) was designed for absorption by high-capacity transporters expressed throughout the intestine and undergoes rapid postabsorption hydrolysis to gabapentin. GEn extended-release tablets provide sustained, dose-proportional gabapentin exposure. This study assessed the efficacy of GEn vs placebo and compared the pharmacokinetics of gabapentin after oral dosing of GEn or gabapentin in patients with PHN. METHODS: In this double-blind, randomized study, 115 patients with PHN completed a 7-day baseline period and 11-day gabapentin run-in period. Eligible patients were randomized and 101 received double-blind GEn 1,200 mg (624 mg-equivalents gabapentin) (n = 47) or placebo (n = 54), twice daily for 14 days. We evaluated patient-reported pain, sleep, mood, global improvement, and adverse events, plus gabapentin pharmacokinetics. RESULTS: The improvement in mean weekly pain scores from baseline to the end of treatment (primary endpoint) was significantly greater for GEn (-2.1) vs placebo (-1.2), P = 0.0321. Significant improvements from GEn vs placebo were also seen in sleep, mood, and patient global assessment (P < 0.05). With a 31% lower daily dose of gabapentin equivalents, GEn tablets provided a significant increase in average steady state gabapentin concentrations vs gabapentin capsules in the same patients (n = 42; P = 0.0050). CONCLUSIONS: GEn was effective in providing PHN pain relief, improved gabapentin exposure compared with gabapentin capsules, and was generally safe and well tolerated in patients with PHN.

Velusetrag accelerates gastric emptying in subjects with gastroparesis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 study.

BACKGROUND: Gastroparesis is a serious gastrointestinal (GI) condition characterised by delayed gastric emptying (GE). Velusetrag-a potent, selective, pan-gastrointestinal 5-hydroxytryptamine type 4 receptor agonist-is under investigation for treatment of GI motility disorders including gastroparesis. AIMS: To assess the efficacy and safety of velusetrag for accelerating GE in subjects with diabetic or idiopathic gastroparesis. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, three-period fixed-sequence crossover phase 2 study, subjects with diabetic or idiopathic gastroparesis received oral velusetrag (5, 15 or 30 mg) or placebo once daily for 7 days each. The primary outcome was proportion of subjects achieving ≥20% reduction in GE half-time (GE t1/2 ) from each treatment period baseline on day 7. Absolute and percent changes from baseline GE t1/2 were also assessed. GE was measured using a [13 C]-octanoate breath test. Safety was evaluated from treatment-emergent adverse events (TEAEs). RESULTS: Thirty-four subjects (67.6% female; mean age, 46.3 years; 52.9% with diabetic gastroparesis) were included. Treatment with velusetrag 30 mg significantly increased the proportion of subjects with ≥20% reduction from baseline GE t1/2 compared with placebo (52% vs 5%, P = 0.002), and GE t1/2 was numerically reduced following all three doses of velusetrag relative to placebo treatment. Efficacy was similar between subjects with diabetic and idiopathic gastroparesis. Velusetrag treatment was generally well tolerated; most TEAEs were mild and related to GI transit acceleration. CONCLUSIONS: Velusetrag accelerates GE in subjects with diabetic or idiopathic gastroparesis and is generally well tolerated in this population (Clinicaltrials.gov NCT01718938).

The first evaluation of a novel vitamin K antagonist, tecarfarin (ATI-5923), in patients with atrial fibrillation.

BACKGROUND: Tecarfarin (ATI-5923) is a novel oral vitamin K antagonist. Unlike warfarin, it is metabolized by esterases, escaping metabolism by the cytochrome P450 system and thereby avoiding cytochrome P450-mediated drug-drug or drug-food interactions as well as genetic variations found in the cytochrome P450 system. Both tecarfarin and warfarin can be monitored with the international normalized ratio. We hypothesized that the time in therapeutic range for tecarfarin will exceed values usually experienced with warfarin. METHODS AND RESULTS: This was a 6- to 12-week open-label, multicenter, phase IIA study of 66 atrial fibrillation patients with a mild to moderate risk of stroke to determine the safety and tolerability of tecarfarin and to ascertain an optimal tecarfarin dosing regimen. Sixty-four subjects (97%) were taking warfarin at enrollment and were switched to tecarfarin. After the initial 3 weeks of tecarfarin treatment, the mean interpolated time in therapeutic range was 71.4%. Only 10.9% of patients had time in therapeutic range of <45%. Times in extreme international normalized ratio ranges of <1.5 and >4.0 were 1.2% and 1.2%, respectively. The median daily dose (for an individual patient) to maintain an international normalized ratio between 2 and 3 was 15.6 mg (range, 6 to 29 mg). CONCLUSIONS: This is the first study of tecarfarin in patients with atrial fibrillation. It appears that tecarfarin may possess advantages over the currently available standard of care, warfarin, by improving time in therapeutic range. Adequately powered prospective trials are warranted to definitively compare tecarfarin with warfarin in clinical settings for which warfarin is indicated.

A randomized, double-blind, placebo-controlled, crossover study of XP13512/GSK1838262 in the treatment of patients with primary restless legs syndrome.

STUDY OBJECTIVE: To evaluate the efficacy and tolerability of XP13512/ GSK1838262, an investigational nondopaminergic agent for the treatment of moderate-to-severe primary restless legs syndrome (RLS). DESIGN: Randomized, double-blind, placebo-controlled, crossover trial. SETTING: Nine US clinical sites. PATIENTS: Thirty-eight treatment-naive subjects with RLS (mean +/- SD age 50.1 +/- 13.2 years). INTERVENTIONS: XP13512 1800 mg/day followed by placebo or placebo followed by XP13512 1800 mg/day for 14 days, with a 7-day washout between treatment periods. MEASUREMENTS AND RESULTS: The primary endpoint was mean change from baseline International RLS Study Group rating scale (IRLS) total score on Day 14, analyzed using analysis of variance with sequence, period, and treatment as fixed effects and subjects within sequence as a random effect. XP13512 significantly reduced IRLS total score on Day 14 compared with placebo (mean +/- SD: XP13512 -12.1 +/-6.5, placebo -1.9 +/- 6.3; P < 0.0001). Polysomnographic data showed that XP13512 significantly improved sleep architecture on Day 14 compared with placebo (mean +/- SD change from baseline sleep time [minutes]: stage 1: XP13512 -9.8 +/- 23.9, placebo 0.4 +/-23.2; adjusted P<0.0054, nominal P<0.0001; stage 3/4 (slow-wave sleep): XP13512 22.8 +/- 40.8, placebo 1.4 +/- 34.3; adjusted P=0.0092, nominal P=0.0002). The most frequently reported adverse events were somnolence (XP13512 30.6%, placebo 2.8%) and dizziness (XP13512 27.8%, placebo 5.6%). CONCLUSIONS: XP13512 1800 mg/day significantly reduced RLS symptoms, improved sleep, and was generally well tolerated in subjects with moderate-to-severe primary RLS across 14 days of treatment.

Clinical pharmacokinetics of XP13512, a novel transported prodrug of gabapentin.

Gabapentin absorption occurs in only a limited region of the small intestine and saturates at doses used clinically, resulting in dose-dependent pharmacokinetics, high interpatient variability, and potentially ineffective drug exposure. XP13512/GSK1838262 is a novel transported prodrug of gabapentin that is absorbed throughout the entire length of the intestine by high-capacity nutrient transporters. In 4 studies of healthy volunteers (136 subjects total), the pharmacokinetics of XP13512 immediate- and extended-release formulations were compared with those of oral gabapentin. XP13512 immediate-release (up to 2800 mg single dose and 2100 mg twice daily) was well absorbed (>68%, based on urinary recovery of gabapentin), converted rapidly to gabapentin, and provided dose-proportional exposure, whereas absorption of oral gabapentin declined with increasing doses to <27% at 1200 mg. Compared with 600 mg gabapentin, an equimolar XP13512 extended-release dose provided extended gabapentin exposure (time to maximum concentration, 8.4 vs 2.7 hours) and superior bioavailability (74.5% vs 36.6%). XP13512 may therefore provide more predictable gabapentin exposure and decreased dosing frequency.

Pharmacokinetics and pharmacodynamics of tecarfarin, a novel vitamin K antagonist oral anticoagulant.

Tecarfarin is a vitamin K antagonist (VKA) with reduced propensity for drug interactions. To evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety of tecarfarin, we performed single ascending dose (SAD) (n=66), multiple ascending dose (MAD) (n=43), and tecarfarin versus warfarin (n=28) studies in human volunteers. In the SAD, tecarfarin was administered to 5 of 6 subjects (1 received placebo) in each of 11 cohorts. AUC0-∞ exhibited linearity and dose proportionality. Elimination T1/2 ranged from 87-136 hours (h) across all doses. In the MAD, tecarfarin was administered to 5 of 6 volunteers in each of 7 cohorts. The starting dose was continued until the subject's INR reached the target range (TR) of 1.7 to 2.0. Dosing was down-titrated if the TR was achieved. Elimination T1/2 ranged from 107-140 h. Doses <10 mg had insignificant effect on INR. Higher doses raised INRs and required down-titration to maintain the TR. Steady state INR dosing was 10-20 mg. INR declined promptly after discontinuation. In the comparative study, subjects received tecarfarin or warfarin and dose titrated to a TR of 1.5-2.0. Mean dose after TR was achieved was 13.9 mg (range 10.0-25.5 mg) for tecarfarin and 5.3 mg (range 2.5-9.0 mg) for warfarin. At similar INR levels, the concentration of coagulation factors II, VII, IX, and X were similar for tecarfarin and warfarin. Tecarfarin was tolerated well without serious adverse events in all three studies.

A randomised, double blind comparison of tecarfarin, a novel vitamin K antagonist, with warfarin. The EmbraceAC Trial.

Tecarfarin is a novel vitamin K antagonist that is metabolised by carboxyl estererase, thereby eliminating the variability associated with cytochrome-mediated metabolism. EmbraceAC was designed to compare the quality of anticoagulation with tecarfarin and warfarin as determined by time in therapeutic range (TTR). In this phase 2/3 randomised and blinded trial, 607 patients with indications for chronic anticoagulation were assigned to warfarin (n=304) or tecarfarin (n=303). Dosing of study drugs was managed by a centralised dose control centre, which had access to genotyping. The primary analysis tested superiority of tecarfarin over warfarin for TTR. Patients were recruited between May 12, 2008 and May 12, 2009. TTR with tecarfarin and warfarin were similar (72.3 % and 71.5 %, respectively; p=0.51). In those taking CYP2C9 interacting drugs, the TTR on tecarfarin (n=92) was similar to that on warfarin (n=87, 72.2 % and 69.9 %, respectively; p=0.15). In patients with mechanical heart valves, the TTR of tecarfarin (n=42) was similar to that of warfarin (n=42, 68.4 % and 66.3 %, respectively; p=0.51). The same was true for the TTR in patients with any CYP2C9 variant allele and on CYP2C9-interacting drugs (tecarfarin, n=24, 76.5 % vs warfarin, n=31, 69.5 %; p=0.09). There was no difference in thromboembolic or bleeding events. In conclusion, superiority of tecarfarin over warfarin for TTR was not demonstrated. The TTR with tecarfarin was similar to that with well-controlled warfarin and tecarfarin appeared to be safe and well tolerated with few major bleeding and no thrombotic events. Favourable trends in certain subpopulations make tecarfarin a promising oral anticoagulant that deserves further study.

Electrocardiographic and cardiovascular diagnostic characteristics of patients receiving long-term opioid therapy for pain.

OBJECTIVE: To examine cardiovascular and electrocardiogram (ECG) abnormalities seen in patients with chronic pain receiving long-term opioid therapy and to compare them with findings in normal subjects. SETTING: Clinical pharmaceutical drug trial in a phase I pharmacology unit (normal subjects) and multiple phase 2b study sites (pain patients). PATIENTS: Four hundred sixty-one pain patients with constipation due to long-term opioid therapy who were screened for a clinical trial of an investigational treatment for opioid-induced constipation. INTERVENTIONS: None; all data used in this study were obtained prior to drug treatment. MAIN OUTCOME MEASURES: This is a retrospective analysis of ECG abnormalities and clinical cardiovascular abnormalities in study participants compared with those in a normal reference group of 36,999 subjects. RESULTS: Numerical ECG values were modestly but not clinically significantly different in the pain patients requiring opioids (mean heart rate +1.5 BPM, PR +5.2 milliseconds, QRS -4.7 milliseconds, and QT corrected for heart rate using the Fridericia formula +7.2 milliseconds). The largest difference in ECG diagnoses between the two groups was a fivefold greater incidence of previous myocardial infarction in the pain patient group (4.1 percent vs 0.8 percent). In addition, 50 percent of the pain patient group had a clinical cardiovascular diagnosis. CONCLUSIONS: Patients with significant chronic pain requiring opioids have underlying clinical disorders that may be associated with abnormal cardiovascular physiology and ECGs. Clinicians who manage patients with chronic pain should be aware of the higher incidence of cardiovascular disease in this group.

A randomized trial of budiodarone in paroxysmal atrial fibrillation.

OBJECTIVE: The aim of this study was to investigate the preliminary safety and efficacy of three doses of budiodarone in patients with paroxysmal atrial fibrillation. BACKGROUND: Budiodarone is a chemical analogue of amiodarone and shares its mixed ion channel electrophysiological properties. It has a shorter half-life than amiodarone. METHODS: Patients with paroxysmal atrial fibrillation and a previously implanted dual-chamber pacemaker capable of storing electrograms for at least 4 weeks were enrolled. Pacemaker memories were used to quantify atrial tachycardia/atrial fibrillation burden (AT/AFB). All antiarrhythmic drugs were stopped for greater than five half-lives and amiodarone greater than 3 months prior to enrollment. Following a 4-week baseline period to assess AT/AFB off antiarrhythmic drugs, patients with AT/AFB between 3% and 70% were blindly randomized to placebo, 200, 400, or 600 mg BID of budiodarone for 12 weeks followed by a 4-week washout period. Pacemakers were interrogated and safety assessed every 4 weeks. Pacemaker-derived electrograms were adjudicated blinded to treatment assignment. The primary study endpoint was percent change from baseline AT/AFB over 12 weeks of treatment compared to placebo. RESULTS: Of 72 randomized patients, 61 completed the study. The median reduction of AT/AFB for the 400 and 600 mg BID groups vs. placebo was 54% and 74% (p = 0.01 and 0.001), respectively. The budiodarone dose-response was statistically significant (p < 0.001). Number and duration of AT/AF episodes were reduced. CONCLUSIONS: In this preliminary study, budiodarone at both higher doses significantly reduced AT/AFB. The study is novel because dual-chamber pacemakers, previously placed for standard clinical indications, were successfully used to monitor AT/AFB.

Tecarfarin, a novel vitamin K reductase antagonist, is not affected by CYP2C9 and CYP3A4 inhibition following concomitant administration of fluconazole in healthy participants.

Comparative pharmacokinetics of vitamin K epoxide reductase antagonists tecarfarin and warfarin were assessed before and after coadministration for 21 days of the CYP450 inhibitor fluconazole in a randomized, open-label, single-center drug interaction study. Twenty healthy adult participants were randomized 1:1 to receive approximately equipotent single oral doses of tecarfarin (50 mg) or warfarin (17.5 mg). Following 7 days of baseline serial blood level collections, each participant received oral fluconazole 400 mg daily for 21 days. A second identical single oral dose of tecarfarin or warfarin was given 14 days after starting fluconazole with serial pharmacokinetic sampling. Key pharmacokinetic parameters C(max), t(max), AUC(0-168), apparent clearance, and t(1/2) demonstrated no tecarfarin-fluconazole interaction but a strong warfarin-fluconazole interaction. The ratio of log-transformed mean AUC(0-168) with versus without fluconazole for tecarfarin was 91.2% (90% confidence interval [CI]: 83.3-99.8) and for racemic warfarin was 213% (90% CI: 202-226). The 90% CI was entirely within the standard 80% to 125% bioequivalence interval for tecarfarin but well outside the bioequivalence interval for warfarin, confirming a clinically significant pharmacokinetic interaction between warfarin and fluconazole. In contrast, tecarfarin pharmacokinetics were apparently unchanged by fluconazole.

Antithrombotic activity of the novel oral anticoagulant, Tecarfarin [Sodium 3-[4-((1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yloxy) carbonyl) benzyl]-2-oxo-2H-chromen-4-olate] in animal models.

The antithrombotic activity of tecarfarin, a novel orally active vitamin K epoxide reductase inhibitor, was assessed in canine and rabbit thrombosis models. In dogs, once-daily oral doses of 0.5mg/kg tecarfarin selectively reduced the levels of the vitamin K-dependent coagulation factors (factors II, VII, IX, and X) and prolonged the prothrombin time (PT). A 4 to 7day course of oral tecarfarin (0.05 - 0.5mg/kg) prolonged the PT by 3 to 5-fold and reduced thrombus formation in arterial and venous segments subjected to a combination of electrical injury and flow-limiting constriction. To compare the effects of tecarfarin with those of warfarin, rabbits were given once-daily oral doses of 1mg/kg tecarfarin, 1.5mg/kg warfarin, or saline for 2days. After verifying increases in the PT with tecarfarin and warfarin, blood loss from standardized ear incisions was measured to assess hemorrhagic potential. Then, after intravenous injection of (125)I-labeled rabbit fibrinogen, thrombosis was induced in an isolated jugular vein segment by a combination of balloon catheter-induced endothelial denudation and venous occlusion. Compared with the saline control, both tecarfarin and warfarin prolonged the PT, increased blood loss from the ear incisions, and attenuated thrombus formation. Thus, like warfarin, tecarfarin attenuates venous and arterial thrombus formation in animal models by reducing the levels of the vitamin K-dependent coagulation factors.

Gabapentin enacarbil in restless legs syndrome: a phase 2b, 2-week, randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Assess the efficacy and tolerability of gabapentin enacarbil (GEn), a transported prodrug of gabapentin with improved gabapentin exposure, in adults with moderate-to-severe primary restless legs syndrome. METHODS: This 14-day, double-blind, randomized, controlled trial of GEn at 1200 or 600 mg or placebo taken once daily, evaluated the mean change from baseline International Restless Legs Scale (IRLS) total score at end of treatment (day 14:primary comparison, GEn at 1200 mg vs placebo). Secondary end points included Clinical Global Impression-Improvement scale outcomes at day 14. RESULTS: Ninety-five subjects were randomized (GEn: 1200 mg, n = 33 and 600 mg, n = 29; placebo, n = 33); 2 subjects (GEn at 1200 mg) withdrew because of adverse events. At day 14,the mean (SD) change from baseline IRLS total score was significantly greater with GEn at 1200 mg (-16.1 [7.93]) compared with placebo (-8.9 [7.72]; adjusted mean treatment difference, -7.2; P < 0.0001). Investigator-rated Clinical Global Impression-Improvement scale responses also significantly favored GEn at 1200 mg compared with placebo (P G 0.0001).The mean (SD) change from baseline IRLS total score with GEn at 600 mg at day 14 was -9.1 (5.95), similar to placebo. The most commonly reported treatment-emergent adverse events were somnolence (GEn: 1200 mg, 36% and 600 mg, 14%; placebo,15%) and dizziness (GEn: 1200 mg, 18% and 600 mg, 14%; placebo, 3%), most of which were rated mild or moderate in intensity. CONCLUSIONS: Gabapentin enacarbil at 1200 mg significantly improved restless legs syndrome symptoms compared with placebo. Efficacy outcomes for GEn at 600 mg were similar to placebo. Both GEn doses were generally well tolerated.