Evaluation of Quality of Life, Functioning, Disability, and Work/School Productivity Following Treatment with an Extended-Release Hydrocodone Tablet Formulated with Abuse-Deterrence Technology: A 12-month Open-label Study in Patients with Chronic Pain.

BACKGROUND: This phase 3 study evaluated quality of life, functioning, and productivity after treatment with extended-release (ER) hydrocodone formulated with CIMA® Abuse-Deterrence Technology platform. METHODS: Patients with chronic pain were rolled over from a 12-week placebo-controlled hydrocodone ER study or were newly enrolled. Hydrocodone ER doses were titrated (15 to 90 mg every 12 hours) to an analgesic dose, and patients received up to 52 weeks of open-label treatment. Assessments included Clinician Assessment of Patient Function (CAPF), Patient Assessment of Function (PAF), Brief Pain Inventory-Short Form (BPI-SF), 36-item Short-Form Health Survey (SF-36), Sheehan Disability Scale (SDS), and World Health Organization Health and Work Performance Questionnaire-Short Form (HPQ-SF). RESULTS: Of 330 enrolled patients, 291 composed the full analysis population. By week 4, ≥ 50% of patients showed improvement from baseline in all 5 CAPF domains (general activities, walking, work/daily living, relationships, and enjoyment of life) and 6 of 7 PAF domains (work attendance, work performance, walking, exercise, socializing, and enjoying life). Mean decreases from baseline of 2 to 3 points were noted for BPI-SF pain interference questions from week 4 through endpoint. Mean improvements from baseline to endpoint in SF-36 subscales ranged from 3.3 to 22.3, and SDS scores improved from moderate (4.8 to 5.1) to mild (2.5 to 2.8) disruptions in work/school, social life, and family life. At endpoint, mean HPQ-SF absolute absenteeism scores decreased from 13.6 to 10.0 hours lost/month and absolute presenteeism scores improved from 67.0 to 77.1. CONCLUSIONS: Patients receiving hydrocodone ER showed early numeric improvements in functioning that continued throughout this 12-month study.

Twelve-month, open-label assessment of long-term safety and abuse potential of hydrocodone extended-release formulated with abuse-deterrence technology in patients with chronic pain.

OBJECTIVE: To evaluate long-term safety of hydrocodone extended-release (ER) formulated with CIMA(®) Abuse-Deterrence Technology platform. DESIGN: Phase 3, open-label study. SETTING: Sixty-one US study centers. PATIENTS: Patients with chronic pain newly enrolled or rolled over from a 12-week, placebo-controlled hydrocodone ER study; 330 patients enrolled, 329 patients received study drug, and 189 completed the study. INTERVENTION: After titrating to an analgesic dose (15-90 mg every 12 hours), patients received ≤ 52 weeks of open-label treatment. SAFETY: adverse events (AEs), vital signs, laboratory values, electrocardiograms, and audiometry. Abuse potential: drug loss and diversion, Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), Addiction Behaviors Checklist (ABC), Current Opioid Misuse Measure (COMM) questionnaires, and Patient Global Assessment (PGA) of pain control. RESULTS: Of 329 patients who received ≥ 1 hydrocodone ER dose, 284 (86 percent) reported ≥ 1 AE and 27 (8 percent) experienced ≥ 1 serious AE. Sixty-two (19 percent) patients withdrew because of AEs, and two AEs leading to death were reported. No serious AEs or AEs leading to death were considered treatment related by the investigator. There were no clinically meaningful trends in other safety assessments. SOAPP-R, ABC, and COMM scores demonstrated low risk of aberrant drug-related behavior. Good/excellent PGA responses were reported by 20 percent of patients at baseline and 75 percent at endpoint. The incidence of drug loss (11 percent) and diversion (2 percent) was low. CONCLUSIONS: Hydrocodone ER demonstrated acceptable safety when administered for ≤ 12 months in patients with chronic pain. Low occurrence of aberrant drugrelated behavior may support the abuse-deterrence properties of hydrocodone ER.

Efficacy and safety of a hydrocodone extended-release tablet formulated with abuse-deterrence technology in patients with moderate-to-severe chronic low back pain.

OBJECTIVE: To evaluate efficacy and safety of hydrocodone bitartrate extended release (ER) tablets developed with CIMA(®) Abuse-Deterrence Technology (ADT) versus placebo in alleviating moderate-to-severe pain in patients with chronic low back pain. DESIGN: Phase 3, randomized, double-blind study consisting of a screening period (7-14 days), open-label titration period (≤ 6 weeks), and double-blind treatment period (≤ 12 weeks). SETTING: Seventy-eight US centers. MAIN OUTCOME MEASURES: Changes from baseline at week 12 in weekly average of daily worst pain intensity (WPI; primary efficacy measure), weekly average pain intensity (API; secondary efficacy measure), adverse events (AEs), and study drug loss and diversion. RESULTS: Patients (N = 625) who entered open-label dose titration and identified the analgesic hydrocodone ER dose (30-90 mg every 12 h) providing optimal pain relief with minimal AEs were randomized to hydrocodone ER (n = 191) or placebo (n = 180) for double-blind treatment at the identified dose; 297 patients completed the study. Least squares means [SE] changes from baseline were significantly greater (worsening pain; 11-point scale) with placebo than hydrocodone ER in weekly average of daily WPI (0.74 [0.15] vs 0.11 [0.14]; p < 0.001) and weekly API (0.55 [0.14] vs -0.03 [0.12]; p < 0.001). The most common AEs with hydrocodone ER were constipation (14 percent) and nausea (10 percent). Study drug loss (≤ 4 percent) and diversion (≤ 2 percent) rates were low. CONCLUSIONS: Hydrocodone ER formulated with ADT was significantly more effective than placebo in alleviating chronic low back pain and demonstrated a safety profile consistent with that of opioids, with a low occurrence of study drug loss and diversion.

Dose titration of intramuscular interferon beta-1a reduces the severity and incidence of flu-like symptoms during treatment initiation.

BACKGROUND/OBJECTIVE: Flu-like symptoms (FLS) are common side effects of interferon beta (IFNß) therapy and can negatively affect the willingness of patients with multiple sclerosis to initiate therapy. Although dose titration is commonly used to reduce the severity and incidence of IFNß-related FLS during treatment initiation, these benefits have not been confirmed in a well controlled study. The objective of this randomized, dose-blinded, parallel-group study was to assess the effect of dose titration on the severity and incidence of FLS during the initial 8 weeks of once-weekly intramuscular (IM) IFNß-1a administration. METHODS: Healthy volunteers were randomized 1:1:1 to one of three IM IFNß-1a regimens: 3-week titration (weekly quarter-dose increments over 3 weeks to full dose [30 µg]); 6-week titration (biweekly quarter-dose increments over 6 weeks to full dose); or no titration (full dose over 8 weeks). At weekly clinic visits, the severity of each FLS was rated 1 hour pre-injection and 4-6 hours and 12-15 hours post-injection. Study endpoints included post-injection change in FLS severity and post-injection FLS incidence (percentage of subjects with a ≥2-point increase in total FLS severity score) at each time point. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01119677. RESULTS: Of 234 subjects enrolled, 194 (83%) completed the study. At 8 weeks, FLS severity was significantly reduced at both post-injection time points with 3-week titration (76% reduction at 4-6 hours, p < 0.001; 37% reduction at 12-15 hours; p < 0.001) and 6-week titration (50% reduction at 4-6 hours, p < 0.001; 32% reduction at 12-15 hours; p = 0.002) compared with no titration. The incidence of FLS was also significantly reduced at both time points with both titration regimens. Safety profiles for both titration regimens were consistent with the current IM IFNß-1a label. Study limitations included that there is currently no validated assessment tool for evaluating the severity of FLS, that the study enrolled healthy volunteers, that different proportions of females were randomized to the 3-week-titration group than to the 6-week and no-titration groups, and that evaluation of the potential impact of titration on symptoms occurring substantially later after injection was not part of the study protocol. CONCLUSION: Dose titration during initiation of IM IFNß-1a reduces FLS severity and incidence in healthy volunteers compared with no titration.

The impact of posture on cardiac repolarization: more than heart rate?

INTRODUCTION: The effect of standing on heart rate and QT is well known but its impact on QTc is less clear. METHODS: Serial supine and standing 12-lead ECGs (seven pairs each day) were recorded from 54 healthy volunteers each day of a three-day period. ECGs were captured digitally and over-read by a cardiologist. RESULTS: A statistically significant shortening of RR (216 ms), QT (40 ms), and decreases in QTc-F (Fridericia) and QTc-LR (Framingham) were demonstrated on standing (8.3 and 6.9 ms, respectively). In contrast, QTc-B (Bazett's) significantly increased by 9.6 ms. Two subject-individualized correction methods were derived using each subject's supine measurements. Both showed significant decreases in QTc of approximately 13-14 ms upon standing. Using the bin analysis method, comparisons between positions using 25 ms interval RR bins revealed significant QT shortening of up to 15 ms upon standing. CONCLUSION: We have demonstrated a postural effect on cardiac repolarization independent of heart rate using two individualized correction methods, as well as QTc-F and QTc-LR, and the bin method. Characterization of postural differences in QT/QTc (other than QTc-B) may provide a safe and inexpensive physiological control to validate the ECG methodology used in clinical trials to assess potential drug-induced QT interval changes.