Efficacy and Safety Study of ARC-4558 for Management of Pain Associated With Painful Diabetic Neuropathy

Pain in the feet was scored daily at bedtime by the subject on a 0-10 numeric pain rating scale (NPRS) through Day 84. Subjects were asked to record average pain in the feet over the past 24 hours. A score of 0 indicated no pain and a score of 10 was worst possible pain. The change in pain is represented as Week 12 minus Baseline, so greater negative numbers represent more improvement (more pain relief).

Time frame: Baseline (average of Days -7 to -1) and Week 12 (Average of Days 78 to 84)

Population: One treated subject had no recorded scores and could not be included. Imputation was mLOCF (modified Last Observation Carried Forward): LOCF for subjects who discontinued early, except if withdrawal was associated with an adverse event (AE) potentially related to study medication (in which case Baseline Observation Carried Forward (BOCF) was used).

Pain in the feet was scored daily at bedtime by the subject on a 0-10 numeric pain rating scale (NPRS). Subjects were asked to record average pain in the feet over the past 24 hours. A score of 0 indicated no pain and a score of 10 was worst possible pain. A weekly average was calculated from the daily scores for each week. The change in pain is represented as the average weekly score minus Baseline, so greater negative numbers represent more improvement (more pain relief).

Time frame: Baseline (average of Days -7 to -1) and Weeks 1 through 12 (weekly averages)

Population: One treated subject had no recorded scores and could not be included. Imputation was a modified LOCF (LOCF for subjects who discontinued early, except if withdrawal was associated with an adverse event (AE) potentially related to study medication, in which case BOCF was used). Additional BOCF analyses have been published (Pain 2012, see citation)

The Brief Pain Inventory was completed by the subject at clinic visits. The Severity Scale (of 0 to 40) is a composite score, which is the sum of the individual ratings for worst pain, least pain, average pain, and current pain. Each individual question is rated on a scale of 0 to 10, where 0 indicates No Pain and 10 indicates Pain as bad as you can imagine. The change in pain severity is represented as Week 12 minus Baseline, so greater negative numbers represent greater improvement (pain relief).

Time frame: Baseline and Week 12

Population: One subject in the active Clonidine Gel group was lost to follow-up before Baseline pain scores were confirmed and before any post-baseline efficacy evaluations were performed. This subject was excluded from the efficacy analyses.

The Brief Pain Inventory was completed by the subject at clinic visits. The Functional Interference Scale (of 0 to 70) is a composite score that measures the degree to which pain interferes with mood, walking, work, relationships, sleep, general activity, and enjoyment of life. The composite score is a sum of the seven individual question scores. Each individual question is rated in reference to pain over the past 24 hours on a scale of 0 to 10, where 0 indicates that pain does not interfere and 10 indicates that pain completely interferes with that function, so lower scores represent better outcomes on this scale. The change in functional interference is represented as Week 12 minus Baseline, so greater negative numbers represent more improvement.

Time frame: Baseline and Week 12

Population: One subject in the active Clonidine Gel group was lost to follow-up before Baseline pain scores were confirmed and before any post-baseline efficacy evaluations were performed. This subject was excluded from the efficacy analyses.

Subjects rated overall quality of sleep over the past week using a 100 mm Visual Analog Scale (VAS) where 100=Excellent and 0=Very Poor. This scale was completed during clinic visits. Change from Baseline is a positive value where quality of sleep improved.

Time frame: Baseline and Week 12

Population: One subject in the active Clonidine Gel group was lost to follow-up before Baseline pain scores were confirmed and before any post-baseline efficacy evaluations were performed. This subject was excluded from the efficacy analyses.

The HADS was completed at the Baseline and Week 12 clinic visits. The Anxiety Score component of the HADS includes 7 questions, each with 4 possible answer choices (rated 0 to 3). The composite score is created by adding the scores of the 7 individual questions. A score of 0 to 7 is Normal, 8-10 indicates Mild Anxiety, 11-14 indicates Moderate Anxiety, and 15-21 indicates Severe Anxiety. The change from Baseline is calculated as the Week 12 composite score minus the Baseline composite score.

Time frame: Baseline and Week 12

Population: One subject in the active Clonidine Gel group was lost to follow-up before Baseline pain scores were confirmed and before any post-baseline efficacy evaluations were performed. This subject was excluded from the efficacy analyses.

The HADS was completed at the Baseline and Week 12 clinic visits. The Depression Score component of the HADS includes 7 questions, each with 4 possible answer choices (rated 0 to 3). The composite score is created by adding the scores of the 7 individual questions. A score of 0 to 7 is Normal, 8-10 indicates Mild Depression, 11-14 indicates Moderate Depression, and 15-21 indicates Severe Depression. The change from Baseline is calculated as the Week 12 composite score minus the Baseline composite score.

Time frame: Baseline and Week 12

Population: One subject in the active Clonidine Gel group was lost to follow-up before Baseline pain scores were confirmed and before any post-baseline efficacy evaluations were performed. This subject was excluded from the efficacy analyses.

The McGill Pain Questionnaire asks subjects to rate 15 different kinds of pain, each on a scale of 0 to 3 (0=None, 1=Mild, 2=Moderate, 3=Severe). The total score is a sum of the individual ratings and has a range from 0 to 45, where higher numbers indicate more pain. The 15 types of pain assessed are throbbing, shooting, stabbing, sharp, cramping, gnawing, hot-burning, aching, heavy, tender, splitting, tiring-exhausting, sickening, fearful, and punishing-cruel. This scale was completed at the Baseline and Week 12 clinic visits. The change from Baseline is calculated as the Week 12 total score minus the Baseline total score, so greater negative numbers indicate more improvement (pain relief).

Time frame: Baseline and Week 12

Population: One subject in the active Clonidine Gel group was lost to follow-up before Baseline pain scores were confirmed and before any post-baseline efficacy evaluations were performed. This subject was excluded from the efficacy analyses.

Pain in the feet was scored daily at bedtime by the subject on a 0-10 numeric pain rating scale. Subjects were asked to record the worst pain in their feet over the past 24 hours. A score of 0 indicated no pain and a score of 10 was worst possible pain. The change in pain is represented as Week 12 minus Baseline, so greater negative numbers represent greater improvement (greater pain relief).

Time frame: Baseline (average of Days -7 to -1) and Week 12 (average of Days 78 to 84)

Population: One treated subject had no recorded scores and could not be included. Imputation was a modified LOCF (LOCF for subjects who discontinued early, except if withdrawal was associated with an adverse event (AE) potentially related to study medication, in which case BOCF was used). Additional BOCF analyses have been published (Pain 2012, see citation).

Systolic and Diastolic Blood Pressure were measured at clinic visits. This outcome assesses the change in blood pressure from Baseline to Week 12 of treatment.

Time frame: Baseline and Week 12

Population: ITT (Intent-to-Treat)

At Week 12, the Investigator was asked to independently rate the subject's total improvement relative to Baseline, whether or not, in their judgement, it was due entirely to study drug treatment or not. Answer choices were: (+3) very much improved, (+2) much improved, (+1) minimally improved, (0) no change, (-1) minimally worse, (-2) much worse, (-3) very much worse.

Time frame: Week 12

Population: All subjects with a CGIC score were analyzed.

At Week 12 the subject was asked to rate their total improvement relative to Baseline, whether or not, in their judgement, it was due entirely to study drug treatment or not. Answer choices were: (+3) very much improved, (+2) much improved, (+1) minimally improved, (0) no change, (-1) minimally worse, (-2) much worse, (-3) very much worse.

Time frame: Week 12

Population: All subjects with a PGIC score were analyzed.

Pain in the feet was scored daily at bedtime by the subject on a 0-10 numeric pain rating scale (NPRS). Subjects were asked to record average pain in the feet over the past 24 hours. A score of 0 indicated no pain and a score of 10 was worst possible pain.

Time frame: Baseline (average of Days -7 to -1) and Week 12 (average of Days 78 to 84)

Population: One treated subject had no recorded scores and could not be included. Imputation was a modified LOCF (LOCF for subjects who discontinued early, except if withdrawal was associated with an adverse event (AE) potentially related to study medication, in which case BOCF was used). Additional BOCF analyses have been published (Pain 2012, see citation).

Pain in the feet was scored daily at bedtime by the subject on a 0-10 numeric pain rating scale (NPRS). Subjects were asked to record average pain in the feet over the past 24 hours. A score of 0 indicated no pain and a score of 10 was worst possible pain.

Time frame: Baseline (average of Days -7 to -1) and Week 12 (average of Days 78 to 84)

Population: One treated subject had no recorded scores and could not be included. Imputation was a modified LOCF (LOCF for subjects who discontinued early, except if withdrawal was associated with an adverse event (AE) potentially related to study medication, in which case BOCF was used). Additional BOCF analyses have been published (Pain 2012, see citation).