Treatment of Unfavorable Bleeding Patterns in Contraceptive Implant Users: a Randomized Clinical Trial of Curcumin
Phase: PHASE4
Conditions: Bleeding, Implants, Breakthrough Bleeding
Sponsor: Oregon Health and Science University

PI Edelman, A                                   Implant Breakthrough Bleeding 
 
 
 
 
Official title: 
Treatment of unfavorable bleeding patterns in contraceptive implant users: a randomized clinical 
trial of curcumin 
 
 
Principal Investigator: 
Alison Edelman, MD, MPH 
 
 
 
 
 
 
NCT No: 
04205929 
 
 
 
Protocol Version Date: 
October 15, 2019 
 
 
 

PI Edelman, A                                   Implant Breakthrough Bleeding 
 
Title: Treatment of unfavorable bleeding patterns in contraceptive implant users: a randomized 
1 
clinical trial of curcumin 
2 
 
3 
PI: Alison Edelman, MD, MPH 
4 
Oregon Health & Science University 
5 
3181 SW Sam Jackson, UHN 50 
6 
Portland, OR 97239 
7 
503-418-2585 
8 
edelmana@ohsu.edu 
9 
 
10 
Co-I: Jeffrey Jensen, MD, MPH 
11 
Marci Messerle Forbes, FNP 
12 
Andrea O’Donnell, FNP 
13 
 
14 
Funder: Investigator initiated 
15 
 
16 
Background: 
17 
The etonogestrel (ENG) subdermal contraceptive implant (ENG implant) is a highly effective 
18 
method of preventing pregnancy, but it has bleeding side effects that make it unappealing for 
19 
many women. Given that the ENG implant is 20 times more effective at pregnancy prevention 
20 
than oral contraceptive pills, strategies to increase its acceptability will translate into improved 
21 
prevention of unplanned pregnancies [1].  Many medications have been studied with progestin-
22 
only contraceptives such as the ENG implant to manage irregular bleeding.  Concurrent use of 
23 
oral contraceptives (OCs) with the implant does stop bleeding but bleeding returns when OCs 
24 
are stopped [2, 3]. The only study to demonstrate a sustained reduction in bleeding lasting for 
25 
two months was the selective estrogen receptor modulator (SERM) tamoxifen in users of the 
26 
levonogestrel (LNG) contraceptive implant [4].  We conducted a small clinical trial to evaluate 
27 
the effects of a 7-day course of tamoxifen in users of Nexplanon© with bothersome 
28 
breakthrough bleeding, and demonstrated that tamoxifen treatment reduces bleeding/spotting 
29 
days during the first 30 days after use as compared to placebo [5]. Recently, we successfully 
30 
completed a study that expanded on our original tamoxifen work and found similar results over a 
31 
90-day time period (Merck IIS, paper under development).  
32 
 
33 
We have proven that tamoxifen is a successful strategy to stop breakthrough bleeding in implant 
34 
users but providers and patients do have concerns about this particular drug since it is used for 
35 
cancer.  Tamoxifen also has a small increased risk of venous thromboembolism (VTE) with 
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continuous use in a menopausal population. Healthly reproductive-age woman with short-term 
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exposure to tamoxifen have not been shown to have a risk of VTE but the concern is still 
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present as well as the stigma that it is a ‘cancer’ drug. If another agent without these concerns 
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could be found to improve bleeding in implant users then this drug might be more widely 
40 
adopted. 
41 
 
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The exact mechanism of progestin-induced bleeding is unknown but it is likely multi-factorial 
43 
with the end result of angiogenesis, ‘leaky’ fragile vasculature, and inflammation. Curcumin, the 
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active ingredient in turmeric, has been demonstrated to be anti-inflammatory, anti-proliferative, 
45 
and anti-angiogenic which may make it an ideal agent for the management of break-through 
46 
bleeding. The FDA has determined curcumin is safe and categorizes it as ‘generally regarded 
47 
as safe’ (GRAS).  Studies have demonstrated that curcumin is extremely well-tolerated. 
48 
Curcumin has a significant body of evidence as an adjunct treatment in patients with cancer, 
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cardiovascular disease and auto-immune/inflammatory conditions. In terms of women’s health, 
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curcumin was better than placebo in a randomized control trial in attenuating the severity of 
51 

PI Edelman, A                                   Implant Breakthrough Bleeding 
 
PMS symptoms but has not been studied for uterine bleeding. Anecdotally, naturopaths and 
52 
herbalists use it for treatment of heavy menstrual bleeding.  
53 
 
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[1] 
Winner B, Peipert JF, Q Z, C B, Madden TE, Allsworth JE, et al. Effectiveness of Long-
55 
Acting Reversible Contraception. New England Journal of Medicine 2012;366:1998–
56 
2007. 
57 
[2] 
Guiahi M, McBride M, Sheeder J, Teal S. Short-term treatment of bothersome bleeding 
58 
for etonogestrel implant users using a 14-day oral contraceptive pill regimen: a 
59 
randomized controlled trial. Obstet Gynecol 2015; 126: 508-13 
60 
[3] 
Hou MY, McNicholas, C, Creinin MD. Combined oral contraceptive treatment for 
61 
bleeding complaints with the etonorgestrel contraceptive implant: a randomized 
62 
controlled trial. Eur J Contracept Reprod Health Care 2016; 21:361-6. 
63 
 [4] 
Abdel-Aleem H, Shaaban OM, Amin AF, Abdel-Aleem AM. Tamoxifen treatment of  
64 
 
bleeding irregularities associated with Norplant use. Contraception 2005;72:432–7. 
65 
[5]         Simmons K, Edelman A, Fu Rochelle, Jensen JT. Tamoxifen for the treatment of 
66 
breakthrough bleeding with the etonogestrel implant: a randomized controlled trial. 
67 
Contraception 2017: 95:198-204. 
68 
 
69 
Hypothesis: 
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1) In etonorgestrel (ENG) users with troublesome bleeding, daily treatment with curcumin 
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will result in more days of amenorrhea than placebo in a 30-day reference period. 
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Objectives: 
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To identify a successful treatment for troublesome bleeding and spotting in users of the ENG 
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contraceptive subdermal implant. 
76 
 
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Primary objective: 
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1. Total number of amenorrhea days in a 30-day reference period  
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Secondary objectives: 
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1. Each 30-day reference period outcomes between treatment and placebo (double 
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blind placebo-controlled RCT): 
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a) Total number of bleeding/spotting days  
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b) Total number of consecutive bleeding-free days    
84 
c) Total number of spotting days 
85 
d) Total number of bleeding days 
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e) Time (days) to stop bleeding 
87 
2. Overall outcomes:  
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a) Drop out  
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b) Patient satisfaction with bleeding pattern 
90 
c) Continuation of implant or anticipation of continuation 
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d) Side effects 
92 
 
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Study design/Clinical Plan: 
94 
We are proposing a randomized, double blind placebo-controlled clinical trial over a 30-day 
95 
reference period for treatment of women experiencing bothersome bleeding while using the 
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ENG contraceptive implant.   
97 
 
98 
The primary outcome of the study will be the total number of amenorrhea days in a 30-day 
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reference period.  The study has a number of secondary outcomes (see above, study 
100 
objectives) focused around the efficacy of oral curcumin to stop bleeding/spotting and for how 
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long.  
102 

PI Edelman, A                                   Implant Breakthrough Bleeding 
 
 
103 
The intervention will consist of study drug exposure (curcumin or placebo) daily for 30 days. The 
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first dose will be taken at the start of enrollment if the subject is on the 3rd day of active bleeding 
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or if not bleeding, on day 3 of the next bleeding episode.  The study will be conducted at Oregon 
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Health & Science University (OHSU) in Portland, Oregon  
107 
 
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Each subject’s involvement will be up to approximately 60 days as study drug will not be 
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initiated at the time of enrollment unless they are experiencing bleeding/spotting that day and 
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the two prior days to enrollment.  Study drug will be started on the 3rd day of an active bleeding 
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episode. If no active bleeding episodes happen in the first 30 days from enrollment then the 
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participant will be withdrawn from the study. The study will require up to 3 in-person study visits 
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[screening (V1), enrollment (V2), and a close out visit or study exit (V3)], as well as a daily 
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response to a text or email message about bleeding and use of study medication. Additional 
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phone and email contact may occur with the participant to ensure clarity of diary entry or 
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completion or to ensure drug initiation and compliance.  The electronic diary only takes a few 
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seconds to complete..  
118 
 
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Eligibility: 
120 
Inclusion:  
121 
• 
English speaking women 15-45 years of age currently using the ENG implant who have 
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experienced frequent or prolonged bleeding while using the device:  
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o To be eligible, women will need to have >7 days of continuous bleeding/spotting 
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in the last 30 days, OR 2 or more episodes of bleeding/spotting in the last 30 
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days.  
126 
• 
Implant use for at least 30 days prior to screening visit.   
127 
• 
Willing to continue using the implant for at least 30 days from study enrollment.  
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• 
Access to a reliable cell phone and must be willing to receive and respond to a daily text 
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or email message to assess bleeding and use of study drug   
130 
• 
Implant must be palpable to prove that an ENG implant is in place at time of screening 
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and enrollment. 
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• 
Negative gonorrhea/chlamydia screening performed at screening visit 
133 
 
134 
Exclusion criteria:  
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• 
Postpartum within six months 
136 
• 
Post-abortion within six weeks 
137 
• 
Currently pregnant 
138 
• 
Currently breast-feeding (to be eligible, must be 4-6 weeks from cessation of 
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breastfeeding) 
140 
• 
Undiagnosed abnormal uterine bleeding pre-dating placement of contraceptive implant 
141 
• 
Bleeding dyscrasia 
142 
• 
Anticoagulation use 
143 
• 
Active cervicitis 
144 
• 
Allergy to curcumin or turmeric  
145 
• 
History of venous thromboembolism 
146 
• 
Current or past breast or uterine malignancy 
147 
• 
Use of P450 pathway inducing drug 
148 
• 
Implant is due to be switched out in 2 months or less from enrollment  
149 
• 
Currently using oral contraceptives in addition to implant (to be eligible, needs to have a 
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4-6 week washout period) 
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PI Edelman, A                                   Implant Breakthrough Bleeding 
 
• 
Prior pregnancy occurred while Nexplanon/Implanon was in place 
152 
   
153 
Study procedures 
154 
 
155 
Screening (Visit 1, V1). Estimated 1 hour 
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Eligibility and study consent will be signed at this visit. Baseline demographic information will be 
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collected by interview, including menstrual history, contraception history including timing of 
158 
implant placement, sexual and pregnancy history, BMI/weight, ethnicity, age, and baseline use 
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of panty liners (as advised by Mishell et al 2007 to avoid confounding data on bleeding/spotting 
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days).  A series of questions will be asked to quantify number of bleeding and spotting days and 
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frequency and duration of bleeding episodes over the preceding three months of implant use (or 
162 
since placement, if less than three months).  Current implant use will be confirmed via palpation.  
163 
 
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Physical exam including blood pressure check, pelvic examination, urine pregnancy test, 
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cervical cytology evaluation (if not completed within the ASCCP recommended screening 
166 
interval), and testing for gonorrhea and chlamydia.  A baseline assessment of satisfaction with 
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baseline bleeding pattern will also be performed.  
168 
 
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Once negative results from the subject’s gonorrhea and chlamydia testing are demonstrated, 
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visit 2 can be scheduled (enrollment). 
171 
 
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Enrollment (V2), estimated 30 minutes 
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This visit could be combined with the screening visit. Randomization for part 1 of the study will 
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occur at this visit. Pregnancy test and blood pressure will be performed. The Subject Study Drug 
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Information Handout will be provided and explained. Study drug will be provided.  Subject will 
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only start study drug at this visit if they are experiencing an active bleeding episode and this is 
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the 3rd day of bleeding/spotting. Study coordinator will instruct how to start tracking bleeding via 
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text message. Subjects will receive training on the use of the electronic bleeding diary 
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procedures.  This includes instruction on use of the text or email message bleeding diary.  
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End of study (V3), estimated 30 minutes 
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The final visit will take place approximately 90 days after enrollment or at the time of study 
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withdrawal/exit.  Repeat STI testing only if indicated by a change in partners during the study.  
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Vital signs will be performed and a review of bleeding diary, medications, AEs, and health 
185 
changes.  A short satisfaction questionnaire will be performed. Participation is complete after 
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this visit.  Unused study drug will be retuned at these visits.   
187 
 
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Visit 
Details 
Visit 1-Screening 
• 
Informed consent 
• 
Review medications 
• 
Confirm implant use 
• 
Physical exam with vitals (blood pressure, pulse, 
weight, height)  
• 
Urine pregnancy test 
• 
Review eligibility criteria 
• 
Gonorrhea and chlamydia test 
• 
Pap (if indicated) 
• 
Baseline questionnaire 

PI Edelman, A                                   Implant Breakthrough Bleeding 
 
Visit 2– enrollment  
 
• 
Review bleeding diary with staff 
• 
Review medications 
• 
Vitals (blood pressure, pulse, weight, height) 
• 
Confirm implant use 
• 
Receive placebo or study drug and instructions 
• 
Review any health changes 
Visit 3- end of study 
• 
Urine pregnancy test if indicated 
• 
Repeat Gonorrhea and chlamydia test if change in 
partner occurs during study. 
• 
Review medications 
• 
Return any unused medication 
• 
Vitals (blood pressure, pulse, weight, height) 
• 
Confirm implant use 
• 
Review bleeding diary with staff 
• 
Review health changes 
• 
Exit questionnaire 
 
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Description of intervention/study drug 
190 
Participants will be instructed to begin use of the study medication daily. A study coordinator 
191 
(SC) will prospectively follow electronic bleeding diaries at a minimum of three times weekly for 
192 
each individual study subject to ensure data integrity and correct day of drug initiation. Any 
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unused study drug will be counted and returned at the conclusion of the study.  
194 
 
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Failure to complete the texting diary will prompt a phone call or email from the SC. If we are 
196 
unable to reach a subject by phone, email, letter  over a 2-week time period, their participation 
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will be terminated. Any data obtained up to this point will be analyzed in accordance to with 
198 
intention to treat. 
199 
 
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Study procedures and data collection other than side effects and AEs will last 30-days from 
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enrollment.  
202 
 
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Compensation 
204 
Participants will be compensated up to $250 for their participation in this study. Study visit 
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compensation breakdown is as follows: 
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• 
Visit 1- Screening:                           $50 
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• 
Visit 2- Enrollment:                          $50 
208 
• 
Visit 3- Study end                            $50 
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• 
Diary Completion:                            $100 
210 
 
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Subjects will only be compensated for the visits they complete. For example, if a subject 
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withdraws after visit 2, they will only be compensated for those two visits ($50 + $50).  
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Diary compensation 
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Diary completion is defined as responding to 1 daily text message per day. A subject can miss 
215 
up to 2 days of responses in the up to 60-day study period and still receive diary compensation. 
216 
If a subject misses 3 or more days of diary entry in a given 30 days, they will not receive this 
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PI Edelman, A                                   Implant Breakthrough Bleeding 
 
compensation. Study coordinators will be tracking diary responses, and response rates. If a 
218 
subject withdraws early from the study, they will only receive compensation for visits that they 
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have completed and not the compensation for diary completion. 
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221 
 
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Sample size 
223 
Our primary outcome is the total number of amenorrhea days in a 30-day reference between 
224 
curcumin and placebo groups.  Our prior tamoxifen study demonstrated a 6-day difference in 
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overall amenorrhea days in the first 30-day reference period.  
226 
 
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Based on our recent tamoxifen study, a sample size of 44 women allows us to demonstrate a 6-
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day difference between groups; 80% power at an alpha 0.05 = 22 women per each group. To 
229 
account for drop out, we have increased the sample size by approximately 30% for a total 
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sample size of 58.  
231 
 
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Study drug 
233 
Curcumin an active ingredient in the spice Tumeric is a natural polyphenol. It is purported to 
234 
have multiple health benefits mostly based in its anti-inflammatory and anti-oxidant properties. 
235 
Curcumin dosing has been demonstrated to be well tolerated in humans up to 12,000mg/day 
236 
but dosing as a cancer treatment adjunct or as an autoimmune therapy are in the 400-
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600mg/day range [1,2]. In general, subjects seem to experience no side effects from curcumin 
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but in a dose escalation study to determine safety and tolerability, 7 of 34 subjects experienced 
239 
headache, rash, and yellow stool.  At higher doses, some nausea and diarrhea have also been 
240 
reported. Curcumin may have a beneficial effect on cholesterol and triglycerides. Curcumin has 
241 
poor bioavailability and combining it with piperine, a known bioenhancer derived from black 
242 
pepper, has been shown to improve curcumin bioavailability by 2000% [3]. However, curcumin 
243 
without a bioenhancer has also demonstrated therapeutic impact in randomized controlled trials.  
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We plan to use Theracurcumin by Immunovites, 600 mg curcumin, as they report quality testing 
245 
and have combined curcumin with a bioenhancer for improved bioavailability. This product also 
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contains ginger root powder and bioperine (derived from black pepper). 
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(https://immunovites.com/products/theracurmin-hp-max). 
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Curcumin is considered a supplement by the US Food and Drug Administration. The FDA has 
249 
determined curcumin is safe and categorizes it as ‘generally regarded as safe’ (GRAS).  Our 
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IRB chair has recommended that we seek the FDA’s opinion regarding the need for an IND for 
251 
this study as curcumin is a supplement.  However, this study is not intended to support a 
252 
significant change in advertising for curcumin. It is also debatable whether its use is for 
253 
“treatment” of a disorder or a study of the impact of curcumin on biological function.   
254 
 
255 
[1] Esmaily, H.; Sahebkar, A.; Iranshahi, M.; Ganjali, S.; Mohammadi, A.; Ferns, G.; Ghayour-
256 
Mobarhan, M. An investigation of the effects of curcumin on anxiety and depression in obese 
257 
individuals: A randomized controlled trial. Chin. J. Integr. Med. 2015, 21, 332–338. 
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[2] Lao CD, Ruffin MT, Normolle D, Heath DD, Murray SI, Bailey JM, et al. Dose escalation of a 
259 
curcuminoid formulation. BMC Complement Altern Med. 2006;6:10. 
260 
[3] Shoba, G.; Joy, D.; Joseph, T.; Majeed, M.; Rajendran, R.; Srinivas, P.S. Influence of 
261 
piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 
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1998, 64, 353–356. 
263 
 
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PI Edelman, A                                   Implant Breakthrough Bleeding 
 
Risks to Subjects  
265 
Human Subjects Involvement and Characteristics 
266 
Reproductive-aged (15-45 year old), healthy women currently using a contraceptive implant with 
267 
no contraindications to the study medication and not at risk for or seeking pregnancy will 
268 
constitute the target population for this study.  
269 
 
270 
All enrollment and clinical evaluations will be performed at OHSU in Portland, Oregon.  
271 
Gonorrhea and chlamydia testing and pap testing (if indicated) will be sent to the OHSU core 
272 
lab for routine processing.  
273 
 
274 
Sources of Materials 
275 
The sources of research material for the clinical portion of this proposal will be new specimens 
276 
obtained purely for this research protocol.  The study investigators and/or research 
277 
assistants/nurses will perform all study procedures.   
278 
 
279 
Potential Risks 
280 
One risk to taking part in this study is that the study drug may not be effective in helping to treat 
281 
bleeding.  
282 
 
283 
The study drug is extremely well tolerated even up to extremely high doses and is considered 
284 
safe by the FDA. At the highest doses, which we are not utilizing here, a few subjects reported 
285 
nausea and diarrhea.  
286 
 
287 
Some parts of the study may be inconvenient including the text messaging to collect data.  
288 
These are regular text or email messages and will count towards text messages or data on a 
289 
subject’s cell phone plan.  The subject will be asked detailed questions about her bleeding and 
290 
gynecologic history.  Some of these questions may seem very personal or embarrassing.  
291 
Women may refuse to answer any of the questions that they do not wish to answer.  
292 
 
293 
Adequacy of Protection Against Risk 
294 
Recruitment and Informed Consent 
295 
Attempts to enroll a diverse study population will be made through placement of IRB approved 
296 
flyers in the community, community outreach (radio and print ads) and through the availability of 
297 
foreign language interpreters and research staff.  Women may also learn of the study through 
298 
their routine visits in clinics or by working at OHSU. We also intend to utilize an EPIC Cohort 
299 
search to identify and contact potential participants via phone, email, letter, and/or MyChart 
300 
messages. We intend to use REDCap for batch emailing. We also intend to use Trialspark and 
301 
Google AdWords as well as Facebook and Instagram for community outreach. 
302 
 
303 
Women will be screened for eligibility and if they meet the basic criteria and agree to participate, 
304 
they will undergo informed written consent. The protocols and consent will be reviewed and 
305 
approved by the OHSU IRB prior to initiation of the study. 
306 
 
307 
Protection Against Risk 
308 
The drug utilized in this study will be used in accordance with dose and routes that the FDA has 
309 
determined to be safe.  Women will be informed that they will be using a supplement and this is 
310 
not an FDA approved drug but that we have specifically chosen a dose and length of exposure 
311 
time to the drug or compound with extremely low potential for significant side effects or serious 
312 
risks. Women will undergo screening for any known contraindications to the study drugs. 
313 
 
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PI Edelman, A                                   Implant Breakthrough Bleeding 
 
Confidentiality of personal health information will be maintained according to HIPAA 
315 
requirements for research.  All subjects will receive a study number to which all subsequent 
316 
data will refer.  Personal identifiers will not be on questionnaires, data, abstract sheets, or in the 
317 
main database.  All data will be kept in locked files or a password protected computer in the 
318 
Principal Investigator’s (PI) office.  
319 
 
320 
Data and safety monitoring of plans for clinical trials 
321 
The PI and study staffs are responsible for recording the data, and they will be verifying its 
322 
accuracy throughout the process. The PI will be reviewing the data in-depth upon completion of 
323 
the study.  The PI will also be overseeing that the study procedures are being carried out as per 
324 
the approved protocol via close supervision of study visits and procedures and through frequent 
325 
communication with the study staff. The PI will also be conducting an initial assessment and 
326 
periodic assessments of the study and its procedures. If any safety concerns arise, a data 
327 
safety monitoring board will be convened to review the study.  As this study will be performed in 
328 
conjunction with the Women’s Health Research Unit’s (WHRU), an independent chart audit to 
329 
ensure data integrity and completeness will be performed after the first 5 subjects have been 
330 
enrolled and then at regular 6 months intervals.     
331 
 
332 
The PI will adhere to OHSU’s Institutional Review Board (IRB) policies regarding protection of 
333 
human subjects and the reporting of study deviations and adverse events. In the rare case of an 
334 
adverse event, she will utilize the WHRU data safety monitoring board (DSMB) to review the 
335 
event and rule on a course of action. The WHRU DSMB is made up of individuals 
336 
knowledgeable about women’s reproductive health and therapies and will have no conflict of 
337 
interest with the study or its outcomes.  
338 
 
339 
Data Storage 
340 
Data for this project will be stored in OCTRI's installation of REDCap, a highly secure and robust 
341 
web-based research data collection and management system. 
342 
Features of REDCap that protect participants' privacy and data security include: 
343 
o 
Physical Security: OCTRI's REDCap software is housed on servers located in ITG's 
344 
Advanced Computing Center providing locked physical security 
345 
o 
Electronic Security: The REDCap servers are housed behind both the OHSU firewall 
346 
and a second ACC firewall.  All web-based data transmissions are encrypted with 
347 
industry-standard SSL methods.   
348 
o 
Controlled User Access: REDCap is employs a robust multi-level security system that 
349 
enables researchers to easily implement "minimum necessary" data access for their 
350 
research staff, including specification of data fields that are identifiers. This feature 
351 
includes “single click” ability to provide completely deidentified (removing all identified 
352 
data fields and shifting dates) for analysis or other purposes.  User activities are 
353 
logged to enable auditing of all data access.   Access is integrated with OHSU's 
354 
network such that users who are also OHSU employees are authenticated against 
355 
their OHSU network credentials.   
356 
o 
Data Integrity: REDCap is jointly managed in accordance with OHSU Information 
357 
Security Directives by ACC staff and members of OCTRI's Biomedical Informatics 
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PI Edelman, A                                   Implant Breakthrough Bleeding 
 
Program, ensuring fidelity of database configuration and back-ups.  User activities are 
359 
logged to enable auditing of all data changes. 
360 
Data Sharing 
361 
 
362 
We intend to use “Box” to share study documents and spreadsheets.  
363 
 
364 
Potential Benefits of the Proposed Research to the Subjects and Others 
365 
There are no direct benefits to study participants. 
366 
 
367 
Importance of Knowledge to be Gained 
368 
This study will increase the knowledge regarding breakthrough bleeding and contraceptive 
369 
implants.  It may help to prolong continuation of contraceptive implant use which in turn could 
370 
help women avoid unplanned pregnancies.  
371 
 
372