Clinical trial NCT05803096
Conditions: Prostate Disease Malignancy Benign Prostatic Hyperplasia Prostate Cancer Prostate Adenocarcinoma Anxiety and Fear Pain
Keywords: prostate biopsy nitrous oxide prostate cancer ambulatory patient experience of care
Sponsor: Beth Israel Deaconess Medical Center
Start date: 2021-12-12; Completion date: 2022-09-09
Enrollment: 143 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Transrectal prostate biopsy is a commonly performed ambulatory procedure for diagnosing prostate cancer. Prostate biopsy are associated with pain or anxiety. Nitrous oxide (or laughing gas) is a well-known inhaled anesthetic which is frequently used in dental offices and for pediatric procedures to alleviate a patient's anxiety and pain. This study seeks to determine whether administration of nitrous oxide at the time of prostate biopsy will improve a patient's experience of care.

Detailed description:
Nitrous oxide is a well-tolerated inhaled anesthetic 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. When used as a single agent at concentrations ≤50%, the American Society of Anesthesiologists (ASA) classifies nitrous oxide as Minimal Sedation, producing a state in which a patient responds normally to verbal commands, maintains airway reflexes, and spontaneous ventilation. 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 Federal Drug Administration (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 United States in Urology practices, but to date, there have been no studies evaluating patient outcomes and possible risks with the adjunct use of SANO. This study is 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.

Arms: arm 1: Patients will receive SANO in addition to periprostatic bupivacaine nerve block for the duration of prostate biopsy.

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%. 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. arm 2: Patients will receive 100% oxygen at 10 Liters/minute for the duration of prostate biopsy.
Interventions: intervention 1: Self-Administered Nitrous Oxide intervention 2: Oxygen
Intervention descriptions: intervention 1: Nitrous oxide administered at concentrations of mild sedation (20-45%) for the duration of prostate biopsy. intervention 2: Oxygen will be administered at 10 Liters/min for the duration of prostate biopsy.

Protocol documents:
Prot_SAP_001.pdf: 
(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. 


(CCI) Committee on Clinical Investigations 
Page 2 of 15 
 
Study Description – Part B 
CCI Form:  9-2015 
 
 
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 


(CCI) Committee on Clinical Investigations 
Page 3 of 15 
 
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 
Page 4 of 15 
 
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 
Page 5 of 15 
 
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 


(CCI) Committee on Clinical Investigations 
Page 6 of 15 
 
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 
Page 7 of 15 
 
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 


(CCI) Committee on Clinical Investigations 
Page 8 of 15 
 
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. 
 


(CCI) Committee on Clinical Investigations 
Page 9 of 15 
 
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  
 
  
 
 


(CCI) Committee on Clinical Investigations 
Page 10 of 15 
 
Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date:  
November 10, 2022 
 
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. 


(CCI) Committee on Clinical Investigations 
Page 11 of 15 
 
Study Description – Part B 
CCI Form:  9-2015 
 
 
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 


(CCI) Committee on Clinical Investigations 
Page 12 of 15 
 
Study Description – Part B 
CCI Form:  9-2015 
 
 
PI Revision Date:  
November 10, 2022 
 
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 


(CCI) Committee on Clinical Investigations 
Page 13 of 15 
 
Study Description – Part B 
CCI Form:  9-2015 
 
 
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.  
 
 
 

ICF_000.pdf: 
[CCI] Committee on Clinical Investigations 
 
Page 1 of 14 
 
Informed Consent – Part D 
CCI Form: 7-2020 
PI Revision Date: July 11, 2022 
 
**FOR CCI USE ONLY** 
Approved by the Beth Israel Deaconess Medical Center  
Committee on Clinical Investigations:  
 
Consent Approval Date:   
08/08/022 
 
 
 
Protocol Number:  
2021P000715 
 
   
 
 
 
 
INFORMED CONSENT FORM TO TAKE PART IN A RESEARCH STUDY 
 
SUBJECT’S NAME:        
TITLE OF RESEARCH PROTOCOL: Self-Administered Nitrous Oxide (SANO) During Transrectal 
Prostate Biopsy to Reduce Patient Anxiety and Pain 
PRINCIPAL INVESTIGATOR: Heidi Rayala, MD PhD 
PROTOCOL NUMBER:       2021P-000715 
 
KEY INFORMATION 
 
The following is a short summary of this study to help you decide whether or not to be a part of this study. 
More detailed information is listed later on in this form.  
Why am I being invited to take part in a research study?  
We invite you to take part in a research study because you are scheduled to have a prostate biopsy soon.  
What should I know about a research study?  
• 
Someone will explain this research study to you. 
• 
Whether or not you take part is up to you. 
• 
Your participation is completely voluntary. 
• 
You can choose not to take part. 
• 
You can agree to take part and later change your mind. 
• 
Your decision will not be held against you.   
• 
Your refusal to participate will not result in any consequences or any loss of benefits that you are 
otherwise entitled to receive. 
• 
You can ask all the questions you want before you decide. 
• 
If you choose not to take part, or if you leave the study, your decision will in no way harm your 
relationship with any member of the research team or any other individuals at Beth Israel Deaconess 
Medical Center. 
Why is this research being done?  
The transrectal prostate needle biopsy is a very common procedure in the US.  For some patients, a prostate 
biopsy can be associated with anxiety or discomfort. Nitrous oxide (or laughing gas) is a well-known sedative 
which is frequently used in dental offices and for pediatric procedures to alleviate a patient’s anxiety and pain.  
We would like to determine whether administration of nitrous oxide at the time of prostate biopsy will improve 
a patient’s experience of care.   
 
How long will the research last and what will I need to do?  
We expect that you will be in this research study for up to seven days after your prostate biopsy.  
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
08/07/2023


[CCI] Committee on Clinical Investigations 
Page 2 of 14 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: SELF-ADMINISTERED NITROUS OXIDE 
(SANO) IN PROSTATE BIOPSY TO REDUCE PATIENT ANXIETY AND PAIN 
PRINCIPAL INVESTIGATOR'S NAME: HEIDI RAYALA, MD PHD  
PROTOCOL #: 2021P000715 
 
Informed Consent – Part D 
CCI Form: 7-2020 
PI Revision Date: July 11, 2022 
 
 
You will either receive self-administered nitrous oxide or oxygen during your prostate biopsy. This 
administration of the gas will be done by our staff and you won’t be responsible for administering the nitrous 
oxide. We will adjust the dose based on your comfort level but you won’t be allowed to request more gas. To 
check on the effectiveness of the treatment, we will ask you to answer questions regarding your 
demographics, medical history, current health condition, anxiety and pain. 
More detailed information about the study procedures can be found under “DESCRIPTION OF STUDY 
DETAILS”. 
 
 
Is there any way being in this study could be harmful to me?  
There are some potential side effects when using nitrous oxide. About 1 in 200 patients who are given nitrous 
oxide can experience mild nausea and vomiting from the nitrous oxide gas. Other people have reported 
sweating, drowsiness, or lightheadedness when using nitrous oxide.    
More detailed information about the risks can be found under “RISKS AND DISCOMFORTS”. 
Will being in this study help me in any way?  
We cannot promise any benefits to you or others from your taking part in this research. However, possible 
benefits include decreased anxiety and pain during your prostate biopsy. The results of the research will 
improve scientific understanding of the impact of self-administered nitrous oxide on anxiety and pain for 
prostate biopsy and other medical procedures.  
What happens if I do not want to be in this research? 
Participation in research is completely voluntary. You can decide to participate or not to participate. Your 
alternative to participating in this research is not to participate and you will receive the standard pain control 
measures done for prostate biopsies at BIDMC. 
Currently we do not offer Nitrous Oxide to patients outside of this research study.  However, one option for 
men who are concerned about the biopsy is to receive a prescription for an anti-anxiety pill (a 
benzodiazepine) that they can take before the procedure.  However, if you decide to take the anti-anxiety pill, 
you will not be eligible to be part of this research study. 
 
DETAILED INFORMATION SECTION  
 
 
 
 
 
 
 
          
Please read this consent form carefully and ask the investigators or study staff to explain any words or 
information that you do not clearly understand.  Once you read this consent form and understand what 
your participation in this study will involve, you will be asked to sign this form if you wish to take part.  
You will be given a signed copy of the form to keep for your records. 
 
DISCLOSURE OF SPECIAL INTERESTS OF BIDMC AND INVESTIGATORS 
 
This study is being conducted by Dr. Heidi Rayala and is funded by Sedation Systems LLC. The 
funding agency in this study, Sedation Systems LLC, is paying Beth Israel Deaconess Medical Center 
to perform this research.  BIDMC and Dr. Rayala have no additional interests in this research project.  
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
08/07/2023


[CCI] Committee on Clinical Investigations 
Page 3 of 14 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: SELF-ADMINISTERED NITROUS OXIDE 
(SANO) IN PROSTATE BIOPSY TO REDUCE PATIENT ANXIETY AND PAIN 
PRINCIPAL INVESTIGATOR'S NAME: HEIDI RAYALA, MD PHD  
PROTOCOL #: 2021P000715 
 
Informed Consent – Part D 
CCI Form: 7-2020 
PI Revision Date: July 11, 2022 
 
 
 
WHOM TO CONTACT IF YOU HAVE QUESTIONS OR PROBLEMS 
 
If you have any questions, concerns or complaints about this research or experience any problems, 
you should contact Dr. Heidi Rayala at [617] 667-3739.  
 
PURPOSE 
 
Over one million patients have transrectal prostate biopsies in the US every year. Although generally 
well tolerated, some men experience some anxiety and pain while having a biopsy. Nitrous oxide, also 
known as laughing gas, is a safe drug commonly used by dental and pediatric offices to reduce anxiety 
and pain. It is also being adopted in many Urology clinics across the country for office based 
procedures.  
We are doing this study to understand whether using nitrous oxide reduces anxiety and pain and 
improves the patient experience during prostate biopsy. In addition, we want to see whether it is 
practical for urologists to use nitrous oxide for their procedures. If we find that nitrous oxide reduces 
anxiety and pain for prostate biopsy, it might lead to improvements to anxiety and pain for future 
patients. 
 
As part of the study, we are using the The Nitrouseal® system. Nitrouseal® is a gas mask that releases 
nitrous oxide in a safe manner similar to other gas masks for medical gases, while preventing the gas 
from leaking into the air. It is different from other similar devices as it can be connected to an FDA-
cleared exhaled waste gas scavenger, the Miniscav®.  Together, they prevent nitrous oxide from 
leaking out and affecting clinical staff. This is important because long-term exposure to nitrous oxide 
may have negative effects on health. Nitrouseal® will be used to deliver the gas you receive during your 
biopsy. 
 
 
 
STUDY PARTICIPANTS 
 
You have been asked to be in the study because you are scheduled to have a prostate biopsy.  
 
Approximately 130 people will take part in this study at Beth Israel Deaconess Medical Center. 
 
DESCRIPTION OF STUDY DETAILS 
 
If you agree to be in this study, you will be in this research study for about one week.   
 
After you sign the consent form, the following things will happen: 
 
1. Screening Procedures:  Screening procedures are tests and procedures that will be done to 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
08/07/2023


[CCI] Committee on Clinical Investigations 
Page 4 of 14 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: SELF-ADMINISTERED NITROUS OXIDE 
(SANO) IN PROSTATE BIOPSY TO REDUCE PATIENT ANXIETY AND PAIN 
PRINCIPAL INVESTIGATOR'S NAME: HEIDI RAYALA, MD PHD  
PROTOCOL #: 2021P000715 
 
Informed Consent – Part D 
CCI Form: 7-2020 
PI Revision Date: July 11, 2022 
 
 
determine if you are eligible to take part in the research study.  For this research study, the 
screening procedures include: the completion of a baseline questionnaire. This questionnaire 
will ask you information about your demographics, medical history, and other relevant study 
information. Based on your answers, you may not be found to qualify for the study. In that 
scenario, your participation in the study will end and you will not need to do any other 
procedures as part of the study. 
 
2. Randomization Procedures: It is not clear at this time which of the treatments in this study 
would be better for you.  For this reason, the treatment plan offered to you will be picked by 
chance [like the flip of a coin].  You will not be able to choose which treatment you receive.  
The chances of receiving either of the treatments are approximately equal. After the 
randomization, you will be assigned to one of the following groups: 
 
A) Self-Administered Nitrous Oxide (SANO) 
 
B) Oxygen (Placebo) 
 
If one treatment arm is found to be less effective than the other while you are taking 
part in the study, you will be informed and further treatment will be discussed. 
 
Depending upon the group to which you are assigned, you may receive a placebo (i.e. 
oxygen) instead of the study drug.  A placebo is an inactive treatment that looks like 
the study drug, but a placebo contains no active medication.  Placebos are used to 
help determine if the results of the study are truly from the study drug.  You will not 
know whether you will be receiving the study drug or the placebo.  However, this 
information can be learned in case of an emergency. 
 
3. Research Procedures:  If you qualify to take part in this research study and agree to 
participate, you are required to have someone to drive you home after the procedure. On the 
day of the biopsy, you will undergo these research procedures:  
 
 On the day of your biopsy, a member of the research team will ask you some questions 
about your anxiety and pain before your procedure. We expect the questionnaires to 
take 30 minutes of your time.  
 The length of the procedure is not expected to take longer, but there will be an 
additional 5 minutes to set up the nitrous oxide or oxygen before the biopsy begins. 
 During your biopsy, you will wear the Nitrouseal® mask. Please note you will be able to 
place and remove the mask as needed. You will be able to converse during the 
procedure and this will help the research team adjust amount of gas you receive.  
 Oxygen will be released through the mask until the Urologist is ready to insert the 
rectal probe. You will be asked to take several deep breathes at this time. If you were 
assigned to the SANO group, nitrous oxide will be released instead of oxygen. As 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
08/07/2023


[CCI] Committee on Clinical Investigations 
Page 5 of 14 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: SELF-ADMINISTERED NITROUS OXIDE 
(SANO) IN PROSTATE BIOPSY TO REDUCE PATIENT ANXIETY AND PAIN 
PRINCIPAL INVESTIGATOR'S NAME: HEIDI RAYALA, MD PHD  
PROTOCOL #: 2021P000715 
 
Informed Consent – Part D 
CCI Form: 7-2020 
PI Revision Date: July 11, 2022 
 
 
mentioned before, you will not be told whether or not you will receive nitrous oxide 
unless there is an emergency. At the end of the procedure, nitrous oxide (if used) will 
be stopped and only oxygen will continue to flow through the mask. You will continue to 
wear the mask for a few minutes while you breathe normal oxygen.  A trained and 
qualified staff member will monitor your condition and oxygen levels throughout the 
biopsy to ensure your safety and well-being. 
o You may choose to remove the mask and stop your treatment with the gas for 
any reason at any time. Please inform the monitor in that situation and they will 
assist you.  
 After you are moved to the recovery room following your biopsy, we will ask you some 
questions on your anxiety and pain. We will also check with you about any potential 
side-effects at this time. 
 We will ask your Urologist how easy or difficult it was to perform the biopsy. 
 We expect you to be fully recovered from the effects of SANO within five minutes of 
stopping the gas. While in the recovery room, the study team will administer two brief 
cognitive tests to assess your ability to safely drive home. These tests will primarily 
evaluate your hand-eye coordination. 
 If you feel you do not feel comfortable driving after your biopsy, and you do 
not already have an escort planned, we will coordinate with you and your emergency 
contact to arrange a ride home. 
 
4. Monitoring/Follow-Up Procedures.  Procedures performed to evaluate the effectiveness and 
safety of the research procedures are called “monitoring” or “follow-up” procedures.  For this 
research study, the monitoring/follow-up procedures include: 
 
 Members of the research team will review your medical record to track your health 
status and any potential side effects. 
 
Study Visit 
Timeline 
Prior to 
Day of 
Biopsy 
Before 
Biopsy 
During 
Biopsy 
After 
Biopsy 
7 Days 
After 
Biopsy 
Consent /Assent 
X 
 
 
 
 
Online Questionnaire 
X 
 
 
 
 
Pain and Anxiety 
Measurements 
 
X 
 
X 
 
Study Treatment 
 
 
X 
 
 
Safety Follow-Up 
 
 
 
 
X 
 
Individual Research Results 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
08/07/2023


[CCI] Committee on Clinical Investigations 
Page 6 of 14 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: SELF-ADMINISTERED NITROUS OXIDE 
(SANO) IN PROSTATE BIOPSY TO REDUCE PATIENT ANXIETY AND PAIN 
PRINCIPAL INVESTIGATOR'S NAME: HEIDI RAYALA, MD PHD  
PROTOCOL #: 2021P000715 
 
Informed Consent – Part D 
CCI Form: 7-2020 
PI Revision Date: July 11, 2022 
 
 
Your study doctor will disclose any clinically relevant research results to you, including if we find any 
unexpected side effects of the nitrous oxide. 
 
Most tests done on samples in research studies are only for research and have no clear meaning for 
health care. The research testing done in this study is just a stepping stone to learning more about 
the use of nitrous oxide during prostate biopsy.    
 
While you should not expect to receive any results from the research testing, if we find that research 
results from your sample are of high medical importance, we may attempt to contact your medical 
provider to discuss the results. In some situations, follow up testing might be needed in a Clinical 
Laboratory Improvement Amendments (CLIA) certified clinical lab. You and your medical insurer 
may be responsible for the costs of these tests and any follow up care, including deductibles and co-
payments. It is possible that you will never be contacted with individual research findings. This does 
not mean that you don’t have or won’t develop an important health problem.  
 
Information and Biological Samples 
Your information and biological samples will be used and shared with the sponsor and the 
researchers involved in this study to conduct the research.  The consent form provides information 
on who will have access to identifiable information and identifiable biological samples during the 
study.  We also want you to know that your information or biological samples may be stripped of any 
identifiers (for example your name, medical record number or date of birth) and used for future 
research studies or distributed to another researcher for future research studies without additional 
informed consent. BIDMC researchers or other third party researchers may use your information and 
samples in other scientific research, product testing or commercial development. It is unknown whether 
a product will ultimately be developed from the research described in this consent form or from any 
such work that may be performed by BIDMC or other third parties receiving your information or 
biological samples.  In signing this consent form, you are acknowledging and voluntarily consenting to 
the possibility that your information and biological samples may be used for commercial purposes.   For 
example, your samples and information may be used to develop a new product or medical test to be 
sold. BIDMC and other researchers may benefit if this happens. There are no plans to pay you if your 
samples and information are used for this purpose. 
 
If your identifiers are removed, we will not be able to destroy or remove your information or biological 
samples from distributed information or samples.  As part of this research program and as further 
explained in this form, samples of your tissue and/or information about your medical history may be 
provided to other researchers and/or outside collaborators.  
 
RISKS AND DISCOMFORTS 
As a result of your participation in this study, you are at risk for side effects listed in this section.  You 
should discuss these with the investigator and with your regular doctor if you choose. 
 
More Common 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
08/07/2023


[CCI] Committee on Clinical Investigations 
Page 7 of 14 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: SELF-ADMINISTERED NITROUS OXIDE 
(SANO) IN PROSTATE BIOPSY TO REDUCE PATIENT ANXIETY AND PAIN 
PRINCIPAL INVESTIGATOR'S NAME: HEIDI RAYALA, MD PHD  
PROTOCOL #: 2021P000715 
 
Informed Consent – Part D 
CCI Form: 7-2020 
PI Revision Date: July 11, 2022 
 
 
There are no common risks associated with the study. 
 
Less Common  
There are no less common risks associated with the study. 
 
Rare 
The following rare risks are associated with the use of nitrous oxide: 
 
 About 1 in 200 patients experience mild nausea and vomiting. 
 Other people have reported tachycardia, facial flushing, sweating, drowsiness, or 
lightheadedness when using nitrous oxide.    
 
The following rare risks are associated with the use of oxygen: 
 Pure oxygen at high pressures can cause nausea, dizziness, muscle twitching. These side 
effects are not expected at the concentration we will be administering.  
 
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. 
Therefore, continuous oxygen saturation and heart rate monitoring will be done by the member of 
the study team assisting with nitrous oxide administration. 
 
Loss of confidentiality  
 
There is the potential for loss of confidentiality by participating in this study.  Every effort will be 
made to protect the confidentiality of your identifiable information.   
 
CONFIDENTIALITY 
 
Information learned about you during this research program will be maintained confidentially by the 
research staff as described in this form.  
 
Information learned from your participation in this study and from your medical record may be 
reviewed and photocopied by the Food and Drug Administration (FDA) and/or other federal and state 
regulatory agencies, and by the device manufacturer, Sedation Systems, LLC., accreditation 
agencies, the Committee on Clinical Investigations, the Human Subjects Protection Office and others 
involved in research administration of the Beth Israel Deaconess Medical Center.  Information 
resulting from this study and from your medical record may be used for research purposes and may 
be published; however, you will not be identified by name in such publications. 
 
MEDICAL RECORD 
A copy of this consent form and information collected during this research may become part of your 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
08/07/2023


[CCI] Committee on Clinical Investigations 
Page 8 of 14 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: SELF-ADMINISTERED NITROUS OXIDE 
(SANO) IN PROSTATE BIOPSY TO REDUCE PATIENT ANXIETY AND PAIN 
PRINCIPAL INVESTIGATOR'S NAME: HEIDI RAYALA, MD PHD  
PROTOCOL #: 2021P000715 
 
Informed Consent – Part D 
CCI Form: 7-2020 
PI Revision Date: July 11, 2022 
 
 
medical record, if the information is relevant to the care you receive at Beth Israel Deaconess 
Medical Center.  Medical records are considered permanent records; therefore, information cannot 
be deleted from the record.  Medical records are available to health care professionals at Beth Israel 
Deaconess Medical Center and may be reviewed by staff when carrying out their responsibilities, as 
well as by external parties such as health care insurers and others in certain circumstances.  If you 
are not currently a patient at Beth Israel Deaconess Medical Center and do not have a medical 
record at Beth Israel Deaconess Medical Center, one may be created for you for your participation in 
this research.  You may also be required to register as a patient of Beth Israel Deaconess Medical 
Center in order to participate in this research. 
 
POSSIBLE BENEFITS 
It is not possible to predict whether you will benefit directly from participation in this study. However, 
your participation may help others in the future as a result of knowledge gained from the research. 
Use of Nitrous Oxide may possibly decrease anxiety and pain during your prostate biopsy. The 
results of the research may improve scientific understanding of the impact of self-administered 
nitrous oxide on anxiety and pain for prostate biopsy and other medical procedures.   
 
OTHER AVAILABLE OPTIONS 
Taking part in this study is voluntary.  Instead of being in this study, you have the following options: 
Your alternative to participating in this research is not to participate and undergo your prostate 
biopsy per your urologist’s standard of care. This includes the use of pain control measures that they 
normally use.  
 
If you are concerned about the biopsy you may receive a prescription for an anti-anxiety pill (a 
benzodiazepine) that can be taken before the procedure.  However, if you decide to take the anti-
anxiety pill, you will not be eligible to be part of this research study. 
 
It is important to note that it is possible to get nitrous oxide at other institutions even if you do not 
take part in the study. Please be aware that not all doctors may agree to prescribe this drug for you, 
and health insurance companies may not pay for the drug when it is prescribed for prostate biopsies. 
 
This research study is not meant to diagnose or treat medical problems not specifically stated in this 
informed consent document.  Participation in this research study does not take the place of routine 
physical examinations or visits to your regular doctor. 
 
We recommend that you discuss these and other options with the investigator and your regular 
doctor so that you can make a well-informed decision about participating in this study. 
 
IF YOU DECIDE NOT TO TAKE PART IN THE STUDY 
 
Participation in this study is voluntary.  You have the right to decide not to take part in this study.  If 
you choose to participate, you have the right to leave the study at any time. Your decision to not 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
08/07/2023


[CCI] Committee on Clinical Investigations 
Page 9 of 14 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: SELF-ADMINISTERED NITROUS OXIDE 
(SANO) IN PROSTATE BIOPSY TO REDUCE PATIENT ANXIETY AND PAIN 
PRINCIPAL INVESTIGATOR'S NAME: HEIDI RAYALA, MD PHD  
PROTOCOL #: 2021P000715 
 
Informed Consent – Part D 
CCI Form: 7-2020 
PI Revision Date: July 11, 2022 
 
 
participate will not result in any penalties or loss of benefits to you. The investigators will tell you 
about new information that may affect your willingness to stay in this study.  
 
If you decide not to participate in the study or decide to leave the study early, your decision will not 
affect your relationship with the research team or any other individual at Beth Israel Deaconess 
Medical Center.   
 
INVESTIGATORS RIGHT TO STOP THE STUDY 
 
The investigators have the right to end your participation in this study if they determine that you no 
longer qualify to take part, or if it would be dangerous for you to continue, or if you do not follow 
study procedures as directed by the investigators.  Beth Israel Deaconess Medical Center or the 
funding source may stop the study at any time. 
 
COSTS AND/OR PAYMENTS TO YOU 
 
COSTS COVERED BY STUDY 
You will not be charged for the medical gases, study device and treatment that are part of this 
research study.  However, you and your insurance company will be charged for other tests, 
procedures or medications that are considered standard for a prostate needle biopsy.   
 
CO-PAYMENT/DEDUCTIBLE STATEMENT 
You will be responsible for any co-payments or deductibles that are standard for your insurance 
coverage.   
 
PAYMENTS TO YOU: 
You will not be paid for participating in this study. 
 
COST OF RESEARCH RELATED INJURY: 
 
If you are injured as a direct result of your participation in this study, you should contact the 
Investigator at the number provided under the section “Who to Call if You Have Questions” in this 
form.  You will be offered the necessary care to treat your injury. We reserve the right to bill your 
insurance company or the sponsor, if appropriate, for the care you get for the injury.   We will try to 
get these costs paid for, but you may be responsible for some of them.  You may be responsible for 
all co-payments and deductibles required under your insurance.   At this time there is no plan to 
reimburse you for items such as lost wages or lost time from work.  By signing this consent form you 
have not given up any legal rights. 
 
AUTHORIZATION FOR USE AND DISCLOSURE OF YOUR PROTECTED HEALTH 
INFORMATION 
As part of this study, we will be collecting, using and sharing with others information about you.  
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
08/07/2023


[CCI] Committee on Clinical Investigations 
Page 10 of 14 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: SELF-ADMINISTERED NITROUS OXIDE 
(SANO) IN PROSTATE BIOPSY TO REDUCE PATIENT ANXIETY AND PAIN 
PRINCIPAL INVESTIGATOR'S NAME: HEIDI RAYALA, MD PHD  
PROTOCOL #: 2021P000715 
 
Informed Consent – Part D 
CCI Form: 7-2020 
PI Revision Date: July 11, 2022 
 
 
Please review this section carefully as it contains information about the federal privacy rules and the 
use and disclosure of your information.   
 
DESCRIPTION OF PROTECTED HEALTH INFORMATION [PHI] 
By signing this informed consent document, you are allowing the investigators and other authorized 
personnel to use and disclose health information about you.  This may include information about you 
that already exists (for example: your medical records and other sources of health information, 
demographic information, and the results of any laboratory tests as well as any new information 
generated as part of this study.  This is your Protected Health Information. 
 
PEOPLE/GROUPS AT BIDMC WHO WILL SHARE AND USE YOUR PROTECTED HEALTH INFORMATION 
Your Protected Health Information may be shared with and used by investigators working on this 
study, including the supporting research team (such as research assistants and coordinators, 
statisticians, data managers, laboratory personnel, pharmacy personnel, and administrative 
assistants), and may also be shared with and used by other health care providers at BIDMC who 
have treated you in the past and have information relevant to the research, or who provide services 
to you in connection with the research.  Your Protected Health Information may also be shared with 
the members and staff of the Committee on Clinical Investigations of Beth Israel Deaconess Medical 
Center, which is responsible for reviewing studies for the protection of the research subjects, so that 
it can carry out its oversight responsibilities with respect to the study.  
 
PEOPLE/GROUPS OUTSIDE OF BIDMC TO WHOM YOUR PROTECTED HEALTH INFORMATION WILL BE 
DISCLOSED (SHARED) AND WHO MAY USE YOUR PROTECTED HEALTH INFORMATION 
We will take care to maintain confidentiality and privacy about you and your Protected Health 
Information.  We may share your Protected Health Information with the following groups so that they 
may carry out their duties related to this research study: 
 
 The funding source and/or sponsor of this study, Sedation Systems, LLC., and, where 
applicable, the people and companies that the funding source and/or sponsor use to oversee, 
administer, or conduct the research (for example, clinical research organizations are 
companies that are sometimes hired by research sponsors to help manage and run a clinical 
research study) 
 The other hospitals and medical centers taking part in this study and research collaborators at 
those institutions.  
 Other research collaborators and supporting research team members taking part in this study  
 Any external health care providers who provide services to you in connection with this 
research 
 Laboratories not affiliated with BIDMC that are involved in conducting tests related to the 
research 
 Statisticians and other data monitors not affiliated with BIDMC 
 The members and staff of any other IRBs (beyond the BIDMC Committee on Clinical 
Investigations) that oversee the research  
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
08/07/2023


[CCI] Committee on Clinical Investigations 
Page 11 of 14 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: SELF-ADMINISTERED NITROUS OXIDE 
(SANO) IN PROSTATE BIOPSY TO REDUCE PATIENT ANXIETY AND PAIN 
PRINCIPAL INVESTIGATOR'S NAME: HEIDI RAYALA, MD PHD  
PROTOCOL #: 2021P000715 
 
Informed Consent – Part D 
CCI Form: 7-2020 
PI Revision Date: July 11, 2022 
 
 
 Centralized data collectors  
 Your health insurance company 
 The Food and Drug Administration [FDA], the Department of Health and Human Services 
[DHHS], the National Institute of Health [NIH], the Office for Human Research Protections 
[OHRP], and other federal and state agencies that may have jurisdiction over the research 
 Hospital and Clinical Research Accrediting Agencies 
 Data and Safety Monitoring boards that oversee this study (if applicable) 
 
Those who receive your Protected Health Information during the course of the research may not be 
required by the federal privacy regulations to protect it, and they may make further disclosures to 
others and use your information without being subject to penalties under those laws.   
 
 
PURPOSE: WHY WE ARE USING AND SHARING YOUR PROTECTED HEALTH INFORMATION 
The reason for using and sharing your Protected Health Information is to conduct and oversee the 
current, secondary, and future research described in this Informed Consent Document.  There are 
many other reasons beyond the research for which BIDMC may use or disclose your Protected 
Health Information.  Not all of these reasons require your express written authorization.  For 
example, we will use and share your Protected Health Information to ensure that the research meets 
legal, institutional and accreditation requirements and to conduct public health activities.  The various 
ways in which BIDMC may use and disclose your protected health information without your 
authorization are explained in a document called the Notice of Privacy Practices.  If you have not 
received a copy of BIDMC’s Notice of Privacy Practices, please ask us for one and review it before 
signing this form.  In addition to signing this document, you may also be asked to sign a BIDMC 
General Agreement form acknowledging that you have received the BIDMC Notice of Privacy 
Practices.   
 
NO EXPIRATION DATE – RIGHT TO WITHDRAW AUTHORIZATION 
Your authorization for the use and disclosure of your Protected Health Information in this Study shall 
never expire.  However, you may withdraw your authorization for the use and disclosure of your 
Protected Health Information at any time provided you notify the Principal Investigator in writing.  If 
you would like to take back your authorization so that your Protected Health Information can no 
longer be used in this study, please send a letter notifying the Principal Investigator of your 
withdrawal of your authorization to Dr. Heidi Rayala, MD PhD at 330 Brookline Ave., Boston, MA. 
Please be aware that the investigators in this study will not be required to destroy or retrieve any of 
your Protected Health Information that has already been used or disclosed before the Principal 
Investigator receives your letter, and they are permitted to continue to use and disclose your 
previously collected information as necessary to complete the research. 
 
REFUSAL TO SIGN 
Your clinical treatment may not be conditioned upon whether you sign the Authorization for 
Research. However, if you choose not to sign this informed consent document and authorization for 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
08/07/2023


[CCI] Committee on Clinical Investigations 
Page 12 of 14 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: SELF-ADMINISTERED NITROUS OXIDE 
(SANO) IN PROSTATE BIOPSY TO REDUCE PATIENT ANXIETY AND PAIN 
PRINCIPAL INVESTIGATOR'S NAME: HEIDI RAYALA, MD PHD  
PROTOCOL #: 2021P000715 
 
Informed Consent – Part D 
CCI Form: 7-2020 
PI Revision Date: July 11, 2022 
 
 
the use and disclosure of your Protected Health Information, you will not be allowed to take part in 
the research study. 
 
RIGHT TO ACCESS AND COPY YOUR PHI 
If you wish to review or copy your Protected Health Information as it is made part of your medical 
record, you may do so after the completion or termination of the study by sending a letter to the 
Principal Investigator requesting a copy of your Protected Health Information.  You may not be 
allowed to inspect or copy your Protected Health Information until this study is completed or 
terminated. 
 
ADDITIONAL CONTACT FOR QUESTIONS OR CONCERNS 
You may contact the Human Subjects Protection Office at [617] 975-8500 in the event that you 
would like to obtain information or to offer input about the research study. This office is independent 
of the investigator or investigator’s research staff and can also assist with questions relating to your 
rights as a participant in research, which may include questions, concerns or complaints about your 
participation in the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
08/07/2023


[CCI] Committee on Clinical Investigations 
Page 13 of 14 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: SELF-ADMINISTERED NITROUS OXIDE 
(SANO) IN PROSTATE BIOPSY TO REDUCE PATIENT ANXIETY AND PAIN 
PRINCIPAL INVESTIGATOR'S NAME: HEIDI RAYALA, MD PHD  
PROTOCOL #: 2021P000715 
 
Informed Consent – Part D 
CCI Form: 7-2020 
PI Revision Date: July 11, 2022 
 
 
THE FOLLOWING PARAGRAPHS CONTAIN SOME STANDARD INFORMATION WHICH 
GENERALLY APPLIES TO INDIVIDUALS PARTICIPATING IN A RESEARCH STUDY. 
 
CONSENT FORM FOR CLINICAL RESEARCH 
I have read the previous page[s] of the consent form and the investigator has explained the details of the 
study.  I understand that I am free to ask additional questions. 
 
If I wish additional information regarding this research and my rights as a research subject, or if I believe I 
have been harmed by this study, I may contact the Human Subjects Protection Office (HSPO). 
 
I am aware that this is a research project and that unforeseen side effects may occur. 
 
I understand that the Beth Israel Deaconess Medical Center has no formal program for compensating patients 
for medical injuries arising from this research.  Medical treatment will be provided for injuries at the usual 
charge to me or to my insurer unless payment is otherwise provided for in this consent form. 
 
I understand that participation in this study is voluntary and I may refuse to participate or may discontinue 
participation at any time without penalty, loss of benefits, or prejudice to the quality of care which I will receive. 
 
I acknowledge that no guarantees have been made to me regarding the results of the treatment involved in 
this study, and I consent to participate in the study and have been given a copy of this form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Subject or 
 
 
 
 
Date 
Legally Authorized Representative   
(Parent if the subject is a minor) 
 
 
 
 
 
 
 
 
 
 
 
 
Relationship of Legally Authorized Representative to Subject   
 
 
The subject has been given the opportunity to read this consent form and to ask questions before signing, and 
has been given a copy. 
 
___________________________________________________________ 
SIGNATURE OF INVESTIGATOR/Co-Investigator   
DATE 
 
__________________________________________________________ 
PRINT INVESTIGATOR’S/Co-Investigator’s  
NAME 
 
A signing co-investigator must be listed on the study’s approved Research Staffing Form at the time of consent. 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
08/07/2023


[CCI] Committee on Clinical Investigations 
Page 14 of 14 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: SELF-ADMINISTERED NITROUS OXIDE 
(SANO) IN PROSTATE BIOPSY TO REDUCE PATIENT ANXIETY AND PAIN 
PRINCIPAL INVESTIGATOR'S NAME: HEIDI RAYALA, MD PHD  
PROTOCOL #: 2021P000715 
 
Informed Consent – Part D 
CCI Form: 7-2020 
PI Revision Date: July 11, 2022 
 
 
THE FOLLOWING SECTIONS ARE NOT NEEDED FOR ALL STUDIES AND SHOULD BE 
UTILIZED AS INDICATED: 
 
If the subject is able to speak and understand English but is not able to read or write  
 
I was present during the entire oral presentation of the informed consent and witnessed the subject’s agreement to 
participate in the study. 
 
Signature of Witness:  
 
Printed Name of Witness:  
 
Date:   
 
 
If the subject is able to understand English but is not physically able to read or write or see 
 
I was present during the entire oral presentation of the informed consent and witnessed the subject’s agreement to 
participate in the study. 
 
Signature of Witness:  
 
Printed Name of Witness:  
 
Date:   
 
 
 
If the subject is not English speaking and signed the translated Short Form in lieu of the English consent 
document. 
As someone who understands both English and the language spoken by the subject, I interpreted, in the subject’s 
language, the researcher’s presentation of the English consent form.  The subject was given the opportunity to ask 
questions.  
Signature of Interpreter:  
 
Printed name of Interpreter:  
 
Date:  
 
 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
08/07/2023