Efficacy and Safety of Hydrocodone Bitartrate Extended-Release Tablets for Moderate to Severe Chronic Low Back Pain

The WPI was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. Participants selected the number that best described their worst pain intensity over the last 24 hours. Weekly WPI scores averaged daily scores collected over the previous 7 days for each analysis visit. Negative change from baseline scores indicate improvement in pain control.

The analysis included WPI data observed before discontinuation of study drug and was based on the multiple imputations (MI) method to handle missing scores at week 12. Consistent with the recommendations of the National Academy of Sciences (NAS) report (Panel on Handling Missing Data in Clinical Trials 2010), the MI method includes an assumption of missing at random (MAR) and takes into account a potential bias toward the active-drug treatment group for patients who discontinued study drug because of adverse events.

The API over the last 24 hours was recorded daily by patients in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. Participants selected the number that best described the average pain intensity over the last 24 hours. Weekly API scores averaged daily scores collected over the previous 7 days for each analysis visit. Negative change from baseline scores indicate improvement in pain control.

The analysis included API data observed before discontinuation of study drug and was based on the MI method to handle missing scores at week 12. Consistent with the recommendations of the National Academy of Sciences (NAS) report (Panel on Handling Missing Data in Clinical Trials 2010), the MI method includes an assumption of missing at random (MAR) and takes into account a potential bias toward the active-drug treatment group for patients who discontinued study drug because of adverse events.

Time to loss of efficacy was defined as discontinuation of study drug for lack of efficacy or the start of excessive rescue medication while taking study drug. Excessive rescue medication usage was defined as 10 or more days of rescue medication usage in any 14 consecutive days at a total of 15 mg (hydrocodone-equivalent) or higher each day during the post 2-week tapering period of the double-blind treatment period.

The API over the last 24 hours was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. Participants selected the number that best described the average pain intensity over the last 24 hours. Weekly API scores averaged daily scores collected over the previous 7 days for each analysis visit.

The RMDQ is a patient-rated, 24-question evaluation used to assess acute disability associated with low back pain. Each question is answered with a YES or NO response, and each YES response is given 1 point. Scores on the RMDQ range from 0 to 24, with higher scores indicating greater disability. Negative change from baseline scores indicate improvement in level of disability.

An adverse event (AE) was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an inability to carry out usual activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

Pure tone audiometry was performed by a qualified audiologist and was not done at the study center. During the test, the patient wore headphones and was seated in a quiet room; trained personnel manipulated the audiometry equipment to test the patient's hearing. For serial audiograms, the criteria for a clinically significant (CS) hearing change were based on the guidance from the American Speech-Language Hearing Association (ASHA) 1994 (Konrad-Martin et al 2005). These criteria included the following: greater than 20 decibels (dB) pure tone threshold shift at 1 frequency; greater than 10 dB shift at 2 consecutive test frequencies; or threshold response shifting to "no response" at 3 consecutive test frequencies.

The results of the SOWS were collected in the e-diary daily during the first 4 weeks of the double blind treatment period and then during clinic visits at week 12 or early termination. The SOWS was a self-administered questionnaire used to measure a participant's signs and symptoms of withdrawal from opiates. The scale contained 16 symptoms (such as my nose is running; I feel restless), the participant rated the intensity on a scale of 0 (not at all) to 4 (extremely) for a total score of 0-64. The daily total score for the first 4 weeks was the largest score observed during the time period preceding that visit. For example, the week 1 score for each participant was the largest total score on any day between baseline and the night before the week 1 visit; the week 4 score for each participant was the largest score observed between the week 2 visit and the night before the week 4 visit.

COWS is a clinician-rated scale used to measure a participant's signs and symptoms of withdrawal from opiates, with ratings based only on apparent relationship to withdrawal. The COWS was performed at weeks 1, 2, 4, and 12 (double blind treatment period) or early termination. The scale contained 11 signs/symptoms whose intensity the clinician rated on a scale of 0 to 4 or 5.

A total score was calculated as the sum of the responses to the 11 signs/symptoms for a total range of 0-48. Withdrawal severity was classified, based on the total score, as follows:

• 0 to 4=normal
• 5 to 12=mild
• 13 to 24=moderate
• 25 to 36=moderately severe

• 36=severe

Data represents participants with potentially clinically significant abnormal serum chemistry, hematology and urinalysis values.

Significance criteria:

• Blood urea nitrogen: >=10.71 mmol/L
• Creatinine: >=177 μmol/L
• Uric acid: M>=625, F>=506 μmol/L
• Alanine aminotransferase (ALT): >=3* upper limit of normal (ULN)
• Gamma-glutamyl transpeptidase (GGT): >=3* upper limit of normal (ULN)
• Serum white blood cells: <=3.0 * 10^9/L
• Hemoglobin: M<=115, F<=95 g/dL
• Hematocrit: M<0.37, F<0.32 L/L
• Eosinophils: >=10.0 %
• Absolute neutrophils: <=1.0 * 10^9/L
• Urinalysis: Glucose: >=2 unit increase from baseline

Data represents participants with potentially clinically significant (PCS) vital sign values.

Significance criteria

• Pulse - high: >=120 and increase of >= 15 beats/minute from baseline
• Pulse - low: <=50 and decrease of >=15 beats/minute
• Systolic blood pressure - high: >=180 and increase >=20 mmHg
• Systolic blood pressure - low: <=90 and decrease >=20 mmHg
• Diastolic blood pressure - high: >=105 and increase of >=15 mmHg
• Diastolic blood pressure - low: <=50 and decrease of >=15 mmHg

Data represents the number of participants with potentially clinically significant (PCS) electrocardiogram findings on the final study visit.