Painful Diabetic Neuropathy
Conditions
Keywords
Diabetic Neuropathic Pain
Brief summary
The primary objective of this study is to assess the efficacy of Eslicarbazepine acetate (ESL) as therapy in subjects with Diabetic Neuropathic Pain (DNP) over a 15 week treatment phase.
Detailed description
Diabetic neuropathic pain (DNP) is one of the most common complications of diabetes mellitus. It currently affects about 1% of the population but its prevalence is expected to increase in coming years (European Medicines Agency 2007) in step with the increase in diabetes mellitus prevalence, which is expected to affect 220 million people by 2010 The clinical development of ESL to treat neuropathic pain is based on its chemical and pharmacodynamic relationship to sodium channel blockers, including carbamazepine, which is effective for treating some neuropathic pain conditions. Preclinical data supports the theoretical background. This study will examine the efficacy, safety, tolerability and pharmacokinetics of Eslicarbazepine acetate for the treatment of diabetic neuropathic pain.
Interventions
Tablets will be used.
DRUGPlacebo
Tablets will be used.
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female outpatients aged 18 years or older. Female subjects are of nonchildbearing potential, defined as surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or at least 2 years postmenopausal (spontaneous amenorrhea for at least 24 months before Visit 1), or if of childbearing potential, subjects agree to use a medically acceptable nonhormonal method of contraception. * Diagnosis of Type 1 or Type 2 diabetes mellitus. * Pain due to bilateral peripheral polyneuropathy caused by Type 1 or Type 2 diabetes mellitus. * Have stable glycemic control, as assessed by the investigator, and have glycosylated hemoglobin proportion of less or equal than 11% before randomization. * A mean score between 4.0 and 9.0, inclusive, on the 24 hour average pain intensity assessment and Visit 3 (ie, 5 of 7 days, 6 of 8 days, 7 of 9 days, or 7 of 10 days). * Compliance with patient diary completion. * If not used to treat DNP, subjects are permitted to take nonsteroidal anti inflammatory drugs and selective serotonin reuptake inhibitors if they were kept on a stable dose for 1 month prior to Screening and are foreseen to remain stable throughout the study. * Competent and able to freely give own informed consent. * Female subjects of childbearing potential, who are not currently breastfeeding, must have a negative serum pregnancy test at Visit 1.
Exclusion criteria
* Historical exposure to drugs known to cause neuropathy. * Significant skin lesions (active infection, ulcer, etc). * Peripheral vascular disease with a history of amputation, except amputation of toes. * Known intolerance to ESL or to other carboxamide derivatives (eg, carbamazepine or oxcarbazepine) or frequent or severe allergic reactions with multiple medications. * Subjects who previously participated in a clinical study with ESL. * Major psychiatric disorders. * Serious or unstable disease that could compromise participation cause hospitalization during the study. * Second or third degree atrioventricular blockade not corrected with a pacemaker or any clinically significant abnormality in the 12 lead electrocardiogram as determined by the investigator. * Subjects taking the following drug classes and individual drugs are excluded: benzodiazepines (except short half life sleep agents), skeletal muscle relaxants, orally administered steroids, capsaicin, mexiletine, centrally acting analgesics (dextromethorphan, tramadol), opiates, topical lidocaine, anticonvulsants, tricyclic antidepressants, and serotonin norepinephrine reuptake inhibitors. These drugs require a minimum washout period of at least 5 times the half life and should be tapered appropriately using product label instructions as a guide. * Relevant clinical laboratory abnormality that, in the investigator's opinion, can compromise the subject's safety. * History of drug abuse or dependence (drug categories defined by DSM IV) within the past year, excluding nicotine and caffeine. * Subjects who, in the previous 30 days, received treatment with a drug that had not received regulatory approval for any indication at the time of study entry. * History of recurrent epileptic seizures except febrile seizures. * History of severe gastroparesis or gastric bypass surgery. * Neurolytic treatment for DNP. * Injected anesthetics or steroid use within 30 days of Visit 1. * Malignancy within past 2 years. * History of chronic hepatitis B or C within the past 3 months or human immunodeficiency virus infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Endpoint in Mean Pain | baseline up to endpoint 15 weeks (3-week titration phase and 12-week treatment maintenance phase) | Study was prematurely halted. The efficacy analysis was restricted to the primary efficacy variable in the interim analysis population. The intended treatment period, starting on the day of the randomization and ending at the efficacy cut-off date (31st October 2011), was the basis for the efficacy analysis; patients with less than 20 days of study medication were excluded from the analysis, except those with early discontinuation. Primary efficacy variable was the difference between the mean values of 7 daily pain scores preceding the efficacy cut-off date (endpoint mean pain score), and before randomization (baseline mean pain score), respectively. The daily pain scores were based on the morning response to the 11-point Numeric Rating Pain Scale (NRPS) question relating to average pain intensity over the last 24 hours. The NPRS is an 11-point scale from 0-10 \[0 = no pain; 10 = the most intense pain imaginable\] |
Countries
Portugal
Participant flow
Recruitment details
Fifty nine (59) clinical sites in 10 countries Study period: Date of first admission: 2010.12.06 Date of last visit: 2012.04.24
Participants by arm
| Arm | Count |
|---|---|
| Esl 1600 mg Eslicarbazepine acetate (Esl) (BIA 2-093) mg once daily (QD): Tablets will be used. | 84 |
| Esl 1200 mg Eslicarbazepine acetate (BIA 2-093) mg QD: Tablets will be used. | 83 |
| Esl 800 mg Eslicarbazepine acetate (BIA 2-093) mg QD: Tablets will be used. | 83 |
| Placebo Placebo: Tablets will be used. | 82 |
| Total | 332 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 23 | 16 | 16 | 7 |
| Overall Study | Discontinuation of the study by Sponsor | 0 | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 1 | 1 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 2 | 3 | 3 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 |
| Overall Study | Pregnancy | 1 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 2 | 3 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 | 3 | 2 |
Baseline characteristics
| Characteristic | Esl 1600 mg | Esl 1200 mg | Esl 800 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 57.6 years STANDARD_DEVIATION 10.93 | 59.0 years STANDARD_DEVIATION 11.38 | 58.0 years STANDARD_DEVIATION 13.33 | 59.5 years STANDARD_DEVIATION 10.25 | 58.5 years STANDARD_DEVIATION 11.51 |
| Race/Ethnicity, Customized Asian | 26 participants | 28 participants | 25 participants | 24 participants | 103 participants |
| Race/Ethnicity, Customized Black | 2 participants | 3 participants | 1 participants | 2 participants | 8 participants |
| Race/Ethnicity, Customized Other | 1 participants | 2 participants | 2 participants | 6 participants | 11 participants |
| Race/Ethnicity, Customized White | 55 participants | 50 participants | 55 participants | 50 participants | 210 participants |
| Sex: Female, Male Female | 45 Participants | 35 Participants | 37 Participants | 33 Participants | 150 Participants |
| Sex: Female, Male Male | 39 Participants | 48 Participants | 46 Participants | 49 Participants | 182 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 53 / 84 | 38 / 83 | 35 / 83 | 10 / 82 |
| serious Total, serious adverse events | 5 / 84 | 3 / 83 | 1 / 83 | 6 / 82 |
Outcome results
Primary
Change From Baseline to Endpoint in Mean Pain
Study was prematurely halted. The efficacy analysis was restricted to the primary efficacy variable in the interim analysis population. The intended treatment period, starting on the day of the randomization and ending at the efficacy cut-off date (31st October 2011), was the basis for the efficacy analysis; patients with less than 20 days of study medication were excluded from the analysis, except those with early discontinuation. Primary efficacy variable was the difference between the mean values of 7 daily pain scores preceding the efficacy cut-off date (endpoint mean pain score), and before randomization (baseline mean pain score), respectively. The daily pain scores were based on the morning response to the 11-point Numeric Rating Pain Scale (NRPS) question relating to average pain intensity over the last 24 hours. The NPRS is an 11-point scale from 0-10 \[0 = no pain; 10 = the most intense pain imaginable\]
Time frame: baseline up to endpoint 15 weeks (3-week titration phase and 12-week treatment maintenance phase)
Population: FAS = Full Analysis Set (comprised all randomized subjects with mean pain score at baseline and mean score after randomization; subjects with less than 20 days of study medication of the cut-off date were excluded from the dataset, except those that prematurely withdrew; this was the primary population used in the efficacy analysis)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Esl 1600 mg | Change From Baseline to Endpoint in Mean Pain | -1.56 units on a scale | Standard Error 0.232 |
| Esl 1200 mg | Change From Baseline to Endpoint in Mean Pain | -0.90 units on a scale | Standard Error 0.237 |
| Esl 800 mg | Change From Baseline to Endpoint in Mean Pain | -1.73 units on a scale | Standard Error 0.236 |
| Placebo | Change From Baseline to Endpoint in Mean Pain | -1.13 units on a scale | Standard Error 0.231 |
p-value: 0.3726Dunnett's test (analysis of covariance)
p-value: 0.8034Dunnett's test (analysis of covariance)
p-value: 0.1391Dunnett's test (analysis of covariance)