A Safety and Efficacy Study for Tapentadol (CG5503) Extended Release for Patients With 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 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
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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.

Official Title
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A Randomized-Withdrawal Phase 3 Study Evaluating the Safety and Efficacy of CG5503 Extended Release (ER) in Subjects With Painful Diabetic Peripheral Neuropathy

Conditions
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Diabetic Neuropathy

Intervention / Treatment
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* Drug: CG5503
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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

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 |
| --- | --- |
| Placebo Comparator: Placebo<br>placebo matching placebo twice daily for 12 weeks | Drug: placebo<br>* matching placebo twice daily for 12 weeks<br>|
| Experimental: CG5503<br>CG5503 100, 150, 200, 250mg twice daily given for up to 15 weeks | Drug: CG5503<br>* 100, 150, 200, 250 mg twice daily given for up to 15 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Start of Open Label and at 12 weeks of Double Blind | 
| 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) | 12 week endpoint | 
| 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. | 12 week endpoint (change from baseline) | 
| 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. | Baseline and 12 week endpoint | 
| 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. | Baseline and12 week endpoint | 

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