Diabetic Neuropathy
Conditions
Keywords
Diabetic neuropathy, Painful Diabetic Polyneuropathy, Polyneuropathy, Peripheral neuropathy
Brief summary
The purpose of this study is to evaluate the effectiveness (level of pain control) and safety of Tapentadol (CG5503) extended release (ER) (base) compared to placebo in patients with moderate to severe pain from diabetic peripheral neuropathy.
Detailed description
The primary objective of this randomized-withdrawal (randomized means study medication assigned to patients by chance and withdrawal means to stop using), multicenter, double-blind (neither patient nor investigator knows the study medication), placebo-controlled, Phase 3 study is to determine the effectiveness and safety of orally administrated Tapentadol (CG5503) extended release (ER) (base) at doses of 100-250 mg twice daily in patients with moderate to severe pain from diabetic peripheral neuropathy. The study is being conducted for registration and approval of CG5503 in the US and outside US. The trial will consist of two phases: Phase I is open-label and Phase 2 is double- blind. In the Open-Label Phase 1 there will be four periods: screening (to assess eligibility), washout (dependent on the pain medication the patient was previously taking), pain intensity perctoris evaluation (over a 3 day period), and open-label titration (study drug will be titrated to an optimal dose starting with 50 mg twice a day and adjusted to an optimal dose for a period of 3 weeks). Patients with at least a 1-point reduction in the average pain intensity score at the end of the open-label titration period, as compared with pre-titration will be eligible for randomization in the double-blind phase. In the double-blind Phase 2, there will be two periods: double-blind maintenance period (take drug for 12 weeks), and follow-up (a visit within 4 days of the intake of the last dose of study drug and a follow-up call approximately 10-14 days after the intake of the last dose of the study drug). The patient will maintain the dose level achieved at the end of the Phase 1 during the double-blind treatment phase. The study hypothesis is that the study drug will be different from placebo in the change in pain intensity. Titrate Tapentadol (CG5503) extended release (ER) 50 mg to patient's optimal dose ranging between 100mg and 250mg twice a day; Placebo (no active ingredients). All doses of trial treatment will be taken orally with or without food, for a maximum timeframe of 15 weeks.
Interventions
DRUGCG5503
100, 150, 200, 250 mg twice daily given for up to 15 weeks
DRUGplacebo
matching placebo twice daily for 12 weeks
Sponsors
Grünenthal GmbH
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with Type 1 or Type 2 diabetes mellitus must have a documented clinical diagnosis of painful diabetic peripheral neuropathy with symptoms and signs for at least 6 months, and pain present at the time of screening * The investigator considers the patient's blood glucose to be controlled by diet, or hypoglycemics, or insulin for at least 3 months prior to enrolling in the study (this control should be documented by figures of glycated hemoglobin \[HbA1c\] no greater than 11% at screening) * Patients have been taking analgesic medications for the condition for at least 3 months prior to screening (patients taking opioid analgesics must be dissatisfied with current treatment, and patients taking non-opioid analgesics must be dissatisfied with current analgesia) * Patients currently requiring opioid treatment must be taking daily doses of an opioid-based analgesic equivalent to \<=160 mg of oral morphine
Exclusion criteria
* No significant pulmonary, gastrointestinal, endocrine, metabolic (except diabetes mellitus), neurological, psychiatric disorders (resulting in disorientation, memory impairment or inability to report accurately as in schizophrenia, Alzheimer's disease), or any other clinically significant disease that in the Investigator's opinion may affect efficacy or safety assessments or may compromise patient's safety during trial participation * no history of moderate to severe hepatic impairment such as chronic hepatitis B or C, presence of active hepatitis B or C within the last 3 months or impaired hepatic function with ALT or AST greater than 3-fold ULN * No patients with severely impaired renal function * No laboratory values above or below limits of normal unless considered not clinically relevant by the Investigator * No significant cardiac disease (e.g., unstable angina pectoris, angina pectoris Canadian Cardiovascular Society (CCS) class III-IV, acute myocardial infarction within the last 3 months, cardiac insufficiency New York Heart Association (NYHA) class III-IV) or significant vascular disease (e.g., peripheral arterial occlusive disease (PAOD) Fontaine class IIb-IV) * no life-long history of seizure disorders or epilepsy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (at Randomization) in Average Pain Intensity on an 11-point Numerical Rating Scale (NRS) Over the Last Week of the Double-blind Maintenance Period at Week 12 | Baseline and 12 weeks | For this twice daily pain assessment, the subjects were to indicate the level of pain experienced over the previous 12 hours 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Patients Achieving at Least 30% Improvement in Pain Score at Week 12 of the Double-blind Maintenance Period From the Start of the Open Label Period. | Start of Open Label and at 12 weeks of Double Blind | The number of patients achieving at least 30% improvement in pain score at Week 12 of the double-blind maintenance period on an 11-point numerical rating scale compared with the start of the open-label period. |
| Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change Over the Last Week of the Maintenance Period at Week 12 | 12 week endpoint | Percentage of patients who reported very much improved (1) or much improved (2) based on an ordinal measure indicating change from start of double blind treatment (on a scale of 7 = Very much worse to 1 = Very much improved) |
| Change From Baseline in EuroQol-5 (EQ-5D) Health Status Index to Week 12 | 12 week endpoint (change from baseline) | Change from baseline to end point in EuroQol-5 Dimension Questionnaire. A higher score indicates an improvement in health in the Health Status Index. The EuroQol-5 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 were 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. |
| Change From Baseline in Sleep Latency Time in Hours Over the Last Week of the Maintenance Period at Week 12. | Baseline and 12 week endpoint | A Sleep Questionnaire addressed the following question: How long after bedtime/lights out did you fall asleep last night (hours)? 12 week endpoint-mean changes from baseline at endpoint for sleep latency. Decrease in time (hours) indicates improvement. |
| Change From Baseline in Brief Pain Inventory (BPI) Total Pain Score Over the Last Week of the Maintenance Period at Week 12. | Baseline and12 week endpoint | Total pain score where zero equals no pain to ten equals pain as bad as you can imagine from 12 week endpoint vs baseline. |
Participant flow
Recruitment details
The recruitment period for this out-patient, multicenter study occurred between 15 March 2007 and 20 August 2008.
Pre-assignment details
The study consisted of a 2-week screening period followed by a 3-week open-label phase where all subjects received tapentadol extended release (ER) and were titrated to an optimal dose, and a 12-week double-blind phase where subjects were randomly assigned to receive tapentadol ER or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Tapentadol ER Tapentadol ER dose of 100 to 250mg twice a day (BID) for 12 weeks during the double blind period. The study medication was provided as tablets taken orally. | 196 |
| Placebo Placebo tablets taken orally twice a day (BID) for 12 weeks during the double blind period. | 193 |
| Total | 389 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind Tapentadol ER vs Placebo | Adverse Event | 29 | 15 |
| Double Blind Tapentadol ER vs Placebo | All other | 4 | 6 |
| Double Blind Tapentadol ER vs Placebo | Lack of Efficacy | 8 | 29 |
| Double Blind Tapentadol ER vs Placebo | Lost to Follow-up | 3 | 3 |
| Double Blind Tapentadol ER vs Placebo | Study drug non compliant | 4 | 2 |
| Double Blind Tapentadol ER vs Placebo | Withdrawal by Subject | 15 | 7 |
| Open Label Tapentadol Extended Release | Adverse Event | 100 | 0 |
| Open Label Tapentadol Extended Release | All other | 33 | 0 |
| Open Label Tapentadol Extended Release | Lack of Efficacy | 23 | 0 |
| Open Label Tapentadol Extended Release | Lost to Follow-up | 3 | 0 |
| Open Label Tapentadol Extended Release | Study drug non-compliant | 13 | 0 |
| Open Label Tapentadol Extended Release | Withdrawal by Subject | 24 | 0 |
Baseline characteristics
| Characteristic | Tapentadol ER | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 60 Participants | 73 Participants | 133 Participants |
| Age, Categorical Between 18 and 65 years | 136 Participants | 120 Participants | 256 Participants |
| Age Continuous | 59.9 years STANDARD_DEVIATION 10.68 | 60.6 years STANDARD_DEVIATION 10.56 | 60.2 years STANDARD_DEVIATION 10.62 |
| Region of Enrollment Canada | 5 participants | 4 participants | 9 participants |
| Region of Enrollment United States | 191 participants | 189 participants | 380 participants |
| Sex: Female, Male Female | 77 Participants | 77 Participants | 154 Participants |
| Sex: Female, Male Male | 119 Participants | 116 Participants | 235 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 87 / 196 | 48 / 193 |
| serious Total, serious adverse events | 10 / 196 | 3 / 193 |
Outcome results
Primary
Change From Baseline (at Randomization) in Average Pain Intensity on an 11-point Numerical Rating Scale (NRS) Over the Last Week of the Double-blind Maintenance Period at Week 12
For this twice daily pain assessment, the subjects were to indicate the level of pain experienced over the previous 12 hours 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.
Time frame: Baseline and 12 weeks
Population: Intent to Treat (ITT) analysis set included all randomized subjects who took at least one dose of study medication during the double blind maintenance period with the exception of 3 subjects who were enrolled in the study twice.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol ER | Change From Baseline (at Randomization) in Average Pain Intensity on an 11-point Numerical Rating Scale (NRS) Over the Last Week of the Double-blind Maintenance Period at Week 12 | -0.1 scores on a scale | Standard Deviation 1.69 |
| Placebo | Change From Baseline (at Randomization) in Average Pain Intensity on an 11-point Numerical Rating Scale (NRS) Over the Last Week of the Double-blind Maintenance Period at Week 12 | 1.3 scores on a scale | Standard Deviation 2.41 |
Comparison: Analysis of Covariance Model with factors of treatment, country, prior opioid use, and baseline dose level and start of DB pain score as factors.p-value: <0.00195% CI: [-1.7, -0.92]ANCOVA
Secondary
Change From Baseline in Brief Pain Inventory (BPI) Total Pain Score Over the Last Week of the Maintenance Period at Week 12.
Total pain score where zero equals no pain to ten equals pain as bad as you can imagine from 12 week endpoint vs baseline.
Time frame: Baseline and12 week endpoint
Population: Intent to Treat (ITT) analysis set included all randomized subjects who took at least one dose of study medication during the double blind maintenance period with the exception of 3 subjects who were enrolled in the study twice.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol ER | Change From Baseline in Brief Pain Inventory (BPI) Total Pain Score Over the Last Week of the Maintenance Period at Week 12. | -3.1 Scores on a scale | Standard Deviation 2.13 |
| Placebo | Change From Baseline in Brief Pain Inventory (BPI) Total Pain Score Over the Last Week of the Maintenance Period at Week 12. | -2.2 Scores on a scale | Standard Deviation 2.17 |
Secondary
Change From Baseline in EuroQol-5 (EQ-5D) Health Status Index to Week 12
Change from baseline to end point in EuroQol-5 Dimension Questionnaire. A higher score indicates an improvement in health in the Health Status Index. The EuroQol-5 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 were 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.
Time frame: 12 week endpoint (change from baseline)
Population: Intent to Treat (ITT) analysis set included all randomized subjects who took at least one dose of study medication during the double blind maintenance period with the exception of 3 subjects who were enrolled in the study twice.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol ER | Change From Baseline in EuroQol-5 (EQ-5D) Health Status Index to Week 12 | 0.7 scores on a scale | Standard Deviation 0.21 |
| Placebo | Change From Baseline in EuroQol-5 (EQ-5D) Health Status Index to Week 12 | 0.6 scores on a scale | Standard Deviation 0.26 |
Secondary
Change From Baseline in Sleep Latency Time in Hours Over the Last Week of the Maintenance Period at Week 12.
A Sleep Questionnaire addressed the following question: How long after bedtime/lights out did you fall asleep last night (hours)? 12 week endpoint-mean changes from baseline at endpoint for sleep latency. Decrease in time (hours) indicates improvement.
Time frame: Baseline and 12 week endpoint
Population: Intent to Treat (ITT) analysis set included all randomized subjects who took at least one dose of study medication during the double blind maintenance period with the exception of 3 subjects who were enrolled in the study twice.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol ER | Change From Baseline in Sleep Latency Time in Hours Over the Last Week of the Maintenance Period at Week 12. | -0.2 Hours | Standard Deviation 3.22 |
| Placebo | Change From Baseline in Sleep Latency Time in Hours Over the Last Week of the Maintenance Period at Week 12. | -0.59 Hours | Standard Deviation 2.77 |
Secondary
Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change Over the Last Week of the Maintenance Period at Week 12
Percentage of patients who reported very much improved (1) or much improved (2) based on an ordinal measure indicating change from start of double blind treatment (on a scale of 7 = Very much worse to 1 = Very much improved)
Time frame: 12 week endpoint
Population: Intent to Treat (ITT) analysis set included all randomized subjects who took at least one dose of study medication during the double blind maintenance period with the exception of 3 subjects who were enrolled in the study twice.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tapentadol ER | Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change Over the Last Week of the Maintenance Period at Week 12 | 64 percentage of patients |
| Placebo | Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change Over the Last Week of the Maintenance Period at Week 12 | 38 percentage of patients |
Secondary
The Number of Patients Achieving at Least 30% Improvement in Pain Score at Week 12 of the Double-blind Maintenance Period From the Start of the Open Label Period.
The number of patients achieving at least 30% improvement in pain score at Week 12 of the double-blind maintenance period on an 11-point numerical rating scale compared with the start of the open-label period.
Time frame: Start of Open Label and at 12 weeks of Double Blind
Population: Intent-to-treat analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tapentadol ER | The Number of Patients Achieving at Least 30% Improvement in Pain Score at Week 12 of the Double-blind Maintenance Period From the Start of the Open Label Period. | 105 participants |
| Placebo | The Number of Patients Achieving at Least 30% Improvement in Pain Score at Week 12 of the Double-blind Maintenance Period From the Start of the Open Label Period. | 81 participants |