Transdermal Ethinyl Estradiol and Norelgestromin for Treating Irregular Vaginal Bleeding in Contraceptive Implant Users: A Randomized, Double-Blind, Controlled Trial
Phase: PHASE2
Conditions: Menstruation Disturbances, Metrorrhagia, Uterine Hemorrhage, Contraception Behavior
Sponsor: Chulalongkorn University

Research Protocol 
Version 2 Date 6/5/2025 
Research Proposal 
1. Project Title (Proposal Title) 
Thai: การศึกษาแผ่นแปะคุมกําเนิดชนิดฮอร์โมนรวมอิธินิลเอสตราดิออล 
(Ethinyl Estradiol) และนอร์เอลเจสโทรมิน (Norelgestromin) เพื่อรักษา
อาการเลือดออกทางช่องคลอดผิดปกติในผู้ใช้ยาฝังคุมกําเนิด 
English: Transdermal Ethinyl estradiol and Norelgestromin for 
treating irregular vaginal bleeding in contraceptive implants users: A 
Randomized, Double-Blind, Controlled Trial 
2. Investigators 
Principal Investigator: Tunchanok Juntamongkol M.D. 
●​ Department of Obstetrics and Gynecology, Faculty of Medicine, 
Chulalongkorn University 
●​ King Chulalongkorn Memorial Hospital, Thai Red Cross 
Society 
Co-Investigator: Assoc. Prof. (Special) Dr. Somsook Santibenchakul 
●​ Department of Obstetrics and Gynecology, Faculty of Medicine, 
Chulalongkorn University 
●​ King Chulalongkorn Memorial Hospital, Thai Red Cross 
Society 
Co-Investigator: Dr. Phanupong Phutrakul 
●​ Research Division, Faculty of Medicine, Chulalongkorn 
University 

●​ King Chulalongkorn Memorial Hospital, Thai Red Cross 
Society 
3. Rationale and Background 
●​ Contraceptive implants are highly effective semi-permanent 
contraceptive methods. The most common side effect is 
irregular bleeding (1-2), which is the main reason for 
discontinuation of this method (3-6). 
●​ The exact cause of irregular bleeding is not clearly understood. 
One possible cause is endometrial thinning resulting from 
progestin suppression of Luteinizing Hormone (LH) and 
ovulation. Another possible cause is increased vascular 
permeability, which is controlled by COX-2. Under normal 
conditions, COX-2 is suppressed by LH, and when this 
suppression is disrupted by hormonal changes, it may lead to 
increased vascular permeability and cause bleeding (7). 
●​ Various approaches have been proposed to reduce irregular 
bleeding, targeting different mechanisms such as NSAIDs, 
anti-fibrinolysis, anti-progestin, estrogen, and combined 
hormonal contraceptives (8). 
●​ Previous studies have shown that treatment with oral combined 
hormonal contraceptives can reduce irregular bleeding (9-11). 
●​ However, studies on the use of transdermal contraceptive 
patches for treating irregular bleeding are still limited (12). 
●​ The combined hormonal contraceptive patch available in 
Thailand contains ethinylestradiol 600 micrograms and 
norelgestromin 6 milligrams. The Summary of Product 
Characteristics (SPC) recommends applying the patch to the 
upper torso for 7 days, then removing and applying a new patch. 
The daily hormone release into the bloodstream is Ethinyl 
Estradiol 20 micrograms and Norelgestromin 150 micrograms 
(13). 

●​ Since combined hormonal contraceptive patches do not need to 
be changed daily, this method may be satisfactory for users who 
choose contraceptive implants for their long-acting properties 
and may be as effective as other methods in treating irregular 
vaginal bleeding. Additionally, studies have reported that 
patients using weekly contraceptive methods have significantly 
better compliance compared to daily contraceptive use (14,15). 
4. Literature Review 
●​ Alvarez-Sanchez et al. studied 155 Norplant users with irregular 
vaginal bleeding, comparing oral contraceptive Ethinyl Estradiol 
50 μg + Levonogestrel 250 μg, hormone Ethinyl Estradiol 50 
μg, and placebo. All medications were given for 20 days with 8 
weeks follow-up. The number of bleeding days in the oral 
contraceptive group was significantly lower than the other two 
groups (16). 
●​ Witjaksuno et al. studied 91 Norplant users with irregular 
vaginal bleeding, comparing 90 days before and after treatment. 
Users of oral contraceptive Ethinyl Estradiol 30 μg + 
Levonogestrel 250 μg and hormone Ethinyl Estradiol 50 μg had 
significantly reduced bleeding days compared to the 90 days 
before treatment (17). 
●​ Guiahi et al. studied 32 Etonogestrel implant users with irregular 
vaginal bleeding. The proportion of users in each group 
reporting cessation of irregular bleeding during treatment and 
remaining bleeding-free at the end of treatment was 87.5% in 
the oral contraceptive Ethinyl Estradiol 30 μg + Levonogestrel 
250 μg group and 37.5% in the placebo group, which was 
statistically significant (9). 
●​ Hou et al. studied 26 Etonogestrel implant users with irregular 
vaginal bleeding. In the group receiving oral contraceptive 

Ethinyl Estradiol 30 μg + Levonogestrel 250 μg, all subjects 
reported improvement in irregular vaginal bleeding (11). 
●​ Sinthuchai et al. studied 46 Etonogestrel and Levonogestrel 
implant users with irregular vaginal bleeding. Treatment groups 
were divided into injectable contraceptive Estradiol cypionate 5 
mg + Medroxyprogesterone acetate 25 mg compared to placebo. 
The proportion stopping irregular bleeding after treatment and 
remaining bleeding-free until 21 days post-treatment was 87% 
in the injectable contraceptive group, higher than placebo at 
46% (18). 
●​ Boonkasemsanti et al. studied 120 Norplant users. The group 
receiving transdermal hormone Oestradiol 100 μg reported 
clinical improvement in 23 out of 33 cases, and the placebo 
group reported improvement in 13 out of 31 cases. However, the 
comparison was not statistically significant (12). 
●​ Audet et al. compared efficacy, cycle control, treatment 
compliance, and safety between transdermal combined 
hormonal contraceptive Ethinylestradiol 20 μg + 
Norelgestromin 150 μg and oral contraceptive Ethinyl Estradiol 
30 μg + Levonogestrel 250 μg. Contraceptive efficacy was 
similar, and cycle control ability was comparable (14). 
From the literature review, combined hormonal contraceptives are 
effective in treating irregular vaginal bleeding in contraceptive 
implant users. However, data on transdermal contraceptive patches for 
treating irregular bleeding is limited. This method has been studied to 
provide better user compliance, making the data from this study 
valuable for clinical application. 
5. Research Objectives 
Primary Objective: 

●​ To evaluate the proportion of participants reporting no vaginal 
bleeding during treatment with combined hormonal 
contraceptive patches and remaining bleeding-free on day 14 of 
treatment 
Secondary Objectives: 
●​ To evaluate the proportion of participants reporting no vaginal 
bleeding after treatment with combined hormonal contraceptive 
patches continuously for at least 7 days in the treatment month 
compared to placebo (bleeding free at least 7 days) 
●​ To evaluate the proportion of participants reporting no vaginal 
bleeding during treatment with combined hormonal 
contraceptive patches and remaining bleeding-free on day 7 of 
treatment 
●​ To evaluate the proportion of participants reporting no vaginal 
bleeding during treatment with combined hormonal 
contraceptive patches and remaining bleeding-free on day 21 of 
treatment 
●​ To evaluate the number of treatment days before cessation of 
vaginal bleeding 
●​ To evaluate the number of days of spotting/breakthrough 
bleeding during treatment 
●​ To evaluate the number of days before recurrence of vaginal 
bleeding after stopping treatment 
●​ To evaluate treatment side effects 
●​ To evaluate treatment adherence 
6. Research Question/Hypothesis 
Do combined hormonal contraceptive patches containing Ethinyl 
Estradiol and Norelgestromin effectively treat irregular vaginal 
bleeding caused by contraceptive implant use compared to placebo? 
7. Keywords 

●​ Contraceptive implant 
●​ Abnormal vaginal bleeding 
●​ Bothersome vaginal bleeding 
●​ Transdermal hormonal contraception 
●​ Transdermal Ethinyl Estradiol and Norelgestromin 
●​ Etonogestrel contraceptive implant 
●​ Levonorgestrel contraceptive bleeding 
8. Research Design 
Randomized, double-blind, placebo-controlled trial 
9. Research Methodology 
Population: Contraceptive implant users with irregular vaginal 
bleeding after implant insertion 
Participant Recruitment Approach: Recruit volunteers at the 
Family Planning Clinic, King Chulalongkorn Memorial Hospital, and 
advertise through posters 
Inclusion Criteria: 
1.​Women aged 18 years and older 
2.​Regular menstrual cycles for at least 1 cycle before 
contraceptive implant insertion 
3.​Normal pelvic examination and transvaginal ultrasound results 
4.​Normal cervical cancer screening within 3 years 
5.​Irregular vaginal bleeding (bleeding for more than 8 consecutive 
days or bleeding-free intervals ≤15 days) 
Exclusion Criteria: 
1.​Previous treatment for irregular vaginal bleeding within the past 
3 months 
2.​Pregnancy 

3.​Contraindications to estrogen or progestin use 
4.​Allergy to estrogen or progestin 
5.​Allergy to hormonal patches 
6.​Heavy vaginal bleeding causing anemia symptoms (fatigue, 
fainting) 
Informed Consent Process: Research assistants explain information 
to volunteers, distribute information sheets and consent forms at the 
Family Planning Clinic, King Chulalongkorn Memorial Hospital. 
Participants can take materials home for consideration before deciding 
to participate. 
Research Methods: 
1.​Obtain ethics approval from the Research Ethics Committee, 
Faculty of Medicine, Chulalongkorn University 
2.​Recruit volunteers with informed consent from all participants 
3.​Collect baseline data including demographic data, pelvic 
examination, ultrasound 
4.​Randomization and treatment allocation using Block of 4 
randomization via computer program with stratified 
randomization (etonogestrel contraceptive implant and 
levonogestrel contraceptive implant), prepared by personnel not 
involved in data analysis, with treatment providers blinded to 
study drug vs. placebo 
○​ 4.1 Study group: Combined hormonal contraceptive patch 
containing Ethinyl Estradiol 600 micrograms and 
norelgestromin 6 milligrams for 21 days (1 patch per 7 
days), manufactured by GEDEON RICHTER PLC. and 
imported by Abbott (manufacturers have no conflict of 
interest) 
○​ 4.2 Placebo group: Patches identical in appearance to 
contraceptive patches without active ingredients (1 patch 

per 7 days), manufactured and imported by Convatec 
(manufacturers have no conflict of interest) 
5.​Follow-up at 7 days, 14 days, 21 days, and 3 months. Day 14 
will be onsite follow-up, while days 7, 21, and 3 months will be 
telephone follow-up 
6.​Create official Line account to remind volunteers to change 
patches and allow contact for problems such as patch 
detachment or side effect reporting 
7.​Management protocol for study and control groups reporting 
continued bothersome vaginal bleeding requiring additional 
treatment: On day 21 telephone follow-up, if still reporting 
bothersome daily vaginal bleeding, provide standard treatment 
with oral contraceptive containing Ethinyl Estradiol 300 
micrograms and levonorgestrel 150 micrograms, 1 pack (21 
tablets), 1 tablet daily 
8.​Data recording and evaluation using statistical analysis 
9.​Report research results in appropriate format 
10.​ Summarize research results, discuss findings, and present to 
research committee 
Sample Size Calculation: Based on studies examining combined 
hormonal contraceptive efficacy compared to placebo in treating 
irregular vaginal bleeding in contraceptive implant users, 87.5% in the 
combined hormonal contraceptive group and 37.5% in the placebo 
group reported bleeding cessation after treatment (9). 
Using the formula for calculating sample size for difference between 
two proportions, with 80% power, 0.05 significance level, Z(0.975) = 
1.96, and Z(0.8) = 0.84, the calculated sample size is 14 per group. 
With 30% dropout rate, the sample size is 20 per group, totaling 40 
participants. 
10. Data Collection 

Collect data using case record forms and record in REDCap Database 
11. Data Analysis and Statistics 
Analyze data using SPSS Statistics with Intention-to-treat (ITT) 
analysis: 
●​ Baseline characteristics: Descriptive statistics using percentage 
for categorical variables and mean ± standard deviation (SD) for 
normally distributed continuous variables, median (IQR) for 
non-normally distributed data 
●​ Between-group comparisons: Chi-square test or Fisher's Exact 
test for categorical variables, Two independent sample t-test or 
Wilcoxon Mann-Whitney U test for continuous variables 
●​ Significance level: 0.05 
12. Ethical Considerations 
Respect for Persons: Provide complete information until volunteers 
fully understand and freely decide to consent to participate. Data from 
studies and patient records will be kept confidential, considering 
patient rights as paramount. Data recording will not include 
patient-identifying information, and study results will present overall 
findings without individual data. Researchers must obtain patient 
consent before participation. 
Beneficence/Non-maleficence: Patients will benefit from treatment 
and continuous follow-up. Adverse events can be reported directly to 
researchers. Patients may not benefit and may risk adverse effects 
from study drugs and placebo, such as patch allergies, 
hormone-related thrombosis, breast tenderness. 
Justice: Clear inclusion and exclusion criteria, equal distribution of 
risks and benefits through randomization. 
13. Expected Benefits 

Understanding the efficacy of combined hormonal contraceptive 
patches containing Ethinyl estradiol and Norelgestromin in treating 
irregular vaginal bleeding in contraceptive implant users compared to 
placebo, to guide future clinical use. 
14. Potential Challenges 
Treatment compliance issues such as timely patch changes and 
premature patch detachment: 
●​ Line official system for patient follow-up and patch change 
reminders 
●​ 1 spare patch per volunteer for patch detachment cases 
15. Risks and Investigator Responsibility 
Drug side effects and adverse events: 
●​ System for reporting side effects and drug complications. 
Serious side effects affecting participants will result in drug 
discontinuation and treatment. 
16. Research Timeline 
August 1, 2024 - July 31, 2026 
17. Study Venue 
Family Planning Clinic, Department of Obstetrics and Gynecology, 
Faculty of Medicine, Chulalongkorn University, King Chulalongkorn 
Memorial Hospital, Thai Red Cross Society 
18. Research Management and Activity Schedule 
●​ Research question formulation and literature review: Aug 1 - 
Sep 30, 2024 
●​ Research proposal writing: Oct 1 - Oct 31, 2024 

●​ Ethics committee approval and research funding: Feb 1 - Apr 
30, 2025 
●​ Research implementation after ethics approval: Aug 1, 2025 - 
Aug 1, 2026 
●​ Data collection, statistical analysis, and report writing: Aug 1, 
2026 - Sep 30, 2026 
●​ Revision and research report preparation: Oct 1, 2026 - Nov 30, 
2026 
19. Post-Trial Access to Study Drug 
Available through physician prescription