Pain, Nausea, Vomiting
Conditions
Keywords
Pain, Nausea, Vomiting
Brief summary
To determine the analgesic efficacy of CL-108 5 mg by comparison with placebo and the anti-emetic efficacy of CL-108 5 mg by comparison with hydrocodone 5 mg/acetaminophen 325 mg.
Detailed description
Adult patients with moderate or severe pain after bunionectomy will be randomized to CL-108 5 mg (hydrocodone 5 mg/acetaminophen 325 mg/ promethazine 12.5 mg), hydrocodone 5 mg/ acetaminophen 325 mg, or placebo under double-blind conditions. Over 48 hours they will use the assigned study medication and assess pain intensity, nausea, and vomiting. Uses of supplementary analgesic and antiemetic medications will be documented. Patient responses and adverse effects will also be documented during the 5-day outpatient period, too.
Interventions
DRUGCL-108 5 mg
hydrocodone 5 mg/APAP 325 mg/promethazine 12.5 mg
DRUGNorco
hydrocodone 5 mg/APAP 325 mg
DRUGPlacebo
Placebo matching CL-108
Sponsors
Charleston Laboratories, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Informed consent: Signed informed consent form obtained at screening prior to any procedures being performed. * Gender: Male or non-pregnant and non-lactating female. * Age: 18 years or older at time of consent. * Foot condition: Primary unilateral first metatarsal bunionectomy (osteotomy and internal fixation) with no additional collateral procedures. * Pain Severity: Presence of moderate or severe pain on a categorical pain intensity scale at Baseline * Pain Confirmation: On the 0-10 numerical pain intensity scale at Baseline. * Diary Completion: Be willing and able to record safety and efficacy ratings in the Diaries. * Safe Transportation Home: Patient must have arrangements for transportation home from the research center accompanied by a responsible adult.
Exclusion criteria
* Medical condition: Presence of a serious medical condition, intolerance to NSAIDs, or any other medical condition which, in the opinion of the Investigator, makes the patient unsuitable for participation. * Infection: Acute infection of the surgical site at the time of surgery that could confound post-surgical evaluation. * Drug Allergy: History of hypersensitivity to an opioid drug (such as hydrocodone), promethazine, acetaminophen, NSAID (such as ibuprofen or aspirin), midazolam, propofol, mepivacaine, ropivacaine or ketorolac. * Confounding and Contraindicated Drugs: Other than protocol-permitted medications administered pre-operatively or during surgery: use within 14 days before or during the surgical procedure of any systemic corticosteroid or use within 24 hours or during the surgical procedure of any confounding prescription or non-prescription drug or any drug contraindicated with hydrocodone, acetaminophen, or promethazine. \[Note: Antibiotic for endocarditis prophylaxis (except if known to cause nausea) and aspirin (ASA) ≤ 325 mg for cardiovascular prophylaxis are permitted during the study.\] History of consuming more than 2 alcoholic drinks per day every day for the last month or a positive urine test for opiates, benzodiazepines, barbiturates, tetrahydrocannabinol, methamphetamines, cocaine, oxycodone, cotinine at screening or the morning of surgery will exclude the patient from the trial. * Investigational Drug Use: Use of an investigational drug within the past 30 days. * Participated in Study: Previous participation in this study. * Pregnancy, Lactation: Women who are pregnant or lactating. * Compliance: Inability to swallow capsules whole. * Participant relationship: Employee at the research center, employee of the Principal Investigator, Sub-Investigators, or sponsor or relative of the Investigator, Sub-Investigators or research staff who is involved in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With OINV Over 48 Hours | Up to 48 hours | Number and Percentage of participants With opioid-induced nausea and vomiting (OINV) who experienced any Vomiting / use of Anti-Emetic Medication Over 48 Hours |
| The Sum of Pain Intensity Differences (on PI-NRS) Over 48 Hours (SPID48) | Up to 48 hours | The SPID48 endpoint is calculated from the PI-NRS values at baseline, every 30 minutes until hour 12, then every hour (when awake) until hour 48 as follows: * Each subsequent PI-NRS value is subtracted from the baseline PI-NRS value. * Each difference is weighted by the elapsed time from the previous PI-NRS value to the current one. * The weighed differences are summed to yield the SPID48. Summed pain intensity differences over 48 hours (SPID48) will be compared for patients treated with CL-108 5 mg and those treated with placebo. Pain intensity will be measured on a 0-10 Pain Intensity Numerical Rating Scale (PI-NRS), where 0 is no pain and 10 is severe pain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Any Nausea Over 48 Hours | Up to 48 hours | Percentage of patients with any nausea over 48 hours, comparing CL-108 5 mg to hydrocodone 5 mg/APAP 325 mg |
| Percentage of Patients With Any Nausea or Vomiting Over 48 Hours | Up to 48 hours | Percentage of patients with any nausea or vomiting over 48 hours, comparing CL-108 5 mg to hydrocodone 5 mg/APAP 325 mg |
| Percentage of Patients With Complete Absence of OINV (no Nausea, no Vomiting, and no Use of Anti-emetic Medication) Over 48 Hours | Up to 48 hours | Percentage of patients with complete absence of OINV (no nausea, no vomiting, and no use of anti-emetic medication) over 48 hours comparing CL-108 5 mg to hydrocodone 5 mg/APAP 325 mg) |
| Number of Doses of Study Medication Taken Over Days 3to7 | Day3 to Day7 | Number of doses of study medication taken over Days 3 to 7 |
| Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Day3 to Day7 | Number of doses of study medication taken per day over Days 3 to 7 |
| Percentage of Patients With Any Post-discharge Nausea and Vomiting (PDNV) | Day 3 to 7 | Percentage of patients with any Post-discharge Nausea and Vomiting (PDNV) over Days 3 to 7 |
| Percentage of Patients With Any Vomiting Over 48 Hours | Up to 48 hours | Percentage of patients with any vomiting over 48 hours, comparing CL-108 5 mg to hydrocodone 5 mg/APAP 325 mg |
Countries
United States
Participant flow
Recruitment details
This was a Phase 3, double-blind, randomized, placebo- and active-controlled, multiple-dose study conducted at different research centers in the United States
Pre-assignment details
A total of 349 subjects were enrolled into the study, 128 were Screen Failed and 221 were Randomized, 209 were Completed the study and 12 subjects were discontinued.
Participants by arm
| Arm | Count |
|---|---|
| CL-108 Hydrocodone 5 mg/APAP 325 mg/promethazine 12.5 mg (CL-108 5 mg) bi-layered tablet
CL-108 5 mg: hydrocodone 5 mg/APAP 325 mg/promethazine 12.5 mg | 87 |
| Norco hydrocodone 5 mg/APAP 325 mg
Norco: hydrocodone 5 mg/APAP 325 mg | 90 |
| Placebo Placebo 0 mg matching CL-108
Placebo: Placebo matching CL-108 | 44 |
| Total | 221 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 4 | 1 | 3 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Not provided | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Norco | Total | CL-108 | Placebo |
|---|---|---|---|---|
| Age, Continuous | 43.5 years STANDARD_DEVIATION 14.74 | 44.2 years STANDARD_DEVIATION 13.82 | 43.3 years STANDARD_DEVIATION 12.97 | 47.2 years STANDARD_DEVIATION 13.4 |
| BMI | 27.29 kg/m^2 STANDARD_DEVIATION 5.549 | 28.51 kg/m^2 STANDARD_DEVIATION 6.333 | 28.88 kg/m^2 STANDARD_DEVIATION 6.876 | 30.26 kg/m^2 STANDARD_DEVIATION 6.358 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 22 Participants | 58 Participants | 27 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 68 Participants | 163 Participants | 60 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 165.09 cm STANDARD_DEVIATION 9.133 | 164.90 cm STANDARD_DEVIATION 9.06 | 164.94 cm STANDARD_DEVIATION 9.457 | 164.45 cm STANDARD_DEVIATION 8.256 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 4 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 32 Participants | 12 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 4 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 73 Participants | 175 Participants | 69 Participants | 33 Participants |
| Region of Enrollment United States | 90 participants | 221 participants | 87 participants | 44 participants |
| Sex: Female, Male Female | 77 Participants | 192 Participants | 75 Participants | 40 Participants |
| Sex: Female, Male Male | 13 Participants | 29 Participants | 12 Participants | 4 Participants |
| Weight | 74.56 kg STANDARD_DEVIATION 18.054 | 77.83 kg STANDARD_DEVIATION 20.592 | 79.19 kg STANDARD_DEVIATION 23.427 | 81.86 kg STANDARD_DEVIATION 18.827 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 87 | 0 / 90 | 0 / 44 |
| other Total, other adverse events | 80 / 87 | 79 / 90 | 37 / 44 |
| serious Total, serious adverse events | 1 / 87 | 0 / 90 | 0 / 44 |
Outcome results
Primary
Percentage of Participants With OINV Over 48 Hours
Number and Percentage of participants With opioid-induced nausea and vomiting (OINV) who experienced any Vomiting / use of Anti-Emetic Medication Over 48 Hours
Time frame: Up to 48 hours
Population: Intent-to-Treat (ITT) Population: The ITT Population comprised all patients who were randomized and who received at least 1 dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CL-108 | Percentage of Participants With OINV Over 48 Hours | 8 Participants |
| Norco | Percentage of Participants With OINV Over 48 Hours | 31 Participants |
| Placebo | Percentage of Participants With OINV Over 48 Hours | 4 Participants |
p-value: <0.001Regression, Logistic
Primary
The Sum of Pain Intensity Differences (on PI-NRS) Over 48 Hours (SPID48)
The SPID48 endpoint is calculated from the PI-NRS values at baseline, every 30 minutes until hour 12, then every hour (when awake) until hour 48 as follows: * Each subsequent PI-NRS value is subtracted from the baseline PI-NRS value. * Each difference is weighted by the elapsed time from the previous PI-NRS value to the current one. * The weighed differences are summed to yield the SPID48. Summed pain intensity differences over 48 hours (SPID48) will be compared for patients treated with CL-108 5 mg and those treated with placebo. Pain intensity will be measured on a 0-10 Pain Intensity Numerical Rating Scale (PI-NRS), where 0 is no pain and 10 is severe pain.
Time frame: Up to 48 hours
Population: Intent-to-Treat (ITT) Population: The ITT Population comprised all patients who were randomized and who received at least 1 dose of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CL-108 | The Sum of Pain Intensity Differences (on PI-NRS) Over 48 Hours (SPID48) | 108.5 score on a scale | Standard Deviation 80.66 |
| Norco | The Sum of Pain Intensity Differences (on PI-NRS) Over 48 Hours (SPID48) | 94.8 score on a scale | Standard Deviation 69.53 |
| Placebo | The Sum of Pain Intensity Differences (on PI-NRS) Over 48 Hours (SPID48) | 78.7 score on a scale | Standard Deviation 62.66 |
p-value: 0.052Regression, Logistic
Secondary
Number of Doses of Study Medication Taken Over Days 3to7
Number of doses of study medication taken over Days 3 to 7
Time frame: Day3 to Day7
Population: Intent-to-Treat (ITT) Population: The ITT Population comprised all patients who were randomized and who received at least 1 dose of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CL-108 | Number of Doses of Study Medication Taken Over Days 3to7 | 10.0 doses | Standard Deviation 7.05 |
| Norco | Number of Doses of Study Medication Taken Over Days 3to7 | 8.4 doses | Standard Deviation 7.3 |
| Placebo | Number of Doses of Study Medication Taken Over Days 3to7 | 6.2 doses | Standard Deviation 5.7 |
Secondary
Number of Doses of Study Medication Taken Per Day Over Days 3to7
Number of doses of study medication taken per day over Days 3 to 7
Time frame: Day3 to Day7
Population: Intent-to-Treat (ITT) Population: The ITT Population comprised all patients who were randomized and who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CL-108 | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 6 | 1.8 doses per day | Standard Deviation 1.77 |
| CL-108 | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 5 | 1.9 doses per day | Standard Deviation 1.81 |
| CL-108 | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 3 | 3.0 doses per day | Standard Deviation 1.6 |
| CL-108 | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 4 | 2.1 doses per day | Standard Deviation 1.65 |
| CL-108 | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 7 | 1.1 doses per day | Standard Deviation 1.46 |
| Norco | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 5 | 1.7 doses per day | Standard Deviation 1.73 |
| Norco | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 3 | 2.4 doses per day | Standard Deviation 1.83 |
| Norco | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 4 | 1.9 doses per day | Standard Deviation 1.7 |
| Norco | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 6 | 1.5 doses per day | Standard Deviation 1.72 |
| Norco | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 7 | 0.9 doses per day | Standard Deviation 1.29 |
| Placebo | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 7 | 0.6 doses per day | Standard Deviation 1.06 |
| Placebo | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 6 | 1.0 doses per day | Standard Deviation 1.16 |
| Placebo | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 3 | 2.1 doses per day | Standard Deviation 1.59 |
| Placebo | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 5 | 1.1 doses per day | Standard Deviation 1.4 |
| Placebo | Number of Doses of Study Medication Taken Per Day Over Days 3to7 | Number of Doses of Study Medication Taken over Day 4 | 1.4 doses per day | Standard Deviation 1.45 |
Secondary
Percentage of Patients With Any Nausea or Vomiting Over 48 Hours
Percentage of patients with any nausea or vomiting over 48 hours, comparing CL-108 5 mg to hydrocodone 5 mg/APAP 325 mg
Time frame: Up to 48 hours
Population: Intent-to-Treat (ITT) Population: The ITT Population comprised all patients who were randomized and who received at least 1 dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CL-108 | Percentage of Patients With Any Nausea or Vomiting Over 48 Hours | 37 Participants |
| Norco | Percentage of Patients With Any Nausea or Vomiting Over 48 Hours | 55 Participants |
| Placebo | Percentage of Patients With Any Nausea or Vomiting Over 48 Hours | 16 Participants |
Secondary
Percentage of Patients With Any Nausea Over 48 Hours
Percentage of patients with any nausea over 48 hours, comparing CL-108 5 mg to hydrocodone 5 mg/APAP 325 mg
Time frame: Up to 48 hours
Population: Intent-to-Treat (ITT) Population: The ITT Population comprised all patients who were randomized and who received at least 1 dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CL-108 | Percentage of Patients With Any Nausea Over 48 Hours | 36 Participants |
| Norco | Percentage of Patients With Any Nausea Over 48 Hours | 55 Participants |
| Placebo | Percentage of Patients With Any Nausea Over 48 Hours | 15 Participants |
Secondary
Percentage of Patients With Any Post-discharge Nausea and Vomiting (PDNV)
Percentage of patients with any Post-discharge Nausea and Vomiting (PDNV) over Days 3 to 7
Time frame: Day 3 to 7
Population: Intent-to-Treat (ITT) Population: The ITT Population comprised all patients who were randomized and who received at least 1 dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CL-108 | Percentage of Patients With Any Post-discharge Nausea and Vomiting (PDNV) | 9 Participants |
| Norco | Percentage of Patients With Any Post-discharge Nausea and Vomiting (PDNV) | 12 Participants |
| Placebo | Percentage of Patients With Any Post-discharge Nausea and Vomiting (PDNV) | 6 Participants |
Secondary
Percentage of Patients With Any Vomiting Over 48 Hours
Percentage of patients with any vomiting over 48 hours, comparing CL-108 5 mg to hydrocodone 5 mg/APAP 325 mg
Time frame: Up to 48 hours
Population: Intent-to-Treat (ITT) Population: The ITT Population comprised all patients who were randomized and who received at least 1 dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CL-108 | Percentage of Patients With Any Vomiting Over 48 Hours | 3 Participants |
| Norco | Percentage of Patients With Any Vomiting Over 48 Hours | 19 Participants |
| Placebo | Percentage of Patients With Any Vomiting Over 48 Hours | 2 Participants |
Secondary
Percentage of Patients With Complete Absence of OINV (no Nausea, no Vomiting, and no Use of Anti-emetic Medication) Over 48 Hours
Percentage of patients with complete absence of OINV (no nausea, no vomiting, and no use of anti-emetic medication) over 48 hours comparing CL-108 5 mg to hydrocodone 5 mg/APAP 325 mg)
Time frame: Up to 48 hours
Population: Intent-to-Treat (ITT) Population: The ITT Population comprised all patients who were randomized and who received at least 1 dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CL-108 | Percentage of Patients With Complete Absence of OINV (no Nausea, no Vomiting, and no Use of Anti-emetic Medication) Over 48 Hours | 50 Participants |
| Norco | Percentage of Patients With Complete Absence of OINV (no Nausea, no Vomiting, and no Use of Anti-emetic Medication) Over 48 Hours | 34 Participants |
| Placebo | Percentage of Patients With Complete Absence of OINV (no Nausea, no Vomiting, and no Use of Anti-emetic Medication) Over 48 Hours | 27 Participants |