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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

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: 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. 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. 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. 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. 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: 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. The patient has current evidence of alcohol or other substance abuse with the exception of nicotine or caffeine. 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. The patient is expected to have surgery during the study. The patient is pregnant or lactating. The patient has developed an active malignancy (excluding basal cell carcinoma) during study 3103. The patient has known human immunodeficiency virus (HIV). 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. The patient has developed cardiopulmonary disease that would, in the opinion of the investigator, significantly increase the risk of treatment with opioids. The patient is receiving a monoamine oxidase inhibitor (MAOI). Other exclusion 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| 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. 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<br>* 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.<br>* Other names: Hydrocodone bitartrate extended-release tablets;Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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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) | 

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