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The primary purpose of this study was to evaluate analgesic efficacy and safety of hydrocodone/acetaminophen extended release compared to placebo in moderate to severe pain following primary unilateral first metatarsal bunionectomy.
The bunionectomy was performed under regional anesthesia and propofol sedation. Perioperative anesthesia was standardized for all participants. Upon completion of surgery, designated study personnel ensured continued eligibility per the selection criteria of the protocol.
After an appropriate period of time following bunionectomy, participants who had a pain intensity score of ≥ 40 mm on a 100 mm visual analog scale (VAS) and moderate or severe pain intensity per the categorical pain intensity scale were eligible for randomization, in equal numbers, into 1 of 5 treatment arms. In order to maintain the single-blind nature of the study, all participants were dosed with study drug (active and/or placebo) every 6 hours.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release) plus 1 placebo capsule (for morphine extended release), administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). |
|
| Acetaminophen | Active Comparator | 1 dose of 1 placebo capsule (for morphine extended release) plus 1 acetaminophen tablet, administered once every 12 hours, and 1 dose of 1 acetaminophen tablet, administered once every 6 hours (for a total of 8 doses). |
|
| Morphine Extended Release | Active Comparator | 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release) plus 1 morphine extended release capsule, administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). |
|
| Morphine Extended Release / Acetaminophen | Active Comparator | 1 dose of 1 morphine extended release capsule plus 1 acetaminophen tablet, administered once every 12 hours, and 1 dose of 1 acetaminophen tablet, administered once every 6 hours (for a total of 8 doses). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Hydrocodone/Acetaminophen Extended Release | Drug |
|
| |
| Measure | Description | Time Frame |
|---|---|---|
| Sum of Pain Intensity Difference (SPID) Using the Pain Intensity Visual Analogue Scale (VAS) | Participants assessed pain intensity on a 100 mm visual analogue scale (VAS) with 0 meaning "no pain" and 100 meaning the "worst pain imaginable". The SPID VAS score for 0 to 48 hours following initial study drug dose measured the cumulative pain intensity difference during treatment with higher mean SPID VAS scores indicating greater improvement from Baseline. The SPID score is a measure of the cumulative pain intensity difference during treatment and the area under the curve was estimated using the linear trapezoidal rule. | From time of first study drug administration to 48 hours following first study drug administration |
| Measure | Description | Time Frame |
|---|---|---|
| TOTPAR (Total Pain Relief) | TOTPAR was the time-interval weighted sum of pain relief. Pain relief was assessed by participants' responses to how their pain relief was compared with the pain they had just before receiving the first dose of study drug: no relief, a little relief, some relief, a lot of relief, or complete relief. Higher mean TOTPAR scores indicate better pain relief. The TOTPAR score is a measure of the cumulative pain intensity difference during treatment and the area under the curve was estimated using the linear trapezoidal rule. |
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Inclusion Criteria:
- Subjects who were in general good health, experiencing moderate to severe pain following bunionectomy surgery and who were willing to remain confined for approximately 4 days following surgery for study procedures.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Pedro Quintana Diez, MD | AbbVie | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Site Reference ID/Investigator# 26223 | Peoria | Arizona | 85381 | United States | ||
| Site Reference ID/Investigator# 26302 |
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| Label | URL |
|---|---|
| Related Info | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Acetaminophen | 1 dose of 1 placebo capsule (for morphine extended release) plus 1 acetaminophen tablet, administered once every 12 hours, and 1 dose of 1 acetaminophen tablet, administered once every 6 hours (for a total of 8 doses). |
| FG001 | Morphine Extended Release | 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release) plus 1 morphine extended release capsule, administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). |
| FG002 | Morphine Extended Release / Acetaminophen | 1 dose of 1 morphine extended release capsule plus 1 acetaminophen tablet, administered once every 12 hours, and 1 dose of 1 acetaminophen tablet, administered once every 6 hours (for a total of 8 doses). |
| FG003 | Hydrocodone/Acetaminophen Extended Release | 1 dose of 1 hydrocodone/acetaminophen extended release tablet plus 1 placebo capsule (for morphine extended release), administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). |
| FG004 | Placebo | 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release) plus 1 placebo capsule (for morphine extended release), administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Acetaminophen | 1 dose of 1 placebo capsule (for morphine extended release) plus 1 acetaminophen tablet, administered once every 12 hours, and 1 dose of 1 acetaminophen tablet, administered once every 6 hours (for a total of 8 doses). |
| BG001 | Morphine Extended Release |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Sum of Pain Intensity Difference (SPID) Using the Pain Intensity Visual Analogue Scale (VAS) | Participants assessed pain intensity on a 100 mm visual analogue scale (VAS) with 0 meaning "no pain" and 100 meaning the "worst pain imaginable". The SPID VAS score for 0 to 48 hours following initial study drug dose measured the cumulative pain intensity difference during treatment with higher mean SPID VAS scores indicating greater improvement from Baseline. The SPID score is a measure of the cumulative pain intensity difference during treatment and the area under the curve was estimated using the linear trapezoidal rule. | All randomized participants who received at least 1 dose of study drug. Analyses were performed based on the treatment participants actually received (as-treated). | Posted | Least Squares Mean | Standard Error | scores on a scale | From time of first study drug administration to 48 hours following first study drug administration |
|
AEs were recorded from study drug administration until 30 days following discontinuation of study drug (total 32 days); SAEs were recorded from the time informed consent was obtained until 30 days following discontinuation of study drug (total 51 days).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Acetaminophen | 1 dose of 1 placebo capsule (for morphine extended release) plus 1 acetaminophen tablet, administered once every 12 hours, and 1 dose of 1 acetaminophen tablet, administered once every 6 hours (for a total of 8 doses). |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| CONSTIPATION | Gastrointestinal disorders | MedDRA 12.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Global Medical Services | AbbVie (prior sponsor, Abbott) | 800-633-9110 |
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| ID | Term |
|---|---|
| D010146 | Pain |
| D010149 | Pain, Postoperative |
| ID | Term |
|---|---|
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D011183 | Postoperative Complications |
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| ID | Term |
|---|---|
| D006853 | Hydrocodone |
| D000082 | Acetaminophen |
| D009020 | Morphine |
| ID | Term |
|---|---|
| D003061 | Codeine |
| D009022 | Morphine Derivatives |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
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| Hydrocodone/Acetaminophen Extended Release |
| Experimental |
1 dose of 1 hydrocodone/acetaminophen extended release tablet plus 1 placebo capsule (for morphine extended release), administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). |
|
| Acetaminophen |
| Drug |
|
|
| Morphine Extended Release | Drug |
|
|
| Placebo | Drug |
|
| From time of first study drug administration to 48 hours following first study drug administration |
| Participant's Global Assessment of Study Drug | The participant's overall impression of the study drug was obtained on a 5-point categorical scale: excellent; very good; good; fair; poor. | From time of first study drug administration to 48 hours following first study drug administration |
| Time to Perceptible and Meaningful Pain Relief | The median time (minutes) from first perceptible pain relief (onset of pain relief) and time until first meaningful pain relief. | From time of first study drug administration to 12 hours following first study drug administration |
| Participants With Adverse Events (AEs) | An adverse event (AE) is defined as any untoward medical occurrence in a participant, which does not necessarily have a causal relationship with treatment. If an adverse event meets any of the following criteria, it is considered a serious adverse event (SAE): results in death or is life-threatening, results in admission or prolongation of hospitalization, results in congenital anomaly or persistent or significant disability/incapacity, or is an important medical event requiring medical or surgical intervention to prevent serious outcome. AEs were categorized by severity (mild, moderate, severe) and relationship to treatment (probably, possibly, probably not, not related). Please see Adverse Events section below for more details. | AEs were recorded from study drug administration until 30 days following discontinuation of study drug (total 32 days); SAEs were recorded from the time informed consent was obtained until 30 days following discontinuation of study drug (total 51 days). |
| Number of Participants With Vital Signs Values Meeting Potentially Clinically Significant Criteria | Potentially clinically significant criteria: Systolic blood pressure (BP) ≤90 mm Hg and ≥20 mm Hg decrease (low) or ≥180 mm Hg and ≥20 mm Hg increase (high); Diastolic BP ≤50 mm Hg and ≥15 mm Hg decrease (low) or ≥105 mm Hg and ≥15 mm Hg increase (high). Heart rate ≤50 beats per minute (bpm) and ≥15 bpm decrease (low) or ≥120 bpm and ≥15 bpm increase (high). Respiratory rate <10 respirations per minute (rpm) (low) or >24 rpm (high). | At specified intervals from Screening through 7 days after first dose of study drug |
| Number of Participants With Chemistry Values Meeting Potentially Clinically Significant Criteria | Potentially clinically significant criteria: alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≥3 times upper limit of normal (ULN); calcium ≤1.8 mmol/L. | At specified intervals from Screening through 7 days after first dose of study drug |
| Austin |
| Texas |
| 78705 |
| United States |
| Site Reference ID/Investigator# 26303 | San Marcos | Texas | 78666 | United States |
| Site Reference ID/Investigator# 26304 | West Jordan | Utah | 84088 | United States |
| Dosing Error |
|
| Death in the Family |
|
| Refusal of Blood Draws |
|
1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release) plus 1 morphine extended release capsule, administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). |
| BG002 | Morphine Extended Release / Acetaminophen | 1 dose of 1 morphine extended release capsule plus 1 acetaminophen tablet, administered once every 12 hours, and 1 dose of 1 acetaminophen tablet, administered once every 6 hours (for a total of 8 doses). |
| BG003 | Hydrocodone/Acetaminophen Extended Release | 1 dose of 1 hydrocodone/acetaminophen extended release tablet plus 1 placebo capsule (for morphine extended release), administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). |
| BG004 | Placebo | 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release) plus 1 placebo capsule (for morphine extended release), administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). |
| BG005 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
1 dose of 1 placebo capsule (for morphine extended release) plus 1 acetaminophen tablet, administered once every 12 hours, and 1 dose of 1 acetaminophen tablet, administered once every 6 hours (for a total of 8 doses). |
| OG001 | Morphine Extended Release | 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release) plus 1 morphine extended release capsule, administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). |
| OG002 | Morphine Extended Release / Acetaminophen | 1 dose of 1 morphine extended release capsule plus 1 acetaminophen tablet, administered once every 12 hours, and 1 dose of 1 acetaminophen tablet, administered once every 6 hours (for a total of 8 doses). |
| OG003 | Hydrocodone/Acetaminophen Extended Release | 1 dose of 1 hydrocodone/acetaminophen extended release tablet plus 1 placebo capsule (for morphine extended release), administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). |
| OG004 | Placebo | 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release) plus 1 placebo capsule (for morphine extended release), administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). |
|
|
| Secondary | TOTPAR (Total Pain Relief) | TOTPAR was the time-interval weighted sum of pain relief. Pain relief was assessed by participants' responses to how their pain relief was compared with the pain they had just before receiving the first dose of study drug: no relief, a little relief, some relief, a lot of relief, or complete relief. Higher mean TOTPAR scores indicate better pain relief. The TOTPAR score is a measure of the cumulative pain intensity difference during treatment and the area under the curve was estimated using the linear trapezoidal rule. | All randomized participants who received at least 1 dose of study drug. Analyses were performed based on the treatment participants actually received (as-treated). | Posted | Least Squares Mean | Standard Error | scores on a scale | From time of first study drug administration to 48 hours following first study drug administration |
|
|
|
| Secondary | Participant's Global Assessment of Study Drug | The participant's overall impression of the study drug was obtained on a 5-point categorical scale: excellent; very good; good; fair; poor. | All randomized participants who received at least 1 dose of study drug. Analyses were performed based on the treatment participants actually received (as-treated). | Posted | Number | participants | From time of first study drug administration to 48 hours following first study drug administration |
|
|
|
| Secondary | Time to Perceptible and Meaningful Pain Relief | The median time (minutes) from first perceptible pain relief (onset of pain relief) and time until first meaningful pain relief. | All randomized participants who received at least 1 dose of study drug. Analyses were performed based on the treatment participants actually received (as-treated). | Posted | Median | 95% Confidence Interval | minutes | From time of first study drug administration to 12 hours following first study drug administration |
|
|
|
| Secondary | Participants With Adverse Events (AEs) | An adverse event (AE) is defined as any untoward medical occurrence in a participant, which does not necessarily have a causal relationship with treatment. If an adverse event meets any of the following criteria, it is considered a serious adverse event (SAE): results in death or is life-threatening, results in admission or prolongation of hospitalization, results in congenital anomaly or persistent or significant disability/incapacity, or is an important medical event requiring medical or surgical intervention to prevent serious outcome. AEs were categorized by severity (mild, moderate, severe) and relationship to treatment (probably, possibly, probably not, not related). Please see Adverse Events section below for more details. | All randomized participants who received at least 1 dose of study drug. Analyses were performed based on the treatment participants actually received (as-treated). | Posted | Number | participants | AEs were recorded from study drug administration until 30 days following discontinuation of study drug (total 32 days); SAEs were recorded from the time informed consent was obtained until 30 days following discontinuation of study drug (total 51 days). |
|
|
|
| Secondary | Number of Participants With Vital Signs Values Meeting Potentially Clinically Significant Criteria | Potentially clinically significant criteria: Systolic blood pressure (BP) ≤90 mm Hg and ≥20 mm Hg decrease (low) or ≥180 mm Hg and ≥20 mm Hg increase (high); Diastolic BP ≤50 mm Hg and ≥15 mm Hg decrease (low) or ≥105 mm Hg and ≥15 mm Hg increase (high). Heart rate ≤50 beats per minute (bpm) and ≥15 bpm decrease (low) or ≥120 bpm and ≥15 bpm increase (high). Respiratory rate <10 respirations per minute (rpm) (low) or >24 rpm (high). | All randomized participants who received at least 1 dose of study drug. Analyses were performed based on the treatment participants actually received (as-treated). | Posted | Number | participants | At specified intervals from Screening through 7 days after first dose of study drug |
|
|
|
| Secondary | Number of Participants With Chemistry Values Meeting Potentially Clinically Significant Criteria | Potentially clinically significant criteria: alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≥3 times upper limit of normal (ULN); calcium ≤1.8 mmol/L. | All randomized participants who received at least 1 dose of study drug. Analyses were performed based on the treatment participants actually received (as-treated). | Posted | Number | participants | At specified intervals from Screening through 7 days after first dose of study drug |
|
|
|
| 0 |
| 50 |
| 19 |
| 50 |
| EG001 | Morphine Extended Release | 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release) and 1 morphine extended release capsule, administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). | 0 | 52 | 21 | 52 |
| EG002 | Morphine Extended Release/Acetaminophen | 1 dose of 1 morphine extended release capsule and 1 acetaminophen tablet, administered once every 12 hours, and 1 dose of 1 acetaminophen tablet, administered once every 6 hours (for a total of 8 doses). | 0 | 49 | 26 | 49 |
| EG003 | Hydrocodone/Acetaminophen Extended Release | 1 dose of 1 hydrocodone/acetaminophen extended release tablet and 1 placebo capsule (for morphine extended release), administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). | 0 | 48 | 27 | 48 |
| EG004 | Placebo | 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release) and 1 placebo capsule (for morphine extended release), administered once every 12 hours, and 1 dose of 1 placebo tablet (for hydrocodone/acetaminophen extended release), administered once every 6 hours (for a total of 8 doses). | 0 | 51 | 20 | 51 |
| DIARRHOEA | Gastrointestinal disorders | MedDRA 12.1 | Systematic Assessment |
|
| NAUSEA | Gastrointestinal disorders | MedDRA 12.1 | Systematic Assessment |
|
| VOMITING | Gastrointestinal disorders | MedDRA 12.1 | Systematic Assessment |
|
| ALANINE AMINOTRANSFERASE INCREASED | Investigations | MedDRA 12.1 | Systematic Assessment |
|
| DEHYDRATION | Metabolism and nutrition disorders | MedDRA 12.1 | Systematic Assessment |
|
| DIZZINESS | Nervous system disorders | MedDRA 12.1 | Systematic Assessment |
|
| HEADACHE | Nervous system disorders | MedDRA 12.1 | Systematic Assessment |
|
| SOMNOLENCE | Nervous system disorders | MedDRA 12.1 | Systematic Assessment |
|
AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.
| D010335 | Pathologic Processes |
| D000470 |
| Alkaloids |
| D006571 | Heterocyclic Compounds |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 | Aniline Compounds |
| D000588 | Amines |
| Very Good |
|
| Good |
|
| Fair |
|
| Poor |
|
| Time to Onset of Meaningful Pain Relief |
|
| Any AE at least "possibly" drug related |
|
| Any "severe" AE |
|
| Any SAE |
|
| Any AE leading to discontinuation of study drug |
|
| Any AE leading to death |
|
| Death |
|
| Systolic BP increase |
|
| Diastolic BP decrease |
|
| Diastolic BP increase |
|
| Heart rate decrease |
|
| Heart rate increase |
|
| Respiratory rate < 10 rpm |
|
| Respiratory rate > 24 rpm |
|
| AST >= 3 * ULN |
|
| Calcium <= 1.8 mmol/L |
|