A Study to Evaluate the Efficacy, Safety, and Tolerability of Tapentadol ER Compared With Placebo in Patients With Chronic, Painful Diabetic Peripheral Neuropathy

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized-Withdrawal, Placebo-Controlled, Study Evaluating the Efficacy, Safety, and Tolerability of Tapentadol Extended-Release (ER) in Subjects With Chronic, Painful Diabetic Peripheral Neuropathy (DPN)

Conditions
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Diabetic Peripheral Neuropathy

Intervention / Treatment
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* Drug: Tapentadol extended release (ER)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tapentadol Extended Release (ER)<br> | Drug: Tapentadol extended release (ER)<br>* 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.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Form= tablet, route= oral use. Matching placebo twice daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Double-Blind Baseline and 12 weeks (Primary endpoint is the average pain intensity score during the last week of the maintenance period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Open-label Baseline and End of Double-Blind Treatment at 15 Weeks (3 weeks open-label plus 12 weeks double-blind) | 
| 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' | End of Double-Blind Treatment at 12 Weeks | 
| 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. | Open-label Baseline and End of Double-Blind Treatment at 15 Weeks (3 weeks open-label plus 12 weeks double-blind) | 
| 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. | Double-blind Baseline and End of Double-Blind Treatment at 12 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic Peripheral Neuropathy, Painful, Polyneuropathy, Peripheral neuropathy