Clinical trial NCT00472303: A Study to Evaluate Tapentadol (CG5503) in the Treatment of Chronic Tumor-Related Pain Compared With Placebo and Morphine
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tumor
Pain
Keywords: Opioid
Central acting analgesic
CG5503 PR
Tumor related pain
Cancer related pain
Morphine
Pain assessment
Placebo
Lead sponsor: Grünenthal GmbH
Sponsor class: INDUSTRY
Collaborators: name: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
First posted: 2007-05-11
Enrollment: 622
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants Scored as Responder in Maintenance Phase.
timeFrame: Day 18 through Day 43 (End of Maintenance Phase)
Secondary outcomes:
measure: Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Tapentadol Treatment Arm.
timeFrame: Day 1 through Day 14 (End of Titration Phase)
measure: Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Morphine Treatment Arm.
timeFrame: Day 1 through Day 14 (End of Titration Phase)
measure: Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase.
timeFrame: Day 18 through Day 43 (End of Maintenance Phase)
measure: Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Tapentadol Arm.
timeFrame: Day 1 through Day 14 (End of Titration Phase)
measure: Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Morphine Arm.
timeFrame: Day 1 through Day 14 (End of Titration Phase)
measure: Current Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase.
timeFrame: Day 15 through Day 43 (End of Maintenance Phase)
measure: Use of Rescue Medication in the Titration Phase.
timeFrame: Day 1 through Day 14 (End of Titration Phase)
measure: Number of Participants Using Immediate Release Morphine Rescue Medication in the Maintenance Phase
timeFrame: Day 15 through Day 43 (End of Maintenance Phase)
measure: The Average Mean Total Daily Dose of Rescue Medication.
timeFrame: Day 1 (Start of Titration Phase) through Day 43 (End of Maintenance Phase)
measure: Changes in the Short Form 36® Health Survey (SF-36®) During the Titration Phase.
timeFrame: Day 1 (Start of Titration); Day 14 (End of Titration Phase)
measure: Changes in the Short Form 36® Health Survey (SF-36®) During the Maintenance Phase.
timeFrame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)
measure: Change in the EuroQoL (EQ-5D) Health Status Index (United Kingdom Time Trade-off Value Set) Change From Start of Titration to Endpoint Titration.
timeFrame: Day 1 (Start of Titration); Day 14 (End of Titration Phase)
measure: Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) Titration Phase.
timeFrame: Day 1 (Start of Titration); Day 14 (End of Titration Phase)
measure: 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.
timeFrame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)
measure: Changes in Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) Maintenance Phase.
timeFrame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)
measure: Patient Global Impression of Change
timeFrame: Day 43 (End of Maintenance Phase)
measure: Quality of Sleep (Sleep Questionnaire) in the Titration Phase.
timeFrame: Day 1 (Start of Titration); Day 14 (end of Titration Phase)
measure: Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial.
timeFrame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)
measure: Clinical Opioid Withdrawal Scale (COWS) at the End of the Titration Phase.
timeFrame: Day 14 (End of Titration Phase)
measure: Clinical Opioid Withdrawal Score (COWS) at the End of the Maintenance Phase.
timeFrame: Day 43 (End of Maintenance Phase)
measure: Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Titration Phase
timeFrame: Day 1 (Start of Titration); Day 14 (End of Titration Phase)
measure: Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Maintenance Phase
timeFrame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)
Other outcomes:
Locations:
city: Klagenfurt
country: Austria
facility: Site 043004
city: Vienna
country: Austria
facility: Site 043002
city: Vienna
country: Austria
facility: Site 043001
city: Vienna
country: Austria
facility: Site 043005
city: Gabrovo
country: Bulgaria
facility: Site 359013
city: Pleven
country: Bulgaria
facility: Site 359011
city: Plovdiv
country: Bulgaria
facility: Site 359014
city: Shumen
country: Bulgaria
facility: Site 359004
city: Sofia
country: Bulgaria
facility: Site 359008
city: Varna
country: Bulgaria
facility: Site 359012
city: Osijek
country: Croatia
facility: Site 385007
city: Slavonski Brod
country: Croatia
facility: Site 385001
city: Varazdin
country: Croatia
facility: Site 385004
city: Zabok
country: Croatia
facility: Site 385006
city: Zagreb
country: Croatia
facility: Site 385002
city: Zagreb
country: Croatia
facility: Site 385003
city: Brno
country: Czechia
facility: Site 420005
city: Ceske Budejovice
country: Czechia
facility: Site 420002
city: Hradec Kralove
country: Czechia
facility: Site 420006
city: Liberec
country: Czechia
facility: Site 420007
city: Olomouc
country: Czechia
facility: Site 420008
city: Pilsen
country: Czechia
facility: Site 420001
city: Prague
country: Czechia
facility: Site 420004
city: Tarbes
country: France
facility: Site 033101
city: Berlin
country: Germany
facility: Site 049009
city: Essen
country: Germany
facility: Site 049014
city: Köln
country: Germany
facility: Site 049012
city: Löwenstein
country: Germany
facility: Site 049007
city: Potsdam
country: Germany
facility: Site 049020
city: Waldkirch
country: Germany
facility: Site 049006
city: Wiesbaden
country: Germany
facility: Site 049002
city: Debrecen
country: Hungary
facility: Site 036001
city: Komárom
country: Hungary
facility: Site 036005
city: Mátraháza
country: Hungary
facility: Site 036003
city: Nyiregyhaza
country: Hungary
facility: Site 036002
city: Szekszard
country: Hungary
facility: Site 036010
city: Székesfehérvár
country: Hungary
facility: Site 036006
city: Székesfehérvár
country: Hungary
facility: Site 036009
city: Napoli
country: Italy
facility: Site 039001
city: Chisinau
country: Moldova, Republic of
facility: Site 373001
city: Chisinau
country: Moldova, Republic of
facility: Site 373002
city: Bydgoszcz
country: Poland
facility: Site 048004
city: Gdańsk
country: Poland
facility: Site 048005
city: Poznan
country: Poland
facility: Site 048007
city: Warszawa
country: Poland
facility: Site 048001
city: Brasov
country: Romania
facility: Site 040006
city: Bucharest
country: Romania
facility: Site 040002
city: Bucharest
country: Romania
facility: Site 040003
city: Bucharest
country: Romania
facility: Site 040004
city: Cluj-Napoca
country: Romania
facility: Site 040005
city: Iasi
country: Romania
facility: Site 040001
city: Timisoara
country: Romania
facility: Site 040007
city: Arkhangel'sk
country: Russian Federation
facility: Site 007010
city: Moscow
country: Russian Federation
facility: Site 007003
city: Nizhniy Novgorod
country: Russian Federation
facility: Site 007007
city: Vladikavkaz
country: Russian Federation
facility: Site 007012
city: Yaroslavl
country: Russian Federation
facility: Site 007005
city: Belgrade
country: Serbia
facility: Site 381003
city: Belgrade
country: Serbia
facility: Site 381004
city: Belgrade
country: Serbia
facility: Site 381005
city: Nis
country: Serbia
facility: Site 381002
city: Sremska Kamenica
country: Serbia
facility: Site 381001
city: Banska Bystrica
country: Slovakia
facility: Site 421005
city: Kosice
country: Slovakia
facility: Site 421001
city: Barcelona
country: Spain
facility: Site 034009
city: Barcelona
country: Spain
facility: Site 034005
city: Mahón
country: Spain
facility: Site 034006
city: Pamplona
country: Spain
facility: Site 034012
city: Sevilla
country: Spain
facility: Site 034004
city: Valencia
country: Spain
facility: Site 034002
city: Stockholm
country: Sweden
facility: Site 046001
Study officials:
affiliation: Clinic of Anaesthesiology and Pain Management, AKH Vienna
name: Hans Georg Kress, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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: 10.1002/ejp.875. Epub 2016 Apr 7.