This study was conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable regulatory requirements. The study protocol and amendments were reviewed and approved by Institutional Review Boards. Prior to study enrolment, all patients or their legally acceptable representatives provided their written consent to participate in the study after being provided with information regarding the nature and purpose of the study, participation/termination conditions, and the risks and benefits of treatment. This study was a registration trial in Japan and was requested by the Japanese Pharmaceuticals and Medical Devices Agency.
2.1 Patient Population
This study included men and women who were at least 20 years of age, had been diagnosed with cancer, and were receiving around-the-clock opioid therapy for moderate to severe, chronic malignant tumor–related cancer pain using one of the following: oral morphine SR (≤120 mg/day), oral oxycodone HCl CR (15–80 mg/day), or transdermal fentanyl (Durotep® MT Patch, ≤8.4 mg/patch; Fentos® Tape, ≤4 mg/tape; OneDuro® Patch, ≤3.4 mg/patch). During the 3 days prior to randomization, opioid doses must have been stable and the mean 24-h pain intensity score must have been <4 on an 11-point numerical rating scale (NRS) [0 = “no pain” to 10 = “pain as bad as you can imagine”]. Eligible patients were allowed to use oral morphine immediate release (IR) or oxycodone IR as rescue medication for breakthrough pain. The dose per intake of rescue medication must have been no more than one-sixth of the total daily dose (TDD) of the around-the-clock opioid analgesic, with conversion of the daily dose based on the ratio of morphine:oxycodone:fentanyl of 3:2:0.03; for patients who were taking morphine SR (20 mg/day) or oxycodone HCl CR (15 mg/day), the minimal strengths of rescue medication (morphine HCl IR 5 mg or oxycodone HCl IR 2.5 mg) were used.
Exclusion criteria and prohibited and permitted medications are listed in the Electronic Supplementary Material.
2.2 Study Design
This randomized, open-label, parallel-arm, optimal dose-titration, multicenter study included a 1- to 2-week screening period and an 8-week open-label treatment period. During the study, patients were hospitalized or treated as outpatients. Patients continued taking the same doses of their previous around-the-clock daily opioid analgesics throughout the screening period. Eligible patients with a mean pain intensity score <4 during the 3 days prior to randomization were then randomized (1:1) to receive twice-daily treatment with tapentadol ER or morphine SR (as a reference for assay sensitivity) for 8 weeks. Randomization was stratified by prior opioid treatment to ensure that the treatment assignment was balanced. Morphine SR served as a reference for assay sensitivity, not as an active comparator, to validate the results observed with tapentadol ER. Starting doses of study drug were calculated based on the previous opioid analgesic dose (Table
1). Based on prior estimates of the equianalgesic ratio of tapentadol ER to oxycodone CR (~5:1) [
21,
22] and of the equianalgesic ratio between oxycodone CR, morphine SR, and a fentanyl transdermal system (2:3:0.03) [
23‐
26], conversion ratios between tapentadol ER and oxycodone, morphine, and fentanyl for the initial dose were estimated as tapentadol ER:oxycodone:morphine:fentanyl = 10:2:3:0.03. In patients switching from a fentanyl transdermal system, the system was to be removed at least 12 h before administration of the first dose of study drug. Patients who developed withdrawal symptoms after switching to study treatment could receive oral oxycodone IR or oral morphine IR (at an equivalent dose of one-fourth to one-tenth the TDD of the previously used opioid) for up to 3 days until symptoms disappeared. Patients were also permitted to take oral oxycodone IR or oral morphine IR as rescue medication for breakthrough pain throughout the study (including the screening and open-label treatment periods); the dose of rescue medication had to be no more than one-sixth of the TDD of the around-the-clock opioid analgesics, including study drug. Patients with a daily dose of tapentadol ER <100 mg/day, morphine SR <20 mg/day, or oxycodone HCl CR <15 mg/day were to use the minimal strengths of rescue medication (morphine HCl IR 5 mg or oxycodone HCl IR 2.5 mg).
Table 1
Starting daily dose of study drug based on dose of previous opioid treatment
≥15 to ≤20 | 2.1 (0.3 mg/day) | 1 (0.3 mg/day) | 0.84 (0.3 mg/day) | ≥20 to ≤30 | 100 | 30 |
>20 to ≤30 | – | – | – | >30 to ≤40 | 150 | 40c
|
>30 to ≤40 | 4.2 (0.6 mg/day) | 2 (0.6 mg/day) | 1.7 (0.6 mg/day) | >40 to ≤60 | 200 | 60 |
>40 to ≤60 | 6.3 (1.2 mg/day) | 3 (1.2 mg/day) | 2.54 (1.2 mg/day) | >60 to ≤90 | 300 | 90 |
>60 to ≤80 | 8.4 (1.8 mg/day) | 4 (1.8 mg/day) | 3.4 (1.8 mg/day) | >90 to ≤120 | 400 | 120 |
After at least 2 days of treatment with the initial dose, doses of study drug could be increased to a maximum of tapentadol ER 500 mg/day or morphine SR 140 mg/day based on the investigator’s judgment, which included evaluating if a patient’s 24-h NRS score was ≥4 or had worsened compared with the previous day or if rescue medication for breakthrough pain was given ≥3 times per day. For patients taking doses of tapentadol ER <200 mg/day and morphine SR <60 mg/day, doses could be increased in increments of tapentadol ER 50 mg/day and morphine SR 10–20 mg/day, respectively. For patients taking doses of tapentadol ER ≥200 mg/day and morphine SR ≥60 mg/day, doses could be increased in increments of tapentadol ER 100 mg/day or morphine SR 20–30 mg/day, respectively. Doses could be reduced as needed during the study for safety reasons [e.g., adverse events (AEs)] to a minimum of tapentadol ER 50 mg/day or morphine SR 20 mg/day. Doses were titrated to each individual patient’s optimal dose, balancing effectiveness and tolerability.
2.3 Study Endpoints and Assessments
Effectiveness in this study was evaluated as the ability to convert patients from previous, around-the-clock strong opioid therapy to tapentadol ER (50–250 mg twice daily) without loss of previous pain control. Patients rated their average pain intensity over the previous 24 h once daily on an 11-point NRS throughout the study. The primary effectiveness endpoint was defined as the proportion of patients who maintained pain control during the first week of the open-label treatment period. Pain control was defined as having a change from baseline in the mean 24-h pain intensity score (11-point NRS) of less than +1.5 and using no more than two doses of rescue medication per day for any 3 consecutive days during the first week. Patients were enrolled in the study only if their pain was well-controlled [i.e., pain intensity (NRS) score <4] on their previous opioid therapy; thus, pain was considered to be controlled on study treatment only if patients experienced minimal changes in pain intensity after conversion from prior therapy.
Secondary effectiveness endpoints included average weekly pain intensity scores (11-point NRS), Patient Global Impression of Change (PGIC) ratings, and rescue medication use. The PGIC is a validated measure of global improvement with treatment for chronic pain [
27,
28]. For the PGIC, patients completed the statement “Since the start of this treatment, my cancer-related pain overall is,” using a 7-point scale (1 = “very much improved” to 7 = “very much worse”). The PGIC was completed at Weeks 1, 2, 4, 6, and at the end of study or early withdrawal. The total number of days that patients took rescue medication, number of rescue medication doses taken in a calendar day, and TDD of rescue medication were evaluated for each patient.
Safety assessments included recorded AEs, clinical laboratory parameters, vital signs, 12-lead electrocardiograms (ECGs), and physical examinations. A treatment-emergent AE (TEAE) was defined as any AE that occurred on or after the first intake of study drug or that started before the first intake of study drug and worsened in intensity during the active treatment period. Incidences of TEAEs reported here include all TEAEs that occurred during the 8-week treatment period, and incidences of serious AEs reported here include all serious AEs that occurred during the 8-week treatment period and any spontaneously reported serious AEs within 7 days of the end of treatment.
2.4 Statistical Analyses
Based on results from previous studies with tapentadol and transdermal fentanyl [
29], it was estimated that 49 patients should be included in the tapentadol ER group, assuming that the percentage of patients achieving pain control in this study was 85 % and the lower limit of the 2-sided 95 % confidence interval (CI) was >75 % (−10 %). Morphine SR was used to evaluate assay sensitivity in this study, and the same number of patients were to be enrolled to receive morphine SR treatment as in the tapentadol ER group, bringing the total number of subjects to approximately 100. The estimated number of patients to be enrolled by previous opioid treatment was as follows: morphine SR,
n = 20; oxycodone CR,
n = 40; fentanyl transdermal system,
n = 40.
In this study, the safety population included all randomized patients who received at least one dose of study medication. The full analysis population, which was used for all effectiveness analyses, included all randomized patients who received at least one dose of study medication and had post-baseline effectiveness data.
For baseline and demographic characteristics and study drug dosing data, descriptive statistics were used to summarize continuous variables, and frequency counts were used to summarize categorical variables. Study drug dosing information evaluated included the TDD of study drug, modal (or most frequently used) dose, duration of treatment, and the number of dose adjustments.
For the primary effectiveness analysis, the percentage (with 95 % CI) of patients who maintained pain control during the first week of treatment was calculated. Patients who discontinued after <3 days of treatment or who did not have any available 24-h pain intensity scores (11-point NRS) for 3 consecutive days during the first week of treatment were considered to have not maintained pain control. The proportion of patients who maintained pain control was also evaluated by previous opioid treatment, sex, and age group (<65 and ≥65 years of age).
The average weekly pain intensity score (11-point NRS), change from baseline in average pain intensity, and percentage change from baseline in pain intensity were summarized using descriptive statistics. PGIC ratings were summarized using frequency counts.
The number of doses of rescue medication taken, the TDD of rescue medication (converted into morphine equivalent doses using the conversion rate of dosage from oxycodone to morphine of 1.5), and total number of days with rescue medication during each week of the treatment period and during the overall treatment period were summarized using descriptive statistics.
Frequency counts were used to summarize the incidence of TEAEs, deaths and serious AEs, and AEs leading to treatment discontinuation. The incidence of TEAEs was also analyzed by previous opioid treatment, sex, and age group (<65 and ≥65 years of age).
In the current study, morphine SR served as a reference for assay sensitivity, not as an active comparator, so no formal comparisons of the effectiveness results for tapentadol ER and morphine SR were performed. For that reason, effectiveness data for the patients in the tapentadol ER and morphine SR groups are presented separately; sensitivity analyses (i.e., effectiveness results for morphine SR) are included in the Electronic Supplementary Material. Patient disposition and demographic data are presented together to show that the population analyzed for effectiveness (the tapentadol ER group) was comparable with the population analyzed for assay sensitivity (the morphine SR group). Safety and tolerability data for both treatment groups are presented together to allow for informal comparisons of the tolerability of tapentadol ER with that of an opioid analgesic commonly used for cancer pain management.