Genome-wide association study of abnormal elevation of ALT in patients exposed to atabecestat.

BACKGROUND: Atabecestat, a potent brain penetrable BACE1 inhibitor that reduces CSF amyloid beta (Aß), was developed as an oral treatment for Alzheimer's disease (AD). Elevated liver enzyme adverse events were reported in three studies although only one case met Hy's law criteria to predict serious hepatotoxicity. METHOD: We performed a case-control genome-wide association study (GWAS) to identify genetic risk variants associated with liver enzyme elevation using 42 cases with alanine transaminase (ALT) above three times the upper limit of normal (ULN) and 141 controls below ULN. Additionally, we performed a GWAS using continuous maximal ALT/ULN (expressed as times the ULN) upon exposure to atabecestat as the outcome measure (n = 285). RESULTS: No variant passed the genome-wide significance threshold (p = 5 × 10- 8) in the case-control GWAS. We identified suggestive association signals in genes (NLRP1, SCIMP, and C1QBP) implicated in the inflammatory processes. Among the genes implicated by position mapping using variants suggestively associated (p < 1 × 10- 5) with ALT elevation case-control status, gene sets involved in innate immune response (adjusted p-value = 0.05) and regulation of cytokine production (adjusted p-value = 0.04) were enriched. One genomic region in the intronic region of GABRG3 passed the genome-wide significance threshold in the continuous max(ALT/ULN) GWAS, and this variant was nominally associated with ALT elevation case status (p = 0.009). CONCLUSION: The suggestive GWAS signals in the case-control GWAS analysis suggest the potential role of inflammation in atabecestat-induced liver enzyme elevation.

Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial.

Importance: Atabecestat, a nonselective oral ß-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs). Objective: To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018 after being stopped prematurely. The study was conducted at 143 centers across 14 countries. Participants were permitted to be followed off-treatment by the original protocol, collecting safety and efficacy data. From 4464 screened participants, 557 amyloid-positive, cognitively normal (Clinical Dementia Rating of 0; aged 60-85 years) participants (approximately 34% of originally planned 1650) were randomized before the trial sponsor stopped enrollment. Interventions: Participants were randomized (1:1:1) to atabecestat, 5 mg (n = 189), 25 mg (n = 183), or placebo (n = 185). Main Outcomes and Measures: Primary outcome: change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary outcomes: change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study. Results: Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, -1.09; 95% CI, -1.66 to -0.53; P < .001) and month 12 (least-square mean, -1.62; 95% CI, -2.49 to -0.76; P < .001), and at month 3 for Repeatable Battery for the Assessment of Neuropsychological Status (least-square mean, -3.70; 95% CI, -5.76 to -1.63; P < .001). Cognitive Function Index participant report showed nonsignificant worsening at month 12. Systemic and neuropsychiatric-related treatment-emergent AEs were greater in atabecestat groups vs placebo. After stopping treatment, follow-up cognitive testing and AE assessment provided evidence of reversibility of drug-induced cognitive worsening and AEs in atabecestat groups. Conclusions and Relevance: Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02569398.

Safety and efficacy of fulranumab in osteoarthritis of the hip and knee: results from four early terminated phase III randomized studies.

Objective: To evaluate the safety and efficacy of fulranumab as adjunct or monotherapy in patients with knee or hip pain related to moderate-to-severe osteoarthritis.Methods: Osteoarthritic patients (aged ≥18 years) from four phase 3 randomized, double-blind (DB), placebo-controlled studies were randomized to receive placebo, fulranumab 1 mg every 4 weeks (Q4wk), or 3 mg Q4wk in 16-week DB phase, followed by a 52-week post-treatment follow-up phase. Safety assessments included treatment-emergent adverse events (TEAEs), and neurological, sympathetic, and joint-related events of interest. Efficacy assessments included pain and physical function sub-scales of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores.Results: Of 245 patients from the ITT set (median age = 64 years; 62% women), 84 (34%) completed the DB phase; the majority of discontinuations (57%) were due to early study termination. In the DB phase, the incidence of TEAEs in fulranumab 3 mg (57.8%) and 1 mg (56.8%) was similar to placebo (56.8%). Two events adjudicated as joint-related events of interest include rapidly progressive osteoarthritis and fracture of unknown etiology. There were no new neurological TEAEs. Fulranumab showed evidence of efficacy in improving pain and physical function based on WOMAC sub-scale scores. Due to premature study termination, the number of patients enrolled were too small to make any definitive efficacy claims.Conclusions: Treatment with fulranumab was generally tolerated with no new safety signals. Within the limited sample analyzed, fulranumab showed evidence of improvement of pain and function in patients with moderate-to-severe osteoarthritis who had failed prior therapy and were candidates for joint replacement surgery.Clinical trial registration numbers: NCT02336685; NCT02336698; NCT02289716; NCT02301234KEY POINTSFulranumab as adjuvant or monotherapy was well tolerated with no new safety signalsFulranumab demonstrated evidence suggestive of efficacy in osteoarthritic pain of hip and kneeFulranumab demonstrated evidence suggestive of improvement of pain and physical function in osteoarthritis.

Fulranumab as Adjunctive Therapy for Cancer-Related Pain: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study.

This randomized, double-blind (DB), placebo-controlled, phase 2 study assessed the efficacy and safety of fulranumab as a pain therapy adjunctive to opioids in terminally ill cancer patients. Ninety-eight patients were randomized (2:1) to receive one subcutaneous injection of fulranumab (9 mg) or placebo in the 4-week DB phase. Seventy-one (72%) patients entered the 48-week open-label extension phase and were administered 9 mg of fulranumab every 4 weeks. The study failed to demonstrated efficacy at the end of the DB phase (primary endpoint, mean [SD] change in average cancer-related pain intensity was -.8 (1.26) for fulranumab and -.7 (1.56) for placebo; P = .592). However, potential benefit is suggested based on secondary endpoints (30% responder rate [P = .020], Brief Pain Inventory-Short Form [BPI-SF] pain intensity subscale [P = .003], and pain interference subscale [P = .006]). The most commonly reported treatment-emergent adverse events were (fulranumab vs placebo): asthenia (16% vs 10%), decreased appetite (12% vs 6%), fatigue (10% vs 0%), and malignant neoplasm progression (10% vs 0%). Although no differences were seen between fulranumab and placebo groups on the primary endpoint, improvements in BPI-SF pain subscale scores and responder rates support further research of anti-nerve growth factor therapy in cancer-related pain. PERSPECTIVE: Efficacy and safety of fulranumab as adjunctive pain therapy in terminally ill cancer patients were assessed. Results suggest that anti-NGF agents may prove to be novel additions in helping to optimize pain relief in cancer patients who fail to respond adequately to opioids and other common co-analgesics.

Fulranumab in patients with interstitial cystitis/bladder pain syndrome: observations from a randomized, double-blind, placebo-controlled study.

BACKGROUND: This study was designed to evaluate the efficacy and safety of fulranumab, a fully human monoclonal antibody directed against nerve growth factor (NGF), for pain relief in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: In this multicenter, double-blind study, adults with IC/BPS (i.e., interstitial cystitis symptom index [ICSI] total score ≥8) accompanied by chronic, moderate-to-severe pain were randomized to fulranumab 9 mg or matching placebo, administered subcutaneously at weeks 1, 5, and 9. The primary efficacy endpoint was change from baseline to study endpoint (week 12 or at withdrawal) in average daily pain intensity score. Key secondary endpoints included change from baseline to study endpoint in worst pain intensity score, ICSI total score, Pelvic Pain and Urgency/Frequency total score, Patient Perception of Bladder Condition score, and global response assessment. RESULTS: This study was terminated prematurely based on concern that this class may be associated with rapidly progressing osteoarthritis or osteonecrosis. Thirty-one patients (of the targeted 70 patients) were randomized, 17 to placebo and 14 to fulranumab, with 15 and 10 patients, respectively, receiving all 3 doses of double-blind treatment. In ANOVA analyses, there was no statistically significant difference between treatment groups for the primary endpoint (LS mean difference [95% CI] vs. placebo, -0.2 [-1.52, 1.10]) or any of the secondary endpoints. Fulranumab was well tolerated, with no patient discontinuing due to an adverse event or experiencing a joint-related serious adverse event over a 26-week follow-up period. No events related to the neurologic or motor systems were reported. CONCLUSIONS: Efficacy was not demonstrated in the present study with the single dose tested and a limited sample size, leading to lack of statistical power. These findings do not exclude the possibility that fulranumab would provide clinical benefit in a larger study and/or specific populations (phenotypes) in this difficult to treat pain condition. TRIAL REGISTRATION: NCT01060254 , registered January 29, 2010.

Fulranumab in Patients With Pain Associated With Postherpetic Neuralgia and Postraumatic Neuropathy: Efficacy, Safety, and Tolerability Results From a Randomized, Double-blind, Placebo-controlled, Phase-2 Study.

OBJECTIVE: Fulranumab is an antibody that specifically neutralizes the biological activity of human nerve growth factor. This multicenter, phase-2, randomized, double-blind (DB), placebo-controlled study evaluated the analgesic efficacy and safety of fulranumab in postherpetic neuralgia (PHN) and posttraumatic neuropathy (PTN) patients. METHODS: Patients (18 to 80 y) with inadequately controlled moderate-to-severe pain received study medication (subcutaneous injection) every 4 weeks. PHN patients were randomized (3:2:2:3) to receive either placebo or one of 3 doses of fulranumab: 1 mg (1 mgQ4 wk), 3 mg (3 mgQ4 wk), or 10 mg (10 mgQ4 wk). PTN patients were randomized (1:1) to receive either placebo or fulranumab 10 mgQ4 wk. RESULTS: The US Food and Drug Administration placed a clinical hold (December 23, 2010) on all trials of antinerve growth factor drugs, including fulranumab, due to identified risks of osteonecrosis or rapidly progressing osteoarthritis; therefore, only 49 (of 150 planned) PHN patients and 34 (of 50 planned) PTN patients completed the DB efficacy evaluation. There was no significant difference (P>0.05, fulranumab vs. placebo) for change in 7-day average of daily pain intensity scores from DB baseline to end of 12-week DB efficacy phase in PHN or PTN patients (primary endpoint). No significant difference was found with fulranumab versus placebo (P>0.05) in other efficacy measures in either PHN or PTN patients. The most common treatment-emergent adverse events (>10% incidence) in PTN patients were sinusitis, carpal tunnel syndrome, and headache, whereas in PHN patients it was arthralgia. DISCUSSION: Fulranumab did not demonstrate efficacy in either PHN or PTN patients, but was generally well-tolerated in this small underpowered and abbreviated study.

Long-Term Safety and Efficacy of Fulranumab in Patients With Moderate-to-Severe Osteoarthritis Pain: A Phase II Randomized, Double-Blind, Placebo-Controlled Extension Study.

OBJECTIVE: To evaluate the long-term safety and efficacy of fulranumab in patients with knee or hip pain caused by moderate-to-severe chronic osteoarthritis (OA). METHODS: In this phase II double-blind, placebo-controlled extension study, patients who were randomized in equal proportions to receive subcutaneous doses of either placebo or fulranumab (1 mg every 4 weeks, 3 mg every 8 weeks, 3 mg every 4 weeks, 6 mg every 8 weeks, or 10 mg every 8 weeks) in the 12-week double-blind efficacy phase and who completed this double-blind efficacy phase were eligible to continue the dosage throughout a 92-week double-blind extension phase, followed by a 24-week posttreatment follow-up period. Safety assessments included evaluation of treatment-emergent adverse events (TEAEs), pre-identified AEs of interest, and joint replacements. Efficacy assessments included changes from baseline to the end of the double-blind extension phase in scores on the patient's global assessment and the pain and physical function subscales of the Western Ontario and McMaster Universities Osteoarthritis Index. RESULTS: Overall, 401 of the 423 patients who completed the 12-week double-blind efficacy phase entered the extension study. Long-term sustained improvements were observed in all efficacy parameters following fulranumab treatment (1 mg every 4 weeks, 3 mg every 4 weeks, and 10 mg every 8 weeks) as compared with placebo. Similar percentages of patients in both groups experienced TEAEs (88% taking placebo and 91% taking fulranumab; all phases). Across all fulranumab groups, arthralgia (21%) and OA (18%) (e.g., exacerbation of OA pain) were the most common TEAEs. The most common serious TEAEs were the requirement for knee (10%) and hip (7%) arthroplasty, with 80% occurring during the posttreatment follow-up period. Neurologic-related TEAEs (28%; all phases) were generally mild-to-moderate. Overall, 81 joint replacements were performed in 71 patients (8 [11%] receiving placebo and 63 [89%] receiving fulranumab); 15 patients (21%) had rapid progression of OA (RPOA). All cases of RPOA occurred in fulranumab-treated patients who were concurrently receiving nonsteroidal antiinflammatory drugs and occurred in joints with preexisting OA. CONCLUSION: Long-term treatment with fulranumab was generally well-tolerated and efficacious. RPOA was observed as a safety signal. Future studies are warranted to demonstrate whether the risk of RPOA can be reduced in patients taking fulranumab.

Efficacy, Safety, and Tolerability of Fulranumab as an Adjunctive Therapy in Patients With Inadequately Controlled, Moderate-to-Severe Chronic Low Back Pain: A Randomized, Double-blind, Placebo-controlled, Dose-ranging, Dose-loading Phase II Study.

PURPOSE: Fulranumab is an investigational, fully human recombinant monoclonal antibody (IgG2) that neutralizes the biological actions of human nerve growth factor. Low back pain is a common cause of noncancer chronic pain and represents one of the most significant socioeconomic health-related problems in developed countries. This randomized, double-blind, placebo-controlled study was conducted to evaluate the analgesic effect of fulranumab in patients with moderate-to-severe chronic low back pain. METHODS: Patients (aged 18-80 years) were randomized to receive subcutaneous injections every 4 weeks in 1 of 5 parallel treatment groups: placebo or fulranumab 1mg (1mgQ4wk), 3mg (3mgQ4wk), 3mg after a 6mg loading dose (6mgLD+3mgQ4wk), or 10mg (10mgQ4wk) every 4 weeks. FINDINGS: A total of 385 patients (median age, 53 years; women, 54%) received at least 1 injection of study medication. No statistically significant differences were observed in improvement of pain intensity scores between the fulranumab treatment regimens and the placebo group at week 12 (primary end point; mean [SD], placebo: -2.0 [2.17], 1mgQ4wk: -1.9 [2.14], 3mgQ4wk: -2.2 [1.89], 6mgLD+3mgQ4wk: -2.0 [1.72] and 10mgQ4wk: -2.1 [2.18]). Results for secondary efficacy parameters (change in the Oswestry Disability Index, Brief Pain Inventory-Short Form, and Patient Global Assessment scales) were consistent with the primary outcome. A placebo effect was observed; the overall percentage of patients with treatment-emergent adverse events (TEAEs) was similar between the placebo (76%) and fulranumab treatment groups (77%-90%). Across all phases, the most common TEAEs in at least 10% of patients (combined fulranumab group vs placebo) were arthralgia (15% vs 12%), back pain (15% vs 18%), upper respiratory tract infection (15% vs 8%), paresthesia (14% vs 8%), diarrhea (12% vs 4%), headache (12% vs 8%), hypoesthesia (11% vs 5%), pain in extremity (11% vs 8%), sinusitis (10% vs 5%), and nasopharyngitis (10% vs 9%). Across all phases, neurologic TEAEs were less frequent in the placebo group (14%) versus the fulranumab treatment groups (25%). In the posttreatment phase, 8 patients had joint replacement operations, which were considered a result of normal progression of osteoarthritis. One case in the 10-mg group was determined to be rapid progession of osteoarthritis and was considered to be possibly related to study drug. IMPLICATIONS: Fulranumab did not demonstrate efficacy compared with placebo in patients with chronic low back pain but was generally well-tolerated. ClinicalTrials.gov identifier: NCT00973024.

Fulranumab for treatment of diabetic peripheral neuropathic pain: A randomized controlled trial.

OBJECTIVE: To assess efficacy and safety of fulranumab, a fully human monoclonal antibody against nerve growth factor, in patients with diabetic peripheral neuropathic pain (DPNP). METHODS: In this phase II, double-blind, placebo-controlled trial, patients with moderate to severe DPNP were randomized to treatments with fulranumab (1, 3, or 10 mg) or placebo administered subcutaneously every 4 weeks. RESULTS: Because of early study termination (clinical hold) by the US Food and Drug Administration, 77 (intent-to-treat) of the planned 200 patients were enrolled. The primary endpoint, the mean reduction of average daily pain at week 12 compared with baseline, showed a positive dose-response relationship (p = 0.014, 1-sided); the pair-wise comparison between the 10-mg group and placebo was significant (unadjusted p = 0.040, 2-sided). An exploratory responder analysis revealed that a greater proportion of patients in the 10-mg group reported ≥30% reduction in the average DPNP intensity compared with placebo at week 12 (p = 0.006). Although not statistically significant, several secondary endpoints showed directionally similar results to the primary efficacy dose-response relationship. During the combined efficacy and safety extension phases, the top 3 treatment-emergent adverse events in the combined fulranumab group were arthralgia (11%), edema peripheral (11%), and diarrhea (9%). No cases of joint replacement or death were reported. CONCLUSION: Despite early study termination, fulranumab treatment resulted in dose-dependent efficacy and was generally well tolerated. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with DPNP, fulranumab 10 mg reduces pain by 1.2 points on an 11-point scale compared with placebo.

Efficacy, safety, and tolerability of fulranumab, an anti-nerve growth factor antibody, in the treatment of patients with moderate to severe osteoarthritis pain.

Nerve growth factor (NGF) is increased in chronic pain conditions. This study examined analgesic efficacy and safety of fulranumab, a fully human monoclonal anti-NGF antibody, in adults with chronic osteoarthritis pain. Patients (n=466, intent-to-treat) were randomized to receive, in addition to their current pain therapy, subcutaneous injections in 1 of 6 parallel treatment groups: placebo (n=78), fulranumab 1 mg (n=77) or 3 mg (n=79) every 4 weeks (Q4wk), 3 mg (n=76), 6 mg (n=78), or 10 mg (n=78) every 8 weeks (Q8wk). Primary efficacy results showed that fulranumab significantly reduced the average pain intensity score (P < or = 0.030) from baseline to week 12 compared with placebo in the 3mgQ4wk, 6mgQ8wk, and 10mgQ8wk groups. Secondary efficacy outcomes indicated that significant improvement occurred compared with placebo at week 12 on the Western Ontario and McMaster Universities Osteoarthritis Index subscales of pain, stiffness, and physical function (P < 0.040) across all fulranumab groups except 1mgQ4wk, on the Brief Pain Inventory-Short Form subscales of pain intensity (P < or = 0.016) and pain interference (P < or = 0.030) in the 3mgQ4wk and 10mgQ8wk groups, and on the Patient Global Assessment score (P < or = 0.040) in the 3mgQ4wk, 6mgQ8wk, and 10mgQ8wk groups. The most common (> or = 5% of patients) treatment-emergent adverse events in overall fulranumab groups during the first 12weeks included paresthesia (7%), headache (5%), and nasopharyngitis (5%). Most neurologic-related treatment-emergent adverse events were mild or moderate and resolved at the end of week 12. Serious adverse events occurred in 3 patients, but they were not neurologically related and resolved before study completion. Fulranumab treatment resulted in statistically significant efficacy in pain measures and physical function versus placebo and was generally well tolerated.

Results of a double-blind, placebo-controlled, fixed-dose assessment of once-daily OROS® hydromorphone ER in patients with moderate to severe pain associated with chronic osteoarthritis.

OBJECTIVE: Opioids are recommended for patients with moderate to severe pain due to osteoarthritis (OA), who do not receive adequate analgesia from nonopioid treatment. The objective of this study was to evaluate the efficacy and safety of OROS hydromorphone extended-release (ER) compared with placebo in patients with moderate to severe pain associated with OA. METHODS: This was a randomized, placebo-controlled, double-blind, fixed-dose study. Patients received placebo or fixed-dose OROS hydromorphone ER (8 or 16 mg). The primary efficacy measure was pain intensity score (11-point Numeric Rating Scale) at Maintenance Week 12, analyzed with baseline observation carried forward (BOCF) imputation for missing data. RESULTS: This study did not meet the primary efficacy measure using the BOCF imputation. Study discontinuation was high (52%). When analyzed using last observation carried forward (LOCF) imputation, the prespecified alternate method, OROS hydromorphone ER 16 mg provided significantly better analgesia than placebo (P = 0.0009). Treatment was associated with significant improvements in patient global assessment (P = 0.01), the overall Western Ontario and McMaster Osteoarthritis Index (WOMAC) (P = 0.0003), and its subscales: pain (P = 0.0001), stiffness (P = 0.0023), and physical function (P = 0.0006). Gastrointestinal adverse events, such as constipation and nausea, were common among patients receiving OROS hydromorphone ER. CONCLUSIONS: OROS hydromorphone ER failed to achieve statistical significance for the primary endpoint using the prespecified imputation method (BOCF), likely due to the high discontinuation rate associated with the fixed-dose design. When data were analyzed according to an alternate method of imputation (LOCF), OROS hydromorphone ER demonstrated statistically significant improvements in pain, stiffness, and physical function.

Efficacy of the sustained-release hydromorphone in neuropathic pain management: pooled analysis of three open-label studies.

This pooled analysis was designed to determine whether the analgesic response to treatment with OROS hydromorphone, as measured by the "pain on average" scale of the Brief Pain Inventory (BPI), was different in patients with neuropathic pain compared to those with nociceptive pain, after adjusting for differences in baseline characteristics. Three open-label studies on patients with neuropathic and nociceptive malignant and nonmalignant chronic pain were analyzed. A mixed model for repeated measures linear regression analysis was used to compare the effect of OROS hydromorphone on patients with neuropathic and nociceptive pain, adjusting for potentially confounding factors. Data from patients with pure neuropathic pain and mixed pain were also compared. Safety and tolerability was assessed by recording the number of adverse events. The primary outcome was "pain on average" (BPI item 5) over time. Secondary outcomes were the effect of OROS hydromorphone on other BPI items including "pain relief" and "interference with sleep." Patients with neuropathic pain showed a similar response to treatment with OROS hydromorphone to those patients with nociceptive pain. There was no statistically significant difference between the pain groups (difference between groups -0.552 at visit 7; P = .060 for overall difference between groups). For some outcome variables, treatment was more effective for patients with neuropathic pain. The treatment was generally well tolerated. This pooled analysis shows that treatment with OROS hydromorphone had similar efficacy for neuropathic and nociceptive pain.

Evaluation of the abuse potential of extended release hydromorphone versus immediate release hydromorphone.

Immediate release (IR) hydromorphone has experienced significant misuse and abuse. An extended release (ER) hydromorphone formulation has been developed to provide sustained pain relief and may reduce the likelihood for abuse by delaying absorption. In this double-blind, placebo-controlled, randomized, 2-part crossover study, the abuse potential of single oral doses of hydromorphone ER (intact: 16-, 32-, and 64-mg; milled: 8-mg) was compared with 8-mg hydromorphone IR and placebo. After drug administration, subjects with a history of recreational opioid use completed a series of assessments, including subjective effects visual analog scales (eg, drug liking) and Addiction Research Center Inventory With Cole Modification, at several timepoints up to 48 hours postdose. Independent of formulation, maximum at-the-moment drug liking was higher for hydromorphone versus placebo. Maximum drug liking occurred earlier and was higher for 8-mg IR versus 16-mg ER but similar to 32- and 64-mg ER. Most positive effects were lower after 16-mg ER compared with other doses, including 8-mg IR. Bad drug effects were higher for hydromorphone ER, particularly the 64-mg dose. Milled 8-mg ER produced similar subjective effects to 8-mg IR. Comparison of scores after administration of 8-mg IR on 2 separate occasions showed that most assessments exhibited good test-retest reliability, although some scores declined marginally between test and retest. Delayed onset of good drug effects and prominent bad drug effects of hydromorphone ER suggest that, when administered intact, this formulation may have lower abuse potential than hydromorphone IR.

Open-label study on the long-term efficacy, safety, and impact on quality of life of OROS hydromorphone ER in patients with chronic low back pain.

OBJECTIVE: To investigate the efficacy, safety, and impact on quality of life of long-term administration of OROS hydromorphone ER (8-128mg) in patients with chronic low back pain. DESIGN: A total of 113 adults with chronic low back pain who completed a 6-week open-label study were enrolled in this 6-month extension study. OUTCOME MEASURES: The primary end point was the daily pain relief rating obtained during monthly study visits. Secondary end points included Investigator and Patient Global Evaluations, Brief Pain Inventory scores obtained at monthly study visits, and quality-of-life measures (Medical Outcomes Study Questionnaire and 36-Item Short-Form Health Survey score) obtained at monthly intervals. RESULTS: Mean±SD change from baseline in pain relief with OROS hydromorphone ER for the Month 6 visit was 0.9±2.55 (P=0.0007) and for the last assessment of the extension study was 0.9±2.53 (P=0.0002). At the Month 6 visit, 81.3% of investigators and 71.0% of patients rated their satisfaction of pain relief with OROS hydromorphone ER treatment as good, very good, or excellent. Changes on the 36-item Short Form Health Survey, a quality-of-life measure, were statistically significant for the physical composite scores for all extension phase time points, including Month 6 (2.1±5.34; P<0.0001) and the last assessment (2.4±5.56; P<0.0001) and mental composite scores for all extension phase time points, including Month 6 (3.3±9.52; P=0.0006) and the last assessment (3.1±9.5; P=0.0008). Treatment with OROS hydromorphone ER also resulted in significant improvement in sleep disturbances. Adverse events included gastrointestinal and central nervous system symptoms. CONCLUSIONS: The results support the long-term use of OROS hydromorphone ER in managing chronic moderate to severe low back pain.

An open-label, 1-year extension study of the long-term safety and efficacy of once-daily OROS(R) hydromorphone in patients with chronic cancer pain.

BACKGROUND: Opioid analgesics have proven efficacy in the short-term management of chronic cancer pain, but data on their long-term use is more limited. OROS(R) hydromorphone is a controlled-release formulation of oral hydromorphone that may be particularly well suited to long-term management of chronic cancer pain because it provides stable plasma concentrations and consistent analgesia with convenient once-daily dosing. The objective of this study (DO-118X) was to characterise the pain control achieved with long-term repeated dosing of OROS(R) hydromorphone in patients with chronic cancer pain. METHODS: In this multicentre, phase III, open-label, single treatment, 1-year extension study, OROS(R) hydromorphone was administered to 68 patients with moderate-to-severe chronic cancer pain, who had successfully completed a short-term equivalence study, and whose pain was controlled with a stable dose of medication (>/= 8 mg OROS(R) hydromorphone or equivalent controlled-release morphine). Patients were started on the dose of OROS(R) hydromorphone equivalent to the opioid dose on which they achieved dose-stable pain control in the equivalence study; dose adjustments were made as necessary and breakthrough pain medication was permitted. Efficacy was assessed with the Brief Pain Inventory (BPI) and patient and investigator global evaluations of treatment effectiveness. No formal statistical analysis was done. RESULTS: The mean (standard deviation) duration of exposure to study medication was 139 (129.9) days and the mean (standard deviation) average daily consumption of OROS(R) hydromorphone was 43.7 (28.14) mg/day. All scores were maintained at a mild to moderate severity throughout the study; however, BPI scores for pain at its worst, pain at its least, pain on average, pain right now, and pain relief were slightly worsened at end point compared with baseline. Mean BPI pain interference with daily activities and patient and investigator global evaluation scores also remained generally stable. Treatment effectiveness was rated as fair to good throughout the study. The most frequently reported adverse events were nausea (n = 24, 35.3%), constipation (n = 22, 32.4%), and vomiting (n = 15, 22.1%). CONCLUSION: The results of this extension study suggest that long-term repeated dosing with once-daily OROS(R) hydromorphone can be beneficial in the continuing management of persistent, moderate-to-severe cancer pain.

Long-term safety, tolerability, and efficacy of OROS hydromorphone in patients with chronic pain.

OBJECTIVE: To assess the safety and efficacy of long-term repeated dosing of OROS hydromorphone in chronic pain patients. DESIGN: This multicenter, open-label extension trial enrolled patients from three short-term OROS hydromorphone trials. SETTING: Fifty-six centers in the United States and Canada. PATIENTS: Adults with chronic cancer pain or chronic nonmalignant pain who were receiving stable doses of OROS hydromorphone (> or = 8 mg/day). Three hundred and eighty-eight patients were enrolled, 106 patients completed at least 12 months of therapy. INTERVENTIONS: OROS hydromorphone (individualized doses) was administered once daily. MAIN OUTCOME MEASURES: Safety and efficacy (Brief Pain Inventory and patient and investigator global evaluations) were assessed at monthly visits. RESULTS: The median duration of extended OROS hydromorphone therapy was 274 days. The median daily dose of study medication was 32.0 mg at extension-study baseline, 40.0 mg at month 3, and 48.0 mg at months 6, 9, and 12, respectively. The most frequently reported adverse events were nausea (n = 93, 24.0 percent) and constipation (n = 75, 19.3 percent). The analgesic effects of OROS hydromorphone, assessed using the Brief Pain Inventory, were maintained throughout the extension. At 12 months, 72.4 percent of patients and 75.9 percent of investigators rated overall treatment as good, very good, or excellent. CONCLUSIONS: Once-daily OROS hydromorphone is an osmotically driven, controlled-release preparation that may be particularly well suited to long-term use, because it provides consistent plasma concentrations and sustained around-the-clock analgesia. In this study, the benefits of OROS hydromorphone attained in short-term studies were maintained in the long-term when daily administration was continued.

A randomized, double-blind comparison of OROS(R) hydromorphone and controlled-release morphine for the control of chronic cancer pain.

BACKGROUND: Long-acting opioid formulations are advocated for maintaining pain control in chronic cancer pain. OROS(R) hydromorphone is a sustained-release formulation of hydromorphone that requires dosing once daily to maintain therapeutic concentrations. The objective of this study was to demonstrate the clinical equivalence of immediate-release and sustained-release formulations of hydromorphone and morphine for chronic cancer pain. METHODS: 200 patients with cancer pain (requiring 70% of investigators and patients rated both treatments as good to excellent. The safety profiles of hydromorphone and morphine were similar and typical of opioid analgesics. CONCLUSION: Equivalence was demonstrated for immediate-release formulations of hydromorphone and morphine, but not for the sustained-release formulations of OROS(R) hydromorphone and controlled-release morphine. The direction of the mean difference between the treatments (-0.8) and the out-of-range lower limit of the 95% CI (-1.6) were in favor of OROS(R) hydromorphone. TRIAL REGISTRATION: ClinicalTrials.gov: NCT0041054.

Efficacy and tolerability of once-daily OROS hydromorphone and twice-daily extended-release oxycodone in patients with chronic, moderate to severe osteoarthritis pain: results of a 6-week, randomized, open-label, noninferiority analysis.

OBJECTIVE: This study compared the efficacy and tolerability of a once-daily controlled-release formulation of hydromorphone (OROS) hydromorphone, Janssen-Cilag, Beerse, Belgium) and twice-daily extended-release (ER) oxycodone in patients with chronic, moderate to severe osteoarthritis (OA) pain. OROS hydromorphone is currently available only in Europe. METHODS: Adults who met American College of Rheumatology clinical criteria for OA of the knee or hip with moderate to severe mean daily pain intensity despite chronic use of stable doses of NSAIDs or other nonsteroidal, nonopioid therapies were eligible for participation in this randomized, open-label study. The study consisted of a 14-day dose-titration and stabilization phase and a 28-day maintenance phase. OROS hydromorphone and ER oxycodone were initiated at dosages of 8 mg QD and 10 mg BID, respectively. Patients maintained diaries in which they rated their pain (from 0 = none to 3 = severe) and pain relief (from 0 = no relief to 4 = complete relief). Other assessments completed every 14 days included patient and investigator global evaluations of treatment effectiveness (scale from 1 = poor to 5 = excellent), the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index, and the Medical Outcomes Study (MOS) Sleep Scale. Adverse events (whether observed by study personnel, identified in response to questioning, or spontaneously reported) and vital signs were monitored throughout the study. The primary efficacy measures were the mean pain relief score at end point and the time from initiation of treatment to the third day of moderate to complete pain relief, as reported in the patient diary. Noninferiority analyses were conducted on all primary and secondary efficacy variables. RESULTS: One hundred thirty-eight patients (71 OROS hydromorphone, 67 ER oxycodone) received treatment (safety population), and 83 (60.1%) completed the study. Data from 124 patients were included in the efficacy analyses; the majority of these patients were white (85.5%) and female (69.4%), with a mean age of 63.6 years. The most commonly affected joint was the knee (79.8 %). At end point, the OROS hydromorphone group had a mean pain relief score of 2.3 (median, 2.0) and the ER oxycodone group had a mean pain relief score of 2.3 (median, 2.3) (95% CI, -0.30 to infinity). The mean time to the third day of moderate to complete pain relief was 6.2 days (median, 4.0) in the OROS hydromorphone group and 5.5 days (median, 5.0) in the ER oxycodone group (95% CI, -0.31 to infinity). Mean pain intensity decreased from baseline to end point by 0.6 point in the OROS hydromorphone group and by 0.4 point in the ER oxycodone group. Mean scores on the patient global evaluation improved by a respective 1.2 and 1.0 points (median, 1 in both groups). Approximately two thirds of patients in each group (67.2% and 66.7%) rated the overall effectiveness of treatment as good to excellent at end point. There were no statistically significant differences between groups in total WOMAC scores at end point, and similar improvements from baseline in the WOMAC physical function, stiffness, and pain scales were observed in both groups. Whereas MOS sleep outcomes scores improved from baseline in both groups, OROS hydromorphone was associated with a significantly greater improvement on the MOS Sleep Problems Index I compared with ER oxycodone (P < 0.045). Adverse events were comparable in both groups; the most frequently reported adverse events were nausea (35.2% and 29.9%), constipation (29.6% and 25.4%), somnolence (25.4% and 17.9%), vomiting (16.9% and 11.9%), and dizziness (14.1% and 22.4%). Adverse events led to study discontinuation in 35.2% (25/71) of patients in the OROS hydromorphone group and 32.8% (22/67) in the ER oxycodone group. Discontinuations due to adverse events during the titration phase were numerically greater in the OROS hydromorphone group (29.6% [21/71]) than in the ER oxycodone group (19.4% [13/67]). Only 1 serious adverse event (diarrhea in a patient receiving OROS hydromorphone) was considered possibly related to study drug. CONCLUSIONS: Once-daily OROS hydromorphone and twice-daily ER oxycodone provided similar pain relief in these patients with OA of the knee or hip. The tolerability profiles of the 2 agents were similar.

Efficacy and safety evaluation of once-daily OROS hydromorphone in patients with chronic low back pain: a pilot open-label study (DO-127).

OBJECTIVE: To evaluate the safety, tolerability, and efficacy of once-daily osmotic controlled-release oral delivery system (OROS) hydromorphone in patients with chronic low back pain of moderate-to-severe intensity. RESEARCH DESIGN AND METHODS: This was a 6-week, multicenter, nonrandomized, noncomparative, open-label, repeat-dose study of chronic (> or = 6 weeks) low back pain. The study comprised three periods: prior opioid stabilization (2-7 days); OROS hydromorphone conversion, titration, and stabilization (3-14 days); and OROS hydromorphone maintenance (28 days). Patients were evaluated weekly. Baseline pain assessment was performed at the end of prior opioid stabilization. For pain relief rating, endpoint was defined as the mean pain relief score from the last 2 nonmissing days before study termination. For other assessments, endpoint was defined as the last post-baseline evaluation. RESULTS: Of the 207 patients who received the study drug, 131 completed the trial. Scores (mean +/- SD) for Brief Pain Inventory 'worst pain in the last 24 hours' decreased significantly from baseline to endpoint (-0.8 +/- 2.06, p < 0.0001). The proportions of patients and investigators rating the global effectiveness as good, very good, or excellent increased from 31.6% at baseline while patients were on prior opioids to 63.2% at endpoint while patients received OROS hydromorphone, and from 29.8% at baseline while patients were on prior opioids to 65.8% at endpoint while patients received OROS hydromorphone, respectively. Daily pain relief ratings also increased significantly (+0.26 +/- 1.084, p = 0.0008). Significant improvements in health-related quality of life and sleep problems were observed. Adverse events were mild to moderate in severity; the most common of these were constipation, nausea, headache, and somnolence. The limitations of this study include its pilot-type design and the lack of comparison of OROS hydromorphone with a placebo or another drug. Additional comparative and longer-term studies are needed to confirm these findings. CONCLUSIONS: OROS hydromorphone may be an effective treatment for chronic low back pain of moderate-to-severe intensity. Adverse events were typical of those associated with opioid therapy.

Pharmacokinetic profile of a 24-hour controlled-release OROS formulation of hydromorphone in the presence and absence of food.

BACKGROUND: The objective of this study was to compare the pharmacokinetic profile of a novel, once-daily, controlled-release formulation of hydromorphone (OROS hydromorphone) under fasting conditions with that immediately after a high-fat breakfast in healthy volunteers. The effect of the opioid antagonist naltrexone on fasting hydromorphone pharmacokinetics also was evaluated. METHODS: In an open-label, three-way, crossover study, 30 healthy volunteers were randomized to receive a single dose of 16 mg OROS hydromorphone under fasting conditions, 16 mg OROS hydromorphone under fed conditions, or 16 mg OROS hydromorphone under fasting conditions with a naltrexone 50-mg block. Plasma samples taken pre-dose and at regular intervals up to 48 hours post-dose were assayed for hydromorphone concentrations. Analysis of variance was performed on log-transformed data; for mean ratios of 0.8 to 1.2 (20%), differences were considered minimal. Bioequivalence was reached if 90% confidence intervals (CI) of treatment mean ratios were between 80% and 125%. RESULTS: The mean geometric ratios of the fed and fasting treatment groups for maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-t; AUC0-infinity) were within 20%. Confidence intervals were within 80% to 125% for AUC0-t and AUC0-infinity but were slightly higher for Cmax (105.9% and 133.3%, respectively). With naltrexone block, the hydromorphone Cmax increased by 39% and the terminal half-life decreased by 4.5 hours. There was no significant change in Tmax, AUC0-t or AUC0-infinity. CONCLUSION: Standard bioavailability measures show minimal effect of food on the bioavailability of hydromorphone from OROS hydromorphone. Naltrexone co-administration results in a slight increase in the rate of absorption but not the extent of absorption.