Clinical Trial Results with OROS Ò Hydromorphone

Vol. 33 No. 2S February 2007 Journal of Pain and Symptom Management S25 Advances in the Long-Term Management of Chronic Pain: Recent Evidence with OROS Ò Hydromorphone, a Novel, Once-Daily, Long-Acting Opioid Analgesic Clinical Trial Results with OROS Ò Hydromorphone Mark S. Wallace, MD, and John Thipphawong, MD Center for Pain and Palliative Medicine (M.S.W.), Department of Anesthesiology, University of California, San Diego School of Medicine, La Jolla, California; and ALZA Corporation (J.T.), Mountain View, California, USA Abstract OROS Ò hydromorphone is a unique drug delivery system being evaluated for the once-daily oral treatment of moderate to severe chronic pain. Results of dose conversion studies indicate that most patients can be successfully titrated from prior opioid therapy to OROS Ò hydromorphone using a 5:1 ratio to convert oral morphine equivalents to OROS Ò hydromorphone in up to two dose titration steps. OROS Ò hydromorphone is effective in both chronic cancer pain and chronic noncancer pain of moderate to severe intensity. It is at least as effective at controlling chronic pain, reducing the impact of pain on functionality, and improving quality of life as controlled-release morphine (cancer pain) and extended-release oxycodone (osteoarthritis pain). In all studies, OROS Ò hydromorphone was generally well tolerated, with an adverse event profile similar to that of other long-acting opioid analgesics. J Pain Symptom Manage 2007;33:S25eS32. Ó 2007 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Hydromorphone, pain, osteoarthritis, low back pain, opioid analgesics Introduction OROS Ò hydromorphone is an osmotically controlled delivery system that was designed by ALZA Corporation (Mountain View, CA, USA) to provide sustained relief from chronic pain with once-daily oral administration. Early investigations confirmed that hydromorphone is released from this unique delivery system Address reprint requests to: Mark S. Wallace, MD, University of California San Diego Medical Center, 9500 Gilman Drive, #0924, La Jolla, CA 92093, USA. E-mail: mswallace@ucsd.edu Accepted for publication: September 1, 2006. Ó 2007 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. continuously over a 24-hour period, 1 producing sustained, dose-dependent, long-acting analgesia. 2 The use of OROS Ò hydromorphone has been evaluated in clinical studies involving more than 700 patients with chronic pain in North America and Europe. 3 The populations studied include patients with chronic cancer pain and those with chronic noncancer pain (including low back pain and osteoarthritis). This article reviews recently released data from several short-term studies, including dose conversion studies and comparison studies with other commonly prescribed longacting opioids (twice-daily controlled-release morphine and twice-daily extended-release oxycodone). 0885-3924/07/$esee front matter doi:10.1016/j.jpainsymman.2006.09.008

S26 Wallace and Thipphawong Vol. 33 No. 2S February 2007 Dose Conversion Studies Hydromorphone is a potent opioid analgesic that was introduced clinically for the treatment of pain in 1926; 4 initial doses for patients switching from other oral opioids to oral hydromorphone typically are calculated using conversion ratios of 5:1 to 7.5:1 morphine equivalents to oral hydromorphone (in milligrams). 5 Results of early nonrandomized, open-label, dose conversion studies support a 5:1 ratio to convert oral morphine equivalents to OROS Ò hydromorphone. 6 These studies were conducted at 48 U.S. and Canadian centers. All studies were conducted in three phases: a prior opioid-stabilization phase, a conversion phase, and a maintenance phase. During the initial phase, doses of opioids were titrated to stability (stable dose requiring #3 doses of rescue medication per day for three consecutive days). The duration of this phase ranged from 3 to 40 days. In the second phase, investigators used a 5:1 ratio to convert oral morphine equivalents to once-daily OROS Ò hydromorphone and titrated doses to stability. The duration of the second phase ranged from 3 to 21 days. OROS Ò hydromorphone therapy was continued at stable doses for 14 days in the final phase. Efficacy was evaluated using the Brief Pain Inventory (BPI), 7 rescue-medication use, pain relief assessment, and patient and investigator evaluations of overall effect. A total of 404 patients participated in these studies (54% women; mean age, 50 years). Approximately 68% of patients completed the studies, with 38 (9%) and 50 (12%) patients discontinuing prematurely because of lack of efficacy and adverse events, respectively. The studies included 73 (18%) patients with chronic cancer pain as well as 331 (82%) patients with chronic noncancer pain. At baseline, approximately 81% of patients were receiving single-entity opioid therapy, and 19% were receiving multiple opioids (overall, oxycodone [38%], morphine [24%], hydrocodone [16%], fentanyl transdermal therapeutic system [9%], hydromorphone [8%], methadone [7%], or codeine [3%]) at doses equivalent to 15 to 2028 mg of morphine daily (mean, 150.3 mg) (Table 1). The mean initial dose of OROS Ò hydromorphone was 31.8 mg. Most of the patients (73.8%) underwent successful conversion from prior opioid therapy to stable OROS Ò hydromorphone Table 1 Baseline Characteristics of Subjects Participating in Dose Conversion Studies Mean Daily Oral Morphine Equivalent Requirement (mg): Amount (range) Total patients 150.3 (15e2028) Chronic cancer pain 166.4 (32e960) Chronic noncancer pain 146.8 (15e2028) Prior opioid class Number (%) of patients Single entity 326 (80.7) Combination 78 (19.3) Data on file, ALZA Corporation. 3 doses, with 20.8% of these patients requiring no dose titration, 49.3% requiring one or fewer titration steps, and 70.1% requiring two or fewer dose titration steps. After seven days, significant reductions in the interference of pain with daily function were observed (Fig. 1). These findings indicate that conversion from other opioids (in morphine equivalents) to OROS Ò hydromorphone should be initiated using a 5:1 ratio. Efficacy and Safety Chronic Cancer Pain: OROS Ò Hydromorphone Versus Sustained-Release Morphine Results of a randomized, double-blind study conducted in 37 centers in Europe and Canada showed that once-daily OROS Ò hydromorphone is at least as effective as twice-daily, sustained-release morphine for the management of severe chronic cancer pain. 8 A total of 200 patients with chronic cancer pain participated in this two-phase study, they were assigned randomly to receive either immediate-release hydromorphone for 2 to 9 days followed by once-daily OROS Ò hydromorphone for 10 to 15 days or immediate-release morphine for 2 to 9 days followed by twice-daily, controlled-release morphine for 10 to 15 days. The primary efficacy outcome measure was the BPI worst pain in the past 24 hours item, which is scored on a scale of 0 to 10 (higher scores indicating greater pain). Equivalence was predefined as a 95% confidence interval (CI) of the treatment difference at end point within 1.5 and 1.5. Secondary outcome

Vol. 33 No. 2S February 2007 OROS Ò Hydromorphone Clinical Trial Results S27 Mean (±SD) Pain Interference Score 10 9 8 7 6 5 4 3 Pretreatment Endpoint 2 1 0 General Activity Mood Walking Ability Normal Work Relationships With Others Sleep Enjoyment of Life P < 001 Fig. 1. Interference of chronic pain with daily activities before and after oral administration of OROS Ò hydromorphone once daily for at least 7 days. 6 measures included other scales of the BPI, Investigator and Patient Global Assessment, the Eastern Cooperative Oncology Group (ECOG) performance scale, 9 the Mini-Mental State Examination (MMSE), 10 time to OROS Ò hydromorphone dose stabilization, and breakthrough pain medication use. A total of 133 patients completed both phases of the study. At the end of the study, mean (SD) scores on the BPI worst pain in the past 24 hours item were 3.5 (2.5) in the OROS Ò hydromorphone group and 4.1 (2.7) in the controlled-release morphine group (mean difference 0.8; 95% CI: 1.6, 1). Mean scores on other BPI scales in each group were also similar or the same, as follows: least pain in last 24 hours, 1.8 in both groups (95% CI: 0.5, 0.6); average pain in last 24 hours, 3.3 in both groups ( 0.6, 0.7); current pain (AM), 2.5 and 2.8 in the OROS Ò hydromorphone and controlled-release morphine groups, respectively ( 1.4, 0.3); current pain (PM), 2.6 and 3.3, respectively ( 1.4, 0.1); and total pain relief (on a scale of 0 to 100 with higher numbers indicating greater pain relief), 70 and 69, respectively ( 7.0, 8.0). At end point, the level of interference of pain with daily activities was similar in both groups (Fig. 2). As indicated, all CIs included a zero value, suggesting no significant difference between therapies for the BPI variables associated with activity, functionality, and quality of life. Patients in the hydromorphone group used significantly less breakthrough pain medication than patients in the morphine group during Mean BPI Item Score 6.0 5.0 4.0 3.0 Treatments deemed equivalent if 95% CI of difference at endpoint lies between (-1.5, 1.5) -1.2, 0.5 -, 0.7-0.9, 0.9-1.2, 0.9-0.6, -1.2, 0.4-0.9, OROS hydromorphone SR morphine General Activity Mood Walking Ability Normal Work Relationships Sleep Enjoyment of Life Fig. 2. Interference of chronic cancer pain with daily activities after OROS Ò hydromorphone once daily or controlled-release morphine twice daily for $12 days. 3 BPI scored from 0 (no interference) to 10 (complete interference).

S28 Wallace and Thipphawong Vol. 33 No. 2S February 2007 2.5 Phase I 2.5 Phase II Mean Daily Use of Breakthrough Pain Medication 1.5 0.5 1.5 0.5 IR hydromorphone OROS hydromorphone P < 5 IR morphine SR morphine Fig. 3. Breakthrough medication use in patients with chronic cancer pain. 3 the immediate-release phase, but not during the sustained-release phase of the study, thus providing further evidence of the equivalence of the two long-acting agents (Fig. 3). Scores for other secondary measures were also similar between groups. Mean MMSE scores were 28.9 and 29.1 in the OROS Ò hydromorphone and controlled-release morphine groups, respectively (95% CI: 1.1, 0.6), and mean ECOG performance scores were 1.8 and 1.7, respectively ( 0.1, 0.3). Most patients and investigators (>70%) rated the treatments as good, very good, or excellent at the end of each phase of the study (Fig. 4). There was no significant difference between groups in the time it took to achieve dose stability during the OROS Ò hydromorphone/controlled-release morphine phase (4.3 vs. 4.6 days). Approximately one half of patients in each group used breakthrough pain medication within the 2 days preceding the end of the study, with mean administration frequencies of 1.7 and 1.5 times per day, respectively (P ¼ NS). The adverse event profiles of OROS Ò hydromorphone and controlled-release morphine were similar and typical of opioid analgesia, with the most common events affecting the gastrointestinal and central nervous systems. 10 Phase I 10 Phase II % Rating Treatment as Good, Very Good, or Excellent 8 6 4 2 8 6 4 2 P < 0.1 Patient Investigator IR hydromorphone IR morphine Patient Investigator OROS hydromorphone SR morphine Fig. 4. Global evaluation of therapy among patients with chronic cancer pain treated with once-daily OROS Ò hydromorphone or twice-daily controlled-release morphine. 3

Vol. 33 No. 2S February 2007 OROS Ò Hydromorphone Clinical Trial Results S29 100 43.8% Improvement 80 60 Patient Response (%) Overall Pain Relief 40 20 0 20 40 60 80 100 Baseline Week 6 LOCF [Week 1-2] Poor Pain Relief Fair Pain Relief Good Pain Relief Very Good Pain Relief Excellent Pain Relief Fig. 5. Improvements in overall pain relief among patients with chronic low back pain treated with OROS Ò hydromorphone. 11 Low Back Pain OROS Ò hydromorphone has also demonstrated efficacy in patients with chronic ($6 weeks) moderate to severe low back pain. An open-label, multicenter U.S. study included only patients who were receiving daily therapy with a strong opioid before participation with no change in medication during the previous 30 days (N ¼ 208). 11 After doses of prior opioid therapies were stabilized (Phase I), patients were switched directly to OROS Ò hydromorphone therapy using a 5:1 ratio to convert morphine equivalents to hydromorphone and titrated to adequate analgesic effect (stable dose requiring #3 doses of rescue medication per day for three consecutive days; Phase II). Patients then received established doses of OROS Ò hydromorphone (8, 16, 32, or 64 mg) for four weeks (Phase III). The primary efficacy outcome measure was the change in patient-evaluated pain relief (poor, fair, good, very good, or excellent) over time. Secondary efficacy end points included the BPI, 7 the Medical Outcomes Survey Mean Brief Pain Inventory Score 1 9.0 8.0 7.0 6.0 5.0 4.0 3.0 Baseline [Week 1-2] # # Week 3 Week 4 Week 5 Week 6 Last Assessment Item 3 (Worst Pain in Past 24 Hours) Item 5 (Pain on Average) P 001 vs. baseline; # P < 5 vs. baseline Improvement LOCF Item 4 (Least Pain in Past 24 Hours) Item 6 (Pain Right Now) Fig. 6. BPI pain severity in patients with low back pain treated with OROS Ò hydromorphone in a 7-week, open-label study. 11 BPI scored from 0 (no interference) to 10 (complete interference).

S30 Wallace and Thipphawong Vol. 33 No. 2S February 2007 1 Baseline (Week1-2) Last Assessment BPI Item (+SD) Score 8.0 6.0 4.0 # Pain at Pain at Pain on Pain Right General Its Worst Its Least Average Now Activity P 001; # P < 5 Mood Walking Ability Normal Work Relationships Sleep Enjoyment of Life Fig. 7. Effect of OROS Ò hydromorphone on quality of life in patients with moderate to severe low back pain. 11 (MOS) Short-Form 36, 12,13 the MOS sleep assessment, 14 and Physician and Patient Global Evaluations of Efficacy. A total of 131 patients completed all three phases of the study. The mean exposure to OROS Ò hydromorphone during the maintenance phase was 44.3 mg/day. Overall, pain relief improved over the course of the study (Fig. 5). Mean pain relief scores improved over the course of the study and were statistically greater than baseline (the last two days responses reported before conversion) at all post-baseline assessments (P < 5). Significant reductions in pain severity (Fig. 6) and improvements in quality of life (Fig. 7) also were observed. As expected, the most frequently occurring treatment-emergent adverse events (those occurring in $10% of patients) were constipation, nausea, vomiting, headache, and somnolence. The adverse event profile of OROS hydromorphone is similar to that of other long-acting opioid analgesics used in the long-term treatment of chronic pain. Osteoarthritis Pain: OROS Ò Hydromorphone versus Sustained-Release Oxycodone The efficacy of OROS Ò hydromorphone has also been demonstrated in opioid-naive patients with chronic moderate to severe osteoarthritis pain despite therapy with nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 Change From Baseline Scores (+SD) 2.5 1.5 0.5-0.5 - -1.5 - -2.5 Treatments considered equivalent if 1-sided difference in pain relief 0.46 (-0.35, ) Change From Baseline Pain Relief Score OROS hydromorphone (n=64) (-0.53, ) Change From Baseline Pain Intensity Score SR oxycodone (n=60) Fig. 8. Mean changes from baseline pain relief and pain intensity associated with OROS Ò hydromorphone and extended-release oxycodone in patients with chronic osteoarthritis pain.

Vol. 33 No. 2S February 2007 OROS Ò Hydromorphone Clinical Trial Results S31 Table 2 Effects of OROS Ò Hydromorphone and Extended-Release Oxycodone in Patients with Chronic Moderate to Severe Osteoarthritis Pain OROS Ò Hydromorphone (n ¼ 64) Extended- Release Oxycodone (n ¼ 60) 95% CI Pain relief 2.3 (0.95) 2.3 (0) 0.2, N Pain intensity 1.5 (0.77) 1.6 (0.88) 0.4, N Days to third day of pain relief a 6.2 (4.00) 5.5 (2.57) 1.96, N Change from baseline: pain relief score 0.9 (1.12) 0.9 (1.15) 0.35, N Change from baseline: pain intensity score 0.6 (0.80) 0.4 (1.15) 0.53, N All values are expressed as mean (SD). Data from Roth et al. 15 a Pain relief defined as moderate to complete pain relief. inhibitors. 15 A total of 140 patients participated in a six-week, open-label comparative study, which included a dose titration phase (#14 days) and a maintenance phase (28 days). Patients were assigned randomly to receive OROS Ò hydromorphone at a starting dose of 8 mg once daily or sustained-release oxycodone 10 mg twice daily. Doses were titrated every two days if needed, using predefined dose titration steps (16, 24, 32, 48, and 64 mg for OROS Ò hydromorphone and 10/20 [AM/PM], 20/20, 20/30, 30/40, 40/50, 60/60, and 80/80 mg for sustained-release oxycodone). Patients who required #64 mg/day of OROS Ò hydromorphone or #160 mg/day of sustained-release oxycodone and reported moderate to complete pain relief on their final titrated dose for a minimum of three days were entered into the maintenance phase of the study. Data from all treated patients were included in the safety analysis. Data from one study site were excluded from the efficacy analysis because of protocol violations; therefore, efficacy analyses were based on data from 124 patients (OROS Ò hydromorphone, n ¼ 64; sustained-release oxycodone, n ¼ 60). During the maintenance phase, the two agents were similarly effective. The mean change from baseline pain relief scores was similar in both groups (Fig. 8). At end point, pain relief was moderate to good in both groups Change From Baseline Scores - -4.0-6.0-8.0-1 -1-14.0 P = 448 P = 981 Improvement -16.0 MOS Sleep Problems Index I MOS Sleep Problems Index II OROS hydromorphone (n=64) SR oxycodone (n=60) Fig. 9. Mean changes from baseline in MOS sleep Indices I and II after treatment with OROS Ò hydromorphone or extended-release oxycodone in patients with chronic osteoarthritis pain. Sleep problems Index I is derived from items 4 (get enough sleep to feel rested upon waking in the morning), 5 (awaken short of breath or with a headache), 7 (have trouble falling asleep), 8 (awaken during your sleep time and have trouble falling asleep again), 9 (have trouble staying awake during the day), and 12 (get the amount of sleep you needed) of the MOS sleep assessment; higher scores indicate greater sleep problems. Sleep problems Index II is derived from items 1 (time to fall asleep), 3 (feel that sleep was not quiet), 4, 5, 6 (feel drowsy or sleepy during the day), 7, 8, 9, and 12 of the MOS sleep assessment; higher scores indicate greater sleep problems.

S32 Wallace and Thipphawong Vol. 33 No. 2S February 2007 (mean [SD] pain relief scores, 2.3 [.95] and 2.3 [0] in the OROS Ò hydromorphone and extended-release oxycodone groups, respectively). Pain relief was achieved at a similar rate in both groups, with mean (SD) times to the third day of moderate to complete pain relief of 6.2 (4.00) days in the OROS Ò hydromorphone group and 5.5 (2.57) days in the sustained-release oxycodone group (Table 2). OROS Ò hydromorphone demonstrated a greater propensity to improve sleep and other measures of health-related quality of life (Fig. 9). As in the other studies, adverse effects were predictable and included gastrointestinal and central nervous system effects. Summary OROS Ò hydromorphone is an effective long-acting opioid analgesic agent for the long-term management of chronic pain. In a clinical study program involving more than 700 patients, OROS Ò hydromorphone was shown to provide effective pain control and improve quality of life. The beneficial effects of OROS Ò hydromorphone were seen both in patients established on opioid therapies and in opioid-naive patients. Dose conversion results confirmed that conversion from established therapies should be initiated using a 5:1 ratio for morphine equivalents to OROS Ò hydromorphone. Throughout the clinical trials, OROS Ò hydromorphone generally was well tolerated, with an adverse event profile similar to those of other long-acting opioid analgesics. References 1. Drover DR, Angst MS, Valle M, et al. Input characteristics and bioavailability after administration of immediate and a new extended-release formulation of hydromorphone in healthy volunteers. Anesthesiology 2002;97:827e836. 2. Angst MS, Drover DR, Lötsch J, et al. Pharmacodynamics of orally administered sustained-release hydromorphone in humans. Anesthesiology 2001; 94:63e73. 3. Data on file. ALZA Corporation, Mountain View, CA; July 1, 2005. 4. Murray A, Hagen NA. Hydromorphone. J Pain Symptom Manage 2005;29(5 Suppl):S57eS66. 5. Sarhill N, Walsh D, Nelson KA. Hydromorphone: pharmacology and clinical applications in cancer patients. Support Care Cancer 2001;9: 84e96. 6. Palangio M, Northfelt DW, Portenoy RK, et al. Dose conversion and titration with a novel once-daily, OROS Ò osmotic technology, extendedrelease hydromorphone formulation in the treatment of chronic malignant or nonmalignant pain. J Pain Symptom Manage 2002;23:355e368. 7. Daut R, Cleeland C, Flanery R. Development of the Wisconsin Brief Pain Questionnaire to assess pain in cancer and other diseases. Pain 1983;17: 197e210. 8. Hanna M. The safety and efficacy of OROS hydromorphone in patients with chronic cancer pain. J Pain 2006;7(Suppl):S35. Abstract 733. 9. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649e655. 10. Folstein MF, Folstein SE, McHugh PR. Mini- Mental State. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189e198. 11. Wallace M, Hewitt D, Khanna S, Thipphawong J. Efficacy and safety evaluation of OROS Ò hydromorphone in patients with chronic low back pain. Presented at the 11th World Congress on Pain. Sydney, Australia, August 21e26, 2005, Abstract 688-P294:247. 12. Ware JJ, Sherbourne CD. The MOS-36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30: 473e483. 13. Ware JE. The MOS 36-Item Short Form Health Survey (SF-36). In: Sederer L, Dickey B, eds. Outcomes assessment in clinical practice. Baltimore: Williams & Wilkins, 1996. 14. Stewart AL, Ware JE, eds. Your Sleep. I: Measuring functioning and well-being. Durham, NC: Duke University Press, 1992: 399e499. 15. Roth S, Damask M, Khanna S, Thipphawong J. To evaluate the efficacy and safety of OROS Ò hydromorphone versus extended-release oxycodone for the management of moderate to severe chronic pain in patients with osteoarthritis of the knee or hip, regularly using NSAIDs with or without the addition of opioid analgesia. Presented at the 11th World Congress on Pain. Sydney, Australia, August 21e26, 2005, Abstract 688-P295:247-248.