Clinical trial NCT01352741: Comparison of Increasing Doses of Tapentadol Versus a Combination of Tapentadol and Pregabalin
Official title: Evaluation of the Effectiveness, Safety, and Tolerability of Tapentadol PR Versus a Combination of Tapentadol PR and Pregabalin in Subjects With Severe Chronic Low Back Pain With a Neuropathic Pain Component
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Low Back Pain
Neuropathic Pain
Keywords: low back pain
neuropathic
pain assessment
centrally acting tapentadol pregabalin
severe chronic
Lead sponsor: Grünenthal GmbH
Sponsor class: INDUSTRY
First posted: 2011-05-12
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 main objective of the study is to evaluate the effectiveness, safety, and tolerability of increasing doses of tapentadol prolonged release (PR) (500 mg per day) versus a combination of tapentadol PR (300 mg per day) and pregabalin (to 300 mg per day) in subjects requiring additional analgesia after titration to tapentadol PR 300 mg per day.

This is a clinical effectiveness trial designed to establish a link between anticipated clinical outcomes and the clinical practice by means of selected measures of clinical and subject reported outcomes. Since, severe low back pain with a neuropathic component, the targeted study population, is frequently treated with a combination therapy (monotherapy is often not effective enough) it is of interest to determine if tapentadol alone (combining 2 mechanisms of action in a single molecule) could be as effective as a combination of tapentadol plus pregabalin. Furthermore, the tolerability profiles of monotherapy versus combination are of interest.

Detailed description: Participants with a diagnosis of chronic low back pain (defined as pain lasting for at least 3 month) and requiring a strong analgesic (World Health Organization \[WHO\] Step III) as judged by the investigator and having a positive or unclear score using the painDETECT diagnostic screening questionnaire will enter the open-label titration tapentadol prolonged release (PR) period. In total participants will have 11 planned scheduled visits scheduled over 105 days. At the Enrollment Visit \[Day -14 (3 to 14 days prior to the Baseline Visit)\] the inclusion and exclusion criteria will be checked to evaluate the participant's eligibility for the trial. Participants on previous analgesics will start a washout period three days up to 2 weeks.The duration of the washout period will depend on previous opioid analgesics and co-analgesics and their respective doses, down-tapering steps. Participants who do not need a washout of previous analgesic treatment (e.g. WHO Step I analgesics), a baseline visit can be scheduled as soon as clinical laboratory monitoring results are available.

At the Baseline Visit (Day 1) participants will start the 3 week open-label titration period tapentadol prolonged release (PR) at doses of 2 x 50 mg per day and will be titrated upwards in steps of 100 mg (2 x 50 mg) on a weekly basis.

Participants who do not qualify for randomization may continue the trial in the open-label continuation arm if they have already reached a satisfactory level of pain relief.

Participants qualifying for randomization in the comparative period (Day 22 to 77) will be allocated to 1 of 2 treatment arms and will continue treatment.

Either they continue on tapentadol prolonged release (PR) with increasing doses of tapentadol PR

* After the randomization visit, participants will titrate up to a total daily dose of 400 mg.
* 1 week after the randomization visit, will titrate up to a total daily dose of 500 mg. Participants in this treatment arm will receive a final dose of 500 mg tapentadol PR per day.

Or start on a combination of tapentadol PR 300 mg per day with pregabalin

* After the randomization visit, participants will continue their previous regimen of tapentadol PR 2 x 150 mg per day plus pregabalin 2 x 75 mg (total daily dose of 150 mg pregabalin).
* 1 week after the randomization visit, participants will continue their previous regimen (end of titration period) of tapentadol PR 2 x 150 mg per day plus pregabalin 2 x 150 mg (total daily dose of 300 mg pregabalin). Participants in this treatment arm will receive a final dose of 300 mg tapentadol PR and 300 mg pregabalin.

Participants in the Comparative Period can be assigned to the open-label pick-up arm and will be treated with a stable dose of tapentadol PR 300 mg per day or 400 mg per day if they experience treatment emergent adverse events (at least possibly related to investigational medicinal product).The open-label pick-up period theoretically starts on Day 29, i.e. one week after the Randomization Visit.

The Final Evaluation (Day 77) is planned to take place 8 weeks after randomization.

After the Final Evaluation a Follow-up Period (blinded tapering down/out of IMP in Week 12 and Follow-up Visit (up to Day 91) will take place. Tapering down/out of medication will be performed according to the Summary of Product Characteristics.

Eligibility criteria: Inclusion Criteria:

* Subjects must have a diagnosis of chronic low back pain; chronic pain defined as pain lasting for at least 3 months.
* Subject's pain must require a strong analgesic (defined as World Health Organization (WHO) step III) as judged by the investigator.
* The painDETECT diagnostic screening questionnaire score must be:

  * "positive" or
  * "unclear".or If the subject is being treated with a stable regimen of centrally acting analgesics (opioids) and/or co-analgesics, even a "negative" painDETECT score (but of at least 9) at the enrollment visit will be acceptable.
* If under regular daily pretreatment with a WHO step II/step III opioid analgesic and/or a centrally acting co-analgesic:

  * Subjects must be taking a WHO step II or step III analgesic or co- analgesic on a daily basis for at least 2 weeks prior to the enrollment visit.
  * Subjects pretreated with a WHO step II opioid analgesic and/or a centrally acting co-analgesic must have reported an average pain intensity score of at least 5 points (NRS-3≥5) during the last 3 days prior to the enrollment visit. or If under regular, daily pretreatment with a WHO step I analgesic monotherapy or if no regular analgesic pretreatment is reported:
  * Subjects must have an average pain intensity score of at least 6 points NRS-3≥6) in the last 3 days prior to the enrollment visit.

Exclusion Criteria:

* Presence of concomitant painful conditions other than low back pain that could confound the subject's trial assessments or self-evaluation of the index pain, e.g., syndromes with widespread pain such as fibromyalgia.
* Low back pain caused by cancer and/or metastatic diseases.
* Any painful procedures planned during the trial period (e.g., major surgery) that may, in the opinion of the investigator, affect the effectiveness or safety assessments of the Investigational Medicinal Product (IMP).
* Pending litigation or application for insurance/governmental benefits due to chronic pain or disability and, if granted, benefits might be influenced by a successful participation in the trial.
* Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, lactose intolerance.

Primary outcomes:
measure: Change in the Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3)
timeFrame: Randomization (Day 22); Final Evaluation Visit (Day 77)
Secondary outcomes:
measure: Open-label Titration Period: Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3)
timeFrame: Enrollment (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Open-label Continuation Period: Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3)
timeFrame: Enrollment (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)
measure: End of Open-label Pick-up Period: Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3)
timeFrame: Final Evaluation Visit (Day 77)
measure: Open-label Titration Period: Radiating Pain
timeFrame: Enrollment Visit (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Open-label Titration Period: Radiating Mean Pain Intensity Score for the Comparative Period Population
timeFrame: Enrollment Visit (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Double-blind Comparative Period: Change in NRS-3 Pain Intensity Score for the Radiating Pain
timeFrame: Randomization Visit (Day 22); End of Evaluation Visit (Day 77)
measure: Open-label Titration Period: Worst Mean Pain Intensity Scores Over the Past 24 Hours
timeFrame: Enrollment Visit (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Open-label Titration Period: Comparative Double-blind Period Population Worst Mean Pain Intensity Scores Over the Past 24 Hours
timeFrame: Enrollment Visit (Day-12); Baseline Visit (day 1); Randomization Visit (Day 22)
measure: Double-blind Comparative Period: Change in Worst Pain Intensity Over the Past 24 Hours
timeFrame: Randomization Visit (Day 22); Final Evaluation Visit (Day 77)
measure: Open-label Titration Period: painDETECT Assessments
timeFrame: Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Open-label Titration Period: Comparative Double-blind Period Population painDETECT Assessment
timeFrame: Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Double-blind Comparative Period: Change in painDETECT Final Assessment
timeFrame: Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)
measure: Open-label Titration Period: Neuropathic Pain Symptom Inventory (NPSI) Overall Score Assessment
timeFrame: Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Open-label Titration Period: Neuropathic Pain Symptom Inventory (NPSI) Overall Score Assessment in the Double-blind Comparative Period Population
timeFrame: Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)
measure: Double-blind Comparative Period: Change in Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment
timeFrame: Randomization Visit (Day 22); Final Evaluation Visit (Day 77)
measure: Open-label Titration Period: Comparative Double-blind Period Population Short Form Health Survey (SF-12) Physical Health Composite Score (PCS)
timeFrame: Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Double-blind Comparative Period: Changes in the Short Form Health Survey (SF-12) Physical Health Composite Score (PCS)
timeFrame: Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)
measure: Open-label Titration Period: Comparative Double-blind Period Population Short Form Health Survey (SF-12) Mental Health Composite Score (MCS)
timeFrame: Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Double-blind Comparative Period: Change in Short Form Health Survey (SF-12) Mental Health Composite Score (MCS)
timeFrame: Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)
measure: Open-label Titration Period: EuroQol-5 Dimension (EQ-5D) Health Status Index Score for the Double-blind Comparative Period Population
timeFrame: Enrollment Visit (day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Double-blind Comparative Period: Change EuroQol-5 Dimension (EQ-5D) Health Status Index
timeFrame: Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Double-blind Comparative Period: Patient Global Impression of Change (PGIC)
timeFrame: Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)
measure: Double-blind Comparative Period: Clinician Global Impression of Change (CGIC)
timeFrame: Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)
measure: Open-label Titration Period: Hospital Anxiety and Depression Scale - Anxiety in the Double-blind Comparative Period Population
timeFrame: Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Double-blind Comparative Period: Change in Hospital Anxiety and Depression Scale - Anxiety in the Double-blind Comparative Period Population
timeFrame: Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)
measure: Open-label Titration Period: Hospital Anxiety and Depression Scale - Depression in the Double-blind Comparative Period Population
timeFrame: Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Double-blind Comparative Period: Change in Hospital Anxiety and Depression Scale - Depression in the Double-blind Comparative Period Population
timeFrame: Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)
measure: Open-label Titration Period: Sleep Evaluation Questionnaire - Latency
timeFrame: Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Open-label Titration Period: Sleep Evaluation Questionnaire - Latency in the Double-blind Comparative Period Population
timeFrame: Enrollment Visit (Day -12); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Double-blind Comparative Period Sleep Evaluation Questionnaire: Change in Latency
timeFrame: Baseline Visit (Day 1); Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)
measure: Open-label Titration Period: Sleep Evaluation Questionnaire - Number of Awakenings
timeFrame: Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Open-label Titration Period: Sleep Evaluation - Number of Awakenings in the Double-blind Comparative Period Population
timeFrame: Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Double-blind Comparative Period: Change in the Number of Awakenings
timeFrame: Baseline Visit (Day 1); Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)
measure: Open-label Titration Period: Sleep Evaluation Questionnaire - Time Slept
timeFrame: Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Open-label Titration Period: Sleep Evaluation Questionnaire - Number of Hours Slept in the Double-blind Comparative Period Population
timeFrame: Enrollment Visit (Day -12); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Double-blind Comparative Period: Sleep Evaluation Questionnaire - Change in the Number of Hours Slept
timeFrame: Baseline Visit (Day -12); Randomization Visit (Day 1); Final Evaluation Visit (Day 77)
measure: Open-label Titration Period: Sleep Evaluation Questionnaire - Overall Quality of Sleep
timeFrame: Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)
measure: Open-label Titration Period: Sleep Evaluation Questionnaire - Overall Quality of Sleep in the Double-blind Comparative Period Population
timeFrame: Enrollment Visit (Day-12)
measure: Open-label Titration Period: Sleep Evaluation Questionnaire - Overall Quality of Sleep in the Double-blind Comparative Period Population
timeFrame: Baseline Visit (Day 1)
measure: Open-label Titration Period: Sleep Evaluation Questionnaire - Overall Quality of Sleep in the Double-blind Comparative Period Population
timeFrame: Randomization Visit (Day 22)
measure: Double-blind Comparative Period: Change in the Overall Quality of Sleep
timeFrame: Randomization Visit (Day 22) to Final Evaluation (Day 77)
measure: Open-label Titration Period: Subject's Satisfaction With Treatment
timeFrame: End of Open-label Titration Period at Randomization Visit (Day 22)
measure: Double-blind Comparative Period: Subject's Satisfaction With Treatment
timeFrame: End of Comparative Period at Final Evaluation Visit (Day 77)
Other outcomes:
Locations:
city: Klagenfurt
country: Austria
facility: Site 506
city: Senftenberg
country: Austria
facility: Site 503
city: Wien
country: Austria
facility: Site 501
city: Wien
country: Austria
facility: Site 502
city: Wien
country: Austria
facility: Site 504
city: Wien
country: Austria
facility: Site 505
city: Dour
country: Belgium
facility: Site 605
city: Genk
country: Belgium
facility: Site 602
city: Gozee
country: Belgium
facility: Site 603
city: Ham
country: Belgium
facility: Site 604
city: Pellenberg
country: Belgium
facility: Site 601
city: Copenhagen
country: Denmark
facility: Site 702
city: Frederiksberg
country: Denmark
facility: Site 704
city: Glostrup
country: Denmark
facility: Site 701
city: Ringsted
country: Denmark
facility: Site 703
city: Berlin
country: Germany
facility: DE 118
city: Berlin
country: Germany
facility: Site 107
city: Böhlen
country: Germany
facility: Site 111
city: Cottbus
country: Germany
facility: Site 115
city: Hamburg
country: Germany
facility: Site 103
city: Hamburg
country: Germany
facility: Site 110
city: Kiel
country: Germany
facility: Site 101
city: Kiel
country: Germany
facility: Site 114
city: Köln
country: Germany
facility: Site 105
city: Köln
country: Germany
facility: Site 116
city: Leipzig
country: Germany
facility: Site 113
city: Lübeck
country: Germany
facility: Site 109
city: Rendsburg
country: Germany
facility: Site 106
city: Schönau
country: Germany
facility: Site 108
city: Weimar
country: Germany
facility: Site 117
city: Westerstede
country: Germany
facility: Site 112
city: Wiesbaden
country: Germany
facility: Site 104
city: Amsterdam
country: Netherlands
facility: Site 803
city: Eindhoven
country: Netherlands
facility: Site 804
city: Enschede
country: Netherlands
facility: Site 805
city: Heerenveen
country: Netherlands
facility: Site 802
city: Sliedrecht
country: Netherlands
facility: Site 801
city: Bydgoszcz
country: Poland
facility: Site 309
city: Gdansk
country: Poland
facility: Site 312
city: Katowice
country: Poland
facility: Site 303
city: Krakow
country: Poland
facility: Site 308
city: Krakow
country: Poland
facility: Site 310
city: Krakow
country: Poland
facility: Site 311
city: Lublin
country: Poland
facility: Site 307
city: Ostrów Mazowiecka
country: Poland
facility: Site 306
city: Poznan
country: Poland
facility: Site 304
city: Warsaw
country: Poland
facility: Site 301
city: Warszawa
country: Poland
facility: Site 302
city: Wroclaw
country: Poland
facility: Site 305
city: A Coruna
country: Spain
facility: Site 904
city: Alicante
country: Spain
facility: Site 908
city: Badalona
country: Spain
facility: Site 901
city: Barcelona
country: Spain
facility: Site 905
city: Centelles
country: Spain
facility: Site 902
city: Granada
country: Spain
facility: Site 907
city: Madrid
country: Spain
facility: Site 909
city: Madrid
country: Spain
facility: Site 910
city: Oviedo
country: Spain
facility: Site 903
city: Valencia
country: Spain
facility: Site 911
Study officials:
affiliation: Neurological pain research and therapy Clinic for Neurology Campus Kiel, University Clinic Schleswig-Holstein, Schittenhelmstr. 10, 24105 Kiel, Germany
name: Ralf Baron, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Baron R, Martin-Mola E, Muller M, Dubois C, Falke D, Steigerwald I. Effectiveness and Safety of Tapentadol Prolonged Release (PR) Versus a Combination of Tapentadol PR and Pregabalin for the Management of Severe, Chronic Low Back Pain With a Neuropathic Component: A Randomized, Double-blind, Phase 3b Study. Pain Pract. 2015 Jun;15(5):455-70. doi: 10.1111/papr.12200. Epub 2014 Apr 17.
citation: Baron R, Kern U, Muller M, Dubois C, Falke D, Steigerwald I. Effectiveness and Tolerability of a Moderate Dose of Tapentadol Prolonged Release for Managing Severe, Chronic Low Back Pain with a Neuropathic Component: An Open-label Continuation Arm of a Randomized Phase 3b Study. Pain Pract. 2015 Jun;15(5):471-86. doi: 10.1111/papr.12199. Epub 2014 Apr 18.