Ignite Creation Date:
2024-05-06 @ 5:48 PM
Last Modification Date:
2024-10-26 @ 2:36 PM
Study NCT ID:
NCT05444361
Status:
ENROLLING_BY_INVITATION
Last Update Posted:
2024-05-30
First Post:
2022-06-24
Brief Title:
Ultrasound-Guided Percutaneous Cryoneurolysis to Treat Postoperative Pain After Mastectomy
Sponsor:
University of California San Diego
Organization:
University of California San Diego
Study Overview
Official Title:
Eliminating Post-Mastectomy Pain and Opioids With Percutaneous Cryoneurolysis A Single-Administration Non-Opioid Non-Addictive Multiple-Month Analgesic
Status:
ENROLLING_BY_INVITATION
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Breast cancer is the most common type of cancer in women Removal of the breast called mastectomy is performed either when there is cancer-or an increased risk of cancer-in the breast This can result in a lot of pain during the months after surgery Opioids-narcotics-are the most common pain control method provided to patients but they frequently do not relieve enough pain have undesirable side effects like vomiting and constipation and are sometimes misused which can lead to addiction Mastectomy also frequently results in long-term pain which can interfere with physical and emotional functioning and the more pain patients have immediately after surgery the greater the risk of developing long-term pain Numbing the nerves with local anesthetic can decrease the amount of short- and long-term pain experienced by patients but even the longest types of these nerve blocks last for hours or days and not the 1-2 months of pain typically following mastectomy So there is reason to believe that if the nerve blocks could be extended so that they last longer than the pain from surgery short- and long-term pain might be avoided completely without the need for opioids A prolonged nerve block may be provided by freezing the nerve using a technique called cryoneurolysis With cryoneurolysis and ultrasound machines a small needle-like probe may be placed through anesthetized skin and guided to the target nerve to allow freezing The procedure takes about 5 minutes for each nerve involves little discomfort has no side effects and cannot be misused or become addictive After 2-3 months the nerve returns to normal functioning The investigators have completed a small study suggesting that a single cryoneurolysis treatment may provide potent pain relief after mastectomy The ultimate objectives of the proposed research study are to determine if temporarily freezing the nerves that go to the breast will decrease short-term pain opioid use physical and emotional dysfunction and long-term pain following mastectomy when added to current and customary postoperative analgesics
The current project is a pragmatic multicenter randomized triple-masked investigators participants statisticians shamplacebo-controlled parallel-arm human-subjects post-market clinical trial to determine if cryoneurolysis is an effective non-opioid treatment for pain following mastectomy
The current project is a pragmatic multicenter randomized triple-masked investigators participants statisticians shamplacebo-controlled parallel-arm human-subjects post-market clinical trial to determine if cryoneurolysis is an effective non-opioid treatment for pain following mastectomy
Detailed Description:
All participants will continue to receive standard and customary postoperative analgesics of their local treatment center so there is no risk of participants receiving a lower degree of analgesia than if they otherwise did not enroll in the study The cryoneurolysis procedure will be done in addition to standard local institutional standard analgesic treatments
The investigators propose a pragmatic multicenter randomized triple-masked investigators participants statisticians shamplacebo-controlled parallel-arm human-subjects clinical trial to determine if cryoneurolysis is an effective non-opioid treatment for pain following mastectomy Participants will be individuals undergoing unilateral or bilateral mastectomy recruited at 6 centers
Walter Reed National Military Medical Center Bethesda Maryland
UC San Diego San Diego California
University of Florida Gainesville Florida
Cedars-Sinai Los Angeles California
Cleveland Clinic Cleveland Ohio
For women of childbearing age with the possibility of pregnancy a sample of urine will be collected before any study interventions to confirm a non-pregnant state Participants will have a peripheral intravenous IV catheter inserted standard noninvasive monitors applied blood pressure cuff pulse oximeter 5-lead ECG and oxygen administered via a facemask Midazolam and fentanyl IV will be titrated for patient comfort as needed throughout the procedure while ensuring that patients remain responsive to verbal cues
Peripheral nerve block Not all enrolling centers provide peripheral blocks as part of their standard-of-care Due to the pragmatic design of this trial study participation will not alter an institutions current practice If the local practice includes a postoperative continuous peripheral nerve block a perineural catheter will be inserted 2-5 cm beyond the needle tip the needle withdrawn over the catheter the catheter affixed with an occlusive sterile dressing
Participants will be allocated to one of two treatments
1 cryoneurolysis
2 sham cryoneurolysis placebo control
Randomization will be stratified by enrolling institution surgical site unilateral vs bilateral and axillary involvement nonebiopsy vs dissection in a 11 ratio and in randomly chosen block sizes Randomization lists will be created using Statistical Analysis Software computer-generated tables by the informatics division of the Department of Outcomes Research Cleveland Clinic Cleveland OH Treatment group assignment will be conveyed to the enrolling sites via the same secure web-based system REDCap used to collect and collate all post-intervention endpoints
There are multiple types of cryoneurolysis machines cleared by the US FDA all of which work on the same principle of a gas being passed through a small annulus resulting in a dramatic pressure drop and accompanying temperature drop due to the Joule-Thomson effect This study will utilize two different consoles second option added May 8 2023 the Epimed International Farmers Branch TX and Varian Medical Systems Palo Alto CA machines Which machine is used is determined simply by the machine that each enrolling center has at its disposal
Varian This machine uses argon for the freeze cycle and helium to help decrease the thaw period duration Sham probes are not available for this type of machine and therefore an active probe will be used for all participants For participants randomized to active treatment the probe will be connected to the machine as usual the argon and helium passed through the probe and then back into the machine and finally vented out from the console For participants randomized to sham treatment the probe will be connected to an inactive connector on the back of the machine For these participants the gas will simply be ejected directly from the console without ever having passed through the probe The investigator administering the study intervention will access the treatment group assignment using the secure web-based system and attach the probe active or leave the tubing end close to the machine sham Therefore all investigators participants and clinical staff will be masked to treatment group assignment with the only exception being the unmasked individual who performs the procedure and will not have subsequent contact with the participant
Epimed This machine uses nitrous oxide for the freeze cycle with a passive thaw no gas flow Cryoneurolysis probes are available that either 1 pass nitrous oxide to the distal end inducing freezing temperatures or 2 vent the nitrous oxide at the proximal end of the probe so that no gas reaches the distal end resulting in no temperature change The latter is a sham procedure since without the temperature change no ice ball forms and therefore the target nerve is not affected Importantly these probes are indistinguishable in appearance and will be differentiated only by an identifying stamp on the underside of the connector which is not visible during use
The investigator administering the study intervention will access the treatment group assignment using the secure web-based system and attach the appropriate probe to the cryoneurolysis device Therefore all investigators participants and clinical staff will be masked to treatment group assignment with the only exception being the unmasked individual who performs the procedure and will not have subsequent contact with the participant For both types of machines it is impossible to mask the individual performing the cryoneurolysis procedure because the ice ball forming at the distal end of the probe-with active treatment-is clearly visible by ultrasound and the lack of an ice ball for placebo participants is equally clear It is essential to continuously visualize the probe and target nerve throughout the freezethaw cycles to ensure the entire nerve diameter is adequately treated and remains relatively motionless This cannot be achieved if the ultrasound is turned off during gas administration in an attempt to mask the provider
Study intervention The 2nd-6th thoracic intercostal nerves will be treated on the ipsilateral surgical side bilaterally for bilateral surgical procedures Using a curved-array transducer the intercostal nerve will be visualized using ultrasound just inferior to each treated rib immediately distal to the costotransverse joint For participants without a paravertebral block a skin wheal of lidocaine 1 will be raised immediately inferior to the transducer to anesthetize the skin An IV-like hollow-bore introducer may be inserted through the skin and guided to the target nerve--this is based on operator personal preference For participants without anesthetized intercostal nerves from a peripheral nerve block lidocaine 15-20 2 mL may be injected through the introducer prior to the cryoneurolysis probe introduction to provide anesthesia during the cryoneurolysis cycles although this is not universally applied they cryoneurolysis treatment itself induces anesthesia
A portable cryoneurolysis device Varian CryoCare or Epimed PainBlocker will be used The probe will be inserted adjacent to the intercostal nerve
Varian The cryoneurolysis device will be triggered using 1 cycle of 55-minute all but 4 participants 064-067 or 3 minutes only 4 participants 064-067 change based on new laboratory data then changed back based on inadequate freeze argon activation 2000 psi and 100 power followed by a 30-second helium defrost
Epimed The cryoneurolysis device will be triggered using 2 cycles of 2-minute gas activation active or sham separated by a 1-minute defrost
The introducer and probe will be withdrawn and this process repeated for each additional intercostal nerve to be treated For bilateral mastectomies the study intervention will be repeated on the contralateral side with the same probe
Intraoperative course Due to the pragmatic nature of this trial the investigators aim to change each centers standard practice as little as possible and rather investigate the results of adding the intervention to current practice The investigators will therefore record intraoperative factors such as type of general anesthetic axillary dissection opioid administration and local anesthetic supplementation however the investigators will not require changes to current standard practice
Postoperative course Standard local supplemental analgesics will be used due to the pragmatic design of this trial For analysis purposes all opioids will be converted to oral oxycodone equivalents Following a cryoneurolysis treatment no action is required by patients regarding this intervention For example in contrast to epidural infusions there is no infusion pump to manage or anesthetic fluid to replenish At enrolling centers that provide a postoperative continuous peripheral nerve block the ropivacaine or bupivacaine infusions will be administered per local protocol with the catheters removed on postoperative day 1 or 2 prior to hospital discharge
Following study completion the results will be mailed electronically or by the United States Postal Service to all enrolled participants in written form using non-technical eg layperson language
Outcome Measurements End Points The investigators have selected outcome measures that have established reliability and validity with minimal inter-rater discordance and are recommended for pain-related clinical trials by the World Health Organization and the Initiative on Methods Measurement and Pain Assessment in Clinical Trials IMMPACT consensus statement Table 1 below5 End points will be evaluated at baseline prior to surgery on postoperative day 0 as well as postoperative days 1 2 3 4 7 21 30 45 and months 2 3 6 9 and 12
Statistical Plan and Data Analysis
Primary Specific Aim To determine the effect of cryoneurolysis on postoperative opioid requirements and analgesia following mastectomy
Hypothesis 1 Opioid consumption will be significantly decreased in the first two months following surgery with cryoneurolysis compared with usual and customary analgesia
Hypothesis 2 Surgical pain will be significantly decreased within the first two months following surgery with cryoneurolysis compared with usual and customary analgesia measured with a Numeric Rating Scale
Primary end point In order to claim that cryoneurolysis is superior to usual and customary analgesia at least one of Hypotheses 1 and 2 above must be superior while the other at least noninferior
Secondary Specific Aims To determine the effect of cryoneurolysis on physical and emotional functioning and chronic pain following mastectomy
Hypothesis 3 Physical and emotional functioning will be significantly improved within the first two months following surgery with cryoneurolysis as compared with usual and customary analgesia measured with the Interference Domain of the Brief Pain Inventory
Hypothesis 4 The incidence of chronic pain will be significantly decreased 6 and 12 months following surgery with cryoneurolysis as compared with usual and customary analgesia
Hypothesis 5 The intensity of chronic pain will be significantly decreased 6 and 12 months following surgery with cryoneurolysis as compared with usual and customary analgesia measured with a Numeric Rating Scale
Balance on baseline covariates will be assessed using absolute standardized difference ASD50 ie difference in means or proportions divided by the standard deviation ASD 01 will be considered to indicate imbalance and these variables will be adjusted for in the statistical analyses Analyses will be carried out using modified intention-to-treat ie patients who received any study treatment will be analyzed according to the group to which they were randomized The overall type I error rate of the study will be controlled using a parallel gatekeeping procedure see Study-wide Type I error rate control
Primary Objective Hypotheses 1 and 2 The investigators will estimate the treatment effect of cryoneurolysis on opioid consumption Hypothesis 1 and average pain score Hypothesis 2 using a joint hypothesis-testing framework The investigators will conclude that cryoneurolysis is more effective compared to the standard of care if it is noninferior on both opioid consumption and pain score and superior for at least one of the outcomes during the first 2 months after surgery No adjustment for multiple testing is needed for noninferiority testing since the investigators require noninferiority on both pain score and opioid consumption outcomes
Noninferiority Testing
Hypothesis 1 Opioid consumption Cumulative opioid assumption is typically log-normally distributed The investigators will therefore assess the treatment effect on the log-transformed cumulative opioid consumption at 2 months using a linear regression model The investigators will test for NI of cryoneurolysis to standard of care using a 1-tailed test assuming alpha of 0025 and NI delta of 12 for the ratio of geometric means treatmentplacebo All opioids will be converted to oral oxycodone equivalents
Hypothesis 2 Average pain score The investigators will test for noninferiority NI of cryoneurolysis to standard of care using 1-tailed tests and assuming a 1-tailed alpha of 0025 The primary pain outcome will be the area under the curve AUC of patient average pain scores over the first 2 months 60 days AUC-60 For this outcome the noninferiority NI delta will be a ratio of geometric means of 12 in the AUC-60 Since AUC-60 is expected to be skewed and to have some proportion of zero values the investigators will estimate the treatment effect a 2-sample t-test on the log-transformed AUC-60 1 Noninferiority will be concluded if the upper 95 confidence interval of the ratio of geometric means is below the NI delta
Superiority Testing If NI is found on both pain and opioid use the investigators will test for superiority on each of cumulative opioid consumption and average pain AUC-60 using 1-tailed tests using the primary analyses specified above with overall 1-tailed alpha of 0025 Since there are 2 tests for superiority the investigators will apply a Holm-Bonferroni correction and use a significance criterion of 00252 for the smaller P-value and 0025 for the larger Similar tests will be conducted for the sensitivity analyses for pain score Cryoneurolysis will be concluded more effective at pain management than standard care and the joint null hypothesis rejected if found superior on at least pain score or opioid consumption and at least noninferior on both
Secondary pain outcomes in first 60 days For each of average current least and worst pain score as well as the pain with ipsilateral arm raise the investigators will conduct all of the analyses describe above for average pain score as well as 1 assessing the treatment-by-time interaction in a linear mixed effects model using all measurements over time and 2 estimating and reporting the treatment effect at each time point while controlling type I error across time points within each outcome variable using the Holm-Bonferroni procedure
Sensitivity analyses for average pain score methodology In addition to analyzing the AUC the investigators will assess the treatment effect on patient average pain scores over time using a linear mixed effects model assuming an autoregressive AR1 correlation structure across scores for the same individual over time Factors will be intervention time categorical and baseline average pain score The investigators will then test for noninferiority with a 1-tailed t-test in which the numerator is the estimated treatment effect minus the NI delta of 1 point and the denominator is the standard error of the estimated treatment effect In another sensitivity analysis the investigators will use a mixed effects proportional odds model with an autoregressive correlation structure to assess the treatment effect on pain score as an ordinal outcome
Hypothesis 3 Physical and emotional functioning Physical and emotional functioning of patients will be assessed using 1 the interference domain of the Brief Pain Inventory BPI and 2 the Patient Health Questionnaire PHQ-2 For the BPI Interference subscale the effect of the intervention will be assessed over the first 2 months as in Hypotheses 2 and 3 -- using patient AUC as primary analysis and a linear mixed model adjusting for baseline BPI-Interference domain score as secondary The investigators will further analyze the outcome over the entire first 12 months in a linear mixed effects model and compare the treatment groups at each time point controlling type I error as specified in the primary objective under Secondary pain outcomes in first 60 days The effect of the intervention on depression as assessed by the Patient Health Questionnaire PHQ-2 at 3-12 months will be analyzed by Wilcoxon rank-sum tests at each time with treatment effect estimated as median difference 95 CI1920 In addition a proportional odds logistic regression analysis adjusting for clinical site will be conducted for each time point
Hypotheses 4 and 5 chronic pain The effect of the intervention on the maximumworst pain ordinal scale experienced by patients at each of 6 and 12 months will be assessed by separate Wilcoxon rank-sum tests at each time point with treatment effect estimated as median difference 95 CI In addition a proportional odds logistic regression analysis adjusting for clinical site will be conducted for each time point Second the effect of the intervention on presence of any pain binary - yesno at each of 6 and 12 months will be assessed using chi-square analyses and relative risk 95 CI as well as Cochran-Mantel-Haenszel tests stratified by clinical site
Study-wide Type I error control The investigators will use a parallel gatekeeping procedure to control the study-wide type I error at 005 For this procedure the investigators therefore have prioritized a priori the study outcomes into 7 ordered sets Table 5 following page Analysis will proceed in that order and testing will proceed through each gate to the next set if and only if at least one outcome in the current set reaches significance The significance level for each set will be 005 times a cumulative penalty for non-significant results in previous sets ie a rejection gain factor equal to the cumulative product of the proportion of significant tests across the preceding sets Within a set a multiple comparison procedure Holm-Bonferroni correction will be used as needed to control the type I error at the appropriate level Although the first set represents the 1-tailed joint hypothesis tests for noninferiority and superiority at alpha0025 without modifying the joint hypothesis test the investigators will use the corresponding 2-tailed alpha level of 005 for the gatekeeping as all other sets involve 2-tailed tests Some of the outcomes listed in the gatekeeping table are overall assessments over repeated measures As detailed in statistical methods treatment effects may also be assessed at individual time points Such assessments will proceed according to the gatekeeping framework such that 1 type I error will be controlled across repeated measurements and 2 inference will not be made on outcome variables that are excluded from formal testinginference due to the gatekeeping results
Parallel gatekeeping procedure revised December 12 2022 after 7 participants were enrolled because the study is a pragmatic trial and not all enrolling centers include peripheral nerve blocks andor perineurial local anesthetic infusions as part of their standard care and therefore anticipated opioid consumption and pain scores will be higher across all groups relative to the single-center pilot study
Sets Time frame Required to pass to next set
1 H1H2 - Joint hypothesis - opioids and pain Requires NI both superiority on at least one 2 months Reject joint H0 1 joint test
2 H3 - BPI interference subscale 2 months Significance on this outcome
3 H4H5 - Chronic pain 1 incidence and 2 worst pain 6 months Significance on either outcome H4H5
4 H4H5 - Chronic pain 1 incidence and 2 worst pain 12 months Significance on either outcome H4H5
5 H2 - Percentage of each group that required 3 opioid tablets from recovery room discharge through 2 mos
6 H1 - Percentage of each group that experienced no more than moderate NRS 7 pain at all time points 2 months Significance on either outcome 5 or 6
7 H3 - Depression screen PHQ-2 6 12 months Significance on either outcome
Interim Analyses The investigators will use a group sequential design with a non-binding futility boundary and conduct an interim analysis at 50 of the maximum planned enrollment to assess the efficacyfutility of the intervention Specifically the investigators will maintain the overall alpha level monitoring efficacy at 0025 using gamma parameter of -4 and power at 90 monitoring beta type II error using gamma parameter of -4 Under the alternative hypothesis the cumulative probability of crossing an efficacy and futility in parentheses boundary at the 1st and 2nd analyses will be 033 001 and 090 010 Under the joint hypothesis testing framework the investigators aim to have 90 power to detect NI on both outcomes and superiority on any one outcome
Sample Size Justification and Power Analyses Sample size calculations and power analyses for the full study were informed by estimates from the pilot trial The investigators plan to have 90 power for rejecting the joint hypothesis test for the primary aim
Opioids In the pilot study N30 the median quartiles of cumulative opioid consumption over 60 days was 91 15 146 in the control group and 3 0 15 in the treatment group The ratio of geometric means 95 CI was 013 003 054 indicating an 87 estimated relative percent reduction in cumulative opioid consumption at 60 days The investigators observed a coefficient of variation CV of 14 Noninferiority Assuming a geometric mean ratio of 070 a NI delta of 12 alpha of 0025 and CV of 14 the investigators would have 962 power to reject the null hypothesis Superiority A sample size of 108 patients in each group would yield 950 power to detect a geometric mean ratio of 057 treatment placebo assuming a CV of 14 a 1-tailed alpha of 00125 and after adjusting for interim analyses
Pain In the pilot study N30 the median quartiles of AUC-60 was 29 16 67 in the control group and 1 0 4 in the treatment group The ratio of geometric means 95 CI was 010 004 027 indicating a 90 estimated relative percent reduction in pain score at 60 days in treatment versus placebo The investigators observed a coefficient of variation CV of 14 Noninferiority Assuming a true ratio of geometric means in AUC-60 of 071 a NI delta of 12 a 1-tailed alpha of 0025 and CV of 14 a sample size of 108 patients per group would yield 953 power to detect noninferiority of cryoanalgesia versus control after adjusting for interim analyses Superiority A sample size of 108 patients in each group would yield 950 power to detect a geometric mean ratio of 057 treatmentplacebo assuming a CV of 14 a 1-tailed alpha of 00125 and after adjusting for interim analyses With the same sample size the investigators would have 924 power to detect a decrease of 1 point in the pain score assuming alpha 00125 standard deviation of 25 intraclass correlation coefficient ICC of 055 and an average cluster size measurements per participant of 7
Power for Joint Hypothesis test The investigators will have 90 power to reject the joint null hypothesis eg 95 power for superiority on pain score times 96 power for noninferiority on opioids 91 assuming independence between the two outcomes
Loss to follow-up Within our pilot study n30 there were no lost patients for the full 1-year follow-up period However this might be a unique subset of patients which may differ from a future cohort at the same or other enrolling centers Based on previous multicenter clinical trials the investigators estimate that at most 7 of participants in each group are expected to drop out of the study before reaching the 2-months primary outcome assessment For those missing data the investigators will use intent-to-treat and multiple imputation multiple imputation for chained equations MICE using data on all observed baseline and outcome data
Sample size re-estimation At the first interim analysis 50 of maximum enrollment the investigators will estimate variance and ICC of the pain scores and CV for opioids and re-estimate the required sample size All analyses will either adjust for clinical site eg in a regression model or consider it as a stratification variable eg in a Cochran-Mantel-Haenszel relative risk analysis Statistical Analytic Software Carey North Carolina R programming language The R Project for Statistical Computing and East 53 software Cytel Inc will be used for all analyses
The investigators propose a pragmatic multicenter randomized triple-masked investigators participants statisticians shamplacebo-controlled parallel-arm human-subjects clinical trial to determine if cryoneurolysis is an effective non-opioid treatment for pain following mastectomy Participants will be individuals undergoing unilateral or bilateral mastectomy recruited at 6 centers
Walter Reed National Military Medical Center Bethesda Maryland
UC San Diego San Diego California
University of Florida Gainesville Florida
Cedars-Sinai Los Angeles California
Cleveland Clinic Cleveland Ohio
For women of childbearing age with the possibility of pregnancy a sample of urine will be collected before any study interventions to confirm a non-pregnant state Participants will have a peripheral intravenous IV catheter inserted standard noninvasive monitors applied blood pressure cuff pulse oximeter 5-lead ECG and oxygen administered via a facemask Midazolam and fentanyl IV will be titrated for patient comfort as needed throughout the procedure while ensuring that patients remain responsive to verbal cues
Peripheral nerve block Not all enrolling centers provide peripheral blocks as part of their standard-of-care Due to the pragmatic design of this trial study participation will not alter an institutions current practice If the local practice includes a postoperative continuous peripheral nerve block a perineural catheter will be inserted 2-5 cm beyond the needle tip the needle withdrawn over the catheter the catheter affixed with an occlusive sterile dressing
Participants will be allocated to one of two treatments
1 cryoneurolysis
2 sham cryoneurolysis placebo control
Randomization will be stratified by enrolling institution surgical site unilateral vs bilateral and axillary involvement nonebiopsy vs dissection in a 11 ratio and in randomly chosen block sizes Randomization lists will be created using Statistical Analysis Software computer-generated tables by the informatics division of the Department of Outcomes Research Cleveland Clinic Cleveland OH Treatment group assignment will be conveyed to the enrolling sites via the same secure web-based system REDCap used to collect and collate all post-intervention endpoints
There are multiple types of cryoneurolysis machines cleared by the US FDA all of which work on the same principle of a gas being passed through a small annulus resulting in a dramatic pressure drop and accompanying temperature drop due to the Joule-Thomson effect This study will utilize two different consoles second option added May 8 2023 the Epimed International Farmers Branch TX and Varian Medical Systems Palo Alto CA machines Which machine is used is determined simply by the machine that each enrolling center has at its disposal
Varian This machine uses argon for the freeze cycle and helium to help decrease the thaw period duration Sham probes are not available for this type of machine and therefore an active probe will be used for all participants For participants randomized to active treatment the probe will be connected to the machine as usual the argon and helium passed through the probe and then back into the machine and finally vented out from the console For participants randomized to sham treatment the probe will be connected to an inactive connector on the back of the machine For these participants the gas will simply be ejected directly from the console without ever having passed through the probe The investigator administering the study intervention will access the treatment group assignment using the secure web-based system and attach the probe active or leave the tubing end close to the machine sham Therefore all investigators participants and clinical staff will be masked to treatment group assignment with the only exception being the unmasked individual who performs the procedure and will not have subsequent contact with the participant
Epimed This machine uses nitrous oxide for the freeze cycle with a passive thaw no gas flow Cryoneurolysis probes are available that either 1 pass nitrous oxide to the distal end inducing freezing temperatures or 2 vent the nitrous oxide at the proximal end of the probe so that no gas reaches the distal end resulting in no temperature change The latter is a sham procedure since without the temperature change no ice ball forms and therefore the target nerve is not affected Importantly these probes are indistinguishable in appearance and will be differentiated only by an identifying stamp on the underside of the connector which is not visible during use
The investigator administering the study intervention will access the treatment group assignment using the secure web-based system and attach the appropriate probe to the cryoneurolysis device Therefore all investigators participants and clinical staff will be masked to treatment group assignment with the only exception being the unmasked individual who performs the procedure and will not have subsequent contact with the participant For both types of machines it is impossible to mask the individual performing the cryoneurolysis procedure because the ice ball forming at the distal end of the probe-with active treatment-is clearly visible by ultrasound and the lack of an ice ball for placebo participants is equally clear It is essential to continuously visualize the probe and target nerve throughout the freezethaw cycles to ensure the entire nerve diameter is adequately treated and remains relatively motionless This cannot be achieved if the ultrasound is turned off during gas administration in an attempt to mask the provider
Study intervention The 2nd-6th thoracic intercostal nerves will be treated on the ipsilateral surgical side bilaterally for bilateral surgical procedures Using a curved-array transducer the intercostal nerve will be visualized using ultrasound just inferior to each treated rib immediately distal to the costotransverse joint For participants without a paravertebral block a skin wheal of lidocaine 1 will be raised immediately inferior to the transducer to anesthetize the skin An IV-like hollow-bore introducer may be inserted through the skin and guided to the target nerve--this is based on operator personal preference For participants without anesthetized intercostal nerves from a peripheral nerve block lidocaine 15-20 2 mL may be injected through the introducer prior to the cryoneurolysis probe introduction to provide anesthesia during the cryoneurolysis cycles although this is not universally applied they cryoneurolysis treatment itself induces anesthesia
A portable cryoneurolysis device Varian CryoCare or Epimed PainBlocker will be used The probe will be inserted adjacent to the intercostal nerve
Varian The cryoneurolysis device will be triggered using 1 cycle of 55-minute all but 4 participants 064-067 or 3 minutes only 4 participants 064-067 change based on new laboratory data then changed back based on inadequate freeze argon activation 2000 psi and 100 power followed by a 30-second helium defrost
Epimed The cryoneurolysis device will be triggered using 2 cycles of 2-minute gas activation active or sham separated by a 1-minute defrost
The introducer and probe will be withdrawn and this process repeated for each additional intercostal nerve to be treated For bilateral mastectomies the study intervention will be repeated on the contralateral side with the same probe
Intraoperative course Due to the pragmatic nature of this trial the investigators aim to change each centers standard practice as little as possible and rather investigate the results of adding the intervention to current practice The investigators will therefore record intraoperative factors such as type of general anesthetic axillary dissection opioid administration and local anesthetic supplementation however the investigators will not require changes to current standard practice
Postoperative course Standard local supplemental analgesics will be used due to the pragmatic design of this trial For analysis purposes all opioids will be converted to oral oxycodone equivalents Following a cryoneurolysis treatment no action is required by patients regarding this intervention For example in contrast to epidural infusions there is no infusion pump to manage or anesthetic fluid to replenish At enrolling centers that provide a postoperative continuous peripheral nerve block the ropivacaine or bupivacaine infusions will be administered per local protocol with the catheters removed on postoperative day 1 or 2 prior to hospital discharge
Following study completion the results will be mailed electronically or by the United States Postal Service to all enrolled participants in written form using non-technical eg layperson language
Outcome Measurements End Points The investigators have selected outcome measures that have established reliability and validity with minimal inter-rater discordance and are recommended for pain-related clinical trials by the World Health Organization and the Initiative on Methods Measurement and Pain Assessment in Clinical Trials IMMPACT consensus statement Table 1 below5 End points will be evaluated at baseline prior to surgery on postoperative day 0 as well as postoperative days 1 2 3 4 7 21 30 45 and months 2 3 6 9 and 12
Statistical Plan and Data Analysis
Primary Specific Aim To determine the effect of cryoneurolysis on postoperative opioid requirements and analgesia following mastectomy
Hypothesis 1 Opioid consumption will be significantly decreased in the first two months following surgery with cryoneurolysis compared with usual and customary analgesia
Hypothesis 2 Surgical pain will be significantly decreased within the first two months following surgery with cryoneurolysis compared with usual and customary analgesia measured with a Numeric Rating Scale
Primary end point In order to claim that cryoneurolysis is superior to usual and customary analgesia at least one of Hypotheses 1 and 2 above must be superior while the other at least noninferior
Secondary Specific Aims To determine the effect of cryoneurolysis on physical and emotional functioning and chronic pain following mastectomy
Hypothesis 3 Physical and emotional functioning will be significantly improved within the first two months following surgery with cryoneurolysis as compared with usual and customary analgesia measured with the Interference Domain of the Brief Pain Inventory
Hypothesis 4 The incidence of chronic pain will be significantly decreased 6 and 12 months following surgery with cryoneurolysis as compared with usual and customary analgesia
Hypothesis 5 The intensity of chronic pain will be significantly decreased 6 and 12 months following surgery with cryoneurolysis as compared with usual and customary analgesia measured with a Numeric Rating Scale
Balance on baseline covariates will be assessed using absolute standardized difference ASD50 ie difference in means or proportions divided by the standard deviation ASD 01 will be considered to indicate imbalance and these variables will be adjusted for in the statistical analyses Analyses will be carried out using modified intention-to-treat ie patients who received any study treatment will be analyzed according to the group to which they were randomized The overall type I error rate of the study will be controlled using a parallel gatekeeping procedure see Study-wide Type I error rate control
Primary Objective Hypotheses 1 and 2 The investigators will estimate the treatment effect of cryoneurolysis on opioid consumption Hypothesis 1 and average pain score Hypothesis 2 using a joint hypothesis-testing framework The investigators will conclude that cryoneurolysis is more effective compared to the standard of care if it is noninferior on both opioid consumption and pain score and superior for at least one of the outcomes during the first 2 months after surgery No adjustment for multiple testing is needed for noninferiority testing since the investigators require noninferiority on both pain score and opioid consumption outcomes
Noninferiority Testing
Hypothesis 1 Opioid consumption Cumulative opioid assumption is typically log-normally distributed The investigators will therefore assess the treatment effect on the log-transformed cumulative opioid consumption at 2 months using a linear regression model The investigators will test for NI of cryoneurolysis to standard of care using a 1-tailed test assuming alpha of 0025 and NI delta of 12 for the ratio of geometric means treatmentplacebo All opioids will be converted to oral oxycodone equivalents
Hypothesis 2 Average pain score The investigators will test for noninferiority NI of cryoneurolysis to standard of care using 1-tailed tests and assuming a 1-tailed alpha of 0025 The primary pain outcome will be the area under the curve AUC of patient average pain scores over the first 2 months 60 days AUC-60 For this outcome the noninferiority NI delta will be a ratio of geometric means of 12 in the AUC-60 Since AUC-60 is expected to be skewed and to have some proportion of zero values the investigators will estimate the treatment effect a 2-sample t-test on the log-transformed AUC-60 1 Noninferiority will be concluded if the upper 95 confidence interval of the ratio of geometric means is below the NI delta
Superiority Testing If NI is found on both pain and opioid use the investigators will test for superiority on each of cumulative opioid consumption and average pain AUC-60 using 1-tailed tests using the primary analyses specified above with overall 1-tailed alpha of 0025 Since there are 2 tests for superiority the investigators will apply a Holm-Bonferroni correction and use a significance criterion of 00252 for the smaller P-value and 0025 for the larger Similar tests will be conducted for the sensitivity analyses for pain score Cryoneurolysis will be concluded more effective at pain management than standard care and the joint null hypothesis rejected if found superior on at least pain score or opioid consumption and at least noninferior on both
Secondary pain outcomes in first 60 days For each of average current least and worst pain score as well as the pain with ipsilateral arm raise the investigators will conduct all of the analyses describe above for average pain score as well as 1 assessing the treatment-by-time interaction in a linear mixed effects model using all measurements over time and 2 estimating and reporting the treatment effect at each time point while controlling type I error across time points within each outcome variable using the Holm-Bonferroni procedure
Sensitivity analyses for average pain score methodology In addition to analyzing the AUC the investigators will assess the treatment effect on patient average pain scores over time using a linear mixed effects model assuming an autoregressive AR1 correlation structure across scores for the same individual over time Factors will be intervention time categorical and baseline average pain score The investigators will then test for noninferiority with a 1-tailed t-test in which the numerator is the estimated treatment effect minus the NI delta of 1 point and the denominator is the standard error of the estimated treatment effect In another sensitivity analysis the investigators will use a mixed effects proportional odds model with an autoregressive correlation structure to assess the treatment effect on pain score as an ordinal outcome
Hypothesis 3 Physical and emotional functioning Physical and emotional functioning of patients will be assessed using 1 the interference domain of the Brief Pain Inventory BPI and 2 the Patient Health Questionnaire PHQ-2 For the BPI Interference subscale the effect of the intervention will be assessed over the first 2 months as in Hypotheses 2 and 3 -- using patient AUC as primary analysis and a linear mixed model adjusting for baseline BPI-Interference domain score as secondary The investigators will further analyze the outcome over the entire first 12 months in a linear mixed effects model and compare the treatment groups at each time point controlling type I error as specified in the primary objective under Secondary pain outcomes in first 60 days The effect of the intervention on depression as assessed by the Patient Health Questionnaire PHQ-2 at 3-12 months will be analyzed by Wilcoxon rank-sum tests at each time with treatment effect estimated as median difference 95 CI1920 In addition a proportional odds logistic regression analysis adjusting for clinical site will be conducted for each time point
Hypotheses 4 and 5 chronic pain The effect of the intervention on the maximumworst pain ordinal scale experienced by patients at each of 6 and 12 months will be assessed by separate Wilcoxon rank-sum tests at each time point with treatment effect estimated as median difference 95 CI In addition a proportional odds logistic regression analysis adjusting for clinical site will be conducted for each time point Second the effect of the intervention on presence of any pain binary - yesno at each of 6 and 12 months will be assessed using chi-square analyses and relative risk 95 CI as well as Cochran-Mantel-Haenszel tests stratified by clinical site
Study-wide Type I error control The investigators will use a parallel gatekeeping procedure to control the study-wide type I error at 005 For this procedure the investigators therefore have prioritized a priori the study outcomes into 7 ordered sets Table 5 following page Analysis will proceed in that order and testing will proceed through each gate to the next set if and only if at least one outcome in the current set reaches significance The significance level for each set will be 005 times a cumulative penalty for non-significant results in previous sets ie a rejection gain factor equal to the cumulative product of the proportion of significant tests across the preceding sets Within a set a multiple comparison procedure Holm-Bonferroni correction will be used as needed to control the type I error at the appropriate level Although the first set represents the 1-tailed joint hypothesis tests for noninferiority and superiority at alpha0025 without modifying the joint hypothesis test the investigators will use the corresponding 2-tailed alpha level of 005 for the gatekeeping as all other sets involve 2-tailed tests Some of the outcomes listed in the gatekeeping table are overall assessments over repeated measures As detailed in statistical methods treatment effects may also be assessed at individual time points Such assessments will proceed according to the gatekeeping framework such that 1 type I error will be controlled across repeated measurements and 2 inference will not be made on outcome variables that are excluded from formal testinginference due to the gatekeeping results
Parallel gatekeeping procedure revised December 12 2022 after 7 participants were enrolled because the study is a pragmatic trial and not all enrolling centers include peripheral nerve blocks andor perineurial local anesthetic infusions as part of their standard care and therefore anticipated opioid consumption and pain scores will be higher across all groups relative to the single-center pilot study
Sets Time frame Required to pass to next set
1 H1H2 - Joint hypothesis - opioids and pain Requires NI both superiority on at least one 2 months Reject joint H0 1 joint test
2 H3 - BPI interference subscale 2 months Significance on this outcome
3 H4H5 - Chronic pain 1 incidence and 2 worst pain 6 months Significance on either outcome H4H5
4 H4H5 - Chronic pain 1 incidence and 2 worst pain 12 months Significance on either outcome H4H5
5 H2 - Percentage of each group that required 3 opioid tablets from recovery room discharge through 2 mos
6 H1 - Percentage of each group that experienced no more than moderate NRS 7 pain at all time points 2 months Significance on either outcome 5 or 6
7 H3 - Depression screen PHQ-2 6 12 months Significance on either outcome
Interim Analyses The investigators will use a group sequential design with a non-binding futility boundary and conduct an interim analysis at 50 of the maximum planned enrollment to assess the efficacyfutility of the intervention Specifically the investigators will maintain the overall alpha level monitoring efficacy at 0025 using gamma parameter of -4 and power at 90 monitoring beta type II error using gamma parameter of -4 Under the alternative hypothesis the cumulative probability of crossing an efficacy and futility in parentheses boundary at the 1st and 2nd analyses will be 033 001 and 090 010 Under the joint hypothesis testing framework the investigators aim to have 90 power to detect NI on both outcomes and superiority on any one outcome
Sample Size Justification and Power Analyses Sample size calculations and power analyses for the full study were informed by estimates from the pilot trial The investigators plan to have 90 power for rejecting the joint hypothesis test for the primary aim
Opioids In the pilot study N30 the median quartiles of cumulative opioid consumption over 60 days was 91 15 146 in the control group and 3 0 15 in the treatment group The ratio of geometric means 95 CI was 013 003 054 indicating an 87 estimated relative percent reduction in cumulative opioid consumption at 60 days The investigators observed a coefficient of variation CV of 14 Noninferiority Assuming a geometric mean ratio of 070 a NI delta of 12 alpha of 0025 and CV of 14 the investigators would have 962 power to reject the null hypothesis Superiority A sample size of 108 patients in each group would yield 950 power to detect a geometric mean ratio of 057 treatment placebo assuming a CV of 14 a 1-tailed alpha of 00125 and after adjusting for interim analyses
Pain In the pilot study N30 the median quartiles of AUC-60 was 29 16 67 in the control group and 1 0 4 in the treatment group The ratio of geometric means 95 CI was 010 004 027 indicating a 90 estimated relative percent reduction in pain score at 60 days in treatment versus placebo The investigators observed a coefficient of variation CV of 14 Noninferiority Assuming a true ratio of geometric means in AUC-60 of 071 a NI delta of 12 a 1-tailed alpha of 0025 and CV of 14 a sample size of 108 patients per group would yield 953 power to detect noninferiority of cryoanalgesia versus control after adjusting for interim analyses Superiority A sample size of 108 patients in each group would yield 950 power to detect a geometric mean ratio of 057 treatmentplacebo assuming a CV of 14 a 1-tailed alpha of 00125 and after adjusting for interim analyses With the same sample size the investigators would have 924 power to detect a decrease of 1 point in the pain score assuming alpha 00125 standard deviation of 25 intraclass correlation coefficient ICC of 055 and an average cluster size measurements per participant of 7
Power for Joint Hypothesis test The investigators will have 90 power to reject the joint null hypothesis eg 95 power for superiority on pain score times 96 power for noninferiority on opioids 91 assuming independence between the two outcomes
Loss to follow-up Within our pilot study n30 there were no lost patients for the full 1-year follow-up period However this might be a unique subset of patients which may differ from a future cohort at the same or other enrolling centers Based on previous multicenter clinical trials the investigators estimate that at most 7 of participants in each group are expected to drop out of the study before reaching the 2-months primary outcome assessment For those missing data the investigators will use intent-to-treat and multiple imputation multiple imputation for chained equations MICE using data on all observed baseline and outcome data
Sample size re-estimation At the first interim analysis 50 of maximum enrollment the investigators will estimate variance and ICC of the pain scores and CV for opioids and re-estimate the required sample size All analyses will either adjust for clinical site eg in a regression model or consider it as a stratification variable eg in a Cochran-Mantel-Haenszel relative risk analysis Statistical Analytic Software Carey North Carolina R programming language The R Project for Statistical Computing and East 53 software Cytel Inc will be used for all analyses
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
True
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None