Acute Pain
Conditions
Brief summary
This is a Phase 2 randomized, double-blind, placebo-controlled, 3-arm, parallel design study to evaluate the efficacy and safety of VX-150 in treating acute pain following bunionectomy.
Interventions
DRUGVX-150
Participants received VX-150 1500 milligram (mg) as first dose, followed by VX-150 750 mg dose every 12 hours (q12h) for 2 days.
DRUGHB/APAP
Participants received HB 5 mg/APAP 325 mg every 6 hours (q6h) for 2 days.
DRUGPlacebo
Participants received placebo matched to VX-150 and HB/APAP for 2 days.
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Prior to Surgery: * Body mass index (BMI) of 18.0 to 38.0 kg/m2, inclusive * Be scheduled to undergo a primary unilateral first metatarsal bunionectomy repair, without collateral procedures, under regional anesthesia (Mayo and popliteal sciatic block) not to include base wedge procedure After Surgery: * Subject reported pain of ≥4 on the NPRS, and moderate or severe pain on the Verbal Categorical Rating Scale (VRS) within 9 hours after removal of the popliteal sciatic block on Day 1 * Subject is lucid and able to follow commands * All analgesic guidelines were followed during and after the bunionectomy
Exclusion criteria
Prior to Surgery: * History in the past 10 years of malignancy, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical carcinoma in situ * History of cardiac dysrhythmias requiring anti-arrhythmia treatment(s) * History of abnormal laboratory results ≥2.5 × upper limit of normal (ULN) * History of peripheral neuropathy * A known or clinically suspected infection with human immunodeficiency virus or hepatitis B or C viruses * Prior medical history of bunionectomy or other foot surgery * Intolerant of or unwilling to receive hydrocodone, acetaminophen, or ibuprofen * For female subjects: Pregnant, nursing, or planning to become pregnant during the study or within 90 days after the last study drug dose * For male subjects: Male subjects with a female partner who is pregnant, nursing, or planning to become pregnant during the study or within 90 days after the last study drug dose After Surgery: * Subject had a type 3 deformity requiring a base wedge osteotomy or concomitant surgery such as hammertoe repair; or experienced medical complications during the bunionectomy that, in the opinion of the investigator, should preclude randomization Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-weighted Sum of the Pain Intensity Difference (SPID) Between VX-150 Versus Placebo as Recorded on a Numeric Pain Rating Scale (NPRS) 0 to 24 Hours After the First Dose | 0 to 24 hours after the first dose | SPID was calculated as the sum of the product of time (in hours) elapsed since previous measurements and pain intensity difference. Pain intensity difference was calculated by subtracting the pain intensity score at given post-dose time points from the baseline pain intensity scores (using pain rating score range: 0 =no pain to 10 =worst possible pain). SPID24 was calculated from 0 to 24 hours and the score range was -240 (worst score) to 240 (best score). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Using Rescue Medication After the First Dose VX-150 Versus Placebo | 0 to 24 hours after the first dose and 24 to 48 hours after the first dose | — |
| Time-weighted Sum of the Pain Intensity Difference Between VX-150 Versus Placebo as Recorded on a NPRS 2 to 24 Hours After the First Dose | 2 to 24 hours after the first dose | SPID was calculated as the sum of the product of time (in hours) elapsed since previous measurements and pain intensity difference. Pain intensity difference was calculated by subtracting the pain intensity score at given post-dose time points from the baseline pain intensity scores (using pain rating score range: 0 =no pain to 10 =worst possible pain). SPID22 was calculated from 2 to 24 hours and the score range was -220 (worst score) to 220 (best score). |
| Time-weighted Sum of the Pain Intensity Difference Between VX-150 Versus Placebo as Recorded on a NPRS 0 to 48 Hours After the First Dose | 0 to 48 hours after the first dose | SPID was calculated as the sum of the product of time (in hours) elapsed since previous measurements and pain intensity difference. Pain intensity difference was calculated by subtracting the pain intensity score at given post-dose time points from the baseline pain intensity scores (using pain rating score range: 0 =no pain to 10 =worst possible pain). SPID48 was calculated from 0 to 48 hours and the score range was -480 (worst score) to 480 (best score). |
| Time to Onset of Perceptible Pain Relief After the First Dose of VX-150 Versus Placebo | up to 6 hours after the first dose | Time to onset of perceptible pain relief (any pain relief at all after the first dose) reported based on the first stopwatch assessment. |
| Time to Onset of Meaningful Pain Relief After the First Dose of VX-150 Versus Placebo | up to 6 hours after the first dose | Time to onset of meaningful pain relief (relief that is meaningful to participants after the first dose) reported based on the second stopwatch assessment. |
| Time to First Rescue Medication After the First Dose of VX-150 Versus Placebo | up to 48 hours after the first dose | Time to first rescue medication was the time elapsed from the first dose of VX-150 or placebo until the participants received the first dose of rescue medication. |
| Total Rescue Medication Used After the First Dose of VX-150 Versus Placebo | 0 to 24 hours after the first dose and 24 to 48 hours after the first dose | Total use of rescue medication was calculated as the sum of number of capsules multiplied by capsule strength at each dosing occasion of rescue medication. Rescue medication was ibuprofen (400 mg \[oral\] every 4 hours (q4h) as needed). |
| Maximum Observed Concentration (Cmax) of VRT- 1207355 (Active Moiety) and VRT- 1268114 (Metabolite M5) | Day 1 and Day 2 | — |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of VRT- 1207355 and VRT- 1268114 | Day 1 and Day 2 | — |
| Area Under the Concentration Versus Time Curve From 0 to 12 Hours (AUC0-12h) of VRT- 1207355 and VRT- 1268114 | Day 1 and Day 2 | — |
| Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From Day 1 up to Day 10 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| VX-150 Participants received VX-150 1500 mg as first dose, followed by VX-150 750 mg q12h for 2 days. | 80 |
| HB/APAP Participants received HB 5 mg/APAP 325 mg q6h for 2 days. | 81 |
| Placebo Participants received placebo matched to VX-150 and HB/APAP for 2 days. | 82 |
| Total | 243 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Withdrawal of consent | 5 | 3 | 6 |
Baseline characteristics
| Characteristic | VX-150 | HB/APAP | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 44.4 years STANDARD_DEVIATION 12.87 | 44.8 years STANDARD_DEVIATION 13.04 | 45.0 years STANDARD_DEVIATION 12.43 | 44.7 years STANDARD_DEVIATION 12.73 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 21 Participants | 14 Participants | 27 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 59 Participants | 67 Participants | 55 Participants | 181 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Pain Intensity at Baseline (at 0 hours) as Recorded on Numeric Pain Rating Scale (NPRS) | 6.1 units on scale STANDARD_DEVIATION 1.7 | 6.6 units on scale STANDARD_DEVIATION 1.6 | 6.1 units on scale STANDARD_DEVIATION 1.5 | 6.3 units on scale STANDARD_DEVIATION 1.6 |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Asian | 8 Participants | 1 Participants | 3 Participants | 12 Participants |
| Race/Ethnicity, Customized Race Black or African American | 17 Participants | 22 Participants | 17 Participants | 56 Participants |
| Race/Ethnicity, Customized Race More than one race | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Race White | 52 Participants | 55 Participants | 59 Participants | 166 Participants |
| Sex: Female, Male Female | 64 Participants | 64 Participants | 65 Participants | 193 Participants |
| Sex: Female, Male Male | 16 Participants | 17 Participants | 17 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 80 | 0 / 81 | 0 / 82 |
| other Total, other adverse events | 20 / 80 | 22 / 81 | 23 / 82 |
| serious Total, serious adverse events | 0 / 80 | 0 / 81 | 0 / 82 |
Outcome results
Primary
Time-weighted Sum of the Pain Intensity Difference (SPID) Between VX-150 Versus Placebo as Recorded on a Numeric Pain Rating Scale (NPRS) 0 to 24 Hours After the First Dose
SPID was calculated as the sum of the product of time (in hours) elapsed since previous measurements and pain intensity difference. Pain intensity difference was calculated by subtracting the pain intensity score at given post-dose time points from the baseline pain intensity scores (using pain rating score range: 0 =no pain to 10 =worst possible pain). SPID24 was calculated from 0 to 24 hours and the score range was -240 (worst score) to 240 (best score).
Time frame: 0 to 24 hours after the first dose
Population: Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of study drug. As a standard-of-care reference arm, the HB/APAP arm was not intended for statistical comparisons to VX-150.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| VX-150 | Time-weighted Sum of the Pain Intensity Difference (SPID) Between VX-150 Versus Placebo as Recorded on a Numeric Pain Rating Scale (NPRS) 0 to 24 Hours After the First Dose | 36.14 units on a scale | Standard Error 5.15 |
| Placebo | Time-weighted Sum of the Pain Intensity Difference (SPID) Between VX-150 Versus Placebo as Recorded on a Numeric Pain Rating Scale (NPRS) 0 to 24 Hours After the First Dose | 6.64 units on a scale | Standard Error 5.03 |
p-value: <0.000195% CI: [16.61, 42.4]ANCOVA
Secondary
Area Under the Concentration Versus Time Curve From 0 to 12 Hours (AUC0-12h) of VRT- 1207355 and VRT- 1268114
Time frame: Day 1 and Day 2
Population: PK set. Here Number Analyzed signifies those participants who were evaluable at specified time points. This outcome measure is applicable to VX-150 arm only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VX-150 | Area Under the Concentration Versus Time Curve From 0 to 12 Hours (AUC0-12h) of VRT- 1207355 and VRT- 1268114 | VRT- 1207355 Day 1 | 38.8 microgram*hour per milliliter (mcg*h/mL) | Standard Deviation 15.9 |
| VX-150 | Area Under the Concentration Versus Time Curve From 0 to 12 Hours (AUC0-12h) of VRT- 1207355 and VRT- 1268114 | VRT- 1207355 Day 2 | 45.7 microgram*hour per milliliter (mcg*h/mL) | Standard Deviation 15.5 |
| VX-150 | Area Under the Concentration Versus Time Curve From 0 to 12 Hours (AUC0-12h) of VRT- 1207355 and VRT- 1268114 | VRT- 1268114 Day 1 | 12.9 microgram*hour per milliliter (mcg*h/mL) | Standard Deviation 6.2 |
| VX-150 | Area Under the Concentration Versus Time Curve From 0 to 12 Hours (AUC0-12h) of VRT- 1207355 and VRT- 1268114 | VRT- 1268114 Day 2 | 25.0 microgram*hour per milliliter (mcg*h/mL) | Standard Deviation 7.95 |
Secondary
Maximum Observed Concentration (Cmax) of VRT- 1207355 (Active Moiety) and VRT- 1268114 (Metabolite M5)
Time frame: Day 1 and Day 2
Population: The pharmacokinetic (PK) set included all randomized participants who received at least 1 dose of study drug. Here Number Analyzed signifies those participants who were evaluable at specified time points. This outcome measure is applicable to VX-150 arm only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VX-150 | Maximum Observed Concentration (Cmax) of VRT- 1207355 (Active Moiety) and VRT- 1268114 (Metabolite M5) | VRT- 1207355 Day 1 | 4.95 microgram per milliliter (mcg/mL) | Standard Deviation 2 |
| VX-150 | Maximum Observed Concentration (Cmax) of VRT- 1207355 (Active Moiety) and VRT- 1268114 (Metabolite M5) | VRT- 1207355 Day 2 | 4.92 microgram per milliliter (mcg/mL) | Standard Deviation 1.61 |
| VX-150 | Maximum Observed Concentration (Cmax) of VRT- 1207355 (Active Moiety) and VRT- 1268114 (Metabolite M5) | VRT- 1268114 Day 1 | 1.65 microgram per milliliter (mcg/mL) | Standard Deviation 0.779 |
| VX-150 | Maximum Observed Concentration (Cmax) of VRT- 1207355 (Active Moiety) and VRT- 1268114 (Metabolite M5) | VRT- 1268114 Day 2 | 2.53 microgram per milliliter (mcg/mL) | Standard Deviation 0.797 |
Secondary
Percentage of Participants Using Rescue Medication After the First Dose VX-150 Versus Placebo
Time frame: 0 to 24 hours after the first dose and 24 to 48 hours after the first dose
Population: FAS. As a standard-of-care reference arm, the HB/APAP arm was not intended for statistical comparisons to VX-150.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VX-150 | Percentage of Participants Using Rescue Medication After the First Dose VX-150 Versus Placebo | 0 to 24 hours after the first dose | 83.8 percentage of participants |
| VX-150 | Percentage of Participants Using Rescue Medication After the First Dose VX-150 Versus Placebo | 24 to 48 hours after the first dose | 56.3 percentage of participants |
| Placebo | Percentage of Participants Using Rescue Medication After the First Dose VX-150 Versus Placebo | 0 to 24 hours after the first dose | 89.0 percentage of participants |
| Placebo | Percentage of Participants Using Rescue Medication After the First Dose VX-150 Versus Placebo | 24 to 48 hours after the first dose | 69.5 percentage of participants |
p-value: 0.3358Cochran-Mantel-Haenszel
p-value: 0.0849Cochran-Mantel-Haenszel
Secondary
Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: From Day 1 up to Day 10
Population: The Safety Set was included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VX-150 | Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 25 participants |
| VX-150 | Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 0 participants |
| Placebo | Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 30 participants |
| Placebo | Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 0 participants |
| Placebo | Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 29 participants |
| Placebo | Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 0 participants |
Secondary
Time to First Rescue Medication After the First Dose of VX-150 Versus Placebo
Time to first rescue medication was the time elapsed from the first dose of VX-150 or placebo until the participants received the first dose of rescue medication.
Time frame: up to 48 hours after the first dose
Population: FAS. As a standard-of-care reference arm, the HB/APAP arm was not intended for statistical comparisons to VX-150.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VX-150 | Time to First Rescue Medication After the First Dose of VX-150 Versus Placebo | 2.7 hours |
| Placebo | Time to First Rescue Medication After the First Dose of VX-150 Versus Placebo | 2.3 hours |
p-value: 0.2341Regression, Cox
Secondary
Time to Onset of Meaningful Pain Relief After the First Dose of VX-150 Versus Placebo
Time to onset of meaningful pain relief (relief that is meaningful to participants after the first dose) reported based on the second stopwatch assessment.
Time frame: up to 6 hours after the first dose
Population: FAS. As a standard-of-care reference arm, the HB/APAP arm was not intended for statistical comparisons to VX-150.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VX-150 | Time to Onset of Meaningful Pain Relief After the First Dose of VX-150 Versus Placebo | 53.4 minutes |
| Placebo | Time to Onset of Meaningful Pain Relief After the First Dose of VX-150 Versus Placebo | 75.9 minutes |
p-value: 0.329495% CI: [0.79, 2]Regression, Cox
Secondary
Time to Onset of Perceptible Pain Relief After the First Dose of VX-150 Versus Placebo
Time to onset of perceptible pain relief (any pain relief at all after the first dose) reported based on the first stopwatch assessment.
Time frame: up to 6 hours after the first dose
Population: FAS. As a standard-of-care reference arm, the HB/APAP arm was not intended for statistical comparisons to VX-150.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VX-150 | Time to Onset of Perceptible Pain Relief After the First Dose of VX-150 Versus Placebo | 26.8 minutes |
| Placebo | Time to Onset of Perceptible Pain Relief After the First Dose of VX-150 Versus Placebo | 28.3 minutes |
p-value: 0.046995% CI: [1.01, 2.16]Regression, Cox
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of VRT- 1207355 and VRT- 1268114
Time frame: Day 1 and Day 2
Population: PK set. Here Number Analyzed signifies those participants who were evaluable at specified time points. This outcome measure is applicable to VX-150 arm only.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| VX-150 | Time to Reach Maximum Observed Plasma Concentration (Tmax) of VRT- 1207355 and VRT- 1268114 | VRT- 1207355 Day 1 | 5.58 hours |
| VX-150 | Time to Reach Maximum Observed Plasma Concentration (Tmax) of VRT- 1207355 and VRT- 1268114 | VRT- 1207355 Day 2 | 4.03 hours |
| VX-150 | Time to Reach Maximum Observed Plasma Concentration (Tmax) of VRT- 1207355 and VRT- 1268114 | VRT- 1268114 Day 1 | 8.10 hours |
| VX-150 | Time to Reach Maximum Observed Plasma Concentration (Tmax) of VRT- 1207355 and VRT- 1268114 | VRT- 1268114 Day 2 | 4.03 hours |
Secondary
Time-weighted Sum of the Pain Intensity Difference Between VX-150 Versus Placebo as Recorded on a NPRS 0 to 48 Hours After the First Dose
SPID was calculated as the sum of the product of time (in hours) elapsed since previous measurements and pain intensity difference. Pain intensity difference was calculated by subtracting the pain intensity score at given post-dose time points from the baseline pain intensity scores (using pain rating score range: 0 =no pain to 10 =worst possible pain). SPID48 was calculated from 0 to 48 hours and the score range was -480 (worst score) to 480 (best score).
Time frame: 0 to 48 hours after the first dose
Population: FAS. As a standard-of-care reference arm, the HB/APAP arm was not intended for statistical comparisons to VX-150.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| VX-150 | Time-weighted Sum of the Pain Intensity Difference Between VX-150 Versus Placebo as Recorded on a NPRS 0 to 48 Hours After the First Dose | 112.22 units on a scale | Standard Error 10.57 |
| Placebo | Time-weighted Sum of the Pain Intensity Difference Between VX-150 Versus Placebo as Recorded on a NPRS 0 to 48 Hours After the First Dose | 49.43 units on a scale | Standard Error 10.33 |
p-value: <0.000195% CI: [36.3, 89.27]ANCOVA
Secondary
Time-weighted Sum of the Pain Intensity Difference Between VX-150 Versus Placebo as Recorded on a NPRS 2 to 24 Hours After the First Dose
SPID was calculated as the sum of the product of time (in hours) elapsed since previous measurements and pain intensity difference. Pain intensity difference was calculated by subtracting the pain intensity score at given post-dose time points from the baseline pain intensity scores (using pain rating score range: 0 =no pain to 10 =worst possible pain). SPID22 was calculated from 2 to 24 hours and the score range was -220 (worst score) to 220 (best score).
Time frame: 2 to 24 hours after the first dose
Population: FAS. As a standard-of-care reference arm, the HB/APAP arm was not intended for statistical comparisons to VX-150.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| VX-150 | Time-weighted Sum of the Pain Intensity Difference Between VX-150 Versus Placebo as Recorded on a NPRS 2 to 24 Hours After the First Dose | 34.95 units on a scale | Standard Error 4.93 |
| Placebo | Time-weighted Sum of the Pain Intensity Difference Between VX-150 Versus Placebo as Recorded on a NPRS 2 to 24 Hours After the First Dose | 6.43 units on a scale | Standard Error 4.82 |
p-value: <0.000195% CI: [16.18, 40.88]ANCOVA
Secondary
Total Rescue Medication Used After the First Dose of VX-150 Versus Placebo
Total use of rescue medication was calculated as the sum of number of capsules multiplied by capsule strength at each dosing occasion of rescue medication. Rescue medication was ibuprofen (400 mg \[oral\] every 4 hours (q4h) as needed).
Time frame: 0 to 24 hours after the first dose and 24 to 48 hours after the first dose
Population: FAS. As a standard-of-care reference arm, the HB/APAP arm was not intended for statistical comparisons to VX-150.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VX-150 | Total Rescue Medication Used After the First Dose of VX-150 Versus Placebo | 0 to 24 hours after the first dose | 800 mg | Standard Deviation 341.1 |
| VX-150 | Total Rescue Medication Used After the First Dose of VX-150 Versus Placebo | 24 to 48 hours after the first dose | 577.8 mg | Standard Deviation 289.9 |
| Placebo | Total Rescue Medication Used After the First Dose of VX-150 Versus Placebo | 0 to 24 hours after the first dose | 1084.9 mg | Standard Deviation 478.3 |
| Placebo | Total Rescue Medication Used After the First Dose of VX-150 Versus Placebo | 24 to 48 hours after the first dose | 786.0 mg | Standard Deviation 413.8 |
p-value: 0.0004Wilcoxon rank-sum test
p-value: 0.0035Wilcoxon rank-sum test