Study design and patients
This 4-week, multicenter, open-labeled, randomized, parallel-group, active-control study (ClinicalTrials.gov: NCT01313780) was conducted between May 19, 2011 and November 18, 2013 at seven oncology/hematology centers in Korea. Inclusion criteria were as follows: patient at least 20 years old; moderate to severe cancer-related pain [i.e., a numeric rating scale (NRS) pain score ≥4] that required continuous treatment with a strong opioid analgesic; and opioid-naïve or previously received only weak opioids, or not treated with naloxone or strong opioids (except for occasional as-required use) within 4 weeks before the screening visit. Patients were excluded from the study if they met any of the following criteria: treatment with OXN-CR or OX-CR within 4 weeks or chemotherapy or radiotherapy within 2 weeks before the screening visit; predominantly non-cancer-related pain; treatment with stable doses of laxatives for 1 week or more before the screening visit; major surgery within 1 month before the screening visit or planned surgery; or clinically significant non-cancerous gastrointestinal disease or significant structural abnormalities of the gastrointestinal tract and significant cardiovascular, respiratory, renal, or hepatic impairment.
Ethics, consent, and permissions
The present study was performed in compliance with Good Clinical Practice guidelines and in accordance with the principles set forth in the Declaration of Helsinki. The study protocol was approved by the institutional review board at each site. All patients provided written informed consent prior to participation in the study.
Treatment
Patients were randomized (1:1) using computer-generated randomization lists to receive either OXN-CR tablets or OX-CR tablets, which were taken orally for 4 weeks. The starting dose of OXN-CR was 20 mg/10 mg per day and that of OX-CR was 20 mg/day. Up-titration of OXN-CR (to 80 mg/40 mg per day) and OX-CR (to 80 mg/day) was permitted at the discretion of the investigator for the following reasons: use of analgesic rescue medication at least twice daily; increased NRS pain score compared with that on the previous visit; or inadequate pain control at the existing dose.
An immediate-release formulation of oxycodone (maximum 10 mg/day) was provided as the analgesic rescue medication. Magnesium oxide (MgO) was prescribed by the study investigators as the laxative rescue medication. Patients were instructed on when to take the laxative and to discontinue its use once constipation symptoms resolved.
Patients were permitted to continue analgesics (non-steroidal anti-inflammatory drugs, weak opioid analgesics, and adjuvant analgesics) that were being used at a stable dose prior to the screening visit. The use of opioid antagonists (e.g., single-ingredient naloxone or naltrexone), stimulant laxatives, enemas, lubricants, and other medications affecting gastrointestinal movement were prohibited during the study.
Study assessments
At baseline, week 1, and week 4, patients were asked to indicate the average severity of their pain over the previous 24 h, according to the 11-point NRS, ranging from 0 (“no pain”) to 10 (“unbearable/severe pain”) [15]. The primary efficacy endpoint was the change in NRS pain score from baseline to week 4.
Secondary endpoints included dose, duration of use, and administration frequency of analgesic rescue medication (immediate-release oxycodone) and laxative rescue medication (MgO) used during the study; change in bowel habits from baseline to week 4 as rated by patients according to a three-point Likert scale (“worsened,” “no change”, or “improved”) [16]; and change in QoL from baseline to week 4, as assessed using the self-administered European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) [17]. Adherence to treatment was assessed at each visit by comparing the dose of unused study drugs returned by the patient against the prescribed dose. The adherence rate was computed as follows: adherence rate = total number of doses actually administered/total number of doses prescribed × 100%.
Adverse events (AEs), defined as any undesirable and unintended sign, symptom, or disease temporally associated with the use of OXN-CR and OX-CR, which may or may not be related to both drugs, were reported at each study visit after randomization and graded using the Common Terminology Criteria for Adverse Events v4.0 [18]. An adverse drug reaction (ADR) was defined as an AE that was possibly related to OXN-CR or OX-CR. Clinically significant abnormalities in clinical laboratory tests, electrocardiogram (ECG) data, and vital signs were also assessed.
Statistical analysis
An estimated sample size of 51 patients per treatment group was required to provide a 81% power to detect non-inferiority using a one-sided, two-sample t test with a margin of equivalence of −1.5 and an α of 0.05. Assuming a dropout rate of 20%, it was estimated that 64 patients per treatment group would need to be randomized.
Efficacy endpoints were analyzed for the full analysis set (FAS) population (i.e., all patients with at least one measurement of primary efficacy after treatment, excluding patients not meeting the eligibility criteria). AE data were analyzed for the safety analysis population (i.e., all patients who received at least one dose of OXN-CR or OX-CR). Demographic data and laboratory measurements were analyzed for the FAS population. All analyses were conducted using available data, and no imputation was performed for missing data except for the analysis of the dose for OXN-CR or OX-CR where missing data were handled using last-observation-carried-forward analysis.
The one-sided 95% confidence interval (CI) for the difference in change in NRS pain score from baseline to week 4 between the OXN-CR and OX-CR groups was calculated to determine the non-inferiority of OXN-CR with respect to OX-CR. If the lower limit of the one-sided 95% CI for the difference between OXN-CR and OX-CR groups was −1.5 or higher, OXN-CR was considered non-inferior to OX-CR.
A t test, analysis of variance (ANOVA), or the Mann–Whitney U test was used for continuous variables. The Chi square test, Fisher’s exact test, or Mantel–Haenszel test, using a stratification factor when appropriate, was used for categorical variables. Repeated-measures ANOVA was used to analyze data at different time points and to compare the OXN-CR and OX-CR groups. The percentage of patients experiencing at least one AE was calculated for each treatment group. All statistical analyses were performed using a two-sided test with a significance level of 0.05, unless otherwise stated. All analyses were performed using SAS software (SAS Institute Inc., Cary, NC, USA).