Clinical trial NCT02353247
Conditions: Etonogestrel Contraceptive Implant, Bothersome Bleeding
Sponsor: Norton Healthcare
Start date: 2015-08-01; Completion date: 2017-06-29
Enrollment: 88 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The overall objective of this study is to confirm that oral progesterone is an effective way to manage bothersome bleeding; thus increasing the rate of continuation of the etonogestrel contraceptive implant in adolescents.

Detailed description:
The investigators will conduct a prospective study of adolescents using the etonogestrel contraceptive implant. Participants will be recruited from the Kosair Children's Hospital Gynecology Specialists practice in Louisville, Kentucky. This practice provides care to a diverse population of females, from a wide range of socioeconomic statuses, age birth to 25 years.

All patient presenting and choosing to have an implant placed will be offered participation. All enrollments will be voluntary. Participants will not receive compensation for their participation. After obtaining informed consent and assent, participants will provide baseline demographic information, including: age, race/ethnicity, zip code of residence, health insurance provider, number of current and past partners, use of prior contraceptive methods, concomitant condom use, sexually transmitted infection history,smoking status, weight and height. The date of etonogestrel implant insertion will be confirmed.

All patients using etonogestrel contraceptive implants will receive daily SMS texts in the evening via the Qualtrics SMS program asking them to respond with their bleeding pattern that day. The investigators will record responses according to the World Health Organization definitions of bleeding: (a) bleeding day, (b) spotting day, (c) bleeding--- free day \[see Table I for WHO bleeding definitions\]. At their initial follow---up visit 3 months after Nexplanon insertion, the investigators will identify those who report "bothersome" bleeding patterns. For the purpose of this study, "bothersome" bleeding will be defined as prolonged and/or frequent bleeding, as characterized by World Health Organization---recommended definitions of bleeding. The definitions are listed in Table I.

Bleeding day Any day with vaginal discharge containing blood that required more than 1 sanitary pad or tampon per day

Spotting day Any day with vaginal discharge containing blood that required at most one sanitary pad or tampon per day Bleeding---free day A day during which neither bleeding nor spotting was reported

Bleeding--- spotting episode One or more consecutive days during which bleeding or spotting was entered in the diary, bounded by bleeding---free days

Amenorrhea No bleeding or spotting days throughout the 90---day reference period

Infrequent bleeding Less than three bleeding---spotting episodes in a 90---day reference period, excluding amenorrhea

Normal frequency Three to five bleeding---spotting episodes in a 90---day reference period

Frequent bleeding More than five bleeding---spotting episodes in a 90---day reference period

Prolonged bleeding Any bleeding---spotting episode (uninterrupted) lasting more than 14 days in the 90---day reference period

Table I: WHO bleeding descriptions and patterns

Norethindrone acetate (aygestin) will be used to manage bothersome bleeding. Patients will be prescribed aygestin 5 mg by mouth twice daily for one month, followed by aygestin 5 mg by mouth once daily for two months. Medication will then be discontinued. Patients will be evaluated in the office three months after medication initiation, and then again six months after medication initiation. If the patient is unable to take norethindrone acetate (aygestin) due to medical contraindications or cost, they will receive medroxyprogesterone acetate (provera) 10 mg once daily as alternate oral progesterone. Figure 1 below highlights the study design.

Contraceptive implant inserted \& enrollment in the study

Bleeding patterns recorded via SMS text x 3 months

Office visit

Normal bleeding pattern Bothersome bleeding pattern

Continue to record bleeding pattern Aygestin 5 mg PO BID x 1 month\*

Continue to record bleeding pattern Aygestin 5 mg PO daily x 2 months

Continue to record bleeding pattern No mediation x 3 months

Office visit Office visit

\*Or provera 10 mg PO daily x 3 months

Figure 1: Study design

During the aygestin administration, patients will again receive daily SMS texts in the evening via the Qualtrics SMS program asking them to respond with their bleeding pattern that day. The investigators will record responses according to the World Health Organization definitions of bleeding: (a) bleeding day, (b) spotting day, (c) bleeding--- free day. Patients not reporting bothersome bleeding after the initial 90 days will continue to record bleeding via SMS texts for the next 6 months to serve as the control group (normal bleeding group).

All completed demographic data collection forms and electronic menstrual calendars will be kept in a database, de---identified, and stored on a password--- protected computer. Study size will be a convenience sample. Based on the current rate of etonogestrel implant insertions in our practice, it is anticipated that 30 participants can be recruited over a six---month period of time.

Data Collection and Analysis

All patients who meet the inclusion criteria and enroll in the study will be sent a text message daily for 90 days (3 months). The daily message will prompt the participant to indicate the bleeding level for the day. This single question will have 4 options:

1. Bleeding Day
2. Spotting Day
3. Bleeding Free Day
4. Prefer not to answer today.

On day 90, descriptive tallies of the responses will be done. Using SPSS v20, an algorithm will count the number of bleeding days, spotting days, and bleeding free days and prefer not to answer (PNA) days; the data record for each participant will contain four count variables (bleeding, spotting, free, PNA). Secondly, the algorithm will identify and tally -according to WHO guidelines in Table 1 --- bleeding---spotting episodes (BSE),amenorrhea (AM), infrequent bleeding (IF), normal frequency of bleeding (NF), frequent bleeding (FB), and prolonged bleeding (PB).

Participants who have at least a single episode of FB or PB will be assigned the label of "bothersome bleeding". Those without a single episode of FB or PB will be labeled "normal bleeding". Participants in the Bothersome Bleeding group will be offered aygestin to control the bothersome bleeding. Participants in the Normal Bleeding group will continue as before, with no additional medications. Following the principle of intent---to---treat, data from those in the Bothersome Bleeding group will be assigned to the aygestin group, despite that they are not taking it. During the first month, participants in the Bothersome Bleeding group will take one 5 mg tablets of aygestin twice daily (morning and evening). After 30 days, the dose of aygestin will be halved, such that only one 5 mg tablet is taken daily. Sixty days later, the Bothersome Bleeding group will discontinue aygestin. Ninety days later, both the normal group and the Bothersome Bleeding group will be re-evaluated.

Data Analysis

A descriptive table will be used to sort participants into Normal Bleeding and Bothersome Bleeding. Non---parametric and parametric statistics will be used to compare the demographics of these two groups.

A dose---response curve covering six months will be plotted for the Bothersome Bleeding group to visually reveal the impact of one month of 10 mg of aygestin vs. two months of 5 mg aygestin vs. three months 0 mg of aygestin. Plotted on the curve will be the group averages of the daily bleeding value (1 for no bleeding, .5 for spotting, 0 for bleeding). A second no---dose curve will be added to the X---Y plot for the six months of data from the Normal Bleeding group.

Repeated Measure Multivariate Analysis of Variance (RM---ANOVA) with a Between--- Subjects variable included, will be conducted (assuming sufficient data is available - e.g., low PNA rates) to compare the first 30 day average bleeding value, the 90 day bleeding average, and the 180 day bleeding average between the two groups. Planned post---hoc comparisons will evaluate changes between the control group and intervention group at the three time points. Additional analyses may also include regression analysis to assess for predictive factors related to response to aygestin.

Arms: arm 1: Norethindrone acetate (aygestin) will be used to manage bothersome bleeding. Patients will be prescribed aygestin 5 mg by mouth twice daily for one month, followed by aygestin 5 mg by mouth once daily for two months. Medication will then be discontinued. Patients will be evaluated in the office three months after medication initiation, and then again six months after medication initiation. If the patient is unable to take norethindrone acetate (aygestin) due to medical contraindications or cost, they will receive medroxyprogesterone acetate (provera) 10 mg once daily as alternate oral progesterone. Figure 1 below highlights the study
Interventions: intervention 1: Norethindrone acetate
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Protocol Version Date 11/14/16
USE OF NORETHINDRONE ACETATE FOR MANAGEMENT OF BLEEDING 
ASSOCIATED WITH THE ETONOGESTREL CONTRACEPTIVE IMPLANT
Katherine McCracken, Scott LaJoie, Meredith Loveless, S. Paige Hertweck, Rachael 
Polis, Margaret Abraham
Norton Children’s Gynecology, University of Louisville, Louisville, KY
HYPOTHESIS: 
Oral progesterone is a useful therapy for the management of bleeding associated 
with the etonogestrel contraceptive implant. 
OBJECTIVE:
The overall objective of this study is to confirm that oral progesterone is an effective 
way to manage bothersome bleeding; thus increasing the rate of continuation of the 
etonogestrel contraceptive implant in adolescents. 
BACKGROUND AND SIGNIFICANCE: 
Of the approximately three million pregnancies annually in the United States, 50 
percent are unintended pregnancies. Adolescents bear a significant burden of such 
unintended pregnancies, with 82 percent of adolescent pregnancies being 
unplanned (1). It is well documented that adolescent pregnancies have deleterious 
effects on women’s health and educational attainment, the health of newborns, and 
incur a significant emotional and financial burden, both for the individual and 
society as a whole. Furthermore, greater than one-third of unintended adolescent 
pregnancies end in abortion (2). 
While most sexually active adolescents report using a method of contraception at 
some point in their lifetime - they are not typically selecting the most effective 
methods.  Combined oral contraceptives and condoms are the most popular and 
most requested method of contraception by teenagers (3, 4). Unfortunately, the 
failure rates of both oral contraceptives and condoms among adolescents are higher 
compared with all typical users (5, 6). Specifically, adolescent mothers are 


Protocol Version Date 11/14/16
documented to have a high rate of repeat pregnancy and are more likely to use 
ineffective methods and to use effective methods inconsistently or incorrectly (6). 
 It is encouraging that there has been in increase in the number of adolescents who 
use long-acting reversible contraceptive (LARC) methods, such as the intrauterine 
device or contraceptive implant. With 4.5% of adolescents using such methods in 
2009, compared to only 1.5% in 2007, and just 0.3% in 2002 (7). In fact, when 
adolescents were counseled on the full range of contraceptive options and the 
barrier of cost for LARC methods was removed in a large study, more than two-
thirds of females aged 14 – 20 years chose LARC methods (8).  It is also promising 
that national organizations, such as the American Congress of Obstetricians and 
Gynecologists, have emphasized the importance of LARC method use by adolescents. 
Specifically, ACOG states that LARC methods are safe and appropriate for most 
women and adolescents, and that they provide top-tier effectiveness, high rates of 
satisfaction and continuation (9). Furthermore, the Contraceptive CHOICE project, a 
large prospective cohort study designed to promote the use of LARC methods to 
reduce unintended pregnancy, found that sexually active teens using the 
contraceptive implant or intrauterine device have significantly lower mean annual 
rates of pregnancy, birth, and abortion (34.0, 19.4, and 9.7 per 1000 teens) 
compared to sexually experienced U.S. teens (158.5, 94.0, 41.5 per 1000) (10). Data 
from the contraceptive CHOICE project also demonstrates that teens continued to 
use LARC methods longer than shorter acting methods (i.e. the oral contraceptive 
pill and depot medroxyprogesterone acetate injections) – two thirds of teens in the 
CHOICE project were still using their LARC method at 24 months, as compared with 
only one third of teens using a non-LARC method (11). 
The sub-dermal single rod etonogestrel-only implant offers highly effective, long-
acting, reversible contraception (12). It consists of a single rod (4 cm in length, 2 
mm in diameter) made of ethylene vinyl acetate, containing 68 mg of etonogestrel 
that is released subdermally over three years. Prevention of pregnancy is 
accomplished by several mechanisms – suppression of ovulation, thickening of 


Protocol Version Date 11/14/16
cervical mucus inhibiting sperm penetration into the uterus, and alteration of the 
endometrium. In the clinical trial of 301 Nexplanon (the radiopaque etonogestrel 
implant) users, no woman became pregnant while the implant was in situ, up to and 
including 14 days after implant removal. This resulted in an estimated overall Pearl 
Index of 0.0 (95% CI, 0.0 – 0.56) (12); which translates clinically to >99 percent 
effective at preventing pregnancy. They are documented to be safe for use in the 
adolescent population. However, the implant is currently used by less than 1% of 
U.S. women using contraception, and by 0.5% of those aged 15-19 years (13). 
It is well documented that women using the contraceptive implant can expect 
changes in their menstrual bleeding patterns, and these changes account for the 
most commonly cited reason for method discontinuation.  The bleeding pattern 
women experience in the first three months after insertion is predictive of future 
bleeding patterns throughout the duration of use (14). When analyzing 11 clinical 
trials, bleeding patterns were described as infrequent bleeding in 33.3% of 90-day 
cycles, amenorrhea in 21.4% of cycles, prolonged bleeding in 16.9% of cycles, and 
frequent bleeding in 6.1% of cycles (15). 
There have been studies that propose management options for treating bothersome 
bleeding associated with the etonogestrel contraceptive implant – such options 
include combined oral contraceptive pills, non-steroidal anti-inflammatory agents, 
mefenamic acid, mifepristone, and doxycycline. Unfortunately there is limited 
clinical data supporting the effectiveness of these treatments (16-18).  To our 
knowledge, there have been no studies investigating the use of oral progesterone for 
management of bothersome bleeding associated with the contraceptive implant. 
Given the success of norethindrone acetate in the management of pain and bleeding 
in adolescents with endometriosis (19), we chose to use norethindrone acetate as 
our oral progestin of choice for managing bothersome bleeding associated with the 
contraceptive implant.


Protocol Version Date 11/14/16
When investigating bleeding patterns, a common challenge encountered is that of 
patient compliance with menstrual calendars. The burden of keeping a daily 
menstrual calendar may lead to reduced response rates, incomplete data, and poor 
data fidelity. The widespread popularity of mobile phone technology has increased 
the ability to connect with study participants in real time, thus decreasing the 
reliance on traditional pencil and paper methodology for data collection. There are 
several potential advantages for using short-message service text messaging (SMS) 
for data collection: (a) data is time stamped thus providing accurate real-time 
information, (b) study designers have the ability to ensure data responses conform 
to a set criteria, (c) automatic SMS texts provide prompts for participants to record 
the data of interest, (d) data transfer is instantaneous thus reducing data loss or 
incompleteness, and (e) data collection is more convenient and accessible for 
participants as they are likely to have their mobile phone devices with them and be 
familiar with the SMS texting function of their particular device. To our knowledge 
there have been no studies that use SMS text messaging to record data on daily 
bleeding patterns – essentially creating a real-time electronic menstrual calendar. 
MATERIALS AND METHODS: 
We will conduct a prospective study of adolescents using the etonogestrel 
contraceptive implant. Participants will be recruited from the Norton Children’s 
Gynecology practice in Louisville, Kentucky. This practice provides care to a diverse 
population of females, from a wide range of socioeconomic statuses, age birth to 25 
years. 
Inclusion criteria will include any post-menarchal female presenting to the Norton 
Children’s Gynecology practice, who desires to use the etonogestrel contraceptive 
implant and has access to a mobile phone device. 
All patients presenting and choosing to have an implant placed will be offered 
participation. The study will enroll subjects until 30 active participants are in each 
study arm; for a total of 60 study participants.  In order to achieve the enrollment of 


Protocol Version Date 11/14/16
60 active subjects up to 100 participants will be enrolled.  All enrollments will be 
voluntary. Participants will receive compensation for their participation.   After 
obtaining informed consent and assent, participants will provide baseline 
demographic information, including: age, race/ethnicity, zip code of residence, 
health insurance provider, number of current and past partners, use of prior 
contraceptive methods, concomitant condom use, sexually transmitted infection 
history, age at menarche, menstrual cycle regularity, last menstrual period, weight 
and height. The date of etonogestrel implant insertion will be confirmed.
All patients using etonogestrel contraceptive implants will receive daily SMS texts in 
the evening via the Qualtrics SMS program asking them to respond with their 
bleeding pattern that day.  If the SMS text messages are unable to connect to your 
personal cell phone we request an alternative cell phone number be given in order 
to reach you.    We will record responses according to the World Health 
Organization definitions of bleeding: (a) bleeding day, (b) spotting day, (c) bleeding-
free day [see Table I for WHO bleeding definitions]. At their initial follow-up visit 3 
months after Nexplanon insertion, we will identify those who report “bothersome” 
bleeding patterns. For the purpose of this study,   “bothersome” bleeding will be 
defined as prolonged and/or frequent bleeding, as characterized by World Health 
Organization-recommended definitions of bleeding. The definitions are listed in 
Table I. 


Protocol Version Date 11/14/16
Bleeding day
Any day with vaginal discharge containing blood that required 
more than 1 sanitary pad or tampon per day
Spotting day
Any day with vaginal discharge containing blood that required 
at most one sanitary pad or tampon per day
Bleeding-free 
day
A day during which neither bleeding nor spotting was reported
Bleeding-
spotting episode
One or more consecutive days during which bleeding or 
spotting was entered in the diary, bounded by 
bleeding-free days
Amenorrhea
No bleeding or spotting days throughout the 
90-day reference period
Infrequent 
bleeding
Less than three bleeding-spotting episodes in a 
90-day reference period, excluding amenorrhea
Normal 
frequency
Three to five bleeding-spotting episodes in a 
90-day reference period
Frequent 
bleeding
More than five bleeding-spotting episodes in a 
90-day reference period
Prolonged 
bleeding
Any bleeding-spotting episode (uninterrupted) lasting more 
than 14 days in the 90-day reference period
Table I: WHO bleeding descriptions and patterns
Norethindrone acetate (aygestin) will be used to manage bothersome bleeding. 
Patients will be prescribed aygestin 5 mg by mouth twice daily for one month, 
followed by aygestin 5 mg by mouth once daily for two months. Medication will then 
be discontinued. Patients will be evaluated in the office three months after 
medication initiation, and then again six months after medication initiation. If the 
patient is unable to take norethindrone acetate (aygestin) due to medical 
contraindications or cost, they will receive medroxyprogesterone acetate (provera) 
10 mg once daily as alternate oral progesterone. Figure 1 below highlights the study 
design. 


Protocol Version Date 11/14/16
Contraceptive implant inserted & enrollment in the study

Bleeding patterns recorded via SMS text x 3 months

Office visit 


Normal bleeding pattern 
Bothersome bleeding pattern


Continue to record bleeding pattern
Aygestin 5 mg PO BID x 1 month*


Continue to record bleeding pattern
Aygestin 5 mg PO daily x 2 months


Continue to record bleeding pattern
      No mediation x 3 months


      
       Office visit
      Office visit
*Or provera 10 mg PO daily x 3 months 
Figure 1: Study design
During the aygestin administration, patients will again receive daily SMS texts in the 
evening via the Qualtrics SMS program asking them to respond with their bleeding 
pattern that day. We will record responses according to the World Health 
Organization definitions of bleeding: (a) bleeding day, (b) spotting day, (c) bleeding-
free day. Patients not reporting bothersome bleeding after the initial 90 days will 
continue to record bleeding via SMS texts for the next 6 months to serve as the 
control group (normal bleeding group). 


Protocol Version Date 11/14/16
Participants will be compensated as an incentive to increase daily participation.  The 
participant will receive a pre-paid card if they respond to >70% of text messages 
over each 90-day cycle and attend the scheduled office visit.  Patients will receive a 
$5 pre-paid card at visit one (3 months after insertion of etonorgestrel implant), $10 
pre-paid card at visit two (6 months after insertion of etonorgestrel implant), and a 
$15 pre-paid card at visit three (9 months after insertion of etonogestrel implant).
At the completion of the study, 9 months after enrollment, participants will receive a 
SMS text message via Qualtrics with a link to a 12 question follow up survey.  The 
post study questionnaire will assess overall satisfaction with the etonogestrel 
implant and evaluate participants’ perceptions of text messaging as a tool to collect 
information. See Appendix II.
Participants who have already completed the 9 month study will receive an updated 
copy of the consent and assent form via mail with a request to sign the updated 
consent and assent forms.  See Appendix III for a copy of a letter to be included with 
the updated consent and assent.  Once the updated consent and assent are received 
by the investigators at Norton Children’s Gynecology the post survey follow up will 
be sent to the participant by SMS text message via Qualtrics.  Study participants who 
are seen in the office for their 9 month follow up visit will be re-consented in the 
office.
Patients diagnosed with a sexually transmitted infection during the course of the 
study will be removed from the study and their data will be excluded from analysis. 
All completed demographic data collection forms and electronic menstrual 
calendars will be kept in a database, de-identified, and stored on a password-
protected computer. Study size will be a convenience sample. Based on the current 
rate of etonogestrel implant insertions in our practice, it is anticipated that 30 
participants can be recruited over a six-month period of time. 


Protocol Version Date 11/14/16
Data Collection and Analysis
All patients who meet the inclusion criteria and enroll in the study will be sent a text 
message daily for 90 days (3 months). The daily message will prompt the 
participant to indicate the bleeding level for the day. This single question will have 4 
options: 
1. Bleeding Day
2. Spotting Day
3. Bleeding Free Day
4. Prefer not to answer today.
On day 90, descriptive tallies of the responses will be done. Using SPSS v20, an 
algorithm will count the number of bleeding days, spotting days, and bleeding free 
days and prefer not to answer (PNA) days; the data record for each participant will 
contain four count variables (bleeding, spotting, free, PNA). Secondly, the algorithm 
will identify and tally –according to WHO guidelines in Table 1 - bleeding-spotting 
episodes (BSE), amenorrhea (AM), infrequent bleeding (IF), normal frequency of 
bleeding (NF), frequent bleeding (FB), and prolonged bleeding (PB).
Participants who have at least a single episode of FB or PB will be assigned the label 
of “bothersome bleeding”.  Those without a single episode of FB or PB will be 
labeled “normal bleeding”.  Participants in the Bothersome Bleeding group will be 
offered aygestin to control the bothersome bleeding. Participants in the Normal 
Bleeding group will continue as before, with no additional medications. Following 
the principle of intent-to-treat, data from those in the Bothersome Bleeding group 
will be assigned to the aygestin group, despite that they are not taking it.
During the first month, participants in the Bothersome Bleeding group will take one 
5 mg tablets of aygestin twice daily (morning and evening). After 30 days, the dose 
of aygestin will be halved, such that only one 5 mg tablet is taken daily. Sixty days 


Protocol Version Date 11/14/16
later, the Bothersome Bleeding group will discontinue aygestin. Ninety days later, 
both the normal group and the Bothersome Bleeding group will be re-evaluated.
Data Analysis
A descriptive table will be used to sort participants into Normal Bleeding and 
Bothersome Bleeding. Non-parametric and parametric statistics will be used to 
compare the demographics of these two groups.
A dose-response curve covering six months will be plotted for the Bothersome 
Bleeding group to visually reveal the impact of one month of 10 mg of aygestin vs. 
two months of 5 mg aygestin vs. three months 0 mg of aygestin. Plotted on the curve 
will be the group averages of the daily bleeding value (1 for no bleeding, .5 for 
spotting, 0 for bleeding). A second no-dose curve will be added to the X-Y plot for 
the six months of data from the Normal Bleeding group.
Repeated Measure Multivariate Analysis of Variance (RM-ANOVA) with a Between-
Subjects variable included, will be conducted (assuming sufficient data is available – 
e.g., low PNA rates) to compare the first 30 day average bleeding value, the 90 day 
bleeding average, and the 180 day bleeding average between the two groups. 
Planned post-hoc comparisons will evaluate changes between the control group and 
intervention group at the three time points.
Additional analyses may also include regression analysis to assess for predictive 
factors related to response to aygestin.


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TIMELINE: 
October 2014
IRB Submission
November 2014
Anticipated IRB Approval
November 2014 – 
Data Collection
July 2015
August – September 2015
Data Analysis
October 2015
Submission of preliminary data to the North 
American Society for Pediatric and Adolescent 
Gynecology (NASPAG) Annual Clinical and 
Research Meeting Board
April 2016
Present at the North American Society for 
Pediatric and Adolescent Gynecology (NASPAG) 
Annual Clinical and Research Meeting
May 2016
Final manuscript composition and submission 
for publication
APPENDICES: 
Appendix I:
Demographic Data Collection Form
INFORMED CONSENT / ASSENT: 
See the attached University of Louisville Biomedical Informed Consent and Assent 
Forms. 


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REFERENCES: 
1. Finer LB, Aolna MR. Unintended pregnancy in the United States: incidence 
and disparities, 2006. Contraception 2011; 84:478-85.
2. The Alan Guttmacher Institute. U.S. Teenage Pregnancy Statistics. National 
and State Trends and Trends by Race and Ethnicity, 2006, The Alan 
Guttmacher Institute, New York, 2009. 
3. The Alan Guttmacher Institute. U.S. Teenage Pregnancy Statistics. National 
and State Trends and Trends by Race and Ethnicity, 2006, The Alan 
Guttmacher Institute, New York, 2009.
4. Abma JC, Martinez GM, Copen CE. Teenagers in the United States: sexual 
activity, contraceptive use, and child bearing. National Survey of Family 
Growth 2006-2008. National Center for Health Statistics. Vital Health Stat 23 
2012;(30):1-47.
5. Fu H, Darroch JE, Haas T, Ranjit N. Contraceptive failure rates: new estimates 
from the 1995 National Survey of Family Growth, Fam Plann Perspect 31: 58, 
1999. 
6. Speroff L, Darney PD. A Clinical Guide for Contraception, 5th ed. 11: 360, 
2011. 
7. Finer LB, Jerman J, Kavanaugh MD. Changes in the use of long-acting 
contraceptive methods in the United States, 2007-2009. Fertil Steril 2012; 
98(4):893-97.
8. Mestad R, Secura G, Allsworth JE, Madden T, Zhao Q, Peipert JF. Acceptance of 
long-acting reversible contraceptive methods by adolescent participants in 
the Contraceptive CHOICE Project. Contraception 2011; 84:493-8. 
9. “Adolescents and Long-Acting Reversible Contraception: Implants and 
Intrauterine Devices.” American College of Obstetricians and Gynecologists 
Committee Opinion #539. October 2012.
10.  Secura GM, Maden T, McNichols C, et al. Provision of no-cost, long-acting 
contraception and teenage pregnancy. N Engl J Med 2014; 371:1316-23. 
11. O’Neil-Callahan M, Peipert JF, Zhao Q, et al. Twenty-four month continuation 
of reversible contraception. Obstet Gynecol 2013; 122:1083-91.
12. Mommers E, Blum G-F, Gent TG, et al. Nexplanon, a radiopaque etonogestrel 
implant in combination with a next-generation applicator: 3 year results of a 
noncomparative multicenter trial. Am J Obstet Gynecol 2012; 207:388.e1-6. 
13. Mosher WD, Jones J. Use of contraception in the United States: 1982 – 2008. 
Vital Health Stat 23 2010; (29): 1-44. 
14. Monsour, D, Korver T, Marintcheva-Petrova M, Fraser IS. The effects of 
Implanon on menstrual bleeding patterns. Eur J Contracept Reprod Health 
Care 2008; 13(suppl 1): 12-28. 
15. Darney P, Patel A, Rosen K, Shapiro LS, Kaunitz AM. Safety and efficacy of a 
single-rod etonogestrel implant (Implanon): results from 11 international 
clinical trials. Fertil Steril 2009;91:1646-53. 
16. Mansour D, Bahamondes L, Critchley H, Darney P, Fraser IS. The management 
of unacceptable bleeding patterns in etonogestrel-releasing contraceptive 


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implant uses. Contraception 2011;83:202-10. 
17. Phaliwong P, Taneepanichskul S. The effect of mefanamic acid on controlling 
irregular uterine bleeding second to Implanon Use. J Med Assoc Thai 
204;87(suppl 3):S64-8. 
18. Weisberg E, Hickey M, Palmer D, O’Connor V, Salamonsen LA, Findlay JK, et 
al. A randomized controlled trial of treatment options for troublesome 
uterine bleeding in Implanon users. Hum Reprod 2009;24:1852-61. 
19. Kaser DJ, Missmer SA, Berry KF et al. Use of norethindrone acetate alone for 
postoperative suppression of endometriosis symptoms. J Pediatr Adolesc 
Gynecol 2012; 25:105-108. 


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APPENDIX I:
DEMOGRAPHIC DATA COLLECTION FORM:
What is your age?
 Years old
Are you Hispanic or Latino?
 Yes, Hispanic or Latino
 No, not Hispanic or Latino
How would you describe yourself? 
Choose one or more from the following 
ethnic/racial groups:
 American Indian or Alaskan Native
 Asian
 Black or African American
 Native Hawaiian or Pacific Islander
 White
What is your zip code?
Health insurance provider
 Private insurance
 Medicaid (i.e. passport)
 No insurance
Sexual partners
 In the past month
 In your lifetime
Use of prior contraceptive methods
 Pills
 Patch
 Ring
 Depo-Provera
 Intrauterine device
 Condoms 
 Spermicide
 Sponge
 Diaphragm
 Withdrawal
Are you currently using condoms?
 Most / All of the time
 Some of the time
 None of the time
Have you ever had a sexually transmitted 
infection?
 Chlamydia
 Gonorrhea
 Trichomonas
 Herpes
 HIV / AIDS
 Hepatitis B
 Hepatitis C
 Syphilis
How old were you when you started having 
periods?
 Years old
Are you currently having a monthly 
menstrual cycle?
 Yes
 No
What was the first day of your last 
menstrual period?
What is your weight?
 Pounds
What is your height?
 Inches
When was your implant put in?
 Date


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Appendix II:
1
How do you feel about using text 
messages as a way of telling the 
researchers about your period or 
break-through bleeding?
Very happy 
Happy
Neutral
Un-happy
Very Un-
happy
2
Did you answer the text messages 
every day?
All of the 
time 
Most of 
the time
Some of 
the time
Hardly 
ever
Never [1]
3
When you were not able to answer 
the text message, what were the 
reasons for not doing so? Choose all 
that apply
Busy doing 
some-thing 
else
Forgot 
about to 
answer 
Lost 
access to 
my phone
Ran out 
of 
minutes/ 
texts
Other
4
Did you ever feel annoyed or 
unhappy about receiving texts from 
the researchers?
No, never
Rarely
Some-
times
About 
once a 
week
Every day
5
Would you be more or less likely to 
enroll in a future study if that study 
also used text messages to collect 
your information?
Much less 
likely to 
enroll
Less 
likely to 
enroll
Makes No 
differ-
ence
More 
likely to 
enroll
Much more 
likely to 
enroll 
6
Text messages were sent at 6pm 
every evening. How did you feel 
about the timing of the texts?
Better 
earlier in 
the day
The 
timing 
was fine
Better 
later in 
the day
7
For this type of research, another 
way of collecting data is to have you 
write your information into a 
paper-based diary each day. Which 
method of data collection would 
you prefer?
Strongly 
prefer 
paper-
based diary
Prefer 
paper 
based 
diary
Either 
would be 
fine
Prefer 
text-
based 
Strongly 
prefer text-
based 
8
Throughout the study period (up to 
270 days), how often did you 
change your cell phone plan (for 
example, get a new phone number, 
change your plan to get more or 
fewer messages, etc.)?
Never
1 time
2 times
3 times
More than 3 
times
9
Did the text message format make it 
easier or harder for you to give your 
answer truthfully?
Much 
Easier
Easier
No differ-
ence
Harder
Much 
Harder 
10
How likely do you think your 
friends would be willing to enroll in 
a study that uses text messaging for 
collecting data?
Very likely
Likely
Neither 
likely nor 
unlikely
Unlikely 
Very 
unlikely 
11
Do you plan to keep your 
Nexplanon for the next 9 months or 
longer?
Already 
removed it
No
Un-
decided
Yes
12
Would you recommend Nexplanon 
to a friend?
Definitely 
no
Maybe 
no
Undecide
d
Maybe 
yes
Definitely 
yes


Protocol Version Date 11/14/16
Appendix II:
1
How do you feel about using text 
messages as a way of telling the 
researchers about your period or 
break-through bleeding?
Very happy 
Happy
Neutral
Un-happy
Very Un-
happy
2
Did you answer the text messages 
every day?
All of the 
time 
Most of 
the time
Some of 
the time
Hardly 
ever
Never 
3
When you were not able to answer 
the text message, what were the 
reasons for not doing so? Choose all 
that apply
Busy doing 
some-thing 
else
Forgot 
about to 
answer 
Lost 
access to 
my phone
Ran out 
of 
minutes/ 
texts
Other
4
Did you ever feel annoyed or 
unhappy about receiving texts from 
the researchers?
No, never
Rarely
Some-
times
About 
once a 
week
Every day
5
Would you be more or less likely to 
enroll in a future study if that study 
also used text messages to collect 
your information?
Much less 
likely to 
enroll
Less 
likely to 
enroll
Makes No 
differ-
ence
More 
likely to 
enroll
Much more 
likely to 
enroll 
6
Text messages were sent at 6pm 
every evening. How did you feel 
about the timing of the texts?
Better 
earlier in 
the day
The 
timing 
was fine
Better 
later in 
the day
7
For this type of research, another 
way of collecting data is to have you 
write your information into a 
paper-based diary each day. Which 
method of data collection would 
you prefer?
Strongly 
prefer 
paper-
based diary
Prefer 
paper 
based 
diary
Either 
would be 
fine
Prefer 
text-
based 
Strongly 
prefer text-
based 
8
Throughout the study period (up to 
270 days), how often did you 
change your cell phone plan (for 
example, get a new phone number, 
change your plan to get more or 
fewer messages, etc.)?
Never
1 time
2 times
3 times
More than 3 
times
9
Did the text message format make it 
easier or harder for you to give your 
answer truthfully?
Much 
Easier
Easier
No differ-
ence
Harder
Much 
Harder 
10
How likely do you think your 
friends would be willing to enroll in 
a study that uses text messaging for 
collecting data?
Very likely
Likely
Neither 
likely nor 
unlikely
Unlikely 
Very 
unlikely 
11
Do you plan to keep your 
Nexplanon for the next 9 months or 
longer?
Already 
removed it
No
Un-
decided
Yes
12
Would you recommend Nexplanon 
to a friend?
Definitely 
no
Maybe 
no
Undecide
d
Maybe 
yes
Definitely 
yes


Protocol Version Date 11/14/16
Appendix III:
Norton Children’s Gynecology 
3991 Dutchmans Lane, Suite 303
Louisville, KY 40207
Dear Study Participant,
You had participated in an etonogestrel contraceptive implant (Nexplanon) study 
for 9 months.  We have created a 12-question follow up survey to evaluate your 
satisfaction with the Nexplanon and your perception of text messaging as a tool to 
collect information.  We would like to send you a text message with a link to the post 
study survey. 
Enclosed you will find an updated copy of the Consent and Assent forms.  You had 
completed these Consent and Assent forms in the office 9 months ago.  These 
updated documents however now include information about the 12-question follow 
up survey.  The Consent is updated on page 2, paragraph 5 and the Assent is 
updated in paragraph 4.  Prior to sending you a text message link to the post study 
survey both the Consent and Assent forms will need to be signed and mailed back to 
our office.
We would appreciate if you could please read the documents and then have the 
participant’s guardian sign the Consent form on page 8 and the study participant 
sign the Assent form on Page 2.  These documents can then be placed in the 
enclosed return envelope and mailed to our office.
Thank you for your participation in the study as we value your input.  Should you 
have any questions about the survey or enclosed documents please call our office to 
speak with study personnel at (502) 559-1750.  
Thank you,
Rachael Polis, DO

SAP_001.pdf: 
Use of Norethindrone Acetate for Management of Bleeding Associated With the Etonogestrel 
Contraceptive Implant 
 
NCT02353247 
Nov. 14, 2016 
 
Data Analysis Plan 
 
The primary hypothesis was analyzed using repeated measures ANOVA (RM-ANOVA) 
with two groups and three measurements (summary statistics at day-90, day-180, and day-270). 
To have at least 80% a-priori power to detect a medium effect size (f = 0.25) at alpha = 0.05, a 
total sample size of 28 was required with approximately equal sized groups. (G*Power version 
3.1.9.21; Faul, Erdfelder, Lang, & Bucher, 2007). Anticipating and reacting to high attrition rates, 
72 participants were enrolled.  
Data cleaning and management was done to identify participants who responded to daily 
SMS surveys at least 189 times (70% of the 9-month trial). Fifteen (21%) of the 72 participants 
provided fewer than 100 responses. Another 14 participants (19%) provided between 100 and 
188 responses. An additional four participants (9.7%) were removed because they did not 
respond at least 70% of the days during each 90-day time period. The final data set consisted of 
39 participants: 18 in the No Intervention arm and 21 in the Intervention arm. Post-hoc analysis 
indicated the study was powered at 93%.    
 
1 NOTE:  Faul, F., Erdfelder, E., Lang, A.-G., & Buchner, A. (2007). G*Power 3: A flexible statistical power 
analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods, 39, 
175-191.  


Data collection was done with Qualtrics™(Provost, Utah) and analyses were done using 
Microsoft Excel (Redman, Washington) and IBM SPSS Statistics for Macintosh (version 24, 
Chicago, Illinois).