Analgesic efficacy, safety, and tolerability of a long-acting abuse-deterrent formulation of oxycodone for moderate-to-severe chronic low back pain in subjects successfully switched from immediate-release oxycodone.

OBJECTIVES: This post hoc analysis of data from a randomized, double-blind, placebo-controlled, enriched-enrollment randomized-withdrawal Phase III study evaluated the safety, tolerability, and analgesic efficacy of Oxycodone DETERx extended-release (ER), abuse-deterrent capsules (Xtampza® ER) in subjects with chronic low back pain who were successfully transitioned from immediate-release (IR) oxycodone. METHODS: Continuous outcomes were analyzed using a mixed-model repeated-measures approach; binomial outcomes were analyzed using chi-squared; and time-to-event outcomes using Kaplan-Meier analyses. RESULTS: A total of 110 subjects previously prescribed IR oxycodone entered the Open-label Titration Phase. Forty-four subjects were randomized to Oxycodone DETERx (n=22) or placebo (n=22) in the 12-week Double-blind Maintenance Phase. Efficacy results in this subgroup showed a statistically significant difference between Oxycodone DETERx and placebo in average pain intensity scores from Randomization Baseline to Week 12 (least squares mean [± standard error], -1.88 [0.70]; P=0.0078). Additional efficacy results indicated that Oxycodone DETERx vs placebo was associated with a statistically significant benefit in durability of effect from Week 2 through Week 12 (P<0.01), numbers of subjects with a ≥30% (n [%] 10 [45.5%] vs 0 [0%]; P=0.0004) and ≥50% (10 [45.5%] vs 0 [0%]; P=0.0004) improvement in pain intensity, longer time-to-exit (P=0.0014), a greater number of subjects who completed the study (14 [63.6%] vs 4 [18.2%]), and less rescue medication use (acetaminophen; mean [SD], 163.5 [337.8] mg) vs 216.2 [377.3] mg). Adverse event profiles were consistent with opioid class effects and results from the original study; Oxycodone DETERx was well tolerated in subjects previously treated with short-acting oxycodone. CONCLUSIONS: Oxycodone DETERx resulted in clinically meaningful and statistically significant efficacy in subjects with chronic low back pain who were previously prescribed IR oxycodone and were successfully switched to ER Oxycodone DETERx.

The comparative pharmacokinetics of physical manipulation by crushing of Xtampza® ER compared with OxyContin®.

AIM: To further characterize the pharmacokinetics of Xtampza® ER. SUBJECTS & METHODS: This was an open-label, randomized, active-controlled, five-treatment, five-period, naltrexone-blocked, cross-over study. Healthy subjects received five equivalent oxycodone doses: Xtampza ER (intact or crushed), OxyContin® (intact or crushed) or immediate-release (IR) oxycodone (crushed). Blood samples were collected to assess oxycodone concentrations. RESULTS: Crushed and intact Xtampza ER resulted in lower peak plasma concentrations compared with crushed oxycodone IR; crushed and intact Xtampza ER were bioequivalent. Crushed OxyContin exhibited a rapid increase in plasma oxycodone and was bioequivalent to crushed oxycodone IR. CONCLUSION: This second pharmacokinetic study demonstrated that Xtampza ER maintains its ER properties after crushing, unlike OxyContin, which failed to retain its ER properties after crushing. ANZCTR registration number: ACTRN12614000613606.

Tolerability, Safety, and Effectiveness of Oxycodone DETERx in Elderly Patients ≥65 Years of Age with Chronic Low Back Pain: A Randomized Controlled Trial.

TRIAL DESIGN: This was a phase III, randomized withdrawal, double-blind, placebo-controlled, enriched enrollment, parallel-group, multicenter study intended to demonstrate the safety, tolerability, and analgesic efficacy of oxycodone DETERx® (Xtampza™ ER) compared with matching placebo. METHODS: This post hoc analysis was performed using data from a subpopulation of enrolled patients who were ≥65 years of age. The study enrolled male and female patients with a clinical diagnosis of moderate-to-severe chronic low back pain for a minimum of 6 months prior to screening who required around-the-clock opioid therapy. To be eligible for enrollment, patients were required to have an average 24-h pain intensity score of ≥5 and ≤9 on an 11-point (0-10) Pain Intensity-Numerical Rating Scale at the screening visit. The study enrolled both opioid-experienced and opioid-naïve patients. The study consisted of an open-label titration phase followed by a 12-week double-blind maintenance phase. The dose range was 40-160 mg oxycodone hydrochloride equivalent per day. This post hoc analysis evaluated the safety, tolerability, and effectiveness of oxycodone DETERx among patients ≥65 years of age. The effectiveness of oxycodone DETERx was evaluated based on average pain intensity scores, Patient Global Impression of Change, responder analysis, and Kaplan-Meier survival analysis. The safety and tolerability of oxycodone DETERx were also evaluated. Patients were randomized to either oxycodone DETERx or placebo using a blocked randomization scheme in a 1:1 ratio. Randomization was stratified by previous opioid use (naïve or experienced). The study drug was coded in a manner that maintained the blinding. Study personnel and patients remained blinded to the assigned treatments throughout the study. RESULTS: For this post-hoc analysis, the intent-to-treat and randomized safety populations included 52 patients ≥65 years old, 26 each in the oxycodone DETERx and placebo groups, who participated in the study during the titration phase and were randomized to the double-blind maintenance phase. Clinically important pain reduction from screening was achieved with oxycodone DETERx, with the median pain intensity score decreasing from 7.50 at screening to 2.69 at Week 12. A clinically meaningful treatment difference of -0.9 in pain score between oxycodone DETERx and placebo was observed. All 18 elderly patients who completed the study reported improvement in pain, with 62% showing ≥30% improvement and 54% showing ≥50% improvement in pain intensity compared with patients on placebo (p = 0.0128 and p = 0.0501, respectively). Patients on oxycodone DETERx remained in the study longer than those on placebo. Of the 26 patients ≥65 years old randomized to continue oxycodone DETERx during the double-blind maintenance phase, 18 (69%) completed the study; only two patients (8%) in the oxycodone DETERx group discontinued due to adverse events. The safety and tolerability profiles showed no new or unexpected safety concerns. The adverse event profiles were similar between the titration and double-blind maintenance phases. CONCLUSIONS: Oxycodone DETERx was efficacious and generally well tolerated in patients ≥65 years old. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (NCT01685684).

Oral Human Abuse Potential of Oxycodone DETERx® (Xtampza® ER).

Oxycodone DETERx® (Collegium Pharmaceutical Inc, Canton, Massachusetts) is an extended-release, microsphere-in-capsule, abuse-deterrent formulation designed to retain its extended-release properties after tampering (eg, chewing/crushing). This randomized, double-blind, placebo-controlled, triple-dummy study evaluated the oral abuse potential of intact and chewed oxycodone DETERx capsules compared with crushed immediate-release oxycodone. Subjects with a history of recreational opioid use who were nondependent/nontolerant to opioids were enrolled. Treatments included intact oxycodone DETERx (high-fat, high-calorie meal and fasted), chewed oxycodone DETERx (high-fat, high-calorie meal and fasted), crushed immediate-release oxycodone (fasted), and placebo (high-fat, high-calorie meal). Plasma samples were collected to determine pharmacokinetic parameters. The primary endpoint was drug liking at the moment; other endpoints included drug effects questionnaire scores, Addiction Research Center Inventory/Morphine Benzedrine Group score, pupillometry measurements, and safety. Thirty-eight subjects completed the study. Chewed and intact oxycodone DETERx were bioequivalent, unlike crushed immediate-release oxycodone, which yielded higher peak oxycodone plasma concentrations compared with all methods of oxycodone DETERx administration. The mean maximum (peak) effect (Emax ) for drug liking was significantly lower for chewed and intact oxycodone DETERx than for crushed immediate-release oxycodone (P < .01). The time to Emax was significantly longer for chewed and intact oxycodone DETERx than for crushed immediate-release oxycodone (P < .0001). Scores for feeling high and Addiction Research Center Inventory/Morphine Benzedrine Group scores demonstrated lower abuse potential for chewed and intact oxycodone DETERx compared with crushed immediate-release oxycodone. Study treatments were well tolerated; no subjects experienced serious adverse events. These results demonstrate the lower oral abuse potential of chewed and intact oxycodone DETERx than crushed immediate-release oxycodone.

An abuse-deterrent, microsphere-in-capsule formulation of extended-release oxycodone: alternative modes of administration to facilitate pain management in patients with dysphagia.

BACKGROUND: Patients with chronic pain may experience difficulty swallowing, in part due to worsening disease, comorbid conditions, iatrogenic etiology, or age. Patients or caregivers may manipulate extended-release (ER) opioid formulations to facilitate oral dosing due to a lack of therapeutic options that allow for sprinkle or enteral feeding tube administration. If crushed or broken, current oral ER opioids can be associated with adverse sequelae, including risk of potentially fatal overdose. OBJECTIVE: To review the safety, in vitro dissolution data, and in vivo pharmacokinetic data that support alternative modes of administration of oxycodone DETERx (Xtampza ER) via sprinkling onto soft foods for oral ingestion or via enteral feeding tubes. METHODS: A review of oxycodone DETERx data from in vitro and in vivo studies was conducted to demonstrate support for alternative routes and modes of administration. RESULTS: There was no difference in the dissolution profile when administered with various soft foods or when mixed with various liquid vehicles and administered via nasogastric (NG) or gastrostomy (G) tubes, based on in vitro studies. When sprinkled onto applesauce and administered orally, the microspheres were bioequivalent to the intact oxycodone capsules. When crushed or chewed, the formulation maintained its pharmacokinetic profile; no bolus dose of opioid was released. The sprinkle-dose study was limited by the single-dose study design, as well as the small sample size. CONCLUSIONS: Oxycodone DETERx is the first ER oxycodone formulation that can be administered either intact, sprinkled onto soft foods, or via NG/G tubes, thereby providing options for treating pain in patients who have difficulty swallowing.

Evaluation of the durability of pain relief throughout a 12 hour dosing interval of a novel, extended-release, abuse-deterrent formulation of oxycodone.

BACKGROUND: Abuse deterrent formulations (ADF) are designed to prevent the misuse of opioids by tampering (e.g. physical and chemical manipulation) in order to ingest the opioid in a manner other than intended. Extended-release (ER) formulations are formulated with a larger drug load than immediate-release (IR) formulations, which makes ER opioids more desirable to drug abusers than I.R. formulations. ADFs, therefore, are particularly useful with ER opioid agents, which are designed to produce consistent analgesia over prolonged dosing intervals. However, the drug release properties of these formulations vary and sometimes may not provide adequate pain relief throughout the intended dosing interval, requiring patients to take additional medication for pain relief. Oxycodone DETERx* (Xtampza ER * ) is a novel, microsphere-in-capsule opioid formulation, which allows for twice daily dosing (i.e. every 12 hours) and mitigates the ability to tamper with the formulation. OBJECTIVE: To evaluate the durability of pain relief of a novel formulation of oxycodone throughout the 12 hour dosing interval. RESEARCH DESIGN AND METHODS: This study is a post-hoc analysis of 193 subjects in a Phase 3 randomized withdrawal, double-blind, placebo-controlled, enriched-enrollment, parallel-group, multicenter, 12-week clinical study. MAIN OUTCOME MEASURES: The analysis evaluated the frequency and distribution of use of oxycodone ER and rescue medication during the Double-blind Maintenance Phase of the study. RESULTS: Usage patterns captured by an electronic diary indicated limited overall and limited per-day use of rescue medication with no increase in rescue medication consumption 8 to 12 hours post-dose, suggesting that subjects did not experience end-of-dose failure during this time period. LIMITATIONS: This study is limited in that it is a post-hoc analysis based on data gathered electronically from a large, prospective, double-blind, randomized, placebo-controlled, Phase 3 clinical study. CONCLUSION: The evaluation of dosing patterns indicates that this ER oxycodone capsule formulation has durability of effect over the entire 12-hour dosing interval. These data support the use of abuse-deterrent oxycodone ER as a 12-hour dosing formulation.

A phase 3, multicenter, randomized, double-blind, placebo-controlled, safety, tolerability, and efficacy study of Xtampza ER in patients with moderate-to-severe chronic low back pain.

Opioid analgesics are commonly used for the treatment of chronic low back pain (CLBP); however, abuse potential is a major concern. This study used a randomized, double-blind, placebo-controlled, enriched-enrollment randomized-withdrawal study design to evaluate the safety, tolerability, and analgesic efficacy of an abuse-deterrent formulation of extended-release oxycodone, Xtampza ER, in opioid-naive and opioid-experienced adults with moderate-to-severe CLBP. Patients entered an open-label titration phase (N = 740); those who were successfully titrated on Xtampza ER (≥40 to ≤160 mg oxycodone hydrochloride equivalent per day) were randomized to active drug (N = 193) or placebo (N = 196) for 12 weeks. Primary efficacy results showed a statistically significant difference in average pain intensity from randomization baseline to treatment week 12 between the Xtampza ER and placebo groups (mean [±SE], -1.56 [0.267]; P < 0.0001). All sensitivity analyses results supported the primary result of the study. Secondary efficacy outcomes indicated that Xtampza ER vs placebo had more patients with improvement in patient global impression of change (26.4% vs 14.3%; P < 0.0001), longer time-to-exit from the study (58 vs 35 days; P = 0.0102), and a greater proportion of patients with ≥30% (49.2% vs 33.2%; P = 0.0013) and ≥50% (38.3% vs 24.5%; P = 0.0032) improvement in pain intensity. There was less rescue medication (acetaminophen) use in the Xtampza ER treatment group than in the placebo group. Xtampza ER had an adverse event profile consistent with other opioids and was well tolerated; no new safety concerns were identified. In conclusion, Xtampza ER resulted in clinically and statistically significant efficacy in patients with CLBP.

Epigenetic therapy for Friedreich ataxia.

OBJECTIVE: To investigate whether a histone deacetylase inhibitor (HDACi) would be effective in an in vitro model for the neurodegenerative disease Friedreich ataxia (FRDA) and to evaluate safety and surrogate markers of efficacy in a phase I clinical trial in patients. METHODS: We used a human FRDA neuronal cell model, derived from patient induced pluripotent stem cells, to determine the efficacy of a 2-aminobenzamide HDACi (109) as a modulator of FXN gene expression and chromatin histone modifications. FRDA patients were dosed in 4 cohorts, ranging from 30mg/day to 240mg/day of the formulated drug product of HDACi 109, RG2833. Patients were monitored for adverse effects as well as for increases in FXN mRNA, frataxin protein, and chromatin modification in blood cells. RESULTS: In the neuronal cell model, HDACi 109/RG2833 increases FXN mRNA levels and frataxin protein, with concomitant changes in the epigenetic state of the gene. Chromatin signatures indicate that histone H3 lysine 9 is a key residue for gene silencing through methylation and reactivation through acetylation, mediated by the HDACi. Drug treatment in FRDA patients demonstrated increased FXN mRNA and H3 lysine 9 acetylation in peripheral blood mononuclear cells. No safety issues were encountered. INTERPRETATION: Drug exposure inducing epigenetic changes in neurons in vitro is comparable to the exposure required in patients to see epigenetic changes in circulating lymphoid cells and increases in gene expression. These findings provide a proof of concept for the development of an epigenetic therapy for this fatal neurological disease.