A Study to Evaluate Tapentadol (CG5503) in the Treatment of Chronic Tumor-Related Pain Compared With Placebo and Morphine

Pain Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00472303
• Other study ID #: 761101
• Secondary ID: 2006-004997-28KF
• Status: Completed
• Phase: Phase 3
• Start date: July 2007
• Est. completion date: June 2012

Study information

• Verified date: October 2019
• Source: Grünenthal GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 622
• Est. completion date: June 2012
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cancer Pain
• Pain
• Tumor

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
Austria	Site 043004	Klagenfurt
Austria	Site 043001	Vienna
Austria	Site 043002	Vienna
Austria	Site 043005	Vienna
Bulgaria	Site 359013	Gabrovo
Bulgaria	Site 359011	Pleven
Bulgaria	Site 359014	Plovdiv
Bulgaria	Site 359004	Shumen
Bulgaria	Site 359008	Sofia
Bulgaria	Site 359012	Varna
Croatia	Site 385007	Osijek
Croatia	Site 385001	Slavonski Brod
Croatia	Site 385004	Varazdin
Croatia	Site 385006	Zabok
Croatia	Site 385002	Zagreb
Croatia	Site 385003	Zagreb
Czechia	Site 420005	Brno
Czechia	Site 420002	Ceske Budejovice
Czechia	Site 420006	Hradec Kralove
Czechia	Site 420007	Liberec
Czechia	Site 420008	Olomouc
Czechia	Site 420001	Pilsen
Czechia	Site 420004	Prague
France	Site 033101	Tarbes
Germany	Site 049009	Berlin
Germany	Site 049014	Essen
Germany	Site 049012	Köln
Germany	Site 049007	Löwenstein
Germany	Site 049020	Potsdam
Germany	Site 049006	Waldkirch
Germany	Site 049002	Wiesbaden
Hungary	Site 036001	Debrecen
Hungary	Site 036005	Komárom
Hungary	Site 036003	Mátraháza
Hungary	Site 036002	Nyiregyhaza
Hungary	Site 036006	Székesfehérvár
Hungary	Site 036009	Székesfehérvár
Hungary	Site 036010	Szekszard
Italy	Site 039001	Napoli
Moldova, Republic of	Site 373001	Chisinau
Moldova, Republic of	Site 373002	Chisinau
Poland	Site 048004	Bydgoszcz
Poland	Site 048005	Gdansk
Poland	Site 048007	Poznan
Poland	Site 048001	Warszawa
Romania	Site 040006	Brasov
Romania	Site 040002	Bucharest
Romania	Site 040003	Bucharest
Romania	Site 040004	Bucharest
Romania	Site 040005	Cluj-Napoca
Romania	Site 040001	Iasi
Romania	Site 040007	Timisoara
Russian Federation	Site 007010	Arkhangel'sk
Russian Federation	Site 007003	Moscow
Russian Federation	Site 007007	Nizhniy Novgorod
Russian Federation	Site 007012	Vladikavkaz
Russian Federation	Site 007005	Yaroslavl
Serbia	Site 381003	Belgrade
Serbia	Site 381004	Belgrade
Serbia	Site 381005	Belgrade
Serbia	Site 381002	Nis
Serbia	Site 381001	Sremska Kamenica
Slovakia	Site 421005	Banska Bystrica
Slovakia	Site 421001	Kosice
Spain	Site 034005	Barcelona
Spain	Site 034009	Barcelona
Spain	Site 034006	Mahón
Spain	Site 034012	Pamplona
Spain	Site 034004	Sevilla
Spain	Site 034002	Valencia
Sweden	Site 046001	Stockholm

Sponsors (2)

Lead Sponsor	Collaborator
Grünenthal GmbH	Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Countries where clinical trial is conducted

Austria,  Bulgaria,  Croatia,  Czechia,  France,  Germany,  Hungary,  Italy,  Moldova, Republic of,  Poland,  Romania,  Russian Federation,  Serbia,  Slovakia,  Spain,  Sweden, 

References & Publications (2)

Kress HG, Koch ED, Kosturski H, Steup A, Karcher K, Dogan C, Etropolski M, Eerdekens M. Direct conversion from tramadol to tapentadol prolonged release for moderate to severe, chronic malignant tumour-related pain. Eur J Pain. 2016 Oct;20(9):1513-8. doi: — View Citation

Kress HG, Koch ED, Kosturski H, Steup A, Karcher K, Lange B, Dogan C, Etropolski MS, Eerdekens M. Tapentadol prolonged release for managing moderate to severe, chronic malignant tumor-related pain. Pain Physician. 2014 Jul-Aug;17(4):329-43. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Scored as Responder in 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.	Day 18 through Day 43 (End of Maintenance Phase)
Secondary	Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Tapentadol Treatment Arm.	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".	Day 1 through Day 14 (End of Titration Phase)
Secondary	Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Morphine Treatment Arm.	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".	Day 1 through Day 14 (End of Titration Phase)
Secondary	Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the 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".	Day 18 through Day 43 (End of Maintenance Phase)
Secondary	Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Tapentadol Arm.	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".	Day 1 through Day 14 (End of Titration Phase)
Secondary	Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Morphine Arm.	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".	Day 1 through Day 14 (End of Titration Phase)
Secondary	Current Pain Intensity Scores, Averaged Per Week by Treatment, During the 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".	Day 15 through Day 43 (End of Maintenance Phase)
Secondary	Use of Rescue Medication in the 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).	Day 1 through Day 14 (End of Titration Phase)
Secondary	Number of Participants Using Immediate Release Morphine Rescue Medication in the 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.	Day 15 through Day 43 (End of Maintenance Phase)
Secondary	The Average Mean Total Daily Dose of Rescue Medication.	Mean total daily dose of rescue medication morphine sulphate immediate release tablets in milligrams per day (mg/day).	Day 1 (Start of Titration Phase) through Day 43 (End of Maintenance Phase)
Secondary	Changes in the Short Form 36® Health Survey (SF-36®) During the 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.	Day 1 (Start of Titration); Day 14 (End of Titration Phase)
Secondary	Changes in the Short Form 36® Health Survey (SF-36®) During the 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.	Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)
Secondary	Change in the EuroQoL (EQ-5D) Health Status Index (United Kingdom Time Trade-off Value Set) Change From Start of Titration to Endpoint Titration.	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).	Day 1 (Start of Titration); Day 14 (End of Titration Phase)
Secondary	Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) 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.	Day 1 (Start of Titration); Day 14 (End of Titration Phase)
Secondary	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.	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).	Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)
Secondary	Changes in Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) 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.	Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)
Secondary	Patient Global Impression of Change	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.	Day 43 (End of Maintenance Phase)
Secondary	Quality of Sleep (Sleep Questionnaire) in the 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.	Day 1 (Start of Titration); Day 14 (end of Titration Phase)
Secondary	Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial.	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.	Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)
Secondary	Clinical Opioid Withdrawal Scale (COWS) at the End of the 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.	Day 14 (End of Titration Phase)
Secondary	Clinical Opioid Withdrawal Score (COWS) at the End of the 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.	Day 43 (End of Maintenance Phase)
Secondary	Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the 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.	Day 1 (Start of Titration); Day 14 (End of Titration Phase)
Secondary	Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the 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.	Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)