Piroxicam and Levonorgestrel Co-treatment for Emergency Contraception: Randomised Controlled Trial
Phase: PHASE2
Conditions: Emergency Contraception
Sponsor: Dr. Hang Wun Raymond Li

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RESEARCH PROPOSAL 
 
1. 
General Information 
 
Title: 
NCT03614494 
levonorgestrel co-treatment for emergency contraception: randomised controlled trial 
 
Protocol number: PRX 2017-01 (Version 6) 
Clinical Trial Registration: ClinicalTrials.gov (Identifier number: NCT03614494) 
 
Protocol date: 20 November 2022  
 
 
Principle Investigator: 
Dr. LI Hang Wun Raymond 
Associate Professor, Department of Obstetrics and Gynaecology, School of Clinical Medicine, 
LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 
 
Co-Investigators: 
 
Dr. LO Seen Tsing Sue 
Senior Doctor, The Family Planning Association of Hong Kong 
 
Professor Kristina GEMZELL-DANIELSSON 
Honorary Professor, Department of Obstetrics and Gynaecology, School of Clinical Medicine, 
LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 
Professor, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, 
Sweden 
 
Ms. FONG Ho Yi Carol 
Research Officer, Department of Medicine, School of Clinical Medicine, LKS Faculty of 
Medicine, The University of Hong Kong, Hong Kong 
 
Professor HO Pak Chung 
Emeritus Professor, Department of Obstetrics and Gynaecology, School of Clinical Medicine, 
LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 
 
Professor NG Hung Yu Ernest 
Clinical Professor, Department of Obstetrics and Gynaecology, School of Clinical Medicine, 
LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 
 
Correspondence to: 
Dr. LI Hang Wun Raymond 
Department of Obstetrics and Gynaecology, Queen Mary Hospital, 102 Pokfulam Road, Hong 
Kong. 
Tel:  
(852) 22554517 
Fax: 
(852) 28550947 
Email: raymondli@hku.hk 
 

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2. 
Background Information 
 
Emergency contraception (EC) is used to prevent unwanted pregnancy after unprotected 
sexual intercourse (UPSI) or after a recognised contraceptive failure such as condom 
accidents or missing doses of hormonal contraception. Availability of effective EC 
methods is very important for reducing the occurrence of unwanted pregnancies in these 
circumstances. 
 
Oral hormonal EC is the most widely adopted EC method in both Hong Kong and most 
other countries. The EC method currently available for oral use consists of a single dose 
of 1.5 mg levonorgestrel (LNG) to be taken within 72 hours of UPSI, or 30 mg ulipristal 
acetate (UPA) to be taken within 120 hours of UPSI (Glasier et al, 2014; Faculty of Sexual 
and Reproductive Health, 2017).  
 
Studies have shown that LNG is effective as an EC only when given before, but not after, 
ovulation (Novikova et al, 2007; Noe et al, 2010). This may be explained by its 
mechanism of action. LNG prevents pregnancy by blocking or postponing the luteinizing 
hormone (LH) surge, hence disrupting the ovulatory process; this effect is limited to its 
administration before the onset of the LH surge, but not when it is taken after the LH surge 
has commenced, a time when intercourse is most likely to result in pregnancy. The more 
advanced in the follicular phase that LNG is taken, the lower will be its ability to block 
ovulation and thus prevent fertilization after UPSI (Croxatto et al, 2004). Once the 
ovulatory process has been triggered by the LH surge, LNG cannot prevent the follicle 
from rupturing and releasing the oocyte. It was also shown that LNG has no effect on 
sperm function, fertilization and implantation (Cameron et al, 2017). 
 
UPA, another selective progesterone receptor modulator, has more recently been 
introduced as an oral EC. Two randomized controlled trials showed that UPA was as 
effective as LNG for EC within 72 hours of UPSI (Creinin et al, 2006; Glasier et al, 2010). 
When the results of the two RCTs were combined in a meta-analysis, UPA has 
significantly lower failure rate compared to LNG [1.36% (22/1617) vs 2.15% (35/1625), 
p=0.046] (Glasier et al, 2010). The effectiveness of UPA as EC is maintained up to 120 
hours after UPSI, which is currently the licensed indication of UPA. In contrast to LNG 
which has a limited administration period preceding the onset of the LH surge for it to be 
effective, it was demonstrated that a single dose of 30 mg UPA administered up till the 
time immediately before the LH peak could still significantly interfere with follicular 
rupture (Brache et al, 2010). It was initially postulated in some studies that UPA might 
also have some concurrent inhibitory effect on embryo implantation based on changes in 
some molecular and histological parameters induced by UPA, but this was not supported 
by subsequent in-vitro co-culture experiments. One study in Hong Kong also did not 
support a significant clinical effect of UPA as EC when administered post-ovulation (Li 
et al, 2016). Therefore, the journey in search of further improvement in the efficacy of 
oral EC methods, particularly one with effective post- ovulatory action, still continues. 
 
Prostaglandins are “local hormones” that take part in a number of reproductive processes 
including ovulation (Duffy, 2015), fertilisation (Sugimoto et al, 2015), tubal function 
(Wanggren et al, 2006; Wanggren et al, 2008) and embryo implantation (Salleh, 2014). 
Hence, it is postulated that an inhibitor of the cyclo-oxygenase (COX) enzyme, the key 
enzyme involved in prostaglandin production, may potentially confer a “contraceptive” 

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effect and may act synergistically with LNG for EC, particularly to target at the post-
ovulatory events in addition. 
 
Existing clinical trials which explored the effect of several COX-2 inhibitors on ovulatory 
function were reviewed in a recent publication (Weiss and Gandhi, 2016); this included 
six clinical trials exploring the effect of rofecoxib, meloxicam and celecoxib on human 
ovulatory function. It was suggested that administration of these COX-2 inhibitors in the 
follicular phase could disrupt or delay follicle rupture, but in most of these studies the 
drug was administered consecutively for at least 5 days, which would be inconvenient in 
the context of emergency contraception and compliance may be an issue. Only one study 
explored the use of a single dose of meloxicam concurrently with LNG 1.5 mg; a trend of 
increased incidence of unruptured follicles was reported in the LNG plus meloxicam 
group compared to the LNG plus placebo group, and yet statistical significance was not 
reached, probably due to the small sample size (n=41).  There were little data on the 
clinical effect of COX inhibitors on post-ovulatory events such as embryo implantation.  
 
Based on the above information, we hypothesize that inhibition of prostaglandin synthesis 
by a COX inhibitor may confer additional contraceptive action when administered in 
adjunct to the current LNG regimen, as this may result in disruption of both ovulatory and 
post-ovulatory events involved in the establishment of conception. Blocking 
prostaglandin synthesis may retard tubal activities and hence slow down embryo 
transport, leading to delayed arrival of the embryo to the uterine cavity beyond the 
implantation window. Furthermore, any negative effect of reduced prostaglandin 
synthesis on endometrial receptivity may further potentiate its contraceptive action. 
Hence, it is hoped that COX inhibitor and LNG may act synergistically to achieve an 
enhanced efficacy for EC. 
 
We choose to investigate the effect of piroxicam, one of the longest-acting COX inhibitor 
(with half- life over 50 hours) that is commercially available, at a single oral dose of 40 
mg. An oral dose of piroxicam up to 40 mg is used pharmacologically for pain relief. 
Although small clinical studies in women undergoing assisted reproduction treatment 
showed that a low dosage (10 mg) of piroxicam did not interfere with, or might even 
enhance, implantation rate (Moon et al, 2004; Firouzabadi et al, 2007; Dal Prato and 
Borini, 2009; Kumbasar et al, 2017), it is probable that a higher dose may prevent 
implantation. 
 
 
References: 
 
Brache V, Cochon L, Jesam C, Maldonado R, Salvatierra AM, Levy DP, Gainer E, Croxatto 
HB. Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays 
follicular rupture. Hum Reprod 2010;25(9):2256-2263. 
Cameron ST, Li HWR, Gemzell-Danielsson K. Current controversies with oral emergency 
contraception.  BJOG 2017; in press. 
Creinin MD, Schlaff W, Archer DF, Wan L, Frezieres R, Thomas M, Rosenberg M, Higgins 
J. Progesterone receptor modulator for emergency contraception: a randomized controlled 
trial. Obstet Gynecol 2006; 108(5): 1089-1097. 
Croxatto HB,  Brache V,  Pavez M,  Cochon L,  Forcelledo ML,  Alvarez F,  Massai R,  Faundes 
A,  Salvatierra AM. Pituitary-ovarian function following the standard levonorgestrel 

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emergency contraceptive dose or a single 0.75-mg dose given on the days preceding 
ovulation, Contraception 2004; 70: 442-450. 
Dal Prato L, Borini A. Effect of piroxicam administration before embryo transfer on IVF 
outcome: A randomized controlled trial. Reprod Biomed Online 2009; 19:604–609. 
Duffy DM. Novel contraceptive targets to inhibit ovulation: the prostaglandin E2 pathway. 
Hum Reprod Update 2015;21(5):652-670. 
Faculty of Sexual and Reproductive Healthcare.  Clinical guideline: Emergency Contraception.  
Clinical Effectiveness Unit, 2017. 
Firouzabadi RD, Ghandi S, Tayebi N. Effect of administration of single dose piroxicam before 
embryo transfer on implantation and pregnancy rates in IVF cycles. J Biol Sci 2007; 7:123–
126. Gemzell-Danielsson K, Berger C, Lalitkumar PG. Mechanisms of action of oral 
emergency contraception. Gynecol Endocrinol 2014;30(10):685-687. 
Glasier A, Gemzell-Danielsson K, Bouchard P, Genazzani AR, Al-Azzawi F, Berga S, 
Birkhaeuser M, Brincat M, De Melo NR, Foidart JM, Kenemans P, Lunenfeld B, Maruo T, 
Milewicz A, Naftolin F, Ng EHY, Schindler A, Simon C, Simoncini T, Simpson E, Siseles 
N, Smetnik V, Tarlatzis B, von Schoultz B. ISGE statement on oral emergency contraception. 
Gynecol Endocrinol 2014; 30(10):681-682. 
Glasier AF, Cameron ST, Fine PM, Logan SJS, Casale W, Van Horn J, Sogor L, Blithe DL, 
Scherrer B, Mathe H, Jaspart A, Ulmann A, Gainer E. Ulipristal acetate versus levonorgestrel 
for emergency contraception: a randomised non-inferiority trial and meta-analysis. Lancet 
2010; 375(9714):555-562. 
Kumbasar S, Gul O, Sik A. Evaluation of the effect of indomethacin and piroxicam 
administration before embryo transfer on pregnancy rate. J Obstet Gynaecol Res 2017; in 
press. 
Li HWR, Lo SST, Ng EHY, Ho PC. Efficacy of ulipristal acetate for emergency contraception 
and its effect on the subsequent bleeding pattern when administered before or after ovulation. 
Hum Reprod 2016;31(6):1200-1207. 
Moon HS, Park SH, Lee JO, Kim KS, Joo BS. Treatment with piroxicam before embryo 
transfer increases the pregnancy rate after in vitro fertilization and embryo transfer. Fertil 
Steril 2004; 82:816–820. 
Novikova N, Weisberg E, Stanczyk FZ, Croxatto HB, Fraser IS. Effectiveness of 
levonorgestrel emergency contraception given before or after ovulation – a pilot study. 
Contraception 2007;112- 118. 
Noe G, Croxatto HB, Salvatierra AM, Reyes V, Villarroel C, Munoz C, Morales G, Retamales 
A.  Contraceptive efficacy of emergency contraception with levonorgestrel given before or 
after ovulation.  Contraception 2010; 81:414-420. 
Salleh N. Diverse roles of prostaglandins in blastocyst implantation. Scientific World J 
2014;2014:968141. 
Sugimoto Y, Inazumi T, Tsuchiya S. Roles of prostaglandin receptors in female reproduction. 
J Biochem 2015;157(2):73-80. 
Wånggren K, Lalitkumar PG, Stavreus-Evers A, Ståbi B, Gemzell-Danielsson K. 
Prostaglandin E2 and F2alpha receptors in the human Fallopian tube before and after 
mifepristone treatment. Mol Hum Reprod 2006;12(9):577-585. 
Wånggren K, Stavreus-Evers A, Olsson C, Andersson E, Gemzell-Danielsson K. Regulation 
of muscular contractions in the human Fallopian tube through prostaglandins and 
progestagens. Hum Reprod 2008;23(10):2359-2368. 
Weiss EA, Gandhi M. Preferential cyclooxygenase 2 inhibitors as a nonhormonal method of 
emergency contraception: a look at the evidence. J Pharm Pract 2016; 29(2):160-164. 
 
 

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3. 
Objectives: 
 
Aim: To compare the percentage of pregnancies prevented by LNG co-administered with 
piroxicam or placebo for oral emergency contraception by a randomised controlled trial. 
 
Hypothesis to be tested: LNG plus piroxicam has higher percentage of pregnancies prevented 
compared with LNG plus placebo for oral emergency contraception. 
 
 
4. 
Study design: 
 
This will be a randomised placebo-controlled double-blind clinical trial. A dedicated research 
nurse will help coordinate subject recruitment, study administration and follow-up of subjects. 
Subjects who give written consent to participate in this study shall be randomised to either the 
piroxicam arm (Treatment group) or placebo arm (Placebo group) in 1:1 ratio according to a 
computer-generated randomisation list in blocks of 10 in sealed envelopes which are prepared 
by an independent person. The medication will be prepacked by an authorised third party not 
directly involved in this study. The subjects, clinicians and research staff will be blinded to the 
group assignment. The codes for the treatment groups will only be revealed to the investigators 
after completion of the whole study and statistical analyses. It is anticipated that subject 
recruitment shall take 20 months; follow-up of the subjects will be completed in 2 months 
further, and a summary of preliminary results will be available by 24 months. 
 
 
5. 
Subject selection and exclusion 
 
5.1 Inclusion criteria 
Women attending the Family Planning Association of Hong Kong for oral EC will be 
recruited if they fulfil the following criteria: 
(a) healthy women aged 18 years or above; 
(b) requesting emergency contraception within 72 h of a single act of unprotected 
intercourse in the current menstrual cycle; 
(c) having menstrual cycles between 24 and 42 days 
(d) willing to abstain from further acts of unprotected intercourse and; 
(e) available for follow-up over the next 6 weeks. 
 
5.2 Exclusion criteria 
(a) post-abortion or postpartum and period have not yet returned,  
(b) being on the following drugs currently: anticoagulants, cyclosporine, tacrolimus, 
corticosteroids, lithium, serotonin reuptake inhibitors (SSRIs), quinolones  
(c) having unprotected intercourse in this cycle more than 72 hours or more than once 
before attending the clinic,  
(d) being found pregnant at the time of presentation,  
(e) breastfeeding,  
(f) having been sterilized (or partner having been sterilized) or having intrauterine 
contraceptive device in-situ,  
(g) uncertain about the date of the last menstrual period,  
(h) having used hormonal contraceptive (including EC pill) in the current or past one cycle, 
or NSAID in the recent one week, 

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(i) having history of asthma, urticaria or other allergic reactions to piroxicam, aspirin or 
other NSAIDs, 
(j) having history of ischaemic heart disease, heart failure, hypertension or cerebrovascular 
disease 
(k) having history of peptic ulcer disease and/or gastrointestinal bleeding 
 
The proposed start date of this study is 1 August 2018, and it is anticipated that study 
recruitment will last for two years. 
 
 
6. 
Treatment of subjects 
 
6.1 
Baseline assessment: 
• The subject will be assessed and counselled for the use of EC by the clinic nurse or 
doctor as routine.  Suitable subjects will be enrolled for the study after informed 
consent.   
• A menstrual history will be taken.  
• Pregnancy test will be done; only those tested negative will be recruited into study.  
• Blood (5 ml into clotted bottle) will be collected for hormonal assay (LH, oestradiol, 
progesterone).  The serum hormonal levels will be used to estimate the cycle day at 
the time of presentation in relation to the day of ovulation based on the method 
described by Novikova et al (2007). 
 
6.2 
Treatment: 
After counselling and obtaining informed consent, eligible subjects will be randomised 
to receive one of the two treatment regimens, i.e. Treatment group: a single dose of 
LNG 1.5 mg and piroxicam 40 mg, or Placebo group : a single dose of LNG 1.5mg and 
placebo under direct supervision. The subject and the research staff responsible for 
subject follow-up will be blinded to the treatment arm. 
 
The subjects will be advised not to have further acts of coitus before menstruation 
returns. They will be given a diary chart to record vaginal spotting and bleeding, 
possible side effects and further acts of intercourse, if any, and the contraceptive 
method used. 
 
6.3 
Follow-up: 
A follow-up appointment will be arranged about 1-2 weeks after the next expected 
menstruation. Information collected at the follow-up visit will include side effects and 
vaginal bleeding/spotting marked by the subject on her diary card; time of onset, 
duration and amount of menstrual bleeding and any further acts of intercourse and the 
type of contraception used (refer to Appendix 1). 
 
If normal menstrual bleeding has not occurred by that time, a pregnancy test will be 
carried out, and a positive result denotes treatment failure and the woman will be 
counselled accordingly. If the woman opts for continuing with pregnancy, she will be 
referred for antenatal care. An additional research follow-up will be arranged post-
delivery to record any antenatal, postnatal and neonatal complications. If the woman 
opts for terminating the pregnancy, she will be referred to the appropriate services. 
 
 

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7. 
Study outcomes 
 
Primary outcome measure:  
- 
Fraction of pregnancies prevented (%)  
[(expected pregnancies – observed pregnancies] / expected pregnancies)] 
The number of expected pregnancies will be determined by the Trussell’s model 
(Trussell J et al, Contraception 2003; 67:259-265) 
 
Secondary outcome measures: 
- 
Pregnancy rate (%) 
- 
Change in length (shortening / lengthening) of current cycle (days) 
- 
Adverse effects 
 
The data collection sheet is included in Appendix 1.  All the clinical data are part of the 
usual consultations for EC provision. 
 
8. 
Assessment of safety 
 
The study medication has been in the market for long time.  Being a non-steroidal anti-
inflammatory drug (NSAID), it is licensed as an analgesic.  Adverse effects are few, 
and the main side effect is gastrointestinal upset and peptic ulceration.  The use of 
piroxicam for a single dose in this study is not anticipated to be at high risk of causing 
any significant side effects. 
 
Rarely, piroxicam may lead to potentially fatal skin reactions, e.g. Stevens Johnson 
Syndrome. Anaphylactic reactions may occur in patients without known 
hypersensitivity to Piroxicam. Patients with asthma and without known aspirin 
hypersensitivity will be monitored as signs and symptoms of asthma may occur with 
the use of Piroxicam.  If the above adverse events occur, the subject will be attended 
by the on-site medical staff and referred to the nearest Accident and Emergency 
Department. 
 
9. 
Statistics 
9.1 
Statistical tests: 
• The efficacy-evaluable population will include all women who are enrolled into the 
study and can be contacted for a follow-up where the outcome data are collected. 
• Cases with missing data in a certain parameter will not be analysed for that specific 
parameter; no data imputation will be instituted. 
• The percentage of pregnancies prevented will be compared between groups by χ2 
test.  
• Logistic regression model using Firth’s bias reduction method will be applied to 
compare the pregnancy rates between groups. Confidence intervals for regression 
coefficients will be computed by penalised profile likelihood. This is a statistical 
method recommended for rare events (Puhr R, Heinze G, Nold M, Lusa L, 
Geroldinger A. Firth's logistic regression with rare events: accurate effect estimates 
and predictions? Stat Med 2017; 36(14): 2302-2317). 
• The rate of occurrence of menstrual changes will be compared between groups 
using χ2 test (for nominal categorical variables) and χ2 test for trend (for ordinal 
categorical variables).   

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• The rate of occurrence of adverse events will be compared between groups by 
Fisher’s exact test as some of the cells may contain an expected frequency of less 
than 5.  
• Continuous variables between the two groups will be compared by Student’s t-test.  
• Statistical analyses will be performed using SPSS version 28 (IBM Corporation, 
New York, USA), MedCalc version 20 (MedCalc Software Limited, Ostend, 
Belgium) and R package “logistf” Version 4.1.2 (http://www.r-project.org).   
• P-value <0.05 will be considered as statistically significant.  
 
Two subgroup analyses will be performed. The first subgroup analysis will stratify 
participants into pre-ovulatory versus post-ovulatory at the time of EC based on blood 
results of serum oestradiol, progesterone and luteinising hormone level on the day of 
EC (Li et al, 2016). The second subgroup analysis will stratify participants within 
versus over the body weight limits recommended for the usual dose of LNG-EC (by 
the cut-off of body mass index at 26 kg/m2 and that of body weight at 70 kg). 
 
9.2 
Sample size estimation: 
In a previous study on using LNG for EC within 72 hours of UPSI (Glasier et al, 2010), 
the fraction of prevented pregnancies was 51.9% based on the Trussell’s model. With 
the assumption that the fraction of prevented pregnancies in the placebo group is around 
52%, and the fraction of prevented pregnancies in the treatment group should be at least 
10% higher than that in the placebo group for it to be clinically meaningful, a minimum 
of 384 subjects in each group will be required to demonstrate superiority of the 
proposed treatment with a power of 80% and type I error of 0.05. Assuming that around 
10% of the subjects may default follow-up, we plan to recruit a total of 860 subjects. 
 
No interim analysis is planned as it is anticipated that co-administration of oral 
piroxicam with LNG will not adversely reduce its EC efficacy.  
 
 
10. 
Direct access to source data / documents: 
 
Trial-related monitoring, audits and regulatory inspections are allowed.  
 
11. 
Quality control and quality assurance 
 
Not applicable 
 
12. 
Ethics: 
 
Ethics approval will be applied before commencement of study.  The study medication 
has been licensed in Hong Kong as an analgesic.  Side effects associated with a single 
oral dose of piroxicam is expected to be minimal. There should not be any major ethical 
concern. Clinical trial certificate shall be obtained from the Department of Health, Hong 
Kong, before the study is commenced. 
 
The study will be conducted in compliance with the protocol of the International 
Conference on harmonization (ICH) Good Clinical Practice (GCP), as well as 
applicable local regulatory requirement(s) by the Institutional Review Board (IRB), 
The University of Hong Kong (HKU) / Hospital Authority Hong Kong West Cluster 

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(HA-HKWC).  Confidentiality of the study subjects will be preserved in accordance to 
these protocols and regulations. 
 
The patient information sheet will explain the aims of the study, possible adverse effects 
and confidentiality issues.  Informed consent will be obtained before the subjects are 
recruited into this study.  Participation in and withdrawal from the study is voluntary. 
 
13. 
Data Handling and record keeping 
 
All data will be stored and analysed using SPSS. All the investigators will be 
responsible for data management including data coding, monitoring and verification. 
 
14. 
Financing and insurance 
 
Funding will be supported by internal research fund of the Department of Obstetrics 
and Gynaecology, The University of Hong Kong   
 
15. 
Publication policy 
 
The findings of this study will be submitted for consideration for publication in peer-
reviewed scientific journal. 
 
16. 
Supplements 
 
Nil