Conditions: Endometriosis-related Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 22
Healthy volunteers: no

Brief summary:
To evaluate the efficacy of three doses of quinagolide administered as an extended-release vaginal ring compared to placebo on reduction of moderate to severe endometriosis-related pain

Detailed description:

Arms:
arm 1: Vaginal ring containing Quinagolide 360 μg, with daily target release rate of 4.5 μg arm 2: Vaginal ring containing Quinagolide 720 μg, with daily target release rate of 9 μg arm 3: Vaginal ring containing Quinagolide 1080 μg, with daily target release rate of 13.5 μg arm 4: Vaginal ring containing matching placebo

Interventions: intervention 1: Quinagolide 360 µg intervention 2: Quinagolide 720 µg intervention 3: Quinagolide 1080 µg intervention 4: Placebo
Intervention descriptions: intervention 1: Vaginal ring containing quinagolide 360 µg for daily releases intervention 2: Vaginal ring containing quinagolide 720 µg for daily releases intervention 3: Vaginal ring containing quinagolide 1080 µg for daily releases intervention 4: Matching placebo

Protocol document:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor Name 
Ferring Pharmaceuticals Inc. 
NCT Number 
NCT03692403 
Sponsor Trial ID 
000165 
Official title of study 
A randomized, double-blind, placebo-controlled, phase 2 
trial assessing the efficacy, safety and dose-response of 
quinagolide extended-release vaginal rings administered 
sequentially for 4 menstrual cycles in women with 
moderate to severe endometriosis-related pain 
Document Date 
29 May 2020


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Page 1 of 130 
 
 
 
Quinagolide, FE 999051 
Trial Code: 000165  
Vaginal Delivery System  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
CLINICAL TRIAL PROTOCOL 
 
 
A randomized, double-blind, placebo-controlled, phase 2 trial assessing the efficacy, safety 
and dose-response of quinagolide extended-release vaginal rings administered sequentially for 
4 menstrual cycles in women with moderate to severe endometriosis-related pain 
 
RAQUEL 
Randomized Trial Assessing Quinagolide Vaginal Ring for Endometriosis-Related Pain 
 
Trial 000165 
 
 
 
EudraCT Number: 
Not applicable 
 
IND Number: 
135,609 
Investigational Medicinal Product: 
FE 999051, Quinagolide Vaginal Ring 
Indication: 
Endometriosis-related pain  
Phase: 
2 
Name and Address of Sponsor: 
 
Ferring Pharmaceuticals Inc.  
100 Interpace Parkway 
Parsippany, NJ 07054 
United States 
 
GCP Statement: 
This trial will be performed in compliance with GCP. 
 
 
 
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals Inc. or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorized officer of Ferring Pharmaceuticals Inc. or 
another company within the Ferring Group. 


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Quinagolide, FE 999051 
Trial Code: 000165  
Vaginal Delivery System  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
SYNOPSIS 
TITLE OF TRIAL 
A randomized, double-blind, placebo-controlled, phase 2 trial assessing the efficacy, safety and 
dose-response of quinagolide extended-release vaginal rings administered sequentially for 
4 menstrual cycles in women with moderate to severe endometriosis-related pain 
SIGNATORY INVESTIGATOR 
Hugh S. Taylor, M.D., Department of Obstetrics, Gynecology and Reproductive Sciences, Yale 
School of Medicine, United States 
TRIAL SITES 
Approximately 100 sites in North America 
PLANNED TRIAL PERIOD 
Estimated first patient first visit (FPFV): 
 
 
Q3 2018 
Estimated last patient last visit (LPLV): 
 
 
Q3 2022 
CLINICAL PHASE 
2 
BACKGROUND AND SCIENTIFIC JUSTIFICATION FOR CONDUCTING THE TRIAL 
Endometriosis is an estrogen-dependent disease, pathologically characterized by the presence of 
endometrial-like tissue abnormally implanted outside the uterus and primarily located on the pelvic 
peritoneum, ovaries, and rectovaginal septum. Symptoms of endometriosis often present as pain 
associated with menstruation (dysmenorrhea), non-menstrual pelvic pain, and pain during or after 
intercourse (dyspareunia).  
As a novel non-hormonal approach to the management of endometriosis, dopamine receptor 
agonists have been suggested to inhibit the angiogenesis process that is essential for the 
development and maintenance of endometriotic lesions. Quinagolide is a non-ergot-derived, potent 
and selective dopamine receptor 2 agonist, which has been formulated into an extended-release 
vaginal ring for the treatment of endometriosis-related pain. 
Non-clinical and clinical data have suggested evidence of the primary pharmacological effects of 
quinagolide in reduction of endometriotic lesions. In mice with induced endometriosis, a significant 
reduction in the size of active lesions, cellular proliferation index and angiogenic gene expression 
was observed with oral quinagolide (50 or 200 μg/kg per day during a 14-day period) versus 
vehicle. In a proof-of-concept study involving hyperprolactinemic patients with endometriosis, it 
was observed at second-look laparoscopy that oral administration of quinagolide 25 µg to 75 µg 
once daily for 18-20 weeks induced a significant reduction in the overall size of endometriotic 
lesions, in addition to histological evidence of tissue degeneration and down-regulation of vascular 
endothelial growth factors (VEGF) and proangiogenic cytokines.  
Intravaginal administration of quinagolide is well tolerated and has been shown to be associated 
with higher bioavailability than oral administration due to reduced first-pass metabolism. Single 
administration of quinagolide vaginal ring demonstrated a pharmacokinetic (PK) profile of Tmax at 
36-48 hours and slowly declining plasma concentration over time for up to 35 days. No dose 
accumulation was observed following sequential administration of quinagolide vaginal ring for two 
menstrual cycles.  


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Trial Code: 000165  
Vaginal Delivery System  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
OBJECTIVES 
Primary Objective 
• To evaluate the efficacy of three doses of quinagolide administered as an extended-release 
vaginal ring compared to placebo on reduction of moderate to severe endometriosis-related pain 
 
Secondary Objectives  
• To evaluate the effect of quinagolide vaginal ring on reduction of endometriosis-related 
dysmenorrhea, non-menstrual pelvic pain, dyspareunia and analgesic use 
• To evaluate the effect of quinagolide vaginal ring on the subject’s ability to function  
• To evaluate the effect of quinagolide vaginal ring on ovarian function 
• To evaluate the effect of quinagolide vaginal ring on endocrine parameters   
• To evaluate the effect of quinagolide vaginal ring on vaginal bleeding pattern 
• To evaluate the systemic exposure of quinagolide and metabolites after quinagolide vaginal ring 
administration  
• To evaluate the effect of quinagolide vaginal ring on bone turnover markers 
• To evaluate the safety profile of quinagolide vaginal ring including adverse events, symptoms of 
impulse control disorders, electrocardiography (ECG) and echocardiography findings, routine 
safety laboratory parameters and ring acceptability   
• To validate the newly developed patient reported outcome (PRO) tool: Women’s Endometriosis 
Diary [Note: This objective will be reported separately] 
 
Exploratory Objective  
• To explore the effect of quinagolide vaginal ring on endometriosis biomarkers such as 
angiogenic and inflammatory biomarkers  
ENDPOINTS 
Primary Endpoint 
• Changes in the mean daily Numerical Rating Scale (NRS) scores for the worst endometriosis-
related pain at cycle 4 
 
Secondary Endpoints  
• Changes in the mean daily NRS scores for the worst endometriosis-related pain on days with 
menstrual bleeding (i.e. dysmenorrhea) and for the worst endometriosis-related pain on days 
with no menstrual bleeding (i.e. non-menstrual pelvic pain) at cycle 4 
• Changes in the mean daily NRS scores for the worst endometriosis-related pain over 4 menstrual 
cycles 
• Changes in the mean daily NRS scores for the worst dysmenorrhea over 4 menstrual cycles 
• Changes in the mean daily NRS scores for the worst non-menstrual pelvic pain over 4 menstrual 
cycles 


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Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
• Changes in the mean daily NRS scores for the worst dyspareunia on days with sexual intercourse 
over 4 menstrual cycles 
• Frequency of avoiding sexual intercourse due to expected pain over 4 menstrual cycles  
• Changes in the mean daily NRS scores for the worst impact of endometriosis-related pain on the 
subject’s ability to function over 4 menstrual cycles 
• Changes in the mean weekly scores of the Endometriosis Health Profile-30 (EHP-30) pain 
impact domain over 4 menstrual cycles  
• Changes in vaginal bleeding pattern over 4 menstrual cycles 
• Percentage of days with mild and/or strong rescue analgesics used over 4 menstrual cycles 
• Total and average doses of mild and/or strong rescue analgesics used over 4 menstrual cycles 
• Responder rate assessed as ≥30%, ≥50% and ≥70% reduction from the baseline in mean daily 
NRS score for the worst endometriosis-related pain, dysmenorrhea and non-menstrual pelvic 
pain and for the worst endometriosis-related pain impact, over 4 menstrual cycles 
• Changes in the mean individual and total symptom and sign severity scores of the Biberoglu and 
Behrman (B&B) scale at cycle 4   
• Changes in the EHP-30 scores over 4 menstrual cycles   
• Changes in Patient Global Impression of Severity (PGIS) scores at cycle 4 
• Patient Global Impression of Change (PGIC) scores at cycle 4   
• Plasma concentration of quinagolide and metabolites during cycles 1 and 4 
• Serum levels of mid-luteal phase progesterone at cycle 4  
• Proportion of subjects with serum levels of mid-luteal progesterone ≥25 nmol/L (7.9 ng/mL) at 
cycle 4  
• Serum levels of mid-luteal estradiol, prolactin, thyroid-stimulating hormone (TSH) and insulin-
like growth factor-1 (IGF-1) at cycle 4 
• Changes in bone turnover markers, determined by bone resorption marker serum C-terminal 
cross-linking telopeptide of type 1 collagen (s-CTx) and bone formation marker serum 
procollagen type I N propeptide (s-PINP) at cycle 4 
• Changes in ECG parameters including PR interval, QT interval, corrected QT using Fridericia’s 
formula (QTcF) and QRS interval at cycle 4  
• Proportion of subjects with abnormal clinically significant echocardiography findings indicating 
valvular heart disease at cycle 4 
• Proportion of subjects identified with potential impulse control disorders by the questionnaire for 
impulsive-compulsive disorders at cycle 4   
• Frequency and intensity of adverse events 
• Changes in circulating levels of clinical chemistry and hematology parameters, urinalysis 
parameters, and proportion of subjects with markedly abnormal changes  
• Frequency and intensity of ring acceptability parameters over 4 menstrual cycles 
 
Exploratory Endpoint 
• Changes in endometriosis biomarkers such as serum levels of VEGF, placenta growth factor 
(PlGF), interleukin 6 (IL-6) and soluble fms-like tyrosine kinase 1 (sFlt-1) at cycle 4 


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Vaginal Delivery System  
Clinical Trial Protocol 
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CONFIDENTIAL 
METHODOLOGY 
This is a randomized, double-blind, placebo-controlled, phase 2 trial assessing the efficacy, safety 
and dose-response of quinagolide extended-release vaginal rings administered sequentially for 4 
menstrual cycles in women with moderate to severe endometriosis-related pain. In this trial, a 
menstrual cycle is considered the period from day 7 of return of menses (RM+7) in a cycle until the 
following day 7 of return of menses in the next cycle. Visits on RM+7 can be scheduled on 
RM+6-10, i.e. day 6 to day 10 of return of menses.  
The trial consists of the following periods: 
1) Screening: starting immediately after the signing of the informed consent(s) and including a 
run-in period of two complete menstrual cycles (cycles -2 and -1) 
2) Treatment: double-blind, placebo-controlled treatment with three doses of quinagolide 
extended-release vaginal ring administered sequentially for four menstrual cycles (cycles 1, 2, 
3 and 4) 
3) Follow-up: post-treatment follow-up period of one menstrual cycle (cycle 5) 
 
Screening: The screening period includes a wash-out period of approximately one month (only 
applicable to subjects currently using some hormonal products such as contraceptives) and a run-in 
period of two complete menstrual cycles (cycles -2 and -1, applicable to all subjects). Subjects who 
are currently using some hormonal products such as contraceptives, may be eligible for the trial if 
they have completed the wash-out period. In this case, subjects need to sign the informed consent(s) 
before they discontinue those products. Discontinuation of the products should follow the labelling 
(e.g. completing the current cycle of contraceptives before wash-out). Subjects requiring wash-out 
will not be provided with the electronic diary (e-Diary) or rescue analgesics until the completion of 
the wash-out period, i.e. at the run-in visit.  
Before entry into run-in, all subjects will be asked to score the worst endometriosis-related pain 
from a recall of their experience during the past menstrual cycle on a self-administered 11-point 
Numerical Rating Scale (NRS) with 0 indicating “no pain” and 10 indicating “worst imaginable 
pain”. After standardized training of e-Diary use, eligible subjects will be instructed to record 
endometriosis-related pain, vaginal bleeding, occurrence of sexual intercourse and analgesic use in 
the e-Diary on a daily basis. Impact of endometriosis-related pain on functioning will be assessed 
by subjects on both a daily and a weekly basis.  
In this trial, endometriosis-related pain is evaluated as the pain located in the abdominal-pelvic area 
and the lower back area. During the run-in period, subjects will score the worst endometriosis-
related pain during the preceding 24 hours on the NRS before bedtime every night in the e-Diary.   
Vaginal bleeding will be recorded as “yes” or “no” on a daily basis in the e-Diary. If there is 
vaginal bleeding, subjects will be asked to register their bleeding volume (spotting, light, moderate 
or heavy bleeding) and to answer whether they think the bleeding is related to menses or not. Based 
on the subject’s impression of whether she has menstrual bleeding or not, the NRS score obtained 
for the endometriosis-related pain is assigned to dysmenorrhea (endometriosis-related pain on days 
with menstrual bleeding) or to non-menstrual pelvic pain (endometriosis-related pain on days with 
no menstrual bleeding).  
Occurrence of sexual intercourse (“yes” or “no”) will also be recorded in the e-Diary. In case of 
sexual intercourse, subjects will be asked to score the worst pain experienced during or after 


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Ferring Pharmaceuticals 
CONFIDENTIAL 
intercourse (dyspareunia) on the NRS. In case of no sexual intercourse, subjects will be asked if it 
is due to expected pain.  
Rescue analgesics for endometriosis-related pain will be limited to ibuprofen and/or hydrocodone-
acetaminophen in this trial. As a mild analgesic, ibuprofen will be provided to subjects in the form 
of 200 mg oral tablets for their use on an as-needed basis. Subjects will be instructed not to use 
other analgesics unless necessary. If there is a need to change analgesics, subjects should discuss 
with investigators, who may prescribe a strong analgesic, i.e. 5 mg hydrocodone plus 300 mg or 
325 mg acetaminophen. Use of any other analgesics for endometriosis-related pain is prohibited. 
Any prophylactic use of analgesics is also prohibited in this trial. Use of analgesics for 
endometriosis-related pain will be reported by subjects in the e-Diary on a daily basis.   
The impact of the endometriosis-related pain on different aspects of functioning will be assessed by 
subjects both on the NRS on a daily basis and by the modified EHP-30 pain impact domain (i.e. the 
first 11 items plus an additional work item) on a weekly basis.  
Treatment: Subjects will be randomized on RM+7 of cycle -1 (at visit 4) if they, during the run-in 
period, have moderate to severe endometriosis-related pain, which is defined as having a mean 
daily NRS score of ≥4 for the worst endometriosis-related pain during each run-in menstrual cycle. 
Randomization will be performed in a 1:1:1:1 ratio to quinagolide vaginal ring dose load 360 µg at 
a target release rate of quinagolide 4.5 µg/day, quinagolide vaginal ring dose load 720 µg at a target 
release rate of quinagolide 9 µg/day, quinagolide vaginal ring dose load 1080 µg at a target release 
rate of quinagolide 13.5 µg/day or placebo vaginal ring for four menstrual cycles (cycles 1, 2, 3 and 
4).  
Follow-up: Subjects will be followed up for one menstrual cycle (cycle 5). 
From randomization to follow-up (cycle 1 to cycle 5), subjects will continue to use an e-Diary to 
score the endometriosis-related pain, to register vaginal bleeding pattern, occurrence of sexual 
intercourse and the analgesic use as well as to assess the impact of the worst endometriosis-related 
pain on functioning, as they have done in the run-in period.  
During the treatment period, subjects will self-insert the assigned ring in the upper part of the 
vagina on RM+7 of cycle 1 to cycle 4 at the clinic by following standard instructions for use. 
Supervision by the site staff can be provided if needed. After insertion, the vaginal ring will be kept 
in the vagina continuously for one menstrual cycle until being replaced with the next ring on RM+7 
of the next cycle when the subject visits the clinic. Acceptability of the ring will be assessed by 
subjects via a ring acceptability questionnaire at each RM+7 visit during the treatment period. 
Unless under other effective birth control permitted by protocol, subjects will be required to use a 
non-hormonal single-barrier contraception (i.e. condom) from wash-out (if applicable) or run-in to 
end-of-trial. Contraception counselling and condoms will be offered to subjects throughout the trial.  
B&B will be administered electronically at randomization and at cycle 4 (at visits 4 and 10), with 
trained trial coordinators completing the first part based on subjects’ verbal responses and 
investigators completing the second part based on findings of a pelvic examination. Subjects will 
complete the electronic version of the EHP-30 questionnaire at randomization, and at every cycle 
from cycle 1 to cycle 4 (at visits 4, 6, 7, 8 and 10). PGIS scale will be completed electronically by 
subjects at cycle -2, at randomization and at cycle 4 (at visits 2, 4 and 10), while PGIC scale will be 
completed electronically at cycle 4 (at visit 10). 


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Clinical Trial Protocol 
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CONFIDENTIAL 
Blood samples will be collected throughout the trial for the purpose of evaluating mid-luteal phase 
endocrine parameters, bone turnover markers, endometriosis biomarkers, quinagolide and 
metabolites, and routine safety laboratory parameters. In this trial, mid-luteal phase is defined as 
6-9 days after luteinizing hormone (LH) surge (LH+6-9) as tested by subjects at home by means of 
commercially available urinary LH kits. LH+7 visits can be scheduled on LH+6-9, either based on 
an actual LH surge date as indicated by a positive LH surge test or based on an estimated LH surge 
date according to subjects’ cycle length if subjects fail to detect the LH surge. The exact cycle day 
of the LH+7 visit will be derived based on the first menstrual bleeding date of the current cycle 
confirmed at the RM+7 visits. An endocrine panel including estradiol, progesterone, prolactin, TSH 
and IGF-1 will be assessed during the mid-luteal phase of cycles -1 and 4 (at visits 3 and 9). 
Evidence of ovulation will be evaluated by serum levels of mid-luteal progesterone. Fasting blood 
samples for the analysis of a bone formation marker (s-PINP) and a bone resorption marker (s-CTx) 
will be collected during cycles -1 and 4 (at visits 3 and 9). Blood samples for endometriosis 
biomarkers including, but not limited to, VEGF, PlGF, IL-6 and sFlt-1 will also be collected during 
cycles -1 and 4 (at visits 3 and 9). At the same time points, if subjects have provided a separate 
informed consent, additional blood samples for potential analyses of circulating cell-free DNA and 
microRNA will also be collected. Routine safety laboratory tests for clinical chemistry and 
hematology parameters will be performed during cycle -1, at end-of-treatment and end-of-trial (at 
visits 3, 10 and 11). Quinagolide and metabolites will be measured within 1-5 days of first ring 
insertion, at RM+7 visits of cycles 1, 3 and 4 as well as at LH+7 visit of cycle 4 (at visits 5, 6, 8, 9 
and 10) to assess systemic exposure and allow for population PK modelling. Blood samples should 
be taken prior to ring removal at RM+7 visits. If subjects have provided a separate informed 
consent, a blood sample for pharmacogenetic analysis will also be collected at visit 5.  
ECG and echocardiography will be performed at screening and at end-of-treatment to monitor 
cardiovascular safety. ECG and echocardiography at screening can be arranged anytime during 
cycle -1 e.g. at LH+7 visit (visit 3) but results must be available prior to randomization. ECG and 
echocardiography at cycle 4 can be performed within ±2 weeks of visit 10.  
A modified questionnaire for impulsive-compulsive disorders (QICD) will be completed 
electronically by trained trial coordinators based on subjects’ verbal response prior to 
randomization at cycles -1 and 4 (at visits 4 and 10).  
A urine pregnancy test will be performed at each clinic visit (except for visit 5) throughout the trial. 
If the test result is positive and is confirmed by a following serum βhCG test, the subject should be 
discontinued from the trial. Urinalysis is performed before entry into run-in (before or at visit 1) 
and at cycle 4 (at visit 10).  
All subjects will be asked which treatment they believe they have received at the end of treatment. 
A sub-group of 60 subjects including 5 non-completers from selected sites, if they have provided a 
separate informed consent, will be invited to participate in a patient interview at the end of 
treatment to help determine the meaningful treatment benefit from the patients’ perspective and to 
assess the content validity of the questions related to daily functioning in the e-Diary.   
An internal Clinical Monitoring Committee consisting of the responsible medical officer, 
statistician and clinical trial manager will be established to regularly review the trial data including 
data with respect to the pre-defined stopping criteria in a blinded manner. An independent Data 
Monitoring Committee (DMC) consisting of exclusively external members will also be established. 
If the pre-defined stopping criteria on the treatment group or trial level are met, the DMC will be 


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requested to access unblinded safety data presented by treatment group and will recommend 
whether one dose, several doses or the trial should be discontinued. The DMC will also have access 
to the unblinded interim data presented by treatment group and will recommend whether the trial 
should be stopped for futility. In any case, the DMC will keep the data and analyses confidential 
from any persons involved in the conduct of the trial. 
An interim analysis is planned when approximately half of the planned evaluable subjects 
(104 subjects) have completed the treatment period of the trial for the assessment of the primary 
endpoint. The data will be prepared by treatment group by an external statistician. The purpose of 
the interim analysis is to evaluate futility of the trial and to adjust sample size if needed.  
NUMBER OF SUBJECTS 
It is planned to screen around 590 subjects to randomize 280 subjects (70 subjects per treatment 
group) to achieve 208 evaluable subjects at the end of treatment. The sample size will be 
re-estimated by an external statistician during an interim analysis and the number of randomized 
subjects may be adjusted up to 360.  
CRITERIA FOR INCLUSION / EXCLUSION 
Inclusion Criteria 
1. Informed consent(s) signed and dated prior to screening evaluations.  
2. Pre-menopausal females aged ≥18 years at time of signing informed consent(s).  
3. Body mass index (BMI) of 18-42 kg/m2 (both inclusive) at screening. 
4. Documentation of diagnosis by surgical visualization of endometriosis (laparoscopy or 
laparotomy) within the last 10 years before the run-in visit or visualization of persistent 
endometrioma (≥2 cm in diameter) by repeat ultrasound in two separate menstrual cycles 
before subject’s entry into run-in. 
5. Willing and able to use a non-hormonal single-barrier contraception (i.e. condom) from 
wash-out (if applicable) or run-in to the end-of-trial. This is not required if adequate 
contraception is achieved by vasectomy of the male sexual partner, surgical sterilization (e.g. 
tubal ligation and blockage methods such as ESSURE) of the subject, or true abstinence of 
the subject (sporadic sexual intercourse with men still requires condom use).  
6. Willing to avoid the use of vaginal douches or any other intravaginally administered 
medications or devices from randomization to the end of treatment. 
7. Willing to change usual analgesics to rescue analgesics as permitted by protocol for 
endometriosis-related pain from the start of run-in to the end-of-trial.  
8. Willing to avoid any prophylactic use of analgesics from the start of run-in to the end-of-
trial.  
9. Willing to avoid any change in the use of non-drug therapy (e.g. acupuncture and 
physiotherapy) for endometriosis-related pain from the start of run-in to the end-of-trial.  
10. Transvaginal ultrasound documenting a uterus with no clinically significant abnormalities 
(e.g. hysterectomy) and presence of at least one ovary with no clinically significant 
abnormalities with the exception of endometrioma (e.g. no evidence of ovarian cyst ≥5 cm, 
fibroid ≥4 cm, or presence of a submucosal fibroid) at the run-in visit. 


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11. Two regular menstrual cycles of 24-35 days (both inclusive) observed during the run-in 
period.  
12. Having moderate to severe endometriosis-related pain defined as: 
12a) At the run-in visit, on a self-administered 11-point NRS, having an NRS score of ≥5 
for the worst endometriosis-related pain during the past menstrual cycle.   
12b) At randomization, on the self-administered 11-point NRS, having a mean daily NRS 
score of ≥4 for the worst endometriosis-related pain during each run-in cycle. 
13. Completion of the daily e-Diary for at least 80% of the days on average in two run-in cycles, 
from the day the e-Diary is available at the start of cycle -2 through the day before visit 4 at 
the end of cycle -1.  
14. Documentation of a normal cervical cytology or negative results of human papilloma virus 
(HPV) reflex testing within 24 months of the start of run-in. If atypical squamous cells of 
undetermined significance were present on prior tests, additional follow-up HPV test results 
should be negative for high-risk viral subtypes.  
15. Negative cervical swab for gonorrhea and chlamydia at screening.  
16. Willing and able to comply with trial procedures, including filling in the e-Diary in English 
or Spanish, attending scheduled visits and adherence to treatment plan. 
Exclusion Criteria 
1. Use of depot medroxyprogesterone acetate (MPA) within 10 months of the start of run-in. 
2. Use of gonadotropin releasing hormone (GnRH) agonists (3-month depot injection) or 
dopamine agonists within 6 months of the start of run-in. 
3. Use of GnRH agonists (1-month depot injection or nasal spray) or birth control implants (e.g. 
NEXPLANON) within 3 months of the start of run-in. 
4. Use of GnRH antagonists, aromatase inhibitors, danazol, intrauterine devices or hormonal 
contraceptives (including combined oral contraceptive pill, progestin-only pill, transdermal 
patch and contraceptive ring) within 1 month of the start of run-in. 
5. Undiagnosed abnormal vaginal bleeding. 
6. Current vestibulodynia and vulvodynia.  
7. Chronic abdominal, pelvic or lower back pain diagnosed to be of non-endometriosis origin 
(e.g. presumptive adenomyosis as a dominant condition diagnosed by magnetic resonance 
imaging (MRI) or ultrasound, inflammatory bowel disease, interstitial cystitis, spinal disc 
herniation) that would interfere with the assessment of endometriosis-related pain. 
8. Current diagnosis of a chronic pain syndrome (e.g. fibromyalgia, chronic back pain, 
myofascial pain syndrome, chronic headache) or any other condition that requires continuous 
use of analgesic therapy.  
9. Known bone diseases (e.g. osteoporosis, Paget’s disease and osteomalacia) affecting bone 
resorption or bone formation markers. 
10. Chronic endocrine abnormality affecting the hypothalamic-pituitary-gonadal axis or leading 
to ovarian dysfunction except for hyperprolactinemia.  
11. Known positive results of hepatitis B virus, hepatitis C virus and human immunodeficiency 
virus (HIV) antibody tests. 
12. History of no relief of endometriosis-related pain after any medical therapy or surgery. 


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However, history of partial pain relief, discontinuation due to side effects from medical 
therapy or non-adherence to post-surgery medical therapy are not exclusionary.  
13. History of having used more than 2 consecutive weeks of a prohibited long-acting narcotic or 
immediate-release narcotic for treatment of endometriosis-related pain within 6 months of 
the start of run-in.    
14. History of malignancy within 5 years of the start of screening, except for adequately 
managed basal cell carcinoma and squamous cell carcinoma of the skin. 
15. History of recurrent bacterial / fungal vaginal infection or recurrent urinary tract infection 
(all defined as ≥4 episodes within a year).  
16. History of orthostatic hypotension or recurrent syncope. 
17. History of mental illness including occurrence of acute psychosis, bipolar disorders and 
schizophrenia (except for well-controlled anxiety and/or depression with no changes to 
interventions for 6 months prior to start of run-in). 
18. History of impulse control disorders including pathological gambling, compulsive buying, 
hypersexuality, and binge eating or being identified with potential impulse control disorder 
by the questionnaire for impulsive-compulsive disorders (a score ≥2 for any sub-questions of 
Question 3 or a score ≥1 for any sub-questions of Question 4) prior to randomization. 
19. History of valvular heart disease. 
20. History of sudden sleep onset episodes.  
21. Any clinically significant abnormal findings from vital signs, urinalysis, blood tests of 
hematology and clinical chemistry at screening, including a drop of 20 mmHg of systolic 
blood pressure or a drop of 10 mmHg of diastolic blood pressure within three minutes of 
standing from a sitting position, alanine aminotransferase (ALT) >2.5 times upper limit of 
normal (ULN) or bilirubin >1.5 times ULN or creatinine >1.5 mg/dL.  
22. Any clinically significant abnormal findings from blood test of endocrine parameters 
(including signs indicating menopausal status but excluding hyperprolactinemia) at 
screening. 
23. Any clinically significant abnormal findings from physical examination at screening. 
24. Any vaginal or vulvar lesions that could interfere with vaginal ring usage. 
25. Any significant abnormal ECG or echocardiography findings (e.g. valvular regurgitation or 
stenosis) before randomization. 
26. Any recent suicidal ideation of type 4 (i.e. active suicidal ideation with some intent to act, 
without specific plan) or type 5 (i.e. active suicidal ideation with specific plan and intent), or 
suicidal behavior identified by the electronic Columbia-Suicide Severity Rating Scale at 
screening.  
27. Hypersensitivity to any active ingredient, excipients or other component of medicinal 
products used in the trial, including quinagolide vaginal ring, placebo vaginal ring and 
ibuprofen.  
28. Known serious adverse drug reactions to dopamine agonist. 
29. Current or history of gastrointestinal ulcer or gastrointestinal bleeding within 6 months of the 
run-in visit.  
30. Current pregnancy as confirmed by a positive serum βhCG test at screening or planning a 


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pregnancy within the duration of the trial, currently breast-feeding or less than 6 months 
post-partum of the run-in visit. 
31. Planned surgical treatment of endometriosis or planned surgery in the abdominal-pelvic or 
lower back area within the duration of the trial that could interfere with the efficacy 
assessment. 
32. History of drug abuse within 2 years of the start of screening or a current positive urine drug 
screen, unless the cause of the positive result is from opioids and antidepressants that are 
medically indicated and prescribed by a physician.  
33. Current or history of alcohol abuse within 2 years of the start of the run-in visit. 
34. Current or previous participation in a clinical trial involving a non-registered investigational 
medicinal product within 1 month of the run-in visit. If the trial involves a hormonal drug, 
the exclusion criteria 1-4 shall apply. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
Quinagolide vaginal ring is an extended-release system with a dose load of quinagolide 360 µg, 
720 µg and 1080 µg at a target daily release rate of quinagolide 4.5 µg/day, 9 µg/day and 
13.5 µg/day, respectively, for up to 35 days duration. 
– 
Quinagolide vaginal ring dose load 360 µg at a target release rate of quinagolide 4.5 µg/day: 
administered once per menstrual cycle (up to 35 days), sequentially for four menstrual cycles 
– 
Quinagolide vaginal ring dose load 720 µg at a target release rate of quinagolide 9 µg/day: 
administered once per menstrual cycle (up to 35 days), sequentially for four menstrual cycles 
– 
Quinagolide vaginal ring dose load 1080 µg at a target release rate of quinagolide 13.5 µg/day: 
administered once per menstrual cycle (up to 35 days), sequentially for four menstrual cycles 
– 
Placebo vaginal ring: administered once per menstrual cycle (up to 35 days), sequentially for 
four menstrual cycles 
DURATION OF TREATMENT 
 
Subjects will be exposed to placebo vaginal ring or quinagolide vaginal ring for 4 menstrual cycles, 
depending on randomization. 
STATISTICAL METHODS 
Primary Endpoint Analysis  
The primary objective of this trial is to evaluate the efficacy of three doses of quinagolide 
administered as an extended-release vaginal ring compared to placebo on reduction of moderate to 
severe endometriosis-related pain. The primary endpoint is the change in mean daily NRS score for 
the worst endometriosis-related pain at cycle 4. 
The participating subjects will record their NRS score daily throughout each menstrual cycle. For 
each cycle the daily recordings will be averaged to calculate the mean daily NRS score. The mean 
daily NRS score obtained during the two run-in menstrual cycles (cycles -2 and -1) will be 
considered the baseline mean daily NRS score. The primary endpoint will be derived as the 
difference between the mean daily NRS score for cycle 4 and the baseline mean daily NRS score.   
The primary endpoint will be analyzed using a repeated measures analysis of covariance 


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(ANCOVA) model, with the change in mean daily NRS score from baseline measured at cycles 1, 
2, 3 and 4 as dependent variable, the baseline mean daily NRS score and the baseline percentage of 
days on rescue analgesics by type as covariates, as well as treatment group and treatment by cycle 
as fixed effect. Unstructured error-covariance matrices will be used. The treatment contrasts 
between each active treatment versus placebo at cycle 4 will be reported with 95% confidence 
intervals and corresponding p-values.  
The primary analysis will be based on observed cases in the intention-to-treat (ITT) analysis set, 
while the analysis based on the per-protocol (PP) population will be considered supportive and 
serve as one of the sensitivity analyses. Other sensitivity analyses focus, among other things, on: 
• the impact of missing data if assuming missing not at random by applying a placebo-based 
pattern mixture model  
• the heterogeneity of the effect in terms of baseline mean daily NRS score, percentage of 
days on rescue analgesics by type at baseline by testing respective treatment interactions 
• the impact of also adjusting the ANCOVA model for the percentage of days on rescue 
analgesics by type at cycles 1, 2, 3, and 4 (time dependent) and the impact of changing 
baseline NRS score from a daily mean of two run-in cycles to that of the last run-in cycle 
 
Secondary Endpoint Analysis 
Secondary efficacy endpoints are analyzed longitudinally by applying repeated measures 
ANCOVA for continuous endpoints, repeated measures logistic-regression using the generalized 
estimating equation (GEE) approach and logit link function for binary data, and repeated measures 
negative-binomial regression analysis using the GEE approach with log link function for count 
data. Unstructured error-covariance matrices will be used. In addition, time to first occurrence of 
response will be analyzed using proportional odds regression. Secondary safety endpoints will be 
analyzed for the safety analysis set, whereas all other endpoints will be analyzed for both the ITT 
and PP populations.  
 
Interim Analysis 
An interim analysis with the option to stop the trial early due to futility will be performed by an 
external statistician when approximately half of the planned evaluable subjects (104 subjects) have 
completed the treatment period of the trial for the assessment of the primary endpoint using 
unblinded data. The futility bound is set at a conditional power using current trend equal to 5%, i.e. 
the trial could be potentially stopped for futility if the probability of achieving a significant result in 
the highest remaining dose group is lower than 5% based on the observed data at the interim 
analysis. In case of high drop-out rate or discontinuations in the highest dose group, the analysis 
will be performed on the remaining dose(s). No interim analysis intended to stop the trial early due 
to overwhelming efficacy is planned. 
 
Sample Size Calculations 
The sample size calculation is based on demonstrating superiority of quinagolide vaginal ring 
compared with placebo vaginal ring on the primary endpoint of change in mean daily NRS score 
for the endometriosis-related pain at cycle 4.  


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Assuming that the standard deviation of the change in mean daily NRS is 1.5 units, a sample size of 
52 evaluable subjects per group will have at least 90% power to detect a treatment effect difference 
of 1.0 unit using a t-test at a 5% two-sided significance level in a pre-defined hierarchical step-
down procedure starting with testing the highest dose versus placebo, taking into account the 
planned interim analysis for futility at a conditional power using current trend equal to 5%. 
Accounting for an approximately 25% drop-out rate, 70 subjects should be randomized to each 
treatment group, i.e. in total 280 subjects should be randomized. A sample size re-estimation will 
be performed by the external statistician at the same time of the interim analysis. The sample size 
may be increased to 360 subjects. 
 


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TABLE OF CONTENTS 
SYNOPSIS ....................................................................................................................................................... 2 
LIST OF TABLES ........................................................................................................................................ 19 
LIST OF FIGURES ...................................................................................................................................... 20 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................................ 21 
1 
INTRODUCTION ............................................................................................................................. 24 
1.1 
Background ............................................................................................................................. 24 
1.2 
Scientific Justification for Conducting the Trial ..................................................................... 25 
1.3 
Benefit / Risk Aspects ............................................................................................................. 26 
2 
TRIAL OBJECTIVES AND ENDPOINTS ..................................................................................... 30 
2.1 
Objectives ............................................................................................................................... 30 
2.2 
Endpoints ................................................................................................................................ 30 
3 
INVESTIGATIONAL PLAN ........................................................................................................... 32 
3.1 
Overall Trial Design................................................................................................................ 32 
3.1.1 
Trial Design Diagram................................................................................................. 32 
3.1.2 
Overall Design and Control Methods ........................................................................ 33 
3.1.3 
Trial Schedule ............................................................................................................ 36 
3.2 
Planned Number of Trial Sites and Subjects ........................................................................... 36 
3.3 
Interim Analysis ...................................................................................................................... 36 
3.4 
Clinical Monitoring Committee .............................................................................................. 37 
3.5 
Data Monitoring Committee ................................................................................................... 37 
3.6 
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 38 
3.6.1 
Trial Design ............................................................................................................... 38 
3.6.2 
Selection of Endpoints ............................................................................................... 39 
3.6.3 
Blinding...................................................................................................................... 41 
3.6.4 
Selection of Doses in the Trial ................................................................................... 41 
3.6.5 
Selection and Timing of Dose for Each Subject ........................................................ 43 
3.6.6 
Selection of the Trial Population ............................................................................... 44 
3.6.7 
Discontinuation Criteria (Stopping and Withdrawal Criteria) ................................... 44 
3.6.8 
Follow-up Procedures ................................................................................................ 46 
4 
SELECTION OF TRIAL POPULATION ...................................................................................... 47 
4.1 
Trial Population....................................................................................................................... 47 
4.1.1 
Inclusion Criteria ....................................................................................................... 47 
4.1.2 
Exclusion Criteria ...................................................................................................... 48 
4.2 
Method of Assigning Subjects to Treatment Groups .............................................................. 50 
4.2.1 
Recruitment ................................................................................................................ 50 
4.2.2 
Randomization ........................................................................................................... 50 
4.3 
Restrictions ............................................................................................................................. 50 
4.3.1 
Prohibited Medications / Therapies ........................................................................... 50 
4.3.2 
Other Restrictions ...................................................................................................... 52 
4.4 
Subject Replacement ............................................................................................................... 52 
5 
TREATMENTS ................................................................................................................................. 53 
5.1 
Treatments Administered ........................................................................................................ 53 
5.1.1 
Investigational Medicinal Products (IMPs) ............................................................... 53 


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5.1.2 
Non-Investigational Medicinal Product (NIMP) ....................................................... 53 
5.2 
Characteristics and Source of Supply ..................................................................................... 54 
5.2.1 
Investigational Medicinal Product ............................................................................. 54 
5.2.2 
Non-Investigational Medicinal Product ..................................................................... 55 
5.3 
Packaging and Labelling ......................................................................................................... 55 
5.4 
Conditions for Storage and Use .............................................................................................. 55 
5.5 
Blinding / Unblinding ............................................................................................................. 56 
5.5.1 
Blinding...................................................................................................................... 56 
5.5.2 
Unblinding of Individual Subject Treatment ............................................................. 56 
5.6 
Treatment Compliance ............................................................................................................ 57 
5.6.1 
Dispensing and Accountability .................................................................................. 57 
5.6.2 
Assessment of Compliance ........................................................................................ 58 
5.7 
Return and Destruction of Medicinal Products ....................................................................... 58 
5.8 
Auxiliary Supplies................................................................................................................... 58 
6 
TRIAL PROCEDURES .................................................................................................................... 59 
6.1 
Activities between Clinic Visits .............................................................................................. 60 
6.1.1 
Premature Discontinuation ......................................................................................... 60 
6.2 
Screening ................................................................................................................................. 61 
6.2.1 
Wash-out Period (As Applicable) .............................................................................. 61 
6.2.2 
Visit 1 (Start of Run-in) ............................................................................................. 61 
6.2.3 
Visit 2 (RM+7 of Cycle -2) ........................................................................................ 63 
6.2.4 
Visit 3 (LH+7 of Cycle -1) ......................................................................................... 63 
6.3 
Randomization ........................................................................................................................ 64 
6.3.1 
Visit 4 (RM+7 of Cycle -1) ........................................................................................ 64 
6.4 
Treatment ................................................................................................................................ 65 
6.4.1 
Visit 5 (Within 1-5 days of Visit 4) ........................................................................... 65 
6.4.2 
Visit 6 (RM+7 of Cycle 1) ......................................................................................... 66 
6.4.3 
Visit 7 (RM+7 of Cycle 2) ......................................................................................... 66 
6.4.4 
Visit 8 (RM+7 of Cycle 3) ......................................................................................... 67 
6.4.5 
Visit 9 (LH+7 of Cycle 4) .......................................................................................... 68 
6.4.6 
Visit 10 (End-of-Treatment / RM+7 of Cycle 4) ....................................................... 68 
6.5 
Follow-up ................................................................................................................................ 70 
6.5.1 
Visit 11 (End-of-Trial / RM+7 of Cycle 5) ................................................................ 70 
7 
TRIAL ASSESSMENTS ................................................................................................................... 71 
7.1 
Assessments Related to Primary Endpoint ............................................................................. 71 
7.1.1 
Endometriosis-related Pain ........................................................................................ 71 
7.2 
Assessments Related to Secondary Endpoints ........................................................................ 72 
7.2.1 
Assessments Related to Secondary Endpoints in e-Diary .......................................... 72 
7.2.1.1 
Dysmenorrhea and Non-menstrual Pelvic Pain ......................................... 73 
7.2.1.2 
Dyspareunia and Frequency of Avoiding Sexual Intercourse due to 
Expected Pain ............................................................................................ 73 
7.2.1.3 
Pain Impact ................................................................................................ 74 
7.2.1.4 
Vaginal Bleeding Pattern ........................................................................... 76 
7.2.1.5 
Analgesic Use ............................................................................................ 76 
7.2.1.6 
Responder Rate .......................................................................................... 78 
7.2.2 
Assessments Related to Secondary Endpoints at Clinic Visits .................................. 78 
7.2.2.1 
Biberoglu and Behrman (B&B) Scale ....................................................... 78 


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7.2.2.2 
Endometriosis Health Profile-30 (EHP-30) Questionnaire ....................... 79 
7.2.2.3 
Patient Global Impression of Severity (PGIS) Scale ................................. 79 
7.2.2.4 
Patient Global Impression of Change (PGIC) Scale.................................. 80 
7.2.2.5 
Plasma Concentration of Quinagolide and Metabolites ............................ 80 
7.2.2.6 
Mid-luteal Phase Endocrine Parameters and Ovarian Function ................ 80 
7.2.2.7 
Bone Turnover Markers ............................................................................ 80 
7.2.2.8 
Electrocardiography (ECG) ....................................................................... 81 
7.2.2.9 
Echocardiography ...................................................................................... 81 
7.2.2.10 
Impulse Control Disorder .......................................................................... 82 
7.2.2.11 
Adverse Events .......................................................................................... 83 
7.2.2.12 
Clinical Chemistry and Hematology Parameters ....................................... 83 
7.2.2.13 
Urinalysis ................................................................................................... 84 
7.2.2.14 
Ring Acceptability ..................................................................................... 84 
7.3 
Assessment Related to Exploratory Endpoint ......................................................................... 84 
7.3.1 
Potential Endometriosis Biomarkers .......................................................................... 84 
7.3.1.1 
Optional Cell-free DNA and MicroRNA Analyses ................................... 85 
7.4 
Other Assessments .................................................................................................................. 85 
7.4.1 
Numerical Rating Scale (NRS) for Entry into Run-in ............................................... 85 
7.4.2 
Demographics ............................................................................................................ 85 
7.4.3 
Medical History ......................................................................................................... 85 
7.4.4 
Menstrual History ...................................................................................................... 85 
7.4.5 
Reproductive History ................................................................................................. 86 
7.4.6 
Body Measurement .................................................................................................... 86 
7.4.7 
Menstruation Dates .................................................................................................... 86 
7.4.8 
Urine Pregnancy Test ................................................................................................. 86 
7.4.9 
Urine Drug Screen ..................................................................................................... 86 
7.4.10 Luteinizing Hormone Surge ....................................................................................... 86 
7.4.11 Physical Examination ................................................................................................. 86 
7.4.12 Gynecological and Pelvic Examination ..................................................................... 87 
7.4.13 Cervical Swab ............................................................................................................ 87 
7.4.14 Transvaginal Ultrasound ............................................................................................ 87 
7.4.15 Vital Signs .................................................................................................................. 88 
7.4.16 Columbia-Suicide Severity Rating Scale (C-SSRS) .................................................. 88 
7.4.17 Concomitant Medication ............................................................................................ 89 
7.4.18 Drug Accountability ................................................................................................... 89 
7.4.19 End-of-Treatment Question ....................................................................................... 89 
7.4.20 End-of-Treatment Form ............................................................................................. 90 
7.4.21 End-of-Trial Form ...................................................................................................... 90 
7.4.22 Optional Pharmacogenetic Analysis .......................................................................... 90 
7.4.23 Optional Patient Interviews ........................................................................................ 90 
7.5 
Handling of Biological Samples ............................................................................................. 91 
8 
ADVERSE EVENTS ......................................................................................................................... 92 
8.1 
Adverse Event Definition ........................................................................................................ 92 
8.2 
Collection and Recording of Adverse Events ......................................................................... 92 
8.2.1 
Collection of Adverse Events .................................................................................... 92 
8.2.2 
Recording of Adverse Events .................................................................................... 93 
8.3 
Adverse Events of Special Interest ......................................................................................... 95 


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8.3.1 
Dizziness / Pre-syncope ............................................................................................. 95 
8.3.2 
Syncope ...................................................................................................................... 96 
8.3.3 
Dysmenorrhea, Abdominal Pain, Pelvic Pain, Lower Back Pain and 
Dyspareunia ............................................................................................................... 96 
8.3.4 
Vaginal Bleeding ....................................................................................................... 96 
8.3.5 
Ring Acceptability ..................................................................................................... 96 
8.3.6 
Vaginal Irritation and/or Vaginal Infection................................................................ 96 
8.4 
Pregnancy and Pregnancy Outcome........................................................................................ 97 
8.5 
Serious Adverse Events (SAEs) .............................................................................................. 98 
8.5.1 
Serious Adverse Event Definition .............................................................................. 98 
8.5.2 
Collection, Recording and Reporting of Serious Adverse Events ............................. 99 
8.6 
Follow-up of Adverse Events and Serious Adverse Events .................................................. 100 
8.6.1 
Follow-up of Adverse Events with Onset during the Trial ...................................... 100 
8.6.2 
Collection of Serious Adverse Events with Onset after Last Visit in the Trial ....... 100 
9 
STATISTICAL METHODS ........................................................................................................... 101 
9.1 
Determination of Sample Size .............................................................................................. 101 
9.2 
Subject Disposition ............................................................................................................... 102 
9.3 
Protocol Deviations ............................................................................................................... 102 
9.4 
Analysis Sets ......................................................................................................................... 103 
9.4.1 
Intention-to-Treat (ITT) Analysis Set ...................................................................... 103 
9.4.2 
Per-Protocol (PP) Analysis Set ................................................................................ 103 
9.4.3 
Safety Analysis Set .................................................................................................. 103 
9.5 
Trial Population..................................................................................................................... 103 
9.5.1 
Demographics and other Baseline Characteristics ................................................... 103 
9.5.2 
Medical History, Concomitant Medication and other Safety Evaluations ............... 103 
9.6 
Endpoint Assessments........................................................................................................... 104 
9.6.1 
General Considerations ............................................................................................ 104 
9.6.2 
Primary Endpoint ..................................................................................................... 105 
9.6.3 
Secondary and Exploratory Endpoints ..................................................................... 107 
9.7 
Extent of Exposure and Treatment Compliance ................................................................... 110 
9.8 
Safety Endpoints ................................................................................................................... 110 
9.9 
Interim Analysis .................................................................................................................... 112 
10 
DATA HANDLING ......................................................................................................................... 113 
10.1 
Source Data and Source Documents ..................................................................................... 113 
10.2 
e-CRF .................................................................................................................................... 114 
10.3 
Use of Patient Reported Outcome ......................................................................................... 115 
10.4 
Data Management ................................................................................................................. 115 
10.5 
Provision of Additional Information ..................................................................................... 116 
11 
MONITORING PROCEDURES ................................................................................................... 117 
11.1 
Periodic Monitoring .............................................................................................................. 117 
11.2 
Audit and Inspection ............................................................................................................. 117 
11.3 
Confidentiality of Subject Data ............................................................................................. 117 
12 
CHANGES IN THE CONDUCT OF THE TRIAL ...................................................................... 119 
12.1 
Protocol Amendments ........................................................................................................... 119 
12.2 
Deviations from the Protocol ................................................................................................ 119 
12.3 
Premature Trial Termination ................................................................................................. 119 


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13 
REPORTING AND PUBLICATION ............................................................................................ 120 
13.1 
Clinical Trial Report ............................................................................................................. 120 
13.2 
Confidentiality and Ownership of Trial Data ........................................................................ 120 
13.3 
Publications and Public Disclosure ....................................................................................... 120 
13.3.1 Publication Policy .................................................................................................... 120 
13.3.2 Public Disclosure Policy .......................................................................................... 121 
14 
ETHICAL AND REGULATORY ASPECTS ............................................................................... 122 
14.1 
Institutional Review Board ................................................................................................... 122 
14.2 
Regulatory Authorities’ Approval......................................................................................... 122 
14.3 
End-of-Trial .......................................................................................................................... 122 
14.4 
Ethical Conduct of the Trial .................................................................................................. 122 
14.5 
Subject Information and Consent .......................................................................................... 122 
14.6 
Subject Participation Card .................................................................................................... 123 
14.7 
Compliance Reference Documents ....................................................................................... 124 
15 
LIABILITIES AND INSURANCE ................................................................................................ 125 
15.1 
ICH-GCP Responsibilities .................................................................................................... 125 
15.2 
Liabilities and Insurance ....................................................................................................... 125 
16 
ARCHIVING .................................................................................................................................... 126 
16.1 
Investigator File .................................................................................................................... 126 
16.2 
Trial Master File.................................................................................................................... 126 
17 
REFERENCES ................................................................................................................................. 127 
 
 
 
 
APPENDIX 1 
Diaries, Scales and Questionnaires  
 


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LIST OF TABLES  
 
 
Table 5-2 Packaging of Medicinal Products ................................................................................... 55 
Table 6-1 Trial Flow Chart – Procedures at Clinics ........................................................................ 59 
Table 6-2 Trial Flow Chart – Self-assessments by Subjects ........................................................... 60 
Table 8-1 Grading of Vaginal Irritation .......................................................................................... 97 
Table 9-1 Sample Size by Treatment Effect Difference ............................................................... 101 
Table 9-2 Analyses of Secondary and Exploratory Endpoints ...................................................... 109 


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LIST OF FIGURES 
Figure 3-1 Trial Diagram – Trial Period ........................................................................................... 32 
Figure 3-2 Dose Selection for Quinagolide Vaginal Ring ................................................................ 43 
 
Figure 7-1 Location of Endometriosis-related Pain .......................................................................... 71 
Figure 7-2 Modified Endometriosis Health Profile-30 (EHP-30) Pain Impact Domain .................. 75 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
List of Abbreviations 
1-5d 
1-5 days 
2D 
2-dimensional 
5-HT 
5-hydroxytryptamin receptor 
5-HT2B 
5-hydroxytryptamin 2B receptor 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUCtau 
area under the plasma concentration-time curve during a dosing interval 
B&B 
Biberoglu and Behrman  
βhCG 
beta unit of human chorionic gonadotropin 
BMI 
body mass index 
BOCF 
baseline-observation-carried-forward 
BTM 
bone turnover markers 
CBC 
complete blood count 
Cmax 
maximum plasma concentration 
COX2 
cyclooxygenase-2 
COVID-19 
coronavirus disease 2019 
CR 
controlled-release 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP2D6 
cytochrome P450 2D6 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
E2 
estradiol 
ECG 
electrocardiography 
Echo 
echocardiography 
e-CRF 
electronic case report form 
eC-SSRS 
electronic Columbia-Suicide Severity Rating Scale 
e-Diary 
electronic diary 
EHP-30 
Endometriosis Health Profile-30  
EOT 
end-of-trial 
EOTx 
end-of-treatment 
ER 
extended-release 
EudraCT 
European Union Clinical Trial Database 
FDA 
Food and Drug Administration 
FPFV 
first patient first visit 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equation 
GMP 
Good Manufacturing Practice 
GnRH 
gonadotropin releasing hormone 
Gyn exam 
gynecological examination 
h 
hours 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 


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HIV 
human immunodeficiency virus 
HPV 
human papilloma virus 
ICH 
International Conference on Harmonisation 
ICH-GCP 
International Conference on Harmonisation-Good Clinical Practice 
ICMJE 
International Committee of Medical Journal Editors 
IGF-1 
insulin-like growth factor-1 
IL-6 
interleukin 6 
IMP 
investigational medicinal product 
IND 
investigational new drug  
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
intention-to-treat 
kg 
kilogram 
L 
liter 
lab 
laboratory 
LH 
luteinizing hormone  
LH+6-9 
6-9 days after LH surge 
LH+7 
7 days after LH surge  
LOCF 
last-observation-carried-forward 
LPLV 
last patient last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL  
milliliter 
MPA 
medroxyprogesterone acetate 
MRI 
magnetic resonance imaging  
NIMP 
non-investigational medicinal product 
nmol 
nanomol 
NSAIDs 
non-steroidal anti-inflammatory drugs 
NRS 
Numerical Rating Scale 
OHSS 
ovarian hyperstimulation syndrome 
P4 
progesterone 
pg 
picogram 
PG 
pharmacogenetic(s)  
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity  
PK 
pharmacokinetic(s)  
PlGF 
placenta growth factor 
PP 
per-protocol 
PR interval  
the interval between the start of the P wave and the start of the QRS complex, 
corresponding to the time between onset of atrial depolarization and onset of 
ventricular depolarization  
PRO 
patient reported outcome 
QICD 
Questionnaire for Impulsive-Compulsive Disorder  
QRS interval the interval between the start of Q wave to the end of the S wave, corresponding to 
ventricle depolarization  
QTcF 
corrected QT interval using Fridericia’s formula 


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QT interval 
the interval between the start of the Q wave and the end of the T wave, 
corresponding to electrical systole  
QVR 
quinagolide vaginal ring  
RM 
return of menses  
RM+1 
day 1 of return of menses 
RM+6-10 
day 6 to day 10 of return of menses 
RM+7 
day 7 of return of menses 
RNA 
ribonucleic acid 
RR interval 
the interval from the start of one R wave to the next 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
s-CTx 
serum C-terminal cross-linking telopeptide of type 1 collagen 
sFlt-1 
soluble fms-like tyrosine kinase-1 
SOC 
system organ class  
s-PINP 
serum procollagen type I N propeptide 
SUSAR 
suspected unexpected serious adverse reaction  
Tmax  
time to maximum plasma concentration (Cmax) 
TSH 
thyroid-stimulating hormone 
TVU 
transvaginal ultrasound 
µg 
microgram  
ULN 
upper limit of normal 
V 
visit 
VEGF 
vascular endothelial growth factor 
 
 
 
Definition of Terms 
Menstrual cycle 
In this trial, a menstrual cycle is considered the period between day 7 of return 
of menses (RM+7) until the following RM+7 in the next cycle. RM+7 visit can 
be arranged day 6 to day 10 of return of menses. The starting day of return of 
menses (RM) is day 1 of return of menses (RM+1).  
 
Mid-luteal phase 
In this trial, mid-luteal phase is defined as 6-9 days after LH surge (LH+6-9). 
LH+7 visit can be arranged 6-9 days after LH surge.  
 
 
Progesterone Units Conversion Factor  
1 ng/mL=3. 184 nmol/L 
1 nmol/L=0.314 ng/mL 
 
 


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1 
INTRODUCTION 
1.1 
Background 
Endometriosis is an estrogen-dependent disease, pathologically characterized by the presence of 
endometrial-like tissue abnormally implanted outside the uterus and primarily located on the pelvic 
peritoneum, ovaries, and rectovaginal septum.1 Symptoms of endometriosis often present as pain 
associated with menstruation (dysmenorrhea), non-menstrual pelvic pain, and pain during or after 
intercourse (dyspareunia).2,3 Endometriosis is estimated to affect 6% to 10% of women of 
reproductive age and up to 50% of women with infertility.4,5 Affected women can lose up to 10 
working hours weekly, mainly owing to reduced effectiveness whilst working.6 It has been 
estimated that, in the United States, the costs of diagnosing endometriosis and treating associated 
pain and infertility is in excess of $50 billion per annum and yet, treatment options remain 
inadequate.7  
Treatment of endometriosis-related pain currently involves repeated courses of medical therapy, 
surgical therapy, or both. Empirical treatment with analgesics and combined oral contraceptives, 
without prior definitive diagnosis of endometriosis by laparoscopy, is usually the first line treatment 
especially in adolescents.8 Self-administered non-steroidal anti-inflammatory drugs (NSAIDs) are 
commonly used initially to relieve pain symptoms associated with endometriosis, but the 
effectiveness is not well established.3 All established hormonal therapies (progestins, gonadotropin 
releasing hormone (GnRH) agonists, and danazol) are similarly effective. However, some of these 
drugs are associated with anti-ovulatory effect leading to amenorrhea and oligomenorrhea or with 
hypoestrogenic effect such as bone loss and vasomotor symptoms, all of which limit their duration 
of use and result in undesirable iatrogenic sterility in women seeking conception.9,10 Long-term 
treatment of endometriosis without undesirable anti-ovulatory or hypoestrogenic effects remains an 
unmet medical need. 
As a novel non-hormonal approach to the management of endometriosis, dopamine receptor 
agonists have been suggested to inhibit the angiogenesis process that is essential for the 
development and maintenance of endometriotic lesions. Non-clinical and clinical data have 
suggested evidence of the primary pharmacological effects of dopamine receptor agonists in 
reduction of endometriotic lesions.  
Quinagolide is a non-ergot-derived, potent and selective dopamine receptor 2 agonist. Quinagolide 
is available in some countries outside the United States as oral tablets for the treatment of 
hyperprolactinemia with extensive post-marketing experience. In addition, it has been formulated 
into an extended-release vaginal ring for the treatment of endometriosis-related pain. The vaginal 
ring allows extended release of quinagolide for up to 35 days and can be replaced by a new vaginal 
ring in every menstrual cycle.  
For further information regarding quinagolide vaginal ring, please refer to the Investigator’s 
Brochure.11 


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1.2 
Scientific Justification for Conducting the Trial 
As an integral part of the endometriosis pathogenesis, the establishment of a new blood supply is 
essential for survival and growth of endometriotic tissues when implanted outside the uterine 
cavity. This angiogenesis process is a critical mechanism that allows the development of 
endometriosis. The most prominently studied angiogenic factor is vascular endothelial growth 
factor (VEGF), which has been noted in endometriotic lesions, endometriomas and the peritoneal 
fluid of endometriosis patients.12,13,14 A positive correlation between the severity of endometriosis 
and the level of VEGF concentration in peritoneal fluid has been observed.14  
Dopamine 2 receptors are present in ectopic endometrium.15 Dopamine agonist-mediated dopamine 
receptor 2 activation promotes VEGF receptor 2 endocytosis, preventing binding of VEGF to 
VEGF receptor 2. Administration of dopamine receptor 2 agonists was shown to reduce vascular 
permeability without affecting corpus luteum angiogenesis and function by partially inhibiting 
VEGF receptor 2 phosphorylation.16 In addition, it has been shown that dopamine receptor 2 
agonists diminish nerve fibre density in experimental endometriotic lesions.17  
Non-clinical and clinical data have suggested evidence of primary pharmacological effects of 
quinagolide in reduction of endometriotic lesions. In mice with induced endometriosis, a significant 
reduction in the size of active lesions, cellular proliferation index and angiogenic gene expression 
was observed with oral quinagolide (50 or 200 μg/kg per day during a 14-day period) versus 
vehicle.18 In a proof-of-concept clinical trial involving 9 hyperprolactinemic patients with 
endometriosis, it was observed at second-look laparoscopy that oral administration of quinagolide 
25 µg to 75 µg once daily for 18-20 weeks induced a significant reduction in the overall size of 
endometriotic lesions, together with histological evidence of tissue degeneration and down-
regulation of VEGF and proangiogenic cytokines.19  
Three phase 1 trials have been conducted in Germany and the United Kingdom with intravaginal 
administration of quinagolide in healthy volunteers. Intravaginal administration of quinagolide 
tablets has been shown to be associated with higher bioavailability than oral administration due to 
reduced first pass metabolism in a single and multiple ascending dose trial comparing intravaginal 
and oral administration (Trial 000076). Following single administration of quinagolide vaginal ring 
at a target release rate of quinagolide 4.5 µg/day, 9 µg/day or 13.5 µg/day a, Tmax was reached at 36-
48 hours for all three doses and plasma concentration slowly declined over time for up to 35 days 
(Trial 000155). Furthermore, no dose accumulation and no impact on ovarian function or menstrual 
cyclicity were observed following sequential administration of quinagolide vaginal rings for two 
menstrual cycles (Trial 000207).  
 
a 
The three strengths of quinagolide vaginal ring investigated in phase 1 trials are expressed in the content of 
quinagolide hydrochloride instead of quinagolide. The exact quantities of drug substance are minimally adjusted for 
the present trial due to a minor change in ring manufacturing. Quinagolide vaginal rings in phase 1 trials contain a 
dose load of quinagolide hydrochloride 400 µg, 800 µg and 1200 µg corresponding to a target release rate of 
quinagolide hydrochloride 5 µg/day, 10 µg/day and 15 µg/day, respectively, which are equivalent to a target release 
rate of quinagolide 4.5 µg/day, 9 µg/day and 13.5 µg/day.  


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Vaginal ring administration of quinagolide avoids repeated rapid daily rises of quinagolide levels as 
seen with oral administration and thereby has improved tolerability of quinagolide based on safety 
evaluations in phase 1 trials. In addition, an extended-release formulation with replacement of the 
vaginal ring every menstrual cycle is more suitable for the long-term management of endometriosis 
than a daily formulation.  
In summary, as a novel non-hormonal drug inhibiting angiogenesis, quinagolide has the potential to 
address the unmet medical need for long-term treatment of endometriosis. Since quinagolide 
vaginal rings were shown to have favorable pharmacokinetic (PK) profiles without any anti-
ovulatory or other undesirable side effects in the phase 1 trials, it is now possible to investigate the 
effect of quinagolide on reduction of moderate and severe endometriosis-related pain in 
endometriosis patients. The present phase 2 trial therefore aims at assessing the efficacy, safety and 
dose-response of three doses of quinagolide vaginal rings compared to placebo in women with 
moderate and severe endometriosis-related pain. The outcome of the present trial will help identify 
the appropriate dose(s) to be used for future trials.  
 
1.3 
Benefit / Risk Aspects 
Benefits 
Subjects will be randomized in a 1:1:1:1 ratio to placebo or one of the three quinagolide doses for 
four menstrual cycles. This means that 75% of endometriosis patients in the trial will be initially 
randomized to an active treatment and may benefit from relief of their endometriosis-related pain if 
the treatment is effective. All subjects in the trial will be provided with rescue analgesics to manage 
their endometriosis-related pain in case of insufficient pain relief. All subjects included in the trial 
will also benefit from close and comprehensive monitoring of their conditions.  
It should be noted that the treatment and trial-related procedures are provided to the participating 
subjects free of charge, as Ferring compensates the investigational sites for their expenses.  
 
Risks 
The risks associated with this clinical trial, including the risks of investigational medicinal product 
(IMP), clinical and laboratory procedures and concomitant medications, are explained to subjects as 
part of the counselling prior to starting treatment.  
Risks – Investigational Medicinal Product 
In the clinical development program for endometriosis, quinagolide has been investigated 
intravaginally in a total of 111 women in phase 1 trials, of whom 23 were administered tablets at 
daily doses up to 75 µg and 88 were administered vaginal rings at a target release rate of up to 
13.5 µg/day. In all trials, intravaginal administration of quinagolide was generally safe and well 
tolerated. The most common treatment-related adverse events with quinagolide vaginal rings (i.e. at 
a frequency of ≥5%, reported by more than 4 subjects) in phase 1 trials were headache, vaginal 


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discharge, nausea and dizziness. A more detailed description of the safety data from the individual 
trials is provided in the paragraphs below.  
A lower frequency of gastrointestinal adverse events, i.e. nausea and vomiting, was reported 
following intravaginal administration of quinagolide 75 µg tablets once daily for 5 days, compared 
with oral administration (Trial 000076). The most frequently reported adverse events (i.e. reported 
by more than 1 subject) following intravaginal administration of quinagolide tablets were headache, 
dizziness and vaginal discharge. Single administration of quinagolide vaginal ring at a target release 
rate of quinagolide 4.5 µg/day, 9 µg/day and 13.5 µg/day was locally and systemically well 
tolerated with the most frequently reported adverse events being headache, vaginal discharge and 
nausea (Trial 000155). The majority of adverse events occurring in all treatment groups including 
the placebo group started during the first week of treatment and were considered to be of mild or 
moderate intensity. No inhibition of ovulation or modification of the menstrual cycle was observed 
during sequential administration of quinagolide vaginal ring at a target release rate of up to 
13.5 µg/day (Trial 000207). In addition, quinagolide had no clinically significant effects on clinical 
chemistry, hematology or urinalysis parameters, nor on vital signs, electrocardiography (ECG) 
recordings, physical or gynecological examinations in any of the phase 1 trials.  
Insertion and/or removal of the vaginal rings may be associated with mild discomfort or spotting, 
which is expected to be transient. Ring discoloration or breakage at glued junction points could also 
occur but based on the phase 1 data, there has been no safety concerns associated with these 
findings. New rings manufactured in a different way (i.e. injection-molded rings instead of glued 
rings) will be used in the present trial.    
Quinagolide is currently marketed outside the United States as an oral tablet formulation for the 
treatment of hyperprolactinemia. The estimated cumulative exposure of quinagolide until now is 
more than 280,000 patient years, when administered as an oral tablet in the approved dose range of 
25-300 µg or higher. The general safety profile of quinagolide is consistent with the class effects of 
other dopamine agonists, characterized by adverse events involving the gastrointestinal tract and 
central nervous system. The most frequent adverse drug reactions (all reported as very common, i.e. 
at a frequency of ≥10%) in relation to oral administration of quinagolide tablets are nausea, 
vomiting, headache, dizziness and fatigue. They occur predominantly during the first few days of 
the initial treatment or, as a mostly transient event, following dosage increase.  
A serious but very rare risk associated with quinagolide oral tablets is syncope (<0.01%), which can 
be resulted from orthostatic hypotension. Orthostatic hypotension occurs at a frequency of 1-10% 
among patients treated with quinagolide oral tablets. Somnolence rarely (i.e. at a frequency of 
0.01% to 0.1%) occurs during treatment with quinagolide oral tablets. Dopamine agonists other 
than quinagolide have been associated with sudden sleep onset episodes, particularly in patients 
with Parkinson’s disease, and this has resulted in a general warning for the entire class of drugs. In 
rare cases (i.e. at a frequency of 0.01% to 0.1%), treatment with dopamine agonists has been 
associated with the occurrence of acute psychosis, which is reversible upon discontinuation.20 
Impulse control disorders involving pathological gambling, increased libido, hypersexuality, 


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compulsive spending or buying, binge eating and compulsive eating were rarely reported in 
association with the use of dopamine receptor agonists including quinagolide for the treatment of 
Parkinson’s disease.21 Ergot-derived dopamine agonists have been associated with an increased risk 
of fibrosis of the heart valves possibly through activation of 5-hydroxytryptamin 2B receptor (5-
HT2B). Quinagolide is a non-ergot-derived dopamine agonist and does not have any 5-HT-receptor 
activity at clinically relevant doses.22,23 Furthermore, no cases of valvular heart disease have been 
reported with quinagolide. 
Quinagolide is not an embryotoxic or teratogenic agent. No adverse effects on embryos or fetuses 
were observed in the reproductive toxicity studies in rats and rabbits.11 Based on clinical data for 
the treatment of hyperprolactinemia, pregnancy outcome data are available for 145 pregnancies in 
women exposed to quinagolide, with 106 pregnancies leading to live births. Among the 110 live-
born neonates, a total of 5 malformations (4.5%) were reported, which is comparable to the 5-6% 
malformation rate reported among registered births.24 In terms of pregnancy loss, 24 (16.6%) 
spontaneous abortionsb were reported following exposure to quinagolide, which is similar to the 
15-16% spontaneous abortion rate reported in the general population.25 In addition, quinagolide has 
been investigated for the prevention of ovarian hyperstimulation syndrome (OHSS) in an in vitro 
fertilization study, in which 85 live births were reported following treatment with oral quinagolide 
tablets up to 200 µg/day for approximately 20 days without dose titration.26 Quinagolide did not 
appear to show any detrimental effects on implantation, pregnancy or live birth rates.26 In 
conclusion, exposure to quinagolide during early pregnancy has not been shown to increase the risk 
of pregnancy losses or congenital malformations compared with a normal pregnant population. 
Contraception counselling will be offered throughout the trial and condoms will be provided to all 
subjects at each clinic visit to avoid occurrence of pregnancy during participation of the trial. As a 
precautionary measure, a urine pregnancy test will be performed at least once per menstrual cycle 
in the present trial. If the test result is positive and confirmed by a serum βhCG test, the subject will 
be discontinued from the trial immediately and will be followed up until delivery (see section 8.4).  
For further information regarding quinagolide, please refer to the Investigator’s Brochure.11 
Risks – Trial Procedures and Concomitant Medications 
The primary endpoint and secondary efficacy endpoints in this trial are patient-reported outcome 
(PRO) measures that require the subjects’ daily assessments of pain intensity, vaginal bleeding 
pattern, occurrence of sexual intercourse, analgesic use as well as daily and weekly assessments of 
pain impact, all of which impose no risks to subjects participating in the trial.  
A few procedures will be performed at the investigational sites in this trial, i.e. transvaginal 
ultrasound, blood sampling, ECG, echocardiography, urine pregnancy test and urinalysis, which are 
either minimally invasive or non-invasive to subjects. The transvaginal ultrasound examinations 
may be associated with mild discomfort and a very rare risk of infection. The blood sampling might 
be associated with mild discomfort, bruising and a very rare risk of infection. ECG and 
 
b  Other pregnancy losses included 14 induced abortions (with 1 due to malformation) and 1 ectopic pregnancy.  


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echocardiography are harmless and painless tests associated with a very rare risk of mild rash 
where the electrodes are attached. Urine pregnancy tests and urinalysis, simply requiring subjects to 
urinate, impose no risks to subjects.  
All subjects in this trial will be provided with rescue analgesics in the form of ibuprofen 200 mg, 
which is an approved medicinal product for pain relief and considered generally well-tolerated. The 
most frequently reported adverse effects with ibuprofen are gastrointestinal in nature and include 
nausea, vomiting, flatulence and diarrhea. Additional adverse effects may occur at high doses and 
under long-term treatment.27 Clinical studies suggest use of ibuprofen, particularly at high doses 
(2400 mg/day), may be associated with a small increased risk of arterial thrombotic events (e.g. 
myocardial infarction or stroke).27 Upper gastrointestinal ulcers, gross bleeding or perforation can 
occur in approximately 1% of patients treated with ibuprofen for 3-6 months.27  
If needed, a strong analgesic hydrocodone-acetaminophen may be prescribed by the investigator. 
The most frequently reported adverse reactions with hydrocodone-acetaminophen are light-
headedness, dizziness, sedation, nausea and vomiting.28 Additional adverse effects may occur at 
overdose, under long-term treatment and during concomitant intake of alcohol or other drugs. The 
use of hydrocodone-acetaminophen may also cause mental or physical dependence, opioid 
addiction, abuse and misuse, which can lead to overdose and death. Serious, life-threatening or fatal 
respiratory depression may occur with use of hydrocodone-acetaminophen. Acetaminophen has 
been associated with cases of acute liver failure, at times resulting in liver transplant and death. 
Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 
4000 mg per day, and often involve more than one acetaminophen-containing product.28 
The investigator must assess each subject’s risks prior to prescription of hydrocodone-
acetaminophen. 


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2 
TRIAL OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
Primary Objective 
• To evaluate the efficacy of three doses of quinagolide administered as an extended-release 
vaginal ring compared to placebo on reduction of moderate to severe endometriosis-related pain 
 
Secondary Objectives  
• To evaluate the effect of quinagolide vaginal ring on reduction of endometriosis-related 
dysmenorrhea, non-menstrual pelvic pain, dyspareunia and analgesic use 
• To evaluate the effect of quinagolide vaginal ring on the subject’s ability to function  
• To evaluate the effect of quinagolide vaginal ring on ovarian function 
• To evaluate the effect of quinagolide vaginal ring on endocrine parameters  
• To evaluate the effect of quinagolide vaginal ring on vaginal bleeding pattern 
• To evaluate the systemic exposure of quinagolide and metabolites after quinagolide vaginal ring 
administration 
• To evaluate the effect of quinagolide vaginal ring on bone turnover markers  
• To evaluate the safety profile of quinagolide vaginal ring including adverse events, symptoms of 
impulse control disorders, ECG and echocardiography findings, routine safety laboratory 
parameters and ring acceptability  
• To validate the newly developed patient reported outcome (PRO) tool: Women’s Endometriosis 
Diary [Note: this objective will be reported separately] 
 
Exploratory Objective  
• To explore the effect of quinagolide vaginal ring on endometriosis biomarkers such as 
angiogenic and inflammatory biomarkers  
2.2 
Endpoints 
Primary Endpoint  
• Changes in the mean daily Numerical Rating Scale (NRS) scores for the worst endometriosis-
related pain at cycle 4 
 
Secondary Endpoints  
• Changes in the mean daily NRS scores for the worst endometriosis-related pain on days with 
menstrual bleeding (i.e. dysmenorrhea) and for the worst endometriosis-related pain on days 
with no menstrual bleeding (i.e. non-menstrual pelvic pain) at cycle 4 
• Changes in the mean daily NRS scores for the worst endometriosis-related pain over 4 menstrual 
cycles 
• Changes in the mean daily NRS scores for the worst dysmenorrhea over 4 menstrual cycles 
• Changes in the mean daily NRS scores for the worst non-menstrual pelvic pain over 4 menstrual 
cycles 


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• Changes in the mean daily NRS scores for the worst dyspareunia on days with sexual intercourse 
over 4 menstrual cycles 
• Frequency of avoiding sexual intercourse due to expected pain over 4 menstrual cycles  
• Changes in the mean daily NRS scores for the worst impact of endometriosis-related pain on the 
subject’s ability to function over 4 menstrual cycles 
• Changes in the mean weekly scores of the Endometriosis Health Profile-30 (EHP-30) pain 
impact domain over 4 menstrual cycles  
• Changes in vaginal bleeding pattern over 4 menstrual cycles 
• Percentage of days with mild and/or strong rescue analgesics used over 4 menstrual cycles 
• Total and average doses of mild and/or strong rescue analgesics used over 4 menstrual cycles 
• Responder rate assessed as ≥30%, ≥50% and ≥70% reduction from the baseline in mean daily 
NRS score for the worst endometriosis-related pain, dysmenorrhea and non-menstrual pelvic 
pain and for the worst endometriosis-related pain impact, over 4 menstrual cycles 
• Changes in the mean individual and total symptom and sign severity scores of the Biberoglu and 
Behrman (B&B) scale at cycle 4  
• Changes in the EHP-30 scores over 4 menstrual cycles  
• Changes in Patient Global Impression of Severity (PGIS) scores at cycle 4   
• Patient Global Impression of Change (PGIC) scores at cycle 4  
• Plasma concentration of quinagolide and metabolites during cycles 1 and 4   
• Serum levels of mid-luteal phase progesterone at cycle 4  
• Proportion of subjects with serum levels of mid-luteal progesterone ≥25 nmol/L (7.9 ng/mL) at 
cycle 4   
• Serum levels of mid-luteal estradiol, prolactin, thyroid-stimulating hormone (TSH) and insulin-
like growth factor-1 (IGF-1) at cycle 4   
• Changes in bone turnover markers, determined by bone resorption marker serum C-terminal 
cross-linking telopeptide of type 1 collagen (s-CTx) and bone formation marker serum 
procollagen type I N propeptide (s-PINP) at cycle 4  
• Changes in ECG parameters including PR interval, QT interval, corrected QT using Fridericia’s 
formula (QTcF) and QRS interval at cycle 4   
• Proportion of subjects with abnormal clinically significant echocardiography findings indicating 
valvular heart disease at cycle 4 
• Proportion of subjects identified with potential impulse control disorders by the questionnaire for 
impulsive-compulsive disorders at cycle 4    
• Frequency and intensity of adverse events 
• Changes in circulating levels of clinical chemistry and hematology parameters, urinalysis 
parameters, and proportion of subjects with markedly abnormal changes  
• Frequency and intensity of ring acceptability parameters over 4 menstrual cycles 
 
Exploratory Endpoint 
• Changes in endometriosis biomarkers such as serum levels of VEGF, placenta growth factor 
(PlGF), interleukin 6 (IL-6) and soluble fms-like tyrosine kinase 1 (sFlt-1) at cycle 4   


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Trial Design 
3.1.1 
Trial Design Diagram 
 
 
 
 
 
a 
In case of technical issues at the start of the run-in period, subjects are allowed to re-start cycle -2. Subjects that screen fail due to the temporary 
trial hold during the coronavirus disease 2019 (COVID-19) pandemic may be re-screened.  
b 
Blood samples for potential endometriosis biomarkers will be collected for all subjects. If subjects provide a separate informed consent, 
additional blood samples for potential analyses of circulating cell-free DNA and microRNA will also be collected.  
c 
If subjects provide a separate informed consent, a blood sample for pharmacogenetic analysis will be collected. 
d 
ECG and Echo at screening can be arranged anytime during cycle -1 (e.g. at visit 3) but results must be available before randomization. ECG and 
Echo at cycle 4 can be performed within ±2 weeks of visit 10.  
e 
Pain impact will be assessed on both a daily and a weekly basis. 
f 
Scoring of the worst endometriosis-related pain during the past menstrual cycle on the NRS will be performed on paper at the run-in visit. Daily 
scoring of endometriosis-related pain on the NRS is captured by e-Diary. 
g 
Visits on RM+7 or LH+7 can be scheduled RM+6-10 or LH+6-9, i.e. day 6 to day 10 of return of menses or 6-9 days after LH surge, 
respectively. PK visit (visit 5) can be arranged within 1-5 days of randomization (visit 4). 
Figure 3-1 Trial Diagram – Trial Period 
 
e-Diary
Placebo vaginal ring for 4 cycles
QVR dose load 360 µg for 4 cycles
QVR dose load 720 µg for 4 cycles 
Run-in period of 
2 menstrual cycles a
Follow-up
Screening
Treatment
QVR dose load 1080 µg for 4 cycles
Pain impact e
Pain impact e
Vaginal bleeding
Analgesic use
Analgesic use
Vaginal bleeding
Sexual intercourse 
Sexual intercourse 
B&B
B&B
NRS
NRS
NRS(Run-in) f
Endocrine 
Biomarkers b
BTM
PG c
BTM
Biomarkers b
Endocrine
PK
ECGd
Echod
LH surge
TVU 
QICD
PGIS
PGIS
Cycle 4
Cycle -1
Cycle 1
Cycle 2
Cycle 3
Cycle 5
Cycle -2
RM+7 g/ Visit 4
Randomisation
RM+7 g/ Visit 10
End-of-treatment
Informed consent
RM+7 g/ Visit 6
RM+7 g / Visit 2
RM+7 g/ Visit 1 
Run-in
RM+7 g / Visit 7
LH+7 g / Visit 3
LH+7 g / Visit 9
RM+7 g/ Visit 11
End-of-trial
Washout
RM+7 g / Visit 8
PK Visit g/ Visit 5
LH surge
TVU
ECG
Echod
PGIS
EHP-30
EHP-30
EHP-30
EHP-30
EHP-30
PGIC
QICD
PK
PK
PK
PK
C-SSRS
C-SSRS
C-SSRS
C-SSRS
Ring Qs
Ring Qs
Ring Qs
Ring Qs
Ring Qs
Abbreviations: B&B=Biberoglu and Behrman Scale, BTM=bone turnover markers, C-SSRS=Columbia Suicide Severity Rating Scale, 
Echo=echocardiography, ECG=electrocardiography, EHP-30=Endometriosis Health Profile-30 Questionnaire, LH=luteinizing hormone, 
LH+7=7 days after LH surge, NRS=Numerical Rating Scale, PGIC=Patient Global Impression of Change, PGIS=Patient Global Impression of 
Severity, PG=pharmacogenetic(s), PK=pharmacokinetic(s), QICD=questionnaire for impulsive-compulsive disorders, QVR=quinagolide vaginal 
ring, Ring Qs=ring acceptability questions, RM=return of menses, RM+7=day 7 of return of menses, TVU=transvaginal ultrasound 


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3.1.2 
Overall Design and Control Methods 
This is a randomized, double-blind, placebo-controlled, phase 2 trial assessing the efficacy, safety 
and dose-response of quinagolide extended-release vaginal rings administered sequentially for 
4 menstrual cycles in women with moderate to severe endometriosis-related pain. In this trial, a 
menstrual cycle is considered the period from day 7 of return of menses (RM+7) in a cycle until the 
following day 7 of return of menses in the next cycle. Visits on RM+7 can be scheduled on 
RM+6-10, i.e. day 6 to day 10 of return of menses.  
The trial consists of the following periods: 
1) Screening: starting immediately after the signing of the informed consent(s) and including a 
run-in period of two complete menstrual cycles (cycles -2 and -1) 
2) Treatment: double-blind, placebo-controlled treatment with three doses of quinagolide 
extended-release vaginal ring administered sequentially for four menstrual cycles (cycles 1, 2, 
3 and 4) 
3) Follow-up: post-treatment follow-up period of one menstrual cycle (cycle 5) 
 
Screening: The screening period includes a wash-out period of approximately one month (only 
applicable to subjects currently using some hormonal products such as contraceptives c) and a run-
in period of two complete menstrual cycles (cycles -2 and -1, applicable to all subjects). Subjects 
who are currently using some hormonal products such as contraceptives c may be eligible for the 
trial if they have completed the wash-out period. In this case, subjects need to sign the informed 
consent(s) before they discontinue those products. Discontinuation of the products should follow 
the labelling (e.g. completing the current cycle of contraceptives before wash-out). Subjects 
requiring wash-out will not be provided with the electronic diary (e-Diary) or rescue analgesics 
until the completion of the wash-out period, i.e. at the run-in visit.  
Before entry into run-in, all subjects will be asked to score the worst endometriosis-related pain 
from a recall of their experience during the past menstrual cycle on a self-administered 11-point 
Numerical Rating Scale (NRS) with 0 indicating “no pain” and 10 indicating “worst imaginable 
pain”. After standardized training of e-Diary use, eligible subjects will be instructed to record 
endometriosis-related pain, vaginal bleeding, occurrence of sexual intercourse and analgesic use in 
the e-Diary on a daily basis. Impact of endometriosis-related pain on functioning will be assessed 
by subjects on both a daily and a weekly basis.  
In this trial, endometriosis-related pain is evaluated as the pain located in the abdominal-pelvic area 
and the lower back area. During the run-in period, subjects will score the worst endometriosis-
related pain during the preceding 24 hours on the NRS before bedtime every night in the e-Diary.   
 
c  Hormonal products requiring 1 month wash-out include GnRH antagonists, aromatase inhibitors, danazol and 
 hormonal contraceptives (including combined oral contraceptive pill, progestin-only pill, transdermal patch and 
 contraceptive ring). See section 4.3.1.  


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Vaginal bleeding will be recorded as “yes” or “no” on a daily basis in the e-Diary. If there is 
vaginal bleeding, subjects will be asked to register their bleeding volume (spotting, light, moderate 
or heavy bleeding) and to answer whether they think the bleeding is related to menses or not. Based 
on the subject’s impression of whether she has menstrual bleeding or not, the NRS score obtained 
for the endometriosis-related pain is assigned to dysmenorrhea (endometriosis-related pain on days 
with menstrual bleeding) or to non-menstrual pelvic pain (endometriosis-related pain on days with 
no menstrual bleeding).  
Occurrence of sexual intercourse (“yes” or “no”) will also be recorded in the e-Diary. In case of 
sexual intercourse, subjects will be asked to score the worst pain experienced during or after 
intercourse (dyspareunia) on the NRS. In case of no sexual intercourse, subjects will be asked if it 
is due to expected pain.  
Rescue analgesics for endometriosis-related pain will be limited to ibuprofen and/or hydrocodone-
acetaminophen in this trial. As a mild analgesic, ibuprofen will be provided to subjects in the form 
of 200 mg oral tablets for their use on an as-needed basis. Subjects will be instructed not to use 
other analgesics unless necessary. If there is a need to change analgesics, subjects should discuss 
with investigators, who may prescribe a strong analgesic, i.e. 5 mg hydrocodone plus 300 mg or 
325 mg acetaminophen (section 7.2.1.5). Use of any other analgesics for endometriosis-related pain 
is prohibited. Any prophylactic use of analgesics is also prohibited in this trial. Use of analgesics 
for endometriosis-related pain will be reported by subjects in the e-Diary on a daily basis.  
The impact of the endometriosis-related pain on different aspects of functioning will be assessed by 
subjects both on the NRS on a daily basis and by the modified EHP-30 pain impact domain (i.e. the 
first 11 items plus an additional work item) on a weekly basis.d 
Treatment: Subjects will be randomized on RM+7 of cycle -1 (at visit 4) if they, during the run-in 
period have moderate to severe endometriosis-related pain, which is defined as having a mean daily 
NRS score of ≥4 for the worst endometriosis-related pain during each run-in menstrual cycle. 
Randomization will be performed in a 1:1:1:1 ratio to quinagolide vaginal ring dose load 360 µg at 
a target release rate of quinagolide 4.5 µg/day, quinagolide vaginal ring dose load 720 µg at a target 
release rate of quinagolide 9 µg/day, quinagolide vaginal ring dose load 1080 µg at a target release 
rate of quinagolide 13.5 µg/day or placebo vaginal ring for four menstrual cycles (cycles 1, 2, 3 and 
4).  
Follow-up: Subjects will be followed up for one menstrual cycle (cycle 5). 
From randomization to follow-up (cycle 1 to cycle 5), subjects will continue to use an e-Diary to 
score the endometriosis-related pain, to register vaginal bleeding pattern, occurrence of sexual 
intercourse and the analgesic use as well as to assess the impact of the worst endometriosis-related 
pain on functioning, as they have done in the run-in period.  
 
d  The secondary endpoint of changes in the weekly impact scores is based on the original EHP-30 pain impact 
 domain, i.e. the first 11 items. The additional work item is used only for validation. 


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During the treatment period, subjects will self-insert the assigned ring in the upper part of the 
vagina on RM+7 of cycle 1 to cycle 4 at the clinic by following standard instructions for use. 
Supervision by the site staff can be provided if needed. After insertion, the vaginal ring will be kept 
in the vagina continuously for one menstrual cycle until being replaced with the next ring on RM+7 
of the next cycle when the subject visits the clinic. Acceptability of the ring will be assessed by 
subjects via a ring acceptability questionnaire at each RM+7 visit during the treatment period. 
Unless under other effective birth control permitted by protocol (section 4.3.2), subjects will be 
required to use a non-hormonal single-barrier contraception (i.e. condom) from wash-out (if 
applicable) or run-in to end-of-trial. Contraception counselling and condoms will be offered to 
subjects throughout the trial.  
B&B will be administered electronically at randomization and at cycle 4 (at visits 4 and 10), with 
trained trial coordinators completing the first part based on subjects’ verbal responses and 
investigators completing the second part based on findings of a pelvic examination. Subjects will 
complete the electronic version of the EHP-30 questionnaire at randomization, and at every cycle 
from cycle 1 to cycle 4 (at visits 4, 6, 7, 8 and 10). PGIS scale will be completed electronically by 
subjects at cycle -2, at randomization and at cycle 4 (at visits 2, 4 and 10), while PGIC scale will be 
completed electronically at cycle 4 (at visit 10). 
Blood samples will be collected throughout the trial for the purpose of evaluating mid-luteal phase 
endocrine parameters, bone turnover markers, endometriosis biomarkers, quinagolide and 
metabolites, and routine safety laboratory parameters. In this trial, mid-luteal phase is defined as 
6-9 days after luteinizing hormone (LH) surge (LH+6-9) as tested by subjects at home by means of 
commercially available urinary LH kits. LH+7 visits can be scheduled on LH+6-9, either based on 
an actual LH surge date as indicated by a positive LH surge test or based on an estimated LH surge 
date according to subjects’ cycle length if subjects fail to detect the LH surge. The exact cycle day 
of the LH+7 visit will be derived based on the first menstrual bleeding date of the current cycle 
confirmed at the RM+7 visits. An endocrine panel including estradiol, progesterone, prolactin, TSH 
and IGF-1 will be assessed during the mid-luteal phase of cycles -1 and 4 (at visits 3 and 9). 
Evidence of ovulation will be evaluated by serum levels of mid-luteal progesterone. Fasting blood 
samples for the analysis of a bone formation marker (s-PINP) and a bone resorption marker (s-CTx) 
will be collected during cycles -1 and 4 (at visits 3 and 9). Blood samples for endometriosis 
biomarkers including, but not limited to, VEGF, PlGF, IL-6 and sFlt-1 will also be collected during 
cycles -1 and 4 (at visits 3 and 9). At the same time points, if subjects have provided a separate 
informed consent, additional blood samples for potential analyses of circulating cell-free DNA and 
microRNA will also be collected. Routine safety laboratory tests for clinical chemistry and 
hematology parameters will be performed during cycle -1, at end-of-treatment and end-of-trial (at 
visits 3, 10 and 11). Quinagolide and metabolites will be measured within 1-5 days of first ring 
insertion, at RM+7 visits of cycles 1, 3 and 4 as well as at LH+7 visit of cycle 4 (at visits 5, 6, 8, 9 
and 10) to assess systemic exposure and allow for population PK modelling. Blood samples should 
be taken prior to ring removal at RM+7 visits. If subjects have provided a separate informed 
consent, a blood sample for pharmacogenetic analysis will also be collected at visit 5.    


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ECG and echocardiography will be performed at screening and at end-of-treatment to monitor 
cardiovascular safety. ECG and echocardiography at screening can be arranged anytime during 
cycle -1, e.g. at LH+7 visit (visit 3) but results must be available prior to randomization. ECG and 
echocardiography at cycle 4 can be performed within ±2 weeks of visit 10.  
A modified questionnaire for impulsive-compulsive disorders (QICD) will be completed 
electronically by trained trial coordinators based on subjects’ verbal response prior to 
randomization at cycles -1 and 4 (at visits 4 and 10).  
A urine pregnancy test will be performed at each clinic visit (except for visit 5) throughout the trial. 
If the test result is positive and is confirmed by a following serum βhCG test, the subject should be 
discontinued from the trial. Urinalysis is performed before entry into run-in (before or at visit 1) 
and at cycle 4 (at visit 10).  
All subjects will be asked which treatment they believe they have received at the end of treatment. 
A sub-group of 60 subjects including 5 non-completers from selected sites, if they have provided a 
separate informed consent, will be invited to participate in a patient interview at the end of 
treatment to help determine the meaningful treatment benefit from the patients’ perspective and to 
assess the content validity of the questions related to daily functioning in the e-Diary.  
 
3.1.3 
Trial Schedule 
Estimated first patient first visit (FPFV): 
 
 
 
 
Q3 2018 
Estimated last patient last visit (LPLV): 
 
 
 
 
Q3 2022 
 
3.2 
Planned Number of Trial Sites and Subjects 
It is planned to randomize 280 subjects from approximately 100 sites in North America. It is 
estimated that around 590 subjects will be screened to randomize 280 subjects (70 subjects per 
treatment group) to achieve 208 evaluable subjects at the end of treatment. The sample size will be 
re-estimated by an external statistician during an interim analysis and the number of randomized 
subjects may be adjusted up to 360 (see section 9.1).  
 
3.3 
Interim Analysis 
An interim analysis with the option to stop the trial early due to futility will be performed by an 
external statistician, when approximately half of the planned evaluable subjects (104 subjects) have 
completed the treatment period of the trial for the assessment of the primary endpoint. The 
unblinded data will be presented by treatment group. The futility bound is set at a conditional 
power using current trend equal to 5%, i.e. the trial could potentially be stopped for futility if the 
probability of achieving a significant result in the highest remaining dose group is lower than 5% 
based on the observed data at the interim analysis. In case of high drop-out rate or discontinuations 
in the highest dose group, the analysis will be performed on the remaining dose(s).  


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The futility bound is chosen at 5% conditional power using current trend, as it gives a relatively 
high probability (71%) of stopping the trial if the treatment has no effect, and a relatively low 
probability (1.4%) of stopping a trial that would have been successful in the end if the true 
treatment effect difference is 1.0 units. If the conditional power using current trend is between 5% 
and 90%, the sample size will be re-estimated and may be adjusted. 
No interim analysis intended to stop the trial early due to overwhelming efficacy is planned. 
The interim analysis will be performed based on cleaned data and the recruitment shall continue at 
the time of interim analysis unless otherwise notified. 
 
3.4 
Clinical Monitoring Committee  
An internal Clinical Monitoring Committee consisting of the responsible medical officer, 
statistician and clinical trial manager will be established. The Clinical Monitoring Committee will 
meet regularly to evaluate the trial data including data with respect to the pre-defined stopping 
criteria (section 3.6.7). Data will be presented in a blinded manner. 
 
3.5 
Data Monitoring Committee  
An independent Data Monitoring Committee (DMC) consisting of exclusively external members 
will be established for this trial. The DMC members include external clinical experts, an external 
statistician and an ad hoc external cardiologist. None of the DMC members will be involved in the 
conduct of the trial.  
The DMC will have access to the unblinded interim data presented by treatment group and will 
recommend whether the trial should be stopped or not according to the pre-specified futility criteria 
in the interim analysis. The DMC will also recommend whether the sample size should be adjusted. 
If the stopping criteria on treatment group or trial level are met, the DMC will be requested to 
access the unblinded safety data presented by treatment group. The DMC will recommend whether 
one dose, several doses or the trial should be discontinued. 
In any case, the DMC will keep the data and analyses confidential from any persons involved in the 
conduct of the trial. Sponsor representative(s) will only be allowed to attend the open sessions of 
the DMC meetings with no access to unblinded data. 
A trial-specific DMC charter will specify its members, responsibilities and its working procedures.  
 


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3.6 
Discussion of Overall Trial Design and Choice of Control Groups 
3.6.1 
Trial Design 
The primary objective of the trial is to evaluate the efficacy of three doses of quinagolide 
administered as an extended-release vaginal ring compared to placebo on reduction of moderate to 
severe endometriosis-related pain.  
Strict criteria have been incorporated in the design of this dose-finding trial to properly assess the 
treatment effect of quinagolide vaginal ring compared with placebo vaginal ring. In general, 
treatment and timing of ring insertion/removal and mid-luteal phase assessments according to 
individual menstrual cycle length, outcome measures consistent with guidelines for pain scoring 
and with other clinical trials on endometriosis have to a great extent been incorporated in the design 
of this trial. 
This is a randomized, double-blind trial with placebo as the comparator to adequately evaluate the 
efficacy and safety of quinagolide vaginal ring. A placebo group is justified for this trial as there is 
a need to account for the placebo effect on pain relief in order to measure the absolute efficacy of 
the active treatment. In this trial, ethical concerns of using placebo controls have been addressed by 
providing subjects with rescue analgesics for pain relief as needed. Furthermore, the provision of 
rescue analgesics can help prevent dropouts due to lack of efficacy.  
A run-in period of at least two menstrual cycles prior to randomization will provide consistent and 
reliable baseline data on pain scores for selecting subjects who truly experience moderate and 
severe endometriosis-related pain. Although a placebo run-in period has been widely used in 
clinical trials with placebo response, it has been argued that the placebo run-in does not lower the 
placebo response, increase the drug-placebo difference or affect the drug response rate post-
randomization.29 This has been further demonstrated in a recent trial for endometriosis-related pain, 
where the placebo effect did not appear to be diminished by the inclusion of a 4-week placebo 
run-in period.30  
The placebo-controlled treatment period in this trial lasts for four menstrual cycles, which 
approximately corresponds to the active treatment duration of 18-20 weeks in the proof-of-concept 
study, where significant reductions in endometriosis lesions were observed following oral 
administration of quinagolide up to 75 µg.16  
As described in sections 3.3 and 3.5, an interim analysis with the option to stop the trial early due to 
futility is planned when approximately half of the planned evaluable subjects have completed the 
treatment period of the trial. Should the DMC recommend to stop the trial early due to futility, the 
subjects would not need to continue in a trial without any treatment benefit so that an appropriate 
benefit/risk ratio for subjects participating in the trial could be guaranteed.  
A double-blind design will ensure blinding and thereby unbiased evaluations by both the 
investigator and the subject, particularly the latter, as the primary and secondary efficacy endpoints 
in this trial are based on the PRO measures. Similarly, Ferring staff will also remain blinded to the 


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individual subject treatment allocation during the conduct of the trial. Precautions and measures 
taken to ensure double-blinding of the trial are described in detail in section 3.6.3. A multi-center 
setting of the trial will guarantee that the required number of subjects can be recruited within a 
reasonable time and also support subsequent generalization of the results. 
A non-hormonal single-barrier contraception method (i.e. condom) is required for subjects 
participating in the present trial. Condom is the only feasible contraception method in this trial, as 
other contraception methods including hormonal contraceptive agents and intrauterine devices can 
interfere with the assessment of endometriosis-related pain. Throughout the trial, contraception 
counselling and condoms will be offered to avoid occurrence of pregnancy during the trial. In 
addition, as a precautionary measure, a urine pregnancy test will be performed at least once per 
menstrual cycle in the present trial. If the test result is positive and confirmed by a serum βhCG 
test, the subject will be discontinued from the trial immediately. Quinagolide is not an embryotoxic 
or teratogenic agent. No adverse effects on embryos or fetuses were observed in the reproductive 
toxicity studies in rats and rabbits.11 Based on the available clinical data, exposure to quinagolide 
during early pregnancy has not been shown to increase the risk of pregnancy losses or congenital 
malformations compared with a normal pregnant population (see section 1.3).  
All subjects will be asked to continue the e-Diary recording during the follow-up period of one 
menstrual cycle. Data collected from the follow-up period will help evaluate the maintenance of the 
treatment effect.  
 
3.6.2 
Selection of Endpoints 
The primary endpoint of the present trial is the change in the mean daily NRS score for the worst 
endometriosis-related pain compared to placebo at cycle 4. Endometriosis-related pain is assessed 
as pain located in the abdominal-pelvic area and in the lower back area, which is the pain most 
often complained by endometriosis patients. It is considered appropriate to use a single 
“endometriosis-related pain” endpoint as the primary endpoint in this first trial investigating the 
efficacy of quinagolide in endometriosis patients. The major concern for using a summed score 
instead of two separate scores with one each for dysmenorrhea and non-menstrual pelvic pain is 
that the treatment effect of some hormonal drugs is driven by amenorrhea or oligomenorrhea, 
which can make a summed score unrepresentative of the true extent of improvement.31 However, 
quinagolide does not affect ovarian function and thereby does not appear to modify the vaginal 
bleeding pattern.11 It is therefore reasonable to believe that the treatment effect of quinagolide will 
not be driven by amenorrhea or oligomenorrhea and can be adequately measured by a single score 
for “endometriosis-related pain” as the primary endpoint in the present trial. 
Subjects will be instructed to score the endometriosis-related pain at its worst during the preceding 
24 hours every day before bedtime. Since pain assessment relies on memory, a short recall period 
of 24 hours, a response based on the worst experience during the day and standardized timing of 
assessment every night is usually preferable and is in line with clinical experts’ and Food and Drug 
Administration (FDA)’s recommendations.32,33,34 By asking subjects about their worst 


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endometriosis-related pain at the end of every day, the scoring has accounted for the worst pain 
occurring before any potential use of analgesics and has ensured a consistent recall period of 24 
hours. Self-reporting of pain is considered to be the gold standard of chronic pain assessment, 
because it reflects the inherently subjective nature of pain.32 The validated 11-point NRS widely 
used in clinical trials on chronic pain including endometriosis-related pain is selected to quantify 
the pain intensity.30,31,32 
Based on women’s subjective impression of whether they have menstrual bleeding or not, the daily 
NRS score on the worst endometriosis-related pain will be labelled as “endometriosis-related pain 
on days with menstrual bleeding” (dysmenorrhea) or “endometriosis-related pain on days with no 
menstrual bleeding” (non-menstrual pelvic pain). Dysmenorrhea and non-menstrual pelvic pain will 
be evaluated separately as secondary endpoints together with dyspareunia, since these are the three 
most common symptoms of endometriosis.  
In addition to endometriosis-related pain intensity, vaginal bleeding, occurrence of sexual 
intercourse and dyspareunia, the use of rescue analgesics will be captured in an e-Diary as an 
objective measure of the pain relief.  
The impact of the endometriosis-related pain on different aspects of functioning will be self-
assessed both on a daily basis and on a weekly basis.  
The B&B scale35 has been widely used in other endometriosis trials and is selected for a secondary 
endpoint in the present trial for validation of the newly developed endometriosis PRO (i.e. 
Women’s Endometriosis Diary). Since endometriosis patients can also have a compromised quality 
of life, a validated quality of life scale, EHP-30, developed specifically for endometriosis patients36 
will be administered to assess any improvement in functioning associated with treatment. PGIS as a 
static measure of global improvement with treatment and PGIC as a dynamic measure of global 
improvement with treatment37 will both be assessed in the present trial to help determine the 
clinically important difference from the patients’ perspective and thereby establish an appropriate 
definition of responders for future trials.   
Plasma concentration of quinagolide and the active metabolites (M1 and M2) will be assessed to 
allow estimation of population PK parameters and investigation of the exposure-response 
relationships for efficacy over a range of doses to help select the dose(s) to be used in future trials. 
In phase 1 trials, high levels of M1 and M2 were detected in some healthy women after intravaginal 
administration.11 No safety concerns are associated with high levels of metabolites. To investigate a 
relationship between the gene profiles and presence of high levels of metabolites, DNA samples 
will be collected for polymorphism genotyping in the enzymes responsible for the elimination 
processes of quinagolide for those subjects who have provided a separate informed consent.  
Serum progesterone levels will be assessed at mid-luteal phase of cycle 4, corresponding to the end 
of treatment, to evaluate the impact of quinagolide on ovarian function. Other endocrine parameters 
include estradiol, prolactin, TSH and IGF-1. Additionally, to document that quinagolide does not 
have hypoestrogenic side effects on bone metabolism, blood samples will also be collected for the 


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assessment of the bone formation marker s-PINP and the bone resorption marker s-CTx, which are 
the recommended bone turnover markers in clinical trials.38  
Safety endpoints include ECG and echocardiography to assess the cardiovascular risk profile of 
quinagolide, with special attention to drug-induced valvular heart disease. In order to detect any 
pathologic behaviors potentially associated with impulse control disorders during the use of 
dopamine receptor agonists, a modified questionnaire for impulsive-compulsive disorders will be 
completed at baseline and at the end-of-treatment. Other safety endpoints cover adverse events, ring 
acceptability, routine safety laboratory parameters and urinalysis. 
 
3.6.3 
Blinding 
The present trial is double-blind. The subject, the investigator and other trial staff at the site will be 
blinded to treatment allocation during the conduct of the trial. Blinding is achieved by randomizing 
subjects in a 1:1:1:1 ratio to a vaginal ring containing quinagolide dose load 360 µg, 720 µg and 
1080 µg or placebo, all of which are identical in appearance, flexibility and softness.  
Similarly, the Ferring clinical team (e.g. data manager, statistician, clinical trial manager, clinical 
project leader, medical writer, pharmacovigilance physician, pharmacovigilance manager and 
medical officer) will be blinded to treatment allocation until breaking of the blind. The blind will be 
broken when the trial database is declared clean and is released to the responsible statistician.  
As described in section 3.5, an external DMC will have access to unblinded interim data presented 
by treatment group and, if needed, unblinded safety data of some subjects presented also by 
treatment group. In any case, the DMC will keep the data and analyses confidential from the 
Ferring clinical team.  
Since the primary endpoint and the secondary efficacy endpoints in this trial are based on PRO 
measures, precaution must be taken to ensure the blinding of subjects to treatment allocation 
throughout the trial. To avoid potential speculation of treatment allocation by comparing current 
pain scores against previous scores, subjects are not given any access to historically reported data 
after having submitted their answers in the e-Diary. Investigators, trial site staff and Ferring clinical 
team will also be blinded to the results of some laboratory parameters potentially linked to 
quinagolide’s mechanism of action. In addition, all subjects will be asked at the end of treatment 
which treatment (quinagolide or placebo) they believe they have received to evaluate the risk of 
inadvertent unblinding. These practices are in line with FDA PRO guidance.33  
 
3.6.4 
Selection of Doses in the Trial 
In a dose-response trial it is desirable to test a relatively wide span of doses to identify the most 
appropriate dose(s) for future trials. The dose selection should also ensure that it is possible to 
discern clinically meaningful differences within a span that is acceptable with respect to subject 
safety. 


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Selection of doses in this trial is based on safety, tolerability and PK obtained from phase 1 trials. 
Oral administration of quinagolide at doses up to 75 µg once daily for 18-20 weeks appeared to 
reduce the size of lesions in endometriosis patients.16 In the first phase 1 trial (000076), after 
repeated oral administration of 75 µg quinagolide tablets once daily for 5 days, the mean Cmax was 
8 pg/mL, the steady-state trough level was 0.8 pg/mL, and AUCtau was 42.3 h*pg/mL. The 
corresponding values after intravaginal administration of 75 µg tablets was 13 pg/mL, 7 pg/mL and 
225 h*pg/mL, respectively, which was 1.6-fold, 8-fold and 5-fold higher than after oral 
administration, demonstrating that intravaginal administration circumvents the first pass 
metabolism. It also showed that intravaginal administration had a slow absorption with 
approximately 8 hours to reach the maximum concentration compared with oral administration 
(Tmax about 1 hour). Although intravaginal administration of quinagolide tablets up to 75 µg was 
associated with higher exposure, it was well tolerated with lower incidences of treatment-related 
adverse events, compared with oral administration.  
In the subsequent trial (000155), quinagolide vaginal ring at a target release rate of quinagolide 
4.5 µg/day, 9 µg/day and 13.5 µg/day were investigated. The plasma concentration of quinagolide 
increased initially in approximate proportionality. Following the initial peak, the plasma 
concentration declined slowly over the treatment period and the trough levels were maintained 
between 1-10 pg/mL for all three doses for up to 35 days. The median Tmax following 
administration of quinagolide vaginal rings was approximately 36-48 hours for all three doses.  
Selection of the doses in the present trial is based on the PK profiles obtained from these two 
phase 1 trials, which are illustrated in Figure 3-2 showing the mean observed PK parameters of the 
75 µg oral and intravaginal tablets during a daily dosing interval extended to 28 days, compared to 
the PK profiles of quinagolide vaginal rings administered for 28 days. For the highest dose of 
quinagolide vaginal ring, the mean Cmax of 10.9 pg/mL does not exceed the mean Cmax of 13 pg/mL 
observed with the 75 µg intravaginal tablet. Following the initial peak, the concentration is similar 
to the mean Cmax of 8 pg/mL observed with the 75 µg oral tablet. For the lowest dose of quinagolide 
vaginal ring, the mean concentration of quinagolide at day 28 resembles the steady state trough of 
0.8 pg/mL observed with the 75 µg oral tablet. Therefore, for the three proposed doses of 
quinagolide vaginal ring, the maximum concentrations are below the maximum concentration of 
the 75 µg intravaginal tablet and the concentrations after the initial peak are within the 
concentration range of the 75 µg oral tablet.  


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Abbreviations: Conc=concentration, QVR=quinagolide vaginal ring 
Figure 3-2 Dose Selection for Quinagolide Vaginal Ring 
 
The proposed three doses provide a dose span with an equal absolute dose difference (i.e. a target 
release rate difference of 4.5 µg/day) to investigate the treatment effect of quinagolide. The 
outcome of the present trial should allow subsequent examination of the dose-response curve and to 
identify the dose(s) for quinagolide vaginal ring to be used in future trials.   
The doses for the rescue analgesic medications used during this trial are in line with the 
recommendations in the respective product’ labelling for the indication of pain relief. 
 
3.6.5 
Selection and Timing of Dose for Each Subject 
In this clinical trial, the duration of treatment is based on individual subject’s menstrual cycle 
length rather than calendar time points, matching the visits and timings of evaluation with the 
replacement of the vaginal ring. A menstrual cycle is considered the period between day 7 of return 
of menses (RM+7) in a cycle until the following day 7 of return of menses of the next cycle. Visits 
on RM+7 can be scheduled day 6 to day 10 day of return of menses (RM+6-10). 
Subjects will be instructed to insert the assigned ring in the upper part of the vagina at RM+7 visits, 
a timing that corresponds to the stop of menstrual bleeding and is convenient for administration of a 
vaginal product, which can therefore easily be remembered and followed by subjects. The vaginal 
ring will be kept in the vagina continuously for one menstrual cycle until being replaced by the next 
Quinagolide tablets
75 µg intravaginal 
75 µg oral 
QVR target release rate 
13.5 µg/day
9 µg/day
4.5 µg/day


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ring on RM+7 of the next cycle when the subject visits the clinic. Thus, quinagolide will be given 
sufficient time to inhibit the endometriotic lesions prior to return of the menses in the next cycle, 
when the majority of the most severe endometriosis-related pain occurs.   
 
3.6.6 
Selection of the Trial Population 
The trial population consists of surgically confirmed endometriosis patients commonly included in 
clinical trials. After surgical treatment of endometriosis, these subjects still have recurrence of 
symptoms and moderate to severe endometriosis-related pain. Confirmation of endometriosis by 
laparoscopy or laparotomy is considered to be the gold standard for the diagnosis of the disease.39 It 
is increasingly recognized that ultrasound evidence of endometrioma, combined with recurrent 
endometriosis-related pain, is a useful clinical diagnostic measure of endometriosis and can identify 
endometriosis with high accuracy.40,41,42   
Moderate to severe endometriosis pain for this trial is defined as having a mean daily NRS score of 
≥4 for the worst endometriosis-related pain during each run-in menstrual cycle. The cut-off of 4 is 
the most commonly recommended lower limit for moderate pain on NRS. Results of some other 
endometriosis studies were also taken into consideration in choosing this cut-off. In two recently 
completed pivotal phase 3 trials among 1689 endometriosis patients, a mean daily NRS score of 
approximately 5.5 was recorded for endometriosis pain at its worst during a baseline period of 35 
days.43 In an observational study for a minimum of 12 weeks, the 268 subjects reported a mean 
daily NRS score of 3.61 for endometriosis-related pain at its worst as well as a daily NRS score of 
≥7 for at least 4 days.44  
The trial will include pre-menopausal women ≥18 years without an upper age limit and will thereby 
cover the age span of most endometriosis patients.  
The exclusion criteria incorporate the contraindications for the use of dopamine agonists and rescue 
analgesics. 
 
3.6.7 
Discontinuation Criteria (Stopping and Withdrawal Criteria) 
The discontinuation criteria consist of criteria for discontinuation from treatment (stopping criteria) 
and criteria for discontinuation from trial (withdrawal criteria). For any premature discontinuation, 
an end-of-treatment visit (section 6.4.6) should be scheduled as soon as possible (preferably within 
7 days of the last ring removal) and the investigator will obtain all the required details and 
document the date and the main reason of premature discontinuation in the electronic case report 
form (e-CRF).  


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Stopping Criteria (Discontinuation from Treatment) 
Stopping Criteria on Subject Level  
Subjects will be discontinued from the treatment if any of the following stopping criteria are met: 
• Any significant changes in valvular regurgitation or stenosis from baseline associated with 
clinical signs and symptoms  
• Any clinically significant abnormal ECG finding defined as prolongation of QTcF 
≥500 msec or change from baseline QTcF value of ≥60 msec confirmed by the central 
cardiac laboratory 
• Treatment-related syncope (orthostatic collapse associated with an abrupt, transient, 
complete loss of consciousness and inability to maintain postural tone, with rapid and 
spontaneous recovery) incompatible with continuing treatment  
• Treatment-related alteration in consciousness or mental status (such as confusion, amnesia, 
loss of alertness and disorientation) incompatible with continuing treatment 
• Treatment-related pathological behaviors of impulse control disorders including 
pathological gambling, compulsive buying, binge eating, and hypersexuality (see section 
7.2.2.10) incompatible with continuing treatment 
• Treatment-related acute psychosis, e.g. hallucinations/delusion 
 
Stopping Criteria on Trial Level  
The DMC will consider the following SAEs for stopping or modifying the trial (i.e. discontinuing 
one dose, several doses or the trial):  
• One subject discontinued due to a diagnosis of cardiac valvulopathy confirmed by an 
independent cardiologist (see section 7.2.2.9) 
• More than three subjects discontinued due to treatment-related syncope (orthostatic collapse 
associated with an abrupt, transient, complete loss of consciousness and inability to 
maintain postural tone, with rapid and spontaneous recovery) 
• More than three subjects discontinued due to treatment-related significant alteration in 
consciousness or mental status (such as confusion, amnesia, loss of alertness and 
disorientation)  
The DMC will be requested to access the unblinded safety data presented by treatment group and 
will recommend whether one dose, several doses or the trial should be discontinued based on the 
results of the analysis. 
 


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Withdrawal Criteria (Discontinuation from Trial) 
Withdrawal from Trial  
The subjects have the right to withdraw from the trial at any time for any reason, without the need 
to justify their decision. However, the investigator should record the reason for the subject’s 
withdrawal, if possible. The investigator also has the right to withdraw subjects at his/her 
discretion.  
The subject will be withdrawn from the trial if she experiences any of the following:  
• Requiring a medical or surgical treatment that is prohibited by the protocol 
• Becoming pregnant as confirmed by urine and serum βhCG pregnancy tests 
• Becoming menopausal as confirmed by blood tests for endocrine parameters 
Withdrawal may also occur, if the subject is non-compliant with the protocol procedures in a 
manner that could have major impact on efficacy or safety assessments.  
 
Withdrawal of Consent  
If the subject withdraws her consent, no further data will be obtained. However, already obtained 
samples may be analyzed. This will be described in the Informed Consent Documents. The subject 
can request destruction of samples, which would otherwise have been kept in storage. 
 
3.6.8 
Follow-up Procedures 
No specific follow-up procedures are defined after the end-of-trial, except for safety follow-up 
procedures for subjects becoming pregnant during treatment (see section 8.4) and for subjects with 
unresolved adverse events classified as serious or considered to have a reasonable possible 
causality to the IMP (see section 8.6).  
Access to Therapy after End-of-Trial 
Concerning access to therapy after completion of the trial, quinagolide vaginal ring is currently 
under clinical development and cannot be offered to subjects after participation in this trial. 


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4 
SELECTION OF TRIAL POPULATION 
4.1 
Trial Population 
4.1.1 
Inclusion Criteria 
1. Informed consent(s) signed and dated prior to screening evaluations.  
2. Pre-menopausal females aged ≥18 years at time of signing informed consent(s).  
3. Body mass index (BMI) of 18-42 kg/m2 (both inclusive) at screening. 
4. Documentation of diagnosis by surgical visualization of endometriosis (laparoscopy or 
laparotomy) within the last 10 years before the run-in visit or visualization of persistent 
endometrioma (≥2 cm in diameter) by repeat ultrasound in two separate menstrual cycles 
before subject’s entry into run-in. 
5. Willing and able to use a non-hormonal single-barrier contraception (i.e. condom) from 
wash-out (if applicable) or run-in to the end-of-trial. This is not required if adequate 
contraception is achieved by vasectomy of the male sexual partner, surgical sterilization (e.g. 
tubal ligation and blockage methods such as ESSURE) of the subject or true abstinence of 
the subject (sporadic sexual intercourse with men still requires condom use).  
6. Willing to avoid the use of vaginal douches or any other intravaginally administered 
medications or devices from randomization to the end of treatment. 
7. Willing to change usual analgesics to rescue analgesics as permitted by protocol (protocol 
prohibited analgesics in section 4.3.1) for endometriosis-related pain from the start of run-in 
to the end-of-trial.  
8. Willing to avoid any prophylactic use of analgesics from the start of run-in to the end-of-
trial.  
9. Willing to avoid any change in the use of non-drug therapy (e.g. acupuncture and 
physiotherapy) for endometriosis-related pain from the start of run-in to the end-of-trial.  
10. Transvaginal ultrasound documenting a uterus with no clinically significant abnormalities 
(e.g. hysterectomy) and presence of at least one ovary with no clinically significant 
abnormalities with the exception of endometrioma (e.g. no evidence of ovarian cyst ≥5 cm, 
fibroid ≥4 cm, or presence of a submucosal fibroid) at the run-in visit. 
11. Two regular menstrual cycles of 24-35 days (both inclusive) observed during the run-in 
period.  
12. Having moderate to severe endometriosis-related pain defined as: 
12a) At the run-in visit, on a self-administered 11-point NRS, having an NRS score of ≥5 
for the worst endometriosis-related pain during the past menstrual cycle.   
12b) At randomization, on the self-administered 11-point NRS, having a mean daily NRS 
score of ≥4 for the worst endometriosis-related pain during each run-in cycle. 
13. Completion of the daily e-Diary for at least 80% of the days on average in two run-in cycles, 
from the day the e-Diary is available at the start of cycle -2 through the day before visit 4 at 
the end of cycle -1. 


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14. Documentation of a normal cervical cytology or negative results of human papilloma virus 
(HPV) reflex testing within 24 months of the start of run-in. If atypical squamous cells of 
undetermined significance were present on prior tests, additional follow-up HPV test results 
should be negative for high-risk viral subtypes. 
15. Negative cervical swab for gonorrhea and chlamydia at screening.  
16. Willing and able to comply with trial procedures, including filling in the e-Diary in English 
or Spanish, attending scheduled visits and adherence to treatment plan. 
 
4.1.2 
Exclusion Criteria 
 Use of depot medroxyprogesterone acetate (MPA) within 10 months of the start of run-in. 
 Use of GnRH agonists (3-month depot injection) or dopamine agonists within 6 months of 
the start of run-in. 
 Use of GnRH agonists (1-month depot injection or nasal spray) or birth control implants (e.g. 
NEXPLANON) within 3 months of the start of run-in. 
 Use of GnRH antagonists, aromatase inhibitors, danazol, intrauterine devices or hormonal 
contraceptives (including combined oral contraceptive pill, progestin-only pill, transdermal 
patch and contraceptive ring) within 1 month of the start of run-in. 
 Undiagnosed abnormal vaginal bleeding. 
 Current vestibulodynia and vulvodynia.  
 Chronic abdominal, pelvic or lower back pain diagnosed to be of non-endometriosis origin 
(e.g. presumptive adenomyosis as a dominant condition diagnosed by magnetic resonance 
imaging (MRI) or ultrasound, inflammatory bowel disease, interstitial cystitis, spinal disc 
herniation) that would interfere with the assessment of endometriosis-related pain. 
 Current diagnosis of a chronic pain syndrome (e.g. fibromyalgia, chronic back pain, 
myofascial pain syndrome, chronic headache) or any other condition that requires continuous 
use of analgesic therapy.  
 Known bone diseases (e.g. osteoporosis, Paget’s disease and osteomalacia) affecting bone 
resorption or bone formation markers. 
 Chronic endocrine abnormality affecting the hypothalamic-pituitary-gonadal axis or leading 
to ovarian dysfunction except for hyperprolactinemia.  
 Known positive results of hepatitis B virus, hepatitis C virus and human immunodeficiency 
virus (HIV) antibody tests.  
 History of no relief of endometriosis-related pain after any medical therapy or surgery. 
However, history of partial pain relief, discontinuation due to side effects from medical 
therapy or non-adherence to post-surgery medical therapy are not exclusionary. 
 History of having used more than 2 consecutive weeks of a prohibited long-acting narcotic or 
immediate-release narcotic for treatment of endometriosis-related pain within 6 months of 
the start of run-in. 
 History of malignancy within 5 years of the start of screening, except for adequately 
managed basal cell carcinoma and squamous cell carcinoma of the skin. 
 History of recurrent bacterial / fungal vaginal infection or recurrent urinary tract infection 
(all defined as ≥4 episodes within a year). 


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 History of orthostatic hypotension or recurrent syncope. 
 History of mental illness including occurrence of acute psychosis, bipolar disorders and 
schizophrenia (except for well-controlled anxiety and/or depression with no changes to 
interventions for 6 months prior to start of run-in). 
 History of impulse control disorders including pathological gambling, compulsive buying, 
hypersexuality, and binge eating or being identified with potential impulse control disorder 
by the questionnaire for impulsive-compulsive disorders (a score ≥2 for any sub-questions of 
Question 3 or a score ≥1 for any sub-questions of Question 4) prior to randomization. 
 History of valvular heart disease. 
 History of sudden sleep onset episodes.  
 Any clinically significant abnormal findings from vital signs, urinalysis, blood tests of 
hematology and clinical chemistry at screening, including a drop of 20 mmHg of systolic 
blood pressure or a drop of 10 mmHg of diastolic blood pressure within three minutes of 
standing from a sitting position, alanine aminotransferase (ALT) >2.5 times upper limit of 
normal (ULN) or bilirubin >1.5 times ULN or creatinine >1.5 mg/dL. 
 Any clinically significant abnormal findings from blood test of endocrine parameters 
(including signs indicating menopausal status but excluding hyperprolactinemia) at 
screening. 
 Any clinically significant abnormal findings from physical examination at screening. 
 Any vaginal or vulvar lesions that could interfere with vaginal ring usage. 
 Any significant abnormal ECG or echocardiography findings (e.g. valvular regurgitation or 
stenosis) before randomization. 
 Any recent suicidal ideation of type 4 (i.e. active suicidal ideation with some intent to act, 
without specific plan) or type 5 (i.e. active suicidal ideation with specific plan and intent), or 
any recent suicidal behavior identified by the electronic Columbia-Suicide Severity Rating 
Scale at screening.  
 Hypersensitivity to any active ingredient, excipients or other component of medicinal 
products used in the trial, including quinagolide vaginal ring, placebo vaginal ring and 
ibuprofen.  
 Known serious adverse drug reactions to dopamine agonist. 
 Current or history of gastrointestinal ulcer or gastrointestinal bleeding within 6 months of the 
run-in visit.  
 Current pregnancy as confirmed by a positive serum βhCG test at screening or planning a 
pregnancy within the duration of the trial, currently breast-feeding or less than 6 months 
post-partum of the run-in visit.  
 Planned surgical treatment of endometriosis or planned surgery in the abdominal-pelvic or 
lower back area within the duration of the trial that could interfere with the efficacy 
assessment.  
 History of drug abuse within 2 years of the start of screening or a current positive urine drug 
screen, unless the cause of the positive result is from opioids and antidepressants that are 
medically indicated and prescribed by a physician.  
 Current or history of alcohol abuse within 2 years of the start of the run-in visit. 


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 Current or previous participation in a clinical trial involving a non-registered investigational 
medicinal product within 1 month of the run-in visit. If the trial involves a hormonal drug, 
the exclusion criteria 1-4 shall apply. 
 
4.2 
Method of Assigning Subjects to Treatment Groups 
4.2.1 
Recruitment 
The participating subjects will be recruited from clinics included in the trial. Advertisements may 
be used if approved by relevant Institutional Review Boards (IRBs), as applicable to local 
regulations. 
A screening number is allocated to each subject who has given informed consent to participate in 
the trial. A subject must always be assigned to the lowest available screening number at each site. A 
subject screening / enrolment log for all screened subjects must be maintained by the investigator.  
 
4.2.2 
Randomization 
On RM+7 of menstrual cycle -1, eligible subjects will be randomized in a 1:1:1:1 ratio to 
quinagolide vaginal ring dose load 360 µg, quinagolide vaginal ring dose load 720 µg, quinagolide 
vaginal ring dose load 1080 µg or placebo vaginal ring for four menstrual cycles (cycles 1, 2, 3 and 
4).  
An independent statistician at the Ferring Global Biometrics Department will create a computer-
generated randomization list and randomization is performed centrally through the e-CRF prior to 
the insertion of the first vaginal ring. Thereby each subject will receive a unique randomization 
number generated in the e-CRF system. The randomization is stratified by site, i.e. whole blocks 
are assigned to sites.  
 
4.3 
Restrictions 
4.3.1 
Prohibited Medications / Therapies 
Prohibited Medications / Therapies before the Trial and during the Trial 
The following concomitant medications and therapies are prohibited for the following period before 
the start of the run-in to the end-of-trial: 


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Prohibited medications / therapies 
Examples 
Minimum prohibited 
period before run-in  
Depot MPA  
DEPO-PROVERA 
10 months  
GnRH agonist (3-month depot injection)  LUPRON, ZOLADEX 
6 months 
Dopamine agonist 
bromocriptine (PARLODEL) 
cabergoline (DOSTINEX) 
6 months 
GnRH agonist (1-month depot injection 
or nasal spray) 
LUPRON, ZOLADEX, 
SYNAREL 
3 months 
Birth control implants  
NEXPLANON 
3 months 
Intrauterine device (IUD) 
MIRENA 
1 month 
GnRH antagonist  
 
1 month 
Aromatase inhibitor 
 
1 month 
Danazol 
CYCLOMEN 
1 month 
Hormonal contraceptives*   
combined oral contraceptive 
pill, progestin-only pill, 
transdermal patch and 
contraceptive ring (NuvaRing) 
1 month  
*Discontinuation of hormonal contraceptives should follow the labelling of the product (e.g. completing the current cycle of 
contraceptives before wash-out). Emergency contraceptives ELLA 30 mg and levonorgestrel 1.5 mg are allowed from randomization 
to the end-of-trial 
 
Prohibited Medications / Therapies during the Trial 
In addition to medications/therapies listed above, the following medications/ therapies are also 
prohibited from the start of the run-in to the end-of-trial: 
Prohibited medications / therapies 
Examples 
COX2 inhibitors 
CELEBREX  
Immediate-release strong narcotic analgesics 
Oxymorphone 
Hydromorphone 
Morphine (oral and IV) 
Fentanyl (sublingual, IV, injections)  
Any extended-release (ER), controlled-release (CR) or long-
acting narcotic analgesics  
CR/ER morphine 
CR/ER hydromorphone 
CR/ER oxymorphone 
CR/ER oxycodone 
ER tapentadol 
ER tramadol 
Methadone 
Levorphanol 
Fentanyl (transdermal patch) 
Medical marijuana 
 
Prescription amphetamine 
 
RITALIN 
 
Prohibited medications / therapies from randomization to the end-of treatment 
Vaginal douches or any other intravaginally administered medications or devices 


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Prohibited Therapy after the Trial 
It is also prohibited to continue therapy outside the scope of the trial with any medicinal products 
provided specifically for the trial.  
 
4.3.2 
Other Restrictions 
Subjects will be required to fast overnight (no food or drinks except for water after midnight) 
before LH+7 visits of cycles -1 and 4 (visits 3 and 9) due to blood sampling for analysis of bone 
turnover markers. 
Subjects must be willing and able to use an acceptable effective contraception method throughout 
the trial. The method used by subjects must be documented. In the context of this trial, acceptable 
contraception methods include: 
• A non-hormonal single-barrier contraception (i.e. condom)  
• Documented vasectomy of the male sexual partner 
• Surgical sterilization (e.g. tubal ligation or blockage methods such as ESSURE) of the 
subject  
• True abstinence of the subject (sporadic sexual intercourse with men still requires condom 
use)  
 
4.4 
Subject Replacement 
A subject can only be assigned one screening number and one randomization number unless she is 
re-screened. Subjects re-screened due to the COVID-19 pandemic will receive new screening 
numbers. The screening and randomization number are unique and cannot be re-used. Subjects who 
are discontinued prematurely after randomization are not to be replaced. 


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5 
TREATMENTS 
5.1 
Treatments Administered 
5.1.1 
Investigational Medicinal Products (IMPs) 
The investigational medicinal products (IMPs) in the present trial will be supplied as vaginal rings 
containing quinagolide 360 µg, 720 µg, 1080 µg or its matching placebo. Quinagolide vaginal ring 
is a vaginal delivery system which allows for the extended release of quinagolide for up to 35 days. 
The three strengths of quinagolide vaginal rings investigated in the present trial have a target 
release rate of quinagolide 4.5 µg/day, 9 µg/day and 13.5 µg/day, respectively. Quinagolide or 
placebo vaginal ring is inserted on RM+6-10 of a cycle and is kept in the vagina continuously until 
being replaced by a new ring on RM+6-10 of the next cycle.  
On RM+7 of cycle -1 (at visit 4), eligible subjects will be randomized in a 1:1:1:1 ratio to 
quinagolide vaginal ring dose load 360 µg, quinagolide vaginal ring dose load 720 µg, quinagolide 
vaginal ring dose load 1080 µg or placebo vaginal ring, administered once per menstrual cycle and 
sequentially for four menstrual cycles (cycles 1, 2, 3 and 4).  
The vaginal ring will be inserted and removed by the subject herself at the RM+7 visits to clinic by 
following the standard instructions for use provided to each subject, irrespective of whether the 
subject is still experiencing menstrual bleeding. If needed, supervision by site staff can be provided 
and the lubricant allowed for this trial (i.e. KY Jelly) can be used. If the ring is expelled, it can be 
rinsed and re-inserted by the subject at home. In case the ring is expelled during the non-menstrual 
period but is impossible to re-insert, a visit to the clinic for ring replacement must be arranged as 
soon as possible and no later than 3 days after ring expulsion. If the ring is expelled during the 
menstrual period and is impossible to re-insert, it is up to the investigator to decide whether a 
replacement ring is needed or not. Subjects are recommended not to take out the ring for sexual 
intercourse. If a ring is out of the body for more than 24 hours, subjects should not re-insert the ring 
but contact the site for ring replacement. 
 
5.1.2 
Non-Investigational Medicinal Product (NIMP) 
The non-investigational medicinal product (NIMP) in the present trial is 200 mg film-coated, 
capsule-shaped ibuprofen tablets with the trade name MOTRIN IB, which is provided by Ferring as 
mild rescue analgesics to subjects from start of run-in to the end-of-trial. Subjects are allowed to 
take ibuprofen for their pain relief on an as-needed basis but the maximum amount is 800 mg 
(4 tablets) per dose and 3200 mg (16 tablets) per day.27 The specific dosing regimen will be decided 
by the investigator in accordance with the labelling of prescription ibuprofen doses.27  
If required, a strong rescue analgesic hydrocodone-acetaminophen may be prescribed by the 
investigator but this will not be provided by Ferring and is not a NIMP. Details are specified in 
section 7.2.1.5.  


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5.2 
Characteristics and Source of Supply 
5.2.1 
Investigational Medicinal Product  
All IMPs are provided by Ferring and will be handled according to the principles of Good 
Manufacturing Practice (GMP). All sites will be provided with quinagolide and placebo vaginal 
rings in amounts sufficient for the trial. Quinagolide vaginal ring and placebo vaginal ring are 
indistinguishable with identical appearance. All vaginal rings are soft, flexible, off-white, 
translucent, toroid shaped rings with a major diameter of 54 mm and a minor diameter of 4.1 mm. 
The vaginal rings are latex-free. 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
  
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.2.2 
Non-Investigational Medicinal Product 
Ibuprofen is provided by Ferring as MOTRIN IB 200 mg film-coated, capsule-shaped tablets for 
oral administration and will be handled according to the principles of GMP.  
 
5.3 
Packaging and Labelling 
Packaging and labelling of the IMPs and NIMP will be performed under the responsibility of the 
Clinical Trial Supply Department at Ferring Pharmaceuticals A/S in accordance with GMP, 
Annex 13, EudraLex Volume 4 and national regulatory requirements. Details on the packaging of 
each medicinal product are provided in Table 5-2. 
Table 5-2 
Packaging of Medicinal Products 
IMP / NIMP 
Packaging 
IMP: 
Quinagolide / Placebo vaginal ring 
Each vaginal ring is packaged in an individual foil moisture barrier pouch with 
re-closable gripper and tear notches. 
NIMP: 
Ibuprofen 
Ibuprofen is provided in commercial bottles of 50 or 100 film-coated, capsule-
shaped tablets per bottle packed individually in commercial cartons. 
 
The NIMP in the present trial is commercially available and will be purchased centrally. No 
modification to the usual commercial state of the product will be made, except for trial-specific 
labelling. Thus, quinagolide vaginal rings, placebo vaginal rings and ibuprofen will all be labelled 
with trial-specific labels in accordance with applicable requirements in the country(ies) where the 
trial is conducted.   
 
5.4 
Conditions for Storage and Use 
The investigator will ensure that the medicinal products will be stored in appropriate conditions in a 
secure location with controlled access. The storage compartment shall be monitored regularly and 
the temperature shall be documented in accordance with the instructions provided by the sponsor. 
Deviations in storage temperature must be reported to the sponsor as instructed in the IMP/NIMP 
handling guideline.  
Quinagolide and placebo vaginal rings must be stored frozen (-25°C to -10°C) (-13°F to 14°F). The 
rings will be taken out from the freezer at least 30 minutes but not more than 24 hours prior to 
insertion.  
Ibuprofen must be stored at 20°C to 25°C (68°F to 77°F).  
For information on warnings, precautions and treatment of overdose, please refer to the 
Investigator’s Brochure for the IMP and to the approved labelling of the NIMP.11,27 
  


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CONFIDENTIAL 
5.5 
Blinding / Unblinding 
5.5.1 
Blinding 
Quinagolide and placebo vaginal rings, including replacement rings, will be packaged in 
accordance with a computer-generated randomization list prepared for all trial sites.  
All packaged IMP kits will be indistinguishable with identical appearance and will be labelled with 
random identification numbers which are linked to the treatment allocation. Once the subject is 
assigned a unique randomization number in the e-CRF system, the subject’s treatment allocation 
will be transferred automatically to the Interactive Response Technology (IRT) system. Site staff 
will access the IRT system to obtain an identification number for the vaginal ring to dispense to the 
subject, with both the site staff and the subject blinded to the treatment allocation. In case of ring 
replacement, the identification number for the replacement ring will also be obtained from the IRT 
system. All vaginal rings will be indistinguishable with identical appearance, flexibility and 
softness. Subjects, investigators and other site staff as well as in-field monitors will be blinded to 
treatment allocation throughout the trial.  
The personnel at the central laboratory analyzing blood samples for quinagolide and metabolite 
concentration will be unblinded to treatment allocation, but the personnel at the other central 
laboratory analyzing blood samples will be blinded to treatment allocation throughout the trial. As 
described in section 3.5, an external DMC will have access to unblinded interim data presented by 
treatment group and, if needed, unblinded safety data of some subjects presented also by treatment 
group. In any case, the DMC will keep the data and analyses confidential from the Ferring clinical 
team. Ferring clinical team e.g. data manager, statistician, trial manager, clinical project leader, 
medical writer, pharmacovigilance physician, pharmacovigilance manager and medical officer will 
be blinded to treatment allocation until breaking of the blind. The blind will be broken when the 
trial database is declared clean and is released to the responsible statistician.  
The randomization list will not be available to any person involved in the conduct and evaluation of 
the trial until the trial database is declared clean and is released to the responsible statistician, 
except for the release to the external statistician for the interim analysis. Likewise, the treatment 
allocation information will not be accessible to investigators, trial staff at the site or central 
laboratory personnel during the trial. 
 
5.5.2 
Unblinding of Individual Subject Treatment  
An emergency unblinding procedure will be available to the investigator and designated persons at 
Ferring through the e-CRF. It is the investigator’s responsibility to decide whether it is medically 
necessary to know the investigational product the subject receives (i.e. unblinding) to ensure the 
subject’s welfare and safety, and thereby the responsibility to break the blind for individual subjects 
in emergency situations resides with the investigator. Breaking of the blind for individual subjects 
in emergency situations could be required in case of a suspected unexpected serious adverse 


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CONFIDENTIAL 
reaction (SUSAR) or in case of an important adverse event where the knowledge of the IMP in 
question is required for therapeutic decisions for the management of the subject.  
The investigator/person who unblinds a subject’s treatment will use the e-CRF in which he/she is 
required to enter a password and record the reason for unblinding before the treatment code can be 
broken. The e-CRF automatically records when and by whom the code is broken. The investigator 
must record the event of unblinding in the subject’s medical record, including the reason for 
unblinding, but not the treatment allocation if this can be avoided. The investigator should notify 
the IRB about the circumstances for unblinding in accordance with local requirements.  
In case of accidental unblinding, the same procedure as for emergency unblinding must be 
followed, i.e. the person who is accidentally unblinded will enter a password in the e-CRF and must 
record the reason for unblinding, while the e-CRF records when and by whom the code is broken.  
If Ferring needs to unblind a subject’s treatment, the e-CRF will be used for unblinding. It is 
required to enter a password and the reason for unblinding before the treatment code can be broken. 
The e-CRF records also when and by whom the code is broken. The code break will occur 
according to corporate standard operating procedures for unplanned unblinding of trial subjects. It 
may be necessary to unblind an individual subject’s treatment for the purposes of expedited 
reporting to the relevant health authorities and/or IRBs. In that situation, every effort will be made 
to maintain blinding of sponsor personnel involved in data analysis and interpretation. Other 
personnel may be unblinded for SUSARs, including trial site staff as well as staff acting on behalf 
of Ferring. 
Information on whether the blind has been broken for any subjects is available in the e-CRF and 
must be collected before the database is declared clean and is released to the responsible 
statistician. 
In case the e-CRF cannot be accessed and hence the emergency unblinding cannot be performed 
within the e-CRF system, the investigator should contact Ferring Pharmacovigilance using the 
contact details given below. 
Ferring Pharmacovigilance 
 
 
If Ferring Pharmacovigilance cannot access the e-CRF, a back-up procedure involving the e-CRF 
vendor is in place.  
 
5.6 
Treatment Compliance 
5.6.1 
Dispensing and Accountability 
The IMP must only be dispensed to and inserted by subjects who meet the eligibility criteria and 
are randomized to a treatment group in the trial. The site staff will use an IRT system to assign and 
dispense IMP and NIMP kits. The dates and quantities of IMP and NIMP dispensed to and returned 


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by each subject will also be recorded in the IRT system to manage the overall drug accountability 
for each subject. The in-field monitor will review and verify the drug accountability of the IMPs 
and NIMP throughout the trial. Any discrepancies will be documented.  
 
5.6.2 
Assessment of Compliance 
Compliance with IMP treatment regimen is assessed by dates of vaginal ring insertion and ring 
removal for each cycle.  
 
5.7 
Return and Destruction of Medicinal Products  
All used and unused IMPs and all unused NIMP will be returned to Ferring as instructed by the 
Ferring Clinical Trial Supply Department. All used IMPs should be stored frozen (-25°C to -10°C) 
(-13°F to 14°F) until being returned. A subset of the used vaginal rings, returned under temperature 
controlled shipment, will be analyzed for aspects such as residual quinagolide content and ring 
discoloration. Results of such analyses will be reported separately. The return shipment will be 
arranged after drug accountability has been verified by the in-field monitor and signed off by the 
investigator.  
 
5.8 
Auxiliary Supplies 
Ferring will provide the trial sites with lubricants for ring insertion and/or removal. Any unused 
supply of lubricants will be returned or destructed upon trial site closure. 


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CONFIDENTIAL 
6 
TRIAL PROCEDURES 
Table 6-1 
Trial Flow Chart – Procedures at Clinics 
 
Screening a, b 
Treatment b 
Follow-up b 
Wash 
-outa 
Start of  
Run-in  
Run-in period 
Cycle 1 
Cycle 2 Cycle 3 
Cycle 4 
Cycle 5 
Cycle -2 Cycle -1 
~1 cycle 
before 
run-in 
V1 
 
V2 V3 V4 
V5 
 
V6 
 
V7 
 
V8 V9 
V10 
V11 
RM 
+7 
LH 
+7 
RM 
+7 
LH 
+7 
RM 
+7 
1-5d 
of V4 
LH 
+7 
RM 
+7 
LH 
+7 
RM 
+7 
LH 
+7 
RM 
+7 
LH 
+7 
End-of-treatmentc 
RM+7 
End-of-trialc 
RM+7 
Written informed consent(s) 
X 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NRS (last cycle) on paper 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eC-SSRS 
 
Xd 
 
 
 
Xe 
 
 
 
 
Xf 
 
 
 
Xf 
 
Inclusion/exclusion criteria  
X 
Xd 
 
X 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
Demographics, history, BMI 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
 
Xd 
 
 
 
Xe 
Xg 
 
 
 
 
 
 
 
Xg 
 
ECG 
 
 
 
 
 Xg,h 
 
 
 
 
 
 
 
 
 
 Xg,h 
 
Echocardiography (Echo) 
 
 
 
 
Xh 
 
 
 
 
 
 
 
 
 
Xh 
 
Physical exam 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Gynecological (GYN) / pelvic exam i 
 
Xd 
 
 
 
Xj 
 
 
 
 
 
 
 
 
X 
 
Cervical swab  
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transvaginal ultrasound (TVU) 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine pregnancy test k 
 
Xd 
 
X 
X 
Xe 
 
 
Xj 
 
Xj 
 
Xj 
X 
Xj 
X 
Urine drug screen 
 
Xd 
 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood sample (safety lab) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Blood sample (endocrine)  
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Blood sample (fasting BTM) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Blood sample (biomarkers l) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Blood sample (PK)  
 
 
 
 
 
 
X 
 
Xj 
 
 
 
Xj 
X 
Xj 
 
Blood sample (PG m) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
e-Diary review 
 
      X ..................................Xe.......................................................................................................................X 
QICD  
 
 
 
 
 
Xe 
 
 
 
 
 
 
 
 
Xf 
 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
EHP-30 questionnaire 
 
 
 
 
 
Xj 
 
 
Xf 
 
Xf 
 
Xf 
 
Xf 
 
PGIS scale 
 
 
 
X 
 
Xj 
 
 
 
 
 
 
 
 
Xf 
 
PGIC scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
 
B&B scale  
 
 
 
 
 
 Xi,j 
 
 
 
 
 
 
 
 
 Xf,i 
 
Menstruation dates 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Insertion/removal of ring 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Ring acceptability questionnaire 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Drug accountability 
 
 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
Concomitant medications  
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Adverse events 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Dispense/prescribe rescue med. 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Dispense/remind contraception 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
LH surge kit dispensing 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
LH surge test reminders 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
End-of-treatment question & form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
BTM=bone turnover markers, eC-SSRS=electronic Columbia-Suicide Severity Rating Scale, QICD=Questionnaire for Impulsive-Compulsive Disorders, V=visit 
a 
The screening period includes a wash-out period of about 1 month (applicable to some subjects) and a run-in period of 2 cycles (applicable to all subjects)   
b 
In this trial, a menstrual cycle is considered the period between day 7 of return of menses (RM+7) in a cycle until the following RM+7  Visits on RM+7 or LH+7  can 
 
be scheduled on RM+6-10 or LH+6-9, i e  day 6 to day 10 of return of menses or 6-9 days after LH surge, respectively  No visits needed for grayed LH+7 columns  
c 
In case of premature discontinuation, an end-of-treatment visit should be arranged as soon as possible, preferably within 7 days of the last ring removal (section 6 1 1)  
d 
Performed before entry into run-in (before or at visit 1 but not before wash-out visit)  Subjects must receive a signed copy of ICF(s) before trial-related procedures   
e 
Performed before randomization   
f 
Performed prior to other non-PRO procedures at the visit  This requirement also applies to B&B first part  
g 
Performed before blood sampling, when applicable   
h 
ECG and Echo at V3 can be done anytime during cycle -1 but results must be available before randomization  ECG and Echo at V10 can be done ±2 weeks of V10   
i 
GYN exam at V1 and V10; pelvic exam at V4 for B&B second part (section 7 4 12)  B&B first and second parts completed by different staff (section 7 2 2 1)   
j 
Performed after randomization but before ring insertion or removal   
k 
If the urine pregnancy test result is positive, a serum βhCG test must be performed  
l 
Samples for endometriosis biomarkers taken for all subjects  Additional samples for cell-free DNA/microRNA if a separate consent is obtained (section 7 3 1)   
m 
Pharmacogenetic (PG) testing is performed if subjects have provided a separate informed consent (section 7 4 22)  


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CONFIDENTIAL 
The flow of the self-assessments by the subjects in an e-Diary is shown in Table 6-2. The e-Diary 
should be completed by the subjects before bedtime every night throughout the trial.  
Table 6-2 
Trial Flow Chart – Self-assessments by Subjects 
 
Screeninga 
Treatment  
Follow-upa 
V1a 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11a 
Daily self-recording by subjects in e-Diary 
NRS 
    X......................................................................................................................................X 
Ocurrence of sexual intercourse 
    X......................................................................................................................................X 
Pain impact b 
    X......................................................................................................................................X 
Vaginal bleeding  
    X......................................................................................................................................X 
Analgesics use 
    X......................................................................................................................................X 
NRS=Numerical Rating Scale, V=visit  
a 
Subjects should complete the e-Diary before bedtime every night from run-in to follow-up, i.e. from the run-in visit (visit 1) to the end-of-trial 
 
visit (visit 11).  
b 
Pain impact will be assessed by subjects in e-Diary on both a daily and a weekly basis.  
 
6.1 
Activities between Clinic Visits 
In this trial, a menstrual cycle is considered the period between day 7 of return of menses (RM+7) 
in a cycle until the following RM+7. Visits on RM+7 can be scheduled on RM+6-10, i.e. day 6 to 
day 10 of return of menses. Similarly, visits on LH+7 can be scheduled on LH+6-9, i.e. 6-9 days 
after LH surge, which is either assessed by the subject using LH surge kits at home or estimated by 
the site staff based on subject’s cycle length. If subjects do not have menstrual bleeding in a cycle 
during the treatment and follow-up period, the RM+7 visit in that cycle must be arranged within 
35 days of the last RM+7 visit.  
The review of the e-Diary, which covers compliance with e-Diary completion and analgesic use 
should be performed by site staff regularly between clinic visits. 
Contraception counselling and condoms will be offered to subjects as needed throughout the trial. 
 
6.1.1 
Premature Discontinuation 
In case of premature discontinuation, an end-of-treatment visit (see section 6.4.6) should be 
arranged as soon as possible (preferably within 7 days of the last ring removal). Subjects who are 
prematurely discontinued from the treatment due to adverse events will be asked to attend an end-
of-trial visit (see section 6.5.1) within 2 weeks of the end-of-treatment visit. If subjects are 
discontinued for other reasons, the end-of-treatment and end-of-trial visits can coincide.  
If a discontinued subject is found with an ongoing adverse event classified as serious or considered 
to have a reasonable possible causality to the IMP at their last trial visit, the site staff should follow 
up until the event is resolved (see section 8.6).  
 


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6.2 
Screening 
Potential participants will be scheduled to come to the clinic for the screening assessments. The 
screening period includes a wash-out period of approximately one month (only applicable to 
subjects currently using some hormonal products such as contraceptives c) and a run-in period of 
two complete menstrual cycles (cycles -2 and -1, applicable to all subjects).  
In case of technical issues at the start of the run-in period, subjects are allowed to re-start cycle -2 
after undergoing all procedures at visit 2 except for PGIS and LH surge test reminders. Subjects 
that screen fail due to the temporary trial hold during the coronavirus disease 2019 (COVID-19) 
pandemic may be re-screened. In this case, subjects need to repeat the two run-in cycles, but can be 
waived from the echocardiography assessment as applicable.  
 
6.2.1 
Wash-out Period (As Applicable) 
Subjects who are currently using some hormonal products (including GnRH antagonists, aromatase 
inhibitors, danazol and hormonal contraceptives such as combined oral contraceptive pill, 
progestin-only pill, transdermal patch and contraceptive ring) may be eligible for the trial if they 
have completed the wash-out period. In this case, subjects need to sign the informed consent(s) 
before they discontinue those products. Discontinuation of the products should follow the labelling 
(e.g. completing the current cycle of contraceptives before wash-out).  
Subjects requiring wash-out will not be provided with e-Diary or rescue analgesics until the 
completion of the wash-out period, i.e. at the run-in visit. 
The following must take place if a wash-out period is required: 
• Signed and dated written informed consent(s)  
- 
Mandatory for the informed consent covering the participation of the trial [note: this 
must be obtained prior to any trial-related procedures]  
- 
Optional for the informed consent covering the cell-free DNA/microRNA and 
pharmacogenetic sampling [note: this needs to be obtained prior to the sampling] 
- 
Optional for the informed consent covering the patient interview [note: this needs to 
be obtained prior to the patient interview] 
• Allocation of a screening number 
• Check of inclusion and exclusion criteria (those which are possible to check at this stage) 
• Recording of use of any concomitant medications (within the last 3 months prior to the 
signed informed consent for participation in the trial, i.e. the main informed consent) 
• Recording of adverse events (from the date of signed main informed consent) 
• Reminding the subject to attend the RM+7 visit after completion of the wash-out period 
 
6.2.2 
Visit 1 (Start of Run-in) 
Subjects will attend visit 1 (run-in visit), scheduled on RM+6-10 of a cycle prior to cycle -2. Some 
assessments listed below can be performed before visit 1 but not before the wash-out visit. Subjects 


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must receive a signed copy of informed consent form(s) before any trial-related procedures.  
The following must take place for those subjects who do NOT require a wash-out period and can be 
performed either before or at visit 1 (i.e., before subject’s entry into run-in): 
• Signed and dated written informed consent(s)  
- 
Mandatory for the informed consent covering the participation of the trial [note: this 
must be obtained prior to any trial-related procedures]  
- 
Optional for the informed consent covering the cell-free DNA/microRNA and 
pharmacogenetic sampling [note: this needs to be obtained prior to the sampling] 
- 
Optional for the informed consent covering the patient interview [note: this needs to 
be obtained prior to the patient interview] 
• Allocation of a screening number 
 
The following procedures must be performed for all subjects either before or at visit 1 (i.e., before 
subject’s entry into run-in): 
• Asking subjects to score the worst endometriosis-related pain on the NRS on paper based on 
a recall of experience in the past menstrual cycle (see Appendix 1, a score ≥5 for eligibility) 
• Asking subjects to complete the electronic Columbia-Suicidal Severity Rating Scale 
(eC-SSRS)  
• Check of inclusion and exclusion criteria (those which are possible to check at this stage) 
• Demographics (age, ethnicity, race) 
• Collection of the following data: 
- 
Medical history 
- 
Menstrual history 
- 
Reproductive history 
• Body measurement (body weight, height) [note: these are used for calculation of BMI] 
• Vital signs 
• Physical examination 
• Gynecological examination  
• Cervical swab [note: results must be negative] 
• Transvaginal ultrasound  
• Urine pregnancy test [note: results must be negative. If positive, a serum test must be done] 
• Urine drug screen 
• Urinalysis 
 
The following procedures will be performed at visit 1 if subjects are considered eligible for the trial 
based on the inclusion and exclusion criteria assessed at this time point: 
• Training the subject for e-Diary use after helping her with e-Diary installation on her own 
phone or providing her with an e-Diary device  
• Confirmation of the start date and, if applicable, stop date of menses in the current cycle 


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• Recording of use of any concomitant medications (within the last 3 months prior to the 
signed informed consent for participation in the trial, i.e. the main informed consent, or from 
last visit) 
• Recording of adverse events (from the date of signed main informed consent or last visit) 
• Dispensing / prescription of rescue analgesics  
• Dispensing of condoms and reminding the subject to use proper contraception 
• Dispensing of LH surge kits and giving instructions on testing LH surge during cycle -1 
• Reminding the subject to bring back all used and unused ibuprofen to the next visit 
• Reminding the subject to attend the RM+7 visit of cycle -2 
 
6.2.3 
Visit 2 (RM+7 of Cycle -2) 
Subjects will attend visit 2, scheduled on RM+6-10 of cycle -2.  
The following must take place at the visit: 
• e-Diary review and ensure that the subject is still eligible for participation in the trial 
• Urine pregnancy test [note: results must be negative. If positive, a serum test must be done] 
 
The following procedures will be performed if subjects are considered eligible for the trial based on 
the inclusion and exclusion criteria assessed at this time point: 
• Ensure the completion of the PGIS scale by the subject  
• Confirmation of the start date and, if applicable, stop date of menses in the current cycle 
• Drug accountability of ibuprofen as applicable 
• Recording of use of any concomitant medications  
• Recording of adverse events  
• Dispensing / prescription of rescue analgesics  
• Dispensing of condoms and reminding the subject to use proper contraception  
• Reminding the subject to test LH surge during cycle -1 as applicable  
• Reminding the subject to complete the e-Diary before bedtime every day 
• Reminding the subject to bring back all used and unused ibuprofen to the next visit 
• Reminding the subject to attend the LH+7 visit of cycle -1 
 
6.2.4 
Visit 3 (LH+7 of Cycle -1) 
Subjects will attend visit 3, scheduled on LH+6-9 of cycle -1. Subjects will be required to fast 
overnight (no food or drinks except for water after midnight) before the visit. 
The following must take place at the visit: 
• e-Diary review and ensure that the subject is still eligible for participation in the trial [note: 
only compliance can be checked at this visit] 
• Urine pregnancy test [note: results must be negative. If positive, a serum test must be done] 


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The following procedures will be performed if subjects are considered eligible for the trial based on 
the inclusion and exclusion criteria assessed at this time point: 
• ECG [note: this can be performed anytime during cycle -1 but results must be available 
before randomization. ECG must be performed before blood sampling when applicable] 
• Echocardiography [note: this can be performed anytime during cycle -1 but results must be 
available before randomization] 
• Blood collection for analysis of:  
− 
Clinical chemistry and hematology parameters [note: the result must be available 
prior to randomization] 
− 
Endocrine panel (estradiol, progesterone, prolactin, TSH and IGF-1) [note: the result 
must be available prior to randomization] 
− 
Bone turnover markers (s-CTx and s-PINP) 
− 
Endometriosis biomarkers including but not limited to VEGF, PlGF, IL-6 and sFlt-1; 
if the subject has provided a separate informed consent, additional samples for 
potential analyses of cell-free DNA and microRNA will be collected (section 7.3.1) 
• Drug accountability of ibuprofen as applicable 
• Recording of use of any concomitant medications  
• Recording of adverse events  
• Dispensing / prescription of rescue analgesics  
• Dispensing of condoms and reminding the subject to use proper contraception  
• Reminding the subject to complete the e-Diary before bedtime every day 
• Reminding the subject to bring back all used and unused ibuprofen to the next visit 
• Reminding the subject to attend the RM+7 visit of cycle -1 
 
6.3 
Randomization 
6.3.1 
Visit 4 (RM+7 of Cycle -1) 
Subjects will attend visit 4, scheduled on RM+6-10 of cycle -1.  
The following must take place prior to randomization:  
• e-Diary review and ensure that the subject is still eligible for participation in the trial 
• Urine pregnancy test [note: results must be negative. If positive, a serum test must be done]  
• Urine drug screen 
• Vital signs 
• Completing the questionnaire for impulsive-compulsive disorders (QICD) based on the 
subject’s verbal responses   
• Ensure the completion of the eC-SSRS by the subject 
• Check those inclusion and exclusion criteria that were not possible during screening 
 


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If the subject fulfils all inclusion and exclusion criteria, she will proceed to randomization: 
• Randomization, i.e. being assigned to a unique subject number in the e-CRF and thereby 
allocated to placebo vaginal ring or quinagolide vaginal ring dose load 360, 720 or 1080 µg  
 
The following will be performed for eligible subjects before insertion of the ring:  
• Ensure the completion of the EHP-30 questionnaire by the subject   
• Ensure the completion of the PGIS scale by the subject  
• Completing the first part of B&B scale based on the subject’s verbal responses  
• Pelvic examination for the second part of B&B scale (see section 7.2.2.17.4.12) 
• Investigator completing the second part of B&B scale based on findings from an 
examination of pelvic tenderness and induration (see section 7.2.2.1) 
 
Once the above has been completed, the following must be performed: 
• Confirmation of the start date and, if applicable, stop date of menses in the current cycle 
• Access the IRT system to obtain an identification number for a vaginal ring to dispense  
• Subject will be instructed to insert the assigned vaginal ring in the upper part of the vagina. 
Supervision by the site staff can be provided if needed  
• Ensure the completion of the ring acceptability questionnaire (simplified version, with only 
one question about ring insertion) by the subject 
 
Finally, the following must be done before the subject leaves the clinic:  
• Drug accountability of ibuprofen as applicable 
• Recording of use of any concomitant medications  
• Recording of adverse events  
• Dispensing / prescription of rescue analgesics  
• Dispensing of condoms and reminding the subject to use proper contraception  
• Reminding the subject to complete the e-Diary before bedtime every day 
• Reminding the subject to bring back all used and unused ibuprofen to visit 6 
• Reminding the subject to attend the next visit, scheduled within 1-5 days of ring insertion 
 
6.4 
Treatment  
6.4.1 
Visit 5 (Within 1-5 days of Visit 4) 
Subjects will attend visit 5, scheduled within 1-5 days of visit 4. 
The following must take place at the visit: 
• Vital signs [note: vital signs must be performed before blood sampling] 
• Blood collection for analysis of 
− 
Plasma concentration of quinagolide and metabolites   
− 
Pharmacogenetics (only if the subject has provided a separate informed consent)  


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• e-Diary review 
• Recording of use of any concomitant medications  
• Recording of adverse events  
• Dispensing of condoms and reminding the subject to use proper contraception  
• Reminding the subject to complete the e-Diary before bedtime every day  
• Reminding the subject to bring back all used and unused ibuprofen to the next visit 
• Reminding the subject to attend the RM+7 visit of cycle 1 
 
6.4.2 
Visit 6 (RM+7 of Cycle 1) 
Subjects will attend visit 6, scheduled on RM+6-10 of cycle 1. 
The following must take place before ring insertion / removal: 
• Ensure the completion of the EHP-30 questionnaire by the subject  
• Urine pregnancy test [note: results must be negative. If positive, a serum test must be done] 
• Blood collection for analysis of: 
- 
Plasma concentration of quinagolide and metabolites 
 
Once the above has been completed, the following must be performed: 
• e-Diary review 
• Confirmation of the start date and, if applicable, stop date of menses in the current cycle 
• Access the IRT system to obtain an identification number for a new vaginal ring to dispense  
• Removal of the used ring and insertion of the new ring by the subject. Supervision by the site 
staff can be provided if needed  
• Ensure the completion of the ring acceptability questionnaire (full version) by the subject 
• Drug accountability of the ring and ibuprofen as applicable  
• Recording of use of any concomitant medications  
• Recording of adverse events  
• Dispensing / prescription of rescue analgesics  
• Dispensing of condoms and reminding the subject to use proper contraception 
• Reminding the subject to complete the e-Diary before bedtime every day  
• Reminding the subject to bring back all used and unused ibuprofen to the next visit 
• Reminding the subject to attend the RM+7 visit of cycle 2 
 
6.4.3 
Visit 7 (RM+7 of Cycle 2) 
Subjects will attend visit 7, scheduled on RM+6-10 of cycle 2.  
The following must take place before ring insertion / removal: 
• Ensure the completion of the EHP-30 questionnaire by the subject  


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• Ensure the completion of the eC-SSRS by the subject 
• Urine pregnancy test [note: results must be negative. If positive, a serum test must be done] 
 
Once the above has been completed, the following must be performed: 
• e-Diary review  
• Confirmation of the start date and, if applicable, stop date of menses in the current cycle 
• Access the IRT system to obtain an identification number for a new vaginal ring to dispense  
• Removal of the used ring and insertion of the new ring by the subject. Supervision by the site 
staff can be provided if needed  
• Ensure the completion of the ring acceptability questionnaire (full version) by the subject  
• Drug accountability of the ring and ibuprofen as applicable  
• Recording of use of any concomitant medications  
• Recording of adverse events  
• Dispensing / prescription of rescue analgesics  
• Dispensing of condoms and reminding the subject to use proper contraception 
• Dispensing of LH surge test kits and giving instructions on testing LH surge during cycle 4  
• Reminding the subject to complete the e-Diary before bedtime every day 
• Reminding the subject to bring back all used and unused ibuprofen to the next visit 
• Reminding the subject to attend the RM+7 visit of cycle 3 
 
6.4.4 
Visit 8 (RM+7 of Cycle 3) 
Subjects will attend visit 8, scheduled on RM+6-10 of cycle 3. 
The following must take place before ring insertion / removal: 
• Ensure the completion of the EHP-30 questionnaire by the subject  
• Urine pregnancy test [note: results must be negative. If positive, a serum test must be done] 
• Blood collection for analysis of: 
- 
Plasma concentration of quinagolide and metabolites 
  
Once the above has been completed, the following must be performed: 
• e-Diary review  
• Confirmation of the start date and, if applicable, stop date of menses in the current cycle 
• Access the IRT system to obtain an identification number for a new vaginal ring to dispense   
• Removal of the used ring and insertion of the new ring by the subject. Supervision by the site 
staff can be provided if needed  
• Ensure the completion of the ring acceptability questionnaire (full version) by the subject 
• Drug accountability of the ring and ibuprofen as applicable  
• Recording of use of any concomitant medications  
• Recording of adverse events  


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• Dispensing / prescription of rescue analgesics  
• Dispensing of condoms and reminding the subject to use proper contraception  
• Reminding the subject to test LH surge during cycle 4 as applicable  
• Reminding the subject to complete the e-Diary before bedtime every day 
• Reminding the subject to bring back all used and unused ibuprofen to the next visit 
• Reminding the subject to attend the LH+7 visit of cycle 4 
 
6.4.5 
Visit 9 (LH+7 of Cycle 4) 
Subjects will attend visit 9, scheduled on LH+6-9 of cycle 4. Subjects will be required to fast 
overnight (no food or drinks except for water after midnight) before the visit. 
The following must take place at the visit: 
• Urine pregnancy test [note: results must be negative. If positive, a serum test must be done] 
• Blood collection for analysis of:  
− 
Endocrine panel (estradiol, progesterone, prolactin, TSH and IGF-1) 
− 
Bone turnover markers (s-CTx and s-PINP) 
− 
Plasma concentration of quinagolide and metabolites 
− 
Endometriosis biomarkers including but not limited to VEGF, PlGF, IL-6 and sFlt-1; 
if the subject has provided a separate informed consent, additional samples for 
potential analyses of cell-free DNA and microRNA will be collected (section 7.3.1) 
• e-Diary review 
• Drug accountability of ibuprofen as applicable 
• Recording of use of any concomitant medications  
• Recording of adverse events  
• Dispensing / prescription of rescue analgesics  
• Dispensing of condoms and reminding the subject to use proper contraception  
• Reminding the subject to complete the e-Diary before bedtime every day 
• Reminding the subject to bring back all used and unused ibuprofen to the next visit 
• Reminding the subject to attend the RM+7 visit of cycle 4 
 
6.4.6 
Visit 10 (End-of-Treatment / RM+7 of Cycle 4) 
If subjects attend all scheduled visits and complete the treatment, an end-of-treatment visit 
(visit 10) will be scheduled on RM+6-10 of cycle 4. If subjects are discontinued from the treatment 
prematurely, an end-of-treatment visit with the following end-of-treatment assessments should be 
scheduled as soon as possible (preferably within 7 days of the last ring removal).  
The following must take place first:  
• Ensure the completion of the EHP-30 questionnaire by the subject  
• Ensure the completion of the PGIS scale by the subject  


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• Ensure the completion of the PGIC scale by the subject 
• Completing the first part of B&B scale based on the subject’s verbal response 
• Completing the questionnaire for impulsive-compulsive disorders (QICD) based on the 
subject’s verbal responses  
• Ensure the completion of the eC-SSRS by the subject 
 
Once the above has been completed, the following must be performed: 
• Vital signs [note: vital signs must be performed before blood sampling] 
• ECG [note: this can be done within ±2 weeks of the visit and must be performed before 
blood sampling when applicable] 
• Echocardiography [note: this can be done within ±2 weeks of the visit] 
• Physical examination 
• Gynecological examination  
• Transvaginal ultrasound  
• Investigator completing the second part of B&B scale based on findings from an 
examination of pelvic tenderness and induration (see section 7.2.2.1)  
• Urine pregnancy test [note: this is performed prior to ring insertion / removal. Results must 
be negative. If positive, a serum test must be done] 
• Urinalysis 
• Blood collection for analysis of: 
- 
Plasma concentration of quinagolide and metabolites [note: this is performed prior to 
ring insertion / removal] 
- 
Clinical chemistry and hematology parameters  
• Removal of the used ring. Supervision by the site staff can be provided if needed  
• Ensure the completion of the ring acceptability questionnaire (full version) by the subject  
 
Lastly, the following must take place at this visit: 
• e-Diary review 
• Confirmation of the start date and, if applicable, stop date of menses in the current cycle 
• Drug accountability of the ring and ibuprofen as applicable  
• Recording of use of any concomitant medications  
• Recording of adverse events  
• Completion the end-of-treatment question where subjects will be asked which treatment 
(placebo or quinagolide) they believe they have received  
• Completion of end-of-treatment form 
 
For subjects who have completed the treatment, the following must be performed:  
• Dispensing / prescription of rescue analgesics  
• Dispensing of condoms and reminding the subject to use proper contraception  
• Reminding the subject to complete the e-Diary before bedtime every day 


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CONFIDENTIAL 
• Reminding the subject to bring back all used and unused ibuprofen to the next visit 
• Reminding the subject to attend the RM+7 visit of cycle 5  
 
For subjects who are prematurely discontinued from the treatment due to adverse events, the next 
visit is the end-of-trial visit (see section 6.5.16.5.1) scheduled within 2 weeks. For subjects who are 
prematurely discontinued from the treatment for other reasons, the completion of end-of-treatment 
assessments outlined in this section and end-of-trial assessments listed in section 6.5.1 are required 
at their last trial visit.  
 
6.5 
Follow-up  
6.5.1 
Visit 11 (End-of-Trial / RM+7 of Cycle 5) 
If subjects attend all scheduled visits, an end-of-trial visit (visit 11) will be scheduled on RM+6-10 
of cycle 5. If subjects are prematurely discontinued from the treatment due to adverse events, 
subjects will be asked to attend an end-of-trial visit within 2 weeks of the end-of-treatment visit. If 
subjects are prematurely discontinued for other reasons, an end-of-trial visit can be scheduled on 
the same day of the end-of-treatment visit. 
The following end-of-trial assessments must take place at the subject’s last visit: 
• Urine pregnancy test [note: results must be negative. If positive, a serum test must be done] 
• Blood collection for analysis of:  
− 
Clinical chemistry and hematology parameters 
• e-Diary review 
• Uninstallation of e-Diary app or collection of e-Diary device as applicable 
• Confirmation of the start date and, if applicable, stop date of menses in the current cycle 
• Drug accountability of ibuprofen as applicable 
• Recording of use of any concomitant medications  
• Recording of adverse events   
• Completion of the end-of-trial form 
 


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7 
TRIAL ASSESSMENTS 
7.1 
Assessments Related to Primary Endpoint 
7.1.1 
Endometriosis-related Pain 
Endometriosis-related pain, i.e. pain located in the abdominal-pelvic area and the lower back area, 
will be assessed by subjects in an e-Diary on a daily basis from run-in to follow-up (cycle -2 to 
cycle 5). An illustration of a female body with the abdominal-pelvic area and lower back area 
circled will be presented in the instructions (see Figure 7-1). Subjects will be asked to score based 
on the worst pain they experienced in the circled areas during the preceding 24 hours on a self-
administered 11-point NRS and note it down in the e-Diary before bedtimee every night. The daily 
diary will be accessible from 8 pm to 2 am every day. 
 
Figure 7-1 Location of Endometriosis-related Pain 
 
 
e  When subjects have irregular sleep schedules, they shall enter data between 8 pm and 2 am rather than at bedtime. 


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Instructions and the question to be answered are: 
Please think about the worst endometriosis-related pain you experienced in the past 24 hours and 
rate it on a scale from 0 to 10 where 0 is ‘no pain’ and 10 is ‘worst imaginable pain’. Please do not 
include pain from sexual intercourse. 
1. Please rate your worst endometriosis-related pain in the past 24 hours (including pelvic pain, 
abdominal pain, or lower back pain, whichever is the worst).   
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
pain  
 
 
 
 
 
 
 
 
 
Worst 
imaginable 
pain 
The mean of the daily NRS scores obtained during the two run-in menstrual cycles (cycles -2 
and -1) for endometriosis-related pain will be considered baseline. 
If the subject did not complete the daily diary the day before, a question related to reasons for no 
data entry will be asked at the end of the diary.  
The question to be answered is: 
If the subject did not answer the diary yesterday: 
14. Please let us know why you did not complete the diary yesterday.  
 I was in too much pain from endometriosis 
 I forgot 
 Other reason  
 
The answer to this question will be used to impute scores for missing data (section 9.6.1). The 
complete e-Diary including instructions and questions are available in Appendix 1. 
 
7.2 
Assessments Related to Secondary Endpoints  
7.2.1 
Assessments Related to Secondary Endpoints in e-Diary 
Subjects will be instructed to complete the e-Diary on a daily basis from run-in to follow-up (cycle 
-2 to cycle 5). In addition to endometriosis-related pain, they should assess the following items 
during the past 24 hours before bedtime every day in the e-Diary: vaginal bleeding, occurrence of 
sexual intercourse and dyspareunia (if applicable), and analgesic use. The impact of endometriosis-
related pain will be assessed by subjects on both a daily and a weekly basis. Of these assessments, 
questions concerning endometriosis-related pain, vaginal bleeding, occurrence of sexual intercourse 
and pain impact are components of the newly developed PRO tool Women’s Endometriosis Diary.  
The complete e-Diary including instructions and questions are available in Appendix 1. 
 


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CONFIDENTIAL 
7.2.1.1 
Dysmenorrhea and Non-menstrual Pelvic Pain 
Dysmenorrhea is defined as “endometriosis-related pain on days with menstrual bleeding”, while 
non-menstrual pelvic pain is defined as “endometriosis-related pain on days with no menstrual 
bleeding”. The question on endometriosis-related pain (Question 1) is available in section 7.1.1. 
If subjects have any vaginal bleeding, they will be asked whether it is menstrual bleeding or not. 
Based on the woman’s subjective impression of whether she has menstrual bleeding or not, the 
daily NRS score for endometriosis-related pain will be assigned to dysmenorrhea or to non-
menstrual pelvic pain. The questions on vaginal bleeding and menstrual bleeding (Question 9 and 
Question 11) are available in section 7.2.1.4.  
The mean of the daily NRS scores obtained during the two run-in menstrual cycles (cycles -2 
and -1) for dysmenorrhea and for non-menstrual pelvic pain, respectively, will be considered 
baseline scores. 
 
7.2.1.2 
Dyspareunia and Frequency of Avoiding Sexual Intercourse due to Expected Pain 
Occurrence of sexual intercourse (“yes” or “no”) will also be recorded in the e-Diary on a daily 
basis from run-in to follow-up (cycle -2 to cycle 5). In case of sexual intercourse, subjects will be 
asked to score the worst pain they experienced during or after the intercourse (dyspareunia) on the 
NRS. In case of no sexual intercourse, subjects will be asked if it is due to expected pain (“yes” or 
“no”).  
The questions to be answered are  
2. Did you have sexual intercourse in the past 24 hours?  
 No  
 Yes  
 
If the subject did not have sexual intercourse in the past 24 hours: 
3. Did you avoid sexual intercourse in the past 24 hours because of expected endometriosis-related 
pain?  
 No  
 Yes 
 
If the subject had sexual intercourse in the past 24 hours: 
4. Please rate your worst pain during or after sexual intercourse in the past 24 hours. 
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
pain  
 
 
 
 
 
 
 
 
 
Worst 
imaginable 
pain 


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CONFIDENTIAL 
The mean of the NRS scores obtained for dyspareunia on the days with sexual intercourse and the 
frequency of avoiding sexual intercourse during the two run-in menstrual cycles (cycles -2 and -1) 
will be considered baseline of the respective endpoint.  
 
7.2.1.3 
Pain Impact 
Daily Pain Impact on Functioning 
Subjects will assess the worst impact of the endometriosis-related pain on different aspects of 
functioning during the past 24 hours on the NRS before bedtime every day in a daily e-Diary from 
run-in to follow-up (cycle -2 to cycle 5).  
The questions to be answered are  
5. How did your endometriosis-related pain limit your sitting, standing and walking in the past 24 
hours?  
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
limitations 
on activities  
 
 
 
 
 
 
 
 
 
Unable  
to do 
activities 
 
6. How did your endometriosis-related pain limit your daily activities around the house, such as 
doing chores, laundry, cooking, washing dishes, or cleaning in the past 24 hours?  
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
limitations 
on activities  
 
 
 
 
 
 
 
 
 
Unable  
to do 
activities 
 
7. How did your endometriosis-related pain limit your work/school in the past 24 hours?  
  Not applicable, no work or school in the past 24 hours. 
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
limitations 
on activities  
 
 
 
 
 
 
 
 
 
Unable  
to do 
activities 
 
8. How did your endometriosis-related pain limit your social activities with family or friends in the 
past 24 hours?  
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
limitations 
on activities  
 
 
 
 
 
 
 
 
 
Unable  
to do 
activities 
 


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CONFIDENTIAL 
The average of the mean daily NRS scores obtained for the worst endometriosis-related pain impact 
on different aspects of functioning during the two run-in menstrual cycles (cycles -2 and -1) will be 
considered baseline.  
Weekly Pain Impact on Functioning 
In addition to this daily item, a modified EHP-30 pain impact domain consisting of the first 
11 questions of the core EHP-30 questionnaire and an additional work item will be completed by 
subjects on a weekly basis in the e-Diary. The weekly pain impact questionnaire measures the 
frequency of the endometriosis-related pain impact on various aspects of functioning such as doing 
house chores, standing, sitting and walking during the past week, with the response levels of never, 
rarely, sometimes, often and always (see Figure 7-2). The weekly diary will be accessible from 
8 pm on Sundays to 2 am on Tuesdays.  
During the last week, because of your endometriosis, how often have you... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
1. Been unable to go to social events 
because of the pain? 
 
 
 
 
 
2. Been unable to do jobs around the house 
because of the pain? 
 
 
 
 
 
3. Found it difficult to stand because of the 
pain? 
 
 
 
 
 
4. Found it difficult to sit because of the 
pain? 
 
 
 
 
 
5. Found it difficult to walk because of the 
pain? 
 
 
 
 
 
6. Found it difficult to exercise or do the 
leisure activities you would like to do 
because of the pain? 
 
 
 
 
 
7. Lost your appetite and/or been unable to 
eat because of the pain? 
 
 
 
 
 
8. Been unable to sleep properly because of 
the pain? 
 
 
 
 
 
9. Had to go to bed/lie down because of the 
pain? 
 
 
 
 
 
10. Been unable to do the things you want 
because of the pain? 
 
 
 
 
 
11. Felt unable to cope with the pain? 
 
 
 
 
 
12. Been unable to do jobs around the 
house, at work, or at school because of the 
pain? 
 
 
 
 
 
Figure 7-2 Modified Endometriosis Health Profile-30 (EHP-30) Pain Impact Domain  
 


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CONFIDENTIAL 
The additional work item (Question 12 in Figure 7-2) will only be used for validation of the weekly 
e-Diary. The secondary endpoint of changes in the weekly pain impact scores will be based on the 
original EHP-30 pain impact domain, i.e. the first 11 items. The mean of the weekly pain impact 
scores during the two run-in menstrual cycles (cycles -2 and -1) will be considered baseline. 
 
7.2.1.4 
Vaginal Bleeding Pattern 
Subjects will register their vaginal bleeding pattern in the e-Diary every day from run-in to follow-
up (cycle -2 to cycle 5). Subjects will first be asked if they have had any vaginal bleeding (“yes” or 
“no”) during the past 24 hours. In case of any vaginal bleeding, subjects need to assess their 
bleeding volume as spotting (tiny amount of blood on underwear or panty liners), light bleeding 
(requiring 1-3 sanitary pads or tampons per day), moderate bleeding (requiring 4-6 sanitary pads or 
tampons per day) or heavy bleeding (requiring more than 6 sanitary pads or tampons per day). In 
addition, they need to indicate whether their bleeding is menstrual bleeding or not.  
The questions to be answered are  
9. Did you have vaginal bleeding in the past 24 hours?   
 No   
 Yes 
   
If the subject had vaginal bleeding in the past 24 hours: 
10. Please describe your bleeding in the past 24 hours.  
 Spotting (tiny amount of blood on underwear or panty liners) 
 Light (requiring 1-3 sanitary pads or tampons per day) 
 Moderate (requiring 4-6 sanitary pads or tampons per day) 
 Heavy (requiring more than 6 sanitary pads or tampons per day) 
 
11. Was your bleeding related to your period (i.e., menstrual bleeding)?  
 No  
 Yes 
 
Vaginal bleeding pattern is evaluated as the number of no bleeding, spotting, light bleeding, 
moderate bleeding and heavy bleeding days, the duration of menstrual and non-menstrual period, 
and the number of bleeding days during the non-menstrual period. The vaginal bleeding pattern 
during the two run-in menstrual cycles (cycles -2 and -1) will be considered baseline.  
 
7.2.1.5 
Analgesic Use 
Rescue analgesics for endometriosis-related pain will be limited to ibuprofen and/or hydrocodone-
acetaminophen in this trial. As a mild analgesic, ibuprofen will be provided in the form of 200 mg 
oral tablets to subjects for their use on an as-needed basis. The specific dosing regimen of ibuprofen 
will be advised by the investigator but the maximum amount is 800 mg (4 tablets) per dose and 
3200 mg (16 tablets) per day in accordance with the label of prescription ibuprofen doses.27  


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CONFIDENTIAL 
Subjects will be instructed not to use other analgesics unless necessary. If there is a need to change 
analgesics, subjects should discuss with investigators, who may prescribe a strong rescue analgesic 
hydrocodone-acetaminophen at a dose of 5 mg hydrocodone plus 300 mg or 325 mg 
acetaminophen. Only oral tablet formulation of combined hydrocodone-acetaminophen (i.e. 
hydrocodone bitartrate/acetaminophen) is allowed in the present trial. The specific dosing regimen 
of hydrocodone-acetaminophen is decided by the investigator based on subjects’ needs and 
tolerability in accordance with the labelling of the product.  
After subjects’ entry into the run-in period, investigators can either advise ibuprofen dosing 
regimen or prescribe hydrocodone-acetaminophen by taking subjects’ preference and history of 
analgesic use into consideration. Investigators should not take the initiative to suggest any 
modifications to the subject’s current rescue analgesic regimen.  
Subjects will be asked to follow the investigators’ instructions on the type(s) and dose(s) of rescue 
analgesics they can use and whether they can take different rescue analgesics at the same time. Use 
of any other analgesics for endometriosis-related pain is prohibited from the start of run-in to the 
end-of-trial (see section 4.3.1 for prohibited analgesics). Any prophylactic use of analgesics is also 
prohibited from the start of run-in to the end-of-trial. 
In order for sites to perform drug accountability, subjects will be instructed to bring back any 
packages of used and unused ibuprofen to the site at each visit.  
The type and amount of mild and/or strong rescue analgesics used will be reported by subjects 
using the e-Diary. If subjects indicate any use of other analgesics for endometriosis-related pain, the 
specific name and dose of the analgesics will be noted in the e-CRF, while subjects will report the 
number of tablets taken in the e-Dairy.  
Use of analgesics for other reasons than endometriosis-related pain should not be recorded in the 
e-Diary. These medications will be captured in the e-CRF and the reasons for use will be inquired 
and documented for potential reporting of adverse events.  
The questions to be answered are  
The next questions ask about any use of pain medication in the past 24 hours. 
12. Have you taken any medication to reduce your endometriosis-related pain in the past 24 hours? 
 No  
 Yes 
 


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13. Which medication did you take for your endometriosis-related pain in the past 24 hours? Please 
answer “No” or “Yes” for each medication listed below.  
MOTRIN 200 mg 
 No 
 Yes 
Hydrocodone-acetaminophen (prescribed) 
 No 
 Yes 
Other 
 No 
 Yes  
The subjects will be asked to specify the number of tablets taken for each medication where “yes” 
is selected: “Please specify the number of tablets you took.”  
<An arrow spin will be available to list the number of tablets for each medication where “yes” is 
ticked.> 
 
The average percentage of days with rescue analgesic use, the average of the total and mean dose of 
rescue analgesic used by type during the two run-in menstrual cycles (cycles -2 and -1) will be 
considered baseline. 
  
7.2.1.6 
Responder Rate  
Responder rate will be assessed as ≥30%, ≥50% and ≥70% reduction from baseline in mean daily 
NRS score for the worst endometriosis-related pain, dysmenorrhea, non-menstrual pelvic pain and 
the worst endometriosis-related pain impact. The mean of the daily NRS scores for endometriosis-
related pain, dysmenorrhea, non-menstrual pelvic pain and scores for the worst endometriosis-
related pain impact averaged over the two run-in menstrual cycles (cycles -2 and -1) will be 
considered baseline. Responder rate will be assessed for each cycle over 4 menstrual cycles. 
 
7.2.2 
Assessments Related to Secondary Endpoints at Clinic Visits  
7.2.2.1 
Biberoglu and Behrman (B&B) Scale 
B&B scale is a widely used scale for endometriosis that consists of two parts, with the first part 
evaluating symptoms of endometriosis (i.e. different types of endometriosis pain) and the second 
part evaluating signs of endometriosis (see Appendix 1). It is available in English, but a Spanish 
translation can be administered if preferred by the subject.  
The first part of B&B should be completed by trained trial coordinators based on subjects’ verbal 
responses. In the first part, the subject will be asked to grade her pelvic pain (item A), 
dysmenorrhea (item B) and dyspareunia (item C) during the last menstrual cycle as none, mild, 
moderate or severe, corresponding to a score of 0-3. The criteria for being mild, moderate or severe 
are defined differently for each item. The total pelvic pain score is the sum of the three scores, i.e. 
A+B+C.  


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In the second part, the investigator should grade the subject’s pelvic tenderness (item D) and 
induration (item E) based on findings from a pelvic examination as none, mild, moderate or severe, 
corresponding to a score of 0-3. Efforts should be made to ensure this assessment is performed by 
the same investigator for the same subject throughout the trial. The criteria for being mild, moderate 
or severe are defined differently for each item. The total physical sign pain score is the sum of the 
two scores, i.e. D+E. The total symptom and sign severity score is the sum of all five scores, i.e. 
A+B+C+D+E.  
The trial coordinator and the investigator will be provided with different access codes to access 
separate parts of the B&B scale on an electronic tablet. To avoid bias in the assessment, the trial 
coordinator will only be able to access the first part of the scale for scoring while the investigator 
will only be able to access the second part of the scale. It is not allowed to have the same person 
administering both parts of the scale. In addition, the B&B scale should be completed 
independently from subjects’ scorings in the e-Diary in this trial.  
B&B will be administered at randomization and at cycle 4 (at visits 4 and 10). The first part of the 
B&B should always be completed before ring insertion / removal at both visits and also prior to 
non-PRO procedures at cycle 4. The scores obtained at randomization will be used as baseline.  
 
7.2.2.2 
Endometriosis Health Profile-30 (EHP-30) Questionnaire 
The EHP-30 is a quality-of-life questionnaire validated in both English and Spanish for 
endometriosis patients. Subjects will complete the core part of the EHP-30 questionnaire consisting 
of 30 questions measuring the frequency of the endometriosis impact on their quality of life during 
the past 4 weeks, with five options of never, rarely, sometimes, often and always (see Appendix 1).  
An electronic version of the EHP-30 will be completed by the subject prior to ring insertion at 
randomization, and prior to other non-PRO procedures at every cycle from cycle 1 to cycle 4 (at 
visits 4, 6, 7, 8 and 10).  
The scores obtained at randomization (at visit 4) will be used as baseline.  
 
7.2.2.3 
Patient Global Impression of Severity (PGIS) Scale 
PGIS is a static measure of the global treatment benefits from the patients’ perspective. Subjects 
will be asked to evaluate endometriosis-related pain during the last menstrual cycle, during the 
menstrual bleeding days of the last menstrual cycle and during the non-menstrual-bleeding days of 
the last menstrual cycle. In addition, subjects will be asked to evaluate the impact of endometriosis-
related pain on daily activities during the last menstrual cycle, during the menstrual bleeding days 
of the last menstrual cycle and during the non-menstrual-bleeding days of the last menstrual cycle. 
The scale is presented in Appendix 1. Subjects will complete the PGIS scale electronically at the 
site at cycle -2, prior to ring insertion at randomization and prior to other non-PRO procedures at 
cycle 4 (at visits 2, 4 and 10).  


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The scores obtained at cycle -2 (at visit 2) will be used specifically for the validation of the newly 
developed PRO tool: Women’s Endometriosis Diary. The scores obtained at randomization (at 
visit 4) will be used as baseline.  
 
7.2.2.4 
Patient Global Impression of Change (PGIC) Scale 
PGIC is a dynamic measure of the global treatment benefits from the patients’ perspective. Subjects 
will be asked to evaluate change in endometriosis-related pain, change in dysmenorrhea and change 
of non-menstrual pelvic pain since initiation of treatment. In addition, subjects will also evaluate 
the change in the overall impact of endometriosis-related pain on daily activities, the change in 
endometriosis-related pain impact during their menstrual periods and change in the endometriosis-
related pain impact during non-menstrual periods since initiation of treatment. The scale is 
presented in Appendix 1. Subjects will complete the PGIC scale electronically at the site prior to 
other non-PRO procedures at cycle 4 (at visit 10).  
 
7.2.2.5 
Plasma Concentration of Quinagolide and Metabolites  
Blood samples for measurement of plasma concentration of quinagolide and its metabolites M1 and 
M2 will be collected within 1-5 days of first ring insertion, at RM+7 visits of cycles 1, 3 and 4 as 
well as at LH+7 visit of cycle 4 (at visits 5, 6, 8, 9 and 10). Blood samples should be taken prior to 
removal of the ring at RM+7 visits. The analysis of plasma concentration of quinagolide and its 
metabolites will be performed by means of a validated tandem mass spectrometry method.  
   
7.2.2.6 
Mid-luteal Phase Endocrine Parameters and Ovarian Function 
Blood samples for the analysis of endocrine parameters, consisting of estradiol, progesterone, 
prolactin, TSH and IGF-1, will be collected during mid-luteal phase (i.e. LH+7) of cycles -1 and 4 
(at visits 3 and 9). The proportion of subjects with serum levels of mid-luteal progesterone 
≥25 nmol/L (7.9 ng/mL) will be calculated as evidence of ovulation.  
The samples will be analyzed at a central laboratory. The investigator will review and evaluate the 
laboratory results. However, the results of progesterone, prolactin, TSH and IGF-1 after 
randomization will be blinded to investigators, site staff and Ferring clinical team. The laboratory 
report will be signed and dated by the investigator.  
 
7.2.2.7 
Bone Turnover Markers 
Blood samples for the analysis of serum bone turnover markers, consisting of s-CTx and s-PINP, 
will be collected during mid-luteal phase (i.e. LH+7) of cycles -1 and 4 (at visits 3 and 9). Fasting 
overnight (no food or drinks except for water after midnight) is required for the blood sampling.  


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The samples will be analyzed at a central laboratory and data will be transferred directly to the 
database (i.e. not provided to the sites).  
 
7.2.2.8 
Electrocardiography (ECG) 
The 12-lead ECG will be recorded within cycle -1 and at cycle 4 (around visits 3 and 10). ECG at 
screening can be performed anytime during cycle -1, e.g. at LH+7 visit (visit 3) but results must be 
available before randomization. The report must be reviewed, signed and dated by the investigator 
before randomization. Results at randomization will be used as baseline. ECG at cycle 4 can be 
performed within ±2 weeks of visit 10. ECG will be recorded with a calibrated ECG device after 
the subject has been in supine position for at least 5 minutes. ECG must be performed before blood 
sampling when applicable. 
The parameters to be assessed are heart rate, PR interval, RR interval, QRS interval, QT interval 
and QTcF interval (i.e. QT correction according to the Fridericia’s formula QTcF= QT/RR0.33). 
ECG recordings will capture at least four QRS complexes, i.e. 3 evaluable RR intervals. All ECG 
recordings will be sent to a central cardiac laboratory for evaluation as normal or abnormal. If the 
results of central reading are abnormal, the investigator will evaluate whether the abnormal finding 
is clinically significant or not. Any occurrence of de- or re-polarization disorders (QT 
prolongation), arrhythmic disorders or other abnormalities will be assessed in comparison to the 
baseline.  
ECG may be repeated for quality reasons and in this case the repeated assessment will be used for 
analysis. If subject demonstrates a prolongation of QTc interval ≥500 msec or a QTc interval 
change from baseline ≥60 msec, two additional ECG assessments should be acquired 2-5 minutes 
apart and all three ECG assessments should be re-evaluated by the central cardiac laboratory. If the 
averaged values from three consecutive ECG assessments indicate a prolongation of QTcF interval 
≥500 msec or a QTcF interval change from baseline ≥60 msec as confirmed by the central cardiac 
laboratory, the subject should be discontinued from the treatment (see section 3.6.7). 
 
7.2.2.9 
Echocardiography  
Echocardiography will be performed within cycle -1 and at cycle 4 (around visits 3 and 10). 
Echocardiography at screening can be arranged anytime during cycle -1, e.g. at LH+7 visit (visit 3) 
but results must be available prior to randomization. The report must be reviewed, signed and dated 
by the investigator before randomization. Echocardiography at cycle 4 can be performed within 
±2 weeks of visit 10. 
The 2-dimensional (2D) echocardiography and Doppler echocardiography will be used for 
assessment of valvular structure and function with a calibrated echocardiography device. For the 
same subject, all echocardiography assessments in this trial should be performed by the same type 
of echocardiography device at the same center.  


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After the subject has been in supine position for at least 5 minutes, the structure of mitral, tricuspid, 
aortic and pulmonary valves will be assessed semi-qualitatively by 2D echocardiography. Valvular 
regurgitation will be assessed by Doppler echocardiography. All echocardiography video clips at 
each visit will be sent to a central cardiac laboratory and stored for potential further evaluation. 
Assessment performed prior to randomization will be used as baseline and will be compared against 
assessments performed at cycle 4. 
The echocardiography technicians and board-certified cardiologists from the central cardiac 
laboratory will evaluate each assessment as normal or abnormal according to American College of 
Cardiology / American Heart Association guidelines for valvular heart disease. If abnormal, the 
level of valvular regurgitation and valvular stenosis will be specified as mild, moderate or severe 
and valvular structure will be evaluated as well. Criteria are provided in a separate manual.  
At cycle 4, any changes from baseline will be assessed by the primary cardiologist(s) at the central 
cardiac laboratory as significant or not significant. In case of significant change from baseline, 
irrespective of the change level, the echocardiogram will be re-evaluated and confirmed by a 
secondary cardiologist at the central cardiac laboratory. The degree of change in valve stenosis or 
regurgitation will be confirmed by quantitative analysis of gradients and valve area for stenotic 
lesions and by vena contracta width, jet area, and Doppler waveforms for regurgitant lesions. If the 
change is confirmed to be significant by the secondary cardiologist, the finding should be reported 
to the investigator who should evaluate the clinical significance of the finding in relation with 
clinical symptoms and other tests (e.g. ECG and vital signs). The subject will be discontinued from 
the treatment (see section 3.6.7) and will be referred to a cardiologist for further follow-up. A 
repeated echocardiography will be required and all video clips saved previously for the 
discontinued subject will be further evaluated by an external cardiologist for an independent 
evaluation of the findings and for a potential diagnosis of cardiac valvulopathy. 
 
7.2.2.10 
Impulse Control Disorder 
A questionnaire adapted from a validated Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson’s Disease-Rating Scale45 will be used to monitor any significant signs of pathological 
behaviors associated with impulse control disorder during the trial. The questionnaire has four 
primary questions concerning thoughts, urges/desires, behavior controls and engagement, each of 
which is applied to various behaviors associated with impulse control disorders, i.e. gambling, sex, 
buying, eating, performing tasks or hobbies, repeating simple activities and medication use. 
However, the original sub-question on medication use is not appropriate for this trial, as it focuses 
on the medication used for Parkinson’s disease. Therefore this sub-question “taking your 
Parkinson’s disease medications” has been deleted (see Appendix 1). The questionnaire uses a 
5-point Likert scale (score 0-4) to measure the frequency of behaviors (never, rarely, sometimes, 
often and very often).  
The questionnaire will be completed by trained trial coordinators based on subjects’ verbal 
responses on an electronic tablet prior to randomization at cycle -1 (visit 4) and prior to other non-


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PRO procedures at cycle 4 (visit 10). Subjects will be asked to answer questions based on behaviors 
occurring in any 4-week period during the trial at designated visits. An instruction sheet will be 
provided to trial coordinators with examples of the specific behaviors being assessed and a brief 
description of the Likert scale categories for frequency. Subjects indicating a score ≥2 for any sub-
questions of Question 3 or a score ≥1 for any sub-questions of Question 4, i.e. a frequency of 
“sometimes” or even higher for any sub-questions of Question 3 regarding “Difficulty in 
controlling behaviors” or a frequency of “rarely” or even higher for any sub-questions of 
Question 4 regarding “Engage in activities”, will be considered having potential behaviors 
associated with impulse control disorders. The behavior identified will be reported as an adverse 
event. In addition, if this is considered to be treatment-related by the investigator, the subject will 
be discontinued from the treatment (see section 3.6.7) and, if needed, will be referred to psychiatric 
counselling and will be followed up until symptoms are resolved. 
 
7.2.2.11 
Adverse Events 
Adverse events will be recorded from the signing of informed consent(s) for participation in the 
trial until the end-of-trial visit. For each adverse event, the following parameters will be recorded 
by the investigator on the Adverse Event Log: description of event, date and time of onset, 
intensity, causal relation to IMP, action taken to IMP, other actions taken, seriousness of the 
adverse event, date and time of outcome, and outcome. A search for predefined preferred terms and 
reported terms will be conducted on all treatment-emergent adverse events to identify those 
potentially related to behaviors associated with impulse control disorders. See section 8. 
 
7.2.2.12 
Clinical Chemistry and Hematology Parameters 
The following clinical chemistry and hematology parameters will be analyzed at a central 
laboratory:  
CHEM-20: alanine transaminase, albumin, alkaline phosphatase, aspartate aminotransferase, 
bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, 
creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, 
potassium, sodium, total protein, uric acid. 
Complete Blood Count (CBC): red blood cells, red blood cell morphology, white blood cells, white 
blood cell morphology, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, platelets. 
Blood samples will be drawn during mid-luteal phase (i.e. LH+7) of cycle -1 as baseline, at the end 
of treatment / cycle 4 and at the end of trial / cycle 5 (at visits 3, 10 and 11). The investigator will 
review the laboratory results and evaluate and document whether the abnormal results are clinically 
significant or not. The laboratory report will be signed and dated by the investigator. 
 


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7.2.2.13 
Urinalysis  
Urine samples for urinalysis will be collected before entry into run-in (before or at visit 1), and at 
the end of treatment / cycle 4 (at visit 10). Urinalysis will be performed from a sample of mid-
stream urine by a dip-stick test at the local laboratory. Urinalysis parameters include protein, 
glucose, bilirubin, pH, nitrite, ketone, urobilinogen, blood, leukocytes and specific gravity. In case 
of any clinically significantly abnormal finding from the dipstick test, a microscopic test will be 
performed at the central laboratory. If the abnormal finding is confirmed, further examination may 
be initiated at the discretion of the investigator. 
 
7.2.2.14 
Ring Acceptability  
The subject will be asked to evaluate the acceptability of the vaginal ring immediately after each 
time she has inserted and/or removed the ring at the clinic on RM+7 of cycle -1 to cycle 4 (at visits 
4, 6, 7, 8 and 10).  
At randomization (visit 4), a simplified version of the questionnaire with only one question about 
ring insertion (see Appendix 1) will be completed by the subject.  
At RM+7 visits of cycle 1 to cycle 4 (visits 6, 7, 8 and 10), a full version of the ring acceptability 
questionnaire should be completed by the subject. The full version of the questionnaire consists of 
questions related to ring insertion / removal, any feeling of the ring while the ring is in the body, 
any feeling of the ring during sexual intercourse if applicable and any experience of ring falling out 
or breaking (see Appendix 1). If it is confirmed that the ring is broken upon removal, a technical 
complaint form should be completed. If it is noted that the ring has been out of the body for more 
than 24 hours during the cycle, a medication error should be reported.   
The answer must be reviewed by the trial coordinator for the potential reporting of medication error 
before the subject leaves the clinic.  
 
7.3 
Assessment Related to Exploratory Endpoint 
7.3.1 
Potential Endometriosis Biomarkers 
For all subjects, blood samples will be taken for potential endometriosis biomarkers during 
mid-luteal phase (i.e. LH+7) of cycles -1 and 4 (at visits 3 and 9). At each of these visits, 
approximately 1.5 mL of serum and 0.5 mL of platelet-free plasma will be collected and sent to a 
central laboratory for analysis of VEGF, PlGF, IL-6 and sFlt-1.  
In addition, 2 mL of serum and plasma each will be collected from all subjects and stored for 
potential future analyses of other endometriosis biomarkers related to proteins (e.g. angiogenin).  
All of the samples should be processed and stored in accordance with instructions provided in a 
separate laboratory manual. These exploratory data will not be provided to sites. 
 


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7.3.1.1 
Optional Cell-free DNA and MicroRNA Analyses 
If subjects have provided a separate written informed consent for genetic testing (see section 14.5), 
two additional blood samples will be collected at the same time points as detailed above for 
potential analyses of circulating cell-free DNA and microRNA. The informed consent for genetic 
testing signed by the subject must be obtained prior to the sampling.  
All of the samples should be processed and stored in accordance with instructions provided in a 
separate laboratory manual. These exploratory data will not be provided to sites.  
 
7.4 
Other Assessments  
7.4.1 
Numerical Rating Scale (NRS) for Entry into Run-in 
As part of the eligibility criteria check, all subjects will be asked to score the worst endometriosis-
related pain from a recall of their experience during the past menstrual cycle (including days with 
menstrual bleeding and days with no menstrual bleeding) (see Appendix 1) before entry into run-in 
(before or at visit 1) on paper. Eligible subjects must have an NRS score of ≥5 to enter the run-in 
period.  
 
7.4.2 
Demographics 
Demographic information will be obtained before entry into run-in (before or at visit 1), including 
the following: date of birth, ethnicity (Hispanic or Latino, Not Hispanic or Latino) and race 
(American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other 
Pacific Islander, White). 
  
7.4.3 
Medical History 
Any relevant medical history will be recorded before entry into run-in (before or at visit 1). This 
includes the year and method (laparoscopy or laparotomy) of endometriosis diagnosis, 
documentation of a biopsy (if performed), stage of endometriosis at diagnosis, anatomic location of 
endometriosis lesions (if available), history of previous surgical interventions (including method 
(laparoscopy or laparotomy), year and types of surgery (ablation of lesions, excision of lesions, 
lysis of adhesions or other)), and any surgical intervention for other gynecological conditions.  
 
7.4.4 
Menstrual History  
Information about the menstrual history (average cycle length, average number of days with 
menstrual bleeding and amount of menstrual flow) will be obtained before entry into run-in (before 
or at visit 1). In addition, any history of irregular bleeding will be recorded. 
 


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7.4.5 
Reproductive History 
Information about the reproductive history will be obtained before entry into run-in (before or at 
visit 1). This includes number of pregnancies, number of live births and history of infertility (yes/no 
and if yes, reason for infertility). 
 
7.4.6 
Body Measurement 
Body weight and height will be measured without shoes before entry into run-in (before or at 
visit 1). The results obtained will be used to calculate BMI. 
 
7.4.7 
Menstruation Dates 
At each RM+7 visit throughout the trial, the site staff should confirm the subject’s start date of 
menses in the current cycle, i.e. the first menstrual bleeding date (RM+1). If the subject has finished 
her menses when coming to the visit, the site staff should also confirm the stop date of menses in 
the current cycle, i.e. the last menstrual bleeding date.  
 
7.4.8 
Urine Pregnancy Test 
A urine pregnancy test will be performed at each clinic visit (except for visit 5) throughout the trial. 
The test should always be performed before ring insertion / removal at RM+7 visits of the treatment 
period. If the test result is positive, a serum βhCG test must be performed. If both test results are 
positive, the subject will be discontinued from the trial.  
 
7.4.9 
Urine Drug Screen 
A urine drug screen will be performed locally as part of eligibility check before entry into run-in 
(before or at visit 1) and prior to randomization at visit 4. The drug screen will be performed from 
fresh mid-stream urine for the determination of amphetamines / methamphetamine, barbiturates, 
benzodiazepines, cocaine, methylenedioxymethamphetamine, methadone, opiates, oxycodone, 
phencyclidine, tetrahydrocannabinol and tricyclic antidepressants. Subjects with a positive drug 
screen should be excluded unless the cause is from opioids or antidepressants that are medically 
indicated and prescribed by a physician.  
 
7.4.10 
Luteinizing Hormone Surge 
LH kits will be dispensed to subjects at visits 1 and 7 for the assessment of LH surge during 
cycles -1 and 4. Instructions on LH surge testing and reminders of LH surge testing will be given.   
 
7.4.11 
Physical Examination 
A complete physical examination will be performed before entry into run-in (before or at visit 1),  
and at end-of-treatment / cycle 4 (at visit 10). Information will be recorded for general appearance, 


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central and peripheral nervous system, head and neck (including ears, eyes, nose, mouth and 
throat), respiratory system, cardiovascular system, gastrointestinal system, lymphatic system, 
urinary system, musculoskeletal system and skin.  
Before entry into run-in (baseline), each category will be evaluated as normal, abnormal not 
clinically significant or abnormal clinically significant. Abnormal clinically significant findings at 
baseline must be reported on the Medical History Log. 
At cycle 4 / end-of-treatment, potential changes from baseline to cycle 4 or to end-of-treatment will 
be evaluated for each category. In case of changes, these will be evaluated as normal, abnormal not 
clinically significant or abnormal clinically significant. Abnormal clinically significant changes 
from baseline must be recorded as adverse events. 
 
7.4.12 
Gynecological and Pelvic Examination 
A complete gynecological examination will be performed by the investigator before entry into run-
in (before or at visit 1), and at end-of-treatment / cycle 4 (at visit 10). Information will be recorded 
for breast, external genitalia, vagina, cervix, uterus, uterine adnexa (including ovaries and fallopian 
tubes) and cul-de-sac.  
Before entry into run-in (baseline), each category will be evaluated as normal, abnormal not 
clinically significant or abnormal clinically significant. Abnormal clinically significant findings at 
baseline must be reported on the Medical History Log. 
At cycle 4 / end-of-treatment, potential changes from baseline to end-of-treatment will be evaluated 
for each category. In case of changes, these will be evaluated as normal, abnormal not clinically 
significant or abnormal clinically significant. Abnormal clinically significant changes from baseline 
must be recorded as adverse events. 
In connection with the B&B scale scoring, an examination of pelvic tenderness and pelvic 
induration will be performed by the investigator at randomization and at cycle 4 (see section 
7.2.2.1). The pelvic examination at cycle 4 is also part of the gynecological examination at cycle 4. 
 
7.4.13 
Cervical Swab 
As part of eligibility check, a single swab will be obtained from the endocervical area before entry 
into run-in (before or at visit 1) for assessing gonorrhea and chlamydia. Subjects with positive test 
results must be excluded. Standard reporting and referral procedures at the sites will be followed in 
line with local regulations.  
 
7.4.14 
Transvaginal Ultrasound 
A transvaginal ultrasound will be performed by an experienced sonographer before entry into run-in 
(before or at visit 1), and at end-of-treatment / cycle 4 (at visit 10). The transvaginal ultrasound will 


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assess uterus, endometrium and ovaries to evaluate endometrial thickness, number and size of 
endometrioma(s), ovarian cyst(s) and fibroid(s) if presented.  
Endometrial thickness (composed of both layers of the endometrium) will be measured in the 
sagittal view of the uterus from the proximal and distal interfaces between the echogenic 
endometrium and the hypoechoic inner layer of the myometrium. Care should be taken not to 
include the presence of any fluid in the uterine cavity in calculating the endometrial thickness 
value. Endometrial thickness will be recorded in mm.  
Endometrioma, fibroid and ovarian cyst will be recorded as observed or not. If observed, the 
number and size of endometrioma(s), fibroid(s) and ovarian cyst(s) should be recorded.  
 
7.4.15 
Vital Signs 
Systolic and diastolic blood pressure as well as pulse will be measured before entry into run-in 
(before or at visit 1), prior to randomization at cycle -1, during cycle -1 and at end-of-treatment / 
cycle 4 (at visit 4, 5 and 10). Vital signs at randomization will be baseline. Blood pressure and 
pulse should be measured before blood sampling as applicable, by automated oscillometric device 
sequentially, first after the subject is in supine position for at least 3 minutes, then in seated position 
for at least 3 minutes, and then at 1 minute and at 3 minutes after standing. Changes in blood 
pressure will be calculated using the minimum standing measurement minus the seated 
measurement and minus the supine measurement, respectively.  
The investigator will review the results of vital signs and evaluate and document whether the 
finding is clinically significant or not.   
Before entry into run-in (before or at visit 1) and before randomization (at visit 4), subjects with a 
drop of 20 mmHg of systolic blood pressure or a drop of 10 mmHg of diastolic blood pressure from 
sitting to standing will be excluded from the trial. 
At other visits (visits 5 and 10), a drop of 20 mmHg of systolic blood pressure or a drop of 
10 mmHg of diastolic blood pressure from lying to standing or from sitting to standing is 
considered clinically significant and will be reported as adverse events.  
 
7.4.16 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a screening tool to assess the potential risk of suicidality. It is implemented in this 
trial to meet the US regulatory requirements for all neurologic drugs with central nervous system 
activity, even though quinagolide has not been shown to be associated with suicidal ideations 
during its marketing experiences of more than 20 years in Europe.  
The electronic C-SSRS (eC-SSRS) will be self-administered through the interactive voice response 
(IVR) phone system (with a web portal as a back-up solution) before entry into run-in (before or at 
visit 1), prior to randomization at cycle -1, at cycles 2 and 4 (at visits 4, 7 and 10). The results of 


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eC-SSRS will be reviewed by investigators and delegated trial staff to assess the potential risk of 
suicidality, including suicidal ideations of type 4 (active suicidal ideations with some intent to act, 
without specific plan), suicidal ideations of type 5 (active suicidal ideations with specific plan and 
intent) and suicidal behavior.  
Before entry into run-in (before or at visit 1), subjects having suicidal ideations of type 4 or type 5 
during the past 12 months or having suicidal behavior during the past 5 years as identified by the 
eC-SSRS will be excluded from the trial. Prior to randomization at visit 4, subjects having suicidal 
ideations of type 4 or type 5 or having suicidal behavior since last e-CSSRS assessment will also be 
excluded from the trial. It is the investigator’s responsibility to advise subjects excluded from the 
trial due to risk of suicidality to seek help from their own physicians or suicide prevention services.  
During the treatment (at visits 7 and 10), subjects having suicidal ideations of type 4 or type 5 or 
having suicidal behavior as identified by the eC-SSRS should be referred to a mental health 
professional for further assessment and/or treatment. The decision on whether the treatment should 
be discontinued is to be taken by the investigator in consultation with the mental health professional 
to whom the subject is referred. 
 
7.4.17 
Concomitant Medication 
The use of any concomitant medication within the last 3 months prior to informed consent for 
participation in the trial and throughout the trial will be recorded. Recording of concomitant 
medication other than ibuprofen and hydrocodone-acetaminophen will be performed at all visits. 
Any changes in concomitant medications or treatments must be recorded at each visit. 
Investigators’ instructions for ibuprofen dosing and prescriptions of hydrocodone-acetaminophen 
will be recorded in the e-CRF.  
 
7.4.18 
Drug Accountability 
For all vaginal rings, date and time of insertion and removal at the clinics will be recorded. 
Furthermore, the dates and amount of ibuprofen dispensed and returned will be recorded in the IRT 
system. Details on drug dispensing and accountability are provided in section 5.6. 
 
7.4.19 
End-of-Treatment Question 
All subjects, irrespective of whether they completed the treatment or not, will be asked which 
treatment group (placebo or quinagolide) they believe they were randomized to at the end of 
treatment. The question can be phrased as “Do you think you were on a ring with study drug or a 
ring with placebo (i.e. no study drug)?” 
  


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7.4.20 
End-of-Treatment Form 
An end-of-treatment form should be filled in at the subject’s end-of-treatment visit, irrespective of 
whether the subject completes the treatment or not. Completion / discontinuation status will be 
recorded, as well as date and reason for discontinuation in case the subject does not complete the 
treatment.  
 
7.4.21 
End-of-Trial Form 
An end-of-trial form should be filled in at the subject’s last visit, irrespective of whether the subject 
completes the trial or not. Completion / discontinuation status of the follow-up period will be 
recorded. 
 
7.4.22 
Optional Pharmacogenetic Analysis 
If the subject has provided a separate written informed consent for genetic testing (see section 
14.5), a sample of whole blood for extraction and analysis of DNA will be collected within 1-5 
days of the first ring insertion during cycle 1 (at visit 5). The informed consent for genetic testing 
signed by the subject must be obtained prior to the sampling. All samples will be analyzed for the 
presence of polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene, which codes for an 
enzyme involved in the metabolism of quinagolide.  
Additional analysis of other enzymes involved in the elimination processes of quinagolide may be 
performed on samples from subjects who display quinagolide metabolite M1 concentrations at 
similar levels as the parent compound and on a comparable number of control samples from 
subjects with low levels of metabolites (M1<20% of quinagolide levels). Only enzymes responsible 
for the elimination processes (i.e. metabolism, transportation and excretion) of quinagolide will be 
analyzed. Results of the pharmacogenetic analysis will not be provided to the sites. 
 
7.4.23 
Optional Patient Interviews 
A sub-group of 60 subjects including 5 non-completers from selected sites, if they have provided a 
separate informed consent, will be invited to a patient interview at the end of treatment to help 
determine the meaningful treatment benefit from the patients’ perspective and to assess the content 
validity of the questions related to daily functioning in the e-Diary. The timing of the interview, i.e. 
within 2 weeks of subjects’ completion of or discontinuation from the treatment (visit 10), allows 
for both subjects on active treatment and subjects on placebo to report their treatment experiences.  
Subjects will be asked open-ended questions about the changes they have experienced since the 
start of the trial, and about the nature and relevance of these changes by following a semi-structured 
interview guide and a patient interview protocol.46 In addition, the content validity of the daily 
functioning questions in the e-Diary will be assessed. The interviews will be conducted in English 
over the telephone by a trained interviewer from Evidera, a third-party CRO in the United States.  


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All interviews will last for approximately 2 hours, and will be audio-recorded. All subjects 
participating in the patient interview will be identified by using the same subject identification 
number of this trial to guarantee data protection. Both subjects and interviewers will be blinded to 
treatment allocation. Results of the patient interviews will be reported separately. 
 
7.5 
Handling of Biological Samples 
Trial-specific laboratory manuals will be provided to the participating sites, describing in detail 
how to handle, store and transport the biological samples (blood) in this trial. All blood samples 
collected during the trial will be analyzed at central laboratories and will be destroyed within 
2 years after reporting of the trial. Exceptions are the blood samples collected for potential future 
endometriosis biomarkers and for potential analyses of circulating cell-free DNA and microRNA; 
these will be stored for a maximum of 10 years after reporting of the trial prior to destruction in line 
with local regulations. For all biological samples collected in the trial, it applies that any analyses 
beyond those described in the protocol will be performed only after obtaining the required 
approvals. The processes related to handling of biological samples will be described in the 
informed consent documents, and the biobank / data protection legislations including local 
legislation will be adhered to.  


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8 
ADVERSE EVENTS 
8.1 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a subject participating in a clinical trial. It 
includes: 
• Any unfavorable and unintended sign, symptom or disease temporally associated with the 
use of the IMP, whether or not considered to be caused by the IMP. 
• Adverse events commonly observed and adverse events anticipated based on the 
pharmacological effect of the IMP. 
• Any laboratory abnormality, vital signs, ECG, echocardiography or finding from physical or 
gynecological examination including transvaginal ultrasound assessed as clinically 
significant by the investigator [note: findings from assessments and examinations done 
during the screening period are not adverse events, but are recorded as medical history.] 
• Accidental injuries, reasons for any medical, nursing or pharmacy consultation, or reasons 
for admission to hospital or surgical procedures. 
 
All adverse events will be coded by Ferring Pharmacovigilance using MedDRA (the MedDRA 
version will be documented).  
Medication errors of IMP will be captured by ring acceptability questionnaire and/or a medication 
error form in the e-CRF.  
 
8.2 
Collection and Recording of Adverse Events 
8.2.1 
Collection of Adverse Events 
The investigator must monitor the condition of the subject throughout the trial from the time of 
obtaining informed consent until the end-of-trial visit. 
The sources of adverse events cover: 
• The subject’s response to questions about her health (a standard non-leading question such 
as “How have you been feeling since your last visit?” is asked at each visit). 
• Symptoms spontaneously reported by the subject. 
• Investigations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities. 
• Other information relating to the subject’s health becoming known to the investigator (e.g. 
hospitalization). 
 


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8.2.2 
Recording of Adverse Events 
The investigator must record all adverse events in the Adverse Event Log provided in each 
subject’s e-CRF with information about: 
• Adverse event 
• Date and time of onset (time can be omitted, if applicable) [note: if date of onset of an event 
is the same as the date of informed consent or date of IMP administration, time is important 
and should not be omitted] 
• Intensity 
• Causal relationship to IMP 
• Action taken to IMP 
• Other action taken 
• Date and time of outcome (time can be omitted, if applicable) 
• Outcome 
• Seriousness 
 
Each of the items in the Adverse Event Log is described in detail in the following sections. 
Adverse Event 
Adverse events should be recorded as diagnoses, if available. If not, separate signs and symptoms 
should be recorded. One diagnosis / symptom should be entered per record. 
If a subject suffers from the same adverse event more than once and the subject recovers in between 
the events, the adverse events should be recorded separately. If an adverse event changes in 
intensity, a worst-case approach should be used when recording the event, i.e. the highest intensity 
and the longest duration of the event.f 
Note: A procedure is not an adverse event; the reason for conducting the procedure is. 
Hospitalization is not an adverse event; the reason for hospitalization is. Death is not an adverse 
event, but the cause of death is (an exception is sudden death of unknown cause, which is an 
adverse event). 
Date and Time of Onset 
The date of onset is the date when the first sign(s) or symptom(s) were first noted. If the adverse 
event is an abnormal clinically significant laboratory test or outcome of an examination, the onset 
 
f  Exception: if an adverse event with onset before the first IMP administration (i.e. a pre-treatment adverse event) 
changes in intensity after the IMP administration, this must be recorded as two separate events. The initial adverse 
event should be recorded with outcome “not recovered” and the date and time of outcome is when the intensity 
changed. The second adverse event should be recorded with date and time of onset when the intensity changed.  


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date is the date the sample was taken or the examination was performed.  
Intensity 
The intensity of an adverse event must be classified using the following 3-point scale: 
Mild: 
Awareness of signs or symptoms, but no disruption of usual activity. 
Moderate: 
Event sufficient to affect usual activity (disturbing). 
Severe: 
Inability to work or perform usual activities (unacceptable). 
 
Causal Relationship to IMP 
The possibility of whether the IMP caused the adverse event must be classified as one of the 
following: 
Reasonable possibility:  
There is evidence or argument to suggest a causal relationship 
 
between the IMP and the adverse event. The adverse event may occur 
 
as part of the pharmacological action of the IMP or may be 
 
unpredictable in its occurrence. 
 
 
 
 
Examples:  
• 
Adverse events that are uncommon but are known to be strongly 
 
associated with IMP exposure. 
• 
Adverse events that are not commonly associated with IMP 
 
exposure, but the event occurs in association with other  factors 
 
strongly suggesting causation, such as a strong temporal 
 
association with the IMP or the event recurs on rechallenge with 
 
the IMP. 
No reasonable possibility:   There is no reasonable evidence or argument to suggest a causal 
 relationship between the IMP and the adverse event. 
 
 
 
 
Examples: 
• 
Known consequences of the underlying disease or condition  
 
under investigation. 
• 
Adverse events common in the trial population, which are also 
anticipated to occur with some frequency during the course of the 
trial, regardless of IMP exposure. 
 


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Action Taken to IMP 
The action taken to the IMP in response to an adverse event must be classified as one of the 
following: 
• No change (medication schedule maintained or no action taken) 
• Discontinued 
• Interrupted 
 
Other Action Taken 
Adverse events requiring therapy must be treated with recognized standards of medical care to 
protect the health and well-being of the subject. Appropriate resuscitation equipment and medicines 
must be available to ensure the best possible treatment of an emergency situation. 
If medication is administered to treat the adverse event, this medication should be entered in the 
Concomitant Medication Log. 
Date and Time of Outcome 
The date and time the subject recovered or died. 
Outcome 
The outcome of an adverse event must be classified as one of the following: 
• Recovered (fully recovered or the condition has returned to the level observed at initiation 
of trial treatment) 
• Recovered with sequelae (resulted in persistent or significant disability/incapacity) 
• Recovering (the event is improving) 
• Not recovered 
• Fatal 
 
8.3 
Adverse Events of Special Interest 
8.3.1 
Dizziness / Pre-syncope 
Dizziness or symptoms of pre-syncope (e.g. lightheadedness) will be reported as adverse events. 
Subjects will be instructed that they must lie down immediately if experiencing dizziness or any 
symptoms of pre-syncope. If symptoms are not resolved, they should contact the site staff as soon 
as possible for further instructions. 
 


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8.3.2 
Syncope 
Syncope is an adverse event of special interest in this trial and any cases of syncope will be 
reported as adverse events. Syncope is defined as “orthostatic collapse associated with an abrupt, 
transient, complete loss of consciousness and inability to maintain postural tone, with rapid and 
spontaneous recovery”. In case of syncope, further evaluations including vital signs should be 
conducted as soon as the event is reported for the assessment of the causal relationship to the IMP.  
 
8.3.3 
Dysmenorrhea, Abdominal Pain, Pelvic Pain, Lower Back Pain and Dyspareunia 
Endometriosis-related pain, i.e. pain located in the abdominal-pelvic area and the lower back area, 
will be assessed by the subject on the NRS scale on a daily basis. Dyspareunia will also be captured 
in the e-Diary in case of sexual intercourse. These data will be described as part of the primary and 
secondary endpoints based on the subjects’ recordings in the diary.  
Presence of dysmenorrhea, abdominal pain, pelvic pain or lower back pain related to endometriosis 
as well as menstrual cramp and dyspareunia are not to be reported as an adverse event unless it 
fulfils the criteria for an SAE. 
 
8.3.4 
Vaginal Bleeding 
Vaginal bleeding pattern (no bleeding, spotting, light bleeding, moderate bleeding and heavy 
bleeding) will be evaluated by the subject in the e-Diary on a daily basis. These data will be 
described as a secondary endpoint based on the subjects’ recordings in the diary. Abnormal vaginal 
bleeding (e.g. amenorrhea, oligomenorrhea, spotting or menstrual disorder) is not to be reported as 
an adverse event, unless there are any clinically significant changes from baseline that require 
medical or procedural intervention (e.g. prescription of tranexamic acid) or it fulfils the criteria for 
an SAE.  
 
8.3.5 
Ring Acceptability  
Any feeling of the ring will be assessed by the subject in a ring acceptability questionnaire at the 
clinic. Discomfort in connection with the ring insertion and/or removal should not be reported as an 
adverse event unless it requires active management, i.e. discontinuation of IMP. The acceptability 
of vaginal rings constitutes a secondary endpoint and will be evaluated in detail based on the 
subjects’ answers to the questionnaire. Any occurrence of ring expulsion or ring breaking will also 
be captured by ring acceptability questionnaire and should not be reported as an adverse event.  
 
8.3.6 
Vaginal Irritation and/or Vaginal Infection  
Upon spontaneous reporting of vaginal irritation and/or vaginal infection including persistent 
vaginal itching, vaginal dryness, and/or vaginal discharge during the treatment period, an 
unscheduled gynecological examination can be performed. Vaginal irritation should be graded in 
accordance with Table 8-1. Clinically significant findings of vaginal irritation and/or vaginal 


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infection will be reported as an adverse event.  
 
Table 8-1 
Grading of Vaginal Irritation 
VAGINAL IRRITATION 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Vaginal itching 
Itching causing no, mild or 
moderate interference with 
usual social and functional 
activities 
Itching causing inability 
to perform usual social 
and functional activities; 
may require intervention 
NA 
NA 
Vaginal edema 
Mild-moderate 
engorgement 
Loss of rugae and 
friability 
NA 
NA 
Vaginal erythema 
Erythema <50% of vaginal 
surface 
Erythema >50% of 
vaginal surface 
NA 
NA 
Vaginal dryness 
Dryness causing no or 
minimal interference with 
sexual function 
Dryness causing greater 
than minimal interference 
with sexual function or 
causing frequent 
discomfort 
NA 
NA 
Vaginal discharge by 
patient report 
Mild to moderate increase 
in amount above baseline – 
no sanitary protection 
required 
Profuse increase in 
discharge requiring pad or 
tampon use 
NA 
 
NA 
 
Vaginal discharge as 
observed by 
investigator 
No pooling 
Pooling 
NA 
NA 
Adapted from:  Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Addendum 1 (Female 
Genital Grading Table for Use In Microbicide Studies); November 2007. 
 
8.4 
Pregnancy and Pregnancy Outcome 
If a pregnancy occurs, the IMP should be immediately stopped and Ferring Pharmacovigilance 
must be informed by mail to 
 within 3 calendar days. Pregnancy 
should be reported as a non-serious adverse event (for tracking purpose only, pregnancy in itself is 
not an adverse event). If a subject becomes pregnant during treatment or follow-up period and the 
conception date cannot be determined, an ultrasound will be performed as part of the standard 
pregnancy check-up to assess the conception date. The mother and the fetus must be followed up at 
least until the birth of the infant and 4-6 weeks after the birth of the infant. In general, the follow-up 
will include the course; duration and the outcome of the pregnancy as well as neonatal health. If a 
pregnancy results in an abnormal outcome (birth defect/congenital anomaly), this must be reported 
as an SAE to Pharmacovigilance. Abnormal pregnancy outcomes which the investigator and/or 
sponsor consider to be related to the IMP will be treated as expedited reports (see section 8.5.2).  
 


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8.5 
Serious Adverse Events (SAEs) 
8.5.1 
Serious Adverse Event Definition 
Serious Adverse Events during the Trial 
An event is defined a serious 
adverse event if it: 
Guidance 
results in death 
Any event resulting in a fatal outcome must be fully documented and reported, including 
deaths occurring within four weeks after the treatment ends and irrespective of the causal 
relationship to the IMP. The death of a subject enrolled in a trial is per se not an event, 
but an outcome. 
is life-threatening 
The term life-threatening refers to an adverse event in which the subject was at 
immediate risk of death at the time of the event. It does not refer to an event, which may 
have caused death if it were more severe. 
requires in-patient 
hospitalization or 
prolongation of existing 
hospitalization 
The term hospitalization means that the subject was admitted to hospital or that existing 
hospitalization was extended as a result of an event. Hospitalization describes a period of 
at least 24 hours. Over-night stay for observation, stay at emergency room or treatment 
on an out-patient basis do not constitute a hospitalization. However, medical judgement 
must always be exercised and when in doubt the case should be considered serious (i.e. if 
case fulfils the criterion for a medically important event). Hospitalizations for 
administrative or social purposes do not constitute an SAE. Hospital admissions and/or 
surgical operations planned before trial inclusion are not considered adverse events, if 
the illness or disease existed before the subject was enrolled in the trial, provided that the 
condition did not deteriorate during the trial. 
results in persistent or 
significant 
disability/incapacity 
Disability/incapacity means a substantial disruption of a person’s ability to conduct 
normal life functions. In doubt, the decision should be left to medical judgement by the 
investigator. 
is a congenital anomaly/birth 
defect 
Congenital anomaly/birth defect observed in any offspring of the subject conceived 
during treatment with the IMP. 
is an important medical event 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious such as important medical events that might not be 
immediately life-threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result 
in hospitalization, or development of drug dependency or drug abuse. 


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8.5.2 
Collection, Recording and Reporting of Serious Adverse Events 
SAE Reporting by the Investigator 
All SAEs must be reported immediately to Ferring Pharmacovigilance as soon as it becomes 
known to the investigator and not later than within 24 hours of their knowledge of the occurrence of 
an SAE. 
The investigator is responsible for submitting the completed SAE Report Form with the fullest 
possible details within 3 calendar days of his/her knowledge of the SAE. 
SAE Report Form  
The SAE Report Form is included in the e-CRF system, and must be completed and submitted 
according to the instructions provided on the form. In case the e-CRF cannot be accessed and hence 
the SAE Report Form cannot be filled in within the e-CRF system, a paper SAE Report Form 
should be used and sent to Ferring Pharmacovigilance using the contact details below. 
Ferring Pharmacovigilance  
 
 
  
Completion of the Demographics, Adverse Event Log, Medical History Log and Concomitant 
Medication Log are mandatory for initial reports and for follow-up reports if any relevant changes 
have been made since the initial report. Data entries must have been made in the e-CRF for Ferring 
Pharmacovigilance to access the information. 
Additional information relevant to the SAE such as hospital records, results from investigations, 
e.g. laboratory parameters (that are not already uploaded in the e-CRF), invasive procedures, scans 
and x-rays, and autopsy results can be faxed or scanned and e-mailed to Ferring Pharmacovigilance 
using the contact details in the section above. In any case this information must be supplied by the 
investigator upon request from Ferring. On any copies provided, such details such as subject’s 
name, address, and hospital ID number should be concealed and instead subject number should be 
provided. 
The investigator will supply Ferring and the IRB with any additional requested information such as 
results of post-mortem examinations and hospital records. 
Ferring will report all serious adverse events according to local regulations.  
 


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8.6 
Follow-up of Adverse Events and Serious Adverse Events  
8.6.1 
Follow-up of Adverse Events with Onset during the Trial 
During the trial, the investigator must follow-up on each adverse event until it is resolved or until 
the medical condition of the subject is stable. 
After the subject’s last visit, the investigator must follow up on any adverse event classified as 
serious or considered to have a reasonable possible causality to the IMP until it is resolved or until 
the medical condition of the subject is stable. All such relevant follow-up information must be 
reported to Ferring. If the event is a chronic condition, the investigator and Ferring may agree that 
further follow-up is not required. 
 
8.6.2 
Collection of Serious Adverse Events with Onset after Last Visit in the Trial 
If an investigator becomes aware of an SAE after the subject’s last visit, and he/she assesses the 
SAE to have a reasonable possible causality to the IMP, the case will have to be reported to Ferring 
Pharmacovigilance, regardless how long after the end of the trial this takes place. 
 


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9 
STATISTICAL METHODS 
The Global Biometrics Department of Ferring Pharmaceuticals A/S will be responsible for data 
management, statistical analyses (including the sample size calculation and the statistical analysis 
plan), production of tables, listings and figures. This section details the planned statistical analysis 
of the primary endpoints and outlines the planned statistical analysis for the secondary endpoints. 
All analyses and further description of the statistical methodology for primary as well as secondary 
endpoints will be included in the statistical analysis plan (SAP). The SAP will be available before 
breaking the blind.  
The Global Health Economics & Outcome Research Department of Ferring Pharmaceuticals A/S 
will be responsible for the validation of the Women’s Endometriosis Diary and the analysis will be 
described in a separate psychometric analysis plan. The results will be reported separately. 
 
9.1 
Determination of Sample Size 
The sample size calculation is based on demonstrating superiority of quinagolide vaginal ring 
compared with placebo vaginal ring on the primary endpoint of the change in mean daily NRS 
score for endometriosis-related pain at cycle 4. Taking into account of an interim analysis for 
futility at a conditional power of 5% (see section 9.9) and assuming that the standard deviation of 
the change in mean daily NRS is 1.5, a sample size of 52 evaluable subjects per group (in total 
208 subjects) will have at least 90% power to detect a treatment effect difference of 1.0 unit using a 
t-test at a 5% two-sided significance level in a pre-defined hierarchical step-down procedure, 
starting with testing the highest dose versus placebo (see section 9.6.2). Accounting for a 25% 
drop-out rate as observed in a previous trial,30 there should be 70 subjects randomized to each 
treatment group and in total 280 subjects should be randomized. Table 9-1 summarizes the required 
sample size per group for different assumptions of treatment effect difference and power.  
Table 9-1 
Sample Size by Treatment Effect Difference 
Difference in NRS score reduction between  
quinagolide vaginal ring the highest dose 
group and placebo vaginal ring group 
Number of subjects per group a 
Evaluable subjects  
Randomized subjects b 
Power 80% 
Power 90% 
Power 80% 
Power 90% 
0.8 
60 
80 
80 
107 
0.9 
48 
64 
64 
86 
1.0 
40 
52 
54 
70 
1.1 
32 
44 
43 
59 
1.2 
28 
36 
38 
48 
a 
Assuming a standard deviation of 1.5 units and accounting for an interim analysis for futility at a conditional power at current trend of 5%. 
b 
Assuming 25% drop-out rate. 
 
A sample size re-estimation will also be performed at the same time of the interim analysis based 
on the observed standard deviation and drop-out pattern. The sample size may be increased to 360 
subjects in total or 90 subjects per group. 


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9.2 
Subject Disposition 
All subjects screened and randomized will be accounted for. Screened subjects who discontinue 
from the trial prior to randomization are regarded as screening failures. The number of screened but 
not randomized subjects will be summarized by primary reason for screening failure. The number 
of subjects re-screened and subjects randomized after re-screening will also be summarized.    
Subject disposition with respect to the timing of action during the COVID-19 pandemic will be 
tabulated using the intention-to-treat (ITT) analysis set. The status of randomized subjects at the 
time of the temporary trial hold due to the COVID-19 pandemic will be summarized in the 
following categories: randomized and exited before the hold, randomized before and exited during 
or after the hold, as well as randomized and exited after the hold.  
Subject disposition with respect to analysis set will be tabulated by treatment group for all 
randomized subjects.  
All premature discontinuations will be summarized and listed by time of and reason for 
discontinuation.  
The time to discontinuation will be summarized by the Kaplan-Meier estimates, and the treatment 
group difference will be tested using the Log-Rank test.  
 
9.3 
Protocol Deviations 
Major protocol deviations, such as significant non-compliance or other serious unforeseen 
deviations deemed to invalidate the data and affect the conclusions of the trial, will lead to 
exclusion of data from the per-protocol (PP) analysis set. Data will not be excluded from the PP 
analysis set in case of minor protocol deviations. The list of major protocol deviations includes, but 
is not restricted to: 
• Treatment received not in accordance with randomization (only data after the occurrence of 
the mistake to be deleted) 
• Non-compliance with IMP treatment regimen for >20% of days during a non-menstrual 
period (only data after the first occurrence of non-compliance to be deleted) 
• Missing >20% of days of e-Diary recordings during a menstrual cycle (only data of this 
cycle to be deleted from the respective by-cycle PP analysis) 
• Use of prohibited analgesics for >1 day during a menstrual cycle (only data of this cycle to 
be deleted from the respective by-cycle PP analysis) 
 
The detailed criteria of major protocol deviations will be further defined in the SAP. Unforeseen 
deviations deemed to impact the primary endpoint of the trial may additionally be rated as major 
protocol deviations by the Ferring clinical team on the basis of a blinded review of data before 
declaration of clean-file and lock of database.  


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The list of major protocol deviations will be detailed and documented in the clean file document 
prior to database release.  
For the subjects who were on treatment at the time of the temporary trial hold due to COVID-19, a 
listing of selected missing trial assessments will be created. It will include the last trial visit before 
the hold, expected visits during the hold, missing assessments/visits during the hold and the reasons 
for missed assessments/visits. A similar listing of ring insertion/removal schedule will also be 
created for subjects who were on treatment during the hold.   
 
9.4 
Analysis Sets 
9.4.1 
Intention-to-Treat (ITT) Analysis Set  
The ITT analysis set comprises all randomized (as planned) subjects. 
9.4.2 
Per-Protocol (PP) Analysis Set 
The PP analysis set is defined as all randomized subjects except those for whom all data are 
excluded as a result of major protocol deviations as described in section 9.3. 
9.4.3 
Safety Analysis Set 
The safety analysis set comprises all treated subjects and is analyzed according to the actual 
treatment received. 
 
9.5 
Trial Population 
9.5.1 
Demographics and other Baseline Characteristics 
All relevant baseline data will be summarized in tables including the four treatment groups and a 
total column.  
The purpose of these tabulations is to characterize the treatment groups and assess the degree of 
similarity achieved by the randomization. Baseline data will not be compared using statistical tests. 
Unless otherwise noted, tabulations will be produced for both the PP and the ITT analysis sets.  
Continuous variables will be presented with number of subjects, mean, standard deviation, median, 
inter-quartile range, minimum, and maximum. Categorical variables will be presented with number 
and percentage of subjects within each specific category. 
 
9.5.2 
Medical History, Concomitant Medication and other Safety Evaluations 
Medical history will be coded using MedDRA. The version of MedDRA will be documented. 
Medical history will be listed by subject and summarized by System Organ Class (SOC) and 
preferred term.  


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Prior and concomitant medication will be summarized by ATC classification 1st level 
(alphabetically), ATC classification 2nd level (in decreasing order of frequency) and treatment 
group.  
Other baseline evaluations including menstrual history, reproductive history, body measurement 
and vital signs will be presented by descriptive statistics by treatment group.  
 
9.6 
Endpoint Assessments 
9.6.1 
General Considerations 
The primary analysis of the primary endpoint will be based on the ITT analysis set, while the 
analysis of the primary endpoint based on the PP population will be considered supportive and 
serve as one of the sensitivity analyses.  
The analysis of the secondary efficacy endpoints will be performed for both the ITT and PP 
populations. The safety endpoints will be analyzed for the safety analysis set unless otherwise 
noted.  
Statistical tests will be performed using a two-sided test at a 5% significance level. Treatment 
differences will (where appropriate) be presented with 95% confidence intervals and p-values 
corresponding to the statistical test of the hypothesis of “equal effect” against the alternative of 
“different effect”. 
The SAP will detail data-handling conventions on cycle and menstrual period definitions.   
Continuous variables will be presented with number of subjects, mean, standard deviation, median, 
inter-quartile range, minimum, and maximum. Categorical variables will be presented with number 
and percentage of subjects within each specific category. 
Missing Data 
Missing data for endometriosis-related pain 
If a subject has indicated that too much pain is the reason for not completing the diary on some day, 
the missing data for that day will be derived by taking a worst-case approach, i.e. assigning an NRS 
of 10 for endometriosis-related pain. Otherwise the score remains to be missing. 
As endometriosis-related pain is potentially different during the menstrual-bleedings days from 
during the non-menstrual-bleeding days, at least 50% of the NRS scores are required to be observed 
for both the menstrual period and the non-menstrual period to be able to calculate the mean daily 
NRS score for a particular cycle. As missing NRS scores may not be appropriately balanced across 
menstrual period and non-menstrual period, the mean daily NRS score based on observed data will 
be weighted by the lengths of the menstrual period and non-menstrual period to adjust for this 
potential imbalance.   


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So the mean daily NRS score is calculated as  
mp
non
mp
mp
non
mp
non
mp
mp
l
l
x
l
x
l
−
−
−
+
+
 
 
Where mp
l
is the length of the observed menstrual period, 
mp
non
l
−
is the length of the observed 
non-menstrual period, 
mp
x
is the mean daily NRS score based on observed NRS scores during the 
menstrual period, and  
mp
non
x
−
is the mean daily NRS score based on observed NRS scores during 
the non-menstrual period.  
The observed cycle length will be based on the first menstrual bleeding date confirmed at the 
RM+7 visit of each cycle (section 7.4.7). The length of the observed menstrual period will be based 
on the first and last menstrual bleeding dates confirmed at the RM+7 visit of each cycle. If the last 
menstrual bleeding date cannot be confirmed at the RM+7 visit (section 7.4.7), the date of the last 
reported menstrual bleeding day recorded in the e-Diary will be used. The length of the observed 
non-menstrual period will be calculated as the observed cycle length minus the length of the 
observed menstrual period. 
Missing data for dyspareunia 
The mean daily NRS scores for the worst dyspareunia on days with sexual intercourse will be 
considered missing if the subject reports no sexual intercourse during a cycle. The mean score will 
be based on non-missing scores and will not be weighted by menstrual period length.   
Missing data for adverse events 
For adverse events, missing values will be treated as missing, except for causality, intensity, 
seriousness and outcome of adverse events, where a worst-case approach will be used. 
 
9.6.2 
Primary Endpoint 
The primary endpoint is the change in the mean daily NRS score for the worst endometriosis-
related pain at cycle 4, i.e. the difference between the active treatment group and the placebo group 
in the change from baseline in the mean daily NRS score for the worst endometriosis-related pain at 
the end of cycle 4. The baseline is defined as the average of the mean daily NRS scores for 
endometriosis-related pain of the two run-in cycles (cycles -2 and -1).  
The primary endpoint will be analyzed using a repeated measures analysis of covariance 
(ANCOVA) model, with the change in mean daily NRS score from baseline measured at cycles 1, 
2, 3, and 4 as the dependent variable, the baseline mean daily NRS score and the baseline 
percentage of days on rescue analgesics by type as covariates, as well as the treatment group and 
treatment by cycle interaction as fixed effect. The error-covariance matrix will be unstructured. The 


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treatment contrasts between each active treatment versus placebo at cycle 4 will be reported with 
95% confidence intervals and corresponding p-values:  




=
P
Placebo
P
high
QVR
P
P
Placebo
P
high
QVR
P
H
H
4
,
4
,
,
1
1
4
,
4
,
,
1
0
:
:




 




=
P
Placebo
P
medium
QVR
P
P
Placebo
P
medium
QVR
P
H
H
4
,
4
,
,
2
1
4
,
4
,
,
2
0
:
:




 




=
P
Placebo
P
low
QVR
P
P
Placebo
P
low
QVR
P
H
H
4
,
4
,
,
3
1
4
,
4
,
,
3
0
:
:




 
Where (
)
1
0
P
H
,(
)
2
0
P
H
,(
)
3
0
P
H
 are null hypotheses, (
)
1
1
P
H
,(
)
2
1
P
H
,(
)
3
1
P
H
 are alternative hypotheses, and 







=
=
=
=
 
ring
 
placebo
for 
 4 
cycle
at 
 
score
 
NRS
in 
 
baseline
 
from
 
change
mean 
 
The
dose
 
low
 
QVR
for 
 4 
cycle
at 
 
score
 
NRS
in 
 
baseline
 
from
 
change
mean 
 
The
dose
 
medium
 
QVR
for 
 4 
cycle
at 
 
score
 
NRS
in 
 
baseline
 
from
 
change
mean 
 
The
dose
high 
 
QVR
for 
 4 
cycle
at 
 
score
 
NRS
in 
 
baseline
 
from
 
change
mean 
 
The
4
,
4
,
,
4
,
,
4
,
,
P
placebo
P
low
QVR
P
medium
QVR
P
high
QVR




 
In order to control the overall type I error at 5%, a step-down procedure will be implemented. The 
testing sequence starts with testing the null hypothesis for the high dose against placebo (
)
1
0
P
H
, and if 
superiority is established for the high dose(
)
05
.0
1 
P
p
, the testing will continue by testing the null 
hypothesis for the medium dose (
)
2
0
P
H
. Again if superiority is established for the medium dose 
(
)
05
.0
2 
P
p
, the testing will continue by testing the null hypothesis for the low dose (
)
3
0
P
H
. All the 
testing will be done at the 5% significance level. If any of the active treatment groups are stopped 
for safety reasons during the trial, the testing sequence starts with the highest remaining dose. 
The primary analysis is based on observed cases (including those missing due to too much 
endometriosis-related pain) in the ITT population.  
Sensitivity Analyses 
The following sensitivity analyses will be conducted:  
1. To test efficacy in more perfect conditions:  
• The primary analysis in the PP population using observed cases (including those missing 
due to severe endometriosis-related pain) 
 
2. To test sensitivity to missing data: 
• The ITT analysis without assuming a NRS of 10 on days when subjects were in too 
much pain to complete the e-Diary 


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• The ITT analysis based on last-observation-carried-forward (LOCF) method 
• The ITT analysis based on baseline-observation-carried-forward (BOCF) method 
• The ITT analysis using multiple imputation for missing data in a placebo-based pattern 
mixture model (based on a missing-not-at-random condition) as described by Ratitch47 
 
3. To test for heterogeneity of effect: 
• The ITT analysis testing for treatment by baseline percentage of days on rescue 
analgesics interaction. This will be done by type of rescue analgesics  
• The ITT analysis testing for treatment by baseline mean daily NRS score interaction 
 
4. The primary analysis using the actual treatment rather than the planned treatment  
5. To test the sensitivity to adjustment in the statistical model: 
• The ITT analysis also adjusting for the percentage of days on rescue analgesics by type 
at cycles 1, 2, 3, and 4 (time dependent)  
• The primary analysis with the baseline defined as the average NRS score for 
endometriosis-related pain of the last run-in cycle (cycle -1) 
 
Dose-response Model 
To assess the dose-response association between the doses of quinagolide and the primary outcome, 
four dose-response models i.e. a linear dose-response model, an exponential dose-response model, a 
log linear dose response model, and a sigmoidal dose-response model will be fitted. The best fitting 
curve will be illustrated together with the dose specific means and standard errors of the mean.  
 
9.6.3 
Secondary and Exploratory Endpoints 
Secondary endpoints of change from baseline in the mean daily NRS score for the worst 
dysmenorrhea and for the worst non-menstrual pelvic pain at cycle 4 will be analyzed 
longitudinally and similarly to the primary endpoint, with the focus on estimating the treatment 
effect at cycle 4. Sensitivity analyses will not be performed for secondary endpoints. 
Secondary endpoints over all 4 cycles or for cycles pre-specified in endpoints will be analyzed 
longitudinally as follows:   
• Continuous endpoints will be analyzed by repeated measures ANCOVA 
• Responder status endpoints will be analyzed using repeated measures logistic regression 
using the generalized estimating equation (GEE) approach for binary data with logit link 
function and by analyzing the time to event of first response using the proportional odds 
regression model 
• Count data relative to particular cycle days (e.g. number of days of avoiding sexual 
intercourse relative to the total days of either having sexual intercourse or avoiding it 


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due to endometriosis-related pain) will be analyzed using repeated measures negative-
binomial regression using the GEE approach for count data with log link function using 
the appropriate off-set  
These models will include treatment, cycle and treatment by cycle interaction as independent 
factors and the respective baseline by cycle interaction (as applicable) and the percentage of days 
on rescue analgesics by type at baseline as covariates. The error-covariance matrix will be 
unstructured. The possible dependence of the treatment effect on these covariates will be 
additionally investigated by testing for respective treatment interactions.  
The analysis will focus on adjusted treatment contrasts versus placebo during cycles 1-4. Table 9-2 
summarizes the respective analyses for all defined secondary and exploratory endpoints.  


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Table 9-2 
Analyses of Secondary and Exploratory Endpoints 
Endpoint 
Analysis Method 
Cycles  
 
 
Repeated 
measures 
ANCOVA 
(focusing 
on cycle 4) 
Repeated 
measures 
ANCOVA 
Logistic 
regress-
ion 
(GEE) 
Negative 
Binomial 
regression 
(GEE) 
Changes in the mean daily NRS scores for the worst dysmenorrhea and for 
the worst non-menstrual pelvic pain at cycle 4   
X 
 
 
 
4 
Changes in the mean daily NRS scores for the worst endometriosis-related 
pain over 4 menstrual cycles 
 
X 
 
 
1-4 
Changes in the mean daily NRS scores for the worst dysmenorrhea and for 
the worst non-menstrual pelvic pain over 4 menstrual cycles  
 
X 
 
 
1-4 
Changes in the mean daily NRS scores for the worst dyspareunia on days 
with sexual intercourse over 4 menstrual cycles 
 
X 
 
 
1-4 
Frequency of avoiding sexual intercourse due to expected pain over 4 
menstrual cycles 
 
 
 
X 
1-4 
Changes in the mean daily NRS scores for the worst impact of endometriosis-
related pain on the subject’s ability to function over 4 menstrual cycles 
 
X 
 
 
1-4 
Changes in the mean weekly scores of the EHP-30 pain impact domain over 
4 menstrual cycles 
 
X 
 
 
1-4 
Changes in vaginal bleeding pattern over 4 menstrual cycles a 
 
 
 
X 
1-4 
Percentage of days with mild and/or strong rescue analgesics used over 4 
menstrual cycles 
 
 
 
X 
1-4 
Total and average doses of mild and/or strong rescue analgesics used over 
4 menstrual cycles 
 
 
 
X 
1-4 
Responder rate assessed as ≥30%, ≥50% and ≥70% reduction from the 
baseline in mean daily NRS scores for the worst endometriosis-related pain, 
dysmenorrhea, non-menstrual pelvic pain and for the worst endometriosis-
related pain impact over 4 menstrual cycles 
 
 
X 
 
1-4b 
Changes in the mean individual and total symptom and sign severity scores of 
the B&B scale at cycle 4   
 
X 
 
 
4c 
Changes in EHP-30 scores over 4 menstrual cycles  
 
X 
 
 
1-4 
Changes in PGIS scores at cycle 4    
 
X 
 
 
4c 
PGIC scores at cycle 4   
 
X 
 
 
4c 
Plasma concentration of quinagolide and metabolites during cycles 1 and 4  
Descriptive and population PK modelling 
Serum levels of mid-luteal phase progesterone at cycle 4 d 
 
X 
 
 
4c 
Proportion of subjects with serum levels of mid-luteal progesterone 
≥25 nmol/L (7.9 ng/mL) at cycle 4 d 
 
 
X 
 
4c 
Serum levels of mid-luteal estradiol, prolactin, TSH and IGF-1 at cycle 4  
 
X 
 
 
4c 
Changes in bone turnover markers, determined by bone resorption marker 
s-CTx and bone formation marker s-PINP at cycle 4   
 
X 
 
 
4c 
Changes in ECG parameters including PR interval, QT interval, QTcF 
interval and QRS interval at cycle 4   
Descriptive only 
Proportion of subjects with abnormal clinically significant echocardiography 
findings indicating valvular heart disease at cycle 4  
Descriptive only 
Proportion of subjects identified with potential impulse control disorders by 
the questionnaire for impulsive-compulsive disorders at cycle 4   
Descriptive only 
Frequency and intensity of adverse events 
Descriptive only 
Changes in circulating levels of clinical chemistry and hematology 
parameters, urinalysis parameters, and proportion of subjects with markedly 
abnormal changes 
Descriptive only 
Frequency and intensity of ring acceptability and performance parameters 
over 4 menstrual cycles 
Descriptive only 
Changes in endometriosis biomarkers such as serum levels of VEGF, PlGF, 
IL-6 and sFlt-1 at cycle 4  * 
 
X 
 
 
4c 
a Vaginal bleeding pattern is evaluated as the number of no bleeding, spotting, light bleeding, moderate bleeding and heavy bleeding days, the 
duration of menstrual and non-menstrual period, and the number of bleeding days during the non-menstrual period.  
b Responder status is also analyzed by analyzing the time to respective first occurrence of response using the proportional odds regression model. 
c  Analysis reduced to cross-sectional analysis when only one cycle is involved.  
d Only data from visits within the LH+6-9 window will be used.  
Note: Safety endpoints highlighted in grey and exploratory endpoint marked with *. 
 


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All analyses and respective definitions of the endpoints will be further detailed in the SAP. Plasma 
concentration of quinagolide and metabolites will be analyzed descriptively. A population PK 
modelling method will be outlined in a modelling analysis plan under the responsibility of the 
Translational Medicine Department of Ferring Pharmaceuticals A/S and the results will be reported 
separately. 
For the follow-up cycle (cycle 5), only descriptive summary statistics will be provided as 
applicable.  
 
9.7 
Extent of Exposure and Treatment Compliance 
The extent of exposure is defined as the number of days between the first ring insertion until 
removal and will be summarized by cycle and treatment group. The total extent of exposure (across 
all cycles) will be summarized by treatment group and overall. This will be done both including and 
excluding known periods of intermittent removals of the vaginal ring if applicable.  
The number of days of rescue analgesics use and the percentage of days on rescue analgesics will 
be similarly summarized.  
 
9.8 
Safety Endpoints  
General Considerations 
This section describes the descriptive analyses of safety endpoints and routine safety assessments. 
The safety endpoints, highlighted in grey in Table 9-2, will be analyzed for the safety analysis set.  
Changes in Bone-turnover Markers 
Changes in bone-turnover markers will be analyzed by an ANCOVA model, estimating adjusted 
treatment contrasts at cycle 4, as described in Table 9-2 in section 9.6.3. 
ECG and Echocardiography 
Changes in ECG parameters, including PR interval, QT interval, QTcF interval and QRS interval at 
cycle 4 will be summarized by cycle and treatment group and in total.  
The proportion of subjects with clinically significant echocardiography findings will be tabulated 
by cycle and treatment group and in total.  
Questionnaire for Impulsive-Compulsive Disorders 
Frequency-tables for each item of the questionnaire for impulsive-compulsive disorders as well as 
the proportion of subjects having potential behaviors associated with impulse control disorders will 
be presented by cycle, treatment and in total.  


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Adverse Events 
Treatment-emergent adverse eventsg will be summarized overall and tabulated by SOC and 
preferred term using MedDRA. The version of MedDRA will be documented. The total number of 
subjects reporting an adverse event, the percentage of subjects (%) with an adverse event, and the 
number of events reported will be presented. 
Summary tables will be prepared for the following: all adverse events, adverse events by causality 
(reasonable possibility / no reasonable possibility), adverse events leading to death, adverse events 
by intensity (mild / moderate/ severe), adverse reactions by intensity (mild / moderate/ severe), 
SAEs, adverse events leading to discontinuation, adverse events with an incidence of at least 5% in 
any treatment group, non-SAEs with an incidence of at least 5% in any treatment group. A separate 
data listing will be provided for pre-treatment adverse events.h Listings of adverse events will also 
indicate whether or not the adverse event occurs during the COVID-19 trial hold.  
Safety Laboratory Variables 
Safety laboratory variables will be grouped under “hematology” and “clinical chemistry”. 
The baseline is taken on LH+7 of cycle -1. Post-baseline clinical laboratory values are taken on 
LH+7 of cycle 4.  
The circulating levels of clinical chemistry and hematology parameters including changes from 
baseline will be tabulated for each time point for each laboratory variable. 
Shift tables will be prepared to compare baseline values to the values at the respective post-baseline 
visits, using a categorization of low, normal and high values defined according to the reference 
ranges provided by the central laboratory.  
For each laboratory variable, a summary table will be prepared displaying the proportion of 
subjects who have at least one post baseline markedly abnormal value. The denominator will be the 
number of subjects with baseline and at least one post baseline value. The table will also include a 
break-down by classification of the baseline value. Markedly abnormal criteria for the safety 
laboratory values will be specified in the SAP. 
All laboratory values will be listed by subject number and time point. Values outside the reference 
range and markedly abnormal values will be flagged. 
Urinalysis  
Urinalysis parameters will be summarized descriptively.  
 
g A treatment-emergent adverse event is any adverse event occurring after start of IMP and before the end-of-trial 
visit, or a pre-treatment adverse event or pre-existing medical condition that worsens in intensity after start of IMP 
and before the end-of-trial visit. 
h A pre-treatment adverse event is any adverse event occurring after signed informed consent and before start of IMP 
or a pre-existing condition that worsens in intensity after signed informed consent but before start of IMP.   


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Ring Acceptability Parameters  
Frequency-tables for each item (as applicable) of the ring acceptability questionnaire will be 
presented by cycle, treatment group and in total. 
 
Other Safety Variables 
Vital Signs 
Vital signs and the changes in vital signs will be analyzed similarly to routine safety laboratory 
variables. Reference ranges for vital signs will be specified in the SAP.  
Physical and Gynecological Examination 
Physical and gynecological examination findings at end-of-treatment compared to screening will be 
summarized in shift tables and all subjects with any abnormal finding will be listed by subject and 
time point. The list will include both screening and end-of-treatment assessment for comparison.  
Transvaginal Ultrasound 
Endometrial thickness, number and size of fibroids if presented and number and size of ovarian cyst 
if presented will be tabulated by screening, RM+7 visits of cycle 4. 
 
9.9 
Interim Analysis 
An interim analysis with the option to stop the trial early due to futility will be performed by an 
external statistician, when approximately half of the planned evaluable subjects (104 subjects) have 
completed the treatment period of the trial for the assessment of the primary endpoint, using 
unblinded data presented by treatment group.  
The futility bound is set at a conditional power using current trend equal to 5%, which means that 
the trial could potentially be stopped for futility, if the probability of achieving a significant result 
in the highest remaining dose group is lower than 5% based on the observed data at the interim 
analysis. In case of high drop-out rate or discontinuations in the highest dose group, the analysis 
will be performed on the remaining dose(s). If the probability is between 5% and 90%, the sample 
size will be re-estimated by the external statistician based on the unblinded data available at the 
interim analysis and may be increased to a total of 360 subjects.  
No interim analysis intended to stop the trial early due to overwhelming efficacy is planned. 


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10 
DATA HANDLING 
10.1 
Source Data and Source Documents 
Source Data – ICH Definition 
Source data are defined as all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies). 
Source Documents – ICH Definition 
Source documents are defined as original documents, data, and records (e.g. hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical trial). 
Trial-specific Source Data Requirements – Ferring 
Source documents need to be preserved for the maximum period of time permitted by local 
requirements. For each subject screened, the investigator will indicate as a minimum in the source 
documents that informed consent is obtained, whether wash-out is needed, the date and the reason 
for wash-out if applicable and the reason for screening failure if applicable. For each subject 
randomized, the investigator will indicate in the source documents that the subject participates in 
this trial, and will record at least the following information, if applicable:  
• Existence of subject (initials, date of birth) 
• Confirmation of participation in trial (trial ID, subject ID) 
• Informed consent(s) (date of obtaining written informed consent(s)) 
• Eligibility for participation in the trial (documenting all inclusion / exclusion criteria) 
• Relevant medical history and menstrual history 
• Visit dates 
• Dates of insertion/removal of the ring 
• Dispensing of IMP and ibuprofen  
• Dates and doses of concomitant medications 
• Adverse events (description as well as start/stop date and time) 
• Reason for discontinuation  
• Event of unblinding, including the reason for unblinding 
 
The source data for analytical parameters of blood samples will be available at the central 
laboratory.  


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In addition, each subject will use an e-Diary on a daily basis to record the following specific 
protocol data, for which the e-PRO service provider database is considered source data:  
• Assessment of endometriosis-related pain on NRS scale 
• Vaginal bleeding  
• Occurrence of sexual intercourse and assessment of dyspareunia (if applicable) 
• Pain impact (also applicable to the weekly pain impact questions) 
• Analgesic use  
 
Note that part of the analgesic use information, such as prescriptions of hydrocodone-
acetaminophen or information of other analgesics, will be recorded in the e-CRF.  
At a few selected visits, subjects, study coordinators and investigators will access electronic tablets 
separately to record the following data, for which the e-PRO service provider database is 
considered source data:  
• B&B scores  
• EHP-30 scores 
• PGIS and PGIC scores 
• QICD scores 
• Ring acceptability  
 
For the eC-SSRS, the e-PRO service database is also considered source data. The text files of 
transcripts will be considered source documents for patient interviews. 
 
10.2 
e-CRF 
An e-CRF system provided by an independent third-party CRO, Target Health Inc., will be used for 
data capture. The system is validated and access at all levels to the system is granted / revoked 
following Ferring and vendor procedures, in accordance with regulatory and system requirements. 
Trial data should be entered into the e-CRF within a reasonable time after the subject has attended a 
visit or after the data become available, as applicable.   
The investigator will approve / authorize the e-CRF entries for each subject with an electronic 
signature which is equivalent to a handwritten signature.  
The e-CRF system and the database will be hosted at Target Health Inc. After the trial database is 
declared clean and is released to the responsible statistician, a final copy of the database will be 
stored at Ferring. The investigator will also receive a copy of the trial site’s final and locked data 
(including audit trail, electronic signature and queries) as write-protected PDF-files produced by 
Target Health Inc. The PDF-files will be stored in an electronic format and will be provided to the 
investigator before access to the e-CRF is revoked. 


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Entry errors occurring in the e-CRF will be corrected electronically. Such corrections or 
modifications will be automatically tracked by an audit trail detailing the date and time of the 
correction and the name of the person making the correction. 
 
10.3 
Use of Patient Reported Outcome  
A newly developed PRO tool, Women’s Endometriosis Diary, which consists of questions on 
endometriosis-related pain, vaginal bleeding, occurrence of sexual intercourse and the impact of 
endometriosis-related pain on functioning, is to be used in the present trial. Questions on daily 
analgesic use are included in the daily e-Diary, although they are not part of Women’s 
Endometriosis Diary. The development of the PRO is consistent with the FDA’s PRO guidance33 
and follows the patient-focused outcome measurement road map.  
All diary questions are administered electronically through an application-based technology (app) 
on a hand-held device in the form of either the subject’s own phone or a provisional device.  
The e-Diary data will be encrypted to ensure personal data privacy. No personal data will be 
collected by Ferring from the subjects’ own phones, if subjects choose to use their own phones. The 
download and installation process of the app will be controlled through a subject-specific activation 
code, allowing only subjects participating in the trial to download and install the app. The app will 
be PIN-protected to ensure that only the individual subject will be able to access the app. 
The electronic data collection procedure is compliant with FDA 21 CFR part 11 for electronic 
records. Once subjects have submitted their recordings, the data will be transmitted from subjects’ 
own phones or from their provisional devices to a third party database with backup and cyber-
security controls. No access to historically reported data will be given to the subjects once they 
have submitted their recordings. Furthermore, no retrospective data entry will be allowed, i.e. no 
data entry after closure of the entry window, which is from 8 pm to 2 am every day for the daily 
diary and from 8 pm on Sundays to 2 am on Tuesdays for the weekly diary. Reminders will be set 
up to remind subjects of completing the diary when applicable. In the present trial, the investigator 
or the trial coordinator will be encouraged to review the e-Diary data regularly in order to monitor 
subject compliance with the e-Diary completion and analgesic use. No modification of subject 
reported e-Diary data will be made.  
In addition to the PRO collected via e-Diary, B&B, EHP-30, PGIS, PGIC, questionnaire for 
impulsive-compulsive disorders and ring acceptability questionnaire will be completed at the site 
via electronic tablets.  
 
10.4 
Data Management  
A data management plan will be created under the responsibility of the Global Biometrics 
Department of Ferring. The data management plan will be issued before data collection begins and 
will describe all functions, processes, and specifications for data collection and validation. The data 


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management plan will also include information about the intended use of computerized systems, a 
description of the security measures employed to protect the data and a description of the electronic 
data flow. 
 
10.5 
Provision of Additional Information 
On request, the investigator will provide Ferring with additional data relating to the trial, duly 
anonymized and protected in accordance with applicable requirements.  


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11 
MONITORING PROCEDURES 
11.1 
Periodic Monitoring 
The monitor will contact and visit the investigator periodically to ensure adherence to the protocol, 
International Conference on Harmonisation-Good Clinical Practice (ICH-GCP), standard operating 
procedures and applicable regulatory requirements, maintenance of trial-related source records, 
completeness, accuracy and verifiability of e-CRF entries compared to source data, verification of 
drug accountability and compliance to safety reporting instructions.  
The investigator will permit the monitor direct access to all source data, including e-diaries, 
electronic medical records, and/or documents in order to facilitate data verification. The 
investigator will cooperate with the monitor to ensure that any discrepancies that may be identified 
are resolved. The investigator is expected to be able to meet the monitor during these visits. Shortly 
after a subject is screened and determined eligible, a monitoring visit will take place. For this trial, 
the frequency of the monitoring visits per site will be dependent on recruitment rate, observed data 
quality and overall site performance.  
The source data verification process, definition of key variables to be monitored and the monitoring 
strategy will be described in detail in the Monitoring Plan for the trial. 
 
11.2 
Audit and Inspection 
The investigator will make all the trial-related source data and records available at any time to 
quality assurance auditor(s) mandated by Ferring, or to domestic / foreign regulatory inspectors or 
representatives from IRBs who may audit / inspect the trial. 
The main purposes of an audit or inspection are to evaluate trial conduct and compliance with the 
trial protocol, ICH-GCP, the applicable regulatory requirements and standard operating procedures. 
The subjects must be informed by the investigator and in the Informed Consent Documents that 
authorized Ferring representatives and representatives from relevant regulatory authorities and 
IRBs may wish to inspect their medical records. During audits / inspections the auditors / inspectors 
may copy relevant parts of the medical records. No personal identification apart from the 
screening / randomization number will appear on these copies. 
The investigator should notify Ferring without any delay of any inspection by regulatory authorities 
or IRBs. 
 
11.3 
Confidentiality of Subject Data 
The investigator will ensure that the confidentiality of the subjects’ data will be preserved. In the 
e-CRF or any other documents submitted to Ferring, the subjects will not be identified by their 
names, but by an identification system, which consists of an assigned number in the trial. 


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Documents that are not for submission to Ferring, e.g. the confidential subject identification code 
and the signed Informed Consent Documents, will be maintained by the investigator in strict 
confidence. 


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12 
CHANGES IN THE CONDUCT OF THE TRIAL 
12.1 
Protocol Amendments 
Any change to this protocol will be documented in a protocol amendment, issued by Ferring, and 
agreed upon by the investigator and Ferring prior to its implementation. Amendments may be 
submitted for consideration to the approving IRBs and regulatory authorities in accordance with 
local regulations. Changes to the protocol to eliminate immediate hazard(s) to trial subjects may be 
implemented prior to IRBs’ approval or favorable opinion. 
 
12.2 
Deviations from the Protocol 
Deviations from the protocol should not occur. If deviations occur, the investigator must inform the 
sponsor, and a record of protocol deviations will be maintained by the investigator and sponsor. 
  
12.3 
Premature Trial Termination 
Both the investigator (with regard to his/her participation) and Ferring reserve the right to terminate 
the trial at any time. Should this become necessary, the procedures will be agreed upon after 
consultation between the two parties. In terminating the trial, Ferring and the investigator will 
ensure that adequate consideration is given to the protection of the best interests of the subjects. 
Regulatory authorities and IRBs will be informed. 
In addition, Ferring reserves the right to terminate the participation of individual trial sites. 
Conditions that may warrant termination include, but are not limited to, insufficient adherence to 
protocol requirements and failure to enter subjects at an acceptable rate. 
 


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13 
REPORTING AND PUBLICATION 
13.1 
Clinical Trial Report 
The data and information collected during this trial will be reported in a clinical trial report 
prepared by Ferring and submitted for comments and signature to the signatory investigator.  
 
13.2 
Confidentiality and Ownership of Trial Data 
Any confidential information relating to the IMP or the trial, including any data and results from 
the trial will be the exclusive property of Ferring. The investigator and any other persons involved 
in the trial will protect the confidentiality of this proprietary information belonging to Ferring. 
 
13.3 
Publications and Public Disclosure 
13.3.1 
Publication Policy 
At the end of the trial, one or more manuscripts for joint publication may be prepared in 
collaboration between the investigator(s) offered authorship and Ferring. In a multi-site trial based 
on the collaboration of many sites, any publication of results must acknowledge all sites. Results 
from multi-site trials must be reported in entirety in a responsible and coherent manner and results 
from subsets should not be published in advance or without clear reference to the primary 
publication of the entire trial. 
Authorship is granted based on the criteria established by the International Committee of Medical 
Journal Editors (ICMJE) (see current official version http/www.ICMJE.org).48 The total number of 
authors is based on the guideline from the relevant journal or congress. In the event of any 
disagreement in the content of a publication, both the investigator’s and Ferring’s opinion will be 
fairly and sufficiently represented in the publication. 
Any external CRO or laboratory involved in the conduct of this trial has no publication rights 
regarding this trial. 
If the investigator wishes to independently publish / present any results from the trial, the draft 
manuscript / presentation must be submitted in writing to Ferring for comments prior to 
submission. Comments will be given within four weeks from receipt of the draft manuscript. This 
statement does not give Ferring any editorial rights over the content of a publication, other than to 
restrict the disclosure of Ferring’s intellectual property. If the matter considered for publication is 
deemed patentable by Ferring, scientific publication will not be allowed until after a filed patent 
application is published. Under such conditions the publication will be modified or delayed at the 
investigator’s discretion, to allow sufficient time for Ferring to seek patent protection of the 
invention. 
 


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13.3.2 
Public Disclosure Policy  
ICMJE member journals have adopted a trial-registration policy as a condition for publication. This 
policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is the 
responsibility of Ferring to register the trial in an appropriate public registry, i.e. 
www.ClinicalTrials.gov; a website maintained by the National Library of Medicine at National 
Institutes of Health in the United States. A summary of the trial results is made publicly available in 
accordance with applicable regulatory requirements.  
 


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14 
ETHICAL AND REGULATORY ASPECTS 
14.1 
Institutional Review Board  
An IRB will review the protocol and any amendments and advertisements used for recruitment. The 
IRB will review the Subject Information Sheet and the Informed Consent Form, their updates (if 
any), and any written materials given to the subjects. A list of all IRBs to which the protocol has 
been submitted and the name of the committee chairmen will be included in the Clinical Trial 
Report. 
 
14.2 
Regulatory Authorities’ Approval  
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available before a subject is 
exposed to any trial-related procedure, including screening tests for eligibility. 
 
14.3 
End-of-Trial  
The end of the trial is defined as the date of LPLV, i.e. when the last subject completes the end-of-
trial visit. The IRBs will be notified about the completion of the clinical trial according to local 
legislation.  
In the case of early termination for safety reasons, Ferring must notify the end of the trial to the 
relevant regulatory authorities and the concerned IRBs without delay, clearly explain the reasons, 
and describe follow-up measures, if any.  
 
14.4 
Ethical Conduct of the Trial 
This trial will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki, in compliance with the approved protocol, ICH-GCP and applicable 
regulatory requirements. 
 
14.5 
Subject Information and Consent 
This trial will use three sets of Informed Consent Documents: one overall covering the trial 
participation, one specific covering the genetic testing for analysis of pharmacogenetics and for 
potential analyses of cell-free DNA and microRNA as well as one specific covering the patient 
interview. The latter two documents will only describe the aspects relevant to the genetic analysis 
or to the patient interview and should be read in conjunction with the Informed Consent Document 
for the general trial. Participation in the genetic testing and participation in the patient interview are 
both optional.  
The investigator (or the person delegated by the investigator) will obtain a freely given written 
consent from each subject after an appropriate explanation of the aims, methods, sources of 


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funding, any possible conflicts of interest, anticipated benefits, potential hazards, and any other 
aspects of the trial which are relevant to the subject’s decision to participate. The trial subject must 
be given ample time to consider participation in the trial, before the consent is obtained. The 
Informed Consent Documents must be signed and dated by the subject and the investigator who has 
provided information to the subject regarding the trial before the subject is exposed to any trial-
related procedure, including screening tests for eligibility. Subjects must be given the option of 
being informed about the general outcome and the results of the trial. 
The investigator (or the person delegated by the investigator) will explain that the subject is 
completely free to refuse to enter the trial or to withdraw from it at any time, without any 
consequences for her further care and without the need to justify her decision. 
The subject will receive a copy of the Subject Information and her signed Informed Consent 
Form(s) before any trial-related procedures. 
If new information becomes available that may be relevant to the trial subject’s willingness to 
continue participation in the trial, a new Subject Information and Informed Consent Form will be 
forwarded to the IRBs (and regulatory authorities, if required). The trial subjects will be informed 
about this new information and re-consent will be obtained. 
Each subject will be informed that the monitor(s), quality assurance auditor(s) mandated by 
Ferring, IRB representatives or regulatory authorities’ inspector(s), in accordance with applicable 
regulatory requirements, may review her source records and data. Data protection will be handled 
in compliance with regulations of the United States. 
 
14.6 
Subject Participation Card 
The subject will be provided with a Subject Participation Card with the following information: 
• That she is participating in a clinical trial  
• That she is treated with quinagolide (a dopamine agonist) vaginal ring or placebo vaginal 
ring for endometriosis-related pain 
• The name and phone number of the investigator 
• The name and address of Ferring (if required by local regulations) 
The subject will be asked to keep the Subject Participation Card in her possession at all times 
during the trial.  
Additionally, each subject’s primary care physician will be notified of their participation in the trial 
by the investigator, if the subject agrees and if applicable. 
 


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14.7 
Compliance Reference Documents 
The Declaration of Helsinki, the consolidated ICH-GCP, and other national law(s) in the United 
States where the trial takes place shall constitute the main reference guidelines for ethical and 
regulatory conduct. 


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15 
LIABILITIES AND INSURANCE 
15.1 
ICH-GCP Responsibilities 
The responsibilities of Ferring, the monitor and the investigator are defined in the ICH-GCP 
consolidated guideline, and applicable regulatory requirements in the United States where the trial 
takes place. The investigator is responsible for adhering to the ICH-GCP responsibilities of 
investigators, for dispensing the IMP in accordance with the approved protocol or an approved 
amendment, and for its secure storage and safe handling throughout the trial. 
15.2 
Liabilities and Insurance 
Ferring is, as sponsor, responsible for ensuring appropriate general/product liability insurance and, 
as required in accordance with applicable laws and regulations, country-specific liability insurance 
coverage for claims made by a trial subject for injury arising from the subject’s participation in the 
trial. 


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16 
ARCHIVING 
16.1 
Investigator File 
The investigator is responsible for maintaining all the records, which enable the conduct of the trial 
at the site to be fully understood, in compliance with ICH-GCP. The trial documentation including 
all the relevant correspondence should be kept by the investigator for at least 15 years after the 
completion or discontinuation of the trial, if no further instructions are given by Ferring. 
The investigator is responsible for the completion and maintenance of the confidential subject 
identification code which provides the sole link between named subject source records and 
anonymous e-CRF data for Ferring. The investigator must arrange for the retention of this Subject 
Identification Log and signed Informed Consent Documents for at least 15 years after the 
completion or discontinuation of the trial. 
No trial site document may be destroyed without prior written agreement between the investigator 
and Ferring. Should the investigator elect to assign the trial documents to another party, or move 
them to another location, Ferring must be notified. If the investigator retires and the documents can 
no longer be archived by the site, Ferring can arrange having the Investigator File archived at an 
external archive. 
 
16.2 
Trial Master File 
Ferring will archive the Trial Master File in accordance with ICH-GCP and applicable regulatory 
requirements. 


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17 
REFERENCES 
 
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Quinagolide (FE 999051) Investigator’s Brochure. Edition 8, May 2018 
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Novella-Maestre E, Carda C, Ruiz-Sauri A, Garcia-Velasco JA, Simon C, Pellicer A. 
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Novella-Maestre E, Herraiz S, Vila-Vives JM, Carda C, Ruiz-Sauri A, Pellicer A. Effect of 
antiangiogenic treatment on peritoneal endometriosis-associated nerve fibers. Fertil Steril 
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Delgado-Rosas F, Gómez R, Ferrero H, Gaytan F, Garcia-Velasco J, Simón C, Pellicer A. 
The effects of ergot and non-ergot-derived dopamine agonists in an experimental mouse 
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Supersedes: 5.0 
Page 129 of 130 
 
 
 
Quinagolide, FE 999051 
Trial Code: 000165  
Vaginal Delivery System  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
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U.S. Food and Drug Administration (FDA) label information for ibuprofen. 
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U.S. Food and Drug Administration (FDA) label information for hydrocodone-
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42eb-b74d-f302b3f914ee; 
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f86484e69d08; https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2f1c9e91-e5e7-
4b07-8f56-e3719573ef23 [accessed on 29 May 2020] 
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Trivedi MH, Rush H. Does a placebo run-in or a placebo treatment cell affect the efficacy of 
antidepressant medications? Neuropsychopharmacology 1994; 11: 33-43. 
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Diamond MP, Carr B, Dmowski WP, Koltun W, O’Brien C, Jiang P, Burke J, Jimenez R, 
Garner E, Chwalisz K. Elagolix treatment for endometriosis-associated pain: results from a 
phase 2, randomized, double-blind, placebo-controlled study. Reprod Sci 2014; 21: 363-
371. 
31  
Vincent K, Kennedy S, Stratton P. Pain scoring in endometriosis: entry criteria and outcome 
measures for clinical trials. Report from the Art and Science of Endometriosis meeting. 
Fertil Steril 2010; 93: 62-67.   
32  
Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, Kerns RD, 
Stucki G, Allen RR, Bellamy N, Carr DB, Chandler J, Cowan P, Dionne R, Galer BS, Herts 
S, Jadad AR, Kramer LD, Manning DC, Martin S, McCormick CG, McDermott MP, 
McGrath P, Qussy S, Rappaport BA, Robbins W, Robinson JP, Rothman M, Royal MA, 
Simon L, Stauffer JW, Stein W, Tollett J, Wernicke J, Witter J. Core outcome measures for 
chronic pain clinical trials: IMMPACT recommendations. Pain 2005; 113: 9-19. 
33  
Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER), 
Center for Biologics Evaluation and Research (CBER), Center for Devices and Radiological 
Health (CDRH). Guidance for industry: patient-reported outcome measures: use in medical 
product development to support labeling claims, Draft 2009. 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM193282.pdf [accessed on 29 May 
2020] 
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Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER). 
Guidance for Industry Analgesic Indications: Developing Drug and Biological Products, 
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http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/
ucm384691.pdf [accessed on 29 May 2020] 
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Biberoglu KO, Behrman SJ. Dosage aspects of danazol therapy in endometriosis: short term 
and long term effectiveness. Am J Obstet Gynecol 1981; 139: 645-654. 


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E-Study Protocol-20036; Ver.6.0 
Supersedes: 5.0 
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Quinagolide, FE 999051 
Trial Code: 000165  
Vaginal Delivery System  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
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Jones G, Kennedy S, Barnard A, Wong J, Jenkinson C. Development of an Endometriosis 
Quality-of-Life Instrument: The Endometriosis Health Profile-30. Obstet Gynecol 2001; 98: 
258-264. 
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Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on 
subjective outcome measures. J Manipulative Physiol Ther 2004; 27: 26-35. 
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Vasikaran S, Eastell R, Bruyére O, Foldes AJ, Garnero P, Griesmacher A, McClung M, 
Morris HA, Silverman S, Trenti T, Wahl DA, Cooper C, Kanis JA, for the IOF-IFCC Bone 
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Agarwal SK, Chapron C, Giudice LC, Laufer MR, Leyland N, Missmer SA, Singh SS, 
Taylor HS. Clinical diagnosis of endometriosis: a call to action. Am J Obstet Gynecol. 
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non-invasive diagnosis of endometriosis. Cochrane Database Syst Rev 2016; 2: CD009591. 
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SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor Name 
Ferring Pharmaceuticals Inc. 
NCT Number 
NCT03692403 
Sponsor Trial ID 
000165 
Official title of study 
A randomized, double-blind, placebo-controlled, phase 2 trial 
assessing the efficacy, safety and dose-response of 
quinagolide extended-release vaginal rings administered 
sequentially for 4 menstrual cycles in women with moderate 
to severe endometriosis-related pain 
Document Date 
31 May 2022 


Statistical Analysis Plan 
Version: 1.0 
 
Quinagolide  
31MAY2022 
FE 999051 trial 000165 
CONFIDENTIAL 
Page 1 (44) 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
RAQUEL 
Randomized Trial Assessing Quinagolide Vaginal Ring for Endometriosis-Related 
Pain  
A randomized, double-blind, placebo-controlled, phase 2 trial assessing the efficacy, 
safety and dose-response of quinagolide extended-release vaginal rings administered 
sequentially for 8 menstrual cycles in women with moderate to severe endometriosis-
related pain 
 
Trial 000165 
 
 
Investigational Medicinal Product: FE 999051, Quinagolide Vaginal Ring  
 
Indication: 
Endometriosis-related pain  
 
Phase: 
2 
 
Author: 
 
 
Date of issue: 
31MAY2022 
 
Version: 
1.0 
 
 
 
 
 
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or 
another company within the Ferring Group. It is understood that information in this document shall not be 
disclosed to any third party, in any form, without prior written consent of an authorised officer of Ferring 
Pharmaceuticals A/S or another company within the Ferring Group 


Statistical Analysis Plan 
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31MAY2022 
FE 999051 trial 000165 
CONFIDENTIAL 
Page 2 (44) 
 
TABLE OF CONTENTS 
 
Page 
 
 
1 
Introduction .................................................................................................................................. 5 
1.1 
Definitions/ Abbreviations ................................................................................................. 5 
1.1.1 
Definition of Terms ............................................................................................... 5 
1.1.2 
Abbreviations ........................................................................................................ 6 
2 
Trial Objectives and Endpoints .................................................................................................... 7 
2.1 
Primary Objective .............................................................................................................. 7 
2.2 
Secondary Objectives ........................................................................................................ 7 
2.3 
Exploratory Objective ........................................................................................................ 7 
2.4 
Primary Endpoint ............................................................................................................... 7 
2.5 
Secondary Endpoints ......................................................................................................... 7 
2.6 
Exploratory Endpoint ......................................................................................................... 9 
3 
Trial design ................................................................................................................................ 10 
3.1.1 
Trial Design Diagram (protocol version 5.0) ...................................................... 11 
3.2 
General Design Considerations ....................................................................................... 15 
3.3 
Determination of Sample Size ......................................................................................... 15 
4 
Subject Disposition .................................................................................................................... 17 
4.1 
Screened subjects ............................................................................................................. 17 
4.2 
Subject disposition ........................................................................................................... 17 
4.3 
Subject disposition and completion ................................................................................. 17 
4.4 
Subject completion/discontinuation ................................................................................. 17 
4.5 
Listing .............................................................................................................................. 17 
5 
Protocol Deviations .................................................................................................................... 18 
5.1 
Major protocol deviations ................................................................................................ 18 
5.2 
Listing .............................................................................................................................. 18 
6 
Analysis Sets .............................................................................................................................. 19 
6.1 
Intention-To-Treat Analysis Set ...................................................................................... 19 
6.2 
Per Protocol Analysis Set ................................................................................................ 19 
6.3 
Safety Analysis Set .......................................................................................................... 19 
7 
Trial Population.......................................................................................................................... 20 
7.1 
Demographics and Other Baseline Characteristics .......................................................... 20 
7.1.1 
Demographics and body measurements .............................................................. 20 
7.1.2 
Vital Signs at Baseline ........................................................................................ 20 
7.1.3 
History of Disease ............................................................................................... 20 
7.2 
Medical History ............................................................................................................... 20 
7.3 
Prior and Concomitant Medication .................................................................................. 21 
7.4 
Physical Examination ...................................................................................................... 21 
7.5 
Listings ............................................................................................................................ 21 
8 
Exposure and Treatment Compliance ........................................................................................ 22 
8.1.1 
Extent of Exposure .............................................................................................. 22 
8.1.2 
Treatment Compliance ........................................................................................ 22 
8.1.3 
Listings ................................................................................................................ 23 
9 
Efficacy ...................................................................................................................................... 24 
9.1 
Transformation of daily e-Diary data .............................................................................. 24 
9.1.1 
Definition of cycles ............................................................................................. 26 


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9.1.2 
Definition of menstrual period and non-menstrual period .................................. 27 
9.1.3 
Missing data for daily worst endometriosis-related pain question ...................... 28 
9.1.4 
The mean daily NRS score .................................................................................. 28 
9.1.4.1 
The mean daily NRS score for worst endometriosis related pain ....... 28 
9.1.4.2 
The mean daily NRS score for worst dysmenorrhea .......................... 29 
9.1.4.3 
The mean daily NRS score for worst non-menstrual pelvic pain ....... 29 
9.1.4.4 
The mean daily NRS score for worst impact of endometriosis 
related pain on the subject ability to function ..................................... 29 
9.1.5 
Analgesics use ..................................................................................................... 29 
9.1.5.1 
Percentage of days with analgesics use ............................................... 30 
9.1.5.2 
Total and average doses of analgesics ................................................ 30 
9.1.6 
Responder status .................................................................................................. 30 
9.1.7 
Dyspareunia ......................................................................................................... 31 
9.1.7.1 
The mean daily NRS score for worst dyspareunia .............................. 31 
9.1.7.2 
Frequency of avoiding sexual intercourse........................................... 31 
9.1.8 
Vaginal bleeding pattern...................................................................................... 31 
9.2 
Transformation of weekly e-Diary data ........................................................................... 31 
9.3 
General Considerations .................................................................................................... 33 
9.3.1 
Efficacy and exploratory endpoints ..................................................................... 33 
9.4 
Analysis of Pharmacokinetics .......................................................................................... 34 
10 Safety ......................................................................................................................................... 35 
10.1 General Considerations .................................................................................................... 35 
10.2 Adverse Events ................................................................................................................ 35 
10.2.1 Overview of Treatment-Emergent Adverse Events ............................................. 35 
10.2.2 Incidence of Adverse Events ............................................................................... 36 
10.2.3 Incidence of Adverse Events of Special Interest ................................................. 37 
10.2.3.1 Dizziness/Pre-syncope ........................................................................ 37 
10.2.3.2 Dysmenorrhea, Abdominal Pain, Pelvic Pain, Lower Back Pain 
and Dyspareunia .................................................................................. 37 
10.2.3.3 Vaginal bleeding ................................................................................. 37 
10.2.3.4 Syncope ............................................................................................... 37 
10.2.3.5 Vaginal Irritation and/or Vaginal Infection......................................... 38 
10.3 Safety Laboratory Variables ............................................................................................ 38 
10.3.1 Summary Statistics .............................................................................................. 38 
10.3.2 Laboratory Variable Changes Relative to Normal Range ................................... 39 
10.3.3 Data Listings ........................................................................................................ 39 
10.3.4 Urinalysis............................................................................................................. 39 
10.4 Vital Signs and ECG ........................................................................................................ 39 
10.4.1 Vital Signs ........................................................................................................... 39 
10.4.1.1 Summary Statistics .............................................................................. 39 
10.4.1.2 Data Listings ....................................................................................... 39 
10.4.2 ECGs ................................................................................................................... 40 
10.4.2.1 Summary Statistics .............................................................................. 40 
10.4.2.2 Data Listings ....................................................................................... 40 
10.5 Other Safety Variables ..................................................................................................... 40 
10.5.1 Changes in Bone-turnover Markers ..................................................................... 40 
10.5.2 Echocardiography ................................................................................................ 40 
10.5.3 Impulsive-Compulsive Disorders ........................................................................ 41 
10.5.4 Ring Acceptability ............................................................................................... 41 


Statistical Analysis Plan 
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31MAY2022 
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CONFIDENTIAL 
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11 Interim Analyses ........................................................................................................................ 42 
12 Deviations from Protocol Analysis ............................................................................................ 43 
 


Statistical Analysis Plan 
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31MAY2022 
FE 999051 trial 000165 
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1 
Introduction 
This document describes the planned statistical analyses for trial 000165, and is based on 
versions 4.0, 5.0, and 6.0 of the clinical trial protocol dated 9th of July 2018, 27th of March 
2019, and 29th of May 2020.  
 
During this trial subjects were randomized under three consecutive versions of the 
protocol; version 4.0, version 5.0, and version 6.0. As the majority of subjects were 
randomized under protocol version 5.0, this will be used as the basis for the clinical trial 
report. 
These protocol amendments included modifications to the eligibility criteria, modifications 
to the overall trial design, and changes to reflect the impact of the COVID-19 pandemic on 
the conduct of the trial. The change in trial design was in protocol version 6.0, the 
quinagolide extended-release vaginal rings were administered sequentially for 4 menstrual 
cycles instead of 8 menstrual cycles. Therefore, in version 6 subjects completed treatment 
Part A (cycles 1 to 4) only, there was no treatment Part B (cycles 5 to 8), and the follow-up 
period was for one menstrual cycle only (cycle 5).  
 The trial was terminated early. The decision was taken due to the results from the parallel 
phase 2 trial in Europe (Trial 000295) and the continued difficulties with subject 
recruitment. 
Furthermore, due to the low number of subjects recruited, no interim analysis will be 
performed, and no statistical analysis will be performed. Instead results are presented as 
descriptive statistics by treatment group separately for Part A and Part B. In this SAP when 
results are summarized by treatment it means two tables one for Part A (with 4 treatments, 
Placebo and the 3 doses of quinagolide) and one for Part B (with 6 treatments, Placebo 
followed by each of the 3 doses of Quinagolide and continued use of each of the 3 doses of 
quinagolide).  
1.1 
Definitions/ Abbreviations 
 
1.1.1 Definition of Terms 
Terms 
Definitions 
Randomized 
Subject randomized to trial treatment 
Screened 
Subject who enters the screening phase 
 
 


Statistical Analysis Plan 
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31MAY2022 
FE 999051 trial 000165 
CONFIDENTIAL 
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1.1.2 Abbreviations 
 Abbreviations 
Meaning of abbreviations in document 
ITT 
Intention-to-treat 
PP 
IMP 
Per-Protocol 
Investigational Medicinal Product 
ECG 
Electrocardiography 
NRS 
Numerical Rating Scale  
EHP-30 
Endometriosis Health Profile-30  
B&B 
Biberoglu and Behrman  
PGIS 
Patient Global Impression of Severity 
PGIC 
Patient Global Impression of Change  
e-Diary 
Electronic diary  
LH 
Luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
RM 
Return of menses 
ANCOVA 
Analysis of covariance 
GEE 
Generalized estimating equation 
AE 
Adverse event 
TEAE 
Treatment emergent adverse event 
SOC 
System organ class 
PT 
Preferred term 
 
 


Statistical Analysis Plan 
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31MAY2022 
FE 999051 trial 000165 
CONFIDENTIAL 
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2 
Trial Objectives and Endpoints 
2.1 
Primary Objective 
• To evaluate the efficacy of three doses of Quinagolide administered as an extended-
release vaginal ring compared to placebo on reduction of moderate to severe 
endometriosis-related pain 
 
2.2 
Secondary Objectives  
• To evaluate the effect of Quinagolide vaginal ring on reduction of endometriosis-related 
dysmenorrhea, non-menstrual pelvic pain, dyspareunia and analgesic use 
• To evaluate the effect of Quinagolide vaginal ring on the subject’s ability to function  
• To evaluate the effect of Quinagolide vaginal ring on ovarian function 
• To evaluate the effect of Quinagolide vaginal ring on endocrine parameters  
• To evaluate the effect of Quinagolide vaginal ring on vaginal bleeding pattern 
• To evaluate the systemic exposure of Quinagolide and metabolites after Quinagolide 
vaginal ring administration 
• To evaluate the effect of Quinagolide vaginal ring on bone turnover markers  
• To evaluate the safety profile of Quinagolide vaginal ring including adverse events, 
symptoms of impulse control disorders, ECG and echocardiography findings, routine 
safety laboratory parameters and ring acceptability  
• To validate the newly developed patient reported outcome tool: Women’s 
Endometriosis Diary, The reporting of this objective will not be covered by this SAP as 
it will be reported separately. 
 
2.3 
Exploratory Objective  
• To explore the effect of Quinagolide vaginal ring on endometriosis biomarkers such as 
angiogenic and inflammatory biomarkers   
2.4 
Primary Endpoint  
• Changes in the mean daily Numerical Rating Scale (NRS) scores for the worst 
endometriosis-related pain at cycle 4 
2.5 
Secondary Endpoints  
• Changes in the mean daily NRS scores for the worst endometriosis-related pain on days 
with menstrual bleeding (i.e. dysmenorrhea) and for the worst endometriosis-related 
pain on days with no menstrual bleeding (i.e. non-menstrual pelvic pain) at cycle 4 
• Changes in the mean daily NRS scores for the worst endometriosis-related pain over 
8 menstrual cycles 


Statistical Analysis Plan 
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Page 8 (44) 
 
• Changes in the mean daily NRS scores for the worst dysmenorrhea over 8 menstrual 
cycles 
• Changes in the mean daily NRS scores for the worst non-menstrual pelvic pain over 8 
menstrual cycles 
• Changes in the mean daily NRS scores for the worst dyspareunia on days with sexual 
intercourse over 8 menstrual cycles 
• Frequency of avoiding sexual intercourse due to expected pain over 8 menstrual cycles  
• Changes in the mean daily NRS scores for the worst impact of endometriosis-related 
pain on the subject’s ability to function over 8 menstrual cycles 
• Changes in the mean weekly scores of the Endometriosis Health Profile-30 (EHP-30) 
pain impact domain over 8 menstrual cycles  
• Changes in vaginal bleeding pattern over 8 menstrual cycles 
• Percentage of days with mild and/or strong rescue analgesics used over 8 menstrual 
cycles 
• Total and average doses of mild and/or strong rescue analgesics used over 8 menstrual 
cycles 
• Responder rate assessed as ≥30%, ≥50% and ≥70% reduction from the baseline in mean 
daily NRS score for the worst endometriosis-related pain, dysmenorrhea and non-
menstrual pelvic pain and for the worst endometriosis-related pain impact, over 8 
menstrual cycles 
• Changes in the mean individual and total symptom and sign severity scores of the 
Biberoglu and Behrman (B&B) scale at cycles 4 and 8 
• Changes in the EHP-30 scores over 8 menstrual cycles  
• Changes in Patient Global Impression of Severity (PGIS) scores at cycles 4 and 8  
• Patient Global Impression of Change (PGIC) scores at cycles 4 and 8 
• Plasma concentration of quinagolide and metabolites during cycles 1, 4 and 8  
• Serum levels of mid-luteal phase progesterone at cycles 1, 4 and 8 
• Proportion of subjects with serum levels of mid-luteal progesterone ≥25 nmol/L (7.9 
ng/mL) at cycles 1, 4 and 8  
• Serum levels of mid-luteal estradiol, prolactin, thyroid-stimulating hormone (TSH) and 
insulin-like growth factor-1 (IGF-1) at cycles 1, 4 and 8  
• Changes in bone turnover markers, determined by bone resorption marker serum C-
terminal cross-linking telopeptide of type 1 collagen (s-CTx) and bone formation 
marker serum procollagen type I N propeptide (s-PINP) at cycles 4 and 8 
• Changes in ECG parameters including PR interval, QT interval, corrected QT using 
Fridericia’s formula (QTcF) and QRS interval at cycles 4 and 8  
• Proportion of subjects with abnormal clinically significant echocardiography findings 
indicating valvular heart disease at cycles 4 and 8  
• Proportion of subjects identified with potential impulse control disorders by the 
questionnaire for impulsive-compulsive disorders at cycles 4 and 8   
• Frequency and intensity of adverse events 


Statistical Analysis Plan 
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• Changes in circulating levels of clinical chemistry and hematology parameters, 
urinalysis parameters, and proportion of subjects with markedly abnormal changes 
• Frequency and intensity of ring acceptability parameters over 8 menstrual cycles 
2.6 
Exploratory Endpoint 
Changes in endometriosis biomarkers such as serum levels of VEGF, placenta growth 
factor (PlGF), interleukin 6 (IL-6) and soluble fms-like tyrosine kinase 1 (sFlt-1) at cycles 
4 and 8. 


Statistical Analysis Plan 
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31MAY2022 
FE 999051 trial 000165 
CONFIDENTIAL 
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3 
Trial design 
This is a randomized, double-blind, placebo-controlled, phase 2 trial assessing the efficacy, 
safety and dose-response of quinagolide extended-release vaginal rings administered 
sequentially for 4 menstrual cycles in women with moderate to severe endometriosis-
related pain. In this trial, a menstrual cycle is considered the period from day 7 of return of 
menses (RM+7) in a cycle until the following day 7 of return of menses in the next cycle. 
Visits on RM+7 can be scheduled on RM+6-10, i.e. day 6 to day 10 of return of menses.  
The trial consists of the following periods: 
1) Screening: starting immediately after the signing of the informed consent(s) and 
including a run-in period of two complete menstrual cycles (cycles -2 and -1) 
2) Part A: double-blind, placebo-controlled treatment with three doses of quinagolide 
extended-release vaginal ring administered sequentially for four menstrual cycles 
(cycles 1, 2, 3 and 4) 
3) Part B: double-blind, extension treatment with three doses of quinagolide extended-
release vaginal ring administered sequentially for four menstrual cycles (cycles 5, 6, 7 
and 8) 
4) Follow-up: post-treatment follow-up period of two menstrual cycles (cycles 9 and 10) 
 


Statistical Analysis Plan 
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31MAY2022 
FE 999051 trial 000165 
CONFIDENTIAL 
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3.1.1 Trial Design Diagram (protocol version 5.0) 
e-Diary
Screening
Placebo vaginal ring for 4 cycles
QVR dose load 360 µg for 4 cycles
QVR dose load 1080 µg for 4 cycles
QVR dose load 360 µg for 8 cycles
QVR dose load 720 µg for 8 cycles 
Re-allocation for 
placebo group
Run-in period of 
2 menstrual cycles a
Randomization to 
1 of 4 groups
Part B
Follow-up
Part A
QVR dose load 1080 µg for 8 cycles
QVR dose load 720 µg for 4 cycles
Pain impact e
Pain impact e
Vaginal bleeding
Analgesic use
Analgesic use
Vaginal bleeding
Sexual intercourse 
Sexual intercourse 
RM+7 g/ Visit 4
Randomisation
B&B
B&B
RM+7 g/ Visit 16
End-of-treatment
Informed consent
RM+7 g/ Visit 8
B&B
Cycle 6
Cycle 4
Cycle -1
Cycle 1
Cycle 2
Cycle 3
Cycle 5
Cycle 9
Cycle -2
RM+7 g / Visit 2
RM+7 g/ Visit 1 
Run-in
RM+7 g/ Visit 17
RM+7 g / Visit 7
NRS
NRS
RM+7 g / Visit 9
RM+7 g / Visit 11
RM+7 g/ Visit 14
LH+7 g / Visit 3
LH+7 g / Visit 6
LH+7 g / Visit 10
LH+7 g / Visit 15
LH+7 g / Visit 18
Cycle 10
RM+7 g/ Visit 19
End-of-trial
Washout
NRS(Run-in) f
QICD
Cycle 7
Cycle 8
RM+7 g / Visit 13
RM+7 g / Visit 12
PK Visit g/ Visit 5
Endocrine
Endocrine
Endocrine
Biomarkers b
BTM
Biomarkers b
Endocrine
Endocrine 
Biomarkers b
BTM
BTM
QICD
PK
PG c
PK
PK
PK
PK
PK
PK
PK
PK
ECG
Echod
ECGd
Echod
ECG
Echod
LH surge
LH surge
LH surge
LH surge
LH surge
TVU 
TVU
TVU
E2, P4
E2, P4
PGIS
EHP-30
EHP-30
PGIS
PGIS
PGIC
EHP-30
PGIS
PGIC
EHP-30
EHP-30
EHP-30
EHP-30
EHP-30
EHP-30
QICD
 
 
 
 
 
 
a 
In case of technical issues at the start of the run-in period, subjects are allowed to re-start e-Diary recording for cycle -2. 
b 
Blood samples for potential endometriosis biomarkers will be collected for all subjects. If subjects provide a separate informed 
consent, additional blood samples for potential analyses of circulating cell-free DNA and microRNA will also be collected.  
c 
If subjects provide a separate informed consent, a blood sample for pharmacogenetic analysis will be collected. 
d 
ECG and Echo at screening can be arranged anytime during cycle -1 (e.g. at visit 3) but results must be available before 
randomization. Echo at cycles 4 and 8 can be performed within ±2 weeks of visits 11 and 16, respectively.  
e 
Pain impact will be assessed on both a daily and a weekly basis. 
f 
Scoring of the worst endometriosis-related pain during the past menstrual cycle on the NRS will be performed on paper at the run-in 
visit. Daily scoring of endometriosis-related pain on the NRS is captured by e-Diary. 
g 
Visits on RM+7 or LH+7 can be scheduled RM+6-10 or LH+6-9, i.e. day 6 to day 10 of return of menses or 6-9 days after LH 
surge, respectively. PK visit (visit 5) can be arranged within 1-5 days of randomization (visit 4). 
Abbreviations: B&B=Biberoglu and Behrman Scale, BTM=bone turnover markers, E2=estradiol, Echo=echocardiography, ECG=electrocardiography, 
EHP-30=Endometriosis Health Profile-30 Questionnaire, LH=luteinizing hormone, LH+7=7 days after LH surge, NRS=Numerical Rating Scale, 
P4=progesterone, PGIC=Patient Global Impression of Change, PGIS=Patient Global Impression of Severity, PG=pharmacogenetic(s), 
PK=pharmacokinetic(s), QICD=questionnaire for impulsive-compulsive disorders, QVR=quinagolide vaginal ring, RM=return of menses, RM+7=day 7 of 
return of menses, TVU=transvaginal ultrasound 


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Screening: The screening period includes a wash-out period of approximately one month 
(only applicable to subjects currently using some hormonal products such as 
contraceptives) and a run-in period of two complete menstrual cycles (cycles -2 and -1, 
applicable to all subjects). Subjects who are currently using some hormonal products such 
as contraceptives may be eligible for the trial if they have completed the wash-out period. 
In this case, subjects need to sign the informed consent(s) before they discontinue those 
products. Discontinuation of the products should follow the labelling (e.g. completing the 
current cycle of contraceptives before wash-out). Subjects requiring wash-out will not be 
provided with the electronic diary (e-Diary) or rescue analgesics until the completion of 
the wash-out period, i.e. at the run-in visit.  
At the run-in visit, all subjects will be asked to score the worst endometriosis-related pain 
from a recall of their experience during the past menstrual cycle on a self-administered 11-
point Numerical Rating Scale (NRS) with 0 indicating “no pain” and 10 indicating “worst 
imaginable pain”. After standardized training of e-Diary use, eligible subjects will be 
instructed to record endometriosis-related pain, vaginal bleeding, occurrence of sexual 
intercourse and analgesic use in the e-Diary on a daily basis. Impact of endometriosis-
related pain on functioning will be assessed by subjects on both a daily and a weekly basis. 
In this trial, endometriosis-related pain is evaluated as the pain located in the abdominal-
pelvic area and the lower back area. During the run-in period, subjects will score the worst 
endometriosis-related pain during the preceding 24 hours on the NRS before bedtime every 
night in the e-Diary.   
Vaginal bleeding will be recorded as “yes” or “no” on a daily basis in the e-Diary. If there 
is vaginal bleeding, subjects will be asked to register their bleeding volume (spotting, light, 
moderate or heavy bleeding) and to answer whether they think the bleeding is related to 
menses or not. Based on the subject’s impression of whether she has menstrual bleeding or 
not, the NRS score obtained for the endometriosis-related pain is assigned to dysmenorrhea 
(endometriosis-related pain on days with menstrual bleeding) or to non-menstrual pelvic 
pain (endometriosis-related pain on days with no menstrual bleeding).  
Occurrence of sexual intercourse (“yes” or “no”) will also be recorded in the e-Diary. In 
case of sexual intercourse, subjects will be asked to score the worst pain experienced 
during or after intercourse (dyspareunia) on the NRS. In case of no sexual intercourse, 
subjects will be asked if it is due to expected pain.  
Rescue analgesics for endometriosis-related pain will be limited to ibuprofen and/or 
hydrocodone-acetaminophen in this trial. As a mild analgesic, ibuprofen will be provided 
to subjects in the form of 200 mg oral tablets for their use on an as-needed basis. Subjects 
will be instructed not to use other analgesics unless necessary. If there is a need to change 
analgesics, subjects should discuss with investigators, who may prescribe a strong 
analgesic, i.e. 5 mg hydrocodone plus 300 mg or 325 mg acetaminophen. Use of any other 


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analgesics for endometriosis-related pain is prohibited. Any prophylactic use of analgesics 
is also prohibited in this trial. Use of analgesics for endometriosis-related pain will be 
reported by subjects in the e-Diary on a daily basis.  
The impact of the endometriosis-related pain on different aspects of functioning will be 
assessed by subjects both on the NRS on a daily basis and by the modified EHP-30 pain 
impact domain (i.e. the first 11 items plus an additional work item) on a weekly basis (The 
secondary endpoint of changes in the weekly impact scores is based on the original EHP-
30 pain impact domain, i.e. the first 11 items. The additional work item is used only for 
validation.). 
Part A: Subjects will be randomized into Part A of the trial on RM+7 of cycle -1 (at visit 4) 
if they, during the run-in period have moderate to severe endometriosis-related pain, which 
is defined as having a mean daily NRS score of ≥4 for the worst endometriosis-related pain 
during each run-in menstrual cycle. Randomization will be performed in a 1:1:1:1 ratio to 
quinagolide vaginal ring dose load 360 µg at a target release rate of quinagolide 
4.5 µg/day, quinagolide vaginal ring dose load 720 µg at a target release rate of 
quinagolide 9 µg/day, quinagolide vaginal ring dose load 1080 µg at a target release rate of 
quinagolide 13.5 µg/day or placebo vaginal ring for four menstrual cycles (cycles 1, 2, 3 
and 4).  
Part B: Subjects who have received active treatment in Part A will continue with the same 
doses in Part B, and those who have received placebo vaginal ring in Part A will be re-
allocated in a pre-determined 1:1:1 ratio to quinagolide vaginal ring dose load 360 µg, 720 
µg or 1080 µg at a target release rate of quinagolide 4.5 µg/day, 9 µg/day or 13.5 µg/day, 
respectively, administered for four menstrual cycles in Part B (cycles 5, 6, 7 and 8).  
Follow-up: Subjects who complete both Part A and Part B will be followed up for two 
menstrual cycles (cycles 9 and 10). 
From randomization to follow-up (cycle 1 to cycle 10), subjects will continue to use an e-
Diary to score the endometriosis-related pain, to register vaginal bleeding pattern, 
occurrence of sexual intercourse and the analgesic use as well as to assess the impact of the 
worst endometriosis-related pain on functioning, as they have done in the run-in period.  
During the treatment period (Part A and Part B), subjects will self-insert the assigned ring 
in the upper part of the vagina on RM+7 of cycle 1 to cycle 8 at the clinic by following 
standard instructions for use. Supervision by the site staff can be provided if needed. After 
insertion, the vaginal ring will be kept in the vagina continuously for one menstrual cycle 
until being replaced with the next ring on RM+7 of the next cycle when the subject visits 
the clinic. Acceptability of the ring will be assessed by subjects via a ring acceptability 
questionnaire at each RM+7 visit during the treatment period. Unless under other effective 
birth control permitted by protocol, subjects will be required to use a non-hormonal single-


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barrier contraception (i.e. condom) from wash-out (if applicable) or run-in to end-of-trial. 
Contraception counselling and condoms will be offered to subjects throughout the trial.  
B&B will be administered electronically at randomization, at cycles 4 and 8, with trained 
trial coordinators completing the first part based on subjects’ verbal responses and 
investigators completing the second part based on findings of a pelvic examination. 
Subjects will complete the electronic version of the EHP-30 questionnaire at 
randomization, and at every cycle from cycle 1 to cycle 8. PGIS scale will be completed 
electronically by subjects at cycle -2, at randomization and at cycles 4 and 8, while PGIC 
scale will be completed electronically at cycles 4 and 8. 
Blood samples will be collected throughout the trial for the purpose of evaluating mid-
luteal phase endocrine parameters, bone turnover markers, endometriosis biomarkers, 
quinagolide and metabolites, and routine safety laboratory parameters. In this trial, mid-
luteal phase is defined as 6-9 days after luteinizing hormone (LH) surge (LH+6-9) as tested 
by subjects at home by means of commercially available urinary LH kits. LH+7 visits can 
be scheduled on LH+6-9, either based on an actual LH surge date as indicated by a positive 
LH surge test or based on an estimated LH surge date according to subjects’ cycle length if 
subjects fail to detect the LH surge. The exact cycle day of the LH+7 visit will be derived 
based on the first menstrual bleeding date of the current cycle confirmed at the RM+7 
visits. A full endocrine panel including estradiol, progesterone, prolactin, TSH and IGF-1 
will be assessed at the mid-luteal phase of cycles -1, 1, 4, 8 and 10. Evidence of ovulation 
will be evaluated by serum levels of mid-luteal progesterone. A partial endocrine panel 
consisting of estradiol and progesterone only will also be assessed at RM+7 visits of cycles 
4 and 8. Fasting blood samples for the analysis of a bone formation marker (s-PINP) and a 
bone resorption marker (s-CTx) will be collected during cycles -1, 4 and 8. Blood samples 
for endometriosis biomarkers including, but not limited to, VEGF, PlGF, IL-6 and sFlt-1 
will be collected during cycles -1, 4, and 8. At the same time points, if subjects have 
provided a separate informed consent, additional blood samples for potential analyses of 
circulating cell-free DNA and microRNA will also be collected. Routine safety laboratory 
tests for clinical chemistry and hematology parameters will be performed during cycles -1, 
4, 8 and 10. Quinagolide and metabolites will be measured within 1-5 days of first ring 
insertion, at both LH+7 visits and RM+7 visits of cycles 1, 4 and 8 as well as at RM+7 
visits of cycles 3 and 7. Blood samples should be taken prior to ring removal at RM+7 
visits. If subjects have provided a separate informed consent, a blood sample for 
pharmacogenetic analysis will also be collected.    
ECG and echocardiography will be performed to monitor cardiovascular safety. ECG will 
be assessed prior to randomization during cycle -1, at cycles 4 and 8 (prior to or at visit 4, 
at visits 11 and 16). ECG must be performed after vital signs but before blood sampling as 
applicable. ECG and echocardiography at screening can be arranged anytime during cycle 
-1, e.g. at LH+7 visit but results must be available prior to randomization. 


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Echocardiography at cycles 4 and 8 can be performed within ±2 weeks of end-of-cycle 4 
visit and end-of-cycle 8 visit, respectively.  
A modified questionnaire for impulsive-compulsive disorders will be completed 
electronically by trained trial coordinators based on subjects’ verbal response prior to 
randomization at cycle -1, at cycles 4 and 8.  
A urine pregnancy test will be performed at each clinic visit (except for the PK visit during 
cycle 1) throughout the trial. If the test result is positive and is confirmed by a following 
serum βhCG test, the subject should be discontinued from the trial. Urinalysis is performed 
at the run-in visit, at cycles 4 and 8.  
The self-assessments of NRS, occurrence of sexual intercourse, the impact of pain, vaginal 
bleeding and analgesics use will be done by the subjects in the e-Diary. The daily e-Diary 
should be completed by the subjects before bedtime every night throughout the trial that is 
from visit 1 until the end-of-trial visit. Additional assessments of pain impact will be done 
in the weekly e-Diary. The weekly e-Diary should be completed at the end of each week 
throughout the trial that is from visit 1 to end-of-trial visit.  
3.2 
General Design Considerations 
3.3 
Determination of Sample Size 
The sample size calculation is based on demonstrating superiority of Quinagolide vaginal 
ring compared with placebo vaginal ring on the primary endpoint of the change in mean 
daily NRS score for endometriosis-related pain at cycle 4. Taking into account of an 
interim analysis for futility at a conditional power of 5% (see section 11) and assuming that 
the standard deviation of the change in mean daily NRS is 1.5, a sample size of 52 
evaluable subjects per group (in total 208 subjects) will have at least 90% power to detect a 
treatment effect difference of 1.0 unit using a t-test at a 5% two-sided significance level in 
a pre-defined hierarchical step-down procedure, starting with testing the highest dose 
versus placebo. Accounting for a 25% drop-out rate as observed in a previous trial there 
should be 70 subjects randomized to each treatment group and in total 280 subjects should 
be randomized. Table 3-1 summarizes the required sample size per group for different 
assumptions of treatment effect difference and power.  


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Table 3-1 
Sample Size by Treatment Effect Difference 
Difference in NRS score reduction 
between  
quinagolide vaginal ring the highest 
dose group and placebo vaginal ring 
group 
Number of subjects per group a 
Evaluable subjects  
Randomized subjects b 
Power 
80% 
Power 
90% 
Power 
80% 
Power 90% 
0.8 
60 
80 
80 
107 
0.9 
48 
64 
64 
86 
1.0 
40 
52 
54 
70 
1.1 
32 
44 
43 
59 
1.2 
28 
36 
38 
48 
a 
Assuming a standard deviation of 1.5 units and accounting for an interim analysis for futility at a conditional power at current trend 
of 5%. 
b 
Assuming 25% drop-out rate. 
 
A sample size re-estimation was planned to be performed at the same time of the interim 
analysis based on the observed standard deviation and drop-out pattern. The sample size 
could have been increased to 360 subjects in total or 90 subjects per group. 
 


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4 
Subject Disposition 
For the reporting of subject disposition with regard to the Per-Protocol (PP) analysis set the 
definition of being excluded from the PP population is if the subjects cycle 4 data is 
exclude from the PP analysis set.  
4.1 
Screened subjects 
Screened subjects who discontinue prior to randomization are regarded as screening 
failures. All subjects screened will be accounted for (in total and by trial site). The total 
number of screened subjects will be summarized (n and % of total number of screened 
subjects) by: randomized, reason for failure (inclusion /exclusion not met, withdrawal by 
subject, other) and all. 
4.2 
 Subject disposition 
Subject disposition with respect to analysis sets (Safety, ITT, and PP) will be summarized 
by treatment. 
4.3 
Subject disposition and completion 
Subject disposition with respect to analysis sets (Safety, ITT, and PP) and completion of 
treatment and follow-up will be summarized. Completion of treatment will be based on the 
end of treatment form and the timing of the potential discontinuation (is end-of cycle 4 
visit performed or not), and completion of follow-up will be based on the end of trial form. 
4.4 
Subject completion/discontinuation  
Completion of treatment, and follow-up will be defined as in the subsection 4.3.  
Based on the ITT analysis set subjects completion by end of treatment and follow up, will 
be summarised: completed, discontinued (primary reason for discontinuation according to 
end of treatment form), by treatment.  
4.5 
Listing  
The subjects screened but not randomized/allocated to treatment will be presented with the 
reason(s) for screen failure in a data listing. 
Based on the ITT analysis set subject disposition with respect to analysis sets will be listed 
sorted by site, treatment and subject. Subjects who discontinued from the trial will be listed 
sorted by site, treatment, and subject including information on timing of and reason for 
discontinuation. 


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5 
Protocol Deviations 
Protocol deviations will be rated as either minor or major. Protocol deviations impacting 
the primary endpoint and thereby affecting the conclusions of the trial will in this SAP be 
rated as major. Major protocol deviations will lead to exclusion of data from the PP 
analysis set. Data will not be excluded from the data analysis in case of minor protocol 
deviations. 
The list of major protocol deviations includes, but is not restricted to: 
• Treatment received not in accordance with randomization (only data after the 
occurrence of the mistake to be deleted) 
• Non-compliance with IMP treatment regimen for >20% of days during a non-menstrual 
period (only data after the first occurrence of non-compliance to be deleted) 
• Missing >20% of days of e-Diary recordings during a menstrual cycle (only data of this 
cycle to be deleted from the respective by-cycle PP analysis) 
• Use of prohibited analgesics for >1 day during a menstrual cycle (only data of this 
cycle to be deleted from the respective by-cycle PP analysis) 
 
Unforeseen deviations deemed to impact the primary endpoint of the trial may additionally 
be rated as major protocol deviations by the Ferring clinical team on the basis of a blinded 
review of data before declaration of clean-file and lock of database.  
The list of major protocol deviations will be detailed and documented in the clean file 
document prior to database release.  
5.1 
Major protocol deviations 
Based on the ITT analysis set major protocol violations will be summarized (n and %) for 
each category of protocol violation, by treatment and in total. 
5.2 
Listing  
Based on the ITT analysis set subjects with minor or major protocol deviations will be 
listed and the list will be sorted by site, treatment and subject number. The listing will 
include category and description of protocol deviation.  
 


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6 
Analysis Sets 
6.1 
Intention-To-Treat Analysis Set 
The intention-to-treat (ITT) analysis set comprises of all randomized subjects. Treatment 
assignment for summaries and analyses are according to planned treatment.    
6.2 
Per Protocol Analysis Set 
The PP analysis set is defined as all data from the ITT analysis set except data excluded 
due to major protocol deviations as defined in section 5. As defined in section 5 some 
protocol violations will lead to exclusion of parts of a subject’s data, not the entire subject.  
6.3 
Safety Analysis Set  
The safety analysis set comprises all treated subjects and are analysed according to the 
actual treatment received. If more than one treatment is received the highest dose of 
Quinagolide will be used.    


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7 
Trial Population 
Unless otherwise specified all tables and listing in this section will be based on the ITT 
analysis set.  
All summaries in this section will be presented by treatments and a total column 
Categorical data will be summarised using numbers and percentages in addition to the sum 
‘all’. The percentages are based on the total number of subjects with a corresponding 
assessment. Continuous data will be presented, using the number of subjects (n), mean and 
standard deviation, median, 25th percentile, 75th percentile, minimum and maximum.  
7.1 
Demographics and Other Baseline Characteristics 
7.1.1 Demographics and body measurements 
Baseline demographics variables (age, race and ethnic origin, height, weight and BMI) will 
be summarized. 
7.1.2 Vital Signs at Baseline 
Baseline (visit 4) vital signs will be summarised as described in section 10.4.1.   
7.1.3 History of Disease 
The worst endometriosis-related pain on the NRS based on a recall of experience in the 
past menstrual cycle will be summarized as a categorical variable.  
Endometriosis initial diagnosis (time since initial diagnosis, method, stage and 
documentation of histology of biopsy) will be summarised.  
Endometriosis surgical history (Any history (yes/no), time since, method and type of 
surgery) will be summarised.  
Menstrual history and reproductive history will be summarised.  
7.2 
Medical History 
Medical history recorded at screening visit will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) version 20.0. 


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Medical history will be summarised by system organ class (SOC) sorted alphabetically and 
preferred term (PT) sorted in decreasing frequency of occurrence.  
Ongoing and past medical history will be reported separately and the number of subjects 
with any ongoing or past medical history will be included. 
7.3 
Prior and Concomitant Medication 
Prior and concomitant medication will be summarised by ATC classification 1st level 
(alphabetically), ATC classification 2nd level (in decreasing order of frequency) and 
treatment group. These medications will be tabulated separately for: 
1) Prior medication; i.e. medication taken exclusively prior to treatment (i.e. with stop 
date before date of first ring insertion);   
2) Concomitant medication, i.e. medication taken during the treatment period (i.e. 
medication that was not stopped before date of first ring insertion and not started 
after the last ring removal.  
3) Post-treatment medications, i.e. medications starting after the treatment period (i.e. 
with start after the last IMP removal).  
The number of subjects with “any medication” will be included in these tables. If the 
timing of the dose of a concomitant medication cannot be established in relation to the 
administration of IMP, it will be considered as concomitant medication. 
7.4 
Physical Examination 
Subjects with abnormalities at any screening, or post-baseline visit will be listed with all 
physical examination evaluations.  
7.5 
Listings  
Baseline characteristic not listed elsewhere will be listed sorted by site treatment and 
subject number. 
Medical history will be listed sorted by site treatment subject number, SOC and PT. 
All medications will be listed by site treatment, subject number, start date, ATC level 1 and 
ATC level 2. 


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8 
Exposure and Treatment Compliance 
All tables in this section will be based on the ITT analysis set.  
Categorical data will be summarised using numbers and percentages in addition to the sum 
‘all’, the percentages are based on the total number of subjects with a corresponding 
assessment. Continuous data will be presented, using the number of subjects (n), mean and 
standard deviation, median, 25th percentile, 75th percentile, minimum and maximum.  
8.1.1 Extent of Exposure  
Total extent of exposure will be summarised. Total extent of exposure will be based on 
information from the vaginal ring administration log. For part A, the total extent of 
exposure will be the date of ring removal at the end of cycle 4 visit  (if this visit  is not 
performed or if no ring removal is performed at this visit  the last date of ring removal is 
used) minus the date of the first ring insertion. For part B the extent of exposure will only 
be defined if the subject has completed part A and initiated part B (part A is considered 
completed if end-of cycle 4 visit is performed, part B is considered initiated if a ring is 
inserted at end-of-cycle 4 visit). The extent of exposure in part B is defined as the date of 
the last ring removal minus the date of end-of-cycle 4 visit.  
Extent of exposure for each cycle (cycle 1 to 8) will also be summarised. Extent of 
exposure for each cycle will as above be calculated as the difference in ring removal dates 
and insertion dates.   
8.1.2 Treatment Compliance  
The treatment compliance in percent will be summarised. Treatment compliance will be 
based on information about missed dose from the medication errors log.  
The compliance percent will be calculated as 100 times the ratio between the number of 
days exposed to the ring and the expected number of days exposed to the ring.  
For part A: The expected number of days exposed to the ring is; if the subjects completes 
part A the date of end-of-cycle 4 visit  minus the date the first ring insertion; and if the 
subject discontinues treatment during part A the date of discontinuation minus the date of 
visit 4. The number of days exposed to the ring is calculated as the expected number of 
days minus the number of days with missed dose between visit 4 and end-of cycle 4 visit 
(or if the subject discontinues during part A between visit 4 and date of discontinuation).  
For part B: The expected number of days exposed to the ring is, if the subjects completes 
part B the date of end-of-cycle 8 visit minus the date of end-of-cycle 4 visit, and if the 
subject discontinues treatment during part B the date of discontinuation minus the date of 


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end-of cycle 4 visit. The number of days exposed to the ring is calculated as the expected 
number of days minus the number of days with missed dose between end-of cycle 4 visit 
and end-of-cycle 8 visit (or if the subject discontinues during part B between end-of-cycle 
4 visit and date of discontinuation).  
Non-compliance with IMP treatment regimen for >20% of days during a non-menstrual 
period, as defined as a protocol deviation in section 5 will be summarised for each cycle. 
8.1.3 Listings 
Based on the safety analysis set subjects the exposure data from the vaginal ring 
administration log and the medication errors log will be listed and the list will be sorted by 
site, treatment, subject number, and date. The listing will include information on dose, 
dates of insertion and removals, and type and timing of medication error. 


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9 
Efficacy 
9.1 
Transformation of daily e-Diary data 
Subjects will be ask to fill in the daily e-Diary every day from visit 1 to end-of-trial visit. 
Every night between 8 pm and 2 am the subject should answer the following question: 
Instructions and the question to be answered are: 
Please think about the worst endometriosis-related pain you experienced in the past 24 
hours and rate it on a scale from 0 to 10 where 0 is ‘no pain’ and 10 is ‘worst imaginable 
pain’. Please do not include pain from sexual intercourse. 
1. Please rate your worst endometriosis-related pain in the past 24 hours (including pelvic 
pain, abdominal pain, or lower back pain, whichever is the worst).   
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
pain  
 
 
 
 
 
 
 
 
 
Worst 
imaginable 
pain 
 
2. Did you have sexual intercourse in the past 24 hours?  
 No  
 Yes  
 
If the subject did not have sexual intercourse in the past 24 hours: 
3. Did you avoid sexual intercourse in the past 24 hours because of expected 
endometriosis-related pain?  
 No  
 Yes 
 
If the subject had sexual intercourse in the past 24 hours: 
4. Please rate your worst pain during or after sexual intercourse in the past 24 hours. 
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
pain  
 
 
 
 
 
 
 
 
 
Worst 
imaginable 
pain 
 
5. How did your endometriosis-related pain limit your sitting, standing and walking in the 
past 24 hours?  


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 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
limitations 
on 
activities  
 
 
 
 
 
 
 
 
 
Unable  
to do 
activities 
 
6. How did your endometriosis-related pain limit your daily activities around the house, 
such as doing chores, laundry, cooking, washing dishes, or cleaning in the past 24 hours?  
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
limitations 
on 
activities  
 
 
 
 
 
 
 
 
 
Unable  
to do 
activities 
 
7. How did your endometriosis-related pain limit your work/school in the past 24 hours?  
  Not applicable, no work or school in the past 24 hours. 
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
limitations 
on 
activities  
 
 
 
 
 
 
 
 
 
Unable  
to do 
activities 
 
8. How did your endometriosis-related pain limit your social activities with family or 
friends in the past 24 hours?  
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
limitations 
on 
activities  
 
 
 
 
 
 
 
 
 
Unable  
to do 
activities 
 
9. Did you have vaginal bleeding in the past 24 hours?   
 No   
 Yes 
   
If the subject had vaginal bleeding in the past 24 hours: 
10. Please describe your bleeding in the past 24 hours.  
 Spotting (tiny amount of blood on underwear or panty liners) 
 Light (requiring 1-3 sanitary pads or tampons per day) 


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 Moderate (requiring 4-6 sanitary pads or tampons per day) 
 Heavy (requiring more than 6 sanitary pads or tampons per day) 
 
11. Was your bleeding related to your period (i.e., menstrual bleeding)?  
 No  
      Yes 
 
12. Have you taken any medication to reduce your endometriosis-related pain in the past 
24 hours? 
 No  
 Yes 
 
13. Which medication did you take for your endometriosis-related pain in the past 24 
hours? Please answer “No” or “Yes” for each medication listed below.  
MOTRIN 200 mg 
 No 
 Yes 
Hydrocodone-acetaminophen (prescribed) 
 No 
 Yes 
Other 
 No 
 Yes  
The subjects will be asked to specify the number of tablets taken for each medication where 
“yes” is selected: “Please specify the number of tablets you took.”  
<An arrow spin will be available to list the number of tablets for each medication where 
“yes” is ticked.> 
 
If the subject did not answer the diary yesterday: 
14. Please let us know why you did not complete the diary yesterday.  
 I was in too much pain from endometriosis 
 I forgot 
 Other reason  
9.1.1 Definition of cycles  
The e-Diary entries will be assigned to cycles in the following way. 
The duration of cycle -2 is based on the menstruation dates log at visit 1 and visit 2. The 
date of the first day that belongs to cycle -2 is the start date of menses in the current cycle 
from visit 1 +7 days (note that if visit 1 is performed before this date there will be e-Diaries 
not assigned to a cycle, and if visit 1 is performed after this date there will be days in cycle 
-2 without an e-Diary). The last day that belongs to cycle -2 is the start date of menses in 
the current cycle from visit 2 +6 days.  


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The duration of the other cycles are defined in a similar way. The duration of cycle -1 is 
based on the menstruation dates log at visit 2 and visit 4. The duration of cycle 1 is based 
on the menstruation dates log at visit 4 and end-of-cycle 1 visit , and equivalently for cycle 
2 to 10.If the start date of menses in the current cycle is missing at a visit, due to that the 
subject did not have menstrual bleeding just prior to that visit (the RM+7 visit in a cycle 
must be arranged within 35 days of the last RM+7 visit regardless of the subject has had 
menses). Then the two cycles from the RM+7 of previous, cycle to RM+7 of next cycle 
will be divided in two equally long cycles. E.g. if start date of menses in the current cycle 
is missing at end-of-cycle 2 visit (due to that the subject did not report menses), then cycle 
2 will end and cycle 3 begin half way between start date of menses in the current cycle 
from end-of-cycle 1 visit and end-of-cycle 3 plus 7 days.  
If the start date of menses in the current cycle in the menstruation log is missing for any 
other reason than the one mentioned above. Then the first date in that cycle where the 
subject answers yes to both question 9 and 11 in the e-Diary will be used instead. 
9.1.2 Definition of menstrual period and non-menstrual period 
Each cycle is divided into a menstrual period and a non-menstrual period, unless the 
subject does not have a menstrual bleeding during that cycle (see section 9.1.1), then the 
entire cycle will be considered non-menstrual.  
The first day of menses is based on the start date of menses in the current cycle from the 
menstruation dates log. If this is missing for any other reason than the subject did not have 
menses in this cycle, then the first day in that cycle where the subject answers yes to both 
question 9 and 11 in the e-Diary will be used instead. 
The last day of menses is based on the stop date of menses in the current cycle from the 
menstruation dates log. If the subject does have menses and the stop date is missing then 
the first day where the subject answers no to either question 9 or 11 in the e-Diary will be 
used instead. Note that the last day of menses could be in the next cycle relative to the first 
day of menses.  
The menstrual period is defined as the period from the first day of menses to the last day of 
menses, both included.  
The menstrual period of a cycle consists of the bleeding period in the end of the cycle plus 
the potential bleeding part in the beginning of the cycle. If a subject does not bleed in the 
end of the cycle, the entire cycles will be considered non-menstrual. 
The non-menstrual part of the cycle is defined as the part of the cycle that is not considered 
the menstrual part. 


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9.1.3 Missing data for daily worst endometriosis-related pain question 
If the subject do not complete the daily diary, then the day after the subject will be asked 
question 14 in the e-Diary. If the answer to question 14 is “I was in too much pain from 
endometriosis”, the missing data for the previous day will be assigned a NRS of 10 for 
worst endometriosis-related pain (taking a worst-case approach). Otherwise, the daily score 
remains to be missing. 
9.1.4 The mean daily NRS score  
The baseline value for the mean daily NRS scores is defined as the average of the mean 
daily NRS scores of the two run-in cycles (cycles -2 and -1). For all post baseline cycles 
(cycles 1 to 10) the change in the mean daily NRS scores from baseline will be calculated 
using this definition of the baseline value.  
9.1.4.1 The mean daily NRS score for worst endometriosis related pain 
For each cycle, at least 50% of the NRS scores are required to be observed (including the 
imputed values as described in subsection 9.1.3) for both the menstrual period and the non-
menstrual period (as defined in subsection 9.1.2) to be allowed to calculate the mean daily 
NRS score for that particular cycle. So if above 50% of the daily NRS scores are missing 
in either period of that cycle, the mean daily NRS score for worst endometriosis related 
pain for that cycle should be missing.  
As missing daily NRS scores may not be appropriately balanced across menstrual period 
and non-menstrual period, the mean daily NRS score will be weighted by the lengths of the 
menstrual period and non-menstrual period to adjust for this potential imbalance.   
So the mean daily NRS score is calculated as  
mp
non
mp
mp
non
mp
non
mp
mp
l
l
x
l
x
l
−
−
−
+
+
 
 
Where mp
l
is the number of days in the menstrual period of the cycle (as defined in 
subsection 9.1.2), 
mp
non
l
−
is the number of days in the non-menstrual period of the cycle in 
question (as defined in subsection 9.1.2), 
mp
x
is the mean daily NRS score based on the 
observed daily NRS scores (question 1) during the menstrual period (including imputations 
as described in 9.1.3), and 
mp
non
x
−
is the mean daily NRS score (question 1) based on the 
observed daily NRS scores during the non-menstrual period (including imputations as 
described in 9.1.3).  


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If the subject does not have a menstrual period in a cycle the mean daily score is calculated 
as a simple mean, however if more than 50% of the daily NRS scores are missing the mean 
daily NRS will be considered missing 
9.1.4.2 The mean daily NRS score for worst dysmenorrhea 
For each cycle the mean daily NRS score for worst dysmenorrhea is defined as the mean 
daily NRS score for worst endometriosis related pain (question 1) during the menstrual 
period of that cycle (as defined in subsection 9.1.2).  
If above 50% of the daily NRS scores in the menstrual period of a cycle are missing, the 
mean daily NRS score for worst dysmenorrhea for that cycle should be missing.  
9.1.4.3 The mean daily NRS score for worst non-menstrual pelvic pain 
For each cycle the mean daily NRS score for worst non-menstrual pelvic pain is defined as 
the mean daily NRS score for worst endometriosis related pain (question 1) during the non-
menstrual period of that cycle (as defined in subsection 9.1.2).  
If above 50% of the daily NRS scores in the non-menstrual period of a cycle are missing, 
the mean daily NRS score for worst non-menstrual pelvic pain for that cycle should be 
missing.  
9.1.4.4 The mean daily NRS score for worst impact of endometriosis related pain on 
the subject ability to function 
The mean daily NRS score for worst impact of endometriosis related pain on the subject 
ability to function will be based on the mean of question 5 to 8. The mean daily NRS score 
will be calculated if the mean daily NRS score for worst endometriosis related pain is 
calculated, it will be calculated using the same weighting scheme as used in section 
9.1.4.1.  
9.1.5 Analgesics use  
Analgesic use will be used both as an endpoint by itself and as an adjustment variable for 
other endpoints. The baseline value for different measures of analgesics use is defined as 
the average of that measure in cycles -2 and -1.  


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9.1.5.1 Percentage of days with analgesics use  
The percentage of days with analgesics use will be calculated for each cycle and separately 
for mild analgesics, strong analgesics and any analgesics. If the mean daily NRS score for 
worst endometriosis related pain is not calculated for a specific cycle due to many missing 
daily e-Diaries, then the three percentage of days with analgesics should not be calculated 
either. 
The percentage of days with mild analgesics use is based on the first part of question 13. 
The percentage of days with strong analgesics use is based on the second part of question 
13. The percentage of days with any analgesics use is based on both the first and the 
second part of question 13. 
For adjustment of the secondary endpoints worst dysmenorrhea and worst non-menstrual 
pelvic pain similar variables will be needed for mild and strong analgesics just only using 
data from the e-Diary from the menstrual period and non-menstrual period of the cycle, 
respectively. If the mean daily NRS for worst dysmenorrhea or worst non-menstrual pelvic 
pain is not calculated due to to many missing variables the corresponding percentage of 
days with mild analgesics should not be calculated either. 
9.1.5.2 Total and average doses of analgesics 
For each cycle the total dose of mild analgesics is calculated by summing the daily doses 
from the first part of question 13 (if the answer is no, then the dose is 0 mg). For each cycle 
the total dose of strong analgesics is calculated by summing the daily doses from the 
second part of question 13 (if the answer is no, then the dose is 0 mg). The average doses 
are calculated as the total dose divided by the number of times question 13 has been 
answered during that cycle. 
The total and average doses will be calculated if the mean daily NRS score for worst 
endometriosis related pain is calculated, it will be calculated using the weighting scheme as 
described in section 9.1.4.1.  
9.1.6 Responder status  
Twelve different definitions of responder status are being used in this trial, one for each 
combination of the 4 mean daily NRS score defined in section 9.1.4 and the 3 thresholds 
≥30%, ≥50% and ≥70%.  
A subject is defined as being a responder in a specific cycle if the mean daily NRS score is 
reduced with at least the threshold value compared to baseline and that the percentage of 
days on any analgesics has not increased by more than 10% since baseline. 


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9.1.7 Dyspareunia 
9.1.7.1 The mean daily NRS score for worst dyspareunia 
For each cycle, the mean daily NRS score for worst dyspareunia is calculated as the mean 
of the worst pain during or after sexual intercourse (question 4) for that cycle. There are no 
minimal requirements on the number of times question 4 is answer for the mean to be 
calculated. 
9.1.7.2 Frequency of avoiding sexual intercourse  
For the analysis of frequency of avoiding sexual intercourse, two variables are needed, 
firstly the number of days during that cycle that the subject avoids sexual intercourse 
because of expected pain (that is how many times the subject answers yes to question 3) is 
needed. Secondly the number of days during that cycle that the subject does not avoid 
having sexual intercourse because of expected pain (that is how many times the subject 
answers yes to question 2 or no to question 3) is needed.  
9.1.8 Vaginal bleeding pattern 
The vaginal bleeding pattern is evaluated as the number of days per cycle with no bleeding, 
spotting, light bleeding, moderate bleeding and heavy bleeding days, respectively. 
Additionally the duration of menstrual and non-menstrual period, and the number of 
bleeding days during the non-menstrual period, will be calculated. 
9.2 
Transformation of weekly e-Diary data 
Subjects will be asked to fill in the weekly e-Diary every week from visit 1 to end-of-trial 
visit. Every week between Sunday 8 pm and Tuesday 2 am the subject should answer the 
following question: 


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Instructions and the question to be answered are: 
During the last week, because of your endometriosis, how often have you... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
1. Been unable to go to social events 
because of the pain? 
 
 
 
 
 
2. Been unable to do jobs around the 
house because of the pain? 
 
 
 
 
 
3. Found it difficult to stand because of 
the pain? 
 
 
 
 
 
4. Found it difficult to sit because of the 
pain? 
 
 
 
 
 
5. Found it difficult to walk because of 
the pain? 
 
 
 
 
 
6. Found it difficult to exercise or do the 
leisure activities you would like to do 
because of the pain? 
 
 
 
 
 
7. Lost your appetite and/or been 
unable to eat because of the pain? 
 
 
 
 
 
8. Been unable to sleep properly 
because of the pain? 
 
 
 
 
 
9. Had to go to bed/lie down because 
of the pain? 
 
 
 
 
 
10. Been unable to do the things you 
want because of the pain? 
 
 
 
 
 
11. Felt unable to cope with the pain? 
 
 
 
 
 
12. Been unable to do jobs around the 
house, at work, or at school because of 
the pain? 
 
 
 
 
 
 
The additional work item (Question 12) will only be used for validation of the weekly e-
Diary. The secondary endpoint of changes in the weekly pain impact scores will be based 
on the original EHP-30 pain impact domain, i.e. the first 11 items.  
The weekly EHP-30 pain impact score will be calculated based on question 1 to 11 in the 
following way, a raw score will be calculated as the sum of scores from each question were 
an answer of never will be scored as 0, rarely as 1, sometimes as 2,  often as 3, and always 
as 4. This raw score will then be multiplied with 100 and divided by 44, (So that the score 
will be between 0 and 100, 0 indicating the best health status and 100 the worst health 
status).  


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The weekly EHP-30 pain impact score will assigned to cycles in the following way. The 
week mentioned in the questionnaire as last week will be regarded as the week starting on 
a Monday and ending on the Sunday where the questionnaire is opened for access, both 
days included. The weekly score will be assigned to the cycle that cover most of that week. 
So if the first day of the current cycle (the cycle that includes the Sunday where the 
questionnaire is opened for access) is on the Thursday of that week or before the week will 
be assigned to the current cycle. If the first day of the current cycle is on the Friday of that 
week or later the week will be assigned to the previous cycle.   
The mean weekly score is calculated as a simple mean of the weekly scores assigned to 
that cycle. The mean weekly scores will be calculated as long at least one weekly score is 
not missing. The baseline weekly score is the average of the two mean weekly scores from 
cycle -2 and cycle -1. 
9.3 
General Considerations 
All efficacy endpoints will be summarised by treatment using descriptive statistics. 
Categorical data will be summarised using numbers and percentages (n and % of all 
observed) in addition to the sum ‘All’, the percentages are based on the total number of 
subjects with a corresponding assessment in the analysis set. Continuous data will be 
presented, using the number of subjects (n), mean and standard deviation, median, 25th 
percentile, 75th percentile, minimum, and maximum. The primary endpoint will be 
summarized using both the ITT population and the PP population, all other endpoints will 
be summarized using only the ITT population. 
As the trial has been prematurely discontinued, it has been decided, due to the low number 
of subjects, that no statistical analysis will be performed, see section 1 and 12. 
9.3.1 Efficacy and exploratory endpoints 
For the primary endpoint, each of the secondary, and each of the exploratory endpoints 
mentioned in Table 9-1 the absolute value at baseline  and the absolute value at cycle 1 to 4 
(if appropriate), and the change from baseline at cycles 1 to 4 (if appropriate) will be 
summarised by treatment.  


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Table 9-1 Efficacy and Exploratory Endpoints 
Endpoint 
Changes in the mean daily NRS scores for the worst endometriosis-related pain at cycle 4 
Changes in the mean daily NRS scores for the worst endometriosis-related pain over 8 menstrual cycles 
Changes in the mean daily NRS scores for the worst dysmenorrhea and for the worst non-menstrual pelvic 
pain over 8 menstrual cycles  
Changes in the mean daily NRS scores for the worst dyspareunia on days with sexual intercourse over 
8 menstrual cycles 
Frequency of avoiding sexual intercourse due to expected pain over 8 menstrual cycles 
Changes in the mean daily NRS scores for the worst impact of endometriosis-related pain on the subject’s 
ability to function over 8 menstrual cycles 
Changes in the mean weekly scores of the EHP-30 pain impact domain over 8 menstrual cycles 
Changes in vaginal bleeding pattern over 8 menstrual cycles  
Percentage of days with mild and/or strong rescue analgesics used over 8 menstrual cycles 
Total and average doses of mild and/or strong rescue analgesics used over 8 menstrual cycles 
Responder rate assessed as ≥30%, ≥50% and ≥70% reduction from the baseline in mean daily NRS scores 
for the worst endometriosis-related pain, dysmenorrhea, non-menstrual pelvic pain and for the worst 
endometriosis-related pain impact over 8 menstrual cycles 
Changes in the mean individual and total symptom and sign severity scores of the B&B scale at cycles 4 
and 8  
Changes in EHP-30 scores over 8 menstrual cycles  
Changes in PGIS scores at cycles 4 and 8   
PGIC scores at cycles 4 and 8  
Serum levels of mid-luteal phase progesterone f, estradiol, prolactin, TSH and IGF-1 at cycles 4   
 
9.4 
Analysis of Pharmacokinetics 
The pharmacokinetic data will be reported elsewhere.  
 


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10 Safety 
10.1 General Considerations 
Safety parameters will be evaluated for the safety analysis data set. 
All safety summaries will be performed by treatment: 
For adverse events (AE) and concomitant medications the following rules will apply;  
Treatment period 
AE and concomitant medications to be included 
Part A  
Start after start of IMP, and start date before or equal to the date 
of the end-of-cycle 4 visit, if missing use date of premature 
discontinuation  
Part B  
Start date after the date of the end-of-cycle 4visit and before or 
equal to date last ring removal, if missing use date of premature 
discontinuation. 
 
10.2 Adverse Events 
AEs are classified according to MedDRA version 20.0. 
Written narratives will be issued for all serious AEs (including deaths) and AEs leading to 
withdrawal. 
A pre-treatment adverse event is any adverse event occurring after signed informed 
consent and before start of IMP or a pre-existing condition that worsens in intensity after 
signed informed consent but before start of IMP. Pre-treatment AEs will be presented in a 
separate data listing only.  
A treatment-emergent adverse event (TEAE) is any adverse event occurring after start of 
IMP and before the end-of-trial visit, or a pre-treatment adverse event or pre-existing 
medical condition that worsens in intensity after start of IMP and before the end-of-trial 
visit. 
10.2.1 Overview of Treatment-Emergent Adverse Events 
An AE overview summary table will be prepared including the number of subjects 
reporting an AE, the percentage of subjects (%) with an AE, and the number of events (E) 
reported, for the following categories:  
• All TEAEs 


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• TEAEs leading to Deaths  
• Serious TEAEs  
• TEAEs leading to withdrawal  
• Adverse drug reactions (as assessed by investigator) 
• Serious Adverse drug reactions 
10.2.2 Incidence of Adverse Events 
Treatment-emergent adverse events will be summarised 
The tables will display the total number of subjects reporting an AE, the percentage of 
subjects (%) with an AE, and the number of events (E) reported. AEs will be presented by 
SOC sorted alphabetically and PT sorted in decreasing frequency of occurrence. 
Summary tables will be prepared for: 
• All treatment emergent adverse events 
• Treatment emergent adverse events with an incidence ≥ 5% of subjects in any 
treatment group 
• Treatment emergent related adverse events  
• Treatment emergent related serious adverse events  
• Treatment emergent non serious adverse events with an incidence ≥ 5% of subjects 
in any treatment group 
• Treatment emergent unrelated adverse events 
• Treatment emergent adverse events leading to death 
• Treatment emergent adverse events leading to withdrawal  
• Treatment emergent mild adverse events 
• Treatment emergent moderate adverse events  
• Treatment emergent severe adverse events  
• Treatment emergent related mild adverse events 
• Treatment emergent related moderate adverse events  
• Treatment emergent related severe adverse events  
• Treatment emergent serious adverse events  
 
Supporting data listings will be provided for: 
• All adverse events sorted by centre and subject no. 
• All adverse events sorted by MedDRA Preferred Term 
• Serious adverse events  
• Adverse events leading to death 
• Adverse events leading to withdrawal.  


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The listings will include information whether the AE occurred during the COVID-19 trial 
hold. 
10.2.3 Incidence of Adverse Events of Special Interest 
10.2.3.1 Dizziness/Pre-syncope 
Treatment-emergent adverse events of dizziness/pre-syncope will be summarised, similar 
to the tables described in 10.2.2. Two tables will be prepared one with all TEAE and one 
with related TEAE(as assessed by the investigator). An AE is considered to be 
dizziness/pre-syncope if the PT is included in the list below:     
Dizziness 
Dizziness postural 
Dizziness exertional 
Persistent postural-perceptual dizziness 
Procedural dizziness 
Pre-syncope 
Vertigo 
Vertigo positional 
Vertigo CNS origin 
 
10.2.3.2 Dysmenorrhea, Abdominal Pain, Pelvic Pain, Lower Back Pain and 
Dyspareunia 
Dysmenorrhea, Abdominal Pain, Pelvic Pain, Lower Back Pain and Dyspareunia is 
reported as part of the efficacy reporting. 
 
10.2.3.3 Vaginal bleeding  
Vaginal bleeding is reported as part of the efficacy reporting   
 
10.2.3.4 Syncope 
Treatment-emergent adverse events of syncope will be summarised, similar to the tables 
described in 10.2.2. Two tables will be prepared one with all TEAE and one with related 
TEAE (as assessed by the investigator). An AE is considered to be syncope if the PT is 
included in the list below: 


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Syncope 
Loss of consciousness 
Altered state of consciousness 
10.2.3.5 Vaginal Irritation and/or Vaginal Infection  
Treatment-emergent adverse events of Vaginal Irritation and/or Vaginal Infection will be 
summarised, similar to the tables described in 10.2.2. Two tables will be prepared one with 
all TEAE and one with related TEAE(as assessed by the investigator). An AE is 
considered to be Vaginal Irritation and/or Vaginal Infection if the High level term is 
included in the list below: 
vulvovaginal signs and symptoms 
vaginal and vulval infections and inflammation 
 
10.3 Safety Laboratory Variables 
Baseline for all laboratory analyses will be the values obtained at the last assessment prior 
to the first dose of the investigational medicinal product (IMP). Treatment-emergent 
laboratory data will include tests completed after the first dose of IMP through the residual 
time of drug effect. End of trial will include the last post-baseline observation during the 
trial. Safety lab values are planned to be measured four times, at baseline, at end of part A, 
at end of party B, and at end of trial. In case of premature discontinuation an extra 
measurements is planned. If premature discontinuation is during part A the extra 
measurement will be used both as end of part A and end of trial measurement, if premature 
discontinuation is during part B the extra measurement is used as both end of part B and 
end of trial measurement  
Laboratory variables will be grouped under “Haematology”, “Clinical Chemistry” or 
“Urinalysis” 
10.3.1 Summary Statistics 
Mean change and mean percentage (%) change from baseline at end of trial will be 
presented for each laboratory variable. In addition, descriptive statistics, i.e., the number of 
subjects with data, mean (standard deviation), median, minimum, and maximum values, 
will be presented for observed values and change from baseline at each time-point for each 
laboratory variable.   


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10.3.2 Laboratory Variable Changes Relative to Normal Range 
As the trial has been prematurely discontinued, it has been decided, due to the low number 
of subjects, that no shift tables will be prepared. Clinical significant changes in laboratory 
values are presented in the AE tables.  
10.3.3 Data Listings 
Data listings will be prepared by treatment for all subjects with any abnormal laboratory 
value at any time-point (including screening, baseline).  
10.3.4 Urinalysis 
Incidence of changes in urinalysis will be summarised. Summary tables with number of 
subjects with change from Absent at baseline to Present during trial will be summarised.  
10.4 Vital Signs and ECG 
10.4.1 Vital Signs 
Baseline for all vital signs analyses will be the values obtained at the last assessment prior 
to the first dose of IMP. Treatment-emergent vital signs data will include tests completed 
after the first dose of IMP through the time of residual drug effect. End of trial will include 
the last post-baseline observation during the trial. 
10.4.1.1 Summary Statistics 
Mean change and mean percentage (%) change from baseline at end of trial will be 
presented for each vital signs variable. In addition, descriptive statistics, i.e., the number of 
subjects with data, mean (standard deviation), median, minimum, and maximum values, 
will be presented for observed values and change from baseline at each time-point for each 
vital signs variable.  
10.4.1.2 Data Listings 
Data listings will be prepared by centre for all subjects with any abnormal vital signs value 
at any time-point (including screening, baseline). 


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10.4.2 ECGs 
The 12-lead ECG will be recorded prior to randomization at cycle -1 (visit 4), at cycles 4 
and 8. Results at randomization will be used as baseline. The ECG will be recorded with a 
calibrated ECG device after the subject has been in supine position for at least 5 minutes. 
The parameters to be assessed are heart rate, PR interval, RR interval, QRS interval, QT 
interval and QTcF interval (i.e. QT correction according to the Fridericia’s formula QTcF= 
QT/RR0 33, calculated automatically in the e-CRF). ECG recordings will capture at least 
four QRS complexes, i.e. 3 evaluable RR intervals. The investigator will evaluate whether 
the ECG is normal or abnormal and if abnormal, whether it is clinically significant. ECG 
may be repeated for quality reasons and in this case the repeated assessment will be used 
for analysis.  
10.4.2.1 Summary Statistics  
Descriptive statistics, i.e., the number of subjects with data, mean (standard deviation), 
median, minimum, and maximum values, will be presented for observed values and change 
from baseline at each time-point for each ECG variable.  
10.4.2.2 Data Listings 
Data listings will be prepared by treatment and site for all subjects with any abnormal ECG 
value at any time-point. 
10.5 Other Safety Variables 
10.5.1 Changes in Bone-turnover Markers 
Changes in bone-turnover markers will be summarised.  
10.5.2 Echocardiography 
The proportion of subjects with clinically significant echocardiography findings will be 
tabulated by treatment.  


Statistical Analysis Plan 
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10.5.3 Impulsive-Compulsive Disorders 
Frequency-tables for each item of the questionnaire for impulsive-compulsive disorders as 
well as the proportion of subjects having potential behaviours associated with impulse 
control disorders will be summarized by treatment. 
Treatment-emergent adverse events potentially related to behaviours associated with 
impulse control disorder will be summarised, similar to the tables described in 10.2.2. An 
AE is considered to potentially related to behaviours associated with impulse control 
disorder if the PT is included in the SMQ hostility/aggression (broad) or included in the list 
of PTs below: 
Alcohol abuse  
Alcohol problem  
Alcohol use  
Behavioural addiction  
Binge drinking  
Binge eating  
Compulsions  
Compulsive hoarding  
Compulsive sexual 
behaviour  
Compulsive shopping  
Disturbance in sexual 
arousal  
Dopamine dysregulation 
syndrome  
Drug abuse  
Drug abuser  
Eating disorder  
Economic problem  
Emotional disorder  
Emotional distress  
Euphoric mood  
Excessive masturbation  
Exhibitionism  
Gambling  
Gambling disorder  
Gaming disorder  
High risk sexual 
behaviour  
Hyperphagia  
Hypersexuality  
Increased appetite  
Judgement impaired  
Kleptomania  
Libido disorder  
Libido increased  
Male orgasmic disorder  
Mental disorder  
Mental status changes  
Mood altered 
Mood swings 
Obsessive rumination 
Obsessive thoughts 
Obsessive-compulsive 
disorder 
Obsessive-compulsive 
personality disorder 
Obsessive-compulsive 
symptom 
Overconfidence 
Poriomania 
Promiscuity 
Pseudologia 
Restlessness 
Self-esteem inflated 
Sexual activity increased 
Sexually inappropriate 
behaviour 
Stereotypy 
Thinking abnormal 
Weight increased 
 
10.5.4 Ring Acceptability  
Frequency-tables for each item (as applicable) of the ring acceptability questionnaire will 
be presented by cycle and treatment. 


Statistical Analysis Plan 
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11 Interim Analyses 
An interim analysis with the option to stop the trial early due to futility was planned, but as 
the trial was prematurely discontinued, this interim analysis was not performed  
The trial was terminated early. The decision was taken due to the results from the parallel 
phase 2 trial in Europe (Trial 000295) and the continued difficulties with subject 
recruitment.  
Due to the low number of subjects recruited, no interim analysis was performed, and no 
statistical analysis was performed. Instead results are presented as descriptive statistics by 
treatment group separately for Part A and Part B.  
Furthermore, due the low number of subject the shift tables and tables displaying 
proportions of subjects with markedly abnormal values for the safety endpoint will not be 
prepared, the information on change from baseline can be assessed using the listings.  
 


Statistical Analysis Plan 
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12 Deviations from Protocol Analysis 
The trial was terminated early. The decision was taken due to the results from the parallel 
phase 2 trial in Europe (Trial 000295) and the continued difficulties with subject 
recruitment.  
Due to the low number of subjects recruited, no interim analysis was performed, and no 
statistical analysis was performed. Instead results are presented as descriptive statistics by 
treatment group separately for Part A and Part B.  
Due the low number of subjects the shift tables and tables displaying proportions of 
subjects with markedly abnormal values for the safety endpoint will not be prepared, the 
information on change from baseline can be assessed using the listings.  
Due to the low number of subjects the proportion of subjects with serum levels of mid-
luteal progesterone ≥25 nmol/, and the endometriosis biomarkers will not be summarized