Pilot Study of Etonogestrel Contraceptive Implant Insertion at an Alternative Subdermal Scapular Site
Phase: PHASE4
Conditions: Contraception
Sponsor: University of Colorado, Denver

Official Title: Pilot study of etonogestrel contraceptive implant insertion at an alternative 
subdermal scapular site  
NCT Number: NCT04463693 
Document date: 6/15/2020 
Principal Investigator: Aaron Lazorwitz, MD 

Figure 2: Arm 
anatomy highlighting 
neurovascular bundle 
in the sulcus. 
Standard implant 
insertion site marked 
in green 
Figure 1: Manufacturer’s 
recommended insertion site 
I. Hypotheses and Specific Aims:  
 
Specific Aims: 
1. To assess the pharmacokinetics of the etonogestrel contraceptive implant when inserted at 
an alternative scapular site. 
2. To gather preliminary data regarding insertion site and bleeding side effects when the 
etonogestrel contraceptive implant is inserted at an alternative scapular site. 
3. To explore optimal patient positioning for etonogestrel contraceptive implant insertion at 
an alternative scapular site. 
Hypotheses: 
1. We hypothesize that the pharmacokinetics of the etonogestrel contraceptive implant when 
inserted at an alternative scapular site will be similar to the published pharmacokinetics 
with arm insertion. 
2. We hypothesize that women with alternative scapular site insertion of the etonogestrel 
contraceptive implant will report similar insertion site and bleeding side effects as 
compared to known side effects with arm insertion. 
 
 
II. Background and Significance:  
 
The etonogestrel contraceptive implant (Nexplanon®, formerly Implanon®) remains the 
most efficacious hormonal contraceptive method available in the US with increasing 
uptake, particularly among adolescents and young women2,3. The contraceptive 
implant is inserted subdermally on the inner side of the non-dominant arm, roughly 8-
10cm proximal from the medial epicondyle of the humerus (Figure 1)4. The 
manufacturer instructions originally stated that insertion should occur between the 
biceps and triceps muscles, while avoiding insertion deep into this sulcus4. However, 
these instructions were updated in 2018 to move the insertion site 3-5cm inferiorly 
over the triceps muscle and all healthcare providers trained in contraceptive implant 
insertion prior to October 2018 had to undergo a mandatory training module to 
learn about this revised 
insertion site5.  
The etonogestrel 
implant insertion site was moved by the 
manufacturer due to rare complications 
resulting from the underlying vascular and 
neurological structures found in the sulcus 
between the biceps and triceps muscles (Figure 
2) 6. The basilica/brachial vein is located in this 
sulcus and case reports of implants embolizing into the pulmonary 
vasculature proved that intravascular placement of the implant was 
possible7,8. A review of the FDA Adverse Event Reporting System 
found a total of 38 reported cases where the etonogestrel implant 
had migrated to the lung/pulmonary artery, chest wall, other 
vasculature, and other body sites (e.g. neck, shoulder, clavicle, axilla)8. Though these migrations 
and intravascular insertions are very rare, removal of migrated implants often involves 
cardiothoracic surgery with significant potential morbidity and leaving migrated implants in situ 
has been associated with potentially life-threatening complications such as pneumothorax7. 

Figure 3: Subdermal scapular 
insertion of implant from Pragout et 
l
Figure 4a: Areas of neurovascular structures (designated 
in red) superficial to the scapula and subdermal implant 
insertion site (designated in blue) 
Additionally, insertion of the contraceptive implant deep into the sulcus between the biceps and 
triceps muscles can result in peripheral nerve injury at the time of removal given the high 
prevalence of neurovascular structures in the sulcus6,9. These rare injuries and migrations have 
become highly publicized (news reports found on nypost.com, livescience.com, health.com, etc.) 
and some women may not opt for our most effective hormonal contraceptive method due to the 
risks of deep insertion and current lack of an alternative implant insertion site.  
In addition to these rare neurovascular risks, conventional insertion of the contraceptive 
implant may not be ideal for certain populations. Women with psychotic illnesses or decreased 
capacity can often benefit from contraceptive methods not requiring patient compliance (e.g. taking 
a pill every day), but case reports have demonstrated that an easily accessible insertion site can lead 
to picking or even removal attempts that may increase the risk of infection at the insertion site10,11. 
These self-removal attempts can result in significant self-
harm, such as the case report of a young woman who 
used a sharp blade on her palpable implant during an 
acute psychotic episode resulting in lacerations and even 
implant fracture12. For such a case where conventional 
insertion was deemed not appropriate for the patient, 
Pragout et al reported insertion of the contraceptive 
implant in the right lower scapular region (Figure 3)11. 
The patient tolerated the insertion very well, had no side 
effects or discomfort related to the implant, and the 
implant remained superficial and palpable. They measured 
a single serum etonogestrel concentration at 4 months of 
implant use, which was 194pg/mL and well above the threshold for ovulatory suppression 
(>90pg/mL)11,13. A case report of 14 year old twins with global development delay and habitual 
skin picking also found that insertion of the implant over the scapula avoided any implant picking 
issues and led to improved menses for both girls14.  
This scapular subdermal insertion site is an ideal 
alternative insertion site for the contraceptive implant because it is 
distant from any danger zones containing neurovascular structures 
(Figure 4a) and is a less-accessible area of the body15. Furthermore, 
additional populations may benefit from an alternative implant 
insertion site, such as women with muscular dystrophy disorders 
who may have far less muscle tissue in the arm, and thereby less 
tissue barrier between subdermal implant insertion and the 
underlying neurovascular structures16. The scapular subdermal 
insertion site benefits from the bony structure immediately under 
the implant site, which should prevent deep implant 
insertion and thereby protecting any underlying 
neurovascular structures beneath the scapula. 
Furthermore, the infraspinatus fascia that separates the 
subdermal tissue from the underlying scapular musculature is affixed to the borders of the scapula, 
thereby preventing migration of the contraceptive implant beyond the borders of the scapula even 
should deep/subfascial placement occur (Figure 5)1. 
To address the needs of patient populations that may benefit from an alternative insertion 
site for the contraceptive implant, the scapular insertion site warrants further investigation. Patients 

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Figure 4b: Planned 
insertion site in red and 
total length of implant 
t d
 
B. Description of Population to be Enrolled:   
 
We aim to enroll five reproductive age (18-45 years) women interested in using the etonogestrel 
contraceptive implant based on the following crtieria: 
 
Inclusion criteria: 
• 
Healthy women 
• 
English or Spanish speaking 
 
Exclusion criteria 
• 
Any contraindications to etonogestrel implant use based on the US Medical Eligibility 
Criteria for Contraceptive use (defined as class 3 or 4 recommendation)18 
• 
Any known liver conditions that could affect drug metabolism (e.g. cirrhosis, hepatitis) 
• 
Currently taking any medications or supplements known to be CYP3A4 
inducers/inhibitors19 
• 
Body-mass index less than 18.5kg/m2 or greater than 30kg/m2 
 
C. Study Design and Research Methods   
 
We will recruit five English or Spanish speaking reproductive aged women (ages 18-45) 
interested in using the etonogestrel contraceptive implant as their birth control method. We will 
exclude women with any contraindications to etonogestrel implant use based on the US Medical 
Eligibility Criteria for Contraceptive use (defined as a class 3 or 4 recommendation)18. We will also 
exclude women with any known liver conditions that could affect drug metabolism (e.g. cirrhosis, 
hepatitis) or currently taking any medications or supplements known to be CYP3A4 
inducers/inhibitors19. We will also exclude women with a body-mass index (BMI) less than 18.5 
kg/m2 and a BMI greater than 30 kg/m2. Underweight women may have altered metabolism that 
could influence the pharmacokinetic outcomes in this study. We will exclude obese women as this 
pilot study is also exploring the ideal positioning for scapular implant insertion (Aim 3) and 
increased subcutaneous tissue may affect our ability to accurately assess all bony landmarks. We 
will recruit participants for this pilot study using posted flyers on the University of Colorado 
Anschutz Medical Campus, posted flyers at our off-site Comprehensive Women’s Health Center 
clinic, and through online advertisements. 
Interested women will undergo a phone screening prior to scheduling an enrollment visit. 
At the enrollment visit, potential participants will have their vital signs checked and will have their 
height and weight measured for purposes of calculating a body mass index. We will review each 
potential participant’s past medical history and current medications 
to ensure study eligibility. Participants meeting all 
inclusion/exclusion criteria will then undergo informed consent in a 
private clinic room. During the consent process, we will inform 
participants of the exploratory nature of this study and the potential risk 
of unintended pregnancy, and thus will recommend that all participants 
use a back-up contraceptive method or abstinence during the study. 
Participants will be allowed to use any contraceptive method (hormonal 
or non-hormonal) of their preference as long as it does not contain 
etonogestrel, a pro-drug for etonogestrel (e.g. desogestrel), or estrogen. 
Estrogen can have mild effects on the CYP3A4 metabolic system and 
4cm 

we want to avoid any potential confounding for our pharmacokinetic outcomes3. 
After the participant has been consented, we will have the participant trial several positions 
to determine the ideal positioning for identifying the bony landmarks of the scapula. These 
positions will include movement of the shoulders anteriorly and posteriorly, placement of the arms 
on or off the chest wall, elevation or relaxation of the elbows, flexion or extension of the spine, and 
combinations of these positions. We will document the position that provided the most reliable 
identification of the bony landmarks and planned contraceptive insertion site. We will then insert 
the etonogestrel contraceptive implant (Nexplanon®) at the subdermal scapular site as described 
above (Figure 4b) on the participant’s non-dominant side. This will entail marking of the insertion 
of the site with two points located on the inferior angle of the scapula. The area will then prepped 
with chlorhexidine in the typical fashion. We will then inject ~3cc of 1% lidocaine along the 
planned insertion site, as is routine for contraceptive implant insertion. Following the 
manufacturer’s insertion guidelines (see Appendix A), we will insert the device inserter along the 
planned insertion site and then release the contraceptive implant. We will then palpate the implant 
to ensure appropriate subdermal placement. We will clean the insertion area and place a steri-strip 
across the insertion site. We will cover the insertion site with a sterile gauze and tape, which can be 
removed 24 hours after insertion.  
Participants will return to clinic for nine blood draws at the following time points post-
insertion: 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, and 12 
months. We will centrifuge blood drawn at these visits to extract serum samples. We will store 
these serum samples in our -80°F freezer for eventual serum ENG concentration measurement. At 
each follow-up visit, participants will provide urine for a urine pregnancy test and we will also 
assess for insertion site and implant-related side effects. We will conduct brief interviews to assess 
for the circumstances when participants have felt the physical presence of their implant without 
touching the implant itself and to inquire about any insertion site related concerns (e.g. discomfort, 
pain, itching). In terms of implant-related side effects, we will ask participants to report any side 
effects they feel may be related to the implant and we will also specifically assess for 
irregular/frequent bleeding, headaches, weight gain, mood changes, acne changes, libido changes, 
breast tenderness, or vaginal discharge. These assessments are similar to standard clinical practice 
for contraceptive follow-up and will focus on identifying what concerns or side effects are a 
priority for participants. These interviews will occur at each follow-up visit and the research 
personnel conducting the interview (PI, Co-I, or PRA) will document the responses of participants 
for categorization at the end of the study. 
 
At the follow-up visit at 12 months, we will remove the contraceptive implants in the 
standard clinical fashion (see Appendix A). We will clean the area with chlorhexidine, inject 1% 
lidocaine at the removal site, make a 1-2mm skin incision using a scalpel, and grasp the implant 
using a hemostat. We will clean the removal site and place a steri-strip across the skin incision. We 
will then place a sterile gauze and tape over the removal site, which can be removed 24 hours later. 
Participants will then return to clinic in 1 week for their final study visit and an additional blood 
draw. We will similarly centrifuge blood from this draw and store serum for eventual etonogestrel 
concentration analysis. This blood draw will assess the wash-out from removal of the contraceptive 
implant to determine if serum concentrations are similarly close to undetectable at 1 week post-
removal as found with conventional arm insertion. We will then counsel participants on their 
contraceptive options and provide contraception through our routine clinical practice. 
 
After all five participants have completed study procedures, the stored serum samples will 
be de-identified and shipped to Columbia University to undergo serum etonogestrel concentration 

analysis using a validated ultra performance liquid-chromatography mass spectrometry method20. 
This method utilizes an analytical platform comprising a triple quadrupole Waters Xevo TQ-S 
mass spectrometer equipped with an electrospray ionization source and integrated with a Waters 
Acquity UPLC controlled by Mass Lynx Software 4.120. The lower limit of quantification for 
etonogestrel from this assay is 25pg/mL and three levels (low, medium, high) of quality controls 
are included with the samples to assess batch effect. The mean intra-assay precision is 3.2% and 
the inter-assay variability across batches is 1.8%20,21. We will batch analyze all samples to reduce 
assay variability. We will enter all pharmacokinetic and follow up data into a REDCap database, 
which is password protected22. Only the Principal investigator and research staff directly involved 
in this study will have access to this database. All paper consents and follow up documents will be 
stored in a locked cabinet in a locked, secure room.  
 
F.   Data Analysis Plan:   
 
We will perform all statistical analyses using IBM SPSS™ statistical software. We will 
perform descriptive analyses for our primary pharmacokinetic outcomes and determine medians 
and ranges at each follow-up time point. For specific Aim 1, we will determine if the 
pharmacokinetic outcomes obtained during this study fall within the standard definition of 
bioequivalence with previously published pharmacokinetic data from arm insertion of the 
etonogestrel implant. Bioequivalence is defined as within 80-125% of prior pharmacokinetic 
results23. For Specific Aim 2, we will determine the frequency of any insertion site or implant-
related side effects and report these as preliminary findings. For Specific Aim 3, we will report the 
specific characteristics of the position found to be ideal for subdermal scapular implant insertion 
and whether this was consistent across all participants or what variations were required. 
We chose a sample size of five participants for this study based on its pilot nature and the 
limited funding available. Given the repeated pharmacokinetic measurements planned and the high 
cost of the etonogestrel contraceptive implant (~$975 per device), the per participant cost for this 
study restricts our enrollment to no more than five participants to stay within the funding limit. 
However, many landmark pharmacokinetic studies on contraception were conducted with similar 
sample sizes, including the study by Wenzl et al. that established the original pharmacokinetic 
curves for the etonogestrel implant among only eight women13. Thus, this sample size is 
appropriate for our pharmacokinetic pilot study. 
 
 
 H. References: 
 
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Daniels K, Daugherty J, Jones J. Current contraceptive status among women aged 15-44: 
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Hatcher RA, Trussell J, Stewart F, et al. Contraceptive technology. New York: Ardent 
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U.S. Food and Drug Administration Prescribing Information: Nexplanon (etonogestrel 
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Nexplanon Mandatory Training Module Completion. 2018; 
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Lefebvre R, Hom M, Leland H, Stevanovic M. Peripheral nerve injury with Nexplanon 
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