Clinical trial NCT04562597
Conditions: Surgery
Sponsor: Medical University of South Carolina
Start date: 2021-01-20; Completion date: 2022-05-21
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Determine the optimal dose of IV N-acetylcysteine (NAC) to produce opioid reduction following spine surgery and estimate the difference in opioid consumption between placebo and the selected optimal dose.

Detailed description:
First 20 subjects: 5 participants will be randomized to each dose group (placebo, 50, 100, and 150 mg/kg) to estimate the dose response curve and to identify the optimal dose.

If the dose response curve is adequate and the optimal dose identified, 15 additional participants will be randomized to placebo and 15 to the optimal dose to estimate the difference in opioid consumption between participants on placebo vs. the optimal dose. (Total of 50 subjects with 20 from dose response curve and 30 to estimate the difference in opioid consumption.)

If the dose response curve is not adequate after the initial 20 subjects 5 per each dose group, then an additional 5 participants will be randomized and to each dose group (placebo, 50, 100, and 150 mg/kg) to estimate the dose response curve and to identify the optimal dose. Once the optimal dose is identified with these initial 40 patients, 10 additional participants will be randomized to placebo and 10 to the optimal dose to estimate the difference in opioid consumption between participants on placebo vs. the optimal dose. (60 patients total with 40 to create the dose response curve and 20 more to estimate the difference in opioid consumption.)

A sample size of 20 subjects per group (placebo and optimal dose) allows us to estimate a 95% confidence interval for the mean difference in opioid consumption with a width of + 0.64 standard deviations from the mean. 70 subjects may be enrolled to account for withdrawal but the study will be completed once 50 or 60 subjects (based on the number of subjects required to create the dose response curve) have completed the protocol.

Arms: arm 1: 5 participants will be randomized to the placebo group to estimate the dose response curve and to identify the optimal dose. arm 2: 5 participants will be randomized to the N-acetylcysteine 50 mg/kg group to estimate the dose response curve and to identify the optimal dose. arm 3: 5 participants will be randomized to the N-acetylcysteine 100 mg/kg group to estimate the dose response curve and to identify the optimal dose. arm 4: 5 participants will be randomized to the N-acetylcysteine 150 mg/kg group to estimate the dose response curve and to identify the optimal dose. arm 5: Once the optimal N-acetylcysteine dose is identified, 15 additional participants will be randomized to the optimal dose to estimate the difference in opioid consumption between patients on placebo vs. the optimal dose. Primary and secondary outcomes will only be evaluated for the placebo group and optimal NAC group. arm 6: 15 Participants will be randomized to placebo to estimate the difference in opioid consumption between patients on placebo vs. the optimal dose. Primary and secondary outcomes will only be evaluated for the placebo group and optimal NAC group.
Interventions: intervention 1: Dose Response Curve Placebo intervention 2: Dose Response Curve N-acetylcysteine 50 mg/kg intervention 3: Dose Response Curve N-acetylcysteine 100 mg/kg intervention 4: Dose Response Curve N-acetylcysteine 150 mg/kg intervention 5: Opioid Reduction with Optimal N-acetylcysteine Dose intervention 6: Placebo
Intervention descriptions: intervention 1: 5 participants will be randomized to the placebo group to estimate the dose response curve and to identify the optimal dose. intervention 2: 5 participants will be randomized to the N-acetylcysteine 50 mg/kg group to estimate the dose response curve and to identify the optimal dose. intervention 3: 5 participants will be randomized to the N-acetylcysteine 100 mg/kg group to estimate the dose response curve and to identify the optimal dose. intervention 4: 5 participants will be randomized to the N-acetylcysteine 150 mg/kg group to estimate the dose response curve and to identify the optimal dose. intervention 5: Once the optimal N-acetylcysteinedose is identified, 15 participants will be randomized to the optimal dose (50,100, or 150 mg/kg) to estimate the difference in opioid consumption between patients administered optimal N-acetylcysteine dose or placebo. intervention 6: 15 Participants will be randomized to placebo to estimate the difference in opioid consumption between patients administered optimal N-acetylcysteine dose or placebo.

Protocol documents:
Prot_000.pdf: 
A pilot trial to determine the effective dose of N-acetylcysteine for opioid 
reduction in patients undergoing spine surgery. 
NCT04562597 
Protocol Date Approval: 03-08-2022 


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PROTOCOL TITLE: 
A pilot trial to determine the effective dose of N-acetylcysteine for opioid reduction in patients 
undergoing spine surgery. 
PRINCIPAL INVESTIGATOR: 
Sylvia H. Wilson, MD  
  
1.0 
Objectives / Specific Aims 
• 
Objective: Determine the optimal dose of IV N-acetylcysteine (NAC) to produce 
opioid reduction following spine surgery and estimate the difference in opioid 
consumption between placebo and the selected optimal dose.   
• 
The primary outcome will be 12-hour postoperative opioid consumption.   
• 
The secondary outcomes will be 6-hour postoperative opioid consumption.  
• 
Other exploratory outcomes will include intraoperative opioid consumption, 
postoperative anesthesia care unit (PACU) opioid consumption cumulative, non-
opioid analgesic administration, postoperative opioid consumption at additional time 
points, and VAS pain scores.  Patient demographic data, surgical data (procedure, 
operative duration), preoperative opioid consumption, time to hospital discharge will 
also be collected.  
2.0 
Background 
As the opioid epidemic has gained notoriety, opioid sparing strategies have garnered more 
interest to provide analgesia without addictive potential, opioid related side effects, and 
elevated costs. Anesthesiologists and surgeons face the challenge of avoiding long term 
opioid use while still attempting to control the discomfort associated with invasive 
procedure. Additionally, postoperative opioids can lead to abuse by patients or others.1 
N-acetylcysteine (NAC) has been an established drug since the 1960s. It is on the World 
Health Organization’s List of 40 Essential Medicines)a and is FDA approved. NAC is a 
precursor to the amino acid L-cysteine and the antioxidant glutathione (GSH),2 shown to 
promote homeostatic glutamate regulation by astrocytes. The sulfhydryl group (–SH) 
within the NAC molecule directly scavenges reactive oxygen species (ROS),3 modulates 
the redox state of the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) receptors (neurotransmitter effect),4 and inhibits the 
nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) to modulate 
cytokine synthesis (anti/pro-inflammatory effect).5  
NAC is probably best known as the treatment for hepatotoxicity from acetaminophen 
toxicity.6b However, NAC has also been utilized to treat psychiatric disorders (e.g, 
schizophrenia, obsessive compulsive disorders, addiction, compulsivity, anxiety), 
neurodegenerative disease symptoms (e.g., Alzheimer’s disease, Parkinson’s disease), 
 
a World Health Organization. WHO Model List of Essential Medicines: 20th List. March 2017. Available online: 
http://www.who.int/medicines/publications/essentialmedicines/20th_EML2017_FINAL_amendedAug2017.pdf?ua=1 (accessed February 
24, 2020). 
b FDA. Acetadote (acetylcysteine) Injection Package Insert. Available online: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-539_Acetadote.cfm (accessed on 22 February 24, 2020). 


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fertility, oral ulcers, chronic pain, hyperglycemia-induced oxidative damage, traumatic 
brain injury, and numerous other conditions.7-16 There are also case reports of NAC 
helping with improving neurological status in patients comatose from carbon monoxide 
poisoning.17  In the perioperative period, NAC has been primarily studied for its anti-
inflammatory properties18 and was noted to reduce the incidence of atrial fibrillation after 
coronary artery bypass graft surgery.19 Although NAC has been used in outpatient studies 
for patients with chronic pain associated with sickle cell anemia20 and diabetic 
neuropathy,14,21 we are not aware of any studies examining NAC to enhance perioperative 
analgesia and decrease opioid administration. 
3.0 Intervention to be studied  
This study will involve administration of IV NAC or placebo (0.45% NaCl or 0.9% NaCl) 
in the perioperative period to patients scheduled for elective spine surgery and observation 
of postoperative opioid consumption. Our hypothesis is that NAC will reduce 
postoperative opioid consumption. This study will also examine the optimal dose of NAC 
to reduce opioid consumption.  
NAC has a long history of safe administration and is frequently administered to critically 
ill patients.6,17,19 
Medication information: NAC is FDA approved for multiple indications including an 
antidote to poisoning caused by acetaminophen overdose and prevention of acute hepatic 
injury.b It has been utilized to treat critically ill patients for over 60 years. It is generally 
well tolerated and has an excellent safety profile.  Due to this excellent safety profile and 
with the approved dosing, this study will utilize NAC doses equal to the loading dose for 
acetaminophen treatment (150 mg/kg) or less (50 or 100 mg/kg).  
Mechanism: NAC exerts its therapeutic effect through several mechanisms. NAC repletes 
glutathione reserves by providing cysteine, which is an essential precursor in glutathione 
production. NAC by itself also binds to toxic metabolites and scavenges free radicals. It 
also increases oxygen delivery to tissues, by increasing mitochondrial ATP production, and 
altering the microvascular tone to increase blood flow and oxygen delivery to the liver and 
other vital organs.  
 
4.0 
Study Endpoints  
• The primary outcome will be 12-hour postoperative opioid consumption.   
• The secondary outcome will be 6-hour postoperative opioid pain score.  
• Other exploratory outcomes will include intraoperative opioid consumption, 
postoperative anesthesia care unit (PACU) opioid consumption cumulative, non-opioid 
analgesic administration, postoperative opioid consumption at additional time points, 
and VAS pain scores at additional time points.   
• Other collected data will include patient demographic data, surgical data (procedure, 
operative duration), preoperative opioid consumption, time to hospital discharge.  
 
 
 
 


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5.0 
Inclusion and Exclusion Criteria/ Study Population 
• 
Inclusion 
• Undergoing elective spine surgery involving 4 levels or less of the 
thoracic, lumbar, or sacral spine. 
• 18 years of age and older. 
• 
Exclusion  
• Less than 40kg in weight.  
• Unable to provide written, informed consent. 
• History of an adverse or anaphylactoid reaction to acetylcysteine.  
• Active asthma, wheezing, or using inhaled bronchodilators.   
• Pregnant Women 
• Known blood clotting deficiency  
• Insulin dependent diabetes 
6.0 
Number of Subjects 
Sample size: 70 subjects 
First 20 subjects: We will initially randomize 5 patients to each dose group (placebo, 50, 
100, and 150 mg/kg) to estimate the dose response curve and to identify the optimal dose.  
After enrollment of the first 20 patients, the study will undergo review by the study team 
and statistician.  
• If the dose response curve is adequate and the optimal dose identified, 15 additional 
patients will be randomized to placebo and 15 to the optimal dose to estimate the 
difference in opioid consumption between patients on placebo vs. the optimal dose.  
(Total of 50 subjects with 20 from dose response curve and 30 to estimate the 
difference in opioid consumption.) 
• If the dose response curve is not adequate after the initial 20 subjects 5 per each 
dose group, we will randomize and enroll an additional 5 patients to each dose 
group (placebo, 50, 100, and 150 mg/kg) to estimate the dose response curve and to 
identify the optimal dose.  Once the optimal dose is identified with these initial 40 
patients, 10 additional patients will be randomized to placebo and 10 to the optimal 
dose to estimate the difference in opioid consumption between patients on placebo 
vs. the optimal dose. (60 patients total with 40 to create the dose response curve 
and 20 more to estimate the difference in opioid consumption.) 
• A sample size of 20 subjects per group (placebo and optimal dose) allows us to 
estimate a 95% confidence interval for the mean difference in opioid consumption 
with a width of + 0.64 standard deviations from the mean. We will plan to consent 
70 subjects to account for withdrawal but will complete the study once 50 or 60 
subjects (based on the number of subjects required to create the dose response 
curve) have completed the protocol.  
7.0 
Setting 
MUSC surgical clinics or preoperative anesthesia clinics   


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8.0 
Recruitment Methods 
• 
Potential subjects on the surgical schedule undergoing elective surgery of the spine 
involving 4 levels or less will be screened for eligibility. 
• 
Information regarding the study will be presented to subject by a study team member 
in the surgical clinic or preoperative anesthesia clinic or in the preoperative period 
prior to sedation.  On the day of surgery, subjects may then choose to provide written 
consent, decline to participate, or rescind their prior consent.   
9.0 
Consent Process 
• 
Regardless of the preoperative location, the study team will present to the subject 
with risks and benefits of the study and the study medication (NAC). Subjects may 
provide written consent at that time or choose to consider the study until the day of 
surgery. Potential participants will be given time to read the consent and ask 
questions. Consent will be obtained from subjects by an IRB approved CITI certified 
study team member that has been trained on the protocol. Written consent will be 
completed once all questions are answered and exclusion and inclusion verified. 
Copies of all documents will be provided to the patients.  
 
10.0 Study Design / Methods 
Design:  This prospective, double blinded clinical trial will randomize patient to receive 
placebo (0.45% NaCl or 0.9% NaCl) or NAC (50, 100, or 150 mg/kg). The randomization 
will be created by a statistician and shared with Investigational Drug Services (IDS) 
pharmacy prior to patient enrollment.  
IDS pharmacy has planned to set up the study to be dispensed from the main OR 
pharmacy. IDS will prepare numbered kits containing NAC or placebo based on the 
randomization scheme. The kits will be stored in the OR pharmacy and dispensed based on 
the assigned subject number. This will allow enrollment any time of day that the OR 
pharmacy is open.  
Groups: Patients will be randomized to receive NAC: 0 mg/kg (placebo; 0.45% NaCl or 
0.9% NaCl), 50 mg/kg, 100 mg/kg, and 150 mg/kg (Max dose 15,000 mg).  The maximum 
dose considered will be 150 mg/kg as this has been studied for safety in numerous patient 
populations including those with severe comorbidities. As NAC may be reconstituted in 
D5W or 0.45% NaCl, we will reconstitute all NAC doses in 250ml 0.45% NaCl or D5W. 
We will use 250ml 0.45% NaCl or 0.9% NaCl without NAC as our placebo.  
Enrollment:  
Following confirmation of informed written consent, patients will be assigned an 
enrollment number and randomized using the randomization, created by a statistician, to 
one of four IV NAC groups: 0 mg/kg (placebo; 0.45% NaCl or 0.9% NaCl), 50 mg/kg, 100 
mg/kg, or 150 mg/kg. Patients will proceed to the operating room where they will receive 
general anesthesia for their planned, elective surgical procedure. Intraoperatively, the 
designated IV NAC or placebo infusion will be initiated and completed by a clinical care 
team member. Patients will only receive NAC once as a single dose that will run over 60 


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minutes.  Patients will be monitored in the operating room while receiving NAC and in the 
PACU postoperatively consistent with our standard perioperative care at MUSC.  
The recorded anesthesia stop will mark time zero. The primary end point will be 12-hour 
postoperative opioid consumption.  
Patient and procedural characteristic will be recorded throughout the perioperative period.  
Demographic data (age, gender, race, weight, height, body mass index) and preoperative 
opioid consumption will be collected after completion of informed consent (yes or no; and 
consumption quantified if applicable). Surgical data (operative procedure and surgical 
duration) will be collected after surgery. Time of hospital discharge will be collected after 
the patient is discharged from the hospital. 
Other exploratory outcomes will be collected as long as the patient is still in the hospital 
and able to self-report up to 48 hours post-operatively. Data will be collected from subject 
self-reporting their VAS score and using the electronic medical record. These data include 
intraoperative opioid consumption, postoperative anesthesia care unit (PACU) opioid 
consumption cumulative, non-opioid analgesic administration, postoperative opioid 
consumption up to 48 hours or discharge. VAS pain scores will be recorded pre-
operatively, post operatively and at 24 hours unless discharged prior to 24 hours post 
operatively.  
In order to identify the optimal IV NAC dose for perioperative opioid reduction and 
estimate the difference in opioid consumption between placebo and the selected optimal 
dose, the study will progress in two phases. 
• In the first phase (20 subjects), we will attempt to identify the optimal dose. The 
optimal dose is defined as the dose or doses of NAC for which a >20% reduction in 
opioid consumption relative to placebo is expected based on the dose response 
curve.  If 20% reduction is not achieved, the optimal dose will be the maximum 
dose (150 mg/kg) administered during the study.   
• In the second phase, after finding the optimal dose, 15 additional patients will be 
randomized to placebo and 15 to the optimal dose to estimate the difference in 
opioid consumption between patients on placebo vs. the optimal dose (30 subjects).  
A sample size of 20 subjects per group (5 from phase 1 and 15 from phase 2) 
allows us to estimate a 95% confidence interval for the mean difference in opioid 
consumption with a width of + 0.64 standard deviations from the mean. 
• If we are unable to create a dose response curve following the enrollment of the 
first 20 subject, an additional 20 subjects (5 per group) will be enrolled to create the 
dose response curve prior to starting the second phase.  
Research procedures: The IV NAC dose [0 mg/kg (placebo; 0.45% NaCl or 0.9% NaCl), 
50 mg/kg, 100 mg/kg, or 150 mg/kg] will be the only research procedure.  
All other aspects of preoperative (e.g., clinic visits, labs, imaging) intraoperative (e.g, 
surgical procedures, anesthesia medications or procedures), and postoperative care (e.g., 
hospital admission and care, clinic follow-up, labs, imaging) will not be research 
procedures but consistent with planned patient care for a patient having elective spine 
surgery. The patient will be responsible for all charges related to the surgery and 
perioperative care excluding the NAC medication. 
 


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11.0 Data Management  
Research data will be coded. Upon enrollment, subjects will be assigned a randomized 
numerical identifier for the remainder of the study.  This number will be used to label 
research charts and paperwork associated with the subject.  An electronic enrollment log 
will link patient name and MRN with his/her study ID number. This log will be kept 
separate from all research data. All paper information will be kept in a locked cabinet in a 
locked office.  All electronic data will be kept on MUSC's password protected server. 
Electronic data will be kept on a password protected MUSC server and a redcap database.  
All paper documents will be kept in a locked cabinet, in a locked office.  Only IRB 
approved, CITI trained study team members will have access to the data. All data will be 
kept for 6 years per MUSC policy. 
 
 13.0 Provisions to Monitor the Data to Ensure the Safety of Subjects (if applicable) 
Any adverse events related to NAC will be treated according to MUSC Hospital policy and 
procedures and the practice of the Department of Anesthesia. 
The Department of Anesthesia’s DSMB will review the study on an annual basis. Any 
adverse events will be reported and reviewed by the DSMB. Adverse events will be 
reported to MUSC’s IRB per policy. 
All data will be kept in a locked office, in a locked cabinet, and electronic data will be 
stored on a password protected MUSC server or redcap database. Only CITI certified, IRB 
approved study team members will have access to data.  
14.0 Withdrawal of Subjects (if applicable) 
• Circumstances under which subjects will be withdrawn from the research without 
their consent include severe allergy/intolerance to NAC. 
• Subjects may withdraw from the study at any time. If patients voluntarily withdraw 
from the research study, they will receive our institutional standard of care for 
perioperative pain management. 
 15.0 Risks to Subjects 
• IV NAC can cause rate related anaphylactoid reactions in 0.2-18% of patients.22,23c 
Most of the anaphylactoid reactions are mild (6%) or moderate (10%) with severe 
reactions (i.e., bronchospasm and hypotension) rare at 1% or less. Bronchospasm more 
commonly occurs in patients with pre-existing reactive airway diseases, like asthma. 
Bronchodilating agents are effective in treating these patients. To minimize this risk, 
patients with asthma, wheezing, or prescribed bronchodilators will be excluded from 
the study. Similarly, patients with a history of a prior anaphylactoid reactions to 
acetylcysteine will also be excluded.  
If an anaphylactoid events occurs, patients will be treated as described by FDA 
guidelines.b IV NAC will be stopped immediately and the patient treated with 
antihistamine medication (e.g., diphenhydramine) and IV fluids if required. 
Vasopressors are not typically necessary. NAC therapy may be restarted at a slower 
rate after resolution of any possible reaction. However, if an anaphylactoid reaction or 
 
 


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similar symptoms return upon reinitiating NAC treatment or increases in severity, IV 
NAC will be discontinued. Additionally, all possible medication reactions will be 
reported to the Anesthesia DSMB and MUSC IRB.  
There is also a risk of loss of confidentiality.  
16.0 Potential Benefits to Subjects or Others 
• 
IV NAC may provide analgesia with reduced postoperative opioid consumption. 
This may help reduce postoperative opioid administration for numerous patients 
undergoing various types of invasive surgical procedures. Because opioid 
administration is associated with numerous negative side effects, including nausea, 
vomiting, pruritus, constipation, sedation, and respiratory suppression, reduction in 
opioid consumption may, in turn, reduce the frequency/severity of these side effects. 
• 
Patients receiving the placebo may receive no direct benefit from participating but 
will receive current standard care for their surgical procedure.  
17.0 Sharing of Results with Subjects 
 
 
N/A 
 
18.0 Drugs or Devices (if applicable)  
N-acetylcysteine (NAC): N-acetylcysteine (NAC) has been an established drug since the 
1960s. It is on the World Health Organization’s List of 40 Essential Medicines)a and is an 
FDA approved medication. NAC is a precursor to the amino acid L-cysteine and the 
antioxidant glutathione (GSH),2 shown to promote homeostatic glutamate regulation by 
astrocytes. The sulfhydryl group (–SH) within the NAC molecule directly scavenges 
reactive oxygen species (ROS),3 modulates the redox state of the N-methyl-D-aspartate 
(NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors 
(neurotransmitter effect),4 and inhibits the nuclear factor kappa-light-chain-enhancer of 
activated B cells (NF-κB) to modulate cytokine synthesis (anti/pro-inflammatory effect).5  
NAC is probably best known as the treatment for hepatotoxicity from acetaminophen 
toxicity.6b However, NAC has also been utilized to treat psychiatric disorders (e.g, 
schizophrenia, obsessive compulsive disorders, addiction, compulsivity, anxiety), 
neurodegenerative disease symptoms (e.g., Alzheimer’s disease, Parkinson’s disease), 
fertility, oral ulcers, chronic pain, hyperglycemia-induced oxidative damage, traumatic 
brain injury, and numerous other conditions.7-16 There are also case reports of NAC 
helping with improving neurological status in patients comatose with carbon monoxide 
poisoning.17  In the perioperative period, NAC has been primarily studied for its anti-
inflammatory properties18 and was noted to reduce the incidence of atrial fibrillation after 
coronary artery bypass graft surgery.19 Although NAC has been used in outpatient studies 
for patients with chronic pain associated with sickle cell anemia20 and diabetic 
neuropathy,14,21 we are not aware of any studies examining NAC to enhance perioperative 
analgesia and minimize opioid administration. 
 
a World Health Organization. WHO Model List of Essential Medicines: 20th List. March 2017. Available online: 
http://www.who.int/medicines/publications/essentialmedicines/20th_EML2017_FINAL_amendedAug2017.pdf?ua=1 (accessed February 
24, 2020). 
b FDA. Acetadote (acetylcysteine) Injection Package Insert. Available online: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-539_Acetadote.cfm (accessed on 22 February 24, 2020). 


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An IND in not required for this study.  First, NAC is FDA approved for IV administration. 
Next, the doses studied do not exceed the FDA approved doses. Further, this study does 
not and will not seek to change the FDA labeling. Last, NAC has an over 60-year history 
of efficacious and safe use. The history or NAC use at the proposed dosages does not 
suggested a substantial risk or harm to patients.  
Pharmacy: NAC is currently stored in the MUSC OR and inpatient pharmacies.  It is 
easily prepared by reconstituting in D5W or 0.45% NaCl. We will reconstitute in 250 ml of 
D5W or 0.45% NaCl, and 0.45% or 0.9% NaCl will also serve as our placebo.  NAC is 
FDA approved and can currently be ordered by any physician for administration if 
indicated. Study related NAC will be ordered and administered perioperatively following 
enrollment. NAC is stable once prepared for 24 hours.  
IDS pharmacy has planned to set up the study to be dispensed from the main OR 
pharmacy. IDS will prepare numbered kits containing NAC or placebo based on the 
randomization scheme. The kits will be stored in the OR pharmacy and dispensed based on 
the assigned subject number. This will allow enrollment any time of day that the OR 
pharmacy is open.  
 
 
 
 
 


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SAP_001.pdf: 
A pilot trial to determine the effective dose of N-acetylcysteine for opioid 
reduction in patients undergoing spine surgery. 
NCT04562597 
Statistical Analysis Plan Date: June 1, 2020


June 2020 
A pilot trial to determine the effective dose of N-acetylcysteine for opioid reduction in patients 
undergoing spine surgery. 
Statistical Analysis Plan 
An a priori sample size calculation was conducted to determine the precision of the estimated mean 
difference in opioid consumption at 12-hours between treatment groups in phase 2 for a fixed sample size.  
A sample size of 20 subjects per group was needed to estimate a 95% confidence interval for the mean 
difference in opioid consumption with a width of + 0.64 standard deviations from the mean. 
The primary outcome of interest in phase 2 was opioid consumption at 12-hours postoperative. Additional 
opioid outcomes included opioid consumption over time (every 6 hours postoperatively up to 48 hours) 
and difference in opioid consumption between groups. Mean differences between treatment groups in 
opioid consumption at different postoperative times, including the primary outcome of 12 hours 
postoperative, were estimated from a linear mixed model including fixed effects for group, postoperative 
time, and their interaction and a random patient effect to account for correlation between measures 
collected on patients over time.   
Descriptive statistics were calculated for patient and procedural characteristics across all treatment groups 
in phases 1 and 2.  Additional phase 2 outcomes included time to first PACU opioid rescue dose, PACU 
VAS pain score, postoperative NRS pain scores, PACU duration, and time to hospital discharge.  
Descriptive statistics by treatment group were calculated to allow for comparisons between groups.  
Average NRS pain score over postoperative time within and between groups was estimated from a linear 
mixed model including fixed effects for treatment group, postoperative time at pain score measurement, 
and their interaction as well as a random subject effect to account for correlation between pain scores 
collected on the same patient over time.  Confidence intervals for the median time to first opioid rescue 
dose was estimated using the Brookmeyer-Crowley approach using the log-log complement 
transformation.23  Confidence intervals for the median PACU and hospital length of stay confidence limits 
are calculated using the distribution free approach described by Hahn and Meeker.24  All analyses were 
conducted in SAS v. 9.4 (SAS Institute, Cary NC, USA).