Open-Label, Extension Study to Evaluate the Safety of Hydrocodone Bitartrate Extended-Release Tablets

A 6-Month, Open-Label, Extension Study to Evaluate the Safety of Hydrocodone Bitartrate Extended-Release Tablets (CEP-33237) at 15 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

This is a 6-month, nonrandomized, open-label extension study to assess the long-term safety of hydrocodone bitartrate extended-release (ER) tablets in patients with moderate to severe chronic low back pain who require continuous opioid treatment for an extended period of time.

To be eligible for Study 3104, patients were required to have completed the entire double blind treatment period on study drug (either placebo or hydrocodone bitartrate ER tablets) through week 12 of Study 3103 (NCT01789970) and to have met the entry criteria for Study 3104.

Study Overview

• Status: Completed
• Conditions: Low Back Pain
• Intervention / Treatment: Drug: Hydrocodone ER; Drug: Placebo

Detailed Description

Eligible patients from Study 3103 (NCT01789970) were enrolled for participation in this extension study. For these patients, the final study visit in Study 3103 was visit 1 for this study (also referred to as the titration or adjustment baseline visit, depending on whether the patient was enrolled under the original or amended protocol, respectively). The original protocol was amended after 26 patients had been enrolled in the study. Those who were enrolled under the original protocol participated in a double-blind titration period of up to approximately 4 weeks followed by an open-label treatment period of 22 weeks. Those patients who were enrolled under the amended protocol participated in an open-label adjustment period of up to approximately 3 weeks followed by an open-label treatment period of 22 weeks.

• Study Type: Interventional
• Enrollment (Actual): 182
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States
      • Teva Investigational Site 10412
    • Mobile, Alabama, United States
      • Teva Investigational Site 10426
    • Montgomery, Alabama, United States
      • Teva Investigational Site 10436
  • Arizona
    • Phoenix, Arizona, United States
      • Teva Investigational Site 10363
    • Phoenix, Arizona, United States
      • Teva Investigational Site 10366
    • Tucson, Arizona, United States
      • Teva Investigational Site 10437
  • California
    • Anaheim, California, United States
      • Teva Investigational Site 10358
    • Bell Gardens, California, United States
      • Teva Investigational Site 10408
    • Carmichael, California, United States
      • Teva Investigational Site 10425
    • Cerritos, California, United States
      • Teva Investigational Site 10390
    • El Cajon, California, United States
      • Teva Investigational Site 10429
    • Escondido, California, United States
      • Teva Investigational Site 10423
    • Huntington Park, California, United States
      • Teva Investigational Site 10391
    • Los Angeles, California, United States
      • Teva Investigational Site 10370
    • Sherman Oaks, California, United States
      • Teva Investigational Site 10392
    • Thousand Oaks, California, United States
      • Teva Investigational Site 10398
    • Torrance, California, United States
      • Teva Investigational Site 10428
    • Walnut Creek, California, United States
      • Teva Investigational Site 10361
  • Florida
    • DeLand, Florida, United States
      • Teva Investigational Site 10369
    • Fort Lauderdale, Florida, United States
      • Teva Investigational Site 10379
    • Jacksonville, Florida, United States
      • Teva Investigational Site 10365
    • Leesburg, Florida, United States
      • Teva Investigational Site 10445
    • Orlando, Florida, United States
      • Teva Investigational Site 10362
    • Ormond Beach, Florida, United States
      • Teva Investigational Site 10381
    • Plantation, Florida, United States
      • Teva Investigational Site 10357
    • Royal Palm Beach, Florida, United States
      • Teva Investigational Site 10435
  • Georgia
    • Columbus, Georgia, United States
      • Teva Investigational Site 10432
    • Marietta, Georgia, United States
      • Teva Investigational Site 10383
    • Marietta, Georgia, United States
      • Teva Investigational Site 10385
    • Newnan, Georgia, United States
      • Teva Investigational Site 10444
  • Idaho
    • Meridian, Idaho, United States
      • Teva Investigational Site 10431
    • Meridian, Idaho, United States
      • Teva Investigational Site 10743
  • Illinois
    • Chicago, Illinois, United States
      • Teva Investigational Site 10411
  • Indiana
    • Newburgh, Indiana, United States
      • Teva Investigational Site 10440
  • Louisiana
    • New Orleans, Louisiana, United States
      • Teva Investigational Site 10419
    • Shreveport, Louisiana, United States
      • Teva Investigational Site 10359
  • Massachusetts
    • Fall River, Massachusetts, United States
      • Teva Investigational Site 10389
  • Michigan
    • Bay City, Michigan, United States
      • Teva Investigational Site 10388
  • Mississippi
    • Biloxi, Mississippi, United States
      • Teva Investigational Site 10397
  • Missouri
    • Hazelwood, Missouri, United States
      • Teva Investigational Site 10406
    • Saint Louis, Missouri, United States
      • Teva Investigational Site 10401
  • Nebraska
    • Omaha, Nebraska, United States
      • Teva Investigational Site 10376
  • Nevada
    • Las Vegas, Nevada, United States
      • Teva Investigational Site 10399
  • New Jersey
    • Berlin, New Jersey, United States
      • Teva Investigational Site 10409
  • New York
    • Buffalo, New York, United States
      • Teva Investigational Site 10439
    • New York, New York, United States
      • Teva Investigational Site 10410
  • North Carolina
    • Winston-Salem, North Carolina, United States
      • Teva Investigational Site 10414
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • Teva Investigational Site 10446
  • Pennsylvania
    • Duncansville, Pennsylvania, United States
      • Teva Investigational Site 10430
    • Mechanicsburg, Pennsylvania, United States
      • Teva Investigational Site 10386
    • Tipton, Pennsylvania, United States
      • Teva Investigational Site 10373
  • Texas
    • Austin, Texas, United States
      • Teva Investigational Site 10405
    • Dallas, Texas, United States
      • Teva Investigational Site 10364
    • Dallas, Texas, United States
      • Teva Investigational Site 10372
    • Houston, Texas, United States
      • Teva Investigational Site 10371
    • Lake Jackson, Texas, United States
      • Teva Investigational Site 10377
    • Plano, Texas, United States
      • Teva Investigational Site 10374
    • San Antonio, Texas, United States
      • Teva Investigational Site 10378
  • Utah
    • Salt Lake City, Utah, United States
      • Teva Investigational Site 10402
  • Washington
    • Bellevue, Washington, United States
      • Teva Investigational Site 10420
    • Everett, Washington, United States
      • Teva Investigational Site 10433

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients must have participated in and completed the entire double-blind treatment period on study drug through the final study visit (week 12) of study 3103.

   NOTE: Patients who had a final on-treatment visit (i.e. prior to week 12) are not permitted to participate in study 3104.

2. The patient is able to speak English and is willing to provide written informed consent for study 3104, including re-signing a written opioid agreement, to participate in this study.
3. 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.
4. The patient must be willing and able to successfully self-administer the study drug, comply with study restrictions, and return to the study center for scheduled study visits, as specified in the protocol.
5. The patient must not participate in any other study involving an investigational agent (excluding those who participated in study 3103) while enrolled in the present study.

Exclusion Criteria:

1. The patient's current source of pain is different from the low back pain the patient was experiencing at entry into study 3103. NOTE: Any additional source of pain for a patient must be discussed with the medical monitor.
2. The patient has current evidence of alcohol or other substance abuse with the exception of nicotine or caffeine.
3. The patient has developed, during study 3103, a medical or psychiatric disease (including suicidality) that, in the opinion of the investigator, would compromise collected data.
4. The patient is expected to have surgery during the study.
5. The patient is pregnant or lactating.
6. The patient has developed an active malignancy (excluding basal cell carcinoma) during study 3103.
7. The patient has known human immunodeficiency virus (HIV).
8. In the judgment of the investigator, the patient has any clinically significant deviation from normal in the physical examination and/or clinical laboratory test values.
9. The patient has developed cardiopulmonary disease that would, in the opinion of the investigator, significantly increase the risk of treatment with opioids.

10. The patient is receiving a monoamine oxidase inhibitor (MAOI).

    • Other exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both versions of protocol 3104 followed the titration/adjustment period with a open-label treatment period of 22 weeks.

Drug: Hydrocodone ER; Participants were instructed to take hydrocodone ER tablets orally with a glass of water on an empty stomach at least 1 hour before or 2 hours after eating.; Other Names: CEP-33237; Hydrocodone bitartrate extended-release tablets; Drug: Placebo; During the double-blind titration period used in the original protocol, placebo tablets matching each dose of hydrocodone bitartrate ER tablets (active drug) were used to maintain the blind but not for purposes of comparison.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants With Adverse Events	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 the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)
Participants With Potentially Clinically Significant Abnormal Laboratory Values	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; Aspartate aminotransferase (AST): >=3* upper limit of normal (ULN); Alkaline phosphatase: >=3* upper limit of normal (ULN); Gamma-glutamyl transpeptidase (GGT): >=3* upper limit of normal (ULN); Serum white blood cells: >=20 * 10^9/L; Hemoglobin: M<=115, F<=95 g/dL; Hematocrit: M<0.37, F<0.32 L/L; Eosinophils: >=10.0 %; Platelets: <=75 * 10^9/L; Absolute neutrophils: <=1.0 * 10^9/L; Urinalysis: Glucose, Ketones, and Total Protein: >=2 unit increase from baseline	End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)
Participants With Potentially Clinically Significant Abnormal Vital Signs Values	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 of the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)
Participants With Shifts From Normal to Abnormal in Physical Examination Findings	The endpoint visit or early termination visit was an abbreviated exam. Endpoint refers to the last observation carried forward.	End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)
Shifts From Baseline to Endpoint (Treatment Period) in Electrocardiogram (ECG) Findings	A 12-lead ECG was conducted at the final visit for study 3103 which is used as baseline for this study, and at week 22 of the treatment period [or early termination]). A qualified physician at the study center was responsible for providing interpretation of the ECG. Endpoint refers to the last observation carried forward.	Baseline (final visit for study 3103), End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)
Participants With Clinically Significant (CS) Hearing Changes From Baseline to the Final Visit in Pure Tone Audiometry Test Results	Pure tone audiometry was performed by trained personnel. Hearing loss was classified in degrees of hearing from normal to profound. This classification was determined by the hearing threshold (or the softest sound detected at a specific frequency). The exact ranges that classified hearing loss depended on the exact technique used during testing and on the patient's age. These values were provided by each audiology laboratory that performed the test. For serial audiograms, the criteria for a clinically significant hearing change were based on guidance from the American Speech Language Hearing Association (ASHA 1994, cited in [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.	Baseline was within two weeks of the final study visit in study 3103; during study exam was within two weeks of the end of trial visit for study 3104 (up to study week 26)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Weeks 2, 6, 10, 14, 18, 22 and Endpoint of the Treatment Period in Daily Worst Pain Intensity (WPI) Scores During the Previous 24 Hours for Each Visit	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. At each visit, participants selected the number that best described their worst pain intensity over the last 24 hours. Negative change from baseline scores indicate improvement in pain control. Endpoint refers to the last observation carried forward.	Baseline (Day 0 of Treatment Period), Weeks 2, 6, 10, 14, 18, 22 and Endpoint during the Open-Label Treatment Period
Change From Baseline to Weeks 2, 6, 10, 14, 18, 22 and Endpoint of the Treatment Period in Daily Average Pain Intensity (API) Scores During the Previous 24 Hours for Each Visit	The API 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 average pain intensity over the last 24 hours. Negative change from baseline scores indicate improvement in pain control. Endpoint refers to the last observation carried forward.	Baseline (Day 0 of Treatment Period), Weeks 2, 6, 10, 14, 18, 22 and Endpoint during the Open-Label Treatment Period
Percentage of Participants Withdrawn From the Study For Lack of Efficacy	Percentage of patients who withdrew from the study for lack of efficacy, as indicated on the early termination form of the case report form (CRF).	Day 1 of the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)

Collaborators and Investigators

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: August 12, 2013
• First Submitted That Met QC Criteria: August 12, 2013
• First Posted (Estimate): August 14, 2013

Study Record Updates

• Last Update Posted (Actual): November 9, 2021
• Last Update Submitted That Met QC Criteria: November 6, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: low back pain; hydrocodone bitartrate; opioids
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Back Pain; Low Back Pain; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Respiratory System Agents; Antitussive Agents; Hydrocodone
• Other Study ID Numbers: C33237/3104

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No