Self-Administered Nitrous Oxide (SANO) During Transrectal Prostate Biopsy to Reduce Patient Anxiety and Pain
Phase: PHASE4
Conditions: Prostate Disease, Malignancy, Benign Prostatic Hyperplasia, Prostate Cancer, Prostate Adenocarcinoma, Anxiety and Fear, Pain
Sponsor: Beth Israel Deaconess Medical Center

(CCI) Committee on Clinical Investigations 
Page 1 of 15 
 
Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date:  
November 10, 2022 
 
PART B 
STUDY DESCRIPTION 
 
TITLE OF PROTOCOL 
Self-Administered Nitrous Oxide (SANO) During 
Transrectal Prostate Biopsy to Reduce Patient Anxiety 
and Pain 
Principal Investigator 
Heidi Rayala, MD PhD  
 
B1. 
PURPOSE OF PROTOCOL 
Nitrous oxide is a well-tolerated inhaled sedative that has been used for decades in pediatric and 
adult populations and is largely viewed as effective and safe. In addition to analgesic effect, nitrous 
oxide also produces a dissociative euphoria and amnesia that could potentially improve patients' 
anxiety and experience of cancer care.  Over the past several decades nitrous oxide has become 
less common due to concerns of nitrous oxide environmental exposure to the care team.  There 
are now FDA-approved systems that allow patient self-administered nitrous oxide (SANO), and 
importantly, include a scavenger system to eliminate exhaled environmental nitrous oxide.  These 
systems are rapidly being adopted throughout the US in Urology practices, but to date, there have 
been no studies evaluating patient outcomes and possible risks with the adjunct use of SANO.  We 
propose a prospective, randomized, controlled trial to assess patient perceived pain and anxiety 
related to prostate needle biopsy with or without SANO, and the frequency of complications 
associated with SANO.  A secondary aim will be to demonstrate that the SANO at the time of 
prostate biopsy does not significantly increase burden on Urologist productivity, nor increase the 
difficulty of operator ease in performing the prostate needle biopsy. 
Specific Aims:  
Aim 1: To determine the effectiveness of Self-Administered Nitrous Oxide (SANO) in decreasing 
patient perceived anxiety and pain related to prostate needle biopsy.  
Hypothesis 1.1: Patients receiving periprocedural SANO will have decreased anxiety during 
the procedure, as measured by STAI (State-Trait Anxiety Inventory) score, situational pain 
catastrophizing scale (SPCS) and patient vital signs. 
Hypothesis 1.2: Patients receiving periprocedural SANO may have a decrease in pain as 
measure by VAS (visual analogue scale) score and patient vital signs. 
Aim 2: To demonstrate that the SANO at the time of prostate biopsy does not significantly increase 
burden on Urologist productivity, nor increase the difficulty of performing the biopsy. 
Hypothesis 1.1: Administration of periprocedural SANO will not significantly lengthen the 
time of the procedure relative to local anesthetic alone. 
Hypothesis 1.2:  Administration of periprocedural SANO will result in minimal side effects for 
the patients and will allow the patient to drive home independently. 

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Study Description – Part B 
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PI Revision Date:  
November 10, 2022 
 
Hypothesis 1.3: Administration of periprocedural SANO will allow the operating Urologist to 
perform the procedure with the same ease as on those patients who do not have SANO. 
 
 
 
B2. 
SIGNIFICANCE AND BACKGROUND FOR THE STUDY 
Burden of Transrectal Prostate Biopsies in the US 
The number of prostate biopsies performed on US men annually is nearing 2 million (Wolinsky, 
2021).   Transrectal prostate needle biopsy is a very common procedure in the US that is associated 
with significant anxiety and discomfort for men. Historically, a prostate needle biopsy is performed 
via a transrectal ultrasound probe with a lidocaine local anesthetic block, without sedation or 
general anesthesia.  In part, the prostate biopsy is performed without sedation or anesthesia due 
to added cost and time associated with an anesthesia team required for most anesthesia agents.   
Until the early 2000s, prostate biopsy was frequently performed without the aid of local 
anesthetic. Current practice is to perform prostate biopsies with a periprostatic block using 10 ml 
of 1% lidocaine. Even with an anesthetic on board, studies have demonstrated the significant 
psychological impact of prostate needle biopsies, and this is further compounded in those patients 
requiring repeat biopsy.  
  
Factors influencing the development of pain during a prostate biopsy can be divided into patient-
associated factors (younger age, smaller prostate, and pre-biopsy anxiety) and procedure-
associated factors (number of cores, use of local lidocaine block).  With the advent of MRI fusion 
technology, we can now target suspicious areas with greater accuracy. However, this comes with 
the additional probe manipulation within the rectum and additional biopsies of suspicious areas, 
which has been associated with greater patient pain and anxiety (Chesnut, 2020). 
  
Nitrous Oxide as an adjunct for Procedural Pain 
Nitrous oxide has been used in dental offices for decades, accepted for both its analgesic and 
anxiolytic properties. The exact mechanism of action is not clear, but recent studies have 
hypothesized that the analgesic effect is from release of opioid peptides and stimulation of opioid 
receptors. The anxiolytic properties of nitrous oxide have been compared to benzodiazepine 
GABA-ergic pathway, resulting in moderate sedation, thereby reducing anxiety.  Administration 
can be controlled by the patient and the effect of nitrous oxide is realized within 2-3 minutes with 
elimination within 2-3 minutes  Nitrous oxide can be administered either independently or as an 
adjunct to locoregional blocks. These properties of nitrous oxide have led to becoming a standard 
of care in Obstetrics and Gynecology (AWHONN Practice Brief, 2018).  In the United States, spinal 
analgesia is more commonly used than nitrous oxide during childbirth; however, nitrous oxide is 
routinely used elsewhere, with reported rates of 73% in Canada and 62% in the United Kingdoms. 
In Europe, Entonox, a 50% nitrous oxide: 50% oxygen mixture, is widely used in emergency medical 
care of patients in accident scenes and for mild sedation and analgesia. 
  
Administration: 
Inhaled nitrous oxide is typically administered at 30-70% concentration, mixed with oxygen. In 
dental practice, a nasal hood connected to a flometer is used to deliver the nitrous oxide. Typically, 
a separate tube associated with the nasal hood is connected to wall suction to scavenge the 

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Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date:  
November 10, 2022 
 
exhaled waste gas.  One of the key reasons nitrous has fallen out of favor in some settings is 
because the scavenging through a nasal hood is ineffective at containing and eliminating all 
exhaled nitrous.  
The Nitrouseal® system has an adjustable-concentration digital flowmeter and includes an 
FDA-cleared exhaled waste gas scavenger, the 
Miniscav®.  The Nitrouseal® system includes a proprietary disposable single-use full-face mask 
and breathing circuit that collects and contains the exhaled nitrous gas before it is 
scavenged into the Miniscav®. 
It has been used in urology since 2017 in procedures such vasectomies, cystoscopies, UroLift® 
implants, bladder biopsies, prostate biopsies and Botox injections, with reported improvement in 
patient anxiety, relaxation and comfort. However, there have been no randomized controlled 
studies in the US that have studied the effects of nitrous oxide for prostate biopsies thus far.  
 
 
 
 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date:  
November 10, 2022 
 
B3. 
DESCRIPTION OF RESEARCH PROTOCOL 
A. 
Study Design – Overview, Methods, Procedures 
 
METHODS AND PROCEDURES: 
Screening  
After the Urologist has discussed and planned for prostate needle biopsy, the study team will 
examine the list of scheduled biopsies for the week, and a baseline examination by the clinical 
team for eligibility verification will be performed through a medical record review by a trained 
member of the research staff.   
 
Recruitment and Obtainment of Informed Consent 
A member of the research team will reach out by phone call and/or PatientSite email at least 1 
week before their scheduled biopsy. When discussing prostate biopsy with the attending urologist, 
study will be introduced to patient and provide a flyer on laymen terms describing the protocol, 
risks and benefits and information about enrollment. When discussing prostate biopsy with the 
attending urologist, study will be introduced to patient and provide a flyer on laymen terms 
describing the protocol, risks and benefits and information about enrollment.   The phone call (or 
PatientSite message) will give a brief description of the research study.  If the patient expresses 
interest in in learning more about the study during the phone call (or by replying to the PatientSite 
message), a member of the study staff will then send a secure email to the patient with a copy of 
the informed consent form.  Following this, a member of the study staff will call the patient to 
review the consent form and answer questions. Special care will be taken during the consent 
process to ensure subjects are fully competent and understand the nature of the questionnaires, 
as well as the nature of the randomization process (that they may receive Oxygen rather than 
SANO).   If the patient desires to participate in the study, they will be asked to sign the electronic 
consent form on REDCap (Electronic Informed Consent (eIC)).  Study staff will then send subjects 
an email containing a PDF version of the eConsent signed by both the subject and the staff 
member obtaining the consent. 
 
Efforts will be made to attain a mix of study participants in terms of racial/ethnic representation, 
which is reflective of the population of the greater metropolitan Boston area: 63% white, 26% 
African American and 11% other. 
 
Baseline Assessment: 
After informed consent has been obtained, the patient will be directed to a REDCap questionnaire 
that will collect demographics, general medical history, and prior prostate biopsy information (See 
Pre-Procedure Evaluation Survey).  This will be reviewed by research personnel to confirm 
eligibility to participate in the study based on pre-determined inclusion and exclusion criteria. If 
they do not qualify for the study, they will not be randomized to either arm, and will undergo a 
standard template biopsy with local anesthesia only.   
 
In addition, patients will complete the Brief Pain Inventory, a well-validated measure that assesses 
intensity of current pain and interference of pain in the patient's life (Dworkin, 2005). If the patient 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date:  
November 10, 2022 
 
does not complete these two questionnaires electronically before the day of procedure, they will 
be offered the opportunity to complete on the day of their procedure prior to the biopsy. 
 
Randomization 
Subjects will be randomized 1:1 to either SANO (treatment) or oxygen (placebo control) after 
completion of baseline assessment. The results of the randomization will not be disclosed to 
patients as part of the study (patient-blinded). The randomization module in REDCap will be used 
to implement randomization of the subject to our two study groups. 
 
Pre-procedure Evaluation 
On the day of the biopsy, current standard procedure is to bring the patient to an exam room 
(separate from the biopsy room) where pre-procedure vitals are obtained.  At this time, the pre-
procedure STAI and VAS scores will be obtained.  Information of inhaled gas administration and 
how to self-administer will be explained to the patient using templated verbal instructions.  It will 
be emphasized that if at any point during the procedure, the patient feels uncomfortable with the 
inhaled gas, the team will help remove the mask.  
 
Periprocedural Intervention 
The patient will be moved to the biopsy room and standard procedure for lateral positioning and 
explaining prostate biopsy will be done in the routine manner preferred by the individual 
Urologist.  Oxygen saturation monitor will be applied to the patient's finger and monitored 
throughout the procedure. The patient’s heart rate will also be monitored accordingly. 
 
The inhalation gas mask will be positioned on the patient's face, and the patient will then be 
instructed to begin breathing as previously instructed.  Initially the patient will receive 100% 
oxygen at 10 Liters/minute.  In the control group, this will be continued throughout the 
procedure.   
 
After the Urologist describes the procedure, the SANO group will have nitrous oxide turned on to 30%, 
ensuring that the patient is relaxed but still conversant through the procedure.  The nitrous will be 
adjust up or down based on the patient’s response to the question “are you feeling the nitrous” and 
"are you happy at this level”. The range will be between 25 - 45%.  This may take 2-3 minutes.  Both 
groups will be asked these questions.  Both groups will be asked to take several deep breaths before 
inserting the rectal probe. The prostate biopsy for both study and control participants will include the 
normal routine administration of local peri-prostatic nerve block using preferred technique of the 
individual Urologist.  During the procedure, the patient and patient’s oxygen saturation will be 
monitored by a BLS-certified MA, RN, APP, or MD (separate from MD performing the procedure) and if 
at any point in time the patient is unhappy with gas inhalation, the observer will aid the patient in 
removing the mask. At the end of the procedure, the SANO group will be turned down to 0% nitrous 
oxide, and 100% oxygen will be administered through the mask for an additional 2-3 minutes as the 
patient is cleaned up and repositioned to the supine position.  Assessment of the “time in” and “time 
out” of the procedure room will be recorded.   
 
Measuring gas flow: 
Maximum flow for this system is 19 L / min. The amount of gas flow is adjusted to match the patient’s 
minute ventilation in order to maintain the black inspiration bag (inhalation reservoir) on the 

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Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date:  
November 10, 2022 
 
Flowmeter about 3/4 full during the procedure.  This varies from patient to patient depending 
upon respiratory rate, and volume of each breath. Excess gas flow simply flows through the circuit and 
into the scavenger and has no effect on the patient.  
 
 
 
 
Periprocedural Data Collection   
After the biopsy, the patient will be moved to the recovery room for routine post-procedure vitals 
as well as completion of post-procedure STAI score and Situational Pain Catastrophizing Score (S-
PCS) on a tablet computer.  The S-PCS was derived from the Pain Catastrophizing Scale (PCS), a 
validated questionnaire used to measure catastrophic thinking associated with pain.  We will also 
question for side effects of the nitrous oxide including nausea, vomiting, dizziness, drowsiness, 
with an option to enter “other” as a manual entry.  An additional question of whether the patient 
feels comfortable driving home independently will be assessed.  
Patients who do not have an escort planned after their biopsy will be asked to perform two hand-
eye coordination tests after completion of post-procedure surveys. First, the participants will be 
verbally instructed to extend one arm in front of them, and place one finger to the tip of their 
nose. After, the Trail-making test Part B will be administered. This test has been promulgated by 
the American Medical Association to screen for driving fitness. The Trails-making Part B test will 
ask participants to connect numbers (1-13) to letters (A-L) randomly written on a page. This test is 
scored according to accuracy and time required to make the connections (Joseph, 2013). If the 
participant is unable to accurately complete these tests, additional recovery time will be required. 
The participant’s performance and disposition will be included in the documentation of study 
procedures performed during the visit. 
 
The urologist who performed the biopsy procedure will be provided the Operator Survey to assess 
the ease of procedure. 
 
Chart review will be performed to capture any unanticipated ED visits, admissions, or office visits 
for the 7 days following the procedure.  We will also record any phone calls that are made by 
patients within 7 days of procedure that pertain to procedure concerns. 
 
Lastly, participants who completed study procedures during their prostate biopsy will be asked to 
complete a survey 2-10 months following the study biopsy. This brief survey is designed to 
understand participant’s recollection of pain and anxiety during the biopsy. The survey is 
estimated to take 2-3 minutes to complete.  
 
Figure 1. Flowchart of Study Procedures 
 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date:  
November 10, 2022 
 
 
 
Management of Medical Gases Used in Study 
As the research pharmacy does not procure nor dispense gaseous inhalants, medical gases used in 
the study will be managed per protocol and as per BIDMC’s Compressed Gas Cylinder Storage and 
Handling Policy #: EC-62. Nitrous and oxygen cylinders will be procured through the OR materials 
management specialist. The tanks for study gases will be stored in an approved gas cylinder 
storage rack in (Room 385) of the Shapiro Clinic for immediate usage. There is also a gas tank 

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Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date:  
November 10, 2022 
 
storage area in the Shapiro OR (close to the clinic) for additional storage. Both spaces are secured 
and locked off hours. Research staff will only access these supplies as necessary for the study. 
 
 
B. 
Statistical Considerations 
Sample Size Justification 
Based on a previous study by Bringman et al, the mean (SD) of STAI anxiety score is 34(8). A 
clinically meaningful decrease, as determined by the Cochrane review group was 0.5 of SD. 
Our sample size calculation to detect a 4-point change in pain score (p less than 0.05 significance 
level) was 64 patients per group (α=0.05, power=80%). We will inflate out sample size by 15% to 
account for any missing data or any withdrawal from the study; therefore, our estimated sample 
size will be 76 patients per group. 
Data Analysis 
All data will be collected and stored securely using the REDCap system. Data will be managed and 
analyzed by the PI and biostatistical support team at the BIDMC FIRST program. A Data Transfer 
Agreement will be created to allow for the study team’s statistician, Kristin Schreiber MD/PhD at 
Brigham and Women’s Hospital, to obtain and perform statistical analysis on de-identified data. At 
the conclusion of the study, de-identified study data will be exported out of REDCap and sent to 
Dr. Schreiber in a secure file via email message. Data will not be transferred until this agreement is 
approved and fully executed by both parties.    
Primary outcome measure is patient anxiety and pain levels in the N2O group vs the oxygen only 
group as measured by the VAS and VAS A scores. We are specifically interested in the difference in 
scores between the two groups. Prostate biopsy mean VAS score with local anesthetic is around 3-
4. We will also obtain a baseline pain index between the two groups. We will compare the 
perioperative VAS and VAS-A scores to the retrospective VAS and VAS-A scores collected during 
the survey administered 2-10 months after their biopsy.  
We will also be obtaining 6 question Situational Pain Catastrophizing Scores for both groups and 
will compare the variation in response. Patients who have had a prior biopsy will also fill out a 13 
question Pain catastrophizing score, which we will use as a baseline measure for biopsy related 
anxiety and hesitation.  
Additional metric will include duration of biopsy, as measured by time in/time out of the 
procedure room for patients administered either nitrous or control oxygen when compared to 
patients who do not consent to the study (and will have no gas applied).  Operator ease in 
performing the biopsy will be measured by 3 simple questions assessing patient positioning and 
ease of transrectal probe insertion. Prostate biopsies are generally performed as an outpatient 
procedure and patients can drive themselves home in most situations. Post biopsy side effects and 
ability of the patient to drive themselves home will be used as a surrogate to determine 
practicality of administering SANO in the outpatient setting. 
 

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Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date:  
November 10, 2022 
 
C. 
Subject Selection 
Subject Population 
The study population will be all patients aged 21 to 85 years referred for prostate needle biopsy 
(both standard sextant and MRI-fusion guided) to BIDMC within 6 months’ period.  A total of 152 
patients will be enrolled for the study. 
Eligibility Criteria 
Inclusion criteria:  
(1) Biological male 
(2) Aged 21 to 85 years  
(3) Scheduled for prostate needle biopsy 
(4) No learning disabilities  
(5) Suitable for nitrous oxide/oxygen IHS with willingness to be randomized to inhaled SANO or 
inhaled oxygen during the procedure  
(6) Access to an email and computer 
Exclusion criteria:  
(1) Perioral facial hair impeding good mask seal 
(2) Learning disabilities and/or inability to cognitively complete survey questions 
(3) Taken a pre-procedure benzodiazepine or narcotic.  
(4) Has any of the following medical conditions:  
a. Inner ear, bariatric or eye surgery within the last 2 weeks,  
b. Current emphysematous blebs,  
c. Severe B-12 deficiency.   
d. Bleomycin chemotherapy within the past year.  
e. Class III or higher heart failure.  
f. Undergoing novel therapy for prostate cancer  
 
  
 
 

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Study Description – Part B 
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PI Revision Date:  
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B4. 
POSSIBLE BENEFITS 
It is not possible to determine whether a subjects will directly benefit from participation. Patients 
receiving SANO may potentially experience decreased pain and anxiety when undergoing office 
prostate biopsy.  Benefits would not be expected to occur for those patients in the placebo oxygen 
arm.  
Taking part in the study will increase scientific knowledge regarding the ability of the inexpensive, 
commonly available agent to reduce procedural pain and anxiety.  Moreover, as SANO is currently 
being used throughout the United States for prostate biopsies, this study may help us identify risks 
to SANO that are currently not known or described.  
If there is a significant improvement in patient anxiety and pain with the nitrous oxide, this could 
lead to changes in the standard of care for patients undergoing prostate biopsy.  
We also may be able to identify patient factors that in the future allow us to prospectively identify 
patients who would be expected to experience more benefits from nitrous oxide. At the same 
time, this may allow us to identify patients who would not have significant benefit and might 
minimize their risk of exposure to nitrous oxide.  
There is potential to also extend knowledge obtained in this study to other commonly performed 
office procedures that are associated with pain and anxiety, such as LEEPs, vasectomies, 
cystoscopies, and others. 
 
 
 
B5. 
POSSIBLE RISKS AND ANALYSIS OF RISK/BENEFIT RATIO 
Risks related to the use of questionnaires   
Minimal risks associated with the completion of questionnaires include subject fatigue and the 
possibility of increased anxiety in answering questions about baseline pain and pain related to the 
procedure.  Subjects will be informed that they are free to discontinue their participation in the 
study at any time should they choose. 
Risks related to Nitrous Oxide administration 
Nitrous oxide is a well-known drug used in medicine for anesthetic and analgesic purposes since 
1844.  Its use during labor has been shown to be safe and effective, with no known long-term 
effects on the mother and no known effects on the infant.  There are known long-term effects of 
environmental exposure to nitrous oxide, including infertility, when not using a scavenger system 
for the escaped environmental nitrous oxide.  The Miniscav® nitrous waste gas evacuation pump 
has been FDA-approved for use in medical offices with the Nitrouseal® system.  We will not be 
using the Nitrouseal® and Miniscav® nitrous waste gas evacuation pump in any capacity that is not 
already approved by the FDA. 

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Study Description – Part B 
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PI Revision Date:  
November 10, 2022 
 
Nitrous oxide does have a risk of nausea and vomiting.  The reported rates have been reported as 
high as 13% in literature, however these are at higher concentration of nitrous oxide and with 
longer durations.  The reported vomiting risk with the Nitrouseal® system is <0.5%.   For the 
procedure, the patient is maintained in the lateral position, which should minimize any aspiration 
risk.  Sweating, drowsiness, lightheadedness, tachycardia and facial flushing has also been 
reported.  The patients are routinely monitored after the prostate biopsy procedure, and any ill 
effects of the procedure itself or of the nitrous oxide will be assessed and cared for by our study 
team and clinical staff.  Some adults may feel a sense of panic at higher concentrations (60-70%) 
than we will be using in our study (40%).  
Finally, as with any inhaled gas, there can be a concern of hypoxia or apnea with administration of 
nitrous oxide.  This event has not been routinely reported in the literature as a risk or side effect of 
nitrous oxide.  However, this will be one of the side effects that we will be most interested in 
following.  During the procedure, patients will undergo continuous oxygen saturation and heart 
rate monitoring. These values will be documented in REDCap as part of the patient’s study records.  
If there are concerns of hypoxia, either objectively by the oxygen monitoring or subjectively by the 
patient, the protocol will be to immediately turn off the nitrous oxide and administer 100% oxygen 
until vitals return to baseline.  All personnel in the room will have BLS training.  The Shapiro 
Surgical Clinic has a code cart which is readily available.  In addition, the clinic is in close physical 
proximity to the operating rooms, with anesthesiologists responding to Code Blues in the building. 
Possible Unauthorized Use of Nitrous Oxide 
Inhalation of nitrous oxide is used/abused in recreational settings with the purpose of causing 
euphoria and hallucinations.  To prevent potential misuse, the nitrous oxide will be stored within 
the operating room storage area reserved for anesthetic gases during non-office hours.  
Potential for Loss of Confidentiality  
There is a potential for loss of confidentiality for participants in the study. Protections will be 
implemented to mitigate this risk. As detailed in our protocol, we will use REDCap to collect patient 
information and questionnaires.  Though REDCap is generally considered secure for the purposes 
of PHI, it is a web-based application and the data is accessible to study team members on their 
own personal computers.  Access to our REDCap will only be limited to study team members who 
are trained in protecting PHI.  . Any electronic study files or information that is not stored on 
REDCap will be kept on a secure directory on the BIDMC server that is only accessible to research 
staff. 
Only summaries of group data will be reported in any publications or presentations, with no 
identification of individuals. These precautions should serve to protect PHI in accordance with 
HIPPA regulations.  
Reporting of Adverse Events 

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Study Description – Part B 
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PI Revision Date:  
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All adverse events will be reported to the BIDMC Human Research Committee promptly in 
accordance with guidelines. 
Analysis of Risk/Benefit Ratio 
Based on the above risks, the principal investigator views this study as moderate risk. With the 
precautions and procedures to minimize risk as described in this section, we anticipate minimal 
complications and discomfort. In light of the study’s potential benefits, the principal investigator 
believes the risk:benefit ratio to be favorable. 
 
B6. 
RECRUITMENT AND CONSENT PROCEDURES 
Recruitment 
 
The primary Urologist will introduce the SANO study to the patient and provide an informational 
handout at the time they discuss prostate biopsy with the patient. After the Urologist has 
discussed and planned for prostate needle biopsy, the study team will examine the list of 
scheduled biopsies for the week, and a baseline examination by the clinical team for eligibility 
verification will be performed through a medical record review by a trained member of the 
research staff. 
.  Those patients who meet criteria will be reviewed by their Urology Attending for appropriateness 
of study and will provide authorization to contact eligible subjects.  Eligible patients will be sent a 
secure message via PatientSite (See Template Introductory Letter) to introduce the study.  In 
addition, the patient will be called on their preferred clinical contact phone number by a study 
team member.  The study team member will follow a templated introductory contact script (See 
Template Introductory Contact Script).  In attempting to reach the patient, and in accordance with 
BIDMC Human Research procedure, no more than ten (10) phone attempts will be performed, and 
all calls will take place between 10am-9pm Monday thru Friday, and 10am – 5pm Saturday and 
Sunday. If there is no answer, study team member will leave a templated contact script (See 
Template No Answer Contact Script).  
 
To assess interest in completing the post-biopsy survey, a letter will be sent to introduce the 
survey to participants who completed study procedures during their study biopsy (see Re-contact 
Letter script). We will wait for one week before further outreach to patient. For participants 
registered on PatientSite, a REDCap survey link will be sent via secure PatientSite message (see Re-
contact PatientSite script).  For participants who do not prefer PatientSite, we will call the patient 
directly (see Re-contact Telephone script). Patients will be asked to complete the survey via a 
REDCap link sent to the patient’s email. If the patient prefers, we will offer the option to complete 
the survey questions over the phone . No more than three phone attempts will be performed, and 
all calls will take place between 10am – 9pm Monday-Friday, and 10am – 5pm Saturday and 
Sunday. If there is no answer, the study staff member will leave a templated voicemail (see 
Recontact Voicemail script). 
 
In the event that individuals contacted are distressed in any way by the contact, we will contact 
the patient's Urology Attending, who will either personally reach out to the patient to alleviate 

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Study Description – Part B 
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PI Revision Date:  
November 10, 2022 
 
their concerns or have a designated team member reach out to the patient to alleviate their 
concerns. 
Consent 
Informed consent will be obtained for all participants who are potential study candidates. A 
qualified member of the research team will review the informed consent form with all patients 
who express interest in the study. The subject will be allowed to ask questions at any point. Study 
personnel will explain that the subject is free to refuse participation in this research study and that. 
All patients who agree to participate will be asked to sign the ICF electronically through REDCap. 
Consent will be obtained before any study-specific tests or procedures are performed. Study 
personnel will document the consent process. Subjects will be provided an electronic copy of the 
signed ICF. 
Subject Protection 
As subjects in the study may be patients of study investigators, measures will be taken to prevent 
coercion and undue influence. The study team will emphasize that participation is voluntary and 
will not impact their relationship with any individual at BIDMC. Investigators will be trained to 
conduct consent in a manner that does not lead to coercion and undue influence.  
 
B7. 
STUDY LOCATION 
Privacy 
 
The study will be conducted on the premises of BIDMC Longwood Campus.  We will obtain lists of 
patients intended for prostate biopsies in the following week, and study team members will review 
the OMR records for inclusion and exclusion criteria.  The patient will be contacted by phone either 
from in-office phone call or through Doximity phone application (which provides the BIDMC 
Urology office as the caller ID).  We will ask the patient whether they are in a location that affords 
privacy for discussion of medical information.  If they are not, we will arrange an appropriate time 
when the patient will have privacy for study discussion.   Phone interviews by study team members 
will be conducted in private space to avoid the interview being overheard. 
 
Pre-procedure questionnaires will be emailed to private patient email via the REDCap server.  Data 
collected will be kept within the REDCap server.  Access to our REDCap will only be allowed for 
study team members who are trained in protecting PHI. 
 
Operator Surveys will be on paper forms with patient identifying sticker on the form.  At the end of 
the biopsy, the data will be input into the REDCap system by a study team member, and the paper 
version will be disposed of in a disposal unit intended for medical information waste. 
 
Pre-procedure and post-procedure VAS, VAS-A score and Situational Pain Catastrophizing Score (S-
PCS) and Trails-making Part B tests will be obtained in a private exam room where only the patient, 
study team members, and clinical staff measuring vitals will be present.  Questionnaire answers 
will be input by  the patient into a tablet computer.  The tablet computer will be wiped with 
sanitizing wipe between uses given current COVID pandemic. 

(CCI) Committee on Clinical Investigations 
Page 14 of 15 
 
Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date:  
November 10, 2022 
 
 
Physical Location 
 
The biopsy procedure itself will take place in the Shapiro 3 Surgical Subspecialty clinic. Medical 
record reviews will occur at a secure workstation at BIDMC or through BIDMC’s VPN server. 
The nitrous tanks will be stored in an approved gas cylinder storage rack in (Room 385) of the 
Shapiro Clinic for immediate usage. There is also a gas tank storage area in the Shapiro OR (close to 
the clinic) for additional storage. Both spaces are secured and locked off hours.  
 
 
B8. 
DATA SECURITY 
All OMR access and assessment will be performed on the BIDMC server using the BIDMC firewall. As 
detailed in our protocol, we will use REDCap to collect patient information and questionnaires. Input 
of PHI data into the REDCap system by team members will only be through the BIDMC server using 
the BIDMC firewall.  Access to our REDCap will only be allowed for study team members who are 
trained in protecting PHI.  Only summaries of group data will be reported in any publications or 
presentations, with no identification of individuals.  
Operator Surveys will be on paper forms with patient identifying sticker on the form.  At the end of 
the biopsy, the data will be input into the REDCap system by a study team member, and the paper 
version will be disposed of in a disposal unit intended for medical information waste. 
 
B9 
Multi-Site Studies 
 
Is the BIDMC the coordinating site?       
 Yes    
 No  
 
Is the BIDMC PI the lead investigator of the multi-site study?     
 Yes    
 No  
 
B10 
Dissemination of Research Results 
Participants will be thanked for their participation in the research study. Results of research 
conducted through this protocol will be published in peer-reviewed journals and presented in 
scientific conferences. No identifiable information will be published or presented 
 
References 
 
1. Wolinsky, H. (2021, April 21). No more men need to die from transrectal prostate biopsies. 
Medical News. https://www.medpagetoday.com/special-reports/apatientsjourney/92201. 
2. Chesnut GT, Vertosick EA, Benfante N, Sjoberg DD, Fainberg J, Lee T, Eastham J, Laudone 
V, Scardino P, Touijer K, Vickers A, Ehdaie B. Role of Changes in Magnetic Resonance 
Imaging or Clinical Stage in Evaluation of Disease Progression for Men with Prostate Cancer 
on Active Surveillance. Eur Urol. 2020 Apr;77(4):501-507. 
3. Collins, M OGNN - Use of Nitrous Oxide in Maternity Care: AWHONN Practice Brief Number 6. 
Journal of Obstetric, Gynecologic, and Neonatal Nursing Mar 2018 (239-242) 

(CCI) Committee on Clinical Investigations 
Page 15 of 15 
 
Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date:  
November 10, 2022 
 
4. Bringman H, Giesecke K, Thorne A, Bringman S. Relaxing music as pre-medication before 
surgery: a randomised controlled trial. Acta anaesthesiologica Scandinavica. 2009;53(6):759-
764.  
5. Joseph, C. B. (2013). Physician's Guide to assessing and counseling older drivers. second 
edition. Journal of the Medical Library Association : JMLA, 101(3), 230–
231. https://doi.org/10.3163/1536-5050.101.3.017  
6.