No abstract

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.

Background: Long-acting opioid formulations are advocated for maintaining pain control in chronic cancer pain. OROS ® 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.

Aims:The efficacy and safety of monotherapy with fulranumab, a monoclonal antibody that neutralises human nerve growth factor (NGF), was evaluated compared with placebo and an active comparator, controlled-release (CR) oxycodone, in patients with moderate to severe chronic knee pain of primary osteoarthritis (OA). Methods: In this phase-2, double-blind (DB), double-dummy, placebo-and active-controlled study, patients (40-80 years) were randomised (1:1:1:1) to placebo, fulranumab 3 or 9mg every 4 weeks (Q4 wk), or oxycodone CR twice-daily. Primary efficacy end-point: responder rates based on percent improvement in average osteoarthritis-related pain intensity (OAPI) scores from baseline to week-12 or when Food and Drug Administration (FDA) put a clinical hold on all anti-NGF trials, whichever was earlier. Secondary efficacy end-points: average OAPI score (week-16), Western Ontario and McMaster Osteoarthritis Index Global Score and subscales (pain, physical function, stiffness), and Patient Global Assessment. Results: As of an FDA clinical hold on all anti-NGF trials, only 196/300 patients were randomised and 33% (65/196) had completed 12 weeks of the 16-week DB phase. Responders were patients who did not withdraw and whose pain improved. Responder rates were not significantly different between fulranumab treatment groups (3mgQ4wk: 71%, p = 0.739; 9mgQ4wk: 80%, p = 0.843) and placebo (77%), whereas, oxycodone CR (56%) had significantly lower responder rates in comparison to both fulranumab (3mgQ4wk: p = 0.008; 9mgQ4wk: p = 0.012) and placebo (p = 0.0021). Secondary efficacy results were consistent with primary. None of the joint replacements (four in three patients) were adjudicated as rapidly progressing OA/osteonecrosis. Conclusion: Low sample size because of early termination make interpretation of this study difficult, but fulranumab monotherapy resulted in significantly better pain relief and function compared with oxycodone CR (but not against placebo) and was generally well-tolerated. Trial registration: ClinicalTrials.gov: NCT01094262.

There is a need to improve the ability of subunit vaccines to induce CD8(+) CTL responses in humans, especially for vaccines used to prevent illness by organisms that undergo antigenic variation at their major neutralizing antibody sites, e.g., influenza A viruses and human immunodeficiency virus. Murine models have demonstrated the protective role of cross-reactive CTL against influenza A virus antigenic drift. We tested the ability of an adjuvanted carrier (Iscomatrix) to help human antigen-presenting cells present formalin-killed influenza vaccine to human CD8(+) CTL clones in vitro and in vaccinated humans. The results of a randomized, double-blind, controlled clinical study demonstrate that a single dose of a vaccine formulated into Iscom particles increased influenza A virus-specific CTL memory in 50-60% of recipients, compared to 5% of the recipients of the standard influenza vaccine.

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.

Comparable analgesic efficacy was demonstrated between a carefully matched dose of inhaled and intravenous morphine in a postsurgical pain model.

IMPORTANCE Atabecestat, a nonselective oral β-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. RESULTSOf 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.