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

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of hydrocodone bitartrate extended-release tablets at doses of 30 to 90 mg every 12 hours compared with placebo in alleviating moderate to severe pain in patients with chronic low back pain. Patients may be opioid-naïve or opioid-experienced.

Detailed Description
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The study consisted of a screening period of approximately 7 to 14 days, an open label titration period of up to 6 weeks, and a double blind treatment period of 12 weeks. The objective of the open label titration period was to find the successful dose of hydrocodone extended release (ER) tablets that produced stable pain relief without unacceptable adverse events (AEs). Stable pain relief was defined as an average pain intensity (API) score over the previous 24 hours of 4 or less and a worst pain intensity (WPI) score of 6 or less on the 11-point numerical rating scale (NRS-11) (0=no pain to 10=worst pain imaginable) for either 4 consecutive days or 4 out of 7 consecutive days, while the same dose of study drug was maintained for up to 7 days. Scores for WPI and API were recorded daily in individual patient electronic diaries. Patients returned to the study center prior to each dose adjustment. The starting dose of hydrocodone ER tablets depended on whether the subject was opioid-naïve or opioid-experienced. Opioid-naïve participants started at a 15-mg dose of hydrocodone ER tablets every 12 hours. For opioid-experienced participants, the starting dose of hydrocodone ER tablets was to be approximately equivalent to 50% of the dose of opioid analgesic that they were receiving at screening and administered every 12 hours. Investigators switched participants from previous opioid therapy to hydrocodone ER tablets on the basis of predefined dose equivalents. Participants who met the criterion of a stabilized dose were randomly assigned into the 12 week, double-blind, placebo controlled treatment period on the final day of the open label titration period (baseline visit). Participants began treatment with double blind study drug at the effective dose of hydrocodone ER tablets achieved during the titration period or matching placebo. Rescue medication was permitted in addition to the study drug during the double blind treatment period. Participants who participated in the study in compliance with the protocol and complete 12 weeks of double-blind treatment with study drug, were considered to have completed the study and could have been eligible to enroll in a 6-month open-label study (study C32337/3104, NCT01922739).

Official Title
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A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Randomized-Withdrawal Study to Evaluate the Efficacy and Safety of Hydrocodone Bitartrate Extended-Release Tablets (CEP-33237) at 30 to 90 mg Every 12 Hours for Relief of Moderate to Severe Pain in Patients With Chronic Low Back Pain Who Require Opioid Treatment for an Extended Period of Time

Conditions
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Low Back Pain

Intervention / Treatment
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* Drug: Hydrocodone ER
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient has had moderate to severe chronic low back pain for at least 3 months duration before screening. The patient is able to speak English and is willing to provide written informed consent, including a written opioid agreement, to participate in this study. The patient is willing and able to successfully self-administer the study drug, comply with study restrictions, complete the electronic diary, and return to the study center for scheduled study visits, as specified in the protocol. The patient is 18 through 80 years of age at the time of screening. Women of childbearing potential (not surgically sterile or 2 years postmenopausal) must use a medically accepted method of contraception, agree to continue use of this method for the duration of the study and for 30 days after participation in the study, and have a negative pregnancy test at screening. - Acceptable methods of contraception include barrier method with spermicide, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method. NOTE: A woman will be considered surgically sterile if she has had a tubal ligation, hysterectomy, bilateral salpingo-oophorectomy or bilateral oophorectomy, or hysterectomy with bilateral salpingo-oophorectomy. Other criteria apply. Exclusion Criteria: The patient is taking a total of more than 135 mg/day of oxycodone, or equivalent, during the 14 days before screening. The patient's primary painful condition under study is related to any source of chronic pain other than low back pain. The patient has radicular (nerve compression) pain or another type of purely neuropathic pain. The patient has known or suspected hypersensitivities, allergies, or other contraindications to any ingredient in the study drug. The patient has a recent history (within 5 years) or current evidence of alcohol or other substance abuse, with the exception of nicotine. The patient has medical or psychiatric disease that, in the opinion of the investigator, would compromise collected data. Other criteria apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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>Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain during the titration period. During the treatment period, participants were administered placebo tablets twice a day that matched the dosage deemed successful for managing their pain during the titration period. A step-wise, double-blind schedule to tamper off active drug was implemented during the first 2 weeks of the 12-week, double-blind, placebo-controlled treatment period to reduce the risk of withdrawal effects in participants randomly assigned to placebo. | Drug: Hydrocodone ER<br>* During the open-label, titration period, all participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours to identify a dosage deemed successful for managing their pain. Hydrocodone ER was taken by participants randomized to the hydrocodone ER treatment arm during the double-blind treatment period at the dose level identified during the titration period. Participants were instructed to take tablets with a glass of water on an empty stomach at least 1 hour before or 2 hours after eating.<br>* Other names: Hydrocodone bitartrate extended-release tablets;Drug: Placebo<br>* Placebo matching the active drug dose identified during the titration period was taken by participants randomized to the placebo treatment arm during the double-blind treatment period. Participants were instructed to take intervention with a glass of water on an empty stomach at least 1 hour before or 2 hours after eating.<br>|
| Experimental: Hydrocodone ER<br>Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain during the titration period. During the 12-week, double-blind, placebo-controlled treatment period, participants randomly assigned to hydrocodone ER were administered tablets twice a day at the dosage deemed successful for managing their pain during the titration period. | Drug: Hydrocodone ER<br>* During the open-label, titration period, all participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours to identify a dosage deemed successful for managing their pain. Hydrocodone ER was taken by participants randomized to the hydrocodone ER treatment arm during the double-blind treatment period at the dose level identified during the titration period. Participants were instructed to take tablets with a glass of water on an empty stomach at least 1 hour before or 2 hours after eating.<br>* Other names: Hydrocodone bitartrate extended-release tablets;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 of the Treatment Period in Weekly Average of Daily Worst Pain Intensity (WPI) | 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. | Days -6 to 0 of Treatment Period (baseline), Week 12 of Treatment Period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 of the Treatment Period in Weekly Average Pain Intensity (API) | 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. | Days -6 to 0 of Treatment Period (baseline), Week 12 | 
| Kaplan-Meier Estimates for Time to Loss of Efficacy | 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. | Day 1 to Week 12 of Treatment Period | 
| Percentage of Participants With a 30% or Greater Increase in Weekly Average Pain Intensity (API) From Baseline to Week 12 Visit, and an Average API Score of 5 or Higher at Week 12 | 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. | Days -6 to 0 of Treatment Period (baseline), Week 12 | 
| Change From Baseline to Final On-Treatment Visit in Roland Morris Disability Questionnaire (RMDQ) Score | 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. | Days 7-14 of Titration Period (baseline), Week 12 or end of study visit during the Treatment Period | 
| Participants With Adverse Events During Open-Label Titration and Double-Blind Treatment Periods | 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. | Day 1 of Titration Period up to Week 12 of Treatment Period (maximum treatment duration was 127 days) | 
| Participants With Clinically Significant Hearing Changes From Baseline to Final Assessment in Pure Tone Audiometry Test Results | 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. | Days 7-14 of Titration Period (baseline), Day 0 of Treatment Period (last day of Titration Period), Week 12 or end of study visit during the Treatment Period | 
| Subjective Opiate Withdrawal Scales (SOWS) Total Scores During the Double-Blind Treatment Period | 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. | Weeks 1, 2, 4 and Endpoint of the Treatment Period | 
| Clinical Opiate Withdrawal Scales (COWS) Total Scores During the Double-Blind Treatment Period | 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 | Weeks 1, 2, 4 and Endpoint of the Treatment Period | 
| Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period | 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 | Day 1 up to Week 12 of the Treatment Period | 
| Participants With Potentially Clinically Significant Abnormal Vital Sign Values During the Double-Blind Treatment Period | 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 | Day 1 to Week 12 of the Treatment Period | 
| Participants With Potentially Clinically Significant Abnormal Electrocardiogram Findings During the Double-Blind Treatment Period | Data represents the number of participants with potentially clinically significant (PCS) electrocardiogram findings on the final study visit. | Final study visit (week 12 or end of treatment visit) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic low back pain, hydrocodone bitartrate, opioids