Diabetic Peripheral Neuropathy
Conditions
Keywords
Diabetic Peripheral Neuropathy, Painful, Polyneuropathy, Peripheral neuropathy
Brief summary
The purpose of this study is to evaluate the efficacy, safety, and tolerability of orally administered tapentadol extended release (ER) at dosages of 100 to 250 mg twice daily compared with placebo in patients with moderate to severe pain due to chronic, painful diabetic peripheral neuropathy (DPN) who tolerated tapentadol (ER) and have an initial treatment effect (pain improvement) after a 3-week, open-label titration period.
Detailed description
This is a randomized-withdrawal (only patients that have an initial response to tapentadol are assigned to either tapentadol or placebo), placebo-controlled, multicenter study evaluating the efficacy, safety, and tolerability of orally administered tapentadol, using the extended release tamper-resistant formulation (TRF), at dosages of 100 to 250 mg twice daily in patients with moderate to severe pain due to chronic, painful DPN. The study consists of 1) an open-label (all people involved know the identity of the intervention) phase, including a 13-day screening period, a 5-day washout period (where patients are to stop taking their pain medication), a 3-day pre-titration pain-intensity evaluation period (where patients will record their pain intensity twice daily in the morning and evening), and a 3-week, open-label titration period (all patients receive tapentadol study drug), 2) a 12-week, double-blind (neither physician nor patient knows the name of the assigned drug) maintenance phase, and 3) a posttreatment phase of approximately 10 to 14 days. The study will evaluate the effectiveness of orally administered tapentadol ER versus placebo in reducing patients' pain intensity. The pain intensity will be assessed by comparing the baseline pain level to the level at week 12 of the maintenance phase. The total duration of study drug treatment for each patient will be approximately 15 weeks. Safety and tolerability will be evaluated by vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms (ECGs), standardized neurologic examinations, and monitoring of adverse events. Patients will be titrated on tapentadol ER from a starting dose of 50 mg twice daily to the patient's optimal dose ranging between 100 mg and 250 mg twice a day, or placebo. All doses of study medication will be taken orally with approximately 120 ml of water with or without food for a maximum timeframe of 15 weeks.
Interventions
Type= range, unit= mg, number= 100 to 250, form= tablet, route= oral use. Tapentadol ER optimal dose ranging between 100 mg and 250 mg twice daily for 15 weeks.
DRUGPlacebo
Form= tablet, route= oral use. Matching placebo twice daily.
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 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 * Diagnosis must include pain plus reduction or absence of pin sensibility and/or vibration sensibility on Total Neuropathy Score - Nurse (TNSn) examination in lower and/or upper extremities at 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 * 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 \<=160mg of oral morphine
Exclusion criteria
* Significant history of pulmonary, gastrointestinal, endocrine, metabolic (except diabetes mellitus), neurological, psychiatric disorders (resulting in disorientation, memory impairment or inability to report accurately as in schizophrenia) * History of moderate to severe hepatic impairment * Severely impaired renal function * Clinically significant laboratory abnormalities * Clinically significant cardiac disease * History of seizure disorder or epilepsy * History of any other clinically significant disease that in the investigator's opinion may affect efficacy or safety assessments or may compromise patient safety during study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Double-Blind Baseline of the Average Pain Intensity Based on an 11-point Numerical Rating Scale(NRS) Over the Last Week of the Maintenance Period at Week 12 | Double-Blind Baseline and 12 weeks (Primary endpoint is the average pain intensity score during the last week of the maintenance period) | For this twice daily pain assessment, the patients 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 |
|---|---|---|
| Responder Analysis: Proportion of Patients With At Least 50% Improvement From Baseline of Open-Label on the Numerical Rating Scale (NRS) at the Week 12 Endpoint | Open-label Baseline and End of Double-Blind Treatment at 15 Weeks (3 weeks open-label plus 12 weeks double-blind) | The NRS was a twice-daily pain assessment in which patients were to indicate the level of pain experienced over the previous 12 hours on an 11-point scale with a score of 0 indicating no pain and a score of 10 indicating pain as bad as you can imagine. |
| Distribution of Patient Global Impression of Change at Week 12 Endpoint | End of Double-Blind Treatment at 12 Weeks | Patient Global Impression of Change (PGIC) is a patient-rated assessment of overall neuropathic pain since the start of treatment using a categorical scale 1-7, where 1 is 'very much improved' and 7 is 'very much worse' |
| Change From Baseline of Open-Label in the Pain Intensity Subscale of the Brief Pain Inventory (BPI) at the Week 12 Double-Blind Endpoint | Open-label Baseline and End of Double-Blind Treatment at 15 Weeks (3 weeks open-label plus 12 weeks double-blind) | The BPI is a 12-item questionnaire to evaluate the intensity of pain and the degree to which pain interferes with function. It includes 4 items assessing current pain intensity and pain at its worst, least, and on average over the past day using an 11-point scale from 0 = no pain to 10 = pain as bad as you can imagine. The pain intensity subscale score is defined as the mean of the scores from these 4 items. |
| Change From Baseline in the EuroQoL-5 Dimension (EQ-5D) Health Status Index at the Week 12 Endpoint | Double-blind Baseline and End of Double-Blind Treatment at 12 Weeks | EQ-5D has 5 items (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) rated on a categorical scale of 1-3 with 1=no problems, 2=some problems, 3=extreme problems. The health state index is a weighted combination of the 5 items. It has a range of 0 to 1, with 0=deceased and 1=full health. |
Countries
Canada, Puerto Rico, United States
Participant flow
Pre-assignment details
In a 3-week open-label (OL) period, patients titrated to an optimal dose between 100 mg and 250 mg twice daily. Patients with \>=1-point reduction in pain intensity at the end of OL period were randomized. 38 of 358 who completed OL were not randomized: \<1-pt reduction(28), withdrew consent(4), non-compliant(2), adverse events(1), other reason(3).
Participants by arm
| Arm | Count |
|---|---|
| DB Tapentadol ER Tapentadol extended release (ER) 100 150 200 250 mg twice daily for 12 weeks | 166 |
| DB Placebo Double-Blind Placebo Control Group | 152 |
| Total | 318 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-Blind Maintenance | Adverse Event | 0 | 23 | 13 |
| Double-Blind Maintenance | Lack of Efficacy | 0 | 3 | 11 |
| Double-Blind Maintenance | Lost to Follow-up | 0 | 1 | 0 |
| Double-Blind Maintenance | Noncompliance With Study Drug | 0 | 2 | 6 |
| Double-Blind Maintenance | Other | 0 | 6 | 2 |
| Double-Blind Maintenance | Physician Decision | 0 | 2 | 1 |
| Double-Blind Maintenance | Protocol Violation | 0 | 1 | 3 |
| Double-Blind Maintenance | Withdrawal by Subject | 0 | 8 | 9 |
| Open-Label Titration | Adverse Event | 69 | 0 | 0 |
| Open-Label Titration | Lack of Efficacy | 3 | 0 | 0 |
| Open-Label Titration | Lost to Follow-up | 1 | 0 | 0 |
| Open-Label Titration | Noncompliance With Study Drug | 8 | 0 | 0 |
| Open-Label Titration | Other | 7 | 0 | 0 |
| Open-Label Titration | Physician Decision | 1 | 0 | 0 |
| Open-Label Titration | Protocol Violation | 1 | 0 | 0 |
| Open-Label Titration | Withdrawal by Subject | 11 | 0 | 0 |
Baseline characteristics
| Characteristic | DB Tapentadol ER | DB Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 44 Participants | 43 Participants | 87 Participants |
| Age, Categorical Between 18 and 65 years | 122 Participants | 109 Participants | 231 Participants |
| Age Continuous | 58.5 years STANDARD_DEVIATION 10.63 | 59 years STANDARD_DEVIATION 9 | 58.7 years STANDARD_DEVIATION 9.87 |
| Region Enroll Canada | 24 participants | 22 participants | 46 participants |
| Region Enroll USA | 142 participants | 130 participants | 272 participants |
| Sex: Female, Male Female | 67 Participants | 64 Participants | 131 Participants |
| Sex: Female, Male Male | 99 Participants | 88 Participants | 187 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 296 / 459 | 86 / 166 | 37 / 152 |
| serious Total, serious adverse events | 11 / 459 | 8 / 166 | 9 / 152 |
Outcome results
Primary
Change From Double-Blind Baseline of the Average Pain Intensity Based on an 11-point Numerical Rating Scale(NRS) Over the Last Week of the Maintenance Period at Week 12
For this twice daily pain assessment, the patients 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: Double-Blind Baseline and 12 weeks (Primary endpoint is the average pain intensity score during the last week of the maintenance period)
Population: Intent-to-treat (ITT) population. Last observation carried forward (LOCF) was used to impute pain score after discontinuation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Tapentadol ER | Change From Double-Blind Baseline of the Average Pain Intensity Based on an 11-point Numerical Rating Scale(NRS) Over the Last Week of the Maintenance Period at Week 12 | 0.28 units on a scale | Standard Deviation 2.04 |
| DB Placebo | Change From Double-Blind Baseline of the Average Pain Intensity Based on an 11-point Numerical Rating Scale(NRS) Over the Last Week of the Maintenance Period at Week 12 | 1.3 units on a scale | Standard Deviation 2.43 |
Comparison: The primary null hypothesis to be tested for the study was that the tapentadol ER group was not different from the placebo group for the primary endpoint. Assuming the mean treatment group difference of 1.0 with an SD of 2.6, 144 subjects per treatment group were estimated to provide 90% power to show that the tapentadol ER group was statistically different from placebo at an alpha level of 0.05. The total number of subjects to be randomly assigned to a DB treatment group for the study was 300.p-value: <0.00195% CI: [-1.415, -0.493]ANCOVA
Secondary
Change From Baseline in the EuroQoL-5 Dimension (EQ-5D) Health Status Index at the Week 12 Endpoint
EQ-5D has 5 items (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) rated on a categorical scale of 1-3 with 1=no problems, 2=some problems, 3=extreme problems. The health state index is a weighted combination of the 5 items. It has a range of 0 to 1, with 0=deceased and 1=full health.
Time frame: Double-blind Baseline and End of Double-Blind Treatment at 12 Weeks
Population: Intent-to-treat (ITT) population. Last observation carried forward (LOCF) endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Tapentadol ER | Change From Baseline in the EuroQoL-5 Dimension (EQ-5D) Health Status Index at the Week 12 Endpoint | 0.00 units on a scale | Standard Deviation 0.203 |
| DB Placebo | Change From Baseline in the EuroQoL-5 Dimension (EQ-5D) Health Status Index at the Week 12 Endpoint | -0.10 units on a scale | Standard Deviation 0.257 |
Secondary
Change From Baseline of Open-Label in the Pain Intensity Subscale of the Brief Pain Inventory (BPI) at the Week 12 Double-Blind Endpoint
The BPI is a 12-item questionnaire to evaluate the intensity of pain and the degree to which pain interferes with function. It includes 4 items assessing current pain intensity and pain at its worst, least, and on average over the past day using an 11-point scale from 0 = no pain to 10 = pain as bad as you can imagine. The pain intensity subscale score is defined as the mean of the scores from these 4 items.
Time frame: Open-label Baseline and End of Double-Blind Treatment at 15 Weeks (3 weeks open-label plus 12 weeks double-blind)
Population: Intent-to-treat (ITT) population. Last observation carried forward (LOCF) endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Tapentadol ER | Change From Baseline of Open-Label in the Pain Intensity Subscale of the Brief Pain Inventory (BPI) at the Week 12 Double-Blind Endpoint | -3.0 units on a scale | Standard Deviation 2.16 |
| DB Placebo | Change From Baseline of Open-Label in the Pain Intensity Subscale of the Brief Pain Inventory (BPI) at the Week 12 Double-Blind Endpoint | -2.3 units on a scale | Standard Deviation 2.33 |
Secondary
Distribution of Patient Global Impression of Change at Week 12 Endpoint
Patient Global Impression of Change (PGIC) is a patient-rated assessment of overall neuropathic pain since the start of treatment using a categorical scale 1-7, where 1 is 'very much improved' and 7 is 'very much worse'
Time frame: End of Double-Blind Treatment at 12 Weeks
Population: Intent-to-treat (ITT) population. Last observation carried forward (LOCF) end point
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| DB Tapentadol ER | Distribution of Patient Global Impression of Change at Week 12 Endpoint | Very much worse | 1.3 percentage of participants | — |
| DB Tapentadol ER | Distribution of Patient Global Impression of Change at Week 12 Endpoint | Very much improved | 28.7 percentage of participants | 2.04 |
| DB Tapentadol ER | Distribution of Patient Global Impression of Change at Week 12 Endpoint | Much improved | 37.3 percentage of participants | — |
| DB Tapentadol ER | Distribution of Patient Global Impression of Change at Week 12 Endpoint | Minimally improved | 21.3 percentage of participants | — |
| DB Tapentadol ER | Distribution of Patient Global Impression of Change at Week 12 Endpoint | Not changed | 8.0 percentage of participants | — |
| DB Tapentadol ER | Distribution of Patient Global Impression of Change at Week 12 Endpoint | Minimally worse | 2.0 percentage of participants | — |
| DB Tapentadol ER | Distribution of Patient Global Impression of Change at Week 12 Endpoint | Much worse | 1.3 percentage of participants | — |
| DB Placebo | Distribution of Patient Global Impression of Change at Week 12 Endpoint | Very much worse | 2.2 percentage of participants | — |
| DB Placebo | Distribution of Patient Global Impression of Change at Week 12 Endpoint | Not changed | 18.7 percentage of participants | — |
| DB Placebo | Distribution of Patient Global Impression of Change at Week 12 Endpoint | Very much improved | 14.4 percentage of participants | 2.43 |
| DB Placebo | Distribution of Patient Global Impression of Change at Week 12 Endpoint | Much worse | 7.9 percentage of participants | — |
| DB Placebo | Distribution of Patient Global Impression of Change at Week 12 Endpoint | Much improved | 30.9 percentage of participants | — |
| DB Placebo | Distribution of Patient Global Impression of Change at Week 12 Endpoint | Minimally worse | 5.0 percentage of participants | — |
| DB Placebo | Distribution of Patient Global Impression of Change at Week 12 Endpoint | Minimally improved | 20.9 percentage of participants | — |
Secondary
Responder Analysis: Proportion of Patients With At Least 50% Improvement From Baseline of Open-Label on the Numerical Rating Scale (NRS) at the Week 12 Endpoint
The NRS was a twice-daily pain assessment in which patients were to indicate the level of pain experienced over the previous 12 hours on an 11-point scale with a score of 0 indicating no pain and a score of 10 indicating pain as bad as you can imagine.
Time frame: Open-label Baseline and End of Double-Blind Treatment at 15 Weeks (3 weeks open-label plus 12 weeks double-blind)
Population: Intent-to-treat (ITT) population. Last observation carried forward (LOCF) was used to impute pain score after discontinuation.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| DB Tapentadol ER | Responder Analysis: Proportion of Patients With At Least 50% Improvement From Baseline of Open-Label on the Numerical Rating Scale (NRS) at the Week 12 Endpoint | 40.4 percentage of participants | 2.04 |
| DB Placebo | Responder Analysis: Proportion of Patients With At Least 50% Improvement From Baseline of Open-Label on the Numerical Rating Scale (NRS) at the Week 12 Endpoint | 28.9 percentage of participants | 2.43 |