Acetaminophen Tablets (MNK-155): A Phase III, Multicenter, Open-Label Study in Patients With Osteoarthritis or Chronic Low Back Pain

Clinical Therapeutics/Volume ], Number ], 2015

Tolerability of Biphasic-Release Hydrocodone Bitartrate/ Acetaminophen Tablets (MNK-155): A Phase III, Multicenter, Open-Label Study in Patients With Osteoarthritis or Chronic Low Back Pain Yanping Zheng, MD; Kenneth Kostenbader, MD; Thomas Barrett, PhD; Elizabeth Hisaw, BA; Michael J. Giuliani, MD; Yin Chen, MS; and Jim L. Young, PhD Mallinckrodt Pharmaceuticals, Hazelwood, Missouri ABSTRACT Purpose: This study aimed to assess the tolerability of the extended use (r35 days) of MNK-155, a biphasic (immediate-release/extended-release) hydrocodone bitartrate/N-acetyl-p-aminophenol (acetaminophen) (IR/ER HB/APAP) 7.5/325-mg fixed-dose combination analgesic agent, in patients with chronic noncancer pain (CNCP) caused by osteoarthritis or chronic low back pain. IR/ER HB/APAP tablets deliver 25% of the HB dose and 50% of the APAP dose by IR and the remainder by ER over a 12-hour dosing interval. Although IR/ER HB/APAP is being developed for the management of moderate to severe acute pain, this model of CNCP was used for assessing tolerability over a term longer than would be possible in a model of acute pain. Methods: This Phase III, multicenter, open-label study enrolled patients with moderate to severe OA (knee or hip) pain despite the use of nonopioid or opioid analgesic agents, or with moderate to severe CLBP present for several hours per day for Z3 months. Patients received a 3-tablet initial dose of IR/ER HB/ APAP (total dose, 22.5/975 mg) on day 1, followed by 2 tablets of IR/ER HB/APAP (total dose, 15/650 mg) q12h for up to 35 days. Tolerability, the primary end point, was assessed using time to treatment discontinuation, the prevalence of treatment-emergent adverse events (TEAEs), vital sign measurements, pulse oximetry, clinical laboratory tests, and compliance. Secondary outcomes included the modified Brief Pain Inventory–Short Form, the Western Ontario and McMaster Universities Arthritis Index, and The Roland-Morris Low Back Pain and Disability Questionnaire. Findings: Of the 153 patients enrolled (95 women [62.1%]; mean age, 53.9 [14.5] years; OA, n ¼ 73;

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CLBP, n ¼ 80), 37 (24.2%) discontinued the study early (mean time to discontinuation, 21.3 days). Thirteen patients (8.5%) discontinued because of TEAEs. A total of 88 patients (57.5%) reported Z1 TEAE, 65 (42.5%) of whom experienced AEs considered by the investigator as treatment related. The most frequent TEAEs were nausea (16.3%), somnolence (14.4%), and constipation (11.1%). Eight severe TEAEs were experienced by 6 (3.9%) patients and included single occurrences of nausea, fatigue, nasopharyngitis, elevated liver enzymes, headache, nightmare, and ejaculation delay. No serious treatment-related AEs were reported. Clinically significant changes in laboratory values were reported in 13 patients, 6 of whom had abnormal liver function test results that did not meet Hy’s law criteria for acute liver failure. Most laboratory abnormalities were mild and transient. Measures of pain intensity, function, and quality of life improved from baseline but in an open-label study these changes cannot be attributed to treatment. Implications: The safety profile of IR/ER HB/APAP during extended use was consistent with those of other low-dose opioid/APAP combination products. IR/ER HB/APAP is intended for acute pain; its efficacy for relief of CNCP would require further evaluation in an active- or placebo-controlled study. ClinicalTrials. gov Identifier: NCT01722864. (Clin Ther. 2015;]:]]]– ]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved.

Accepted for publication March 18, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.03.019 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics Key words: acetaminophen, chronic low back pain, extended-release, hydrocodone, immediate-release, osteoarthritis.

INTRODUCTION Fixed-dose combination (FDC) opioid analgesic agents provide a multimodal approach to pain relief by combining analgesic agents with complementary mechanisms of action that lack adverse interactions.1 The most commonly prescribed drug in the United States is the FDC analgesic agent immediate-release hydrocodone bitartrate/N-acetyl-p-aminophenol (acetaminophen) (IR HB/APAP).2 Hydrocodone is a centrally acting agent, exerting analgesic effects through agonism at the m- and κ-opioid receptors.3 The precise analgesic mechanism of APAP is not known, but APAP is believed to provide peripheral analgesia at the site of pain.4 It has long been proposed that FDCs incorporating different mechanisms of action and/or targeting different sites may provide synergistic analgesia without a synergistic increase in adverse events (AEs) if the component drugs are administered at the same dose, or similar analgesia with fewer AEs if the component drugs are administered at doses lower than would be administered in monotherapy.1,5,6 Consistent with this proposition, the American Society of Anesthesiologists’ guideline on managing acute perioperative pain7 and the World Health Organization’s guideline on managing cancer-related pain8 each recommend the use of an opioid agent combined with a nonopioid agent over an opioid agent alone. FDC analgesic agents continue to be developed with the aim of achieving an additive analgesic effect at a low dose of each pharmaceutical component to minimize doserelated AEs.1 Acute pain is typically treated with IR opioid analgesic agents because they offer a rapid onset of pain relief,9 whereas extended-release (ER) opioid agents offer less-frequent dosing, sustained analgesia, fewer peaks and troughs in plasma concentration, and less disruption of sleep.10 Few studies have examined the use of ER opioid analgesic agents for the management of acute postoperative pain; generally, their slow onset of effect has either required preoperative administration11 or caused patients to endure hours of pain before experiencing meaningful relief.12 To provide rapid onset and sustained

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analgesia in patients with acute pain, a biphasicrelease mechanism has been developed with IR and ER characteristics. IR/ER HB/APAP 7.5/325 mg (MNK-155) is a biphasic tablet designed with an IR layer that releases HB 1.875 mg and APAP 162.5 mg for a rapid onset of effect and an ER layer* that releases HB 5.625 mg and APAP 162.5 mg over 12 hours for prolonged analgesia.13 The IR/ER HB/APAP 7.5/325-mg tablet formulation, administered as a 3-tablet (22.5/975-mg) initial dose followed by 2-tablet (15/650-mg) doses q12h, has been reported to have efficacy and tolerability in patients after unilateral bunionectomy, an established model of acute pain.14 Although IR/ER HB/APAP is being developed for the management of moderate to severe acute pain, the assessment of tolerability with prolonged use could not be studied in a model of acute pain. To address this knowledge gap, a model of chronic, non–cancerrelated pain (CNCP) (osteoarthritis [OA] or chronic low back pain [CLBP]) was used for assessing the tolerability of IR/ER HB/APAP administered for up to 35 days.

PATIENTS AND METHODS Study Design This Phase III, open-label study was conducted at 35 US clinical practice facilities (ie, office, clinic, and hospital practices of 35 clinician investigators). The study design included a 2-week screening period (including washout) and a 35-day treatment period (Figure 1). The study protocol was approved by an independent institutional review board (Schulman Associates IRB, Inc, Cincinnati, Ohio). The study was conducted in accordance with the principles of ethical conduct set forth in the Declaration of Helsinki regulations. All patients provided written informed consent before participating.

Study Population Inclusion Criteria

Eligible patients were aged Z18 years and had chronic pain associated with a diagnosis of OA of the knee or hip, or CLBP. To identify patients eligible for screening, investigators reviewed patients’ medical histories to confirm that signs and symptoms of OA or CLBP were present for a sufficient period of time Trademark: Acuforms (Depomed, Inc., Newark, California).

*

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Y. Zheng et al.

Telephone Call – Follow-up

Telephone Call

Observation for 4 h postdose

WASHOUT

SCREENING

All Patients Initial Dose: 3 tablets (visit 2 only). Maintenance Dose: 2 tablets q12h

Initial Dose: 3 tablets

( ) Maintenance Dose (2 tablets) at least 2h before clinic visit Clinic Visits Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Days –14 to –3 Day 1 Day 4 Day 8 Day 15 Day 22 Day 29 Day 36 Day 43 End of Treatment Visit 3 and Visits 4 through 8 are ±1day; Visit 9 is ±2 days or Early Termination

Figure 1. Study design.

and with sufficient severity. Eligible patients with OA had been diagnosed Z1 year previously and had experienced moderate to severe daily pain despite long-term use of an NSAID, other nonopioid medication, or therapy that included an opioid agent. Eligible patients with CLBP had experienced moderate to severe pain for at least several hours per day for Z90 days. Patients whose CLBP was related to neuropathy, malignancy, or back surgery were excluded. Diagnoses were confirmed by investigators at the screening visit using the American College of Rheumatology’s criteria for OA of the knee15 or hip16 or the Quebec Task Force’s criteria for spinal disorders.17 Patients eligible for enrollment reported an average pain score (average of current, best, and worst pain experienced over the past 24 hours) of Z3 (moderate) on a 10-point numeric pain rating scale for the 24 hours before screening, and a mean pain-intensity score of Z4 (moderate) for 24 hours before baseline.

Exclusion Criteria Patients with any condition or illness that might have, in the opinion of investigators, interfered with the assessment of pain associated with OA or CLBP, precluded study participation, or increased the risk for opioid-related or NSAID-related AEs were excluded from the study. Conditions that might have confounded pain assessment included any chronic pain condition

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other than OA or CLBP; nerve or plexus block within the 30 days before screening, or botulinum toxin within the 90 days before screening; injection in the OA study joint within the 30 days before screening; surgery on the primary OA joint or for CLBP in the 6 months before screening; and surgical implants in the OA study joint. Conditions that might have precluded study participation or an increase in opioid- or NSAID-related AEs included any uncontrolled/poorly controlled major psychiatric illness, a history of seizure disorders, current or recent (r2 years preceding) history of substance or alcohol abuse, active or recent (r2 years preceding) history of malignancy, and clinically significant ECG abnormalities or uncontrolled hypo- or hypertension. Patients were excluded if they had received a monoamine oxidase inhibitor, antipsychotic agent, or a benzodiazepine within the 14 days before screening, or if they had started treatment with, or had a change in the dosage of, an anticonvulsant agent, selective serotonin reuptake inhibitor, serotonin– norepinephrine reuptake inhibitor, or tricyclic antidepressant within the 30 days before screening. Patients were also excluded if they had liver enzyme abnormalities 42 times the upper limit of normal (ULN); a creatinine level 41.5  ULN; a history (≤2 years preceding) or current evidence of drug or alcohol abuse; or a screening positive for HIV, hepatitis B virus, or hepatitis C virus. Patients with a

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Clinical Therapeutics history of gastric reduction or gastric band surgery were excluded because the ER properties of the IR/ER HB/APAP tablet are achieved using a gastroretentive compound; hence, patients who had undergone a procedure that modifies gastrointestinal transit might have had an atypical treatment experience and would best have been evaluated separately.

Intervention Before treatment, patients taking NSAIDs, 481 mg aspirin daily (for pain management), products containing APAP, and/or opioid agents (r20 mg HB or r40 mg morphine sulfate metabolic equivalents per day) at screening were required to undergo a minimum 3-day washout period before baseline and then were prohibited from taking these medications for the duration of the study. IR/ER HB/APAP was dispensed in high-density polyethylene bottles containing 36 tablets. On day 1 of treatment, patients were instructed to take an initial dose of 3 tablets of IR/ER HB/APAP 7.5/325 mg (total dose, 22.5/975 mg) followed by 2 tablets (total dose, 15/650 mg) 12 hours later. Doses were taken at home, between study visits; therefore, ingestion was not witnessed by investigators or site staff. This initial dose is a part of the planned commercial dosage of IR/ER HB/APAP. Thereafter, patients took 2 tablets of IR/ER HB/APAP 7.5/325 mg q12h for up to 35 days. The use of rescue ibuprofen 400 mg (two 200-mg tablets) up to 4 times daily for the management of breakthrough pain was permitted (total daily dose permitted, 1600 mg). No other rescue medication was allowed.

Assessments Tolerability The primary end point was tolerability, assessed at the screening visit (days 14 to 3); on days 1, 8, 15, 22, and 29; and at the end of treatment (day 36) or early termination. Tolerability outcomes included time to treatment discontinuation; the prevalences of treatmentemergent AEs (TEAEs; assessed at each visit), including TEAEs potentially related to abuse, withdrawal, or overdose; vital sign measurements and pulse oximetry (assessed at each visit); clinical laboratory test results, including chemistry and hematology (assessed at the screening and end-of-treatment [day 36] visits); and liver function test results (LFTs; assessed at baseline and on days 8, 15, 22, and 29). Although AE data were solicited at each visit, patients were encouraged to report AEs at any time during treatment.

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Treatment compliance was added as an additional tolerability outcome because of its potential to identify misuse or diversion. Site personnel monitored compliance by counting unused tablets at each visit (Compliance ¼ [Number of tablets taken]/[Number of tablets expected to have been taken per protocol]  100%). Patients were informed that incidents such as loss or theft of the study drug could lead to discontinuation. The medical monitor evaluated compliance issues and decided whether the participant should have been allowed to continue participation in the study.

Secondary Outcome Measures Secondary outcomes included measures of pain intensity, pain relief, and quality of life. Pain intensity was assessed using the pain-intensity items (questions 1–4) on the modified Brief Pain Inventory–Short Form (mBPI-sf) questionnaire (administered at screening; on days 1, 4, 8, 15, 22, and 29; and at end of treatment or early termination). The mBPI-sf questionnaire uses a numeric rating scale from 0 (no pain) to 10 (pain as severe as imaginable). Pain relief was assessed using the pain-relief item (question 5) on the mBPI-sf, which is scored from 0% (no relief) to 100% (complete relief). Pain-related quality of life was assessed using the paininterference subscale on the mBPI-sf (assessed at screening; on days 1, 4, 8, 15, 22, and 29; and at the end of treatment or early termination). The mBPI-sf pain-interference subscale score was calculated as the mean scores on the 7 pain-interference items (general activity, mood, walking ability, normal work, relations with others, sleep, and enjoyment of life), scored from 0 (does not interfere) to 10 (completely interferes). Finally, disease-specific quality of life was assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire18 (48-hour version) in patients with OA or The Roland-Morris Low Back Pain (LBP) and Disability Questionnaire19 in patients with CLBP. Both assessments were administered on days 1, 8, 15, 22, and 29 and at the end of treatment or early termination. The WOMAC assesses 3 dimensions (pain [maximal score, 20], stiffness [8], and physical function [68]) using 24 items. Each item is rated 0 to 4 (0 ¼ none; 1 ¼ slight; 2 ¼ moderate; 3 ¼ severe; and 4 ¼ extreme). The total score is the sum of the pain, stiffness, and physical function scores (maximal score, 96). On The Roland-Morris LBP and Disability Questionnaire, patients were asked to mark which of the 24 statements applied to them. Each item is a negative statement about disease

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Y. Zheng et al. impact (eg, “I get dressed more slowly than usual because of my back”; or “My appetite is not very good because of my back pain”). Higher scores on the 24-point scale suggest greater levels of disability.

Statistical Analysis Because this was an observational, open-label safety study, no sample size determination was performed. Tolerability results are presented using summary statistics. AEs were classified using the preferred terms as defined in the Medical Dictionary for Regulatory Activities (MedDRA) version 14.1. AEs were stratified by pain etiology and classified on the basis of severity and relationship to study drug. Compliance data are presented using descriptive statistics, as follows: patients considered compliant took between 80% and 120% of prescribed tablets; patients taking o80% or 4120% of prescribed tablets were deemed noncompliant. No formal statistical analyses of tolerability outcomes were performed, as is typically the case in tolerability studies. Summary statistics for actual values and changes from baseline were provided for the mBPI-sf, the WOMAC questionnaire, and The Roland-Morris LBP and Disability Questionnaire on days 1 (baseline), 8, 15, 22, 29, and 36 (end of treatment). Baseline was defined as the time of measurement of the last nonmissing value before the first dose was taken on day 1. For secondary outcome measures, there was no data imputation for missing data, except for WOMAC scores. If the response to 1 WOMAC pain question was missing, the mean score of the other 4 questions was used for the missing response; if the response to 41 question was missing, the pain score was considered as missing. If the response to either stiffness question was missing, the stiffness score was considered as missing. If the responses to r3 physical limitations questions were missing, the mean score of the remaining questions was used for the missing responses; if the responses to 43 questions were missing, then the physical limitations score was considered as missing. If any of the 3 component scores was missing, then the total score was considered as missing.

RESULTS Patient Disposition and Characteristics The baseline demographic and clinical characteristics of the total population and by pain etiology are presented in Table I. The majority of patients were

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female (62.1%) and white (71.2%). There were 73 patients with OA and 80 with CLBP. Compared with patients with CLBP, patients with OA tended to be older (mean age, 58.0 vs 50.1 years), more likely to use Z1 concurrent medication (78.1% vs 63.8%), and more likely to have undergone Z1 surgery (82.2% vs 50.0%). Otherwise, the demographic characteristics were generally similar between the OA and CLBP subpopulations. Although patients taking prohibited medications were not to be enrolled, it was found during the study that protocol-prohibited medications, including NSAIDs, APAP-containing products, and opioid agents, were taken by o10% of patients. A single patient with OA received a systemic corticosteroid that was also prohibited by the protocol. However, none of these events was considered serious enough by the investigators to withdraw these patients from the study. One patient was considered to have had a major protocol deviation—an NSAID injection (ketorolac 60 mg) a prohibited medication, between Visits 6 and 7 for reported worsening of right hand pain. However, because this was a single event, the investigators decided to let this patient continue in the study. The patients’ disposition is summarized in Figure 2. The rates of discontinuation were o30% in both the OA and CLBP subpopulations (28.8% and 20.0%, respectively). Discontinuations due to AEs were more common in the OA subgroup compared with the CLBP subgroup (13.7% vs 3.8%). The most common reasons for treatment discontinuation were AEs in the subgroup with OA and protocol violations in the subgroup with CLBP.

Tolerability The mean (SD) duration of treatment exposure was 31.9 (10.1) days, ranging from 1 to 38 days in the subgroup with OA and 1 to 49 days in the CLBP subgroup (Table II). The mean (SD) number of tablets taken was 124.5 (38.5), with ranges of 3 to 151 and 5 to 164 in the OA and CLBP groups, respectively. The mean duration of exposure and number of tablets taken were slightly greater in the CLBP subpopulation. In total, 37 patients (24.2%) discontinued treatment: 21 (28.8%) with OA and 16 (20%) with CLBP (Table II). The mean (SD) time to discontinuation was 21.3 (12.9) days; this duration was slightly longer in the group with CLBP.

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Clinical Therapeutics

Table I. Baseline demographic and clinical characteristics, by pain etiology. Characteristic Mean (SD) age, y Sex, no. (%) Female Male Race, no. (%) White Black Asian Other Ethnicity, n (%) Hispanic Non-Hispanic BMI, mean (SD), kg/m2

Osteoarthritis (n ¼ 73)

Chronic Low Back Pain (n ¼ 80)

All Patients (N ¼ 153)

58.0 (11.9)

50.1 (15.6)

53.9 (14.5)

50 (68.5) 23 (31.5)

45 (56.3) 35 (43.8)

95 (62.1) 58 (37.9)

47 (64.4) 23 (31.5) 3 (4.1) 0

62 14 2 2

8 (11.0) 65 (89.0) 35.0 (8.3)

(77.5) (17.5) (2.5) (2.5)

109 37 5 2

24 (30.0) 56 (70.0) 31.4 (7.1)

(71.2) (24.2) (3.3) (1.3)

32 (20.9) 121 (79.1) 33.1 (7.9)

BMI ¼ body mass index.

Screening

Assessed for eligibility (N=255)

Enrollment CLBP (n=80) Received intervention (n=80)

OA (n=73) Received intervention (n=73)

Completed the study (n=64 [80.0%]) Discontinued (n=16 [20.0%])

Completed the study (n=52 [71.2%]) Discontinued (n=21 [28.8%])

Follow-Up

Protocol violation (n=4 [5.0%]) AE (n=3 [3.8%]) Lost to follow-up (n=2 [2.5%]) Withdrew (n=2 [2.5%]) Study termination (n=2 [2.5%]) Other (n=3 [3.8%])

AE (n=10 [13.7%]) Protocol violation (n=3 [4.1%]) Lack of efficacy (n=1 [1.4%]) Lost to follow-up (n=1 [1.4%]) Study termination (n=1 [1.4%]) Other (n=5 [6.8%])

Analysis Analyzed, n=80

Analyzed, n=73

Figure 2. Patient disposition. AE ¼ adverse event; CLBP ¼ chronic low back pain; OA ¼ osteoarthritis.

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Table II. Study medication exposure and time to discontinuation, by pain etiology. Parameter Duration of exposure, d Mean (SD) Range Tablets taken* Mean (SD), n Range Discontinued, no. (%) Time to discontinuation, d Mean (SD) Range *

Osteoarthritis (n ¼ 73)

Chronic Low Back Pain (n ¼ 80)

All Patients (N ¼ 153)

30.5 (11.4) 1–38

33.2 (8.7) 1–49

31.9 (10.1) 1–49

118.5 (44.2) 3–151 21 (28.8)

130.1 (31.8) 5–164 16 (20.0)

124.55 (38.5) 3–164 37 (24.2)

19.6 (13.6) 2–40

23.5 (12.0) 6–51

21.3 (12.9) 2–51

One patient in the chronic low back pain group was lost to follow-up.

A total of 57.5% of patients reported Z1 TEAE (Table III), and AEs were deemed treatment related in 42.5% of patients. The most frequent TEAEs were those expected with IR low-dose opioid/APAP

combinations and included nausea (16.3%), somnolence (14.4%), and constipation (11.1%). Most of the TEAEs were mild or moderate in severity. Eight severe TEAEs were experienced by 6 (3.9%)

Table III. Tolerability, by pain etiology. Data are given as number (%) of patients.* Outcome Patients reporting Z1 TEAE Any Severe Treatment-related Serious† Discontinued treatment due to a TEAE Most frequent‡ TEAEs Nausea Somnolence Constipation Headache Vomiting Dizziness

Osteoarthritis (n ¼ 73)

Chronic Low Back Pain (n ¼ 80)

All Patients (N ¼ 153)

(64.4) (6.8) (54.8) (1.4) (13.7)

41 (51.3) 1 (1.3) 25 (31.3) 0 3 (3.8)

88 (57.5) 6 (3.9) 65 (42.5) 1 (0.7) 13 (8.5)

15 (20.5) 11 (15.1) 10 (13.7) 4 (5.5) 11 (15.1) 7 (9.6)

10 (12.5) 11 (13.8) 7 (8.8) 8 (10.0) 0 3 (3.8)

25 (16.3) 22 (14.4) 17 (11.1) 12 (7.8) 11 (7.2) 10 (6.5)

47 5 40 1 10

AE ¼ adverse event; TEAE ¼ treatment-emergent adverse event. * No deaths were reported. † A 40-year-old woman with osteoarthritis in her knee developed serious hypokalemia that was considered unrelated to study drug. ‡ Reported in Z5% of patients.

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Clinical Therapeutics patients and included single occurrences of nausea, fatigue, nasopharyngitis, elevated alanine aminotransferase (ALT), elevated aspartate aminotransferase (AST), headache, nightmare, and ejaculation delay. No serious treatment-related AEs were reported. A 40-year-old woman with OA of the knee developed serious hypokalemia that required hospitalization but was not considered related to treatment. Treatment-emergent, treatment-related, and severe AEs and most of the individual AEs were more prevalent in patients with OA. Gastrointestinal TEAEs and dizziness were more common in patients with OA. Only headache was substantially more frequent in the CLBP group. Discontinuation due to TEAEs was more frequent in patients with OA. Eight patients experienced events listed in the standardized MedDRA query for drug abuse, dependence, and withdrawal (version 15.1), including positive subjective effects (euphoria, feelings of relaxation), disturbances of attention, irritability, feeling abnormal, and agitation. All of these events were mild or moderate in intensity; 3 patients had ongoing events at the end of the study (mild irritability, n ¼ 2; mild disturbance in attention, n ¼ 1). There was no evidence that these 8 patients took too much study drug, as all had compliance r120%, and the 3 patients with ongoing symptoms were 97.3% to 100.8% compliant for 30 to 37 days of treatment. Two patients experienced a TEAE considered potentially related to opioid withdrawal; both events (mild and moderate insomnia) were ongoing at the end of the study. No AEs potentially related to overdose were reported during the study. Mean blood pressure, heart rate, respiratory rate, and body temperature remained virtually unchanged from baseline to the end of treatment (Table IV). No

occurrences of respiratory depression or orthostatic hypotension were reported. Changes in oxygen saturation at each visit and the end of treatment were small and not clinically meaningful. Mean (SD) oxygen saturation values were 96.91% (1.5%) at baseline and 96.87% (1.6%) at the end of treatment. Changes in LFT results and a single occurrence of elevated lactate dehydrogenase were the only laboratory findings considered treatment related. Overall, shifts in LFT results from normal to abnormal (low or high) were infrequent (Table V), generally mild, and usually resolved with treatment discontinuation. Thirteen patients had abnormal laboratory test results considered clinically meaningful, of which 7 were abnormal LFTs. One of these patients discontinued treatment as a result of LFT abnormalities (ALT and AST 43  ULN), after which the results normalized. None of the LFT abnormalities met Hy’s law criteria for acute liver failure (ALT or AST 43  ULN associated with total bilirubin 42  ULN, and serum alkaline phosphatase o2  ULN). Overall, mean treatment compliance was 95.6% and ranged from 48.5% to 152.5%. One hundred forty-eight patients were within the 80% to 120% range, indicating acceptable compliance. Eight patients were o80% compliant. Of 2 patients considered 4120% compliant, 1 was lost to follow-up and the other did not return the study drug kit for the counting of tablets and was discontinued from the study.

Secondary Outcome Measures Mean scores on worst pain in the past 24 hours, least pain in the past 24 hours, average pain in the past 24 hours, and current pain all decreased over the

Table IV. Changes in vital signs and pulse oximetry. Data are given as mean (SD). Parameter Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, beats/min Respiratory rate, breaths/min Body temperature, 1C Oxygen saturation, %

Baseline (n ¼ 153) 126.6 76.8 74.7 16.4 36.55 96.91

(12.3) (8.8) (9.9) (2.2) (0.36) (1.52)

End of Treatment (n ¼ 149) 126.6 77.9 74.6 16.2 36.57 96.87

(12.4) (8.1) (10.3) (1.8) (0.36) (1.64)

Δ –0.1 þ0.8 –0.3 –0.2 0.02 –0.05

(12.2) (8.7) (9.4) (1.7) (0.4) (1.5)

BP ¼ blood pressure.

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Table V. Changes in liver function test values from baseline to end of treatment. Data are given as number (%) of patients. End of Treatment Test/Baseline Category* ALT n Low (o6 U/L) Normal (6–43 U/L) High (443 U/L) Alkaline phosphatase n Low (o31 U/L) Normal (31–129 U/L) High (4129 U/L) AST n Low (o9 U/L) Normal (9–36 U/L) High (436 U/L) Bilirubin n Low (o3 μmol/L) Normal (3–21 μmol/L) High (421 μmol/L) Direct bilirubin n Low† Normal (0–7 μmol/L) High (47 μmol/L) Gamma-glutamyl transferase n Low (o4 U/L) Normal (4–61 U/L) High (461 U/L)

Baseline

Low

Normal

High

148 0 135 (91.2) 13 (8.8)

0 0 0 0

133 0 127 (85.8) 6 (4.1)

15 0 8 (5.4) 7 (4.7)

148 2 (1.4) 140 (94.6) 6 (4.1)

1 1 (0.7) 0 0

144 1 (0.7) 139 (93.9) 4 (2.7)

3 0 1 (0.7) 2 (1.4)

141 0 134 (95.0) 7 (5.0)

0 0 0 0

131 0 127 (90.1) 4 (2.8)

10 0 7 (5.0) 3 (2.1)

148 9 (6.1) 137 (92.6) 2 (1.4)

13 1 (0.7) 12 (8.1) 0

132 8 (5.4) 122 (82.4) 2 (1.4)

3 0 3 (2.0) 0

143 0 143 (100) 0

0 0 0 0

143 0 143 (100) 0

0 0 0 0

148 1 (0.7) 135 (91.2) 12 (8.1)

1 0 1 (0.7) 0

124 1 (0.7) 122 (82.4) 1 (0.7)

23 0 12 (8.1) 11 (7.4)

ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; GGT ¼ γ-glutamyl transferase. * Normal ranges for laboratory values varied slightly across laboratories; ranges in this table represent the lowest “low” and highest “high” values across all laboratories; however, patients were categorized on the basis of the specific range for the laboratory by which they were tested. † There is no “low” value range for direct bilirubin.

course of the study (Figure 3). Decreases from baseline in pain scores occurred early (ie, day 8) and persisted throughout the study, with the greatest decreases usually occurring at day 29.

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The mean percentage of pain relief increased from 13.9% at baseline to 60.4% at day 8 (change, þ46.6%) and 62.6% at the end of treatment (change, þ48.8%). Pain-related quality of life, as measured by

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Clinical Therapeutics

Mean Change From Baseline

0

Worst Pain in Last 24 h

Least Pain in Last 24 h

Average Pain in Last 24 h

Current Pain

–0.5 –1 –1.5 –2 –2.5

–2.4

–2.6

–2.6

–3 –3.5 –4

Baseline =

–3.3 Day 8 (n=140) 7.7

–3.0

–3.1 –3.4 End of Treatment (n=138) 5.7

6.8

–3.7 6.8

Figure 3. Mean changes in modified Brief Pain Inventory–Short Form items from baseline to day 8 and end of treatment.

the mean mBPI-sf pain-interference score, decreased (ie, improved) from 5.1 at baseline to 2.8 at day 8 (change, –2.4) and 2.6 at the end of treatment (change, –2.6). In the group with OA, mean WOMAC pain, stiffness, physical function, and total scores all decreased (ie, improved) from baseline to day 8 and the end of treatment (Figure 4). In patients with CLBP, mean Roland-Morris scores decreased (ie, improved) from baseline (10.6) to day 8 (8.0; change, –2.7) and the end of treatment (7.7; change, –3.0).

0

Pain

Stiffness

DISCUSSION IR/ER HB/APAP administered every 12 hours exhibited a tolerability profile typical of those of low-dose opioid/ APAP combination analgesic agents.4 Overall, 75% of patients completed 36 days of treatment, with o10% discontinuing owing to a TEAE. The most frequent AEs were those typically seen with opioid agents: nausea, somnolence, and constipation. The frequency and severity of TEAEs overall and in terms of individual AEs were greater in the subgroup with OA

Physical Function

Total

Mean Change From Baseline

–1.45 –1.51

–5

–4.47 –4.66

–10

–15

–14.38 –14.35

–20 –20.30 –20.53

–25 Baseline =

Day 8 (n=64) 11.45

End of Treatment (n=68) 4.74

38.23

54.42

Figure 4. Mean changes in Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores from baseline to day 8 and end of treatment.

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Y. Zheng et al. than in the subgroup with CLBP, and AEs were also more likely to have been attributed to treatment in patients with OA. The differences in the frequencies of TEAEs and discontinuations between the 2 subpopulations may have been related to the comparative general health of the 2 subgroups; the OA population tended to be older, more likely to have been taking Z1 concurrent medication, and more likely to have undergone Z1 previous surgery compared with the CLBP population. Nonetheless, most TEAEs were mild or moderate in intensity in both populations, and no serious treatment-related AEs were reported in any of the patients. Changes in vital signs, pulse oximetry, and laboratory values were infrequent and generally not considered clinically relevant or related to treatment. There have been few studies examining the tolerability of hydrocodone-based analgesic agents over a prolonged period (Z30 days). In 2009, 413 consecutive patients who had been taking a hydrocodonebased analgesic agent at doses of up to 50 mg/d for Z6 months for the management of CNCP were interviewed when presenting for interventional pain management. The prevalence of AEs in patients at the time of the interview was 7.5%.20 Although these patients with CNCP had taken hydrocodone over a prolonged period, the prevalence of AEs at a single point in time is difficult to compare with the cumulative frequency of AEs that may occur in this population over several weeks of observation. In a randomized, double-blind, parallel-group, activecomparator study, 153 patients with chronic pain (mainly OA, CLBP, or other musculoskeletal pain) received 4 weeks of therapy with hydrocodone/ibuprofen 7.5/200 mg, 2 tablets every 6 to 8 hours prn. A total of 127 patients (83%) experienced AEs, including nausea (35.9%), constipation (19.6%), and vomiting (13.1%).21 In a 48-week, open-label tolerability study of ER HB for the management of CNCP, 404 patients (63.3%) experienced Z1 AE, including constipation (11.3%), nausea (10.7%), and vomiting (4.1%). That was the only study of the tolerability of a hydrocodone-based product in the literature found to have reported potential evidence of study drug misuse, observing that 32 of 638 patients (5%) in a 48-week study of ER HB for CNCP had drugaccountability problems suggestive of potential misuse or diversion, and 20 (3%) were discontinued from the study for this reason.22 In contrast, none of the

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patients in the present analysis were discontinued for drug-accountability problems. Although 8 patients (5.2%) experienced disturbed attention, irritability, agitation, or feeling euphoric, relaxed, or “abnormal,” which are listed in the MedDRA query for drug abuse, dependence, and withdrawal, these subjective effects are by no means diagnostic of drug abuse, dependence, or withdrawal. Likewise, 2 patients reported mild or moderate insomnia, which is listed in the MedDRA query for opioid withdrawal but is by no means diagnostic of opioid withdrawal. In addition, measures of the effects on the signs and symptoms of OA or CLBP improved over the course of this open-label study; however, these observations cannot be attributed to treatment in an open-label study. Substantial reductions from baseline in pain scores were evident by day 8 and persisted throughout the study. Marked improvements from baseline in percentages of pain relief, pain-related quality of life, and disease-specific quality of life were also observed over the course of the study. Because there was no active- or placebo comparator, one cannot determine whether improvements in measures of pain and physical function reflected treatment effects or the natural history of flare and remission in OA and CLBP.23,24 Nonetheless, these findings with prolonged, open-label treatment are consistent with the efficacy and tolerability results obtained with IR/ER HB/APAP administered for up to 14 days in patients with moderate to severe acute pain after unilateral bunionectomy.14 If approved, IR/ER HB/APAP will be the second biphasic (IR/ER), low-dose opioid/APAP combination therapy approved by the US Food and Drug Administration (FDA) for the management of acute pain. In 2014, IR/ER oxycodone hydrochloride/APAP was approved “for the management of acute pain severe enough to require opioid treatment and for which alternative treatment options are inadequate.”25 The availability of biphasic-release technology for additional opioid molecules may help clinicians to select the most appropriate opioid agent for the needs of individual patients, as has been discussed with the advent of other innovations in drug delivery, such as abuse-deterrent design.26 There were several important limitations to this study. Although the trial population consisted of patients with CNCP, IR/ER HB/APAP is intended only for the treatment of acute pain. The intent of the current study was to assess the tolerability of IR/ ER HB/APAP over a period longer than would be

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Clinical Therapeutics possible with an acute pain model. Trials designed for studying opioid agents for the treatment of CNCP typically assess efficacy over weeks to months and tolerability over months to years.27,28 The FDA requires trials supporting efficacy in the treatment of chronic pain to be “superiority” trials with a placebo or an active comparator and of Z12 weeks’ duration, and to consider the natural history of flare and remission of OA and CLBP symptoms (eg, excluding patients who do not experience a flare of symptoms on discontinuation of an analgesic agent).29 Absent a placebo comparator, we could not ascertain whether the use of rescue medication (ibuprofen), the permitted use of concurrent medications with potential analgesic effects (eg, duloxetine, gabapentin), or protocolprohibited use of analgesic agents (eg, NSAIDs, opioid agents) in a few patients may have confounded the measures of the effects on the signs and symptoms of OA or CLBP. In a randomized, controlled trial of IR/ ER HB/APAP in acute postoperative pain, significantly greater use of ibuprofen rescue medication was observed in the placebo group compared with the IR/ER HB/APAP group14; such a comparison is impossible with an open-label tolerability trial. Finally, by excluding patients with certain medical conditions and taking concurrent medications, the study protocol may have constrained the diversity of the study population compared with that in clinical practice.

CONCLUSION The results of the present study support the tolerability of IR/ER HB/APAP 7.5/325-mg tablets administered as 2 tablets every 12 hours for r35 days in patients with OA or CLBP. IR/ER HB/APAP 7.5/325-mg tablets are intended for the management of acute pain severe enough to require opioid therapy.

ACKNOWLEDGMENTS Editorial support and manuscript development were provided by Jeffrey Coleman, MA, and Robert Axford-Gatley, MD, of C4 MedSolutions, LLC (Yardley, Pennsylvania), a CHC Group company. The sponsor participated in the study conception and design; collection, analysis, and interpretation of the data; and development, review, and decision to submit the manuscript for publication. All of the authors participated in the study conception or design; collection, analysis, and/or interpretation of the data;

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and development or critical review of the manuscript and gave final approval to submit it for publication.

CONFLICTS OF INTEREST This research and editorial support for manuscript development were financially supported by Mallinckrodt Pharmaceuticals (Hazelwood, Missouri). All of the authors are full-time employees of Mallinckrodt, except for Dr. Kostenbader, who is a paid contracted employee of Mallinckrodt. The authors have indicated that they have no other conflicts of interest with regard to the content of this article.

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Address correspondence to: Thomas Barrett, PhD, Mallinckrodt Pharmaceuticals, 675 James S. McDonnell Boulevard, Hazelwood, MO 63134-5840. E-mail: [email protected]

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