Efficacy and Safety of Hydrocodone Bitartrate Extended-Release Tablets for Moderate to Severe Chronic Low Back Pain
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
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).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Placebo 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
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.
Other Names:
Drug: Placebo
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.
|
| Experimental: Hydrocodone ER 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
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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change From Baseline to Week 12 of the Treatment Period in Weekly Average of Daily Worst Pain Intensity (WPI) [Days -6 to 0 of Treatment Period (baseline), Week 12 of Treatment Period]
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.
Secondary Outcome Measures
- Change From Baseline to Week 12 of the Treatment Period in Weekly Average Pain Intensity (API) [Days -6 to 0 of Treatment Period (baseline), Week 12]
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.
- Kaplan-Meier Estimates for Time to Loss of Efficacy [Day 1 to Week 12 of Treatment Period]
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.
- 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 [Days -6 to 0 of Treatment Period (baseline), 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.
- Change From Baseline to Final On-Treatment Visit in Roland Morris Disability Questionnaire (RMDQ) Score [Days 7-14 of Titration Period (baseline), Week 12 or end of study visit during the Treatment Period]
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.
- Participants With Adverse Events During Open-Label Titration and Double-Blind Treatment Periods [Day 1 of Titration Period up to Week 12 of Treatment Period (maximum treatment duration was 127 days)]
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.
- Participants With Clinically Significant Hearing Changes From Baseline to Final Assessment in Pure Tone Audiometry Test Results [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]
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.
- Subjective Opiate Withdrawal Scales (SOWS) Total Scores During the Double-Blind Treatment Period [Weeks 1, 2, 4 and Endpoint of the 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.
- Clinical Opiate Withdrawal Scales (COWS) Total Scores During the Double-Blind Treatment Period [Weeks 1, 2, 4 and Endpoint of the 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
- Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period [Day 1 up to Week 12 of the 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
- Participants With Potentially Clinically Significant Abnormal Vital Sign Values During the Double-Blind Treatment Period [Day 1 to Week 12 of the 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
- Participants With Potentially Clinically Significant Abnormal Electrocardiogram Findings During the Double-Blind Treatment Period [Final study visit (week 12 or end of treatment visit)]
Data represents the number of participants with potentially clinically significant (PCS) electrocardiogram findings on the final study visit.
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Teva Investigational Site 10416 | Anniston | Alabama | United States | |
| 2 | Teva Investigational Site 10382 | Birmingham | Alabama | United States | |
| 3 | Teva Investigational Site 10403 | Birmingham | Alabama | United States | |
| 4 | Teva Investigational Site 10412 | Birmingham | Alabama | United States | |
| 5 | Teva Investigational Site 10426 | Mobile | Alabama | United States | |
| 6 | Teva Investigational Site 10436 | Montgomery | Alabama | United States | |
| 7 | Teva Investigational Site 10363 | Phoenix | Arizona | United States | |
| 8 | Teva Investigational Site 10366 | Phoenix | Arizona | United States | |
| 9 | Teva Investigational Site 10437 | Tucson | Arizona | United States | |
| 10 | Teva Investigational Site 10358 | Anaheim | California | United States | |
| 11 | Teva Investigational Site 10408 | Bell Gardens | California | United States | |
| 12 | Teva Investigational Site 10425 | Carmichael | California | United States | |
| 13 | Teva Investigational Site 10390 | Cerritos | California | United States | |
| 14 | Teva Investigational Site 10429 | El Cajon | California | United States | |
| 15 | Teva Investigational Site 10423 | Escondido | California | United States | |
| 16 | Teva Investigational Site 10740 | Garden Grove | California | United States | |
| 17 | Teva Investigational Site 10391 | Huntington Park | California | United States | |
| 18 | Teva Investigational Site 10422 | La Jolla | California | United States | |
| 19 | Teva Investigational Site 10413 | Laguna Hills | California | United States | |
| 20 | Teva Investigational Site 10442 | Laguna Hills | California | United States | |
| 21 | Teva Investigational Site 10370 | Los Angeles | California | United States | |
| 22 | Teva Investigational Site 10392 | Sherman Oaks | California | United States | |
| 23 | Teva Investigational Site 10398 | Thousand Oaks | California | United States | |
| 24 | Teva Investigational Site 10428 | Torrance | California | United States | |
| 25 | Teva Investigational Site 10361 | Walnut Creek | California | United States | |
| 26 | Teva Investigational Site 10441 | Waterbury | Connecticut | United States | |
| 27 | Teva Investigational Site 10369 | DeLand | Florida | United States | |
| 28 | Teva Investigational Site 10744 | Edgewater | Florida | United States | |
| 29 | Teva Investigational Site 10379 | Fort Lauderdale | Florida | United States | |
| 30 | Teva Investigational Site 10365 | Jacksonville | Florida | United States | |
| 31 | Teva Investigational Site 10445 | Leesburg | Florida | United States | |
| 32 | Teva Investigational Site 10362 | Orlando | Florida | United States | |
| 33 | Teva Investigational Site 10381 | Ormond Beach | Florida | United States | |
| 34 | Teva Investigational Site 12036 | Pembroke Pines | Florida | United States | |
| 35 | Teva Investigational Site 10357 | Plantation | Florida | United States | |
| 36 | Teva Investigational Site 10367 | Royal Palm Beach | Florida | United States | |
| 37 | Teva Investigational Site 10435 | Royal Palm Beach | Florida | United States | |
| 38 | Teva Investigational Site 10742 | Sanford | Florida | United States | |
| 39 | Teva Investigational Site 10432 | Columbus | Georgia | United States | |
| 40 | Teva Investigational Site 10383 | Marietta | Georgia | United States | |
| 41 | Teva Investigational Site 10385 | Marietta | Georgia | United States | |
| 42 | Teva Investigational Site 10444 | Newnan | Georgia | United States | |
| 43 | Teva Investigational Site 10431 | Meridian | Idaho | United States | |
| 44 | Teva Investigational Site 10743 | Meridian | Idaho | United States | |
| 45 | Teva Investigational Site 10411 | Chicago | Illinois | United States | |
| 46 | Teva Investigational Site 10418 | Avon | Indiana | United States | |
| 47 | Teva Investigational Site 10380 | Evansville | Indiana | United States | |
| 48 | Teva Investigational Site 10440 | Newburgh | Indiana | United States | |
| 49 | Teva Investigational Site 10375 | Overland Park | Kansas | United States | |
| 50 | Teva Investigational Site 10419 | New Orleans | Louisiana | United States | |
| 51 | Teva Investigational Site 10359 | Shreveport | Louisiana | United States | |
| 52 | Teva Investigational Site 10389 | Fall River | Massachusetts | United States | |
| 53 | Teva Investigational Site 10388 | Bay City | Michigan | United States | |
| 54 | Teva Investigational Site 10397 | Biloxi | Mississippi | United States | |
| 55 | Teva Investigational Site 10406 | Hazelwood | Missouri | United States | |
| 56 | Teva Investigational Site 10401 | Saint Louis | Missouri | United States | |
| 57 | Teva Investigational Site 10376 | Omaha | Nebraska | United States | |
| 58 | Teva Investigational Site 10396 | Omaha | Nebraska | United States | |
| 59 | Teva Investigational Site 10417 | Henderson | Nevada | United States | |
| 60 | Teva Investigational Site 10399 | Las Vegas | Nevada | United States | |
| 61 | Teva Investigational Site 10409 | Berlin | New Jersey | United States | |
| 62 | Teva Investigational Site 10439 | Buffalo | New York | United States | |
| 63 | Teva Investigational Site 10394 | New York | New York | United States | |
| 64 | Teva Investigational Site 10407 | New York | New York | United States | |
| 65 | Teva Investigational Site 10410 | New York | New York | United States | |
| 66 | Teva Investigational Site 10443 | Raleigh | North Carolina | United States | |
| 67 | Teva Investigational Site 10414 | Winston-Salem | North Carolina | United States | |
| 68 | Teva Investigational Site 10446 | Oklahoma City | Oklahoma | United States | |
| 69 | Teva Investigational Site 10415 | Altoona | Pennsylvania | United States | |
| 70 | Teva Investigational Site 10430 | Duncansville | Pennsylvania | United States | |
| 71 | Teva Investigational Site 10386 | Mechanicsburg | Pennsylvania | United States | |
| 72 | Teva Investigational Site 10373 | Tipton | Pennsylvania | United States | |
| 73 | Teva Investigational Site 10404 | North Charleston | South Carolina | United States | |
| 74 | Teva Investigational Site 10741 | Spartanburg | South Carolina | United States | |
| 75 | Teva Investigational Site 10405 | Austin | Texas | United States | |
| 76 | Teva Investigational Site 10364 | Dallas | Texas | United States | |
| 77 | Teva Investigational Site 10372 | Dallas | Texas | United States | |
| 78 | Teva Investigational Site 10395 | Dallas | Texas | United States | |
| 79 | Teva Investigational Site 10371 | Houston | Texas | United States | |
| 80 | Teva Investigational Site 12035 | Houston | Texas | United States | |
| 81 | Teva Investigational Site 10377 | Lake Jackson | Texas | United States | |
| 82 | Teva Investigational Site 10374 | Plano | Texas | United States | |
| 83 | Teva Investigational Site 10378 | San Antonio | Texas | United States | |
| 84 | Teva Investigational Site 10402 | Salt Lake City | Utah | United States | |
| 85 | Teva Investigational Site 10438 | Roanoke | Virginia | United States | |
| 86 | Teva Investigational Site 10420 | Bellevue | Washington | United States | |
| 87 | Teva Investigational Site 10433 | Everett | Washington | United States |
Sponsors and Collaborators
- Teva Branded Pharmaceutical Products R&D, Inc.
Investigators
- Study Director: Clinical Project Leader, Teva GCO
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- C33237/3103
Study Results
Participant Flow
| Recruitment Details | A total of 845 patients with moderate to severe chronic low back pain were screened at 78 centers in the U.S. |
|---|---|
| Pre-assignment Detail | Of the 625 patients enrolled, 2 patients withdrew consent before taking any study drug. Of 623 patients who were enrolled and received study drug, 371 patients achieved a successful dose of hydrocodone extended-release (ER) tablets and were randomly assigned to receive hydrocodone ER or placebo during the double-blind treatment period |
| Arm/Group Title | Hydrocodone ER (Open-Label Titration Period) | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|---|
| Arm/Group Description | 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. | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. |
| Period Title: Open-label Titration Period | |||
| STARTED | 625 | 0 | 0 |
| Safety Analysis Set | 623 | 0 | 0 |
| COMPLETED | 371 | 0 | 0 |
| NOT COMPLETED | 254 | 0 | 0 |
| Period Title: Open-label Titration Period | |||
| STARTED | 0 | 180 | 191 |
| Full Analysis Set and Safety Set | 0 | 179 | 191 |
| COMPLETED | 0 | 130 | 147 |
| NOT COMPLETED | 0 | 50 | 44 |
Baseline Characteristics
| Arm/Group Title | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) | Total |
|---|---|---|---|
| Arm/Group Description | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered extended-release hydrocodone tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. | Total of all reporting groups |
| Overall Participants | 180 | 191 | 371 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
51.8
(12.51)
|
51.7
(13.48)
|
51.8
(13.00)
|
| Age, Customized (Count of Participants) | |||
| <= 65 years |
154
85.6%
|
156
81.7%
|
310
83.6%
|
| > 65 years |
26
14.4%
|
35
18.3%
|
61
16.4%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
92
51.1%
|
97
50.8%
|
189
50.9%
|
| Male |
88
48.9%
|
94
49.2%
|
182
49.1%
|
| Race (Count of Participants) | |||
| White |
129
71.7%
|
133
69.6%
|
262
70.6%
|
| Black |
41
22.8%
|
39
20.4%
|
80
21.6%
|
| Asian |
8
4.4%
|
13
6.8%
|
21
5.7%
|
| American Indian or Alaska Native |
2
1.1%
|
2
1%
|
4
1.1%
|
| Native Hawaiian or other Pacific Islander |
0
0%
|
1
0.5%
|
1
0.3%
|
| Other |
0
0%
|
3
1.6%
|
3
0.8%
|
| Ethnicity (Count of Participants) | |||
| Hispanic or Latino |
23
12.8%
|
24
12.6%
|
47
12.7%
|
| Non-Hispanic and non-Latino |
156
86.7%
|
167
87.4%
|
323
87.1%
|
| Unknown |
1
0.6%
|
0
0%
|
1
0.3%
|
| Body Mass Index (kg/m^2) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [kg/m^2] |
31.5
(8.22)
|
31.3
(7.37)
|
31.4
(7.78)
|
| Participant Opioid Status (Count of Participants) | |||
| Opioid-naive |
105
58.3%
|
110
57.6%
|
215
58%
|
| Opioid-experienced |
75
41.7%
|
81
42.4%
|
156
42%
|
| Duration Since Diagnosis of Chronic Low Back Pain (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
11.5
(10.35)
|
11.3
(10.29)
|
11.4
(10.31)
|
| Duration of Opioid Therapy (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
2.9
(3.76)
|
3.5
(4.85)
|
3.2
(4.37)
|
| Average Daily Hydrocodone Equivalent Dose (mg) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [mg] |
18.2
(28.55)
|
22.1
(30.18)
|
20.2
(29.43)
|
Outcome Measures
| Title | Change From Baseline to Week 12 of the Treatment Period in Weekly Average of Daily Worst Pain Intensity (WPI) |
|---|---|
| Description | 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. |
| Time Frame | Days -6 to 0 of Treatment Period (baseline), Week 12 of Treatment Period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The full analysis set, which includes all randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline efficacy observation. |
| Arm/Group Title | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Arm/Group Description | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. |
| Measure Participants | 179 | 191 |
| Mean (Standard Error) [units on a scale] |
0.71
(0.145)
|
0.07
(0.134)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo (Double-blind Treatment Period), Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Comments | The least squares means of the change from baseline to week 12 in WPI were compared between the active drug and placebo treatment groups. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | 5% significance level | |
| Method | ANCOVA | |
| Comments | The model included treatment, study center, opioid status, and baseline WPI score. | |
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.63 | |
| Confidence Interval |
(2-Sided) 95% 0.26 to 1.00 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Placebo - Hydrocodone ER | |
| Title | Change From Baseline to Week 12 of the Treatment Period in Weekly Average Pain Intensity (API) |
|---|---|
| Description | 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 Frame | Days -6 to 0 of Treatment Period (baseline), Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The full analysis set, which includes all randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline efficacy observation. |
| Arm/Group Title | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Arm/Group Description | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. |
| Measure Participants | 179 | 191 |
| Mean (Standard Error) [units on a scale] |
0.57
(0.126)
|
0.02
(0.116)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo (Double-blind Treatment Period), Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Comments | The least squares means of the change from baseline to week 12 in API were compared between the active drug and placebo treatment groups. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | 5% significance level | |
| Method | ANCOVA | |
| Comments | The model included treatment, study center, opioid status, and baseline WPI score. | |
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.58 | |
| Confidence Interval |
(2-Sided) 95% 0.25 to 0.91 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Placebo - Hydrocodone ER | |
| Title | Kaplan-Meier Estimates for Time to Loss of Efficacy |
|---|---|
| Description | 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. |
| Time Frame | Day 1 to Week 12 of Treatment Period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The full analysis set, which includes all randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline efficacy observation. |
| Arm/Group Title | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Arm/Group Description | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. |
| Measure Participants | 179 | 191 |
| Median (95% Confidence Interval) [days] |
NA
|
NA
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo (Double-blind Treatment Period), Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.059 |
| Comments | 5% significance level | |
| Method | Wald chi-square | |
| Comments | Cox proportional hazards model with treatment, baseline worst pain intensity (WPI), opioid status, and center in the model | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.68 | |
| Confidence Interval |
(2-Sided) 95% 0.5 to 1.01 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | Days -6 to 0 of Treatment Period (baseline), Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set, including participants with observed weekly average API for week 12 |
| Arm/Group Title | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Arm/Group Description | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. |
| Measure Participants | 133 | 152 |
| API increase >=30% and API >=5 |
18.8
10.4%
|
12.5
6.5%
|
| API increase >=30% |
36.1
20.1%
|
21.1
11%
|
| API >=5 |
24.1
13.4%
|
16.4
8.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo (Double-blind Treatment Period), Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Comments | API increase >=30% and API >=5 | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0293 |
| Comments | 5% significance level | |
| Method | Regression, Logistic | |
| Comments | stratified by center with the following effects: treatment group, baseline API, and opioid status. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.67 | |
| Confidence Interval |
(2-Sided) 95% 0.47 to 0.96 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hydrocodone ER / Placebo | |
| Title | Change From Baseline to Final On-Treatment Visit in Roland Morris Disability Questionnaire (RMDQ) Score |
|---|---|
| Description | 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. |
| Time Frame | Days 7-14 of Titration Period (baseline), Week 12 or end of study visit during the Treatment Period |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set, including participants with RMDQ score for the final on-treatment visit. |
| Arm/Group Title | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Arm/Group Description | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. |
| Measure Participants | 171 | 178 |
| Mean (Standard Deviation) [units on a scale] |
-1.9
(4.47)
|
-1.5
(4.70)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo (Double-blind Treatment Period), Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.557 |
| Comments | 5% significance level | |
| Method | ANCOVA | |
| Comments | Model with the following effects: treatment, study center, opioid status, and baseline RMDQ score. | |
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -0.28 | |
| Confidence Interval |
(2-Sided) 95% -1.20 to 0.65 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Placebo - Hydrocodone ER | |
| Title | Participants With Adverse Events During Open-Label Titration and Double-Blind Treatment Periods |
|---|---|
| Description | 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. |
| Time Frame | Day 1 of Titration Period up to Week 12 of Treatment Period (maximum treatment duration was 127 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set (Titration Period) and Full analysis set (Treatment Period) |
| Arm/Group Title | Opioid-Naive (Open-Label Titration Period) | Opioid-Experienced (Open-Label Titration Period) | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|---|---|
| Arm/Group Description | Opioid-naïve participants were defined as those who were taking tramadol or less than 10 mg per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening. Opioid-naïve participants started at a 15-mg dose of hydrocodone ER tablets every 12 hours. 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. | Opioid-experienced participants were defined as those who were taking 10 mg or more per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening. 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. 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. | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. |
| Measure Participants | 368 | 255 | 179 | 191 |
| Any adverse event |
196
108.9%
|
117
61.3%
|
88
23.7%
|
106
NaN
|
| Severe adverse event |
13
7.2%
|
5
2.6%
|
3
0.8%
|
9
NaN
|
| Treatment-related adverse event |
166
92.2%
|
81
42.4%
|
50
13.5%
|
67
NaN
|
| Deaths |
0
0%
|
0
0%
|
0
0%
|
0
NaN
|
| Serious adverse event |
6
3.3%
|
4
2.1%
|
3
0.8%
|
3
NaN
|
| Discontinued study drug treatment due to AE |
53
29.4%
|
22
11.5%
|
7
1.9%
|
11
NaN
|
| Title | Participants With Clinically Significant Hearing Changes From Baseline to Final Assessment in Pure Tone Audiometry Test Results |
|---|---|
| Description | 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. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set (entire study), Full analysis set (treatment period) |
| Arm/Group Title | Hydrocodone ER (Safety Analysis Set) | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|---|
| Arm/Group Description | All enrolled participants who were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours. Includes days on hydrocodone ER during both the titration and treatment periods. | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. |
| Measure Participants | 623 | 179 | 191 |
| >= 1 CS value during study |
29
16.1%
|
10
5.2%
|
8
2.2%
|
| >= CS value during open-label titration period |
13
7.2%
|
5
2.6%
|
2
0.5%
|
| >= 1 CS during double-blind treatment period |
NA
NaN
|
8
4.2%
|
6
1.6%
|
| >=CS value at endpoint |
NA
NaN
|
8
4.2%
|
7
1.9%
|
| Title | Subjective Opiate Withdrawal Scales (SOWS) Total Scores During the Double-Blind Treatment Period |
|---|---|
| Description | 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. |
| Time Frame | Weeks 1, 2, 4 and Endpoint of the Treatment Period |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set. Participants contributing to each time point are listed in the time point label. |
| Arm/Group Title | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Arm/Group Description | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. |
| Measure Participants | 179 | 191 |
| Week 1 |
6.9
(7.03)
|
6.6
(7.36)
|
| Week 2 |
5.1
(6.10)
|
5.1
(6.89)
|
| Week 4 |
5.0
(5.52)
|
5.5
(6.58)
|
| Endpoint |
5.7
(6.70)
|
6.1
(7.63)
|
| Title | Clinical Opiate Withdrawal Scales (COWS) Total Scores During the Double-Blind Treatment Period |
|---|---|
| Description | 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 |
| Time Frame | Weeks 1, 2, 4 and Endpoint of the Treatment Period |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set. Participants contributing to each time point are listed in the time point label. |
| Arm/Group Title | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Arm/Group Description | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. |
| Measure Participants | 179 | 191 |
| Week 1 |
0.9
(1.66)
|
0.8
(1.33)
|
| Week 2 |
0.8
(1.52)
|
0.7
(1.13)
|
| Week 4 |
0.8
(1.33)
|
0.6
(1.03)
|
| Endpoint |
0.9
(1.49)
|
0.7
(1.12)
|
| Title | Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period |
|---|---|
| Description | 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 |
| Time Frame | Day 1 up to Week 12 of the Treatment Period |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set including participants with laboratory assessments. Participants with a postbaseline result for that test are counted in each laboratory tests' label. |
| Arm/Group Title | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Arm/Group Description | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. |
| Measure Participants | 171 | 178 |
| Blood urea nitrogen |
3
1.7%
|
1
0.5%
|
| Creatinine |
0
0%
|
1
0.5%
|
| Uric acid |
3
1.7%
|
4
2.1%
|
| ALT |
1
0.6%
|
2
1%
|
| GGT |
6
3.3%
|
5
2.6%
|
| White blood cells |
1
0.6%
|
0
0%
|
| Hemoglobin |
1
0.6%
|
2
1%
|
| Hematocrit |
6
3.3%
|
3
1.6%
|
| Eosinophils |
1
0.6%
|
2
1%
|
| Absolute neutrophils |
1
0.6%
|
2
1%
|
| Urine glucose |
2
1.1%
|
3
1.6%
|
| Title | Participants With Potentially Clinically Significant Abnormal Vital Sign Values During the Double-Blind Treatment Period |
|---|---|
| Description | 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 |
| Time Frame | Day 1 to Week 12 of the Treatment Period |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set |
| Arm/Group Title | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Arm/Group Description | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. |
| Measure Participants | 179 | 191 |
| Pulse - high |
2
1.1%
|
1
0.5%
|
| Pulse - low |
1
0.6%
|
1
0.5%
|
| Systolic BP - high |
1
0.6%
|
2
1%
|
| Systolic BP - low |
2
1.1%
|
3
1.6%
|
| Diastolic BP - high |
0
0%
|
3
1.6%
|
| Diastolic BP - low |
0
0%
|
2
1%
|
| Title | Participants With Potentially Clinically Significant Abnormal Electrocardiogram Findings During the Double-Blind Treatment Period |
|---|---|
| Description | Data represents the number of participants with potentially clinically significant (PCS) electrocardiogram findings on the final study visit. |
| Time Frame | Final study visit (week 12 or end of treatment visit) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set |
| Arm/Group Title | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) |
|---|---|---|
| Arm/Group Description | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. |
| Measure Participants | 179 | 191 |
| Count of Participants [Participants] |
2
1.1%
|
2
1%
|
Adverse Events
| Time Frame | - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Hydrocodone ER (Open-Label Titration Period) | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) | |||
| Arm/Group Description | 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. | Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule 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 patients randomly assigned to placebo. | Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. | |||
All Cause Mortality |
||||||
| Hydrocodone ER (Open-Label Titration Period) | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Hydrocodone ER (Open-Label Titration Period) | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 10/623 (1.6%) | 3/179 (1.7%) | 3/191 (1.6%) | |||
| Cardiac disorders | ||||||
| Acute coronary syndrome | 1/623 (0.2%) | 1 | 0/179 (0%) | 0 | 0/191 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Pancreatitis | 0/623 (0%) | 0 | 0/179 (0%) | 0 | 1/191 (0.5%) | 1 |
| General disorders | ||||||
| Chest pain | 1/623 (0.2%) | 1 | 0/179 (0%) | 0 | 0/191 (0%) | 0 |
| Infections and infestations | ||||||
| Cellulitis | 1/623 (0.2%) | 1 | 0/179 (0%) | 0 | 1/191 (0.5%) | 1 |
| Pneumonia | 2/623 (0.3%) | 2 | 0/179 (0%) | 0 | 0/191 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||
| Accidental overdose | 1/623 (0.2%) | 1 | 0/179 (0%) | 0 | 0/191 (0%) | 0 |
| Laceration | 1/623 (0.2%) | 1 | 0/179 (0%) | 0 | 0/191 (0%) | 0 |
| Tracheal injury | 1/623 (0.2%) | 1 | 0/179 (0%) | 0 | 0/191 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||
| Hypernatraemia | 0/623 (0%) | 0 | 1/179 (0.6%) | 1 | 0/191 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Rhabdomyolysis | 0/623 (0%) | 0 | 1/179 (0.6%) | 1 | 0/191 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Papillary thyroid cancer | 0/623 (0%) | 0 | 1/179 (0.6%) | 1 | 0/191 (0%) | 0 |
| Pregnancy, puerperium and perinatal conditions | ||||||
| Abortion spontaneous | 1/623 (0.2%) | 1 | 0/179 (0%) | 0 | 0/191 (0%) | 0 |
| Psychiatric disorders | ||||||
| Bipolar disorder | 0/623 (0%) | 0 | 1/179 (0.6%) | 1 | 0/191 (0%) | 0 |
| Depression | 1/623 (0.2%) | 1 | 0/179 (0%) | 0 | 0/191 (0%) | 0 |
| Panic attack | 0/623 (0%) | 0 | 1/179 (0.6%) | 1 | 1/191 (0.5%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Chronic obstructive pulmonary disease | 1/623 (0.2%) | 1 | 0/179 (0%) | 0 | 0/191 (0%) | 0 |
| Dyspnoea | 1/623 (0.2%) | 1 | 0/179 (0%) | 0 | 0/191 (0%) | 0 |
| Respiratory arrest | 1/623 (0.2%) | 1 | 0/179 (0%) | 0 | 0/191 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||
| Hydrocodone ER (Open-Label Titration Period) | Placebo (Double-blind Treatment Period) | Hydrocodone ER (Double-blind Treatment Period) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 211/623 (33.9%) | 41/179 (22.9%) | 58/191 (30.4%) | |||
| Gastrointestinal disorders | ||||||
| Constipation | 97/623 (15.6%) | 102 | 8/179 (4.5%) | 8 | 27/191 (14.1%) | 29 |
| Nausea | 98/623 (15.7%) | 101 | 14/179 (7.8%) | 16 | 20/191 (10.5%) | 23 |
| Vomiting | 39/623 (6.3%) | 39 | 6/179 (3.4%) | 6 | 8/191 (4.2%) | 8 |
| Infections and infestations | ||||||
| Upper respiratory tract infection | 3/623 (0.5%) | 3 | 9/179 (5%) | 9 | 8/191 (4.2%) | 9 |
| Nervous system disorders | ||||||
| Dizziness | 33/623 (5.3%) | 35 | 4/179 (2.2%) | 4 | 2/191 (1%) | 2 |
| Headache | 42/623 (6.7%) | 44 | 8/179 (4.5%) | 8 | 11/191 (5.8%) | 11 |
| Somnolence | 36/623 (5.8%) | 38 | 2/179 (1.1%) | 2 | 6/191 (3.1%) | 7 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.
Results Point of Contact
| Name/Title | Director, Clinical Research |
|---|---|
| Organization | Teva Branded Pharmaceutical Products, R&D Inc. |
| Phone | 215-591-3000 |
| ustevatrials@tevapharm.com |
- C33237/3103