Clinical trial NCT02903121
Conditions: Bleeding Implants Breakthrough Bleeding
Keywords: Unscheduled bleeding Long acting contraception
Sponsor: Oregon Health and Science University
Start date: 2017-01-20; Completion date: 2019-06-05
Enrollment: 109 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The etonogestrel (ENG) subdermal contraceptive implant (ENG implant) is a highly effective method of preventing pregnancy, but it has bleeding side effects that make it unappealing for many women. The only study to demonstrate a sustained reduction in bleeding lasting for two months was the selective estrogen receptor modulator (SERM) tamoxifen in users of the levonogestrel (LNG) contraceptive implant. Based on the investigators encouraging preliminary data of tamoxifen and ENG implant users, the investigators plan to perform additional studies on the impact of tamoxifen on the breakthrough bleeding experience by ENG implant users.

Detailed description:
The investigators will perform a 2 phase trial for treatment of women experiencing frequent or prolonged bleeding while using the ENG contraceptive implant. The first phase will consist of a randomized, controlled, double blind placebo-controlled clinical trial over a 90-day reference period and the second phase will allow both study arms to receive open-label treatment over an additional 90-day reference period. The primary outcome of the study will be the total number of consecutive bleeding-free days in first 30 days from Day 1 of first treatment (TX1).

Arms: arm 1: Tamoxifen 10 mg (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding arm 2: Placebo (oral) twice daily for 7 days to be started following 3 consecutive days of bleeding
Interventions: intervention 1: Tamoxifen intervention 2: Placebo intervention 3: Tamoxifen (open label)
Intervention descriptions: intervention 1: Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study intervention 2: Placebo orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the first 90 days of the study intervention 3: Tamoxifen 10 mg orally twice daily for 7 days. Treatment to be started after 3 consecutive days of bleeding and can be repeated every 30 days two more times in the second 90 days of the study

Protocol documents:
Prot_001.pdf: 
PI Edelman, A                                   Implant Breakthrough Bleeding 
1 
 
Official title: Treatment of unfavorable bleeding patterns in contraceptive implant users 
 
Principal Investigator: Alison Edelman, MD, MPH 
 
NCT No. 02903121 
 
Protocol Version Date August 7, 2019 
 


PI Edelman, A                                   Implant Breakthrough Bleeding 
2 
 
Title: Treatment of unfavorable bleeding patterns in contraceptive implant users 
1 
 
2 
PI: Alison Edelman, MD, MPH 
3 
Oregon Health & Science University 
4 
3181 SW Sam Jackson, UHN 50 
5 
Portland, OR 97239 
6 
503-418-2585 
7 
edelmana@ohsu.edu 
8 
 
9 
Co-I: Jeffrey Jensen, MD, MPH 
10 
Marci Messerle Forbes, FNP 
11 
Andrea O’Donnell, FNP 
12 
 
13 
Funder: Merck Women’s Health Investigator Initiated Studies Program 
14 
 
15 
Background: 
16 
The etonogestrel (ENG) subdermal contraceptive implant (ENG implant) is a highly effective 
17 
method of preventing pregnancy, but it has bleeding side effects that make it unappealing for 
18 
many women. Given that the ENG implant is 20 times more effective at pregnancy prevention 
19 
than oral contraceptive pills, strategies to increase its acceptability will translate into improved 
20 
prevention of unplanned pregnancies [1].  Many medications have been studied with progestin-
21 
only contraceptives such as the ENG implant to manage irregular bleeding.  The only study to 
22 
demonstrate a sustained reduction in bleeding lasting for two months was the selective estrogen 
23 
receptor modulator (SERM) tamoxifen in users of the levonogestrel (LNG) contraceptive implant 
24 
[2].  We conducted a small clinical trial to evaluate the effects of a 7-day course of tamoxifen in 
25 
users of Nexplanon© with bothersome breakthrough bleeding, and have preliminary data that 
26 
demonstrates that tamoxifen treatment reduces bleeding/spotting days during the first 30 days 
27 
after use as compared to placebo [3]. This sustained post-treatment effect is novel, as prior 
28 
studies of agents such as combined oral contraceptives have only demonstrated improvement 
29 
in bleeding patterns while on treatment.  Further study is needed to determine if our results are 
30 
reproducible in a larger population, and whether the treatment response will be maintained with 
31 
repeat dosing if needed.  
32 
 
33 
[1] 
Winner B, Peipert JF, Q Z, C B, Madden TE, Allsworth JE, et al. Effectiveness of Long-
34 
Acting Reversible Contraception. New England Journal of Medicine 2012;366:1998–
35 
2007. 
36 
[2] 
Abdel-Aleem H, Shaaban OM, Amin AF, Abdel-Aleem AM. Tamoxifen treatment of 
37 
bleeding irregularities associated with Norplant use. Contraception 2005;72:432–7. 
38 
[3]         Simmons K, Edelman A, Fu Rochelle, Jensen JT. A short course of tamoxifen reduces 
39 
unscheduled bleeding in etonogestrel contraceptive implant users. Obstet Gynecol 
40 
2016; 127. (Abstract) 
41 
 
42 
Hypothesis: 
43 
1) In etonorgestrel (ENG) users with troublesome bleeding, a 7-day treatment with 10 mg 
44 
tamoxifen twice daily will result in a significantly longer bleeding-free interval than 
45 
placebo. 
46 
2) In etonorgestrel (ENG) users with troublesome bleeding, a 7-day treatment with 10 mg 
47 
tamoxifen twice daily repeated no sooner than every 30 days if troublesome bleeding 
48 
reoccurs will result in significantly fewer bleeding/spotting days and significantly longer 
49 
bleeding-free intervals over the next 30 days than placebo. 
50 
 
51 


PI Edelman, A                                   Implant Breakthrough Bleeding 
3 
 
Objectives: 
52 
To identify a successful treatment for troublesome bleeding and spotting in users of the ENG 
53 
contraceptive subdermal implant. 
54 
 
55 
Primary objective: 
56 
1. Total number of consecutive bleeding-free days in the first 30 days from Day 1 of 
57 
first treatment (TX1) 
58 
 
59 
Secondary objectives: 
60 
1. First 90-day reference period outcomes between treatment and placebo (double 
61 
blind placebo-controlled RCT): 
62 
a) Total number of bleeding/spotting days in the first 30 days post-Day 1 of TX1, TX2, 
63 
and TX3 
64 
b) Total number of days to bleeding cessation after Day 1 of TX1, TX2, TX3 
65 
c) Total number of TX (1-3) taken during the first 90-day referent period 
66 
d) Total number of bleeding free days and bleeding/spotting days over the first 90-day 
67 
reference period (starting from Day 1 of TX1) 
68 
e) Length of time (days) between each treatment. 
69 
2. Second 90-day reference period outcomes between ongoing treatment and 
70 
placebo now using active treatment (open label): 
71 
a) Total number of bleeding/spotting days in the first 30 days post-Day 1 of TX4, TX5, 
72 
and TX6 
73 
b) Total number of days to bleeding cessation after Day 1 of TX4, TX5, TX6 
74 
c) Total number of TX (4-6) taken during the first 90-day referent period 
75 
d) Total number of bleeding free days and bleeding/spotting days over the first 90-day 
76 
reference period (starting from Day 1 of TX4) 
77 
e) Length of time (days) between each treatment. 
78 
3. Overall outcomes:  
79 
a) Drop out  
80 
b) Patient satisfaction with bleeding pattern 
81 
c) Continuation of implant or anticipation of continuation 
82 
d) Side effects 
83 
e) Total number of bleeding free days and bleeding/spotting days over 180 days (2 
84 
reference periods; starting from Day 1 of TX1) 
85 
f) Stratification of primary and secondary bleeding and bleeding-free analyses by time 
86 
of implant use (6mos, 1 year, 2 years, 3 years). 
87 
 
88 
**Of note, maximal number of potential treatments is 3 during each 90-day reference period. 
89 
However, subjects can initiate TX on the last day of the reference period.  Any outcome related 
90 
to TX initiated less than 30 days from end of study (Day 180 from initiation of TX1) will be 
91 
curtailed at 180 days. Any subject taking study medication 7-days prior to Day 180 or Day 180 
92 
will be scheduled for an end of visit contact one week after TX completion to ensure patient 
93 
safety and capture AE data. 
94 
 
95 
Study design/Clinical Plan: 
96 
We are proposing a 2 phase trial for treatment of women experiencing frequent or prolonged 
97 
bleeding while using the ENG contraceptive implant.  The first phase will consist of a 
98 
randomized, controlled, double blind placebo-controlled clinical trial over a 90-day reference 
99 
period and the second phase will allow both study arms to receive open-label treatment over 
100 
an additional 90-day reference period.  
101 
 
102 


PI Edelman, A                                   Implant Breakthrough Bleeding 
4 
 
The primary outcome of the study will be the total number of consecutive bleeding-free days in 
103 
first 30 days from Day 1 of first treatment (TX1).  The study has a number of secondary 
104 
outcomes (see above, study objectives) focused around the efficacy of oral tamoxifen to: 1) stop 
105 
an episode of bleeding/spotting and for how long; 2) to stop recurrent episodes of 
106 
bleeding/spotting with repeat dosing; and 3) to determine if total number of bleeding/spotting 
107 
days are decreased over each reference period and over the entire study period (approximately 
108 
180 days from ingestion of first treatment).  
109 
 
110 
In phase 1, the intervention will consist of study drug exposure (tamoxifen or placebo) twice 
111 
daily for 7 days. The first dose will be taken when subjects experience at least three consecutive 
112 
days of bleeding/spotting.  Repeat dosing will occur no sooner than 30 days after starting TX.  
113 
Participants can dose up to 3 times in each 90-day reference period. Subjects will be eligible for 
114 
TX if they experience recurrent bleeding/spotting of 3 or more consecutive days. Subjects can 
115 
initiate a TX on the last day of a reference period.  
116 
 
117 
In phase 2, all subjects will enter an open label treatment period over the next 90 days.  The 
118 
intervention will consist of the same study drug exposure as Phase 1 (tamoxifen twice daily for 7 
119 
days).  The first dose will be taken when subjects experience at least three consecutive days of 
120 
bleeding/spotting but no sooner than 30 days after starting the last TX. Participants can dose up 
121 
to 3 times in this 90 day reference period.  Subjects can initiate a TX on the last day of a 
122 
reference period. ; however outcomes related to bleeding patterns will be curtailed at Day 180 
123 
from initiation of TX1). Any subject taking study medication 7-days prior to Day 180 or Day 180 
124 
will be scheduled for an end of visit contact one week after TX completion to ensure patient 
125 
safety and capture AE data. 
126 
 
127 
The study will be conducted at Oregon Health & Science University (OHSU) in Portland, Oregon 
128 
and the University of Hawaii (UH), Manoa. OHSU IRB will oversee regulatory procedures at UH.  
129 
 
130 
Each subject’s involvement will be approximately 180 days from Day 1 of TX1 and will require 
131 
up to 8 in-person study visits (screening, enrollment plus monthly visits scheduled based on 
132 
Day1 of TX1 and a close out visit), as well as a daily response to a text or email message about 
133 
bleeding and use of study medication. Depending on the delay between study enrollment and 
134 
Day 1 of TX1, additional phone and email contact may occur with the participant to ensure 
135 
clarity of when to start study drug.  The electronic diary only takes a few seconds to complete. If 
136 
the participant does not respond to the diary on any given day, then they will receive a call or 
137 
email from the study coordinator to check in.  Additionally, if the participant reports 3 
138 
consecutive days of bleeding and does not report taking study drug, they will receive a call or 
139 
email from the study coordinator.    
140 
 
141 
Eligibility: 
142 
Inclusion:  
143 
 
English speaking women 15-45 years of age currently using the ENG implant who have 
144 
experienced frequent or prolonged bleeding while using the device:  
145 
o To be eligible, women will need to have >7 days of continuous bleeding/spotting 
146 
in the last 30 days, OR 2 or more episodes of bleeding/spotting in the last 30 
147 
days.  
148 
 
Implant use for at least 1 month  
149 
 
Willing to continue using the implant for at least six months from study enrollment.  
150 
 
Access to a reliable cell phone and must be willing to receive and respond to a daily text 
151 
or email message to assess bleeding and use of study drug   
152 


PI Edelman, A                                   Implant Breakthrough Bleeding 
5 
 
 
Implant must be palpable to prove that an ENG implant is in place at time of screening 
153 
and enrollment. 
154 
 
Negative gonorrhea/chlamydia screening performed at screening visit 
155 
 
156 
Exclusion criteria:  
157 
 
Postpartum within six months 
158 
 
Post-abortion within six weeks 
159 
 
Currently pregnant 
160 
 
Currently breast-feeding (to be eligible, must be 4-6 weeks from cessation of 
161 
breastfeeding) 
162 
 
Undiagnosed abnormal uterine bleeding pre-dating placement of contraceptive implant 
163 
 
Bleeding dyscrasia 
164 
 
Anticoagulation use 
165 
 
Active cervicitis 
166 
 
Allergy to tamoxifen 
167 
 
History of venous thromboembolism 
168 
 
Current or past breast or uterine malignancy 
169 
 
Use of medication contraindicated with tamoxifen including: 
170 
o coumadin, letrozole, bromocriptine, rifampicin, aminoglutethimide, phenobarbital 
171 
o All contraindicated medications listed in the consent form 
172 
 
Implant is due to be switched out in 4 months or less from enrollment (It is acceptable if 
173 
their implant is due to be switched out in 5-6 months from enrollment as long as subject 
174 
agrees to keep it in place while on study for approximately 6 months) 
175 
 
Currently using oral contraceptives in addition to implant (to be eligible, needs to have a 
176 
4-6 week washout period) 
177 
 
Prior pregnancy occurred while Nexplanon/Implanon was in place 
178 
   
179 
Study procedures 
180 
 
181 
Screening (Visit 1, V1). Estimated 1 hour 
182 
Eligibility and study consent will be signed at this visit. Baseline demographic information will be 
183 
collected by interview, including menstrual history, contraception history including timing of 
184 
implant placement, sexual and pregnancy history, BMI/weight, ethnicity, age, and baseline use 
185 
of panty liners (as advised by Mishell et al 2007 to avoid confounding data on bleeding/spotting 
186 
days).  A series of questions will be asked to quantify number of bleeding and spotting days and 
187 
frequency and duration of bleeding episodes over the preceding three months of implant use (or 
188 
since placement, if less than three months).  Current implant use will be confirmed via palpation.  
189 
 
190 
Physical exam including blood pressure check, pelvic examination, urine pregnancy test, 
191 
cervical cytology evaluation (if not completed within the ASCCP recommended screening 
192 
interval), and testing for gonorrhea and chlamydia.  A baseline assessment of satisfaction with 
193 
baseline bleeding pattern will also be performed.  
194 
 
195 
Once negative results from the subject’s gonorrhea and chlamydia testing are demonstrated, 
196 
visit 2 can be scheduled (enrollment). 
197 
 
198 
Enrollment (V2), estimated 30 minutes 
199 
Randomization for part 1 of the study will occur at this visit. Pregnancy test and blood pressure 
200 
will be performed. The Subject Study Drug Information Handout will be provided and explained. 
201 
Study drug will be provided. At this visit if the subject happens to currently be bleeding, the 
202 


PI Edelman, A                                   Implant Breakthrough Bleeding 
6 
 
coordinator will have the woman fill out this information on a paper diary.  If she has had 3 
203 
consecutive days of bleeding, then study drug can be started immediately at this visit. If she has 
204 
only had 1 or 2 days, this will be noted on the paper diary and the study coordinator will explain 
205 
the earliest day that she could start the study drug and instruct how to start tracking bleeding via 
206 
text message.  
207 
 
208 
Subjects will receive training on the use of the electronic bleeding diary procedures.  This 
209 
includes instruction on use of the text or email message bleeding diary.  
210 
 
211 
Follow up Visits 3 to 7, estimated 30 minutes each   
212 
The third, fourth, fifth, sixth, and seventh study visits will take place approximately14-25 days 
213 
after the start of study drug. Follow-up visits may need to occur outside of this range due to 
214 
scheduling reasons, but every effort will be made to conduct a study visit within the 14-25 day 
215 
range OR prior to the date when the next study drug bottle can be started.  Follow-up visits will 
216 
occur approximately every 30 days if participant does not need to take the study drug. At these 
217 
visits, bleeding diary will be reviewed with study staff as well as review of medications, AEs, and 
218 
health changes.  Repeat STI testing only if indicated by a change in partners during the study.  
219 
A short satisfaction questionnaire will be performed at study visit 3 and 5. Next dose of study 
220 
drug will be provided.  Unused study drug will be retuned at these visits.   
221 
 
222 
End of study, Visit 8, estimated 30 minutes 
223 
The final visit will take place approximately 180 days after the first day of study drug.  After this 
224 
final visit, participation is complete.  Blood pressure will be performed. 
225 
 
226 
Visit 
Details 
Visit 1-Screening 
 
Informed consent 
 
Review medications 
 
Physical exam with vitals (blood pressure, pulse, 
weight, height)  
 
Urine pregnancy test 
 
Review eligibility criteria 
 
Gonorrhea and chlamydia test 
 
Pap (if indicated) 
 
Baseline questionnaire 
Visit 2-7 
(Visit 2 – enrollment visit) 
(Visit 5 – transition to open-
label) 
 
 
Review bleeding diary with staff 
 
Review medications 
 
Receive placebo or study drug and instructions 
 
Return any unused medication 
 
Blood pressure- Visit 2 only) 
 
Review any health changes 
 
Urine pregnancy test if indicated 
 
Repeat Gonorrhea and chlamydia test if change in 
partner occurs during study. 
 
Questionnaire at visit 3 and 5 
Visit 8- end of study 
 
Review medications 
 
Return any unused medication 
 
Vitals (blood pressure, pulse, weight, height) 
 
Review bleeding diary with staff 
 
Review health changes 


PI Edelman, A                                   Implant Breakthrough Bleeding 
7 
 
 
Exit questionnaire 
Description of intervention/study drug 
227 
Participants will be instructed to begin use of the study medication (tamoxifen 10 mg bid x 7 
228 
days or placebo) on the third day of their next bleeding or spotting episode, and continue to take 
229 
a twice daily oral dose for seven days. The day of treatment will be reference period day 1.  
230 
Subjects will self-initiate subsequent study medication for additional qualifying bleeding 
231 
episodes (3 days of bleeding/spotting) no sooner than 30 days after the first treatment (ref 
232 
period day 30).  A study coordinator will prospectively following electronic bleeding diaries at a 
233 
minimum of three times weekly for each individual study subject and will prompt subjects to 
234 
initiate a treatment course if they are eligible. Subjects reporting at least 3 consecutive days of 
235 
current bleeding at the time of study entry/randomization will be instructed to begin the study 
236 
medication immediately.  In each 90-day reference period, subjects can repeat dosing up to 3 
237 
times.  Subjects will receive one bottle of 14 pills at the start of the study, and then additional 
238 
bottles at follow up visits.  Any unused study drug will be counted and returned at each visit, and 
239 
again at the conclusion of the study.  
240 
 
241 
Failure to complete the texting diary will prompt a phone call from the SC. If we are unable to 
242 
reach a subject by phone, email, letter, or facebook (facilitated only via private message) over a 
243 
2 week time period, their participation will be terminated. Any data obtained up to this point will 
244 
be analyzed in accordance to with intention to treat. 
245 
 
246 
Study procedures and data collection other than side effects and AEs will last 180 days from 
247 
Day 1 of TX1. Participants who do not initiate study drug within the first 30 days of enrollment 
248 
will be discontinued. Any subject taking study medication 7-days prior to Day 180 or Day 180 
249 
will be scheduled for an end of visit contact one week after TX completion to ensure patient 
250 
safety and capture AE data 
251 
 
252 
Compensation 
253 
Participants will be compensated up to $400 for their participation in this study. Study visit 
254 
compensation breakdown is as follows: 
255 
 
Visit 1- Screening:                           $25 
256 
 
Visit 2- Enrollment:                          $25 
257 
 
Visit 3-8:                                          $30/each visit 
258 
 
End of study bonus                          $70 
259 
 
Diary Completion:                            $100 
260 
 
261 
Subjects will only be compensated for the visits they complete. For example, if a subject 
262 
withdraws after visit 3, they will only be compensated for those three visits ($25 + $25+$30). 
263 
Participants will only receive the $70 end of study bonus if they complete all eight study visits.   
264 
Diary compensation 
265 
Diary completion is defined as responding to 2 daily text messages every day. A subject can 
266 
miss up to 2 days of responses per month and still receive diary compensation for the month. If 
267 
a subject misses 3 or more days of diary entry in a given month, they will not receive 
268 
compensation for that month. Study coordinators will be tracking diary responses, and response 
269 


PI Edelman, A                                   Implant Breakthrough Bleeding 
8 
 
rates for the previous month will be reviewed at each visit. A $40 bonus will be given at the end 
270 
of the study to subjects who have adequately completed their diaries each month. Diary 
271 
compensation will be prorated per visit as follows: 
272 
 
Diary @ Visit 3- $10 
273 
 
Diary @ Visit 4- $10 
274 
 
Diary @ Visit 5- $10 
275 
 
Diary @ Visit 6- $10 
276 
 
Diary @ Visit 7- $10 
277 
 
Diary @ Visit-8: $10 
278 
 
End of study diary bonus: $40 
279 
If a subject withdraws early from the study, they will only receive compensation for visits that 
280 
they have completed  
281 
Alternative approaches: 
282 
We could use a different SERM and/or change the way we define study entry or treatment 
283 
initiation. The study medication and current research methods are based on our pilot study as 
284 
well as the published literature.  Only tamoxifen has been studied for treatment of unscheduled 
285 
bleeding in implant users. We believe its impact is due to its effect on estrogen receptor β 
286 
(ERβ); newer SERMs have less selectivity for ERβ [1].  
287 
 
288 
In regard to study eligibility (>7 days of bleeding/spotting or 2 episodes/30 days), we want to 
289 
enroll the average woman with an “annoying” bleeding pattern and not the woman likely moving 
290 
toward implant removal as this would impact our dropout rate. And finally, initiation of study 
291 
medication could occur at >3 days but we believe that women significantly impacted by their 
292 
bleeding patterns will want to initiate treatment as soon as possible. More stringent starting rules 
293 
might adversely impact continuation in the study.  We could also be more liberal in defining 
294 
when to initiate treatment. For instance, recommending medication initiation when 
295 
bleeding/spotting occurs the majority of days per week but not continuously (e.g. 2 days of 
296 
bleeding/spotting – 1 day of no bleeding/spotting – 2 days of bleeding/spotting).  This pattern of 
297 
bleeding is still likely to be unpleasant for women but using an additional criterion for initiation 
298 
may make correct drug initiation more complicated. In our prior study, we used 3 days of 
299 
consecutive bleeding to trigger treatment initiation and that approach has also been used in 
300 
prior studies.  
301 
 
302 
[1]          Komm BS, Mirkin S. An overview of current and emerging SERMs. J Steroid Biochem 
303 
Mol Biol 2014; 143:207-22. 
304 
 
305 
Sample size 
306 
Our primary outcome is the total number of consecutive bleeding-free days between tamoxifen 
307 
and placebo groups following TX1 (starting from Day 1 of treatment until 30 days hence).  
308 
 
309 
Based on our pilot work, a sample size of 80 women allows us to demonstrate a 15-day 
310 
difference between groups [mean tamoxifen 28.8 (SD 24.5) versus placebo 13.6 (SD 19.2)]; 
311 
86% power at an alpha 0.05 = 40 women per each group. To account for drop out, we have 
312 
increased the sample size by approximately 30% for a total sample size of 116. This sample 
313 
size will also provide us with sufficient power to determine the difference in several of our 
314 


PI Edelman, A                                   Implant Breakthrough Bleeding 
9 
 
secondary outcomes including a difference of at least 1 treatment course used in a 90-day 
315 
period and a 12-day difference in amenorrhea over a 90-day reference period.  
316 
 
317 
Study drug 
318 
Tamoxifen is a nonsteroidal agent with antiestrogenic properties.  Following an oral dose of 
319 
20mg, peak plasma concentration occurs about five hours after dosing.  The elimination half life 
320 
is 5-7 days (Package insert).  Administration of 10mg tamoxifen given twice daily for three 
321 
months results in average steady-state plasma concentration of 120ng/ml, which occurs after 
322 
four weeks of continuous dosing.  After oral administration, tamoxifen undergoes metabolism to 
323 
its primary N-desmethyl tamoxifen metabolite, which has similar biologic activity to tamoxifen.  It 
324 
is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and is an inhibitor of P-glycoprotein.  
325 
Excretion is primarily fecal (Package insert).   
326 
 
 
327 
Tamoxifen is approved by the US Food and Drug Administration at doses of 20-40mg daily 
328 
(divided dosing twice daily) and is primarily utilized for its antiestrogen properties as an adjuvant 
329 
therapy to prevent recurrence of estrogen receptor (ER) positive breast carcinoma in post 
330 
menopausal women following mastectomy, axillary dissection and breast irradiation. It is also 
331 
approved to reduce the incidence of breast cancer in high risk women (those with a 5 year 
332 
predicted risk over 1.67% according to the Gail Model.  Usual dose and duration of therapy is 
333 
20-40mg daily taken for up to five years.  
334 
 
335 
When tamoxifen has been used previously at a dose of 10mg twice daily for 10 days in 
336 
premenopausal women as a treatment for progestin-inducted bleeding, side effects were rare 
337 
and did not differ between treatment and placebo. The most common reported effect was 
338 
headache, reported in up to 20% of users [1].  Our pilot study of 10mg twice daily for 7 days in 
339 
premenopausal women (n = 56) as a treatment for irregular bleeding due to the contraceptive 
340 
implant resulted in no serious adverse events. In addition, we also tracked evidence of ovulation 
341 
in a subgroup of participants and no participant demonstrated evidence of ovulation (e.g. no 
342 
evidence of tamoxifen interfering with implant effectiveness) [2].  
343 
 
344 
There are reported serious adverse effects from long term tamoxifen use, but the short course 
345 
of therapy in this study is unlikely to result in any of these adverse events.  Risks with longer 
346 
term use of tamoxifen may include endometrial changes such as hyperplasia, polyps, or 
347 
malignancy, risk of venous thromboembolism, stroke or ovarian cysts.  Of note, venous 
348 
thrombosis events were not reported until at least two consecutive months of use.  Likewise, an 
349 
increased risk of endometrial cancer has only been demonstrated in postmenopausal women 
350 
with use between 1 and 61 months.  Increased incidence of endometrial hyperplasia and polyps 
351 
have been reported only in postmenopausal women.  A few reports of fibroids, endometriosis, 
352 
and ovarian cysts have been observed in a small number of premenopausal women with 
353 
advanced breast cancer receiving tamoxifen (Package insert).  
354 
 
355 
Use of tamoxifen for this study is exempt from the requirements to submit an Investigational 
356 
New Drug application to the FDA.  This study is not intended to be used for support of new FDA 
357 
indication for use or labeling for tamoxifen. This study is also not intended to support a 
358 
significant change in advertising for tamoxifen. Lastly, this study does not use a route of 
359 
administration or dosage level that is known to significantly increase the risks associated with 
360 
use of tamoxifen.  
361 
 
362 
[1] Abdel-Aleem H, Shaaban OM, Amin AF, Abdel-Aleem AM. Tamoxifen treatment of bleeding 
363 
irregularities associated with Norplant use. Contraception 2005;72:432 
364 
 
365 


PI Edelman, A                                   Implant Breakthrough Bleeding 
10 
 
[2] Simmons K, Edelman A, Fu Rochelle, Jensen JT. A short course of tamoxifen reduces   
366 
unscheduled bleeding in etonogestrel contraceptive implant users. Obstet Gynecol 2016; 127.  
367 
(Abstract).  Paper under review. 
368 
 
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Risks to Subjects  
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Human Subjects Involvement and Characteristics 
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Reproductive-aged (15-45 year old), healthy women currently using a contraceptive implant with 
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no contraindications to the study medication and not at risk for or seeking pregnancy will 
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constitute the target population for this study.  
374 
 
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All enrollment and clinical evaluations will be performed at OHSU in Portland, Oregon.  
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Gonorrhea and chlamydia testing and pap testing (if indicated) will be sent to the OHSU core 
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lab for routine processing.  
378 
 
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Sources of Materials 
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The sources of research material for the clinical portion of this proposal will be new specimens 
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obtained purely for this research protocol.  The study investigators and/or research 
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assistants/nurses will perform all study procedures.   
383 
 
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Potential Risks 
385 
One risk to taking part in this study is that the study drug may not be effective in helping to treat 
386 
bleeding.  
387 
 
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The study drug has few side effects and is considered safe by the FDA.  Fewer than 20% of 
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people experience any side effects.  The most common are headache, upset stomach, or 
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fatigue.  There are risks associated with long-term use of the study drug, especially in women 
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after menopause.  These include risk of blood clots, stroke or pre-cancer in the uterus.  
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Because participants are only using the study drug for one week at a time, these risks should 
393 
not apply to the participants.  Rarely women develop ovarian cysts with long-term use of the 
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study drug.  These go away when the drug is stopped.   
395 
 
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The study drug has been used before in women using the contraceptive implant. There is a 
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small possibility that the study drug might make the contraceptive implant less effective but our 
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prior study demonstrated no evidence of increased ovulatory activity following study drug use.   
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There is a small possibility that subjects could become pregnant while participating in this study.   
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The implant does not cause harm to a developing pregnancy.  However, the study drug should 
401 
not be taken during pregnancy.  If subjects are nursing an infant or are pregnant now, they 
402 
cannot be in the study.  This study drug may involve risks to an embryo, fetus, or nursing infant 
403 
that are currently unknown. If pregnancy occurs during the research study, study participation 
404 
would be discontinued, determination of exposure to study drug would be determined, and the 
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PI would provide the subject with counseling and referral.   
406 
 
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Some parts of the study may be inconvenient including the text messaging to collect data.  
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These are regular text or email messages and will count towards text messages or data on a 
409 
subject’s cell phone plan.  The Subject will be asked detailed questions about her bleeding and 
410 
gynecologic history.  Some of these questions may seem very personal or embarrassing.  
411 
Women may refuse to answer any of the questions that they do not wish to answer.  
412 
 
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Adequacy of Protection Against Risk 
414 
Recruitment and Informed Consent 
415 


PI Edelman, A                                   Implant Breakthrough Bleeding 
11 
 
Attempts to enroll a diverse study population will be made through placement of IRB approved 
416 
flyers in the community, community outreach (radio and print ads) and through the availability of 
417 
foreign language interpreters and research staff (see Inclusion of women and minorities).  
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Women may also learn of the study through their routine visits in clinics or by working at OHSU. 
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We also intend to utilize an EPIC Cohort search to identify and contact potential participants via 
420 
phone, email, letter, and/or MyChart messages. We intend to use REDCap for batch emailing. 
421 
We also intend to use Trialspark and Google AdWords as well as Facebook and Instagram for 
422 
community outreach. 
423 
 
424 
 Women will be screened for eligibility and if they meet the basic criteria and agree to 
425 
participate, they will undergo informed written consent. The protocols and consent will be 
426 
reviewed and approved by the OHSU IRB prior to initiation of the study. 
427 
 
428 
Protection Against Risk 
429 
The drug utilized in this study will be used in accordance with the FDA and at a dosage that is 
430 
still considered to be safe.  Women will be informed of this off-label dosing but that we have 
431 
specifically chosen a dose and length of exposure time to the drug or compound with extremely 
432 
low potential for significant side effects or serious risks. Women will undergo screening for any 
433 
known contraindications to the study drugs chosen to trial in women.   
434 
 
435 
Confidentiality of personal health information will be maintained according to HIPAA 
436 
requirements for research.  All subjects will receive a study number to which all subsequent 
437 
data will refer.  Personal identifiers will not be on questionnaires, data, abstract sheets, or in the 
438 
main database.  All data will be kept in locked files or a password protected computer in the 
439 
Principal Investigator’s (PI) office.  
440 
 
441 
Data and safety monitoring of plans for clinical trials 
442 
The PI and study staffs are responsible for recording the data, and they will be verifying its 
443 
accuracy throughout the process. The PI will be reviewing the data in-depth upon completion of 
444 
the study.  The PI will also be overseeing that the study procedures are being carried out as per 
445 
the approved protocol via close supervision of study visits and procedures and through frequent 
446 
communication with the study staff. The PI will also be conducting an initial assessment and 
447 
periodic assessments of the study and its procedures. If any safety concerns arise, a data 
448 
safety monitoring board will be convened to review the study.  As this study will be performed in 
449 
conjunction with the Women’s Health Research Unit’s (WHRU), an independent chart audit to 
450 
ensure data integrity and completeness will be performed after the first 5 subjects have been 
451 
enrolled and then at regular 6 months intervals.     
452 
 
453 
The PI will adhere to OHSU’s Institutional Review Board (IRB) policies regarding protection of 
454 
human subjects and the reporting of study deviations and adverse events. In the rare case of an 
455 
adverse event, she will utilize the WHRU data safety monitoring board (DSMB) to review the 
456 
event and rule on a course of action. The WHRU DSMB is made up of individuals 
457 
knowledgeable about women’s reproductive health and therapies and will have no conflict of 
458 
interest with the study or its outcomes.  
459 
 
460 
Data Storage 
461 
Data for this project will be stored in OCTRI's installation of REDCap, a highly secure and robust 
462 
web-based research data collection and management system. 
463 
Features of REDCap that protect participants' privacy and data security include: 
464 


PI Edelman, A                                   Implant Breakthrough Bleeding 
12 
 
o 
Physical Security: OCTRI's REDCap software is housed on servers located in ITG's 
465 
Advanced Computing Center providing locked physical security 
466 
o 
Electronic Security: The REDCap servers are housed behind both the OHSU firewall 
467 
and a second ACC firewall.  All web-based data transmissions are encrypted with 
468 
industry-standard SSL methods.   
469 
o 
Controlled User Access: REDCap is employs a robust multi-level security system that 
470 
enables researchers to easily implement "minimum necessary" data access for their 
471 
research staff, including specification of data fields that are identifiers. This feature 
472 
includes “single click” ability to provide completely deidentified (removing all identified 
473 
data fields and shifting dates) for analysis or other purposes.  User activities are 
474 
logged to enable auditing of all data access.   Access is integrated with OHSU's 
475 
network such that users who are also OHSU employees are authenticated against 
476 
their OHSU network credentials.   
477 
o 
Data Integrity: REDCap is jointly managed in accordance with OHSU Information 
478 
Security Directives by ACC staff and members of OCTRI's Biomedical Informatics 
479 
Program, ensuring fidelity of database configuration and back-ups.  User activities are 
480 
logged to enable auditing of all data changes. 
481 
Data Sharing 
482 
 
483 
We intend to use “Box” to share study documents and spreadsheets between study sites.  
484 
 
485 
Potential Benefits of the Proposed Research to the Subjects and Others 
486 
There are no direct benefits to study participants. 
487 
 
488 
Importance of Knowledge to be Gained 
489 
This study will increase the knowledge regarding breakthrough bleeding and contraceptive 
490 
implants.  It may help to prolong continuation of contraceptive implant use which in turn could 
491 
help women avoid unplanned pregnancies.  It may go beyond the treatment of a problem, but 
492 
also help in provide the potential mechanism of action and other possible interventions for this 
493 
phenomenon.   
494