Efficacy and safety of fulranumab as monotherapy in patients with moderate to severe, chronic knee pain of primary osteoarthritis: a randomised, placebo- and active-controlled trial.

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.

The pharmacokinetics of a long-acting OROS hydromorphone formulation.

IMPORTANCE OF THE FIELD: New formulations of opiods can provide round-the-clock pain relief to improve pain management and quality of life for patients with chronic pain. AREAS COVERED IN THIS REVIEW: Information and comments on the pharmacokinetic processes associated with a new once-daily formulation of the potent opiod hydromorphone. WHAT THE READER WILL GAIN: This review presents an overview of data from several small pharmacokinetic studies to gain a better perspective on the pharmacokinetic properties of a new long-acting formulation of hydromorphone. TAKE HOME MESSAGE: The development of advanced oral formulation that deliver analgesic drugs over an extended period provides new solutions to improve pain management and quality of life for patients with chronic pain.

Conversion from standard opioid therapy to once-daily oral extended-release hydromorphone in patients with chronic cancer pain.

This open-label, multicenter study assessed the efficacy and tolerability of conversion to once-daily OROS hydromorphone from previous opioid agonist therapy in patients with chronic cancer pain. Patients were stabilized on their previous therapy before conversion at a 5:1 ratio of morphine sulfate to hydromorphone hydrochloride. The OROS hydromorphone dose was titrated over 3 - 21 days to achieve effective analgesia and was maintained for up to 14 days. Efficacy was assessed using the Brief Pain Inventory (BPI). Adverse events and vital signs were monitored. Dose stabilization was achieved in 119 of the 127 (94%) patients who received the study medication; in 77%, stabilization was achieved with no titration steps. Mean BPI pain intensity ratings and BPI pain interference scores decreased significantly after OROS hydromorphone treatment compared with pretreatment values. Mean pain-relief level remained stable after conversion and throughout treatment with OROS hydromorphone. Adverse events were as expected for cancer patients receiving opioid agonists. There were no clinically significant changes in vital signs.

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

OBJECTIVE: The purpose of this study was to investigate the pharmacokinetic properties of a novel, once-daily, controlled-release formulation of hydromorphone (OROS hydromorphone) in the presence of alcohol. RESEARCH DESIGN AND METHODS: In a single-centre, open-label, four-treatment, four-period, four-sequence, crossover study, two groups of 24 healthy subjects (fasted or fed) were randomised to receive four single doses of OROS hydromorphone 16 mg with solutions of either 0%, 4%, 20% or 40% alcohol, and with a naltrexone block. MAIN OUTCOME MEASURES: Plasma samples taken predose and at regular intervals up to 48 h after dosing were assayed for hydromorphone concentrations; a mixed-effect analysis of variance was done on log-transformed data. Bioequivalence was concluded if 90% confidence intervals of treatment mean ratios were between 80% and 125%. RESULTS: Plasma hydromorphone concentrations were slightly higher after dosing with all alcohol treatments in both the fasted and fed subject groups. Median T(max) values were between 12 and 16 h and ranges were similar for all treatments. C(max) values increased after alcohol compared with no alcohol, with the increase slightly lower in the fed state. The greatest mean increase in C(max) observed was 1.3-fold in the fasted state and 1.1-fold in the fed state. Confidence intervals were within 80-125% for AUC but were slightly higher for C(max). CONCLUSIONS: The pharmacokinetics of once-daily OROS hydromorphone were only minimally affected by alcohol, with no dose dumping of hydromorphone. The results indicate that the controlled-release properties of this formulation are maintained in the presence of alcohol.

Once-daily OROS hydromorphone for the management of chronic nonmalignant pain: a dose-conversion and titration study.

BACKGROUND: The use of opioid analgesics for patients with chronic nonmalignant pain is becoming more widely accepted, and long-acting formulations are an important treatment option. AIM: To assess conversion to extended-release OROS hydromorphone from previous stable opioid agonist therapy in patients with chronic nonmalignant pain of moderate-to-severe intensity. METHODS: In this open-label multicentre trial, patients were stabilised on their previous opioid therapy before being switched to OROS hydromorphone at a ratio of 5 : 1 (morphine sulphate equivalent to hydromorphone hydrochloride). The OROS hydromorphone dose was titrated over 3-16 days to achieve effective analgesia, and maintenance treatment continued for 14 days. RESULTS: Study medication was received by 336 patients; 66% completed all study phases. Stabilisation of OROS hydromorphone was achieved by 94.6% of patients, the majority in two or fewer titration steps (mean time, 4.2 days). Mean pain intensity scores, as determined by the Brief Pain Inventory, decreased during OROS hydromorphone treatment (p

Safety and pharmacokinetics of inhaled morphine delivered using the AERx system in patients with moderate-to-severe asthma.

OBJECTIVE: The safety and pharmacokinetics of inhaled morphine in asthmatic subjects were investigated using the AERx System, a novel aerosol system. METHODS: Twenty subjects with asthma received inhaled placebo and inhaled morphine sulfate, 2.2 mg, 4.4 mg and 8.8 mg, on separate days in a single-blind crossover study. Six of the subjects received an additional open-label dose of 17.6 mg on a separate day. Plasma morphine concentrations and safety evaluations including pulmonary function testing were performed. RESULTS: Mean tmax values were similar following all dose groups at approximately 1-2 minutes. Mean AUC(0-->1) values showed dose proportionality for the first 3 dose groups (6.3, 12.3 and 24.3 ng x h x ml(-1)), the mean AUC(0-->1) for the 17.6 mg dose group was 1.6x that of the 8.8 mg dose group. No statistically significant differences in forced expiratory volume in 1 sec (FEV1) were found for the 2.2 mg, 4.4 mg, or 8.8 mg dose groups; at 17.6 mg, a statistically significant but not clinically meaningful reduction in mean FEV1 (-8.18%) from baseline occurred at 10 minutes compared to placebo, spontaneously returning to baseline by 60 min. Four subjects experienced significant but reversible decreases in FEV1 of > or = 20% compared to baseline and across all dose levels including after placebo, but with no associated increase in dyspnea, wheezing or other adverse events. CONCLUSIONS: Inhaled morphine using the AERx System was absorbed rapidly and demonstrated dose-dependent plasma concentrations. It was well-tolerated and did not cause clinically significant bronchoconstriction in most subjects with moderate-to-severe asthma.

Augmentation of human influenza A virus-specific cytotoxic T lymphocyte memory by influenza vaccine and adjuvanted carriers (ISCOMS).

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.

An evaluation of the safety and immunogenicity of a five-component acellular pertussis, diphtheria, and tetanus toxoid vaccine (DTaP) when combined with a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine (PRP-T) in Taiwanese infants.

OBJECTIVE: Immunologic interference particular to the Haemophilus influenzae type b (Hib) response has been observed with previous acellular pertussis-Hib combination vaccines. To test this hypothesis a clinical trial to assess the safety and immunogenicity of a five-component (pertussis toxoid [PT], filamentous hemagglutinin [FHA], pertactin [PRN], and fimbriae 2 and 3 [FIM]), pertussis vaccine combined with diphtheria and tetanus toxoids (DTaP) when given simultaneously with a lyophilized Hib-tetanus toxoid conjugate vaccine (PRP-T) in infants at 2, 4, 6, and 18 months of age was conducted. The study compared two methods of administration: both vaccines combined in a single syringe and administered as a single injection, or both vaccines administered concurrently but at separate sites of injection. METHODS: Healthy 2-month-old infants were enrolled at the National Taiwan University Hospital. DTaP, PRP-T, and oral poliomyelitis vaccine (OPV) were given at 2, 4, 6, and 18 months. Reaction information was collected by telephone 2 days after each vaccination. Serum was collected at 2, 6, 7, 18, and 19 months of age. RESULTS: One hundred thirty-five healthy infants were enrolled in Taiwan, of which 127 (94%) completed the 18-month booster: 68 received the combined vaccine and 67 the separate vaccines. All vaccines were well tolerated. No differences in rates of local and systemic reactions were seen between the two methods of administration. No serious adverse events were reported. Serologic responses were comparable between the groups. Pertussis responses (enzyme-liked immunoabsorbant assay units [EU]/mL) at 7 months were, for combined versus separate, PT (131 vs 105), FHA (116 vs 116), PRN (100 vs 77), and FIM (922 vs 702). At 19 months, pertussis results were, for combined versus separate, PT (216 vs 182), FHA (203 vs 200), PRN (263 vs 197), and FIM (892 vs 732). Only the 7-month PT response in the combined group was significantly higher (combined 131 EU/mL vs separate 105 EU/mL). After the third dose (age 6 months), all subjects achieved serologic serum antibody levels indicative of protection against Hib, diphtheria, tetanus, and poliovirus types 1, 2, and 3. In fact, 96% of children had anti-PRP levels indicative of protection (>/=0.15 microgram/mL) against Hib after only two doses. At 7 months, anti-PRP geometric mean titer values were 11.8 micrograms/mL in the combined group compared with 13.0 micrograms/mL in the separate group. The anti-PRP geometric mean titers after the 18-month booster were 58.5 micrograms/mL in the combined group versus 55.3 micrograms/mL in the separate group. CONCLUSION: The five-component DTaP vaccine may be combined with PRP-T vaccine without clinically significant immunologic interaction when given in a 2-, 4-, 6-, and 18-month schedule.

Safety and immunogenicity of a combined five-component pertussis-diphtheria-tetanus-inactivated poliomyelitis-Haemophilus B conjugate vaccine administered to infants at two, four and six months of age.

Safety, immunogenicity and lot consistency of five-component pertussis combination vaccine (CPDT-IPV//PRP-T) in infants were compared to that of whole cell pertussis combination vaccine (DPT-IPV//PRP-T), as were separate and combined injections of CPDT-IPV and PRP-T. No significant differences in adverse event rates were observed between lots of CPDT-IPV//PRP-T or between separate or combined injections of CPDT-IPV and PRP-T. Minor differences in antibody responses were observed between lots of component pertussis vaccine. Higher concentrations of diphtheria and tetanus antitoxins were induced by separate than by combined injection of CPDT-IPV and PRP-T, but no other differences in immunogenicity were observed. Adverse reactions were more than twice as frequent after whole cell than after component pertussis vaccines. Antibody responses to pertussis toxoid, filamentous hemagglutin and pertactin were significantly greater after component vaccines, while the response to type 3 poliovirus was higher after whole cell vaccine. No significant differences were observed for other vaccine components. CPDT-IPV//PRP-T was safe and immunogenic in infants. Antibody results were similar to those observed in a Swedish field trial that demonstrated CPDT to be 85% effective in preventing clinical pertussis.

Diphtheria and tetanus immunity among blood donors in Toronto.

OBJECTIVE: To determine the diphtheria and tetanus antitoxin levels among blood donors in Toronto. DESIGN: Cross-sectional seroprevalence study. SETTING: Two fixed-site blood-donation clinics in Toronto from September to November 1994. PARTICIPANTS: Blood donors 20 years of age or older were eligible to participate; of the 781 eligible donors, 710 (90.9%) participated in the study. MAIN OUTCOME MEASURES: Diphtheria and tetanus antitoxin levels and factors associated with disease susceptibility, such as vaccination history, country of birth, age and sex. A diphtheria antitoxin level lower than 0.01 lU/mL and a tetanus antitoxin level lower than 0.15 lU/mL were considered nonprotective. RESULTS: Among the participants, 147 (20.7%) had a diphtheria antitoxin level in the nonprotective range, and 124 (17.5%) had a tetanus antitoxin level that was nonprotective. Increasing age and lack of written vaccination records were associated with susceptibility to the 2 diseases. Birth outside Canada was significantly related to tetanus susceptibility. CONCLUSION: Adults over 50 years of age who did not know their vaccination history were the least likely to be protected against diphtheria and tetanus. The greatest benefit of any immunization strategy would be gained by targeting this group.

Evaluation of booster doses of Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in 18-month-old children.

A booster dose of Haemophilus influenzae type b conjugate vaccine in the second year of life is the final step in the recommended series of doses to protect infants from invasive infection. This study assessed the safety and immunogenicity of PRP-T conjugate vaccine booster doses (Act-HIB, Connaught Laboratories Ltd). The participants were 367 healthy children who had taken part in a study of primary immunization with PRP-T. At 18-19 months old, subjects were randomly assigned to receive diphtheria-pertussis-tetanus (DPT) and PRP-T vaccines either mixed in one syringe (n = 183) or separately in opposite limbs (n = 184). Adverse events were monitored for 48 h after immunization. Blood was obtained prior to vaccination in half of the subjects (combined injections group) and following vaccination in all subjects to test for antibodies to each of the antigens administered. Local adverse reactions were infrequent with PRP-T alone and equally frequent at sites of DPT or DPT/PRP-T injection, except for redness > or = 25 mm in diameter which was more frequent after the combined vaccines (25.1 versus 14.1%, p < 0.01). Systemic adverse events did not differ in type or frequency between groups. Before immunization, the geometric mean anti-PRP level in those tested was 0.41 micrograms ml-1; 26.7% had levels below 0.15 micrograms ml-1. Both treatment groups responded strongly to vaccination. In those serially tested, anti-PRP levels rose by over 90-fold, to 38.1 micrograms ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Measles vaccination of infants in a well-vaccinated population.

During outbreaks of measles, measles vaccine is recommended for infants considered to be at risk who are 6 months of age and older. In a prospective trial the serologic response to early measles immunization has been evaluated in 125 infants given monovalent measles vaccine at 6 to 8.5 months of age and measles-mumps-rubella at 15 months. The response to vaccination was measured by plaque reduction neutralization (PRN) assay and enzyme immunoassay. Infants were grouped by the mother's immunization history: natural immunity (n = 60, Group 1); killed followed by live, further attenuated vaccine (n = 22, Group 2); and live, further attenuated vaccine only (n = 43, Group 3). The prevaccination geometric mean titer (GMT) by PRN for Group 1 (GMT = 69) was significantly higher than that of Group 2 (GMT = 18) or 3 (GMT = 13). Seroconversion (4-fold increase in PRN titer) rates after monovalent vaccine were 31, 71 and 76% for Groups 1, 2 and 3, respectively. Seroconversion percentages were higher when measured 6 to 8 weeks after vaccination compared with 4 to 5 weeks. After measles-mumps-rubella > or = 97% of all infants had PRN titers > 120 and were measles IgG-positive by enzyme immunoassay. These data show that as demographics shift to a well-vaccinated maternal population and susceptibility in younger infants, measles vaccination before the currently recommended age will be effective.