Long-term Safety of Once-daily Hydrocodone Bitartrate (HYD) Tablets For Moderate to Severe Chronic Nonmalignant and Nonneuropathic Pain. Includes a 24-week Extension Period.

Study Overview
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Brief Summary
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The primary objective of this study is to characterize the long-term safety of Hydrocodone Bitartrate (HYD) tablets 20 to 120 mg once-daily in subjects with chronic nonmalignant and nonneuropathic pain.

Official Title
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An Open-label, Multicenter Study to Assess the Long -Term Safety of Hydrocodone Bitartrate (HYD) Tablets 20 to 120 mg Once-daily in Subjects With Moderate to Severe Chronic Nonmalignant and Nonneuropathic Pain

Conditions
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Chronic Nonmalignant and Nonneuropathic Pain

Intervention / Treatment
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* Drug: Hydrocodone bitartrate q24h film-coated tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria include: Male and female subjects ≥ 18 years of age with moderate to severe, chronic nonmalignant and nonneuropathic pain (lasting several hours daily) as their predominant pain condition for at least 3 months prior to the screening visit; Subjects deemed by the investigator/medically qualified designee (must be MD or DO) to be appropriate candidates for the protocol specified, around the clock HYD therapeutic regimen; Female subjects who are premenopausal or postmenopausal less than 1 year and who have not had surgical sterilization (ie, tubal ligation, partial or complete hysterectomy) must have a negative serum pregnancy test, be nonlactating, and willing to use adequate and reliable contraception throughout the study (eg, barrier with additional spermicidal foam or jelly, intra-uterine device, hormonal contraception); Subjects who are willing and able to be compliant with the protocol, are capable of subjective evaluation (ie pain scores), are able to read and understand questionnaires, are willing and able to use an electronic diary, and are able to read, understand, and sign the written informed consent form in English. Exclusion Criteria include: Subjects taking opioid analgesic(s) equivalent to > 120 mg/day of oxycodone during the 14 days prior to the screening visit; Subjects who previously participated in an investigational hydrocodone study within 90 days prior to the first dose of study medication ; Subjects who have used any investigational medication other than hydrocodone within 30 days prior to the first dose of study drug; Subjects with any history of seizures (subjects with history of pediatric febrile seizures may participate in the study) or increase in intracranial pressure; Subjects with current uncontrolled depression or other uncontrolled psychiatric disorder (subjects with controlled depression or other psychiatric disorder must be on a stable medication for ≥ 1 month prior to the screening visit to participate in the study); Subjects with a history of alcohol, medication, or illicit drug abuse or addiction and/or history of opioid abuse or addiction at any time; Subjects with clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling pacemaker; Subjects with unstable respiratory disease that, in the opinion of the investigator, precludes entry into this study; Subjects with biliary tract disease, hypothyroidism, adrenal cortical insufficiency, or any other medical condition that, in the opinion of the investigator, is inadequately treated and precludes entry into the study; Subjects with history of malignancy within past 2 years, with exception of basal cell carcinoma that has been successfully treated; Subjects with evidence of impaired liver function upon entry into the study (laboratory test values ≥ 3 times the upper limit of the laboratory reference (normal) range (ULN) for aspartate transaminase [AST/SGOT] or alanine transaminase [ALT/SGPT], or values > 2 times the ULN for alkaline phosphatase), or total bilirubin level > 1.5 times the ULN or, in the opinion of the investigator/medically qualified designee (must be MD or DO), liver function impairment to the extent that the subject should not participate in this study; Subjects with evidence of impaired kidney function upon entry into the study (ie, serum creatinine ≥ 2.5 mg/dL); Subjects with any condition in which opioids are contraindicated, eg, severe respiratory depression with hypoxia and/or hypercapnia, severe chronic obstructive lung disease, cor pulmonale, severe bronchial asthma, or paralytic ileus; Subjects who are allergic to hydrocodone or who have a history of allergies to other opioids. This does not include subjects who have experienced common opioid side effects (eg, nausea, constipation); Subjects receiving monoamine oxidase inhibitors (MAOIs) or who have been taking MAOIs within 2 weeks of the screening visit. Other protocol-specific inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 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 bitartrate<br>Hydrocodone bitartrate (HYD) once daily (q24h) tablets | Drug: Hydrocodone bitartrate q24h film-coated tablets<br>* Hydrocodone bitartrate q24h film-coated tablets 20 - 120 mg once daily<br>* Other names: Hysingla ER;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants With Adverse Events as a Measure of Safety | Safety assessments included AEs, clinical laboratory test results, vital sign measurements, ECG findings, and audiology assessments. | Up to 84 weeks | 
| Daily Average Pain Over the Last 24 Hours | Average pain over the last 24 hours score (on an 11-point numerical rating scale where 0 = no pain and 10 = pain as bad as you can imagine). | Core study: from start to end of maintenance period (up to 52 weeks); Extension study: from start of maintenance to end of extension (up to 76 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain Right Now Score | Pain right now scores were collected using an 11-point scale where 0 = no pain and 10 = pain as bad as you can imagine. The pain right now scores were only collected during the Core Study. Pain right now scores were not assessed during the Extension Period. | Week 12 | 
| Medical Outcomes Study (MOS) Sleep Scale - Revised (MOS Sleep-R) | The MOS Sleep-R is a brief, self-administered 12-item assessment designed to measure key aspects of sleep. It includes a sleep problems index II and 6 subscale scores - sleep disturbance, sleep adequacy, daytime somnolence, snoring, awaken short of breath or with headache, and quantity of sleep. For each individual and time of assessment, quantity of sleep was recorded as the number of hours slept per night. The number of hours it took the subject to fall asleep per night was categorized 1, 2, 3, 4, or 5 corresponding to 0 through 15, 16 through 30, 31 through 45, 46 through 60, or more than 60 minutes, respectively. The other scales were recorded as 1 = all of the time, 2 = most of the time, 3 = some of the time, 4 = a little of the time, or 5 = none of the time. A higher value indicates a better score, therefore a positive change from baseline indicates a better sleep pattern and a negative change from baseline indicates a worsening in sleep pattern. | Baseline and up to 52 weeks in the Core Study maintenance period, and up to 24 weeks in the Extension Period | 
| Brief Pain Inventory Short Form (BPI-SF) | The BPI-SF assessed the severity of pain and interference of pain on daily functions. It consists of 9 sections denoted by Q1 to Q8 and Q9A to Q9G according to their order in the questionnaire, that measure pain location, intensity, pain treatment, and functional interference of pain on mood and every day activities. Scores ranged from 0 (none) to 10 (worst as can be). Four of the items (questions 3 to 6) assess severity of pain and 7 items (questions 9A to 9G) assess interference of pain. The pain interference subscale score was determined by calculating the mean of responses to Q9A - Q9G [Q9A (general activity), Q9B (mood),Q9C (walking), Q9D (working), Q9E (relations with others), Q9F (sleep), and Q9G (enjoyment of life)] and the severity of pain subscale score was determined by calculating the mean of responses to Q3 - Q6 [Q3 (worst pain in last 24 hours), Q4 (least pain in last 24 hours), Q5 (average pain), and Q6 (pain right now)]. A lower score indicates lower pain. | Up to 52 weeks in the Core Study maintenance period, and up to 24 weeks in the Extension Period | 
| Medical Outcomes Study 36-item Short Form (SF-36) | The SF-36 is a generic health survey with 36 items that measure functional health and well-being from the subject's perspective. The 36 questions are grouped into 11 sections. Some of the sections consist of multiple questions. The survey is summarized into 8 dimensions/scales: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. From the 8 health dimensions, physical component summary, and mental component summary measures are derived. Scores on each scale ranged from 0 to 100; a higher score indicates a better perception of health. | Up to 52 weeks in the Core Study maintenance period, and up to 24 weeks in the Extension Period | 
| Patient Global Impression of Change (PGIC) | The PGIC is an ordinal scale of global evaluation that assesses the change in overall status relative to the start of the study. The scale has only 1 item that measures global change of overall status (improvement or worsening) by the subject on a 7-point scale (Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. | At Week 52 in the Core Study maintenance period and at Week 24 in the Extension Period | 
| Treatment Satisfaction Questionnaire (TSQ) - Part I | The TSQ is a self-administered questionnaire that consists of 2 parts. Part I has 6 questions (Q1 to Q6) that ask the subject to rate the experience with use of the study drug in comparison to the prestudy pain medication regarding ease of use, convenience, frequency, pain control, and overall satisfaction. Each question was rated on a scale from 1 (extremely satisfied) to 6 (extremely dissatisfied): Q1=Satisfaction with study drug; Q2=Ease of study drug use to treat pain; Q3=Convenience of study drug to treat pain; Q4=Overall drug satisfaction managing pain; Q5=Satisfaction with frequency of use; Q6=Ease of planning study drug use. The number of subjects with each category (1-6) of response for each individual question (Q1-Q6) was summarized for subjects who entered the core study maintenance period and responded to each question. TSQ - Part I was not administered in the extension period. | At Week 52 or upon early discontinuation at or before Week 4 in the Core Study maintenance period | 
| Treatment Satisfaction Questionnaire (TSQ) - Part II | The TSQ is a self-administered questionnaire that consists of 2 parts. Part II has 2 questions that measure the subject's willingness to continue the use of study drug as pain medication (Q1), and to recommend the study drug to someone else (Q2). Question 1 consists of 6 categories of response rated on a scale from 1 (very willing to continue) to 6 (very unwilling to continue): 1=Very willing to continue; 2=Willing to continue; 3=Somewhat willing to continue; 4=Somewhat unwilling to continue; 5=Unwilling to continue; 6=Very unwilling to continue. Question 2 consists of 3 categories of response: 1=yes; 2=no; 3=undecided. The number of subjects with each category of response for each individual question was summarized for subjects completing the core study maintenance period and for those enrolled in the extension period. | At Week 52 or upon early discontinuation at or before Week 4 in maintenance and at Week 24 in extension | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pain, Nonmalignant pain, Nonneuropathic Pain, Opioid