Management of Etonogestrel Subdermal Implant-related Bleeding in US Women: a Prospective, Randomized, Placebo-controlled Trial.
Phase: PHASE3
Conditions: ESI-related Bleeding
Sponsor: Petra M. Casey

 
 
Management of Etonogestrel 
Subdermal Implant (Nexplanon) 
-related bleeding in US Women: 
a prospective, randomized, 
placebo-controlled trial 
 
 NCT01658995 
 
3/29/2017 

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Management of Etonogestrel Subdermal Implant (Nexplanon) -related bleeding in 
US Women: a prospective, randomized, placebo-controlled trial 
 
 
Principal Investigator:  
Petra M. Casey MD, Associate Professor OBGYN, Mayo Clinic Rochester 
 
 
Co-investigators: 
Margaret E. Long, MD*, Mary L. Marnach MD*, Abimbola O. Famuyide MBBS*, Amy 
Weaver MS** 
 
 
*Department of OBGYN, Mayo Clinic Rochester 
 
** Division of Biomedical Statistics and Informatics, Mayo Clinic Rochester 
 
 
 
Version 2 – 02/10/2012 
Version 2.1 – 08/20/2012 
Version 2.2 – 05/15/2014 
Version 2.3 – 3/29/2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Proposal outline 
1.0 Abstract 
2.0 Specific Aims 
3.0 Hypotheses 
4.0 Background and Significance 
5.0 Experimental Design and Methods 
• Overview 
• Study Population 
o Patient Selection 
o Inclusion Criteria 
o Exclusion Criteria 
• Measure of Study Variables 
o Study process 
o Outcome measurements 
• Statistical analysis 
o Power calculation 
o Statistical analysis  
6.0 Adverse Events 
• Serious Adverse Events 
• Unanticipated Adverse Device Events 
• Anticipated Effects of Implanon placement 
• Anticipated Effects of Doxycycline treatment 
• Reporting of Adverse Events 
• Data and Safety Monitoring Plan 
7.0 Ethical  Considerations (Human Studies) 
8.0 Study expectations and Limitations 
9.0 Future Directions 
10.0 Budget and Budget Justification 
11.0 Consent form  
12.0 Bibliography 
13. 0 Appendices 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 Abstract 
 
Etonogestrel Subdermal Implant (ESI) is an attractive alternative to other long-acting 
reversible contraception as well as a compliance-independent alternative to estrogen- 
containing hormonal contraception.  Though its safety and efficacy has been established 
world-wide, only about 1% of women have been reported to use this method [6].  Its use 
and future expansion is limited by bleeding alterations which result in requests for early 
removal. Unfortunately, published data regarding bleeding changes and ESI in US 
women is limited. A multicenter trial of 330 US women reported a 13.0% removal rate 
for “bleeding pattern changes,” within the first 8 months of use [1], consistent with the 
results of an international trial [2]. We reported on a retrospective cohort of 155 US  
women and developed an algorithm that improved unacceptable bleeding rates in 66% of 
patients using Doxycycline (N=9) allowing method continuation [3, 7] Further, ours was 
the first US study which included women regardless of BMI (mean BMI 28.5) [3]. We 
further report on an expanded cohort of 337 women with an unacceptable bleeding rate of 
28.5%. Where 44% of women who received Doxycycline requested removal, 92% of 
women who received another intervention or declined intervention requested removal. 
[29]  With the proposed prospective randomized placebo-controlled double blinded trial , 
we aim to validate the implementation of a simple, affordable, non-hormonal intervention 
using the most rigorous methodology reported to date.  
  
2.0 Specific Aims 
 
2.1 Specific Aim #1 (primary aim):   
• To determine the effect of Doxycycline vs. placebo on the need for additional 
treatment for unacceptable bleeding at 13 weeks post-randomized treatment.  
2.2 Specific Aim #2 (secondary aim):   
• To determine if initial treatment with Doxycycline results in higher patient 
satisfaction with ESI as compared to placebo at 13 weeks post-randomized 
treatment.  
2.3 Specific Aim #3 (secondary aim):  
• To determine method continuation and patient satisfaction rate at 26 week post- 
randomization in patients who choose secondary treatment with Doxycycline for 
unacceptable bleeding at 13 weeks post-randomized treatment.  
In order to evaluate specific aim #1:  
• All ESI patients will be offered enrollment in the study at ESI insertion and will 
begin prospective diaries. They will be contacted at 13 weeks post insertion. If 
patients report unacceptable bleeding at that time or self-report at any time 
following an initial 13 week interval, they will be offered randomization to 
Doxycycline or placebo. Patients will continue a weekly prospective symptom 
diary for the duration of study.  
• Time to recurrence of unacceptable bleeding post-treatment and need for 
secondary treatment (primary endpoint) will be determined by completion of 
prospective symptom recording by 13 weeks post-randomized treatment. 

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• Side-effects and adverse events associated with medical treatment will be 
documented. 
 
In order to evaluate specific aim #2:  
• A patient satisfaction survey will be administered at randomization and 13 weeks 
post-randomization. The results will be compared between the Doxycycline and 
placebo study arms. 
 
In order to evaluate specific aim #3:   
• Patient satisfaction will be assessed at 13 weeks post-ESI insertion.  
• Patients who report unacceptable bleeding after initial randomized treatment and 
who choose additional treatment will receive secondary treatment with 
Doxycycline and the method continuation rate and patient satisfaction rate at 26 
weeks post randomization will be calculated. 
• In patients who leave the study prior to 26 weeks post-randomization, patient 
satisfaction will be recorded at that time. 
• If ESI is removed prior to 26 weeks post-enrollment, the reason, date of removal 
and alternative contraception will be documented.  
 
3.0 Study Hypotheses 
 
3.1 Study hypotheses for specific aim #1 (primary aim):  
• Doxycycline is more effective than placebo in the initial management of ESI-
related bleeding.  
• Statistically significant difference between the placebo and Doxycycline 
groups will be shown in favor of Doxycycline 
 
3.2 Study hypotheses for specific Aim #2 (secondary aim):  
• Patients in the Doxycycline group will report a higher satisfaction rate with ESI 
scores on a survey as compared to those in the placebo arm at 13 weeks post-
randomization. 
• Statistically significant difference in patient satisfaction rates between the 
placebo and Doxycycline groups will be shown in favor of Doxycycline.   
 
3.3 Study hypotheses for specific aim #3 (secondary aim):  
• In patients who request secondary treatment for unacceptable bleeding, 
administration of Doxycycline will result in a high method continuation rate and 
patient satisfaction rate at 39 weeks post ESI insertion. 
• The above will be supported by method continuation rate of >75% [3, 8] at 26 
weeks post-randomization. 
 
 
4.0 Background and Significance 
Unintended pregnancy continues to be a major public health issue in the United States. In 
2002, nearly half of the 6.4 million pregnancies in the United States were unintended. 

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Almost half of unintended pregnancies end in elective abortion. [9]   Further, 80% of 
adolescent pregnancies are unintended.[10]  The need for a highly effective, safe, 
estrogen-free, compliance independent and rapidly reversible contraception can be 
readily met with ESI.  The etonogestrel subdermal implant has been available worldwide 
since 1998 and received United States Food and Drug Administration approval in 2006. 
Though studies have confirmed its efficacy, convenience, and cost-effectiveness, 
bleeding irregularities account for up to 43% of requests for early removal. [4, 11] though 
the rate of 28.5% was reported in our population. [29] Other reasons for removal 
include weight gain, headaches, mood changes and desire for pregnancy, each accounting 
for about 10-15% of removal requests.[11] Published data regarding bleeding 
management in US women is limited. A multicenter trial of 330 US women reported a 13 
% removal rate for “bleeding pattern changes,” particularly within the first 8 months of 
use, consistent with international studies. [1, 2].  However, prior trials have excluded 
women weighing over 130% of ideal body weight [4]. Our retrospective study was the 
first US study to include women regardless of BMI.[3] Further, an expanded 
retrospective cohort of 337 women confirmed the efficacy of Doxycycline as 44% of 
women who received Doxycycline requested removal and 92% of those who received 
another intervention or declined intervention beyond reassurance requested removal [29]. 
A recent review of the literature includes interventions for bleeding but admits limited or 
anecdotal support for these. Further, the first line intervention contains estrogen, which is 
contraindicated in many ESI users [26.  The intervention in this proposed study is 
hormone-free.   
 
Rationale for using Doxycycline as initial treatment for ESI related bleeding 
Doxycycline 100 mg twice daily for 10 days 
Matrix metalloproteinases cause endometrial fragility, irregular vessel breakdown, influx 
of leukocytes, and bleeding. [15, 16] Tetracyclines inhibit matrix metalloproteinase 
activity independent of their antimicrobial action, with doxycycline being the most potent 
inhibitor among the tetracyclines [17, 18]. Doxycycline also treats Chlamydia and 
Ureaplasma infection, which may cause chronic endometritis that presents as abnormal 
uterine bleeding [19]. A pilot study by Weisberg [21] reported a 50% reduction in ESI-
related bleeding duration with doxycycline for 5 days but no long-term improvement and 
no improvement over placebo in a follow-up study [22]. Doxycycline anti-inflammatory 
effects are dependent on dose and treatment duration in vitro [20] thus supporting a 
longer therapy course. Clinically there is no precedent for increasing dose beyond 100 mg 
BID. While there is a clinical precedent for using 10 days of treatment, there is not for 5 
days of use. This length of administration was likely used in the Weisberg studies( 21,22) 
for blinding purposes [21,22].In our retrospective cohort (N=9), 10 day course of 
Doxycycline resulted in bleeding improvement and method continuation in 66% of 
patients who reported unacceptable bleeding.[3,7]  Of 36 untreated patients, 25 (70%) 
requested early ESI removal.[7] 
.  
The published experience with Doxycycline in the treatment of unacceptable bleeding 
associated with ESI is limited to small, retrospective studies.  The validation and 
subsequent clinical implementation of an evidence-based cost-effective treatment is 
likely to dramatically increase the acceptability and continuation rates of ESI. 

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5.0   Experimental Design and Methods 
5.1   Overview:  
This is a double-blinded, randomized, prospective placebo-controlled clinical trial to be 
conducted within the Mayo Clinic and the Mayo Clinic Health System.   
   
5.2 Study population 
The Mayo Clinic and Mayo Clinic Health System offers a network of collaborative 
practices throughout the Midwest as well as site in Arizona and Florida. During the past 
year, 7100 female patients were seen for contraceptive related needs at Mayo Clinic 
Rochester alone. [26] Electronic medical records are easily accessible for data abstraction 
and patient followup.  Further, the patient population is stable. The loss to followup was 
only 2% in our 27-month retrospective study. [3] In the Obstetrics and Gynecology 
department of Mayo Clinic Rochester alone, over 350 ESI devices have been inserted 
since mid-2007.  Over 150 ESI devices were placed in the last year by 12 practitioners 
and additional practitioners will be trained in November 2011. Additional patients can be 
readily recruited by Implanon providers from the departments of Family Medicine as well 
as regional Mayo Clinic Health System sites in Minnesota, such as Albert Lea, 
Owatonna, Faribault, and Austin, with which close collaborative relationships exist and 
where over 81,000 women between the ages of 18 and 51 were seen as outpatients in 
2009. [25]. 
 
5.2.1 Patient selection 
After appropriate IRB approval, ESI users aged 18-51 years old who meet the inclusion 
and exclusion criteria, and sign a written consent will be enrolled in the study at the 
time of ESI insertion. Every effort will be made to insert ESI on the same day as consent 
unless medically contraindicated. They will complete a prospective symptom diary from 
date of ESI insertion.   All patients will be contacted by study personnel 13 weeks after 
enrollment and queried as to the presence of unacceptable bleeding. Bleeding concerns 
will be objectively assessed using a modification of the Pictorial Blood Loss Assessment 
Chart (PBLAC) [27}.  Patient–initiated contact in with bleeding concerns at any time 
after 13 weeks post ESI insertion will result in enrollment and  randomization at the time 
of contact.   The basis for randomized treatment will be whether or not the bleeding 
is “unacceptable” to the patient.  This is inherently subjective, but constitutes the 
basis for most removal requests. Patients who report unacceptable bleeding at 13 weeks 
post-ESI insertion, and those who call with bleeding concerns after 13 weeks post ESI 
insertion, will be randomized into two groups (Doxycycline or placebo).  Patients who do 
not report unacceptable bleeding will continue to complete diaries and may be eligible for 
randomized treatment if unacceptable bleeding develops. Patients will receive diaries 
sufficient for completion of the study with instructions to contact study personnel if more 
diaries are needed or if diaries are lost.    Patients and investigators will be blinded to the 
group assignment as well as the study coordinator who will be responsible dispensing of 
appropriate study medication by the pharmacy. 

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Patients who continue to have unacceptable bleeding  after 4 weeks  post-randomized 
treatment and wish to have secondary treatment will be treated with Doxycycline.  
Secondary treatment will not be blinded.  Rates of unacceptable bleeding and patient 
satisfaction scores at 26 weeks post-randomized treatment in remaining study participants 
will be calculated. 
 
 5.2.2 Inclusion Criteria 
 
• Premenopausal  women, aged 18-51 years  
• Expressed desire for compliance-independent contraception 
• No current pregnancy or anticipated desire for childbearing within 3 years of 
study enrollment and ESI insertion 
• Agreement to participate in all study related procedures and evaluations as 
documented by  a signed informed consent (see appendix) 
 
5.2.3 Exclusion criteria 
 
• Current or prior use of ESI 
• Current long-term use of Doxycycline for other indications  
• Known structural uterine abnormalities such as polyp, submucosal leiomyoma 
• Prior permanent sterilization or endometrial ablation 
• Pregnancy or desire for childbearing within 3 years  
• Contraindications to or intolerance of etonogestrel 
• Allergy to or intolerance of Doxycycline 
• Inability or unwillingness to complete study related procedures and evaluations, 
and document this agreement by signing the informed consent  
 
 

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N= 470  (approximate)
 Implanon Insertion, consent, enrollment
Prospective diary
Unacceptable bleeding
Randomization (N= 100)
Prospective diary & satisfaction survey
Request for secondary treatment (at >4 wks post-randomized 
treatment)
End of Study
No
Yes
Yes
N=50
Placebo 
N=50
Doxycycline 
Doxycycline 
No Treatment
Patient Process Chart
Patient 
Satisfaction 
Survey
Patient 
Satisfaction 
Survey
Patient 
Satisfaction 
Survey
Removal
No 
removal
End of Study
13 weeks 
13 weeks
No
Continue Diary 
Remuneration q 
13 weeks

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5.3 Measurements of Study Variables 
 
5.3.1 Study Process 
 
a. Enrollment  
Subjects who meet the eligibility criteria will be required to sign an informed consent 
form and HIPAA authorization prior to enrollment.  Subjects will receive identification 
numbers at this time and will be considered enrolled into the study.  Patient demographic 
characteristics, prior contraceptive method, postpartum and breastfeeding status will be 
recorded. All subjects will undergo a history and physical examination including pelvic 
examination, height and weight if this was not done within an age-appropriate interval. A 
baseline BMI will be calculated. A Pap test using ThinPrep® will be obtained if none has 
been taken in the preceding 12 months. A retrospective symptom diary to date of ESI  
insertion and prospective symptom diaries for the duration of the study will be provided 
to the patient with instructions to contact study personnel if materials are lost or more are 
needed.   
b. Randomization 
Patients enrolled in the study at the time of ESI insertion who either report unacceptable 
bleeding when contacted by study personnel at 13 weeks post-ESI insertion or self-report 
unacceptable bleeding after 13 weeks post ESI insertion will be offered randomization to 
placebo or Doxycycline.  Randomization will be done with stratification based on: age (< 
30 years, ≥ 30 years), postpartum status and body mass index (BMI< 30, BMI ≥ 30).  The 
randomization will be performed using a dynamic allocation approach based on the 
Pocock-Simon method to ensure a balance in the treatment groups across the 
stratification levels.  The randomization assignment for each patient will be obtained 
upon entering the patient’s stratification levels into a web-based application created and 
supported by the Division of Biomedical Statistics and Informatics.  Investigators and 
patients will be blinded to group assignment. For this reason, all pills will be made to 
look identical. Enrollment of new patients will continue until approximately 100 
patients are randomized (50 in each group). Additional patients will need to be 
enrolled given the lower than expected reported unacceptable bleeding rates.  
c. Placebo group 
If a patient reports bleeding concerns as described in section 5.2.1 and is randomized to 
the placebo group, she will be given a pill bottle containing placebo made to look 
identical to treatment to be taken twice daily for 10 days. Patient and investigators will be 
blinded as to group assignment. 
d. Doxycycline group 
If patient has bleeding concerns determined in section 5.2.1 and is randomized to the 
Doxycycline group, she will be given a pill bottle containing Doxycycline 100 mg to be 
taken twice daily for 10 days. Patient and investigators will be blinded as to group 
assignment.  Patients who experience unacceptable bleeding but are not bleeding at the 
time of study personnel contact will be instructed to call back if unacceptable bleeding 
recurs for randomization to treatment or placebo. 
e. Treatment compliance process 

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Pill counts at the end of each treatment course will be performed to assess patient 
compliance with treatment.  A pill diary given to patients at the time of randomization 
will provide temporal correlation between treatment initiation and bleeding symptoms. 
f. Symptom recording 
Upon enrollment and ESI insertion, patients will begin a weekly prospective symptom 
diary in order to self-assess bleeding and additional symptoms for a total of 39 weeks 
from study enrollment. A modification of the PBLAC where 1= no bleeding, 2=spotting 
requiring 1-2 panti-liners per 24 hours only, 3= bleeding requiring 1-3 tampons/pads in 
24 hours,  4=bleeding requiring 4-6 tampons/pads per 24 hours, and 5=bleeding requiring 
>6 tampons/pads per 24 hours will be utilized for bleeding recording.[27]  Bleeding 
diaries will be collected every 13 weeks and completion will be required for continued 
enrollment in the study and receipt of remuneration after every 13 week interval. Patients 
will also record any other associated symptoms such as headache, mood changes, acne 
and intolerance to treatment detailed in sections 6.2.2 and 6.2.3.  Prospective symptom 
diary can be captured on a paper formate or  via Mayo Clinic website RED Cap. 
A bleeding episode is defined by the WHO as any set of one or more bleeding days 
(either consecutive or separated by only one bleeding-free day) bounded at each end by 
two or more bleeding-free days. The bleeding pattern will be analyzed within each 13-
week reference period and categorized into 6 groups [4, 13, 14]: 
• Amenorrhea (no bleeding during the reference period),  
• Infrequent bleeding (fewer than 3 bleeding episodes),  
• Normal bleeding frequency (3-5 bleeding episodes). 
• Frequent bleeding (more than 5 bleeding episodes),  
• Prolonged bleeding (1 or more bleeding episodes lasting 14 days or more) 
Subgroup analysis may provide additional insight into the efficacy of treatment for 
various bleeding patterns. 
g. Patient satisfaction surveys 
Patients will be asked to fill out short satisfaction surveys at randomization measuring 
satisfaction prior to any treatment, and at 13 and 26 weeks post randomization (see 
appendix).   If patient has their ESI removed prior to 26 weeks post randomization, she 
will be given a final satisfaction survey at removal.  Patient satisfaction surveys will be 
recorded on a paper formate or via Mayo Clinic website RED Cap. 
Patients will rate their satisfaction with a) ESI and b) bleeding with ESI on a 5-point 
Likert scale ranging from very satisfied to very dissatisfied.  If patient has ESI removed 
prior to 26 weeks post-study enrollment, she will be given a final satisfaction survey at 
removal.  
h. Treatment issues 
At enrollment, patients will be provided with a contact number allowing them to reach 
study personnel at all times with concerns.  Instructions will be provided for instances of 
drug intolerance/allergy, heavy bleeding or other ESI related issues and clinical 
appointments for evaluation scheduled as needed. 
i. Secondary Treatment 
If a patient reports unacceptable bleeding at >4 weeks post randomization to treatment or 
placebo, study participation will be recorded as need for additional treatment, and will 
represent the primary endpoint.  If she wishes to have secondary treatment, she will be 
treated with Doxycycline. Treatment will be limited to two interventions per 13 week 

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interval to allow for assessment of efficacy of each course of Doxycycline. Rates of 
unacceptable bleeding in all patients remaining in the study at 26 weeks post–
randomization will be calculated and participation in the study will end. If patients 
request ESI removal at any time during the study after randomly assigned treatment, 
study participation will be recorded as a removal.  Method satisfaction will be assessed 
at removal and study participation will end. Patients will be provided with alternative 
contraception of choice at their expense. Need for additional treatment at >4 weeks 
post–randomized treatment will represent the primary endpoint. Satisfaction with 
ESI at randomization, and 13 and 26 weeks post randomization, and method continuation 
at 26 weeks post -randomization represent the secondary endpoints. 
j. Post-treatment Followup 
All patients will be contacted by  study personnel at 26 weeks (+ 2 weeks) post -
randomization for final satisfaction survey and weight. Study completion BMI will be 
calculated. All diaries will be collected for analysis and patients will receive 
remuneration. When all patients complete the study, the data will be unblinded for 
analysis. 
k. Special Considerations 
If patients receive randomized treatment toward the end of the 39 week study interval 
(rather than at about 13 weeks post ESI insertion), post-treatment data for at least 13 
weeks will be collected for a maximum study length of  52 weeks post-ESI insertion. 
l. Additional testing 
Additional laboratory testing or imaging for heavy or unusual bleeding will be 
individualized as clinically indicated. 
  
5.3.2 Outcome measurements 
A. Primary treatment efficacy and safety end point (primary endpoint addressing specific 
aim #1)  
• The efficacy of Doxycycline on ESI-related bleeding will be compared to placebo 
based on rates of unacceptable bleeding and weekly prospective symptom diary 
at 13 weeks post-randomization.  
B. Primary treatment efficacy and safety endpoints (secondary endpoints addressing 
specific aim #1) 
• Method continuation rate at 13 weeks post-randomization will be compared for 
women in the Doxycycline vs. placebo group.  
• Bleeding patterns will be quantified based on the PBLAC and WHO classification 
of clinically important bleeding patterns over each 13 week reference 
period.[13,14, 29].  
• Incidence of additional symptoms including acne, headache, mood changes in the 
treatment groups will be compared to placebo at randomization and 13 weeks 
post-randomization based on the  weekly prospective symptom diary  
• Interval to recurrence of unacceptable bleeding post- randomized treatment (i.e., 
need for additional treatment) will be determined  
• Rate of adverse events associated with medical treatment will be documented by 
prospective symptom diary and BMI calculation. These include headache, mood 
changes, acne and change in BMI. 

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C. Patient satisfaction with primary treatment endpoint (primary endpoint addressing 
specific aim #2) 
• Patient satisfaction with ESI at randomization for a baseline pre-treatment 
satisfaction and at  13 weeks post-randomized treatment  following primary 
treatment with Doxycycline vs. placebo will be compared 
D. Patient satisfaction with secondary treatment endpoint (primary endpoint addressing 
specific aim #2)  
• Patient satisfaction with ESI at 26 weeks post–randomized treatment for patients 
with continued unacceptable bleeding following primary treatment who receive 
secondary treatment with Doxycycline will be calculated.  
E. Secondary treatment efficacy and safety endpoint (primary endpoint addressing 
specific aim #3)  
• Method continuation rate at 26 weeks post -randomized treatment for patients 
with continued unacceptable bleeding after primary treatment who undergo 
secondary treatment with Doxycycline will be calculated  
F. Secondary treatment efficacy and safety endpoint (secondary endpoints addressing 
specific aim #3)  
• Rate of ESI removal for bleeding between 13 and 26 weeks post randomization. 
• Rate of ESI removal for reasons other than bleeding with enumeration of  reasons 
for removal between 13 and 26 weeks post -randomization. 
• Alternative contraception chosen if ESI removed will be documented. 
 
5.4 Statistical Analysis: 
Baseline demographic and clinical characteristics will be documented as detailed in 
section 5.3.1a patient enrollment.  
 
5.4.1 Power statements 
Based on prior Mayo data, we anticipate about 30% of patients will develop unacceptable 
bleeding following ESI insertion.[3,29] These patients will be approached for 
participation in this study.  The study plans to randomize a total of 100 patients with 
unacceptable bleeding to either placebo (N=50) or Doxycycline (N=50). The following 
calculations were based on a two-sided chi-square test with a type I error rate of 0.05.   
 
Aim1:  Of the patients with bleeding concerns, based on our prior experience we 
anticipate that 44% of the patients randomized to Doxycycline will request additional 
treatment, and about 80% in the placebo arm.  We are purposely overestimating the 
placebo effect over that noted in our cohort (92% removal requests) to allow for variation 
in the study group. Given the sample size of 50 per treatment arm, the study will have 
>90% power to detect the anticipated difference in the need for additional treatment.  
 
Aim 2: Across the two arms, we anticipate that 66 of the 100 patients will request 
additional treatment and will receive additional treatment with Doxycycline.  Within this 
subset we plan to estimate the method continuation rate following additional treatment. 
Based on a sample size of 66, the ½ width for a 95% CI around an estimate of 75% is 
±10%. 
  

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Aim 4: Among the anticipated 66 patients who will request additional treatment for 
continued unacceptable bleeding at 26 weeks post-ESI insertion, we plan to quantify the 
patient satisfaction rate. If we assume 75% will be “very satisfied” or “satisfied”, then the 
½ width for a 95% CI around this estimate will be ±10%. 
 
5.4.2 Proposed Statistical Analysis:   
Patients will be analyzed according to their randomized treatment arm. All calculated p-
values will be two-sided and p-values less than 0.05 will be considered statistically 
significant.  Analyses will be performed using SAS software package (version 9.2).  
Comparisons of categorical endpoints (e.g. need for additional treatment, bleeding pattern 
based on the WHO classification, presence of adverse event(s), satisfaction survey 
questions) between the two arms will be evaluated using the chi-square test.  Additional 
comparisons of these endpoints, adjusted for potential confounders, will be assessed by 
fitting separate logistic regression models.  Time-to-event methodology (e.g. Kaplan-
Meier method and Cox proportional hazards regression models) will be utilized for 
binary versions of these endpoints if patient follow-up becomes an issue and patients 
don’t comply with the planned follow-up before completing the study.  
Poisson regression models will be used to compare the diary responses between the 
treatment arms.  In the Poisson model, the endpoint will be the number of bleeding and 
spotting days per patient (and likewise the number of days with additional symptoms), 
offset by the total days of diary follow-up per patient. Ninety-five percent confidence 
intervals (95% CI) will be constructed around the estimates for method continuation and 
satisfaction.  
 
6.0 Adverse events  
 
An adverse event is any untoward medical occurrence in a study subject which does not 
necessarily have a causal relationship with the medicinal product. This includes any 
unfavorable and unintended sign (including an abnormal, clinically significant laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not related to the medicinal product. It also includes any pre-existing 
condition that increases in intensity or severity or any new events after the patient has 
given informed consent. 
 
6.1  Serious Adverse Events: 
A serious adverse event is any untoward medical occurrence that results in one of the 
following: 
• Death 
• Life threatening illness or injury 
• Permanent impairment of a body function or structure 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• Medical or surgical intervention to prevent permanent impairment 
• Fetal distress, fetal death, congenital abnormality, or birth defect 
 
 
 

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6.2 Unanticipated Adverse Device Effects: 
Any serious adverse effect on health or safety, any life-threatening problem or death 
caused by, or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the application; or any 
other unanticipated serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects. 
 
6.2.1 Anticipated Adverse Effects of ESI insertion 
• Pain at insertion site 
• Infection at insertion site 
• Non-insertion 
• Deep insertion (non-palpable implant) 
• Pregnancy at time of insertion 
The above is minimized by strict adherence to the ESI insertion technique in the ESI 
prescribing information [4] including exclusion of pregnancy.   
  
6.2.3 Anticipated Adverse Drug Reactions of Doxycycline  
Serious side-effects include 
• pseudotumor cerebri (rare) 
• seizure  
• swelling of face, lips, tongue, or throat  
• headache 
• wheezing 
• chest tightness 
• fever 
Other side effects include 
• abdominal pain 
• Nausea or vomiting.  
• Diarrhea 
• loss of appetite. 
• vaginal yeast infection 
• skin itching and sensitivity to the sun 
• cough 
6.3 Reporting of Adverse Events: 
All adverse events will be recorded on the case report forms.  Serious adverse events 
forms must be completed and faxed to ESI clinical affairs within 3 days of knowledge of 

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the event.  Unanticipated adverse device effect and/or unanticipated adverse drug reaction 
forms must be completed and faxed to ESI Clinical Affairs within 24 hours of knowledge 
of the event.   
 
6.4 Data and Safety Monitoring Plan  
 
The ESI device was FDA approved in 2006 with no major morbidity or mortality 
reported to date. Further, its efficacy in preventing pregnancy is > 99%. [4] In over 300 
procedures performed at Mayo, no complications of insertion or removal have been 
noted. All practitioners involved in ESI insertion and removal have successfully 
completed the FDA mandated training. Further, the principal investigator and Co-
Investigators, Drs. Margaret Long, Abimbola Famuyide and Mary Marnach will monitor 
the safety of the subjects and are available on call 24 hours, 7 days a week. A review of 
the complications data will be performed after the enrollment of 50 patients; any 
unexpected complication or major complication will prompt the PI to notify the IRB. 
7.0  Ethical Considerations (Human Studies): 
Informed consent will be obtained in the Mayo standard written form. Since the 
interventions are a component of routine clinical practice, we do not anticipate any 
ethical issues or risks beyond what is currently deemed as acceptable for standard 
practice.  All insertion and removal procedures will be performed by practitioners who 
have completed the FDA mandated training program.  The risks of medical therapy are 
detailed in sections 6.2.2 and 6.2.3.  
 
7.1 Study Duration  
Patients will be offered enrollment in the study upon ESI insertion. They will begin 
completing weekly prospective symptom diaries at that time. If they report unacceptable 
bleeding at the time of study personnel contact at 13 weeks post ESI insertion or self-
report unacceptable bleeding at > 13 weeks post ESI insertion, they will be offered 
randomization to Doxycycline or placebo. They will continue prospective weekly 
symptom diaries for 26 weeks post randomization or until they discontinue study 
participation.  A patient who self-reports unacceptable bleeding late in the study interval 
will be followed for at least 13 weeks after randomized treatment in order to have a 
meaningful study conclusion.  The maximum study length for such a patient would be 52 
weeks from ESI insertion. Based on current numbers of ESI insertions per year, we 
anticipated that all 100 subjects with unacceptable bleeding will randomized within 
30 months. However, the rate of reported unacceptable bleeding was lower than 
expected and therefore we propose an additional enrollment of 120 patients (total 
470 patients) to achieve 100 randomized patients.  
 
8.0 Study Expectations and Limitations: 
 
This study is a double blinded placebo-controlled randomized prospective trial of 
Doxycycline for the management of ESI-related unacceptable bleeding.   The study will 
include US women regardless of BMI. Randomization will be done using a dynamic 

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allocation process with stratification by age, BMI and postpartum status.  This will avoid 
confounding effects of these variables on our outcomes. 
 
8.1   Limitation of a single center study  
We appreciate that the conduction of the study in one center may limit the external 
validity of results and may be associated with some referral selection bias 
 
Limitation of objectivity in the assessment of ESI-related bleeding 
In the assessment of bleeding and other ESI-related symptoms, we will ask patients to 
keep weekly prospective diaries of bleeding and use a well established system of 
bleeding pattern classification based on the WHO classification of clinical relevant 
bleeding patterns. We understand that unacceptable bleeding is inherently subjective but 
we believe that our method of weekly diary entries and analysis using the above 
mentioned classification will provide the maximal degree of objectivity and meaningful 
interpretation. Weekly recording will minimize recall bias while being practical and 
reasonable for patients. This represents the most rigorous methodology reported to date. 
 
8.2  Limitation relating to recall bias 
We expect some recall bias and late entries to the symptom diary.   
 
8.3 Limitation of discontinuation of study participation 
Patients may discontinue study participation and/or request ESI removal at any time. 
Additional patients may need to be enrolled in order to maintain adequate statistical 
power. However, we believe that lack on invasive procedures associated with the study 
and remuneration upon completion of each 13 week cycle of prospective diary and at 
study completion will provide a powerful incentive for women to enroll and to complete 
the study.  
 
8.4 Impact of Expected results 
The expectation of the study is that we will satisfy our hypotheses and find that 
• The failure of  treatment, assessed as the requiring additional treatment, in 
the Doxycycline group will be statistically significantly lower than in the 
placebo group (primary endpoint) 
• The rate of removal for bleeding at 13 and 26 weeks post-randomized treatment 
will be lower in the Doxycycline group as compared to the placebo group though 
it may not be statistically significantly lower given the expected removal rate [3] 
and study sample size. 
• The rate of patient satisfaction at 13 and 26 weeks post–randomized 
treatment will be statistically significantly higher in the Doxycycline as 
compared to the placebo group 
• The incidence of associated symptoms, adverse events and treatment associated 
events will be low and consistent with prior studies 
• No ESI-related contraceptive failures will be reported regardless of patient BMI. 
 
9.0 Future Directions 
 

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Following the completion of this trial and analysis of results, we plan to explore issues 
which we are not able to address with the proposed study. These will include 
implementation of ESI-related bleeding treatment guidelines and impact on method 
continuation, long term (up to 3 year) followup and treatment of ESI-related bleeding, 
counseling best practices relating to ESI-related bleeding as well as cost analysis of 
various medical treatments. 
 
10.0 Budget (attached separately) 
 
10.1 Budget Justification:  
 
10.1.1 Remuneration 
Patients will receive $25 after each interval of 13 weeks for completion of prospective 
symptom diary (and pill diary if applicable) and satisfaction survey.  Patients who 
discontinue study participation prior to completion of each 13 week set of diaries/ 
satisfaction survey, those who do not turn in all diaries/satisfaction survey or turn in 
incomplete diaries/satisfaction survey will not receive this remuneration.  Patients who 
complete the study will receive $50.00 upon receipt of final set of diaries, satisfaction 
survey and study coordinator clinic visit. 
Dr. Casey Principal Investigator  
• Proposal and associated material preparation 
• IRB approval process 
• patient consent, patient satisfaction surveys, bleeding diary preparation 
• study marketing within Mayo and to MHS sites 
• training and oversight of study personnel, troubleshooting 
• clinical appointments for concerns 
• progress report preparation 
• data analysis 
• manuscript preparation/submission/revision  
 
Dr. Long Co-Investigator  
• study marketing within Mayo and to MHS sites 
• training and oversight of study personnel, troubleshooting 
• clinical appointments for concerns 
Study coordinator  
 
• Patient Consent & Enrollment  
• (available on-call for routine GYN clinic, scheduled for women responding to 
advertising) 
• Available for phone contact by subjects throughout the study (triage of subject 
concerns) 
• Phone contacts at 13 weeks for all subjects (450+) 
• Clinic visits for “unacceptable bleeding” and randomization (150+) 
• Phone contact at 26 weeks for all subjects 
• Clinic visit at 39 weeks for all subjects 

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• Potential additional post-39 week phone contact for limited # subjects with late 
randomization 
 
• Baseline - Consent form copying & scanning 
• Baseline – data collection / case report form completion  
• Subject education re: diary completion, study plan, subject responsibilities 
• Collection of subject diaries at 13 – 26 – 39 weeks 
• Assessing treatment compliance for randomized and secondary treatment 
• Satisfaction surveys at 13 – 26 – 39 weeks 
• Documentation of study participation, randomization, and follow-up in medical 
record  
• Data entry into electronic database (clinical data, diary data, satisfaction survey 
data) 
• Maintain subject binders / folders (150+ complex and 300+ simple) 
• Organize and develop system for follow-up visits and phone calls 
• Scheduling of follow-up visits (prefer to have support of the PAC office)  
• Remuneration for all subjects 
 
• Consent form development 
• Initial IRB submission 
• Annual IRB progress reports 
• Data collection / case report form development  
• Randomization and Electronic database development  
• Maintain regulatory binders 
 
Family Medicine / Primary Care and Mayo Clinic Health System Enrollment 
• Develop a plan for consenting 
• Develop a plan for data collection at baseline 
• Develop a system for follow-up  
• Develop a plan for diary collection 
• Develop a plan for randomization 
• Develop a plan for dispensing study treatment medication 
• Study Training for MCHS personnel  
 
 
11.0 Patient Consent Form (attached separately) 
 
12.0 References 
 
 [1]Funk S, Miller MM, Mishell DR Jr. et al. Safety and efficacy of Implanon, a single-
rod implantable contraceptive containing etonogestrel. Contraception 2005; 71:319-26. 
[2]Mansour D, Korver T, Marintcheva-Petrova M et al. The effects of Implanon on 
menstrual bleeding patterns. Eur J Contracept Report Health Care 2008; 13 (Supp 1):13-
28. 

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[3] Casey PM, Long ME, Marnach ML et al. Bleeding related to etonogestrel subdermal 
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[19]. Cicinelli E, De Ziegler D, Nicoletti R, Colafiglio G, Saliani N, Resta L, et al. 
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[20].Li R, Luo X, Archer DF, Chegini N. Doxycycline alters the expression of matrix 
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