Reduction of Premature Discontinuation of Contraceptive Implants by Advance Provision of an OCP-based Participant Intervention: Randomized Clinical Trial
Phase: PHASE4
Conditions: Contraception Behavior
Sponsor: University of Colorado, Denver

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Study Title: Reduction of premature discontinuation of contraceptive implants by advance 
provision of an OCP-based participant intervention: randomized clinical trial 
 
 
NCT: NCT04828824 
 
Version Date: 07 February 2025 
 
 

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Requirements for Submitting a Full Proposal 
 
Section #1 - MISP Protocol Identification 
 
Study Title: 
 Reduction of premature discontinuation of contraceptive implants by 
advance provision of an OCP-based participant intervention: randomized 
clinical trial 
Request Date: 
 
Institution Name 
 
University of Colorado School of Medicine 
Investigator Contact 
Information: 
­ Full address  
­ Phone No. 
­ Fax  No. 
­ e-mail address 
 
13123 E. 16th Ave. B025 
Aurora, CO 80045 
720-777-4972 
molly.richards@childrenscolorado.org 
 
 
 
Funding 
Investigator initiated funded by Merck  
 
 
 

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Section #2- Core Protocol 
2.1 Objectives & 
Hypotheses  
 
 
 
 
 
Objective: 
To compare rates of etonogestrel implant discontinuation in implant initiators who are 
given advance provision of combined oral contraceptive pills (COCs) and a bleeding 
rescue regimen (COCR intervention) to participants given standard counseling 
(comparator). 
 
Secondary Objectives: 
1. To determine if participants initiating the contraceptive implant who are also 
provided COCR are more likely than participants receiving standard counseling to: 
a. report higher levels of satisfaction with their contraceptive implant at one 
year following initiation 
b. require less clinical follow-up and clinical resources in the year following 
initiation. 
2. To determine if people who did not enroll in this randomized controlled trial are 
similar in characteristics and outcomes to the enrolled group and specifically 
compared to the “usual care” arm.  
 
Primary Hypothesis: We hypothesize that participants who initiate the contraceptive 
implant and are given advance provision of COCR will be significantly less likely to 
discontinue their implant in the year following insertion than those given standard 
counseling 
Secondary Hypothesis: We hypothesize that participants who initiate the 
contraceptive implant and receive the COCR intervention will: 
a. be more satisfied with their contraceptive implant 
b. make and attend fewer follow-up visits in the year after initiation. 
 
2.2 Background & 
Rationale, 
Significance of 
Selected Topic & 
Preliminary Data  
 
 
The contraceptive implant is a highly effective and safe contraceptive method for 
adolescents.  Although usually well tolerated, the most common reason for early 
discontinuation is bleeding.  The contraceptive choice study looked at LARC 
continuation in adolescents (under 20yo) and found that 80% of adolescent 
continued at 1 year and 50.8% of adolescents continued the implant at 3 years.  
Despite this, adolescents who do discontinue often report bleeding as the reason 
(Cohen 2019).  Those who get the implant removed often switch to a less effective 
method. 
 
Studies of interventions for bleeding in implant users have been small, brief and 
have rarely evaluated long term bleeding outcomes, long term continuation or 
satisfaction. 
In a 2015 study by Guiahi et al, 32 women with self-reported bothersome bleeding 
and current bleeding episode of at least 7 consecutive days were randomized to 
COC or placebo for 14 days.  They found an increased likelihood of cessation of 
bleeding with COCs but bleeding often resumed within a week of discontinuation.  
They did not look at participant satisfaction or continuation of their method.  Hou et al 
(2016) also conducted a randomized placebo-controlled trial of bleeding with 26 
participants.  Most women in both arms reported bleeding improvement at 4 weeks, 
although those on COCs were significantly more likely to improve.  They followed 
participants for 2 months after a 4-week treatment trial.  Of 13 COC users, 8 opted to 
continue study treatment after the 4 weeks.  Four of the 26 participants requested 
implant removal by 3 months.  3 of these women had used COCs at some time 
during the study. 
 

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Chen et al (2018) studied concurrent use of implant and COC in a proof of concept 
study.  Two of 19 participants had the implant removed at 6 month follow up but 
neither requested removal for bleeding complaints.  There were no adverse events 
and use of COCs and implant was well tolerated. 
These studies have identified that COCs may be an effective intervention for 
reported bothersome bleeding during implant use and are safe to use in conjunction 
with the implant.  Whether offering a COC intervention increases satisfaction or 
continuation of the implant remains unexplored. 
 
Studies evaluating other interventions for breakthrough bleeding on the 
contraceptive implant have had mixed results.  Mifepristone, a selective 
progesterone receptor modulator, is reported to up regulate endometrial estrogen 
receptors to induce proliferation and reduce vaginal bleeding.  A study on the 
levonorgestrel implant (Cheng 2000) showed some improvement in episodes of 
unscheduled bleeding but a pilot study in etonogestrel implant users did not show 
clinical benefit (Weisberg 2006) 
 
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used to treat irregular 
bleeding and showed some decrease in bleeding episodes when taking three times 
a day for 5 days (Phaliwong P, 2004).  Appropriate medication, dose and regimen 
have not been established. 
 
Other treatments including mifepristone plus estrogen or doxycycline (Weisberg E 
2006), tamoxifen (Simmons 2017) and ulipristal acetate (Zigler 2018) have all been 
shown to have some benefit.  Challenges have been found with all studies in 
improving bleeding patterns long term after intervention has been discontinued. 
 
COC’s have been recommended in expert opinion as a first-choice medication to 
control persistent bleeding due to low cost and the most supporting evidence for 
short term benefit (Mansour 2011). 
 
Hou, et al reported that women who initially requested removal of the implant were 
more likely to continue to desire removal at study conclusion.  It is possible that by 
the time participants have come to clinic for bothersome bleeding they are less 
willing to try an intervention or be satisfied with its outcomes.  If an intervention for 
bleeding was provided at implant insertion to be used as needed, this could give a 
participant a plan for addressing this possible side effect and a sense of control over 
their bleeding patterns. 
 
 
 
 
 
2.3 Study Design 
 
 
This is a randomized controlled open-label clinical intervention trial.  Participants will 
be recruited from the Children’s Hospital Colorado BC4U clinic.  This clinic is a Title 
X supported family planning clinic that offers free, confidential, same-day 
contraception to patients aged younger than 25 years.  Participants will be eligible if 
they are 14-23.9 years old and are new starters of the etonogestrel implant. 
Exclusion criteria will be any contraindications to estrogen-containing birth control, 
and plans to move from the area (where it would not be reasonable to come to the 
clinic) in the next 12 months. All patients seeking contraception in our clinic undergo 
thorough evaluation (personal and familial health history) for contraindications to any 
forms of contraception that are offered as part of the contraceptive assessment and 
counseling process.    For participants under 18 years of age, we will obtain a waiver 
of parental consent from the IRB.  This is available because reproductive services 

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are confidential for all adolescents in the state of Colorado, and the University of 
Colorado IRB recognizes that requiring parental consent for studies which involve 
the same risks as routine contraceptive care is discriminatory against adolescent 
participation. Patients who agree to participate will be randomized to the advance 
provision intervention (COCR) or to standard care (SC).  Standard of care in our 
clinic is to tell all participants initiating the implant to call or follow-up if they have 
undesired side-effects.  If they present with a complaint that is bleeding-related, they 
are told over the phone or in person that they have the option to try COCs for 
bleeding management. Those who desire COCs as an intervention are prescribed 
(over the phone) or given (in person) 3 packs of COCs.  They are told to take one pill 
per day until the first pack is complete and save the remaining 2 packs for possible 
future use. Participants in the SC arm will be offered care according to our 
standardized protocol, which may include STI testing, reassurance and monitoring, 
prescription of COCs if desired, or removal.  Participants in the COCR arm will 
receive three packs of combined oral contraceptive pills (35mcg ethinyl 
estradiol/norgestimate) and a specific protocol for their use for bothersome bleeding, 
as described below.  We chose ethinyl estradiol/norgestimate because it is the main 
oral contraceptive pill that is provided in the family planning clinic through Title X 
governmental grant funding.  Because we do not normally provide patients with pills 
at the time of implant insertion, Merck will cover the additional cost to the clinic for 
purchasing these pills. Participants in this arm may receive additional COCs as 
needed.  Participants who receive COC’s in any arm will be made aware of possible 
side effects of COC’s including breast tenderness, headaches nausea, and bloating.  
Less common side effects could be related to mood or reduction in sexual libido.  
They will also be counseled on rare but more dangerous cardiovascular effects of 
combined contraceptive pills which increase increased blood pressure, venous 
thromboembolism and myocardial infarction or stroke.  These risks are very low with 
the absolute risk of VTE in young women approximately 0.06 per 100 pill years 
(Solymoss S 2011).  The risk of stroke in adolescents on combined oral 
contraceptive pills is 3.4 per 100,000 woman-years (Lidegaard 2012).  The risks of 
VTE, MI and stroke in young woman on the pill are significantly lower than during 
pregnancy or the postpartum period. 
 
There is no clear recommendation for routine follow up visits after initiating combined 
hormonal contraceptives (USSPRCU Curtis KM 2016) but standard of care in the 
family planning clinic is to require a visit annually to monitor weight and blood 
pressure in order to continue use. 
 
All participants will be followed-up at 3 months, 6 months and one year by phone 
and/or online survey per participant preference.  We will assess self-reported 
bleeding pattern, other side-effects, and overall satisfaction with the implant and with 
bleeding patterns. We will query the electronic medical record (Epic, Verona 
Wisconsin) to capture phone calls to clinic regarding the implant, appointments made 
related to the implant, and follow-up appointments attended.  We will also assess 
use of COCs, implant discontinuation, and post-implant contraceptive method.   
 
We will also perform a similar medical record review to include people attending the 
clinic in the same time frame as the randomized trial who met inclusion criteria but 
were not enrolled in the study.  This portion would be medical record review only and 
not include any contact with any patients.  
2.4 Study 
Flowchart 
 
 
Please see study flowchart in section 2.5. 
 
2.5 Study 
Procedures 
 
This is an open-label randomized controlled trial. Participants will be recruited from 
the adolescent family planning clinic (BC4U) if they are new initiators of the 

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contraceptive implant.  Participants will be eligible if they are 14-23.9 years old.  
Exclusion criteria will be any contraindications to estrogen containing birth control.    
We will obtain a waiver of parental consent as reproductive services are confidential 
in all adolescents in the state of Colorado. 
We will use a pragmatic study design.  When an order is placed in the EMR system 
(Epic), a message is generated to the provider to ask the patient about interest in 
participation, to review study procedures and inclusion and exclusion criteria.   If the 
patient qualifies, the consent/assent document is generated, and the provider is 
asked to review and have the patient sign if she desires. All providers are HIPAA and 
GCP-certified.  Participants will be automatically randomized by the EMR after 
consent, and study documents and instructions appropriate to the randomization 
group will be generated. We will use similar methods as those described in Curtis et 
al.  This pragmatic study design is already in use in several protocols at University of 
Colorado Hospital. Providers will do all counseling for participants in either group. 
Participants in the COCR group will receive 3 packages of COC pills.  They will be 
instructed to use the pills if their bleeding is bothersome AND it lasts more than 5 
days.  At day 6 of bleeding they should start the pills and take them daily until they 
finish the pack (21 active pills).  If bleeding continues and is bothersome, they may 
begin the next pack of active pills.  If bleeding stops, but then resumes at any time in 
the course of the study period and is bothersome to them they should start another 
pack.  They can continue this throughout the time of their implant.  They will be given 
refills on COC pills as needed.  They may call and/or come into the clinic for follow 
up as desired.  This information will be provided to the participants graphically, and 
at a 5th grade reading level.   
Participants in the SC group will be counseled as usual on possible bleeding 
patterns with the implant.  They will be told to call or follow up for any concerns with 
the implant, including bothersome bleeding.  They will receive our clinic handout 
about the contraceptive implant. 
We will obtain best and alternate phone numbers and email addresses.  Each 
participant will be contacted by Dr. Richards, Dr. Teal, or the professional research 
assistant within 7 days of enrollment to confirm she has received any study supplies 
and understands her instructions. 
Participants will be informed that we will contact them at 3, 6, and 12 months. 
At that time, we will offer a phone or online survey.  We will make multiple attempts 
to contact them.  We will also query the EMR for telephone calls and follow up 
appointments. 
Participants will receive a $25 gift card for initial study participation and a $25 gift 
card for each follow up survey completed.   
Participants from either group who would like their implant removed can come into 
clinic for removal.  A standardized template will be used to document reason(s) for 
removal. 
In the below flow diagram, all numbers are estimates based on our site’s published 
and recent experience in patient volume, study participation, and follow-up rates.   
 
 
We will also perform an identical medical records review for people who were not 
enrolled in the randomized trial (highlighted in the red box in the study flow diagram 
below) and will extract the variables highlighted in red below in the outcomes table.  
No other information will be examined for these patients.  
 
We hypothesize that patients who are enrolled in the randomized trial and thus 
contacted by clinic staff after implant placement, are more likely to schedule follow-
up visits to discuss bothersome bleeding patterns and less likely to have 
etonogestrel implant removed. The primary outcome for this secondary aim will be 
the number of appointments for breakthrough bleeding and implant removal.   
 

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2.6 Study Duration 
 
We plan to enroll and randomize a total of 600 participants over a period of 12 
months. We will follow all participants for up to 12 months post insertion. After 
completion of all study follow-up medical record review and data cleaning will take 
approximately three months.   
 
Patients initiating the 
contraceptive implant 
1/1/2020 – 12/30/2020 
1,200 
COCR
n = 300 
(50%) 
SC
n = 300 
(50%) 
Eligible for 
randomization
N = 600
Excluded for 
age n=100
Decline participation or 
missed in clinic 
n= 500 (45.5%)
COCR
n = 293
SC
n = 292
COCR
n = 285
SC
n = 285
COCR
n = 250 
(83% of 
randomized)
SC
n = 250
(83% of 
randomized)
Randomized
3 mo f/u
LTFU
n = 15
6 mo f/u
12 mo f/u
LTFU
n = 15
LTFU
n = 70
Figure 1. Study flow diagram
Participants 
randomized to 
COCR will receive 
COC packs and 
COCR instructions
Participants 
randomized to SC 
will receive SC 
instructions
Follow-up 
phone survey
Participants 
will be 
dispensed 
additional 
COCs as 
needed.
Medical records will be reviewed to identify phone calls and clinical appointments made 
related to implant use or questions

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2.7 Statistical 
Analysis and 
Sample Size 
Justification  
 
Dr. Jeanelle Sheeder (Co-Investigator) will be responsible for analyzing the study 
data. This study is a non-blinded randomized controlled trial. Because this study 
involves standard clinical care, study arm will be identified in the electronic medical 
record and will be known to investigators and providers.  However, no data will be 
aggregated or analyzed until study completion.   
 
Variables: 
The primary outcome variable will be retention of the contraceptive implant at 12 
months post-insertion. Discontinuation will be determined through participant report 
at the 3, 6, and 12 month follow-up and by review of medical records. 
 
Secondary outcome variables include: 
Variable 
Assessed by: 
Satisfaction with bleeding profile 
Likert scale (“very satisfied”, “somewhat 
satisfied” and “not satisfied”) 
Satisfaction with method overall 
Likert scale (“very satisfied”, “somewhat 
satisfied” and “not satisfied”) 
Likelihood of recommending implant to a 
friend 
Likert scale (“very likely,” “somewhat 
likely” “not at all likely”) 
Follow up related to implant (visits or 
phone calls) 
EMR review 
Side effects attributed to implant 
Phone/online survey 
 
 
Additional variables include: 
Variable 
Assessed by: 
Age 
EMR 
Race/Ethnicity 
EMR 
BMI 
EMR 
 
Statistical Methods 
 
We will use standard bivariate statistics including Student’s t-tests and non-
parametric medians tests to compare continuous variables. We will use Chi-squared 
and Fisher’s exact tests to compare dichotomous and categorical variables.  The 
primary outcome will be analyzed using the Chi-squared test to generate an odds 
ratio and confidence intervals for continuation by study arm.  Backwards stepwise 
logistic regression will be performed to identify independent predictors of implant 
discontinuation. In the first step, demographic variables will be included if they have 
a significant bivariate relationship to the outcome (p<0.1). In the second step, each 
reproductive characteristic will be considered as a candidate predictor and included if 
it significantly (p<0.1) improves upon the fit of the model from the first step. Study 
arm will be included in the third, final step.  We will also compute estimates of time to 
discontinuation using Cox regression models.  
Multiplicity 
 
If necessary, we will use the Bonferroni method to correct for multiple comparisons.  
 
Power/Sample Size: 
 
Over the last 10 years BC4U clinic has placed approximately 1,200 implants per 
year.  We anticipate that we will be able to enroll a total of 600 of the 1200 implant 
initiators (50%).  Participants will be randomized in a 1:1 ratio. Thus, we will 

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randomize 300 participants to each arm.  Based on prior studies in this clinic 
(Richards 2017, Cohen 2017, Cohen 2019, Green 2019) , we hypothesize that 25% 
of participants in the SC arm will discontinue the implant within 12 months and 15% 
of participants in the COCR group will. With a loss-to-follow-up rate of 17% (from 
prior studies), we will have 80% power to detect this 10 percentage-point difference 
with a two-sided alpha of 0.05. 
 
2.8 Specific Drug 
Supply 
Requirements  
Nexplanons for this study will be purchased by BC4U clinic of Children’s Hospital 
Colorado under the 340B program as per clinical standard of care.  
COCs for this study will be purchased by the BC4U clinic of Children’s Hospital 
Colorado under the 340B program as per clinical standard of care.  
No drugs will be supplied by MSD.  
 
2.9 Adverse 
Experience 
Reporting 
We will use the Model Study Agreement reporting requirements for adverse events.  
2.10 Itemized 
Study Budget  
A preliminary study budget must be provided with the initial proposal submitted to give 
guidance to the MISP Review Committee as to the expected study costs.   A refined 
itemized budget detailing the costs associated with the study should be provided with 
the final protocol or included in the study agreement as Exhibit B.   
2.11 References 
Cohen R, Sheeder J, Teal S. Predictors of discontinuation of long-acting reversible 
contraception before 30 months of use by adolescents and young women. Journal of 
Adolescent Health. 2019 Aug. 65(2):295-302.  
 
Guiahi M, McBride M, Sheeder J, Teal S.  Short-term treatment of bothersome 
bleeding for etonogestrel implant users using a 14-day oral contraceptive pill 
regimen: a randomized controlled trial.  Obstet Gynec.2015;126(3): 508-513. 
 
Hou MY, McNicholas C, Creinin MD.  Combined oral contraceptive treatment for 
bleeding complaints with the etonogestrel contraceptive implant: a randomized 
controlled trial.  Eur J Contracept Reprod Health Care. 2016;21(5): 361-366 
 
Chen MJ, Hsia JK, Creinin MD.  Etonogestrel implant use in women primarily 
choosing a combined oral contraceptive pill: A proof-of-concept trial.  Contraception 
2018;97(6):533-537. 
 
Phaliwong P, Taneepanich.  The effectof of mefenamic acid on uterine bleeding 
second to Implanon.  J MedAssoc Thai. 2004;87(3):S64-8 
 
Cheng L, Zhu H, Wang A, Ren F, Chen J, Glasier A. Once a month administration of 
mifepristone improves bleeding patterns in women using subdermal contraceptive 
implants releasing levonorgestrel. Hum Reprod 2000;15:1969–72 
 
Weisberg E, Hickey M, Palmer D, et al.  A pilot study to assess the effect of three 
short-term treatments on frequent and/or prolonged bleeding compared to placebo in 
women using Implanon.  Hum Reprod.2006;21(1):295-302 
 
Simmons KB, Adelman AB, Fu R, et al.  Tamoxifen for the treatment of breakthrough 
bleeding with the etonogestrel implant: a randomized controlled trial.  Contraception. 
2017;95(2):198-204 
 

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Zigler RE, Madden T, Ashby C, et al.  Ulipristal Acetate for Unscheduled Bleeding in 
Etonogestrel Implant Users: A Randomized Controlled Trial.  Obstet Gynecol. 2018. 
132(4):888-894  
 
Mansour D, Bahamondes L, Critchley H, et al.  The management of unacceptable 
bleeding patterns in etonogestrel-releasing contraceptive implant users.  
Contraception 2011. 83(2):202-210 
 
Solymoss S.  Risk of venous thromboembolism with oral contraceptives.  CMAJ. 
2011.183(18)E1278-9 
 
Lidegaard O, Lokkegaard E, Jensen A, et al.  Thrombotic stroke and myocardial 
infarction with hormonal contraception.  N Engl J Med. 2012;366(24:2257-66 
 
Curtis JR, Foster J, Saag KG. Tools and methods for real-world evidence 
generation: Pragmatic trials, electronic consent, and data linkages.  Rheum Dis Clin 
North Am. 2019 May; 45(2): 275–289. 
 
 
Richards M, Teal SB, Sheeder J. Risk of luteal phase pregnancy with same-day 
initiation of subdermal contraceptive implants. Contraception. 2017 Apr;95(4):364-
370. 
 
Cohen R, Sheeder J, Kane M, Teal SB. Factors associated with contraceptive 
method choice and initiation in adolescents and young women. Journal of 
Adolescent Health. 2017 Oct;61(4):454-460.  
 
 
Green S, Richards M, Sheeder J.  Implant continuation in adolescents with 
bothersome bleeding with and without an intervention.  J Pediatr Adolesc Gynecol. 
2019; 32(2): 244-45. 
 
Green S, Richards M, Sheeder J.  Factors associated with early removal of the 
etonogestrel implant for bothersome bleeding in adolescents.  J Pediatr Adolesc 
Gynecol. 2019; 32(2): 201 
 
 
2.12 Publication 
Plan 
 
This study will be published as an original submission in a high-impact peer-
reviewed journal.  Preliminary considerations are: Obstetrics and Gynecology; the 
American Journal of Public Health; Journal of Adolescent Health; or Contraception.  
We anticipate at least two abstract presentations and two peer-reviewed publications 
from this data.   
The results will be submitted to the Society of Family Planning meetings in 2021 and 
2022.    
 
2.13 Curriculum 
Vitae 
See attached 
2.13 Protocol 
Submission for 
Investigator-
Initiated Studies  
U.S. protocols should be submitted by US investigators directly or through the Global 
Research Specialist at  www.merckiisp.com   
 
Non U.S. protocols should be submitted to the MSD office by the investigators.