CORAL - Cebranopadol Versus Morphine Prolonged-release in Patients With Chronic Moderate to Severe Pain Related to Cancer

Morphine sulfate IR 10 mg tablets were supplied as rescue medication to trial participants. No dose adjustments of the morphine prolonged release or cebranopadol were allowed during the maintenance period. The daily use of morphine sulfate 10 mg IR tablets was documented by each participant in the trial. The total daily amount of morphine IR was subject to an upper limit recommendation. The primary endpoint is the average amount of daily rescue medication intake over the last 2 weeks of the maintenance period.

Time frame: The last 2 weeks of the expected 6-week treatment period.

Population: The Full Analysis Set includes all allocated participants who took at least 1 dose of the investigational medicinal product (IMP) and had at least 1 day with information for the amount of rescue medication intake after the first intake of double-blind IMP (study drug).

Morphine sulfate immediate release (IR) 10 mg tablets were supplied as rescue medication to trial participants. No dose adjustments of the morphine prolonged release or cebranopadol were allowed during the maintenance period. The daily use of morphine sulfate 10 mg IR tablets was documented by each participant in the trial. The total daily amount of morphine IR was subject to an upper limit recommendation. The primary endpoint is the average amount of daily rescue medication intake over the last 2 weeks of the maintenance period.

Time frame: The last 2 weeks of the expected 6-week treatment period.

Population: The Per Protocol Set (PPS) describes a subset of subjects in the Full Analysis Set (FAS). The PPS included all allocated participants who completed at least 2 weeks of treatment in the maintenance phase and had no major protocol deviations relevant for efficacy evaluations.

Each participant indicated the level of pain on an 11-point numerical rating scale (NRS), where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. The participants entered their pain intensity in their diary on a daily basis. The pain intensity score in the 2 weeks prior to the final evaluation in the maintenance period was compared with the baseline, the baseline pain intensity was calculated based on the 3 days prior to treatment allocation. The definition of a clinically relevant pain reduction (yes/no) was the presence of at least 1 of the 3 following conditions: * Average pain intensity (i.e., average of the 24-hour pain intensities over the last 2 weeks of the Maintenance Phase) of less than 4 points on the 11-point NRS, or * Reduction in average pain intensity by at least 30% (compared to the baseline assessment), or * Reduction in average pain intensity by at least 2 points (compared to the baseline assessment).

Time frame: The last 2 weeks of the expected 6-week treatment period.

Population: Full Analysis Set (FAS). Clinically relevant pain reduction (Yes/No) in Maintenance Week 3 and Week 4. Missing data were imputed using a multiple imputation on the weekly average pain intensity. Participants that discontinued from the trial due to a lack of efficacy were classified as non-responders.

The CPSI measures 5 items on 100-mm visual analog scales: trouble falling asleep (CPSI1), needing sleep medication (CPSI2), awakened by pain during the night (CPSI3) and in the morning (CPSI4) \[all with anchors for 0 = never and 100 = always\], and overall quality of sleep (CPSI5) \[with anchors of 0 = very poor and 100 = excellent\]. The sleep problem index is the sum of items CPSI1, CPSI3 and CPSI4. The minimum sleep problem index is 0 mm, the maximum 300 mm, the higher the worse. For the overall quality of sleep, minimum and maximum are 0 and 100 mm, the higher the better. A decrease in the sleep problem index indicates an improvement as does an increase in the overall quality of sleep. Changes from baseline to the End-of-Treatment Visit of the Maintenance Phase (scheduled for Week 6) were calculated.

Time frame: Baseline; End-of-Treatment Visit (6 weeks)

Population: Full Analysis Set

The Physical and Mental Component Scores are calculated from the responses by participants to 12 questions. These 12 questions cover 8 domains, (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role participation with emotional health problems, and mental health) that a participant was asked to rate over the last week. Questions are scored on a Likert-scale. The Physical and Mental Component Scores were not derived as the trial was terminated. Changes in the individual item scores are therefore reported. A higher score indicates a better participant perceived state of health. All domains were scored on a scale from 0 (lowest level of health) to 100 (highest level of health), with 100 representing the best possible health state. If the values are positive there was an improvement. The higher the value the greater the improvement.

Time frame: Baseline; End-of-Treatment Visit (6 weeks)

Population: Full Analysis Set (FAS). End of Treatment (End of Maintenance Period Visit).

Participants will be asked: Please rate your pain by selecting the one number that best describes your pain on average during the last 24 hours. every day in the morning. They will score their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. The weekly mean value of the 24-h average pain intensity will be calculated as a mean score of these daily entries of average pain intensity for each trial week.

Time frame: Baseline; last 2 weeks of the expected 6-week treatment period

Population: Full Analysis Set (FAS)

Participants will be asked: Please rate your pain by selecting the one number that best describes your pain at its worst during the last 24 hours. every day in the morning. They will score their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. The weekly mean value of the 24 h worst pain intensity will be calculated as a mean score of these daily entries of worst pain intensity for each trial week. A positive change from baseline will indicate a worsening, whilst a negative change will indicate an improvement of pain.

Time frame: Baseline; End-of-Treatment Visit (6 weeks)

Population: Full analysis set (FAS)

In the Clinical Global Impression of Change (CGIC) the clinician indicates the perceived change in patient's condition over the treatment period as compared to patient's condition prior to the start of treatment. The clinician is requested to choose one of seven categories. Scores range from very much improved to very much worse.

Time frame: Baseline; End-of-Treatment Visit (6 weeks)

Population: Full Analysis Set (FAS). End of Treatment (End of Maintenance Period Visit). Participants with data available.

The EuroQol-5 Dimension Health Questionnaire is a generic health related quality of life instrument. EuroQoL-5D Health State Visual Analog Scale (VAS) is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. The values indicated represent the change from the baseline, a positive value indicates an improvement.

Time frame: Baseline; End-of-Treatment Visit (6 weeks)

Population: Full Analysis Set; means (standard deviations) are presented for the number of participants at the End-of-Treatment Visit with respective data available.

The EuroQol-5 Dimension Health Questionnaire is a generic health related quality of life instrument. The participants will answer 5 questions on 5 dimensions of their health related quality of life: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each question has 3 possible answers reflecting 3 levels of impact on the quality of life. The weighted EQ-5D health status index values are derived and reported as change from baseline. The responses to the 5 EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score (with 1 indicating full health and 0 representing dead). The higher the values (the closer the value is to 1) the better the health status in a treatment group. A positive change indicates an improvement.

Time frame: Baseline; End-of-Treatment Visit (6 weeks)

Population: Full Analysis Set; means (standard deviations) are presented for the number of participants at the End-of-Treatment Visit with respective data available.

Participants with neuropathic pain (determined by the completion of the Douleur Neuropathique En 4 Questions \[DN4\] questionnaire at allocation) rated their symptoms of neuropathic pain on the Neuropathic Pain Symptom Inventory (NPSI). Ten out of 12 questions were answered on an 11-point scale 0 (no symptom present) to 10 (worst imaginable); 2 out of 12 questions assessed the duration of spontaneous pain and the number of pain attacks and were answered by selecting 1 of 5 possible responses. Mean scores of NPSI were calculated. The overall NPSI score was calculated by the summation of all responses in the ranges between 0 (all symptoms absent) and 1 (all symptoms present and at the worst intensity). A negative change indicates that the intensity of all the neuropathic symptom components have decreased since the start of treatment.

Time frame: Baseline; End-of-Treatment Visit (Week 6)

Population: Subset of participants that were assessed to have Neuropathic Pain (using the DN4 questionnaire) at baseline.

The PAC-SYM is a 12-item self-administered questionnaire that assesses the severity of constipation-related symptoms during past 2 weeks. Items are rated on a 5-point Likert scale, where 0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe.The PAC-SYM contains 3 subscales: stool symptoms (5 items), abdominal symptoms (4 items), rectal symptoms (3 items). If at least 6 items are assessed, the PAC-SYM overall score is calculated as the sum of the scores of all non-missing items divided by number of non-missing items. The minimum overall score is 0, the maximum overall score is 4. If more than 6 items are missing, no overall score is calculated. Changes from baseline for the overall score are presented. If the changes in the overall (or subscale) scores are positive then there is a worsening in symptoms associated with constipation.

Time frame: Baseline; End-of-Treatment Visit (6 weeks)

Population: Safety Set; number of participants with data available.

In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period compared to his condition prior to the start of treatment. The participant is requested to choose one of seven categories. Scores range from very much improved to very much worse.

Time frame: Baseline; End-of-Treatment Visit (6 weeks)

Population: Full Analysis Set (FAS). End of Treatment (End of Maintenance Period Visit). Participants with data available.

Pain intensity will be recorded daily by each participant in the morning on an 11-point Numerical Rating Scale, ranging from 0 (no pain) to 10 (worst imaginable pain). From this, the weekly average 24-hour pain intensity will be calculated. The number of participants with a 0, 10, 20, 30, up to a 100% reduction in weekly mean pain intensity will be reported over each week and over the last 2 weeks of the maintenance period.

Time frame: Baseline; last 2 weeks of the expected 6-week treatment period

Population: Full Analysis Set (FAS). Worsening in 24-hour pain or premature discontinuation due to lack of efficacy or Adverse Event was regarded a non-response, other missing data is imputed using last observation carried forward (LOCF).