Clinical trial NCT02755090
Conditions: Pregnancy Termination in Second Trimester
Keywords: nitrous pain
Sponsor: University of New Mexico
Start date: 2016-07-01; Completion date: 2017-05-01
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a multi-site, double-blinded, randomized, non-inferiority clinical trial of inhaled nitrous oxide with oxygen (N2O/O2) versus intravenous (IV) sedation, with fentanyl and midazolam, for pain management in adult women having a pregnancy termination procedure between 12 and 16 weeks gestational age.

Detailed description:
This study will evaluate whether nitrous oxide is a feasible and acceptable alternative to IV sedation for pain management during early second trimester D\&E. Primary endpoints will include maximum procedural pain using the visual analog scale (VAS) as well as satisfaction with anesthesia using the Iowa Satisfaction with Anesthesia Scale.

Arms: arm 1: Participants in the nitrous oxide group will receive a scented face mask through which nitrous oxide will be administered. The nitrous content of the gas will be titrated up by 20% every 5 breaths with a goal of 70% N2O/ 30% O2 as tolerated by the participant. This group will also receive saline through an IV. All participants will receive local anesthesia in the form of a paracervical block and ibuprofen pre-operatively. arm 2: Within the IV sedation group, women will receive 100mcg fentanyl and 2mg midazolam at least two minutes prior to initiation of the procedure. This group will also receive 100% oxygen by a scented face mask. All participants will receive local anesthesia in the form of a paracervical block and ibuprofen pre-operatively.
Interventions: intervention 1: Nitrous Oxide intervention 2: IV Saline
Intervention descriptions: intervention 1: Participants in the nitrous oxide group will receive a scented face mask through which nitrous oxide will be administered. The nitrous content of the gas will be titrated up by 20% every 5 breaths with a goal of 70% N2O/ 30% O2 as tolerated by the participant. This group will also receive saline through an IV. All participants will receive local anesthesia in the form of a paracervical block and ibuprofen pre-operatively. intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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PROTOCOL TITLE: 
Nitrous Oxide versus IV Sedation for Anesthesia (NOVIA) 
Protocol ID: 16-101 
NCT Number: NCT02755090 
PRINCIPAL INVESTIGATOR: 
Lauren Thaxton, MD 
Rameet Singh, MD MPH 
Eve Espey, MD MPH 
Department of Obstetrics and Gynecology 
University of New Mexico  
VERSION NUMBER: 
5  
DATE: 
August 17, 2017 
REGULATORY FRAMEWORK: 
Please indicate all that apply: 
DOD (Department of Defense) 
DOE (Department of Energy) 
DOJ (Department of Justice) 
ED (Department of Education) 
EPA (Environmental Protection Agency) 
FDA (Food and Drug Administration) 
HHS (Department of Health and Human Services) 
Other: Society of Family Planning 
 
Is this a clinical trial under ICH-GCP E6?    
 Yes    
 No 
If yes, please confirm that the research team is familiar with and agrees to 
comply with the investigator requirements cited in ICH-GCP E6.  
 Yes   
 No  
ICH-GCP E6 can be accessed by copying and pasting this URL into your 
browser: http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf 


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Table of Contents 
1. 
Objectives......................................................................................................
..3 
2. 
Background....................................................................................................
.3  
3. 
Study  
Design...................................................................................................5 
4. 
Inclusion and Exclusion 
Criteria......................................................................6 
5. 
Number of 
Subjects.........................................................................................8 
6. 
Study 
Timelines...............................................................................................9 
7. 
Study 
Endpoints..............................................................................................9  
8. 
Research  
Setting.............................................................................................9 
9. 
Resources  
Available......................................................................................10 
10. 
Prior Approvals ..........................................................................................11 
11. Multi-Site 
Research....................................................................................11 
12. 
Study Procedures ......................................................................................11 
13. 
Data Analysis.............................................................................................15 
16. 
Withdrawal of Subjects  
..............................................................................16 
17. 
Data Management/Confidentiality..............................................................16 
18. 
Data and Specimen Banking  
.....................................................................17 
19. 
Risks to Subjects  
.......................................................................................17 
20. 
Potential Benefits to Subjects  
....................................................................19 
21. 
Recruitment Methods.................................................................................19 
22. 
Provisions to Protect the Privacy Interests of  
Subjects..............................20 
23. 
Economic Burden to Subjects....................................................................20 
24. 
Compensation............................................................................................21 
25. 
Compensation for Research-Related Injury...............................................22 
26. 
Consent  
Process........................................................................................22 


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27. 
Documentation of Consent  
........................................................................23 
28. 
Study Test Results/Incidental Findings......................................................24 
29. 
Sharing Study Progress or Results with  
Subjects......................................24 
30. 
Inclusion of Vulnerable Populations...........................................................24 
31. 
Community-Based Participatory Research................................................25 
32. 
Research Involving American Indian/Native Populations  
..........................25 
33. 
Transnational Research.............................................................................25 
34. 
Drugs or Devices  
.......................................................................................25 
35. 
References……………………………………………………………………...26 
36. 
Checklist Section  
.......................................................................................27 
1. Objectives 
1.1. 
We propose a multi-site, double-blinded, randomized, noninferiority 
clinical trial of inhaled nitrous oxide with oxygen (N2O/O2) versus 
intravenous (IV) sedation, with fentanyl and midazolam, for pain 
management in adult women having an abortion procedure between 12 
and 16 weeks gestational age. We will evaluate whether nitrous oxide is 
a feasible and acceptable alternative to IV sedation for pain 
management during early second trimester D&E. We will measure 
maximum procedural pain using a visual analog scale (VAS) and 
satisfaction with anesthesia using the Iowa Satisfaction with Anesthesia 
Scale (ISAS).  
1. 
2.The contribution of the proposed research is to determine if 
nitrous oxide is a safe and effective alternative to intravenous (IV) sedation 
for second trimester abortion. We hypothesize that women receiving 
nitrous oxide anesthesia will have non-inferior pain and satisfaction scores 
compared to women receiving IV sedation. 
1.2.1. Primary Objective 1: To compare women’s maximum 
procedural pain measured on a visual analog scale during a 
surgical abortion between 12 weeks 0 days to 16 weeks 0 days 
gestational age between women randomized to nitrous oxide 
versus intravenous sedation. Our hypothesis is that women 
receiving nitrous oxide will report non-inferior pain scores as 
compared to women receiving intravenous sedation. 


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1.2.2. Primary Objective 2: To compare women’s satisfaction with 
procedural pain management measured on the Iowa Satisfaction 
with Anesthesia Scale (ISAS) following a surgical abortion between 
12 weeks 0 days to 16 weeks 0 days gestational age between 
women randomized to nitrous oxide versus intravenous sedation. 
Our hypothesis is that women who received nitrous oxide will report 
non-inferior satisfaction scores as compared to women receiving 
intravenous sedation. 
1.3. Secondary Objectives: To compare duration of time from procedure 
completion to ready for clinic discharge, as determined by having an Aldrete 
score of 8 or greater, between the two groups. To compare duration of 
procedure, defined as time from speculum insertion to post-procedure 
speculum removal, between the two groups.  
2. Background 
2.1.Second trimester abortion is a painful procedure(1). Despite the 
importance of pain management in abortion care, options for anesthesia 
in the outpatient setting are limited. According to North American 
members of the National Abortion Federation, the most common pain 
management offered for second trimester abortion is a combination of 
local anesthesia and moderate IV sedation(2). With IV sedation, the 
American Society of Anesthesiologists recommends fasting for 6 hours 
prior to the procedure and extended post-procedure monitoring(3). 
Safety considerations also require that women have a ride home from 
the clinic creating a burden for those with limited resources or who travel 
long distances. An ideal anesthetic would offer women adequate pain 
relief while meeting her need for privacy, rapid recovery, and safety. 
Nitrous oxide is an inhaled gas which can be titrated in conjunction with 
oxygen. Nitrous oxide is attractive in the outpatient clinic setting 
because delivery systems are relatively inexpensive, training is not 
burdensome and administration of the gas is non-invasive. Its onset of 
action is almost immediate and effects can be rapidly reversed with 
administration of 100% oxygen with minimal to no residual side effects. 
Prior research utilizing nitrous oxide for abortion is limited.  
2.2.Two studies have evaluated the use of nitrous oxide (50% nitrous 
oxide/50% oxygen) for first trimester abortion. Both studies used nitrous 
oxide in addition to IV medications. Kan et al found that a 50:50 mix of 
nitrous oxide/oxygen did not additionally reduce pain in women already 


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receiving IV sedation in an operating room setting(4). Agostini et al 
evaluated nitrous oxide versus oxygen alone in women undergoing first 
trimester abortion with local anesthesia and IV paracetamol in an office 
setting(5). There was no difference in mean operative pain scores 
between the study and intervention groups. Our proposed study differs 
from both those studies in the use of a higher concentration of nitrous 
oxide and in its use as the primary agent for pain management.  
One pilot study has examined the use of nitrous oxide as an alternative 
to oral sedation in first trimester abortion with promising results. Mean 
pain scores were similar between groups with maximum procedural 
pain rated 55.7mm ± 20.8 for women randomized to nitrous oxide and  
61.3mm ± 20.2 for oral sedation along a 100mm visual analog scale(6). 
The follow up randomized clinical trial evaluated maximum pain scores 
in an oral sedation group versus a nitrous oxide group. The manuscript 
is under review; personal communication with the principal investigator 
reveals the following preliminary results: Mean maximum procedural 
pain was similar between groups (60.75mm [SD= 24.36] in the oxygen 
group and 55.7mm [SD=20] in the nitrous group). A limitation of this 
study is that pain was evaluated in the study group after the nitrous 
oxide dissipated while pain was evaluated in the control group while still 
under the effects of oral sedation.  In our proposed study, pain will be 
evaluated immediately after the procedure, while both groups are still 
under the influence of the sedation agent.  
Additional studies have been performed at the University of New 
Mexico (UNM) utilizing nitrous oxide for intrauterine device (IUD) 
insertion in nulliparous women as well as for transcervical sterilization. 
These manuscripts are pending publication however personal 
communication has revealed the following information. In the IUD 
study, fixed 50:50 ratio of nitrous oxide was compared to 100% oxygen 
with pain measured after nitrous oxide had dissipated. Women who 
received nitrous oxide did not report lower pain scores however, they 
reported higher rates of satisfaction with pain control. In a randomized 
study of women undergoing transcervical sterilization, a 70:30 nitrous 
oxide concentration group was compared to an oral sedation group. 
Pain scores were evaluated while women were still under the influence 
of medications. This study demonstrated significantly lower pain scores 
(22.8mm compared to 54.5mm control) in the nitrous oxide group. Total 
procedure time for transcervical sterilization was notably shorter for 
women who were randomized to nitrous oxide; however, both groups 


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experienced longer procedure times than IUD insertion and first 
trimester abortion.  
These studies have informed the proposed research by showing that: 
(1) Women are willing to participate in studies of alternative forms 
of anesthesia, including nitrous oxide.  
(2) Fixed 50:50 dosing of nitrous oxide is likely inadequate at 
providing pain relief; rapid titration is a superior methodology. 
(3) Timing of pain score collection is important and should be 
standardized across groups.  
(4) Nitrous oxide appears to be more effective for longer 
procedures.  
2.3.The contribution of the proposed research is to add to the limited 
literature on novel anesthetic options for second trimester abortion and, 
specifically, to evaluate the effectiveness of nitrous oxide as a more 
patient-centered alternative to IV sedation for second trimester abortion. 
This contribution to the literature is significant because current 
anesthetic options are limited and insufficient. 
3. Study Design 
3.1. Selection of Participants/ Target Population:  
We propose a multi-site, double-blinded, randomized, non-inferiority 
clinical trial of inhaled nitrous oxide versus intravenous sedation for 
pain management in adult women receiving an abortion between 12 
and 16 weeks gestational age.  Our study will be conducted at two 
clinical sites: the University of New Mexico Center for Reproductive 
Health Clinic and University of Colorado Comprehensive Women’s 
Health Center. All study endpoints will be collected on the date of 
procedure and thus, no follow up will be necessary. In order to be able 
to show that nitrous oxide is non-inferior on both primary endpoints we 
will recruit 150 women at two treatment sites. 
3.2. Study randomization will occur just prior to initiation of the abortion 
procedure to nitrous oxide or IV sedation. The research coordinator, 
participant and providers will be masked to the treatment allocation. The 
only unmasked member of the team will be the nurse administering the 
medications.  Investigators will utilize a centralized stratified block 
randomization with allocation listed as “study drug 1” and “study drug 2”. 


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Study coordinators will determine allocation and discuss this with clinic 
nurses. The meanings of these labels will be separately revealed to 
clinical nursing staff responsible for administration. 
4. Inclusion and Exclusion Criteria 
4.1.In order to be able to show that nitrous oxide is non-inferior on both 
primary endpoints we will recruit 150 women at two treatment sites. This 
study will be conducted at two separate clinics, both of which provide 
pregnancy termination services up to 22 weeks gestational age.  In New 
Mexico, participants will be recruited from the University of New Mexico 
Center for Reproductive Health (CRH) clinic and in Colorado, 
participants will be recruited from the Comprehensive Women’s Health 
Center (CWHC). These are both outpatient clinics where Family 
Planning fellows, faculty and Ob/Gyn residents perform second 
trimester procedures. Only Attendings and Fellows will perform 
procedures for study participants. 
Eligibility for participation will be determined by clinic staff at initial 
encounter. In order to recruit efficiently, all women seeking pregnancy 
termination between 12w0d and 16w0d gestational age will be 
approached about possible study participation. Women presenting for 
abortion will be screened by clinic providers for eligibility. If determined 
to be eligible for participation and interested, women will meet with 
trained research staff in a private clinic room. The research staff will 
review the study as well as risks and benefits of participation.  
Patients will have ample time to read the study consent and consider 
participation.  Patients will be given the opportunity to ask questions 
regarding study participation. Potential participants will be reassured their 
clinical care will not be affected by their decision. If patients choose not 
to participate, they will not be approached again unless they broach the 
subject. 
Recruitment materials in the form of flyers/brochures (in both English 
and Spanish) will be posted at UNM’s CRH clinic. These materials will 
summarize the study and include a phone number for participants to 
contact research staff to inquire for more details about the study. 
Should the participant contact research staff prior to their appointment 
at CRH, the research coordinators will consult with the patient’s 
provider to ensure eligibility. OB/GYN healthcare providers at UNM will 
also be provided with a flyer describing the study. The flyer will list 
eligibility criteria and will allow the providers to discuss the study with 
their patients should they show interest and meet criteria.  


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4.2.Eligibility criteria include women who desire an outpatient abortion and 
are at least 18 years of age, with a gestational age between 12 weeks 0 
days and 16 weeks 0 days as determined by ultrasound crown rump 
length (for gestations up to 13 weeks) and biparietal diameter and femur 
length (for gestations exceeding 13 weeks), able to read and 
understand English or Spanish, and obtain reliable post-procedure 
transportation and observe fasting guidelines of 6 hours prior to 
procedure. The gestational age range of 12 to 16 weeks was elected as 
later second trimester abortions (>16 weeks) contain more 
heterogeneity of cervical preparation.   
Exclusion criteria include contraindications to outpatient abortion that 
will significantly increase medical risk, such as major medical illness or 
concern for invasive placentation, contraindications to nitrous oxide 
(pernicious anemia, current treatment with bleomycin chemotherapy, 
active upper respiratory illness, or COPD), intrauterine fetal demise, 
chronic narcotic use or known adverse reaction to Fentanyl, Versed, or 
nitrous oxide. Additionally, women who are not felt to be able to safely 
receive the starting dose of IV sedation due to low body mass index 
may be excluded based on provider judgement. 
4.3.In order to decrease medical risk and side effects, the study will also 
exclude patients who have recently undergone middle ear or ocular eye 
surgery, have sinusitis, ear problems, head trauma, bowel obstruction, 
and/or pneumothorax. This study will not recruit adults who are unable 
to consent or women who are currently incarcerated.  
4. 4.This study will be recruiting women who can speak and read English 
and/or Spanish fluently.  
5. Number of Subjects 
5.1.We propose a multi-site, double-blinded, randomized, non-inferiority 
clinical trial of inhaled nitrous oxide versus intravenous sedation for pain 
management in adult women receiving an abortion between 12 and 16 
weeks gestational age.  Our study will be conducted at two clinical sites: 
the University of New Mexico Center for Reproductive Health Clinic and 
University of Colorado Comprehensive Women’s Health Center. All 
study endpoints will be collected on the date of procedure and thus, no 
follow up will be necessary. In order to be able to show that nitrous 
oxide is non-inferior on both primary endpoints we will recruit 150 
women at two treatment sites. 
5.2.Through the University of New Mexico Center for Reproductive Health 
Clinic, we will recruit 75 participants. 


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5.3.Previous studies using the ISAS showed a mean score of 2.0 with a 
standard deviation of 1.3 in their treatment group and a difference of 
0.6U between their group (7). This study evaluated patients who had 
received monitored anesthesia care (MAC), local anesthetic block plus 
or minus dexmedetomidine for different outpatient elective procedures. 
Our goal was to demonstrate non-inferiority between the two treatment 
groups and therefore, we calculated our sample size using a 1-sided, 
2group test of non-inferiority.  With a sample size of 150 (75 in each 
arm), we can detect a difference of 0.6U with 80% power and a Type I 
error of 5%. 
With regard to the outcome of pain we looked to the literature on 
medical termination of pregnancy. A previous study studies reported 
pain scores for expulsion of a second trimester fetus during medical 
induction, with or without fentanyl for pain control.  Median pain on a 
100-mm VAS scale was reported as 70 mm (IQR=50, 80) (7). This 
approximately translates into a mean VAS score = 66.7mm and a SD = 
22.2mm. Our goal was to demonstrate non-inferiority between the two 
treatment groups and therefore, we calculated our sample size using a 
1-sided, 2-group test of non-inferiority.  With a sample size of 100, we 
can detect a noninferiority margin of 15mm with 80% power and a Type 
I error of 5% for the outcome of pain. We plan to recruit 150 participants 
to assess the outcome of satisfaction. Further, we suspect average 
maximum VAS among patients having a surgical abortion may be less 
than for those undergoing second trimester induction. Therefore, we 
calculated differences that could be detected with 75 participants in 
each arm.  If we estimate that our IV sedation group will have an 
average maximum VAS pain score of 50mm, and our nitrous group 
54.8mm (with a SD of 25mm), we will preserve a non-inferiority margin 
15mm and maintain 80% power with a Type I error of 5%.  
6. Study Timelines 
6.1.Investigators of this study anticipate that recruitment will be possible 
beginning as early as the Spring of 2016. Based on prior studies and 
chart review, investigators estimate that the University of New Mexico 
clinic performs approximately ten abortion procedures between 12 and 
16 weeks gestational age a month. Additionally, The University of 
Colorado clinic performs approximately 15 procedures per month in this 
gestational age range.  Investigators assume 80% enrollment based on 
prior abortion studies at the University of New Mexico utilizing nitrous 
oxide(6). Using this information, we approximate that recruitment would 
be complete in 8 months. We anticipate another month of data cleaning 
following end of recruitment and three months of data analysis. 


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This procedure may take one or two days. This would be the case 
regardless of whether or not the participant chose to enroll in the study. 
The extra time needed to participate in this study will be related to the 
amount of time needed to fill out study related questionnaires. We 
estimate this will take a total of less than two hours.  
  
7. Study Endpoints 
7.1.All study endpoints will be collected on the date of procedure and thus, 
no follow up will be necessary. In order to be able to show that nitrous 
oxide is non-inferior on both primary endpoints we will recruit 150 
women at two treatment sites. 
8. Research Setting 
8.1.Our study will be conducted at two clinical sites: the University of New  
Mexico Center for Reproductive Health Clinic and University of 
Colorado Comprehensive Women’s Health Center. These are both 
clinical sites well versed in managing the competing demands of a busy 
clinical schedule and robust research. These two sites have previously 
collaborated as part of a large multi-center study evaluating cervical 
preparation for intrauterine device insertion and have published on this 
experience(8). Both sites are part of a Clinical Translational Science 
Center and projects at both sites will be overseen by well respected 
members of the family planning community in conjunction with family 
planning fellows. Progress on the project will also be followed by the 
Fellowship in Family Planning as part of fellowship graduation 
requirements. 
Clinically, both sites are also well suited for this project. The UNM  
Center for Reproductive Health and the University of Colorado 
Comprehensive Women’s Health Center are both staffed by providers 
specialized in reproductive health and family planning. Additionally, 
nurses at both locations are well versed in outpatient moderate 
sedation. At the Center for Reproductive Health, nurses are trained in 
intravenous sedation and moderate sedation, maintain Advanced 
Cardiac Life Support (ACLS) certification and participate in quarterly 
safety drills. In order to provide nitrous oxide for this study, nursing staff 
and providers will also be responsible for reading material on the 
provision of nitrous oxide, attending a didactic course and successfully 
completing a test to establish proficiency.  
8.2.This study will be conducted at two separate clinics, both of which 
provide pregnancy termination services up to 22 weeks gestational age.  


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In New Mexico, participants will be recruited from the University of New 
Mexico Center for Reproductive Health (CRH) clinic and in Colorado, 
participants will be recruited from the Comprehensive Women’s Health 
Center (CWHC).  
9. Resources Available 
9.1.Our study will be conducted at two clinical sites: the University of New 
Mexico Center for Reproductive Health Clinic and University of Colorado 
Comprehensive Women’s Health Center. These clinics are staffed with 
medical providers well versed in abortion care as well as outpatient 
anesthesia. All providers of nitrous oxide will complete education in 
administration and proficiency will be judged uniformly by successful 
completion of a test.  
9.2.Nurses or physicians will be responsible for administering sedation and 
for monitoring for signs of adequate or over sedation and will have no 
other concurrent responsibilities.  Additionally, nurses at both locations 
are well versed in outpatient moderate sedation. At the Center for 
Reproductive Health, nurses are trained in intravenous sedation and 
moderate sedation, maintain Advanced Cardiac Life Support (ACLS) 
certification and participate in quarterly safety drills. In order to provide 
nitrous oxide for this study, nursing staff and providers will also be 
responsible for reading material on the provision of nitrous oxide, 
attending a didactic course and successfully completing a test to 
establish proficiency. Clinic sites will be equipped for management of 
over sedation including reversal drugs, crash cart inclusive of 
bagmaskvalve device and nasal and oral airways as well as availability 
to transfer to higher level care as needed. Providers will also maintain 
ACLS certification.  
Moderate sedation will be administered according to standardized study 
protocols which are the same at both sites. All participants must have 
observed fasting recommendations of two hours for clear liquids and six 
hours for solids. All participants will require an escort home in order to 
receive sedation. During the procedure, all participants will have 
noninvasive blood pressure and pulse oximetry monitoring. 
9.3.Based on prior studies and chart review, investigators estimate that the 
University of New Mexico clinic performs approximately ten abortion 
procedures between 12 and 16 weeks gestational age a month. 
Additionally, The University of Colorado clinic performs approximately 
15 procedures per month in this gestational age range.  Investigators 


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assume 80% enrollment based on prior abortion studies at the 
University of New Mexico utilizing nitrous oxide(6). Using this 
information, we approximate that recruitment would be complete in 8 
months. We anticipate another month of data cleaning following end of 
recruitment and three months of data analysis. 
Research Staff and/or coordinators will provide study support by 
assisting with collecting data and adhering to study protocol. Staff have 
undergone the required training to manage and collect patient 
information.  Data will be entered into RedCap on date of procedure by 
research staff at each respective site. Research staff will have 
completed institutional training in RedCap prior to initiation of study. 
10. 
Prior Approvals 
10.1. 
This protocol is also being reviewed by the University of Colorado    
IRB and a copy of that protocol is attached.  
11. 
Multi-Site Research 
11.1. 
This study is proposed as a multi-site randomized clinical trial 
design. All sites have the most current version of the protocol, consent 
document, and HIPAA authorization. Additionally, data will be shared 
across sites for quarterly reporting to the DSMB as well as for final data 
analysis and reporting. There may be times when we are required by 
law to share information. However, protected health information (PHI) 
will not be used in any published reports about this study.   
Information collected as part of the study will be labeled with a study 
number. De-identified information will be entered into a computer 
database/locked file cabinet in the Principal Investigator's office.  Dr. 
Singh, Dr. Teal and their associates will have access to this study 
information. 
All engaged participating sites will safeguard data as required by law.  
12. 
Study Procedures  
12.1.Following enrollment, participants will be instructed in the use of the 
face mask and be instructed on completion of the VAS score. The 
participant will fill out baseline demographic information as well as 
baseline and anticipated VAS pain scores prior to the procedure. The 
patient will then either proceed to the procedure or cervical preparation 
as determined by the clinician. Cervical preparation and timing of 


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procedure (i.e. whether or not the patient requires a two day procedure) 
will be recorded in study documents.  
Study randomization will occur just prior to initiation of the abortion 
procedure to nitrous oxide or IV sedation. The research coordinator, 
participant and providers will be masked to the treatment allocation. 
The only unmasked member of the team will be the nurse administering 
the medications.  Investigators will utilize a centralized stratified block 
randomization with allocation listed as “study drug 1” and “study drug 
2”. Study coordinators will determine allocation and discuss this with 
clinic nurses. The meanings of these labels will be separately revealed 
to clinical nursing staff responsible for administration. 
Within the IV sedation group, women will receive 100mcg fentanyl and 
2mg midazolam at least two minutes prior to initiation of the procedure. 
IV sedation with midazolam and fentanyl was chosen as the 
comparison group as it is the most frequently used method of pain 
control for outpatient second trimester procedures (2), as well as the 
current standard of care for both clinical recruitment sites.  This group 
will also receive 100% oxygen by scented face mask. Women in the 
nitrous oxide group will receive an identical scented face mask through 
which nitrous oxide will be administered. The nitrous content of the gas 
will be titrated up by 20% every 5 breaths with a goal of 70% N2O/ 30% 
O2 as tolerated by the patient. If the participant is noted to have signs of 
over sedation or other uncomfortable side effects, the ratio will be 
titrated down to a lower concentration until side-effects or over sedation 
has resolved. If there is concern for over sedation, the nurse will 
provide initial management by decreasing nitrous in the nitrous group or 
providing 100% oxygen in the IV sedation group. If these initial 
interventions do not rapidly resolve over-sedation, the abortion provider 
will be unmasked to treatment allocation in order to appropriately 
participate in management. The nurse will be instructed to seek the 
help of the physician at any point to ensure patient safety. If the 
physician is at any point concerned about participant health or safety, 
treatment allocation will be revealed so optimal management can be 
provided. If allocation is unmasked to the treatment team, this will be 
recorded. Nitrous oxide will be administered for at least 2 minutes 
before the procedure is initiated. Maximum ratio will be recorded in 
study documents.   
The abortion procedure will proceed in the usual fashion with the 
following standardized procedures: 
- 
All providers will be family planning fellows or attendings. 
  


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- 
All patients will receive 600 mg of ibuprofen prior to the 
procedure. 
- 
Participants will receive a bimanual exam at beginning of 
procedure. This will define the beginning of the procedure and 
this time will be recorded.  
- 
Osmotic dilators, if present, will either be removed at this time or 
following insertion of the speculum.  
- 
Following insertion of the speculum and surgical site preparation 
with betadine, or alternative for those allergic to iodine, a 
cervical block will be performed. This will be done with 2cc 1% 
buffered lidocaine injected intracervically at the tenaculum site, 
followed by 18cc 1% buffered lidocaine injected paracervically 
at the 4 and 8 o’clock positions.  
- 
Rigid cervical dilation will be performed using Pratt or Denniston 
dilators to a cervical dilation which facilitates placement of the 
appropriately sized suction curette. 
- 
Cervical preparation and dilation will not be standardized, but 
number and type of osmotic dilators as well as maximal 
diameter and type of rigid dilators used will be recorded.   
The only laboratory and diagnostic procedures involved in this study are 
those that are part of standard care for second trimester abortion and are 
unrelated to study participation. For example, physicians will continue to 
perform preoperative ultrasound to establish gestational age by 
measurement of either crown rump length or biparietal diameter and 
femur length as well as establish placentation and position. Additionally, 
all participants will receive standard labs including preoperative 
hemoglobin as well as blood type.  
If a participant verbalizes inadequate pain control, the physician will 
evaluate whether or not additional pain medications are needed based 
on clinical judgment and request additional anesthesia accordingly. If 
there is no risk of excessive bleeding or other procedural risk, the 
procedure will be halted for three minutes while the participant receives 
100% oxygen. This waiting period allows time for participants in the 
nitrous oxide group to clear the gas prior to conversion to IV sedation. 
Following three minutes, participants in the IV sedation group will be 
given another 50 mcg of fentanyl. If pain control remains inadequate as 


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determined by the physician, the participant will be given another 50mcg 
of fentanyl. If pain control is still inadequate, procedure again will halt 
and additional midazolam will be given, to a maximum dosing of 200mcg 
fentanyl and 4mg midazolam. In the nitrous oxide group, following three 
minutes of 100% oxygen, the participant will be converted to IV sedation, 
at an initial dose of 100mg Fentanyl and 2 mg Midazolam. The physician 
will wait two minutes prior to resumption of procedure. All medications 
received will be recorded. 
The D&E procedure will not be standardized between clinic and 
providers but procedure data including vacuum source, use of forceps 
and training of the provider will be collected. We will also collect 
information on any patients receiving intrauterine contraception. Timing 
of completion of the procedure will be defined by removal of the 
speculum. Successful procedure completion will be confirmed by each 
clinic’s standard practices including uterine cri, ultrasound with thin 
endometrial complex, and/or tissue examination.  
Immediately after procedure completion, participants in both groups will 
receive a VAS of maximum procedural pain. After completion of the VAS 
no further IV meds will be given and those in the nitrous oxide group will 
be converted to 100% oxygen.  All participants will receive 100% oxygen 
for a minimum of three minutes.  
Women will be monitored in the clinic for a minimum of 30 minutes 
following procedure. Discharge criteria will include a minimum Aldrete 
Scale score of 8 and receipt and verbalized understanding of discharge 
instructions.  At this point, the participant will receive and complete an 
ISAS and VAS again recalling maximum procedural pain as well as 
current pain.  
We will assess pain using the VAS at baseline (T0), immediately 
following removal of the speculum (which defines completion of the 
procedure [T1]), and at least thirty minutes following procedure (T2). Our 
first outcome is maximum pain experienced during the procedure; this 
will be obtained at T1. At T2, we will also assess satisfaction as 
measured using the ISAS.  
Pain will be assessed using an unmarked 100mm VAS scale, with 
anchors at 0mm (left) being “no pain” and 100mm (right) being “pain as 
bad as it could be”. Providers will also rate their perception of the amount 
of pain the participant experienced during the procedure using the same 
VAS scale. 


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Satisfaction will be assessed using the ISAS, a validated patient 
satisfaction measurement tool. This survey was specifically designed to 
assess participant satisfaction with anesthetic care itself.  It consists of 
11 questions, related to anesthetic care, each assessed on a Likert type 
scale ranging from “Disagree very much” to “Agree very much.”  These 
items are then scored from -3 to +3 and an average score obtained.  
This instrument has been validated in multiple studies involving 
monitored anesthesia care, including multi-site studies(9). 
All study end points will be collected on the date of the procedure.  
Participants will be followed up clinically as per each clinic's standards 
for follow up after D&E. 
13. 
Data Analysis 
13.1 
Immediate post procedure VAS pain scores and ISAS scores will be 
analyzed using a 1-sided, 2-group test of non-inferiority with 80% power 
and a type I error of 5%. Randomization will be stratified according to 
gestational age by week as we suspect pain scores will be higher 
among women at later gestational ages. We set a non-inferiority margin 
of 15mm on the VAS scale based on clinical experience. The non-
inferiority margin for the ISAS was set at 0.6U based on prior literature. 
Data will be analyzed according to intent to treat analysis followed by 
per protocol analysis. Only data obtained from patients following 
randomized treatment allocation will be analyzed among intent to treat 
analysis and all deviations from protocol including premature 
discontinuation or missing data excluded. If non inferiority is evident, we 
will assess for superiority of nitrous oxide using a two-group one-sided 
ttest of means.  
14. 
Provisions to Monitor the Data to Ensure the Safety of 
Subjects 
14.1. 
This study will utilize a data safety monitoring board (DSMB) with 
pre-determined stopping rules.  A committee of external reviewers 
knowledgeable in Family Planning and abortion care, not involved in the 
study, will be recruited to review the data every 38 patients recruited.  
Review of clinic data from the past year at the University of Colorado’s 
clinic reveals that among women undergoing abortion in our target 
gestational age, 24+/-7% (CI 95%) received additional IV pain 
medication (dosing greater than 100mcg fentanyl or greater than 2mg 
midazolam) during their procedures.  On quarterly enrollment review, if 


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greater than 35% of women in either group are requiring additional pain 
medications, the study will be halted and a full review triggered.  
Adverse event reporting will follow guidelines as proposed by Good 
Clinical Practice and collected as they occur or are reported by patients. 
These reports will be compiled for review by the DSMB quarterly; 
except for serious adverse events which will be reported to the IRB and 
DSMB within 24 hours of the occurrence. All subjects will have access 
to clinical care which is not dependent on study participation and will be 
notified of the availability of that care. Additionally, data will be shared 
across sites for quarterly reporting to the DSMB as well as for final data 
analysis and reporting. There may be times when we are required by 
law to share information. However, protected health information (PHI) 
will not be used in any published reports about this study.   
15. 
Withdrawal of Subjects 
15. 
1.The research team will provide thorough screening to see if the 
patient will meet inclusion and exclusion criteria. Staff does not anticipate 
any circumstances which subjects may be withdrawn from the study 
without their consent.  
15.2. Participants that require unmasking of study allocation or conversion to 
IV sedation will continue to be enrolled in the study and data will be 
analyzed according to intention to treat analysis.  
15.3.There will be no collection of data bio specimens – N/A 
15.4.Participants may withdraw from study involvement at any point in time 
and this will not affect their ability to obtain standard clinical care that 
day. All data points will be collected on the date of the procedure and 
therefore we anticipate loss to follow up and withdrawal rates will be 
low. Participants will be given the information on how to withdraw in the 
study consent. 
16. 
Data Management/Confidentiality 
16. 
1.Only IRB-approved study team members will have access to 
RedCap and participant materials.  
16.2.A study identification number will be assigned to each participant in lieu 
of using their personal information for identification (e.g., name).  All 
participant data will be de-identified. 
Participant data will be stored separately from any identifiers to protect 
patient privacy. 
We will use de-identified cover sheets for document packets containing 
PHI. 


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16.3.This study will not be collecting information considered extremely 
sensitive or require additional protections such as HIV, genetic test 
results, mental health information, substance abuse information, and/or 
criminal records.   
16.4.Data will be entered into RedCap on date of procedure by research 
staff at each respective site. Research staff will have completed 
institutional training in RedCap prior to initiation of study.  
16. 
5.Study packets will be stored in a secure file cabinet located in the 
clinics at each respective site. These cabinets will be kept locked at all 
times. In a separately locked file cabinet, stored in the same room, the 
study consents will be stored. This second file cabinet is locked with a 
second, separate key from all other study materials. 
16.6. DSMB members will be given remote access to RedCap in order to 
review quarterly. The list that links participant information to the study 
identification number will be destroyed after data analysis is 
complete. Data will be stored for five years, and then will be 
destroyed. 
16.7. As mentioned above, data will be entered into RedCap on date of 
procedure by research staff at each respective site.  
16.8. The study will not be collecting photographs of patients – N/A 
16.9. To help us protect your privacy, we have obtained a Certificate of 
Confidentiality from the National Institutes of Health. The researchers 
can use this Certificate to legally refuse to disclose information that 
may identify you in any federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings, for example, if there 
is a court subpoena. The researchers will use the Certificate to resist 
any demands for information that would identify you, 
The Certificate cannot be used to resist a demand for information 
from personnel of the United States federal or state government 
agency sponsoring the project and that will be used for auditing or 
program evaluation of agency funded projects or for information that 
must be disclosed in order to meet the requirements of the federal 
Food and Drug Administration (FDA). You should understand that a 
Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or 
your involvement in this research. If an insurer, medical care 
provider, or other person obtains your written consent to receive 


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research information, then the researchers will not use the Certificate 
to withhold that information. 
17. 
Data and Specimen Banking – N/A  
18. 
 Risks to Subjects 
18.1. 
Nitrous oxide and the IV pain medications have been associated 
with mild side effects including headache, dizziness, lightheadedness, 
or nausea and vomiting.  Oxygen will be administered with either 
treatment to prevent any problems with a decrease in oxygenation.  
Everyone taking part in the study will be followed carefully for any side 
effects.  
18.1.1. The UNM Center for Reproductive Health and the University 
of Colorado Comprehensive Women’s Health Center are both 
staffed by providers specialized in reproductive health and 
family planning. Additionally, nurses at both locations are well 
versed in outpatient moderate sedation. At the Center for 
Reproductive Health, nurses are trained in intravenous sedation 
and moderate sedation, maintain Advanced Cardiac Life 
Support (ACLS) certification and participate in quarterly safety 
drills. 
18.1.2. Moderate sedation will be administered according to 
standardized study protocols which are the same at both sites. 
All participants must have observed fasting recommendations of 
two hours for clear liquids and six hours for solids. All  
participants will require an escort home in order to receive 
sedation. During the procedure, all participants will have 
noninvasive blood pressure and pulse oximetry monitoring. 
Nurses or physicians will be responsible for administering 
sedation and for monitoring for signs of adequate or over 
sedation and will have no other concurrent responsibilities.  
Clinic sites will be equipped for management of over sedation 
including reversal drugs, crash cart inclusive of bag-mask-valve 
device and nasal and oral airways as well as availability to 
transfer to higher level care as needed. Providers will also 
maintain ACLS certification. 


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18.2. 
We will take measures to protect the security of all personal 
information, but we cannot guarantee confidentiality of all study data.  
18.2.1. To minimize the privacy risk, the research team will do the 
following: Information contained in study records is used by 
study staff alone. The University of New Mexico and the 
University of Colorado Institutional Review Board (IRB) that 
oversee human subject research and/or other entities may be 
permitted to access records. Additionally, data will be shared 
across sites for quarterly reporting to the DSMB as well as for 
final data analysis and reporting. There may be times when we 
are required by law to share information. However, protected 
health information (PHI) will not be used in any published 
reports about this study.   
Information collected as part of the study will be labeled with a 
study number. De-identified information will be entered into a 
computer database/locked file cabinet in the Principal 
Investigator's office.  Dr. Singh, Dr. Teal and their associates 
will have access to this study information. Data will be stored 
for five years, and then will be destroyed.  
A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law.  
18.2.2. A study participant’s privacy interests will be protected 
through the following measures: 
The study will be thoroughly explained to the potential participant 
using the HRPO-approved consent form.  As part of the informed 
consent process, the recruiting co-investigator or research 
assistant will provide as much time as needed for the potential 
participant to consider study participation.  If any privacy 
interests are expressed by the patient, they will be addressed 
immediately by the research team member and if necessary, the 
issue will also be considered by the principal investigator.   
A study identification number will be assigned to each participant 
in lieu of using their personal information for identification (e.g., 
name).  All participant data will be de-identified. 
Participant data will be stored separately from any identifiers to 
protect patient privacy. 


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We will use de-identified cover sheets for document packets 
containing PHI. 
19. 
Potential Benefits to Subjects 
19.1. 
The completion of this pain score and satisfaction analysis will show 
whether women randomized to nitrous oxide will report noninferior pain 
and satisfaction compared to women randomized to receive standard IV 
sedation. The contribution of the proposed research is to determine if 
nitrous oxide is a safe and effective alternative to intravenous sedation 
for second trimester abortion. This contribution to the literature is 
significant because current anesthetic options are limited and 
insufficient and there is a need for more patient-centered options. 
19.2. 
Participants will receive no direct benefit by participating in the 
study, which will also be verbalized to the patient by trained research 
staff.  
20. 
Recruitment Methods 
20.1. 
This study will be conducted at two separate clinics, both of which 
provide pregnancy termination services up to 22 weeks gestational age.  
In New Mexico, participants will be recruited from the University of New 
Mexico Center for Reproductive Health (CRH) clinic and in Colorado, 
participants will be recruited from the Comprehensive Women’s Health  
Center (CWHC). These are both outpatient clinics where Family 
Planning fellows, faculty and Ob/Gyn residents perform second 
trimester procedures. Only Attendings and Fellows will perform 
procedures for study participants. 
20.2. 
Eligibility for participation will be determined by clinic staff at initial 
encounter. In order to recruit efficiently, all women seeking pregnancy 
termination between 12w0d and 16w0d gestational age will be 
approached about possible study participation. Women presenting for 
abortion will be screened by clinic providers for eligibility. If determined 
to be eligible for participation and interested, women will meet with  
trained research staff in a private clinic room.   
20.3. Recruitment materials in the form of flyers/brochures (in both English 
and Spanish) will be posted at UNM’s CRH clinic. These materials will 
summarize the study and include a phone number for participants to 
contact research staff to inquire for more details about the study. Should 
the participant contact research staff prior to their appointment at CRH, 


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the research coordinators will consult with the patient’s provider to ensure 
eligibility.  
OB/GYN healthcare providers at UNM will also be provided with a flyer 
describing the study. The flyer will list eligibility criteria and will allow the 
providers to discuss the study with their patients should they show 
interest and meet criteria.  
21. 
Provisions to Protect the Privacy Interests of Subjects 
21.1. 
We will take measures to protect the security of all personal 
information, but we cannot guarantee confidentiality of all study data.  
To minimize the privacy risk, the research team will reassure the patient 
of the following:  Information contained in study records is used by 
study staff alone. The University of New Mexico and the University of 
Colorado Institutional Review Board (IRB) that oversee human subject 
research and/or other entities may be permitted to access records. 
Additionally, data will be shared across sites for quarterly reporting to 
the DSMB as well as for final data analysis and reporting. There may 
be times when we are required by law to share information. However, 
protected health information (PHI) will not be used in any published 
reports about this study.   
Information collected as part of the study will be labeled with a study 
number. De-identified information will be entered into a computer 
database/locked file cabinet in the Principal Investigator's office.  Dr. 
Singh, Dr. Teal and their associates will have access to this study 
information. Data will be stored for five years, and then will be 
destroyed.  
A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law.  
21.2. 
A study participant’s privacy interests during recruitment and data 
collection will be protected through the following measures: 
The study will be thoroughly explained to the potential participant using 
the HRPO-approved consent form.  As part of the informed consent 
process, the recruiting co-investigator or research assistant will provide 
as much time as needed for the potential participant to consider study 
participation.  If any privacy interests are expressed by the patient, they 
will be addressed immediately by the research team member and if 


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necessary, the issue will also be considered by the principal 
investigator.   
21.2.1. Participants will be recruited and consented in a private clinic 
setting. This will also include the recruitment and screening 
process as well as the data collection procedures. 
22. 
Economic Burden to Subjects 
22.1. 
Patients will not be billed for the cost of tests and procedures 
directly associated with this study. They will be informed that their third 
party payer (i.e. insurance company) is responsible for all other costs 
related to clinical treatment.  This would be the case regardless of study 
involvement. There is no additional cost for the nitrous oxide over and 
above the cost of the procedure.   Please see the table below. 
 
22.2.Participants will not be charged additionally for the nitrous oxide over 
and above the cost of the procedure.  
22. 
3.Patients will be informed during the consent process that if they 
become sick as a result of this study, the University of Colorado Hospital  
(UCH) or University of New Mexico Health Sciences Center 
(UNMHSC) will provide emergency treatment at their cost.   


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No commitment is made by UCH or UNMHSC to provide free medical 
care or money for injuries to participants in this study.   
22.4. 
In the event that the patient has an injury or illness that is caused by 
participation in this study, patients will be reminded of the following:  
reimbursement for all related costs of care will be sought from the 
patient’s insurer, managed care plan, or other benefits program. If they 
do not have insurance, they may be responsible for these costs. 
Patients will also be responsible for any associated co-payments or 
deductibles required by your insurance.  
23. 
Compensation 
23.1. 
Each participant will receive a $35 gift card as compensation for 
completing surveys in clinic. 
24. 
Compensation for Research-Related Injury 
24.1. 
In the event that the patient has an injury or illness that is caused by 
participation in this study, patients will be verbally reminded of the 
following during the consent process:  reimbursement for all related 
costs of care will be sought from the patient’s insurer, managed care 
plan, or other benefits program. If they do not have insurance, they may 
be responsible for these costs. Patients will also be responsible for any 
associated co-payments or deductibles required by your insurance.  
25. 
 Consent Process 
25.1. 
In summary, patients presenting for abortion between 12 weeks 0 
days and 16 weeks 0 days gestation will be screened by the abortion 
provider for eligibility criteria, only after participant has signed 
appropriate clinical consent forms for the abortion procedure. Enrollment 
in this study will in no way affect the patient decision to proceed with an 
abortion as patients will only be approached about the study after they 
have met eligibility criteria, ie desire to have a surgical abortion. If 
eligible, the woman will be approached for possible participation by a 
research assistant in a private clinic room.  She will again be screened 
for eligibility and undergo informed consent for study enrollment if 
eligible and willing to participate. All participants determined eligible and 
approached will be documented per CONSORT guidelines.  
25.1.1. The inclusion and exclusion criteria for study participation will 
be reviewed by a member of the research team to confirm 
eligibility. Prior to consent, the study will be described verbally to 
women, and potential subjects will receive a copy of the consent 


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form to read.  If patients are comfortable enrolling in the study at 
that point, they may do so.  All potential participants will be 
reassured that declining study participation will have no effect 
on the care that they receive.  If patients choose not to 
participate, they will not be approached again unless they 
broach the subject.  Women who elect to participate will be 
informed about the standard risks, benefits and alternatives of 
the procedure per standard of care. Co-investigators or trained 
research staff will follow HRPO regulations for written 
documentation of consent. 
25.1.2. The consent discussion will take approximately 5-10 minutes 
after the consent has been read by the potential participant. 
Research staff will review the consent with the potential 
participant and provide ample opportunity for the subject to ask 
questions in a private setting. 
25.1.3. Steps that will be taken to minimize the possibility of coercion 
or undue influence include providing ample opportunity for the 
subject to ask questions they may have about research and 
providing privacy for subjects. 
25.1.4. Research staff will confirm the participant’s interest and allow 
more opportunity for questions before the consent form is finally 
signed by the patient.  
25.1.5. Steps that will be taken to ensure understanding include 
providing ample time for the potential participant to read the 
consent.  The recruiting co-investigator or trained research 
assistant will speak directly to potential subjects about the aims 
of the study and participant involvement in this study.  Potential 
subjects will be asked if they understand the study and its 
importance, and side effects will also be emphasized as well as 
the voluntary nature of participation.  
25.1.6. Spanish-speaking patients will be recruited using a UNMH 
certified Spanish interpreter service or a fluent Spanishspeaking 
research team member. Spanish-speaking patients will be 
provided with a hard copy of the Spanish consent form. 
25.1.7. This study will not be recruiting women who are cognitively 
impaired and/or unable to consent.  
25.1.8. This study will not be recruiting women under the age of 18.  
 
25.2. 
HIPAA Authorization 
This study will obtain HIPAA authorization prior to enrollment. HIPAA 
authorization is imbedded within the study consent form which will be 
reviewed with all participants by the research coordinator. Specific 
information that will be obtained includes prior medical history, 
surgical history, reproductive health history including child bearing, 


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and drug allergies. This information will obtained by health care 
providers, not research coordinators, as deemed necessary for a 
more complete and accurate medical history of the patient. 
26. 
Documentation of Consent 
26.1.Patients presenting for abortion between 12 weeks 0 days and 16 
weeks 0 days gestation will be screened by the abortion provider for 
eligibility criteria, only after participant has signed appropriate clinical 
consent forms for the abortion procedure.   
26.2.This study will not be collecting tissue samples.  
26.3.Consent will be obtained in-person. The patient will be provided with a  
hard copy of the consent form and will read and discuss the study with 
trained research staff. Before signing the consent form, staff will  
confirm the patient’s interests in participating as well as answer any 
remaining questions. After signing the consent form, the patient will 
receive a copy for their own personal records.  
27. 
Study Test Results/Incidental Findings 
27.1. 
Since the patient’s participation in this study is limited to the day of 
their procedure, no new information will be known before the 
participation in this study concludes.  
28. 
Sharing Study Progress or Results with Subjects 
28.1. The patient’s participation in this study is limited to the day of their 
procedure, and it is a double-blind study. The participants will be blinded 
to their study arm and this information will not be disclosed during the 
length of the study to guard against bias. Women that are interested in 
study results will have contact information of the study staff and may 
inquire about overall study results only once the study is complete. Study 
results for individual participants will not be shared.  
29. 
Inclusion of Vulnerable Populations 
29.1. This research involves women over the age of 18 who are seeking 
termination of their pregnancy. Research staff and providers will be 
unable to approach these participants outside of this study site. 
Research staff will not have permission to approach these women 


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unless they 1) show interest and 2) meet eligibility criteria as determined 
by staff and their provider. Should they show interest, to reduce 
coercion, research staff will conduct a thorough consent process and 
reiterate that their participating is completely voluntary 
29.1.1. This research will not include vulnerable individuals who have 
contraindications to outpatient abortion, such as patients with 
a major medical illness. This study will also exclude patients 
with contraindications to nitrous oxide. This includes 
pernicious anemia, chemotherapy, active upper respiratory 
illness, COPD, intrauterine fetal demise, and chronic narcotic 
use.  
29.1.2. Please refer to the Pregnant Women checklist included 
below. 
29.1.3. This study will not include women who are incarcerated.  
29.1.4. This study will not include women under the age of 18.  
29.1.5. This study will not include women with cognitive impairments 
and/or are unable to understand the consent process.  
30. 
Community-Based Participatory Research – N/A 
 
30.1. 
This is not a Community-Based Participatory Research study.  
31. 
Research Involving American Indian/Native Populations – 
N/A 
31. 
1.This research study focuses on women seeking abortion and pain 
management options. This study is inclusive to all women of varying 
ethnic backgrounds so long as they are English or Spanish –speaking.  
This study does not focus solely on women of American Indian heritage.  
32. 
Transnational Research 
32.1.This study will not be conducted outside of Colorado and New Mexico.   
33.Drugs or Devices 
33.1. This study will involve the use of nitrous oxide. The nitrous oxide 
equipment will be stored in the clinic and maintained by clinic personnel 
meeting appropriate training requirements. Nitrous oxide will be similarly 


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delivered by physicians and nurses who have completed training in the 
administration of the gas and possess appropriate training certification.  
References 
1. Taylor D, Postlethwaite D, Desai S, James EA, Calhoun AW, Sheehan K, et 
al. Multiple Determinants of the Abortion Care Experience From the Patient’s 
Perspective. Am J Med Qual. 2013;28(6):510–8. 
2. O’Connell K, Jones HE, Lichtenberg ES, Paul M. Second-trimester surgical 
abortion practices: a survey of National Abortion Federation members. 
Contraception. 2008 Dec;78(6):492–9.  
3. by Non-Anesthesiologists A. Practice guidelines for sedation and analgesia 
by non-anesthesiologists. Anesthesiology. 2002;96(4):1004–17.  
4. Kan ASY, Caves N, Wong SYW, Ng EHY, Ho PC. A double-blind, 
randomized controlled trial on the use of a 50:50 mixture of nitrous 
oxide/oxygen in pain relief during suction evacuation for the first trimester 
pregnancy termination. Hum Reprod. 2006 Oct 1;21(10):2606–11.  
5. Agostini A, Maruani J, Roblin P, Champion J, Cravello L, Gamerre M. A 
double-blind, randomized controlled trial of the use of a 50:50 mixture of 
nitrous oxide/oxygen in legal abortions. Contraception. 2012 Jul;86(1):79–83.  
6. Singh RH, Espey E, Carr S, Pereda B, Ogburn T, Leeman L. Nitrous oxide for 
pain management of first trimester surgical abortion — a randomized 
controlled pilot study. Contraception. 2015 Feb;91(2):164–6.  
7. Mentula M, Kalso E, Heikinheimo O. Same-day and delayed reports of pain 
intensity in second-trimester medical termination of pregnancy: a brief report. 
Contraception. 2014 Dec;90(6):609–11.  
8. Turok DK, Espey E, Edelman AB, Lotke PS, Lathrop EH, Teal SB, et al. The 
methodology for developing a prospective meta-analysis in the family 
planning community. Trials. 2011;12(1):104.  
9. Dexter F, Candiotti KA. Multicenter Assessment of the Iowa Satisfaction with 
Anesthesia Scale, an Instrument that Measures Patient Satisfaction with 
Monitored Anesthesia Care: Anesth Analg. 2011 Aug;113(2):364–8.  


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Checklist Section 
This section contains checklists to provide information on a variety of topics that require special 
determinations by the IRB.  Please complete all checklists relevant to your research. 
I. 
Waivers or Alterations of Consent, Assent, and HIPAA Authorization – NOT 
APPLICABLE 
A. Partial Waiver of Consent for Screening/Recruitment 
Complete this checklist if you are requesting a partial waiver of consent so that you 
can review private information to identify potential subjects and/or determine 
eligibility prior to approaching potential subjects for consent or parental permission. 
1. Describe the data source that you need to review (e.g., medical records): 
2. Describe the purpose for the review (e.g., screening):       
3. Describe who will conducting the reviews (e.g., investigators, research staff):       
4. Do all persons who will be conducting the reviews already have permitted 
access to the data source?  Yes 
 No. Explain:       
5. Verify that each of the following are true or provide an alternate justification 
for the underlined regulatory criteria: 
a) The activity involves no more than minimal risk to the subjects 
because the records review itself is non-invasive and the results of the 
records review will not be used for any purposes other than those 
described above.  True 
 Other justification:       
b) The waiver or alteration will not adversely affect the rights and 
welfare of the subjects because eligible subjects will be approached 
for consent to participate in the research and are free to decline.  
Further, the information accessed during the records review will not 
be disclosed to anyone without a legitimate purpose (e.g., verification 
of eligibility).  True 
 Other justification:       
c) 
The research could not practicably be carried out without 
the waiver or alteration because there is no other reasonably 


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efficient and effective way to identify who to approach for possible 
participation in the research.   True 
 Other justification:       
d) Whenever appropriate, potentially eligible subjects will be presented 
with information about the research and asked to consider 
participation.  (Regulatory criteria: Whenever appropriate, the 
subjects will be provided with additional pertinent information after 
participation.)  True 
 Other justification:       
Partial Waiver of HIPAA Authorization for Screening/Recruitment 
Complete the following additional questions/attestations if the records you will review 
to identify potential subjects and/or determine eligibility include Protected Health 
Information (PHI). 
6. Will you be recording any PHI when conducting the records review to identify 
potential subjects and/or determine eligibility? 
 
  Yes. Describe:       No 
7. If you answered “Yes” to question 6 above, please describe when you will 
destroy identifiers (must be the earliest opportunity consistent with the 
conduct of the research) or provide justification for why they must be 
retained: 
      
8. The PHI accessed or recorded for identification/screening purposes will not be 
reused or disclosed to (shared with) any other person or entity, except as 
required by law, for authorized oversight of the research study, or for other 
research for which the use or disclosure of the PHI would be permitted under 
the Privacy Rule. 
 True 
 False 
B. Waiver of Documentation of Consent 
Complete this checklist if you intend to obtain consent verbally but will not be 
obtaining signatures from subjects on a consent form to document consent.  Waivers 
of documentation of consent are commonly requested when using scripts, information 
sheets, or email or survey introductions to present the elements of consent instead of 
using a traditional consent form. 


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1. Are you requesting a waiver of documentation of consent for some or all 
subjects? 
 All 
 Some. Explain:       
2. Provide justification for one of the following: 
a) That the only record linking the subject and the research would be the 
consent document and the principal risk would be potential harm 
resulting from a breach of confidentiality. Each subject will be asked 
whether the subject wants documentation linking the subject with the 
research, and the subject's wishes will govern. 
      
b) That the research presents no more than minimal risk of harm to 
subjects and involves no procedures for which written consent is 
normally required outside of the research context. 
      
3. Do you intend to provide subjects with a written statement regarding the 
research in lieu of a traditional consent form? 
 Yes. Please attach a copy to your submission in Click.   
No 
C. Alteration of Consent 
Complete this checklist if you intend to obtain consent but will be eliminating or 
altering one or more of the required elements of consent. Alterations of consent are 
commonly requested for research involving deception or for minimal risk research 
when an abbreviated consent is desired and one or more of the required element are 
not relevant to the research. 
Note: FDA-regulated research is not eligible for an alteration of consent. 
1. Which element(s) of consent do you wish to eliminate and why?       
2. Which element(s) of consent do you wish to alter and why?       
3. Provide justification for each of the following regulatory criteria: 
a) The research involves no more than minimal risk to the subjects: 
      


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b) The waiver or alteration will not adversely affect the rights and 
welfare of the subjects: 
      
c) The research could not practicably be carried out without the waiver or 
alteration: 
      
d) Whenever appropriate, the subjects will be provided with additional 
pertinent information after participation: 
      
D. Full Waiver of Consent/Parental Permission 
Complete this checklist if you are requesting a full waiver of consent for all subjects 
or certain subject groups (e.g., retrospective cohort).  Full waivers of consent are 
commonly requested when the research does not include any opportunity for 
interaction with subjects (e.g., chart review). 
Note: FDA-regulated research is not eligible for a full waiver of consent using these 
criteria.  If you believe that your FDA-regulated research may be eligible for a waiver 
under another mechanism, such as planned emergency research, contact the HRPO 
for assistance in determining what information to provide to the HRRC. 
1. Are you requesting a waiver for some or all subjects? 
 All 
 Some. Explain:       
2. Provide justification for each of the following regulatory criteria: 
a) The research involves no more than minimal risk to the subjects: 
      
b) The waiver or alteration will not adversely affect the rights and 
welfare of the subjects: 
      
c) The research could not practicably be carried out without the waiver or 
alteration: 
      
d) Whenever appropriate, the subjects will be provided with additional 
pertinent information after participation: 


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E. Full Waiver of Consent/Parental Permission (Public Benefit or Service 
Programs) Complete this checklist if you are requesting a full waiver of consent for 
all subjects or certain subject groups (e.g., retrospective cohort) and the research 
involves the evaluation of a public benefit or service program.   
1. Are you requesting a waiver for some or all subjects? 
 All 
 Some. Explain:       
2. Provide justification for each of the following regulatory criteria: 
a) The research or demonstration project is to be conducted by or subject 
to the approval of state or local government officials and is designed to 
study, evaluate, or otherwise examine: (i) public benefit or service 
programs; (ii) procedures for obtaining benefits or services under 
those programs; (iii) possible changes in or alternatives to those 
programs or procedures; or (iv) possible changes in methods or levels 
of payment for benefits or services under those programs: 
      
b) The research could not practicably be carried out without the waiver or 
alteration. 
      
F. Full Waiver of HIPAA Authorization 
Complete this checklist if you are requesting a full waiver of the requirement to 
obtain HIPAA authorization for all subjects or certain subject groups (e.g., 
retrospective cohort).  Full waivers of HIPAA authorization are commonly requested 
when the research does not include any opportunity for interaction with subjects (e.g., 
chart review). 
1. Are you requesting a waiver of authorization for some or all subjects? 
 All 
 Some. Explain:       
2. Describe your plan to protect health information identifiers from improper use 
and disclosure: 
      


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3. Describe your plan to destroy identifiers at the earliest opportunity consistent 
with conduct of the research (absent a health or research justification for 
retaining them or a legal requirement to do so): 
      
4. Describe why the research could not practicably be conducted without the 
waiver or alteration: 
      
5. The PHI accessed or recorded for identification/screening purposes will not be 
reused or disclosed to (shared with) any other person or entity, except as 
required by law, for authorized oversight of the research study, or for other 
research for which the use or disclosure of the PHI would be permitted under 
the Privacy Rule. 
 True 
 False 
G. Other Waiver Types 
If you are seeking another waiver type (e.g., Planned Emergency Research, Waiver of  
Parental Permission to Protect Child Participants, Enforcement Discretion for In 
Vitro Diagnostics, etc. contact the HRPO office for assistance in determining what 
information to submit for the HRRC’s consideration. 
 
II. Vulnerable Populations 
A. Adults with Cognitive Impairments – NOT APPLICABLE 
Complete this checklist if the subject population will include adults with cognitive 
impairments.   
This checklist does not need to be completed if the research doesn’t involve 
interactions or interventions with subjects and will be conducted under a waiver of 
consent. 
1. Describe why the objectives of the study cannot be met without inclusion of 
adults with cognitive impairments. 
      
2. Describe how capacity to consent will be evaluated.       


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3. If subjects may regain capacity to consent, or if subjects may have fluctuating 
capacity to consent, describe your plans to evaluate capacity to consent 
throughout the research and to obtain consent to continue participation if 
capacity is regained. 
      
4. Describe your plans, if any, to provide information about the research to 
subjects and the steps you will take to assess understanding.       
5. Describe your plans to obtain assent, including whether assent will be 
obtained from none, some, or all subjects. 
      
6. Describe why risks to subjects are reasonable in relation to anticipated 
benefits to the subjects. 
      
7. If this study involves a health or behavioral intervention, describe why the 
relation of the anticipated benefit to the risk of the research is at least as 
favorable to the subjects as that presented by alternative procedures.       
8. Describe your plans for monitoring the well-being of subjects including any 
plans to withdraw subjects from the research if they appear to be unduly 
distressed. 
      
B. Children – NOT APPLICABLE 
Complete this checklist if the subject population will include children. 
1. Select the category of research that you believe this research falls within and 
provide justification for any associated criteria.  If there are different 
assessments for different groups of children or arms (e.g., placebo vs. drug), 
include a memo to provide an assessment for each group.   
 Research not involving greater than minimal risk. (Minimal risk means 
that the probability and magnitude of harm or discomfort anticipated 
in the research are not greater in and of themselves than those 
ordinarily encountered in daily life or during the performance of 
routine physical or psychological examinations or tests.) 
 Research involving greater than minimal risk but presenting the 
prospect of direct benefit to the individual subjects. 
Provide justification for each of the following criteria: 


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(1) The risk is justified by the anticipated benefit to the subjects: 
      
(2) The relation of the anticipated benefit to the risk is at least as favorable to the 
subjects as that presented by available alternative approaches: 
      
 Research involving greater than minimal risk and no prospect of direct 
benefit to individual subjects, but likely to yield generalizable 
knowledge about the subject's disorder or condition. 
Provide justification for each of the following criteria: 
(1) The risk represents a minor increase over minimal risk:       
(2) The intervention or procedure presents experiences to subjects 
that are reasonably commensurate with those inherent in their 
actual or expected medical, dental, psychological, social, or 
educational situations: 
      
(3) The intervention or procedure is likely to yield generalizable 
knowledge about the subjects' disorder or condition which is of 
vital importance for the understanding or amelioration of the 
subjects' disorder or condition 
      
C. Pregnant Women and Fetuses 
Complete this checklist if the subject population will include pregnant women and 
fetuses. 
This checklist does not need to be completed if the research is both minimal risk and 
is not conducted, funded, or otherwise subject to regulation by DHHS, DOD, or EPA. 
Provide justification for each of the following: 
1. Where scientifically appropriate, preclinical studies, including studies on 
pregnant animals, and clinical studies, including studies on non-pregnant 
women, have been conducted and provide data for assessing potential risks to 
pregnant women and fetuses. 
Nitrous oxide is an inhaled gas which can be titrated in conjunction with 
oxygen. It has been shown to be safe an effective for sedation in a 
number of other clinical settings including emergency departments, 
labor and delivery and dentistry. It has also been used in prior abortion 
studies within the first trimester with benign safety profile. This study 


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will collect adverse events which will be reported and monitored by the 
DSMB.  
2. The risk to the fetus is caused solely by interventions or procedures that hold 
out the prospect of direct benefit for the woman or the fetus; or, if there is no 
such prospect of benefit, the risk to the fetus is not greater than minimal and 
the purpose of the research is the development of important biomedical 
knowledge which cannot be obtained by any other means.  
There is no direct benefit to the woman for participating in this 
research, as outlined in the benefits section of this protocol. This will 
also be explained to the participant. In order to participate, the patient 
must voluntarily elect to seek an abortion. Patients will not be 
approached about study participation until they have expressed desire 
for abortion to eliminate coercion.  
3. Any risk is the least possible for achieving the objectives of the research. 
The clinical sites wherein recruitment will take place are both well 
equipped to manage adverse events including over sedation or other 
risks of the procedure. Notably, these are risks inherent to the 
procedure and unrelated to study involvement. If adverse events are 
felt to be disproportionately represented in a single group, this will 
prompt review by the DSMB and possible early cessation of the study. 
D. Neonates of Uncertain Viability or Nonviable Neonates – NOT APPLICABLE 
Complete this checklist if the subject population will include neonates of uncertain 
viability. 
Provide justification for each of the following: 
1. Where scientifically appropriate, preclinical and clinical studies have been 
conducted and provide data for assessing potential risks to neonates.       
2. Each individual providing consent is fully informed regarding the reasonably 
foreseeable impact of the research on the neonate. 
      
3. Individuals engaged in the research will have no part in determining the 
viability of a neonate. 
      
4. The research holds out the prospect of enhancing the probability of survival of 
the neonate to the point of viability, and any risk is the least possible for 


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achieving that objective, or, the purpose of the research is the development of 
important biomedical knowledge which cannot be obtained by other means 
and there will be no added risk to the neonate resulting from the research       
E. Nonviable Neonates- NOT APPLICABLE 
Complete this checklist if the subject population will include nonviable neonates. 
Provide justification for each of the following: 
1. Where scientifically appropriate, preclinical and clinical studies have been 
conducted and provide data for assessing potential risks to neonates.       
2. Each individual providing consent is fully informed regarding the reasonably 
foreseeable impact of the research on the neonate. 
      
3. Individuals engaged in the research will have no part in determining the 
viability of a neonate. 
      
4. The purpose of the research is the development of important biomedical 
knowledge that cannot be obtained by other means. 
      
Verify each of the following: 
5. Vital functions of the neonate will not be artificially maintained 
 True 
 False 
6. The research will not terminate the heartbeat or respiration of the neonate 
 True 
 False 
7. There will be no added risk to the neonate resulting from the research 
 True 
 False 
F. Biomedical and Behavioral Research Involving Prisoners – NOT APPLICABLE 
Complete this checklist if the subject population will include prisoners. 


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Note: Minimal risk for research involving prisoners is the probability and magnitude 
of physical or psychological harm that is normally encountered in the daily lives, or 
in the routine medical, dental, or psychological examination of healthy persons. 
1. Select and justify which allowable category of research involving prisoners 
this research falls within: 
 Study of the possible causes, effects, and processes of incarceration, and of 
criminal behavior, provided that the study presents no more than minimal 
risk and no more than inconvenience to the subjects 
      
 Study of prisons as institutional structures or of prisoners as incarcerated 
persons, provided that the study presents no more than minimal risk and 
no more than inconvenience to the subjects 
      
 Research on conditions particularly affecting prisoners as a class (for 
example, vaccine trials and other research on hepatitis which is much 
more prevalent in prisons than elsewhere; and research on social and 
psychological problems such as alcoholism, drug addiction, and sexual 
assaults) 
      
 Research on practices, both innovative and accepted, which have the intent 
and reasonable probability of improving the health or well-being of the 
subject 
      
 Epidemiologic studies in which the sole purpose is to describe the 
prevalence or incidence of a disease by identifying all cases or to study 
potential risk factor associations for a disease, the research presents no 
more than Minimal Risk and no more than inconvenience to the 
subjects, and Prisoners are not a particular focus of the research.       
2. Provide justification for each of the following regulatory criteria: 
a) Any possible advantages accruing to the prisoner through his or her 
participation in the research, when compared to the general living 
conditions, medical care, quality of food, amenities and opportunity 
for earnings in the prison, are not of such a magnitude that his or her 
ability to weigh the risks of the research against the value of such 
advantages in the limited choice environment of the prison is impaired 
      


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b) The risks involved in the research are commensurate with risks that 
would be accepted by nonprisoner volunteers 
      
c) Procedures for the selection of subjects within the prison are fair to all 
prisoners and immune from arbitrary intervention by prison authorities 
or prisoners. Unless justification is provided, control subjects must be 
selected randomly from the group of available prisoners who meet the 
characteristics needed for that particular research project 
      
d) The information is presented in language which is understandable to 
the subject population 
      
e) Adequate assurance exists that parole boards will not take into account 
a prisoner's participation in the research in making decisions regarding 
parole, and each prisoner is clearly informed in advance that 
participation in the research will have no effect on his or her parole 
      
f) When appropriate, adequate provision has been made for follow up 
examination or care after research participation, taking into account 
the varying lengths of individual prisoners' sentences, and for 
informing participants of this fact 
      
 
III.Medical Devices – NOT APPLICABLE 
Complete this checklist if the research evaluates the safety or effectiveness of a medical device.  
If more than one medical device is being evaluated, provide the requested information for each. 
A. Device Name:       B. Manufacturer:        
C. Does the research involve a Significant Risk Device under an IDE? 
 Yes. Include documentation of the FDA approval of the IDE with your submission.  
Acceptable methods of documentation include: (1) FDA letter noting IDE number 
and approval status; (2) Industry sponsor letter noting IDE number and FDA 
approval status; or (3) FDA-approved industry sponsor protocol with IDE number 
noted  No 
D. Is the research IDE-exempt? 


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 Yes. Include a FDA letter with your submission noting the determination that the 
research is IDE-exempt or a letter from the sponsor (or sponsor-investigator) 
justifying why they believe the research is IDE-exempt*.  
 No 
E. Does the research involve a Non-Significant Risk (NSR) Device? 
 Yes. Include a FDA letter with your submission noting the determination that the 
research is NSR or a letter from the sponsor (or sponsor-investigator) justifying why 
they believe the research is NSR**.   
 No 
* This FDA guidance includes a description for when a device study is exempt from the 
IDE requirements: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127067.pdf  
**This FDA guidance includes information on how to differentiate between Significant 
Risk and Non-Significant Risk device studies:  
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf