A Study to Evaluate Tapentadol (CG5503) in the Treatment of Chronic Tumor-Related Pain Compared With Placebo and Morphine
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| ClinicalTrials.gov Identifier: NCT00472303 |
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Recruitment Status :
Completed
First Posted : May 11, 2007
Results First Posted : May 7, 2014
Last Update Posted : November 4, 2019
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The purpose of this study will be to determine whether tapentadol (CG5503) is effective and safe in the treatment of chronic tumor related pain compared to placebo. In addition tapentadol (CG5503) will also be compared to morphine controlled release, also referred to as slow release (SR).
*Tapentadol prolonged-release (PR) is the term used in the European Union and is referred to as extended release (ER) in the United States.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Tumor Pain | Drug: Tapentadol Extended Release Drug: Matching Placebo after Tapentadol in the Titration Phase. Drug: Morphine Sulphate Controlled Release | Phase 3 |
Normally chronic tumor related pain is controlled when participants receive repeated doses of opioid analgesics. However, opioid therapy is commonly associated with side effects such as nausea, vomiting, sedation, constipation, addiction, tolerance, and respiratory depression. Tapentadol (CG5503), a newly synthesized drug with an prolonged release (PR) formulation, also acts as a centrally acting pain reliever but has 2 mechanisms of action. The aim of this trial is to investigate the effectiveness (level of pain control) and safety (side effects) of tapentadol (CG5503) PR compared with no drug (placebo) and corresponding dose of morphine (an opioid commonly used to treat tumor related pain). This trial is a randomized, double-blind (neither investigator nor patient will know which treatment was received), active- and placebo-controlled, parallel-group, randomized withdrawal design, multicenter trial.
The trial includes a 2 week titration phase starting with either 40 mg morphine (PR) bid (bid = twice daily dosing, one dose in the morning and one dose in the evening) or 100 mg tapentadol (CG5503) PR bid. Based on effectiveness and side effects subjects can up-titrate in steps of 50 mg tapentadol (CG5503 PR) to a maximal dose of 250 mg tapentadol (CG5503) PR bid or 100 mg morphine PR bid. If participants meet the stabilisation criteria at the end of the titration phase they will be re-randomized to either placebo or active treatment and will continue 4 weeks at the last dose level in the maintenance phase. Only participants on tapentadol in the titration phase will be re-randomized to either matching placebo or to tapentadol. To maintain the blinding nature of the trial participants in the morphine arm during the titration phase will also be re-randomized however they will all remain on morphine controlled release in the maintenance phase. Placebo to match tapentadol tablets, as well as placebo to match morphine capsules, will be used to mask the treatment allocation.
Participants will be issued with an electronic diary (eDiary) to capture Numeric Rating Scale (NRS) pain intensities.
Assessments of pain relief include the pain intensity numeric rating scale (NRS) and patient global impression of change (PGIC). Safety evaluations include monitoring of adverse events, physical examinations, clinical laboratory tests and electrocardiograms. Venous blood samples will be collected for the determination of serum concentrations of tapentadol (CG5503).
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 622 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | A Randomized Withdrawal, Active- and Placebo-controlled, Double-blind, Multi-center Phase III Trial Assessing Safety and Efficacy of Oral CG5503 (Tapentadol) PR* in Subjects With Moderate to Severe Chronic Malignant Tumor-related Pain |
| Study Start Date : | July 2007 |
| Actual Primary Completion Date : | June 2012 |
| Actual Study Completion Date : | June 2012 |
| Arm | Intervention/treatment |
|---|---|
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Placebo Comparator: Matching Placebo after Tapentadol in Titration Phase
Oral Tapentadol 100 mg to 250 mg twice daily. Participants randomized to placebo in the maintenance phase received 100 mg tapentadol prolonged release twice daily for 3 days to taper them off the tapentadol dose they had received in the Titration Phase. From the 4th day (Day 18) all participants received matching placebo in the maintenance (i.e. randomized withdrawal) phase.
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Drug: Tapentadol Extended Release
Tablet taken orally, twice daily, morning & evening with preferably 12 hours (not less than 6 hours) between doses. Titration phase: Starting at 100 mg, increasing at a minimum of 3 day intervals by 50 mg, with a maximum dose of 250 mg.
Other Names:
Drug: Matching Placebo after Tapentadol in the Titration Phase. Tablet taken orally, twice daily, morning & evening with preferably 12 hours (not less than 6 hours) between doses. In the maintenance phase only to participants that were randomized to tapentadol in the titration phase. |
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Active Comparator: Morphine Controlled Release
Oral Morphine 40 mg to 100 mg twice daily. Capsule taken orally, twice daily, morning & evening with preferably 12 hours (not less than 6 hours) between doses. Maintenance phase: continuing on dose level established in titration phase.
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Drug: Morphine Sulphate Controlled Release
Capsule taken orally, twice daily, morning & evening with preferably 12 hours (not less than 6 hours) between doses. Titration phase: Starting at 40 mg, increasing at a minimum of 3 days intervals by 20 mg, with a maximum dose of 100 mg. Maintenance phase: continuing on dose level established in titration phase.
Other Name: MST® CONTINUS® |
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Experimental: Tapentadol Prolonged Release
Oral Tapentadol 100 mg to 250 mg twice daily. Tablet taken orally, twice daily, morning & evening with preferably 12 hours (not less than 6 hours) between doses.
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Drug: Tapentadol Extended Release
Tablet taken orally, twice daily, morning & evening with preferably 12 hours (not less than 6 hours) between doses. Titration phase: Starting at 100 mg, increasing at a minimum of 3 day intervals by 50 mg, with a maximum dose of 250 mg.
Other Names:
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- Number of Participants Scored as Responder in Maintenance Phase. [ Time Frame: Day 18 through Day 43 (End of Maintenance Phase) ]
A "responder" is a participant in the study that:
- completed 28 days of the maintenance phase
- had a numeric rating scale score below 5 on the 11 point scale (where 0 indicates no pain and 10 indicates worst possible pain. This twice daily current pain score was averaged over Day 18 to Day 43.
- did not use more than 20 mg of rescue medication per day on average in the 28 day maintenance period (from Day 18 to Day 43).
A participant that met all 3 of the above-mentioned criteria is counted as a responder, in other words the participant benefited from the assigned drug treatment. A participant that failed to meet only 1 of the 3 criteria is not counted as a responder.
- Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Tapentadol Treatment Arm. [ Time Frame: Day 1 through Day 14 (End of Titration Phase) ]Participants were asked to record their "average pain over the last 24 hours" pain intensity each evening. Average pain scores are the averages of all scores recorded during each week. The participant scored 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".
- Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Morphine Treatment Arm. [ Time Frame: Day 1 through Day 14 (End of Titration Phase) ]Participants were asked to record their "average pain over the last 24 hours" pain intensity each evening. Average pain scores are the averages of all scores recorded during each week. The participant scored 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".
- Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase. [ Time Frame: Day 18 through Day 43 (End of Maintenance Phase) ]Participants were asked to record their "average pain over the last 24 hours" pain intensity each evening. Average pain scores are the averages of all scores recorded during each week. The participant scored 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".
- Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Tapentadol Arm. [ Time Frame: Day 1 through Day 14 (End of Titration Phase) ]Participants were asked to record their current pain intensity in the morning and evening. Average pain scores are the averages of all scores recorded during each week. The participant scored 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".
- Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Morphine Arm. [ Time Frame: Day 1 through Day 14 (End of Titration Phase) ]Participants were asked to record their current pain intensity in the morning and evening. Average pain scores are the averages of all scores recorded during the during each week. The participant scored 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".
- Current Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase. [ Time Frame: Day 15 through Day 43 (End of Maintenance Phase) ]Participants were asked to record their current pain intensity in the morning and evening. Average pain scores are the averages of all scores recorded during the 3 days prior to re-randomization or during each week. The participant scored 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".
- Use of Rescue Medication in the Titration Phase. [ Time Frame: Day 1 through Day 14 (End of Titration Phase) ]
The number of participants using rescue medication morphine sulfate immediate release 10 mg tablets in the titration phase were counted. This data was captured in an electronic diary.
During the trial, morphine immediate release 10 mg was allowed as required without a maximum dose defined. However, participants were only re-randomized if their mean consumption of rescue medication was less or equal to 2 doses (20 mg) per day during the last 3 days of the titration phase).
- Number of Participants Using Immediate Release Morphine Rescue Medication in the Maintenance Phase [ Time Frame: Day 15 through Day 43 (End of Maintenance Phase) ]Participants were issued morphine 10 mg immediate release medication. The number of participants using rescue medication morphine sulfate immediate release 10 mg tablets in the maintenance phase were counted. This use of morphine immediate release was captured in each participant's electronic diary.
- The Average Mean Total Daily Dose of Rescue Medication. [ Time Frame: Day 1 (Start of Titration Phase) through Day 43 (End of Maintenance Phase) ]Mean total daily dose of rescue medication morphine sulphate immediate release tablets in milligrams per day (mg/day).
- Changes in the Short Form 36® Health Survey (SF-36®) During the Titration Phase. [ Time Frame: Day 1 (Start of Titration); Day 14 (End of Titration Phase) ]The Short Form 36 (SF-36) includes several brief questions on 8 aspects, (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health) that a participant was asked to score over the last week. Low scores on the Physical Component Summary measure indicate limitations in physical functioning, e.g. a high degree of bodily pain and physical limitations etc. For the Mental Component Summary measure, a low score is indicative of frequent psychological distress, social and role disability due to emotional problems etc. The theoretical range for the physical component score is 12.3279 to 59.6503. The theoretical range for the mental component score is 13.5313 to 59.6503. Positive values for changes in the component scores indicate an improvement.
- Changes in the Short Form 36® Health Survey (SF-36®) During the Maintenance Phase. [ Time Frame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase) ]The Short Form 36 (SF-36) includes several brief questions on 8 aspects, (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health) that a participant was asked to score over the last week. Low scores on the Physical Component Summary measure indicate limitations in physical functioning, e.g. a high degree of bodily pain and physical limitations etc. For the Mental Component Summary measure, a low score is indicative of frequent psychological distress, social and role disability due to emotional problems etc. The theoretical range for the physical component score is 12.3279 to 59.6503. The theoretical range for the mental component score is 13.5313 to 59.6503. Positive values for changes in the component scores indicate an improvement.
- Change in the EuroQoL (EQ-5D) Health Status Index (United Kingdom Time Trade-off Value Set) Change From Start of Titration to Endpoint Titration. [ Time Frame: Day 1 (Start of Titration); Day 14 (End of Titration Phase) ]
The participant scores the EuroQol-5D. The EuroQoL-5D is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1 = no problems, 2 = some problems, 3 = extreme problems).
The responses to the five EQ-5D dimensions are scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead. A positive change in the mean indicates that during this phase the health status improved. A positive change indicates an improvement in health. The minimal important difference is 0.074 (range -0.011 to 0.140).
- Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) Titration Phase. [ Time Frame: Day 1 (Start of Titration); Day 14 (End of Titration Phase) ]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 better health. The values indicated represent the change from Day 1, a positive value indicates an improvement since the start of treatment.
- Change in the EuroQoL (EQ-5D) Health Status Index (United Kingdom Time Trade-off Value Set) Over Time in the Maintenance Phase for Tapentadol and the Placebo Randomized Withdrawal Treatment Arms. [ Time Frame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase) ]
The participant scores the EuroQol-5D. The EuroQoL-5D is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1 = no problems, 2 = some problems, 3 = extreme problems).
The responses to the five EQ-5D dimensions are scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead. A negative change in the mean indicates a worsening in health status since the beginning of the maintenance phase. A positive change indicates an improvement in health. The minimal important difference in the Health Status Index is 0.074 (range -0.011 to 0.140).
- Changes in Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) Maintenance Phase. [ Time Frame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase) ]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 Day 15, a negative mean value indicates a worsening of health-related quality of life since the start of the maintenance phase.
- Patient Global Impression of Change [ Time Frame: Day 43 (End of Maintenance Phase) ]In the Patient Global Impression of Change (PGIC) the participant is asked "Since I began study treatment, my overall status is". The participant is asked to circle one of seven categories. Scores range from very much improved to very much worse. The question was asked at the end of the maintenance phase with reference to the start of the maintenance phase where the participant continued at the dose that was effective at the end of the Titration Phase.
- Quality of Sleep (Sleep Questionnaire) in the Titration Phase. [ Time Frame: Day 1 (Start of Titration); Day 14 (end of Titration Phase) ]Participants were asked the following question: "Please rate the overall quality of your sleep last night?" The quality of sleep from the start of the titration phase to the end of the titration phase was measured. The participant could choose one of the following options: Excellent, good, fair and poor.
- Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial. [ Time Frame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase) ]Participants were asked the following question: "Please rate the overall quality of your sleep last night?" The quality of sleep from the start of maintenance to the completion of treatment is reported. The participant could choose one of the following options: Excellent, good, fair and poor.
- Clinical Opioid Withdrawal Scale (COWS) at the End of the Titration Phase. [ Time Frame: Day 14 (End of Titration Phase) ]
This instrument was developed by the National Institute on Drug Abuse. The physical components of withdrawal are primarily evaluated and based on questions and clinical observations. The possible opioid withdrawal effects are assessed using the Clinical Opioid Withdrawal Score (COWS). The COWS is a clinician rated 11-item scale that primarily evaluates the physical components of opioid withdrawal and is based on questions and clinical observations. Responses are rated on a Likert-type scale ranging from 0 to 4 or 5 depending on the item. The total COWS score is the sum of all individual items.
The following withdrawal categories are based on the total COWS score:
- None: total score below 5;
- Mild: total score from 5 to 12;
- Moderate: total score 13 to 24;
- Moderately Severe: total score 25 to 36;
- Severe: total score above 36. The investigator completes the COWS after participants discontinued trial medication 2 to less than 5 days after last intake of trial medication.
- Clinical Opioid Withdrawal Score (COWS) at the End of the Maintenance Phase. [ Time Frame: Day 43 (End of Maintenance Phase) ]
This instrument was developed by the National Institute on Drug Abuse. The physical components of withdrawal are primarily evaluated and based on questions and clinical observations. The possible opioid withdrawal effects are assessed using the Clinical Opioid Withdrawal Score (COWS). The COWS is a clinician rated 11-item scale that primarily evaluates the physical components of opioid withdrawal and is based on questions and clinical observations. Responses are rated on a Likert-type scale ranging from 0 to 4 or 5 depending on the item. The total COWS score is the sum of all individual items.
The following withdrawal categories are based on the total COWS score:
- None: total score below 5;
- Mild: total score from 5 to 12;
- Moderate: total score 13 to 24;
- Moderately Severe: total score 25 to 36;
- Severe: total score above 36. The investigator completes the COWS after participants discontinued trial medication 2 to less than 5 days after last intake of trial medication.
- Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Titration Phase [ Time Frame: Day 1 (Start of Titration); Day 14 (End of Titration Phase) ]The Constipation Assessment (PAC-SYM) is a 12-item self-report questionnaire that assesses the severity of symptoms of constipation. Participants are asked "How severe have each of these symptoms been in the last two weeks?" e.g. "Pain in your stomach". There are 3 subscales: 4 questions on Abdominal symptoms, 3 questions on rectal symptoms and 5 questions on stool symptoms. Responses are rated on a 5-point Likert Scale ranging from 0 (absence of symptom) to 4 (very severe symptoms). The changes in overall mean and in each of the mean sub-scores vary theoretically from -4 to +4 (where a change of +4 would indicate a change from not present to very severe symptom). If the changes in the overall or subscale mean scores are positive then there is a worsening in symptoms associated with constipation from the start to the end of the titration phase.
- Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Maintenance Phase [ Time Frame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase) ]The Constipation Assessment (PAC-SYM) is a 12-item self-report questionnaire that assesses the severity of symptoms of constipation. Participants are asked "How severe have each of these symptoms been in the last two weeks?" e.g. "Pain in your stomach". There are 3 subscales: 4 questions on Abdominal symptoms, 3 questions on rectal symptoms and 5 questions on stool symptoms. Responses are rated on a 5-point Likert Scale ranging from 0 (absence of symptom) to 4 (very severe symptoms). The changes in overall mean and in each of the mean sub-scores vary theoretically from -4 to +4 (where a change of +4 would indicate a change from not present to very severe symptom). If the changes in the overall or subscale mean scores are positive then there is a worsening in symptoms associated with constipation from the start to the end of the maintenance phase. A negative mean change indicates an improvement.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria
- Male and non-pregnant, non-lactating female subjects.
- Of at least 18 years of age with chronic malignant tumor-related pain with a mean pain intensity (NRS) of 5 points or higher.
- Subjects who are opioid-naïve or pretreated with an equianalgesic dose range equivalent of up to 160 mg oral morphine per day and are dissatisfied with prior treatment.
- Women must be postmenopausal, surgically sterile, or practicing or agree to practice an effective method of birth control throughout the trial.
- Expected course of the disease and the pain that would permit compliance with the trial protocol over the entire trial period.
Exclusion Criteria
Key Exclusion Criteria:
- Subjects will be excluded from the study if they have a history of seizure disorder or epilepsy;
- known history and/or presence of cerebral tumor or cerebral metastases.
- history of alcohol or drug abuse;
- uncontrolled hypertension,
- clinical laboratory values reflecting severe renal insufficiency,
- moderate or severe hepatic impairment,
- hepatitis B or C, HIV,
- inadequate bone marrow reserve
- currently treated with radiotherapy,
- pain-inducing chemotherapy,
- anti-parkinsonian drugs, neuroleptics, monoamine oxidase inhibitors, serotonin norepinephrine reuptake inhibitor (SNRI) or any other analgesic therapy than investigational medication or rescue medication during the trial.
- selective serotonin reuptake inhibitor (SSRI) treatments are allowed if taken for at least 30 days before the screening period of the study at an unchanged dose.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00472303
Show 71 study locations
| Principal Investigator: | Hans Georg Kress, Dr. | Clinic of Anaesthesiology and Pain Management, AKH Vienna |
| Responsible Party: | Grünenthal GmbH |
| ClinicalTrials.gov Identifier: | NCT00472303 |
| Other Study ID Numbers: |
761101 2006-004997-28 ( EudraCT Number ) KF5503/15 ( Other Identifier: Grünenthal ) |
| First Posted: | May 11, 2007 Key Record Dates |
| Results First Posted: | May 7, 2014 |
| Last Update Posted: | November 4, 2019 |
| Last Verified: | October 2019 |
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Opioid Central acting analgesic CG5503 PR Tumor related pain |
Cancer related pain Morphine Pain assessment Placebo |
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Cancer Pain Pain Neurologic Manifestations Morphine Tapentadol Analgesics, Opioid Narcotics Central Nervous System Depressants Physiological Effects of Drugs |
Analgesics Sensory System Agents Peripheral Nervous System Agents Adrenergic Uptake Inhibitors Neurotransmitter Uptake Inhibitors Membrane Transport Modulators Molecular Mechanisms of Pharmacological Action Adrenergic Agents Neurotransmitter Agents |