Suzetrigine for Non-Mastectomy Breast Surgery

This is a single-center clinical study to investigate the efficacy of a Food and Drug Administration-approved analgesic, suzetrigine, to treat pain following non-mastectomy breast surgery in concert with a single-injection paravertebral nerve block.

Following written, informed consent, the investigators will collect baseline anthropomorphic information (e.g., age, sex, height, and weight). For individuals of childbearing potential, a sample of urine will be collected before any study interventions to confirm a non-pregnant state (this is standard procedure for all surgical patients).

The University of California San Diego Investigational Drug Service will distribute the study medication (suzetrigine) to the investigators (7 suzetrigine tablets, each 50 mg) and labeled with the appropriate dosing. The first dose of study medication (2 tablets = 100 mg) will be delivered preoperatively: 2 tablets to the participant. In addition, all participants will be given oral acetaminophen (975-1000 mg) per our standard-of-care.

Paravertebral nerve blocks (standard of care). All subjects will have a peripheral intravenous catheter inserted, standard noninvasive monitors applied, and oxygen delivered by facemask. The paravertebral nerve block site(s) will be cleansed with chlorhexidine gluconate and isopropyl alcohol. Intravenous sedation/analgesia with midazolam and/or fentanyl will be titrated for patient comfort as is standard for peripheral nerve block administration. A low-frequency curvilinear ultrasound transducer (6-2 MHz) will be used to identify the T1 through T5 transverse processes and paravertebral spaces. The target nerves will be visualized with ultrasound using a transverse cross-sectional (short axis) view and a skin wheal of local anesthetic will be raised inferior to the transducer to anesthetize the skin and then the track towards the target. A 20-gauge Tuohy needle will be inserted into the appropriate plane/space under direct ultrasound guidance via an in-plane parasagittal approach. Local anesthetic (0.5% ropivacaine) with 1:400,000 of epinephrine will be injected at the appropriate levels after negative aspiration (20 mL for unilateral surgery, 16 mL on each side for bilateral surgery). A two-level injection technique will be performed: T2 and T4 for surgeries involving axillary work or T3 and T5 for surgeries not involving axillary work. Blocks will be considered successful if, within 30 min, the subject experiences decreased sensation to cold temperature over the level of the ipsilateral fourth thoracic dermatome at the level of anterior axillary line. For subjects undergoing a bilateral surgical procedure, blocks using the same protocol will be administered on the contralateral side.

Intraoperative and postoperative management. Surgery will be performed under general anesthesia with a combination of inhaled and intravenous anesthetics. Intraoperative fentanyl will be administered at the discretion of the masked anesthesia team based on cardiovascular responsiveness to noxious stimuli, and total fentanyl use will be recorded. Subjects will be extubated, taken to the postanesthesia care unit and received by a nurse masked to treatment group assignment. A standard postoperative opioid algorithm will be used which involves: 1) intravenous fentanyl 25 µg for Numeric Rating Scale (NRS) pain scores of less than 5, 2) intravenous fentanyl 50 µg for NRS of 5 or greater, 3) intravenous hydromorphone 0.5 mg for NRS of 5 or greater if fentanyl deemed ineffective, and 4) oxycodone 5 mg for NRS of 4 to 6 if able to tolerate oral medications. It is rare that patients with a paravertebral nerve block require any analgesics in the recovery room. Participants and their caretakers will have the study protocol reviewed with them and then be discharged home with 5 tablets of study medication (suzetrigine 50 mg), a prescription for rescue oxycodone, and written instructions. Participants will be instructed to take 1 tablet every 12 hours following the initial dose through the evening of postoperative day 2. They will be instructed to avoid food or drink containing grapefruit until postoperative day 4 (contraindicated with suzetrigine).

Comparison group. The collected data will be compared with study participants from two previously completed randomized, controlled trials in which half of all participants received a placebo/sham intervention. Therefore, the historic controls all received University of California San Diego's standard analgesics and no investigational intervention [1,2]

Outcome measurements. The investigators have selected outcome measures that have established reliability and validity, with minimal inter-rater discordance, and are recommended for pain clinical trials by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus statement. Median value of the maximum ("worst") pain scores from postoperative days 1-3 as measured with the 0-10 NRS. Data collection will be conducted by daily telephone calls on postoperative days 1, 2, 3, 4, 5, and 7, as well as month 6. The Principal Investigator has reached over 97% of participants in similar studies involving breast surgery over the previous 2 decades. During the calls on postoperative days 1-3, participants' dosing the previous night will be confirmed, and participants reminded to take their next dose the evenings of postoperative days 1 and 2.

Each time the questionnaire is applied, participants will be instructed to respond for the previous 24 hours. The exception will be on Day 1 because at these time points, the interest is in participants' experiences subsequent to discharge from the recovery room. During this day only, participants will be instructed to respond for the period of time since they were discharged from the recovery room.

The investigators will record basic anthropomorphic characteristics (e.g., age, physiological sex, height, and weight, surgical characteristics (e.g., surgical duration), and protocol deviations / adverse events.

All data collection following the day of the intervention (postoperative day 0) will be collected by telephone from the University of California San Diego by the investigators, Program Manager, and/or research coordinators specifically trained in these instruments' application, minimizing inter-rater discordance. Each data collection phone call will require approximately 5 minutes.

In addition to the outcomes described below, the investigators will record awakenings due to pain at each data collection phone call.

Hypothesis 1: Following breast surgery, analgesia will be improved in the first 3 postoperative days with suzetrigine added to the current standard-of-care analgesics (as measured with the NRS). Current/present, worst, least, and average surgical pain will be assessed using the NRS as part of the BPI (short form) on postoperative day 2, with the "worst" (maximum) and "average" pain scores collected on postoperative days 1, 2, 3, 4 and 7 as well as Month 6. The designated primary endpoint is the median value of the maximum ("worst") pain scores from postoperative days 1-3 as measured with the 0-10 NRS. The NRS is a highly-sensitive measure of pain intensity with numbers ranging from 0 to 10, zero equivalent to no pain and 10 equivalent to the worst imaginable pain. The NRS has been demonstrated to be a valid and reliable measure in multiple pain states and following analgesic interventions. In addition, NRS scores correlate well with other measures of pain intensity, and demonstrate high test-retest reliability in chronic nociceptive and neuropathic pain states.

Hypothesis 2: Following breast surgery, opioid consumption will be reduced in the first 3 postoperative days with suzetrigine added to the current standard-of-care analgesics (measured in oxycodone equivalents). Opioid analgesic consumption will be recorded at all time points, with a secondary outcome measure being the percentage of each group completely avoiding post-recovery room opioid consumption. Cumulative opioid consumption from discharge through postoperative day 3 will also be assessed. The two treatment groups' daily opioid consumption will also be compared at all timepoints. While the investigators will collect this information, opioid consumption after resolution of the paravertebral nerve block has been extremely low in historic controls, so the investigators do not anticipate identifying superiority with the intervention. Opioid consumption comparisons will therefore be placed lower in the gatekeeping protocol (see statistical section).

Hypothesis 3: Following breast surgery, pain's interference with physical and emotional functioning will be reduced on postoperative day 2 with suzetrigine added to the current standard-of-care analgesics (as measured with the Brief Pain Inventory interference scale). It is well-recognized that, "pain is a complex, multidimensional, sensory, and emotional experience that is individually perceived and described in many different ways." This observation has led to consensus recommendations that "multiple core domains and related measures be considered in pain treatment trials," that "tap into a wider experience of pain over time and its impact on functioning and quality of life." Therefore, the proposed trial will include the Brief Pain Inventory, an instrument that includes-in addition to pain intensity scales-seven measures evaluating the pain's interference with physical and emotional functioning, such as sleep, relations with others, and enjoyment of life. It is this 7-question Interference Scale that will be used specifically for Hypothesis 3. The BPI has been used and validated in countless clinical pain-related studies. This instrument is associated with minimal subject burden and is easily interpreted by participants of all ages and education levels. It has high test-retest reliability and correlates well with much longer questionnaires, including the McGill measures and EuroQol. The secondary outcome measures of greatest interest after pain and opioid consumption will be the Interference Scale (0-70) recorded on Day 2.

Hypothesis 4: Following breast surgery, chronic pain will be reduced after 6 months (as measured with the NRS). Acute can transition into chronic postoperative pain (persistent post-surgical pain). One of the best predictors of chronic pain is the level of acute pain. It is therefore hypothesized-though not yet proven-that improving analgesia in the immediate postoperative period may decrease the incidence and severity of chronic pain.

Sample Size Estimation. 120 analyzed participants. This will be a superiority study using patients from two of the Principal Investigator's previous clinical trials that enrolled the same patient population to determine the sample size. These previous participants were randomized to receive the sham intervention and who therefore received solely a paravertebral nerve block, scheduled acetaminophen 975mg four times each day, and oxycodone 5 mg in case of pain as will the standard-of-care group of the proposed trial. Participants were queried by telephone the first 7 postoperative days for multiple outcome measures, including their worst (maximum) pain from the previous 24 hours measured using the 0-10 NRS. The mean of these 3 pain scores was calculated for each participant, and the mean (SD) pain intensity was 4.0 (3.0). The investigators will use ≥ 2 on the NRS as the smallest clinically important change in acute pain for individuals [3]. However, clinically relevant differences between two treatment groups is usually smaller than for individual patients [4,5]. Therefore, the investigators will use a difference of 1.6 on the NRS as the smallest clinically important difference between the two treatment groups, which will require a sample size of 110 total participants using a significance level (alpha) of 5% and power (1-beta) of 80%. To account for increased variability in the outcome distribution, the investigators will enroll 10 additional participants for a total of 120 participants, who will be compared with the 30 historic controls (https://clincalc.com/Stats/SampleSize.aspx). Of note, all comparisons between treatment groups will use median [IQR] values.

Statistical analysis plan. A total of 120 individuals are required for analysis; however, an additional 30 may be enrolled to account for participants lacking the primary outcome measure (e.g., dropouts, lost to follow-up). The investigator therefore are requesting a maximum of 150 participants be enrolled. Baseline characteristics of the randomized groups will be summarized with means, standard deviations, and quartiles. Balance between groups will be assessed following the approach described by Schober [6]. Specifically, standardized differences will be calculated using Cohen's d whereby the difference in means or proportions is divided by the pooled standard deviation estimates. Any key variables (age, sex, height, weight, body mass index, and surgical procedure) with a high absolute standardized difference will be noted and included in a sensitivity analysis with a generalized linear model (e.g. linear regression for pain severity NRS or logistic regression for incidence rates) to obtain an estimate of the treatment effect adjusted for the imbalanced covariate(s). If key model assumptions are violated (i.e. homoscedasticity or Gaussian distribution for linear models), data transformations and/or alternative generalized linear models will be applied as appropriate. Missing data is expected to be negligible. In the event of unexpected missing data, multiple imputation by chained equations [Stef van Buuren, Karin Groothuis-Oudshoorn (2011)]. Multivariate Imputation by Chained Equations in R. Journal of Statistical Software, 45(3), 1-67) will be applied to obtain estimates of treatment effects under the assumption of missing at random. The imputation model will exhaustively consider all measured baseline covariates and longitudinal observations to maximize the likelihood that the missing at random assumption is met.

The primary analytic approach will be an unadjusted two-sample Mann-Whitney U test of the median value of each participant's worst daily NRS collected on postoperative days 1, 2, and 3 (both the active treatment and historic controls). If any key variables are imbalanced at baseline, a linear regression model, or appropriate generalized linear model, adjusting for those variables will be applied. The p-value and 95% confidence interval associated with the estimated group difference in average daily NRS will be provided. P<0.05 will be considered statistically significant for the primary outcome.

Continuous endpoints will be analyzed with the same approach as the primary endpoint. Binary endpoints will be analyzed with Fisher's Exact test for two proportions, or logistic regression in the event of imbalance on key baseline variables. Ordinal endpoints will be analyzed with the Armitage trend test, or cumulative link regression model as warranted. The investigators will test key secondary outcomes using a serial gatekeeping procedure. Nominal 95% confidence intervals will be provided for secondary analyses.

Study-wide Type I error control. The investigators will use a serial gatekeeping procedure to control the study-wide type I error at 0.05 [7]. For this procedure the investigators therefore have prioritized (a priori) the study outcomes (list below). Analysis will proceed in that order, and testing will proceed through each "gate" to the next set if and only if the outcome in the current set reaches significance. The significance level for each set will be 0.05 times a cumulative penalty for non-significant results in previous sets (i.e., a "rejection gain factor" equal to the cumulative product of the proportion of significant tests across the preceding sets). The investigators will use the corresponding 2-tailed alpha level of 0.05 for the gatekeeping, as all sets involve 2-tailed tests. Treatment effects will also be assessed at individual time points regardless of preceding gatekeeping results, and no other adjustments will be made for testing multiplicity:

1. Maximum NRS evaluated on postoperative day 2
2. Average NRS evaluated on postoperative day 2
3. Brief Pain Inventory interference subscale on postoperative day 2
4. Percentage of each group completely avoiding post-recovery room moderate pain (NRS>3)
5. Percentage of each group completely avoiding post-recovery room severe pain (NRS>6)
6. Percentage of each group completely avoiding post-recovery room opioid consumption
7. Maximum NRS evaluated on postoperative day 1
8. Average NRS evaluated on postoperative day 1
9. Maximum NRS evaluated on postoperative day 3
10. Average NRS evaluated on postoperative day 3
11. Cumulative opioid consumption following recovery room discharge through postoperative day 3
12. Incidence of chronic pain evaluated after 6 months

Additional secondary outcomes (no adjustment for multiple comparisons):

1. Surgical duration
2. Maximum NRS evaluated on each of postoperative days 4-7
3. Average daily NRS evaluated on each of postoperative days 4-7
4. Least NRS evaluated on postoperative day 2
5. Current NRS evaluated on postoperative day 2
6. Daily opioid consumption on each of postoperative days 1-7
7. Awakenings from sleep due to surgical pain on each of postoperative evenings 0-6
8. Discharge from hospital on postoperative day 1 or greater
9. Adverse events

Following study completion, the results will be mailed electronically to all enrolled participants in written form using non-technical (e.g., "layperson") language.