medication on at least one occasion during the seven days of observation .

The corresponding numbers for the previous four-hour interval (from 16 to 20 hours after morning dose) were eight patients in the ADPREM group and 11 patients in the CRM group . Exploratory sensitivity analyses , excluding subjects with no rescue use , showed similar results for rescue medication and BTP endpoints (n 30) . The average pain intensity scores for the two treatments were comparable , and all differences between the treatments were small and statistically nonsignificant (Table 3) . The current pain intensity at the morning evaluation , 24 hours after the most recent exposure to ADPREM and 12 hours after the most recent exposure to CRM , showed similar low mean values , indicating that both ADPREM and CRM provided effective pain control at the end of their respective dosing intervals . Exploratory correlation analyses for rescue use and pain intensity ratings demonstrated a very high within-patient correlation between treatment periods (Fig . 2) . The median

value for assessment of the drugs by patients was 3 (good) for both treatments . The ranges were 1 (poor) to 4 (very good) for the ADPREM treatment and 1 (poor) to 5 (excellent) for the CRM treatment , with an estimated difference of 0.00 (95% CI 0.50 , 0 .50 , P=1.0) . Thirteen (37.1%) patients expressed a preference for ADPREM , 14 (40.0%) patients expressed a preference for CRM , eight (22 .9%) patients had no preference , and one value was missing . No difference between the two treatments was found (P= 1.0) . There were no differences between the treatments in plasma concentrations of morphine , M-3-G , or M-6-G at trough level 24 hours after the last dose of ADPREM and 12 hours after the last dose of CRM (Table 4) . Safety The pattern of the overall and treatment-related AEs did not differ between treatments , and this was what a clinician would reasonably expect in a population with advanced malignancy and chronic use of opioids . Treatment-related AEs occurred in five (12.8%) patients during treatment with ADPREM and six

(15.0%) patients during treatment with CRM . The most common treatment-related AEs were constipation (one [2 .6%] patient during ADPREM treatment and three [7.5%] patients during CRM treatment) followed by somnolence (one [2 .6%] patient during ADPREM treatment and two [5.0%] patients during CRM treatment) . All other treatment-related AEs were single episodes . Discussion When treating patients with chronic pain , the goal is to provide adequate 24-hour pain relief . In this study , a low incidence of BTP and a limited requirement for rescue medication was observed in both treatment arms , demonstrating that both ADPREM dosed once daily and CRM dosed twice daily provide effective pain control around the clock . A number of endpoints were included in this study to assess if the analgesic effect of ADPREM lasted for the entire 24-hour dosing interval . No differences between treatments were observed in use of rescue medication , number of BTP episodes

, or pain intensity in the hours preceding the morning dose , indicating a similar 24-hour pain control with both treatments . In addition , the small number of patients experiencing BTP even once during the final four hours of the dosing interval and the absence of a trend for increasing numbers of patients with BTP episodes at the end of the dosing interval suggest that , in these patients , episodes of BTP were not attributable to the analgesic effect wearing off . Overall , the results , therefore , indicate that ADPREM provides effective pain control for the entire 24-hour dosing interval . In support of the similarities between the treatments for the pharmacodynamic endpoints , the trough plasma levels of morphine and its metabolites , 24 hours after the last dose of ADPREM and 12 hours after the last dose of CRM , were similar . A 90% CI within the 0 .80e1 .25 bioequivalence limits was nearly met in this small exploratory study (Table 4); retrospective calculations show that 80% power to achieve these equivalence margins in a future study would require 91 subjects . Patient ratings of satisfaction and preference provide important information about the overall perception of

treatment

effect

for

the

individual

patient

and

are

recommended to support repeated measurements of pain intensity .15 In this study , the assessment of the drugs was similar for the two treatments , and neither treatment was clearly preferred , supporting the similarity of ADPREM and CRM in the integrated treatment effect on pain , physical functioning , emotional state , and AEs . This study had some limitations . The trough concentrations measured were not exactly at 12 and 24 hours after the previous doses of CRM and ADPREM , respectively; the samples were collected between 11 hours and 20 minutes and 11 hours and 55 minutes after the last dose of CRM and between 23 hours and 30 minutes and 24 hours after the last dose of ADPREM . However , the steadystate plasma concentration vs . time profiles are almost horizontal from 11 to 12 hours after last dose of CRM16 and from 12 to 24 hours after last dose of ADPREM (Egalet a/s , unpublished data) . Hence , collecting the samples within the allowed one-hour window before the next dose would not lead to any significant differences in the estimated end-of-dose concentrations .

Few subjects took IR rescue morphine during the early morning hours before the phar-macokinetic sampling . To assess the potential influence of IR rescue use on the trough levels of morphine and its metabolites , the analysis of end-of-dose concentration was performed for the FAS and for the subset of subjects who had not taken rescue medication during the fourhour interval before sampling . The results were similar . This study was the first one with ADPREM in a patient population . It was designed as an exploratory study in a relatively small population to provide proof of concept for the analgesic efficacy of ADPREM morphine dosed once daily and provide a basis for sample size estimation for a future full-scale proof of efficacy . Hence , no prospective sample size calculation was performed and no preplanned equivalence margin was defined . A retrospective power calculation showed that the present study had greater than 99% power to show noninferiority in the number of rescue doses with a margin of less than one rescue dose/ day . Requiring or not requiring a dose of rescue medication is a valid indicator of the patients perception of pain and has been considered a clinically

appropriate outcome measurement to study the efficacy of the basal therapy .17 The high intrapatient correlation for rescue use and pain ratings was expected , considering that pain is a highly subjective experience ,18 and supports the rationale for a crossover design in early analgesic studies . A risk when performing crossover studies in a population of patients with a progressive disease , such as cancer , is that pain intensity and , hence , doses of morphine are often increased over time; however , no effect of period was detected in any of the analyses of the present study . Contrary to the narrow CIs for the endpoints related to the experience of pain , the CIs for the trough concentrations were relatively wide . This may be because patient characteristics only predict minor parts of the variability in plasma concentration of morphine and metabolites ,19 and the variability of PK parameters has been reported to be higher in patients than in healthy volunteers .20 The polymer-based erodible matrix has proven to be a simple way to provide a stable steady-state morphine concentration through once-daily oral dosing . As an additional advantage , a

recent noninterventional interview study in recreational drug users has confirmed that the physical and chemical properties of ADPREM may give rise to low abuse and tampering attractiveness compared with seven well-known marketed opioids .21 In conclusion , the results of this exploratory first-in-patients study show that ADPREM dosed once daily provides similar trough plasma levels of morphine and analgesic efficacy as CRM , another commonly used CR morphine product , dosed twice daily in cancer patients with chronic pain . No end-ofdose failure was detected at the end of the 24-hour dosing interval for ADPREM , confirming the intended once-daily dosage regimen for the formulation . With a once-daily dosage regimen and low tampering potential , ADPREM is considered a highly relevant new oral formulation of morphine sulfate .