Clinical trial NCT03749109
Conditions: Endometriosis
Keywords: Endometrioma Adenomyosis Deep infiltrating endometriosis
Sponsor: Ferring Pharmaceuticals
Start date: 2019-08-19; Completion date: 2021-07-18
Enrollment: 67 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This will be a randomized, double-blind, placebo-controlled, proof-of-mechanism phase 2 trial investigating the effect of quinagolide extended-release vaginal ring on reduction of lesions assessed by high-resolution magnetic resonance imaging in women with endometrioma, deep infiltrating endometriosis, and/or adenomyosis.

Detailed description:

Arms: arm 1: Vaginal ring containing Quinagolide 1080 µg, with daily target release rate of 13.5 µg. arm 2: Vaginal ring containing matching placebo
Interventions: intervention 1: Quinagolide 1080 µg intervention 2: Placebo
Intervention descriptions: intervention 1: Vaginal ring containing Quinagolide 1080 µg for daily releases intervention 2: Matching placebo

Protocol documents:
Prot_000.pdf: 
 
 
 
Cover page for Protocol 
 
Sponsor name 
Ferring Pharmaceuticals A/S 
NCT Number 
NCT03749109 
Sponsor trial ID:  
000295 
Official title of study 
A randomised, double-blind, placebo-controlled, 
proof-of-mechanism phase 2 trial investigating 
the effect of quinagolide extended-release 
vaginal ring on reduction of lesions assessed by 
high-resolution magnetic resonance imaging in 
women with endometrioma, deep infiltrating 
endometriosis, and/or adenomyosis 
Document Date 
12 November 2019 
 


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Trial Code:  000295
Vaginal Delivery System  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
CLINICAL TRIAL PROTOCOL 
 
 
A randomised, double-blind, placebo-controlled, proof-of-mechanism phase 2 trial 
investigating the effect of quinagolide extended-release vaginal ring on reduction of lesions 
assessed by high-resolution magnetic resonance imaging in women with endometrioma, deep 
infiltrating endometriosis, and/or adenomyosis 
 
Trial 000295  
 
Quinagolide Vaginal Ring on Lesion Reduction Assessed by MRI in Women with 
Endometriosis/Adenomyosis  
(QLARITY) 
 
EudraCT Number: 
2018-000915-26 
Investigational Medicinal Product: 
FE 999051, Quinagolide Vaginal Ring 
Indication: 
Endometriosis  
Phase: 
2 
Name and Address of Sponsor: 
Ferring Pharmaceuticals A/S 
Global Clinical R&D 
International PharmaScience Center 
Kay Fiskers Plads 11 
2300 Copenhagen S 
Denmark 
 
 
GCP Statement: 
This trial will be performed in compliance with GCP. 
 
 
 
 
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. 
 
 


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Quinagolide, FE 999051 
Trial Code:  000295
Vaginal Delivery System  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
SYNOPSIS 
TITLE OF TRIAL 
A randomised, double-blind, placebo-controlled, proof-of-mechanism phase 2 trial investigating 
the effect of quinagolide extended-release vaginal ring on reduction of lesions assessed by 
high-resolution magnetic resonance imaging in women with endometrioma, deep infiltrating 
endometriosis, and/or adenomyosis 
SIGNATORY INVESTIGATOR 
Antonio Pellicer, MD PhD, Professor of Obstetrics and Gynaecology, University Medical School, 
Valencia 
TRIAL SITES 
Approximately 8-12 sites in Europe 
PLANNED TRIAL PERIOD 
First patient first visit (FPFV) 
 
 
Q3 2019 
Last patient last visit (LPLV)  
 
 
Q2 2021 
CLINICAL PHASE 
2 
OBJECTIVES 
Primary Objective 
• To evaluate the effect of quinagolide vaginal ring compared to placebo on reduction of 
lesions for endometrioma, deep infiltrating endometriosis (DIE) and adenomyosis assessed 
by high-resolution magnetic resonance imaging (MRI) 
 
Secondary Objectives  
• To evaluate the effect of quinagolide vaginal ring compared to placebo on reducing the 
sizes of endometrioma assessed by transvaginal ultrasound (TVU) 
• To evaluate the effect of quinagolide vaginal ring on patient reported outcomes (PROs) 
• To evaluate the plasma concentrations of quinagolide and its metabolites 
• To evaluate the effect of quinagolide vaginal ring on serum endocrine parameters 
• To evaluate the effect of quinagolide vaginal ring on menstrual bleeding pattern 
• To evaluate the safety profile of quinagolide vaginal ring including adverse events and 
routine safety laboratory parameters 
 
Exploratory Objectives  
• To explore the effect of quinagolide vaginal ring on the MRI-derived perfusion imaging 
biomarkers of angiogenesis and on the MRI-derived diffusion imaging biomarkers of lesion 
tissue structure  
• To explore the effect of quinagolide vaginal ring on reducing the size of uterine fibroids 
assessed by both MRI and TVU 
• To explore the effect of quinagolide vaginal ring on endometriosis biomarkers 


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ENDPOINTS 
Primary Endpoint 
• Changes in the sizes (mm) of endometrioma, DIE and adenomyosis lesions summed by 
type on MR images at cycle 4 
 
Secondary Endpoints 
• Percentage of changes in the sizes of endometrioma, DIE and adenomyosis lesions summed 
by type on MR images at cycle 4 
• Proportion of lesions by type with a decrease in a size of ≥5 mm on MR images at cycle 4 
• Proportion of subjects with a lesion of any type decreased in a size of ≥5 mm on MR 
images at cycle 4 
• Number of new or disappearing endometrioma, DIE and adenomyosis lesions summed by 
type on MR images at cycle 4 
• Changes in the volumes (mm3) of endometrioma and DIE lesions summed by type on MR 
images at cycle 4 
• Changes in the sizes of endometrioma assessed by TVU at cycle 4 
• Changes in the mean individual and total symptom and sign severity of scores of the 
Biberoglu and Behrman (B&B) scale at cycle 4  
• Changes in the Numerical Rating Scale (NRS) pain scores per cycle at cycles 1, 2, 3 and 4 
• Changes in the Endometriosis Health Profile-30 (EHP-30) scores at cycles 2 and 4 
• Changes in the menstrual bleeding pattern over 4 cycles 
• Serum levels of prolactin, thyroid-stimulating hormone (TSH), insulin-like growth factor-1 
(IGF-1) during cycle 1, at cycles 2 and 4 
• Plasma concentrations of quinagolide and its metabolites during cycles 1 to 4  
• Changes in clinical chemistry and haematology parameters and proportion of subjects with 
markedly abnormal changes 
• Frequency and intensity of adverse events  
 
Exploratory Endpoints 
• Changes in the MRI-derived perfusion imaging biomarkers of AUC, Ktrans, kep, ve, vp at 
cycle 4  
• Changes in the MRI-derived diffusion imaging biomarkers of ADC, D, D* and f at cycle 4  
• Changes in the sizes of uterine fibroids on MR images at cycle 4  
• Changes in the sizes of uterine fibroids assessed by TVU at cycle 4 
• Changes in circulating levels of VEGF, placental growth factor (PlGF), interleukin 6 (IL-6), 
cancer antigen 125 (CA125) and soluble fms-like tyrosine kinase 1 (sFlt-1) at cycle 4 
METHODOLOGY 
This is a randomised, double-blind, placebo-controlled, phase 2 trial investigating the effect of 
quinagolide extended-release vaginal ring on reduction of lesions, assessed by high-resolution 


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CONFIDENTIAL 
MRI, in women with endometrioma, DIE and/or adenomyosis.  
In this trial, quinagolide vaginal ring or placebo vaginal ring will be administered sequentially for 
four menstrual cycles, where a menstrual cycle is considered the period between day 7 after return 
of menses (RM+7) in a cycle until the following day 7 after return of menses of the next cycle. The 
RM+7 visits in this trial can be scheduled within the period of 6-10 days after return of menses 
(RM+6-10). 
The trial consists of the following periods: 
1) Screening: starting from the signing of informed consent to randomisation (approximately 
4 months) and including a wash-out period (only applicable to subjects using some hormonal 
products) and a screening cycle (cycle -1, applicable to all subjects) 
2) Treatment: double-blind, placebo-controlled treatment with quinagolide vaginal ring or 
placebo vaginal ring administered sequentially for four menstrual cycles (cycles 1, 2, 3 and 4) 
3) Follow-up: about 1 month after end-of-treatment 
Screening: Subjects should be screened for eligibility within approximately 4 months of 
randomisation. Subjects who are currently using some hormonal products (e.g. combined oral 
contraceptive pill, progestogen and levonorgestrel-releasing intrauterine device (IUD)) may be 
eligible for the trial if they have completed the wash-out period and have return of menses. In this 
case, subjects need to sign the informed consent before they discontinue those products. 
Discontinuation of the products should follow their labelling (e.g. completing the current cycle of 
contraceptives before discontinuation). Subjects who are not using exclusionary hormonal products 
can enter the screening cycle directly. Prescriptions of analgesics for pain management are allowed 
in this trial. 
After having completed the wash-out period (if applicable) and having return of menses, subjects 
will attend the screening RM+7 visit to undergo initial screening assessments, including a MRI 
examination by a high resolution 3-tesla (3T) machine. Depending on facilities at sites, MRI may 
not necessarily be scheduled at the same screening visit, but it must be scheduled on a day without 
bleeding to avoid biases and to ensure the availability of the central MRI reading report prior to 
randomisation. The MRI at screening, used as baseline, should not be obtained more than 1 
menstrual cycle before randomisation.  
Eligible subjects must have at least one of the following three types of lesions with the following 
sizes identified by MRI: endometrioma (≥20 mm), DIE (≥15 mm), and/or adenomyosis (maximum 
junctional zone thickness ≥12 mm or focal lesion ≥15 mm). If a subject has more than one type of 
lesions, she will be grouped under the more rare type in the ranking of DIE, adenomyosis and 
endometrioma. For example, a subject with both DIE and endometrioma will be included in the 
DIE sub-group but both types of lesions should be measured. Every measurable lesion (defined as 
≥10 mm in size) of any type should be recorded and should be summed up by type for primary 
analysis. For DIE and endometrioma, lesions will be measured both in size and in volume. For 
uterine fibroid, only size will be measured. Size will be recorded in mm as the longest diameter in 
the plane of measurement. Volume will be recorded in mm3 using a semi-automated method based 
on 3D region-growing algorithm, adjusted with manual correction. For adenomyosis, the maximum 
junctional zone thickness (applicable to diffuse adenomyosis) or the size of the largest focal lesion 


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(applicable to focal adenomyosis) will be measured. All MRIs should be uploaded into a specific 
image repository allocated for this trial within 2 business days for central reading and analyses by a 
specialised imaging laboratory. Subject eligibility with regard to inclusion criterion no. 6 must be 
determined based on the central MRI reading report.  
Subjects are required to fast for 3-4 hours before the MRI examination. The preparations for MRI 
examination should follow the trial-specific MRI manual. The MRI procedures will include the 
following main sequences:  
• Fast spin echo – T2-weighted images (FSE-T2)  
• Diffusion weighted (DW-IVIM) images with more than 2 b-values 
• Gradient echo (GRE) – T1-weighted images with varying flip angles (GRE-T1-VFA)  
• Dynamic, contrast-enhanced, spoiled GRE T1-weighted images (DCE-PKM-Gd)  
• Late gadolinium enhancement spoiled GRE T1-weighted images (GRE-T1-LATEGd)  
Other details for the MRI examination will be specified in the MRI manual. Prior to the start of the 
trial, site radiologists will be trained on the MRI manual. Site radiologists must follow the MRI 
manual for the preparation and the execution of the MRI assessment.  
In addition to MRI, a TVU should be performed at the screening RM+7 visit to assess uterus, 
endometrium, and ovaries and to measure the size(s) of any endometrioma and/or fibroid.  
Subjects will be required to use a non-hormonal single-barrier method for contraception (i.e. 
condom) from screening to end-of-treatment. 
Treatment: Eligible subjects in each sub-group will be randomised at the end of cycle -1 in a 2:1 
ratio to receive quinagolide vaginal ring or placebo vaginal ring for four menstrual cycles (cycles 
1, 2, 3 and 4). Approximately 24 subjects will be randomised in each sub-group, adding up to a 
total of 72 subjects in this trial. Quinagolide vaginal ring contains a dose load of quinagolide 
1080 µg at a target daily release rate of quinagolide 13.5 µg. 
After randomisation, subjects will self-insert the assigned ring in the upper part of the vagina at 
sites 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 by the next ring at RM+7 visit of the next cycle.  
Subjects who have discontinued during or after cycle 2 should come for an end-of-treatment visit 
with MRI, scheduled within 2 weeks of discontinuation. Subjects who have completed the 
scheduled treatment should come for an MRI examination at or close to the RM+7 visit of cycle 4. 
The MRI at end-of-treatment / cycle 4 must be performed using the same machine, following the 
same procedures and sequences as at screening (detailed in the MRI manual).  
To measure permeability, perfusion imaging biomarkers of the one-compartmental metric (AUC) 
and the two-compartmental metrics (Ktrans, kep, ve, vp) will be derived from the dynamic perfusion 
series. In addition, diffusion metrics (ADC, D, D* and f) of lesion tissue structure will be obtained 
using the intra-voxel incoherent motion (IVIM) model. All perfusion and diffusion parameters at 


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screening and at end-of-treatment will be assessed and analysed by the central imaging laboratory. 
All lesions will be segmented in 3D by two radiologists for the analyses of imaging biomarkers.  
Transvaginal ultrasound will be performed at end-of-treatment / cycle 4, preferably by the same 
sonographer as at screening, to measure the sizes of endometrioma and/or uterine fibroid.  
B&B will be administered at randomisation and at end-of-treatment / cycle 4, with trial 
coordinators completing the first part based on subjects’ verbal response and investigators 
completing the second part based on findings of a pelvic examination. At each RM+7 visit from 
randomisation to cycle 4, subjects will score the worst pain they experienced during the past 
menstrual cycle on a self-administered NRS, with 0 indicating no pain and 10 indicating worst 
imaginable pain. In addition, they will complete the EHP-30 questionnaire at randomisation, at 
cycle 2 and at end-of-treatment / cycle 4. All PROs will be administered on paper at sites.    
At each RM+7 visit from randomisation to end-of-treatment / cycle 4, the site staff should inquire 
about the bleeding pattern of the subject’s immediate past menstrual period, including the start and 
stop dates (if available) of menstrual bleeding and the amount of menstrual flow.  
Blood samples are collected throughout the trial for the purpose of evaluating endocrine profile, 
plasma concentrations of quinagolide and its metabolites, routine safety laboratory parameters as 
well as endometriosis biomarkers. Endocrine parameters, consisting of prolactin, TSH and IGF-1, 
will be assessed at randomisation, within 1-5 days of randomisation, at cycle 2 and at end-of-
treatment / cycle 4. To measure the plasma concentrations of quinagolide and its metabolites, blood 
samples will be taken within 1-5 days of randomisation, within 7-14 days of randomisation and 
prior to ring removal at RM+7 visits of cycles 1 to 4. Routine safety laboratory tests for clinical 
chemistry and haematology parameters will be performed at screening and at end-of-treatment / 
cycle 4. Blood samples for serum and plasma endometriosis biomarkers of VEGF, PlGF, IL-6, 
CA125 and sFlt-1 will be collected at randomisation and at end-of-treatment. 
A follow-up telephone call will be made to all subjects at about 1 month after the end-of-treatment 
/ cycle 4 visit to collect information about adverse events and concomitant medications since the 
visit, and reasons for resuming medications indicated for endometriosis / adenomyosis.  
NUMBER OF SUBJECTS 
It is estimated that 100 subjects will be screened to randomise 72 subjects in this trial, with 
approximately 24 subjects in each sub-group. 
CRITERIA FOR INCLUSION / EXCLUSION 
Inclusion Criteria 
1. Informed consent signed and dated prior to any trial-related procedures.  
2. In good physical and mental health to participate in the trial. 
3. Pre-menopausal females between the ages of 18-45 years (both inclusive) at the time of 
signing the informed consent. 
4. A menstrual cycle of 24-35 days (both inclusive) based on observation made in the absence 


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of drugs that can affect the cycle length (e.g. oral contraceptives) prior to the screening visit.  
5. Body mass index (BMI) of 18-35 kg/m2 (both inclusive) at screening. 
6. Confirmation of deep infiltrating endometriosis (DIE) (lesion size ≥15 mm), endometrioma 
(≥20 mm) or adenomyosis (maximum junctional zone thickness ≥12 mm or focal lesion 
≥15 mm) by high-resolution MRI at screening. 
7. Transvaginal ultrasound documenting a uterus with no abnormalities of endometrium and 
presence of at least one ovary with no clinically significant abnormalities at screening. Note 
that presence of uterine fibroids are not exclusionary but presence of any submucosal 
fibroids or polyps are exclusionary.  
8. Willing and able to use a non-hormonal single-barrier method (i.e. condom) for 
contraception from the start of screening to the end-of-treatment. This is not required if 
adequate contraception is achieved by vasectomy of the male sexual partner, surgical 
sterilisation (e.g. tubal ligation and blockage methods such as ESSURE) of the subject, or 
true abstinence of the subject (sporadic sexual intercourse with men requiring condom use).  
9. Willing to avoid the use of vaginal douches or any other intravaginally administered 
medications or devices (except for tampons) from randomisation to the end of treatment. 
10. Documentation of normal cervical cytology or negative human papilloma virus (HPV) 
results for high-risk viral subtypes upon presence of atypical squamous cells of 
undetermined significance, based on test(s) performed within 24 months of randomisation.  
11. Willing and able to comply with trial procedures, including attending scheduled visits and 
adherence to treatment plan. 
Exclusion Criteria 
1. Use of depot medroxyprogesterone acetate (MPA) within 10 months prior to the screening 
visit. 
2. Use of gonadotropin-releasing (GnRH) agonists (3-month depot) or dopamine agonists 
within 6 months prior to the screening visit. 
3. Use of GnRH agonists (1-month depot or nasal spray), GnRH antagonists, aromatase 
inhibitors, danazol, birth control implants (e.g. NEXPLANON), progestogen or 
levonorgestrel-releasing intrauterine device (IUD) within 3 months prior to the screening 
visit. 
4. Use of hormonal contraceptives (including combined oral contraceptive pill, transdermal 
patch, and contraceptive ring) and copper IUDs within 1 menstrual cycle prior to the 
screening visit.  
5. Undiagnosed abnormal vaginal bleeding within the last 3 months of the screening visit. 
6. History of recurrent bacterial, fungal or viral vaginal infection (i.e. ≥4 episodes within a 
year). 
7. History of malignancy within 5 years prior to the screening visit, except for adequately 
managed basal cell carcinoma and squamous cell carcinoma of the skin. 
8. History of orthostatic hypotension or recurrent syncope. 
9. History of mental illness including occurrence of acute psychosis, bipolar disorder and 
schizophrenia (except for well-controlled mild or moderate anxiety and/or depression with 
no changes to interventions for 3 months prior to the screening visit). 


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10. History of sudden sleep onset episodes.  
11. Known diagnosis of impulse control disorders including pathological gambling, compulsive 
buying, hypersexuality, and binge eating. 
12. Known positive results of Human Immunodeficiency Virus (HIV) antibody tests. 
13. Any other incidental, clinically significant abnormal findings than endometriotic / 
adenomyotic lesions identified at the screening MRI examination (e.g. suspected tumour).  
14. Any clinically significant abnormal findings from vital signs, blood tests of haematology 
and clinical chemistry at screening, including alanine aminotransferase (ALT) >2.5 times 
upper limit of normal (ULN) or bilirubin >1.5 times ULN or creatinine >1.5 times ULN.  
15. Any clinically significant abnormal findings at physical examination at screening.  
16. Any vaginal or vulvar lesions that would interfere with vaginal ring usage. 
17. Current pregnancy as confirmed by a positive serum pregnancy test at screening or planning 
a pregnancy within the duration of the trial, or currently breast-feeding or less than 6 months 
post-partum prior to the screening visit. 
18. Planned surgical treatment of endometriosis or adenomyosis during the duration of the trial. 
19. Continuous use of strong opioids (e.g. morphine) and/or illicit drugs (e.g. marijuana and 
amphetamine) for more than 2 weeks within 6 months prior to the screening visit.  
20. Alcohol abuse (>14 units of alcohol a week) within 2 years prior to the screening visit.  
21. Previous or current participation in a clinical trial involving a non-registered investigational 
medicinal product within 1 month of screening. If the trial involves a hormonal drug, the 
exclusion criteria 1-4 shall apply. 
22. Contraindications to MRI such as having internal/external metallic devices and/or 
accessories (e.g. cardiac pacemakers and leg braces). 
23. Hypersensitivity to any active ingredients, excipients or other components of medicinal 
products used in the trial, including quinagolide vaginal ring, placebo vaginal ring and any 
products used for MRI examination. 
MEDICINAL PRODUCTS 
Quinagolide vaginal ring is an extended-release system with a dose load of quinagolide 1080 µg at 
a target daily release rate of quinagolide 13.5 µg for up to 35 days duration. 
– 
Quinagolide vaginal ring dose load 1080 µg at a target daily release of quinagolide 13.5 µg : 
administered once per menstrual cycle (up to 35 days), sequentially for 4 menstrual cycles 
– 
Placebo vaginal ring: administered once per menstrual cycle (up to 35 days), sequentially for 
4 menstrual cycles 
DURATION OF TREATMENT 
Subjects will be exposed to quinagolide vaginal ring or placebo vaginal ring for a maximum of 
four menstrual cycles. 
STATISTICAL METHODS 
The primary objective of this trial is to evaluate the effect of quinagolide vaginal ring on reduction 
of three different types of lesions, i.e. endometrioma, DIE and adenomyosis. For each type of 


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lesion, the primary endpoint is the change in the sum of the lesion sizes after 4 menstrual cycles. 
The primary analyses will be based on all lesions with a size ≥10 mm at baseline. For each type of 
lesion, the primary endpoint will be analysed using an analysis of covariance (ANCOVA) model, 
with the change in the sum of lesion sizes from baseline measured at cycle 4 as the dependent 
variable, the baseline sum of lesions as covariate, the treatment group and site as fixed effect. The 
treatment difference between the active treatment versus placebo will be reported with 95% 
confidence interval and corresponding p-value for each of the three lesion types. The Hochberg 
procedure will be used to adjust the three primary analyses for multiplicity.  
The primary analyses will be based on the full analysis set, including all treated subjects as 
randomised. If a subject has prematurely discontinued from the trial without an end-of-treatment 
MRI, the missing measurement will be imputed using a multiple imputation strategy. Sensitivity 
analyses, including a completer analysis and an analysis of both measurable and non-measurable 
lesions, will be performed. 
Continuous secondary efficacy endpoints, for which a baseline measurement is available, will be 
analysed in a similar manner as the primary endpoint or using a repeated measure ANCOVA. 
Percentage of changes in lesion sizes will be analysed using a similar ANCOVA model log 
transforming both the dependent variable and the baseline measurement. Continuous secondary 
efficacy endpoints where no baseline measurement is available will be analysed using an 
ANCOVA model. Count data will be analysed using negative binomial regression. Binary 
endpoints will be analysed using logistic regression or proportional regression. Safety endpoints 
will be summarised using descriptive statistics. 
Sample size calculation  
Randomisation will be performed in a 2:1 ratio to quinagolide or placebo vaginal ring. The sample 
size calculation is based on the primary endpoint, assuming an equal magnitude of treatment effect 
for all three types of lesions. For example, for adenomyosis, by assuming a baseline lesion of 
18 mm and a standard deviation of 4.5 mm, a sample size of 24 randomised subjects (16 on active 
treatment and 8 on placebo) will have 83% power to detect a treatment effect difference of 6 mm 
(corresponding to a 33% reduction in lesion size) using a two-sample t-test at a 5% two-sided 
significance level. Similar assumptions are made for DIE and endometrioma to conclude 
24 subjects to be randomised per sub-group. In total, 72 subjects will be randomised in this trial. If 
the drop-out rate in any of the sub-group is larger than 10%, the sample size of randomised 
subjects may be increased to up to 30 for that sub-group. 


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TABLE OF CONTENTS 
SYNOPSIS ....................................................................................................................................................... 2 
LIST OF TABLES ........................................................................................................................................ 14 
LIST OF FIGURES ...................................................................................................................................... 14 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................................. 15 
1 
INTRODUCTION ............................................................................................................................. 18 
1.1 
Background ............................................................................................................................. 18 
1.2 
Scientific Justification for Conducting the Trial ..................................................................... 19 
1.3 
Benefit / Risk Aspects ............................................................................................................. 21 
2 
TRIAL OBJECTIVES AND ENDPOINTS ..................................................................................... 25 
2.1 
Objectives ............................................................................................................................... 25 
2.2 
Endpoints ................................................................................................................................ 25 
3 
INVESTIGATIONAL PLAN ........................................................................................................... 27 
3.1 
Overall Trial Design................................................................................................................ 27 
3.1.1 
Trial Design Diagram................................................................................................. 27 
3.1.2 
Overall Design and Control Methods ........................................................................ 27 
3.1.3 
Trial Schedule ............................................................................................................ 30 
3.2 
Planned Number of Trial Sites and Subjects ........................................................................... 30 
3.3 
Interim Analysis ...................................................................................................................... 31 
3.4 
Data Monitoring Committee ................................................................................................... 31 
3.5 
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 31 
3.5.1 
Trial Design ............................................................................................................... 31 
3.5.2 
Selection of Endpoints ............................................................................................... 32 
3.5.3 
Blinding...................................................................................................................... 33 
3.5.4 
Selection of Dose in the Trial .................................................................................... 34 
3.5.5 
Selection and Timing of Dose for Each Subject ........................................................ 34 
3.5.6 
Selection of the Trial Population ............................................................................... 35 
3.5.7 
Follow-up Procedures ................................................................................................ 35 
4 
SELECTION OF TRIAL POPULATION ...................................................................................... 36 
4.1 
Trial Population....................................................................................................................... 36 
4.1.1 
Inclusion Criteria ....................................................................................................... 36 
4.1.2 
Exclusion Criteria ...................................................................................................... 36 
4.2 
Method of Assigning Subjects to Treatment Groups .............................................................. 38 
4.2.1 
Recruitment ................................................................................................................ 38 
4.2.2 
Randomisation ........................................................................................................... 38 
4.3 
Restrictions ............................................................................................................................. 38 
4.3.1 
Prohibited Medications / Therapies ........................................................................... 38 
4.3.2 
Other Restrictions ...................................................................................................... 39 
4.4 
Withdrawal Criteria................................................................................................................. 39 
4.5 
Subject Replacement ............................................................................................................... 40 
5 
TREATMENTS ................................................................................................................................. 41 
5.1 
Treatments Administered ........................................................................................................ 41 
5.1.1 
Investigational Medicinal Products ............................................................................ 41 
5.1.2 
Non-Investigational Medicinal Product ..................................................................... 41 


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5.2 
Characteristics and Source of Supply ..................................................................................... 41 
5.3 
Packaging and Labelling ......................................................................................................... 42 
5.4 
Conditions for Storage and Use .............................................................................................. 42 
5.5 
Blinding / Unblinding ............................................................................................................. 43 
5.5.1 
Blinding...................................................................................................................... 43 
5.5.2 
Unblinding of Individual Subject Treatment ............................................................. 44 
5.6 
Treatment Compliance ............................................................................................................ 45 
5.6.1 
Dispensing and Accountability .................................................................................. 45 
5.6.2 
Assessment of Compliance ........................................................................................ 45 
5.7 
Return and Destruction of Medicinal Products ....................................................................... 45 
5.8 
Auxiliary Supplies................................................................................................................... 45 
6 
TRIAL PROCEDURES .................................................................................................................... 46 
6.1 
Trial Flow Chart ...................................................................................................................... 46 
6.2 
Screening ................................................................................................................................. 47 
6.2.1 
Wash-out (As Applicable) ......................................................................................... 47 
6.2.2 
Screening Visit / Visit 1 (Start of Cycle -1) ............................................................... 47 
6.2.3 
Randomisation / Visit 2 (RM+7 of Cycle -1) ............................................................ 48 
6.3 
Treatment Period ..................................................................................................................... 49 
6.3.1 
Visit 3 (Within 1-5 days of Visit 2) ........................................................................... 49 
6.3.2 
Visit 4 (Within 7-14 days of Visit 2) ......................................................................... 49 
6.3.3 
Cycle 1 Visit / Visit 5 (RM+7 of Cycle 1) ................................................................. 50 
6.3.4 
Cycle 2 Visit / Visit 6 (RM+7 of Cycle 2) ................................................................. 50 
6.3.5 
Cycle 3 Visit / Visit 7 (RM+7 of Cycle 3) ................................................................. 51 
6.3.6 
End-of-Treatment / Cycle 4 Visit / Visit 8 (RM+7 of Cycle 4) ................................. 51 
6.4 
Follow-up ................................................................................................................................ 52 
6.4.1 
Follow-up Phone Call (About 1 Month after Visit 8) ................................................ 52 
7 
TRIAL ASSESSMENTS ................................................................................................................... 53 
7.1 
Assessments Related to Primary Endpoint ............................................................................. 53 
7.1.1 
Magnetic Resonance Imaging (MRI) ......................................................................... 53 
7.2 
Assessments Related to Secondary Endpoints ........................................................................ 54 
7.2.1 
Transvaginal Ultrasound (TVU) ................................................................................ 54 
7.2.2 
Biberoglu and Behrman (B&B) Scale........................................................................ 55 
7.2.3 
Numerical Rating Scale (NRS) .................................................................................. 56 
7.2.4 
Endometriosis Health Profile-30 (EHP-30) Questionnaire ........................................ 56 
7.2.5 
Menstrual Bleeding Pattern ........................................................................................ 56 
7.2.6 
Endocrine Parameters ................................................................................................ 56 
7.2.7 
Plasma Concentrations of Quinagolide and Its Metabolites ...................................... 57 
7.2.8 
Clinical Chemistry and Haematology Parameters ..................................................... 57 
7.2.9 
Adverse Events .......................................................................................................... 57 
7.3 
Assessments Related to Exploratory Endpoints ...................................................................... 57 
7.3.1 
MRI-Derived Perfusion and Diffusion Imaging Biomarkers ..................................... 57 
7.3.2 
Serum and Plasma Endometriosis Biomarkers .......................................................... 58 
7.4 
Other Assessments .................................................................................................................. 58 
7.4.1 
Demographics ............................................................................................................ 58 
7.4.2 
Medical History ......................................................................................................... 58 
7.4.3 
Menstrual History ...................................................................................................... 58 


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7.4.4 
Reproductive History ................................................................................................. 59 
7.4.5 
Body Measurement .................................................................................................... 59 
7.4.6 
Urine Pregnancy Test ................................................................................................. 59 
7.4.7 
Vital Signs .................................................................................................................. 59 
7.4.8 
Physical Examination ................................................................................................. 59 
7.4.9 
Gynaecological Examination ..................................................................................... 60 
7.4.10 Cervical Cytology Test .............................................................................................. 60 
7.4.11 Concomitant Medications .......................................................................................... 60 
7.4.12 Drug Accountability ................................................................................................... 61 
7.4.13 End-of-Treatment Form ............................................................................................. 61 
7.4.14 Follow-up Phone Call ................................................................................................ 61 
7.5 
Handling of Biological Samples ............................................................................................. 61 
8 
ADVERSE EVENTS ......................................................................................................................... 62 
8.1 
Adverse Event Definition ........................................................................................................ 62 
8.2 
Collection and Recording of Adverse Events ......................................................................... 62 
8.2.1 
Collection of Adverse Events .................................................................................... 62 
8.2.2 
Recording of Adverse Events .................................................................................... 63 
8.3 
Adverse Events of Special Interest ......................................................................................... 65 
8.3.1 
Dysmenorrhea, Pelvic Pain and Dyspareunia ............................................................ 65 
8.3.2 
Menstrual Bleeding .................................................................................................... 66 
8.4 
Pregnancy and Pregnancy Outcome........................................................................................ 66 
8.5 
Serious Adverse Events .......................................................................................................... 67 
8.5.1 
Serious Adverse Event Definition .............................................................................. 67 
8.5.2 
Collection, Recording and Reporting of Serious Adverse Events ............................. 68 
8.6 
Follow-up of Adverse Events and Serious Adverse Events .................................................... 69 
8.6.1 
Follow-up of Adverse Events with Onset during the Trial ........................................ 69 
8.6.2 
Collection of Serious Adverse Events with Onset after Last Visit in the Trial ......... 69 
9 
STATISTICAL METHODS ............................................................................................................. 70 
9.1 
Determination of Sample Size ................................................................................................ 70 
9.2 
Subject Disposition ................................................................................................................. 71 
9.3 
Protocol Deviations ................................................................................................................. 71 
9.4 
Analysis Sets ........................................................................................................................... 71 
9.4.1 
Full Analysis Set (FAS) ............................................................................................. 71 
9.4.2 
Per Protocol (PP) Analysis Set ................................................................................... 71 
9.4.3 
Safety Analysis Set .................................................................................................... 72 
9.5 
Trial Population....................................................................................................................... 72 
9.5.1 
Demographics and other Baseline Characteristics ..................................................... 72 
9.5.2 
Medical History, Concomitant Medication and Other Safety Evaluations ................ 72 
9.6 
Endpoint Assessments............................................................................................................. 72 
9.6.1 
General Considerations .............................................................................................. 72 
9.6.2 
Primary Endpoint ....................................................................................................... 73 
9.6.3 
Secondary Endpoints ................................................................................................. 75 
9.6.4 
Exploratory Endpoints ............................................................................................... 75 
9.7 
Extent of Exposure and Treatment Compliance ..................................................................... 76 
9.8 
Safety ...................................................................................................................................... 76 
9.9 
Interim Analysis ...................................................................................................................... 77 


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10 
DATA HANDLING ........................................................................................................................... 78 
10.1 
Source Data and Source Documents ....................................................................................... 78 
10.2 
e-CRF ...................................................................................................................................... 79 
10.3 
Data Management ................................................................................................................... 79 
10.4 
Provision of Additional Information ....................................................................................... 79 
11 
MONITORING PROCEDURES ..................................................................................................... 80 
11.1 
Periodic Monitoring ................................................................................................................ 80 
11.2 
Audit and Inspection ............................................................................................................... 80 
11.3 
Confidentiality of Subject Data ............................................................................................... 81 
12 
CHANGES IN THE CONDUCT OF THE TRIAL ........................................................................ 82 
12.1 
Protocol Amendments ............................................................................................................. 82 
12.2 
Deviations from the Protocol .................................................................................................. 82 
12.3 
Premature Trial Termination ................................................................................................... 82 
13 
REPORTING AND PUBLICATION .............................................................................................. 83 
13.1 
Clinical Trial Report ............................................................................................................... 83 
13.2 
Confidentiality and Ownership of Trial Data .......................................................................... 83 
13.3 
Publications and Public Disclosure ......................................................................................... 83 
13.3.1 Publication Policy ...................................................................................................... 83 
13.3.2 Public Disclosure Policy ............................................................................................ 84 
14 
ETHICAL AND REGULATORY ASPECTS ................................................................................. 85 
14.1 
Independent Ethics Committee (IEC) ..................................................................................... 85 
14.2 
Regulatory Authorities’ Notification ...................................................................................... 85 
14.3 
End-of-Trial and End-of-Trial Notification ............................................................................ 85 
14.4 
Ethical Conduct of the Trial .................................................................................................... 85 
14.5 
Informed Consent .................................................................................................................... 85 
14.6 
Subject Participation Card ...................................................................................................... 86 
14.7 
Compliance Reference Documents ......................................................................................... 86 
15 
LIABILITIES AND INSURANCE .................................................................................................. 87 
15.1 
ICH-GCP Responsibilities ...................................................................................................... 87 
15.2 
Liabilities and Insurance ......................................................................................................... 87 
16 
ARCHIVING ...................................................................................................................................... 88 
16.1 
Investigator File ...................................................................................................................... 88 
16.2 
Trial Master File...................................................................................................................... 88 
17 
REFERENCES ................................................................................................................................... 89 
 
 


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LIST OF TABLES  
 
 
Table 6-1 Trial Flow Chart – Procedures at Clinic Visits ............................................................... 46 
Table 9-1 Sample Size by Treatment Effect Difference ................................................................. 70 
 
 
LIST OF FIGURES 
Figure 3-1 Trial Diagram – Trial Period ........................................................................................... 27 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
List of Abbreviations 
2D 
2-dimension(al) 
3D 
3-dimension(al) 
3T 
3-tesla 
5-HT2B 
5-hydroxytryptamin 2B receptor 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical classification system 
βhCG 
beta unit of human chorionic gonadotropin 
B&B 
Biberoglu and Behrman 
BMI 
body mass index 
CA125 
cancer antigen 125 
CRO 
contract research organisation 
d 
day(s) 
DCE 
dynamic, contrast-enhanced 
DIE 
deep infiltrating endometriosis 
DW 
diffusion weighted 
e-CRF 
electronic case report form 
EHP-30 
Endometriosis Health Profile-30 
EOT 
end-of-treatment 
EU 
European Union 
EudraCT 
European Union Clinical Trial Database 
FAS 
full analysis set 
FPFV 
first patient first visit 
FSE 
fast spin echo 
GCP 
Good Clinical Practice 
Gd 
gadolinium 
GEE 
generalised estimating equation 
GMP 
Good Manufacturing Practice 
GnRH 
gonadotropin-releasing hormone 
GRE 
gradient echo 
HIV 
human immunodeficiency virus 
HPV 
human papilloma virus 
i 
insertion 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IGF-1 
insulin-like growth factor-1 
IL-6 
interleukin 6 
IMP 
investigational medicinal product 


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IRT 
Interactive Response Technology  
IUD 
intrauterine device 
IVIM 
intra-voxel incoherent motion 
LATEGd 
late gadolinium enhancement acquisition 
LPLV 
last patient last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
mens. pattern 
menstrual bleeding pattern  
mm 
millimetre 
MPA 
medroxyprogesterone acetate 
MRI 
magnetic resonance imaging 
MS 
multi-slice 
ms 
millisecond 
NRS 
Numerical Rating Scale 
PK 
pharmacokinetic(s) 
PlGF 
placental growth factor 
PP 
per protocol 
PRO 
patient reported outcome 
r 
removal 
RECIST 
Response Evaluation Criteria in Solid Tumours   
RM 
return of menses  
RM+6-10 
6-10 days after return of menses 
RM+7 
day 7 after return of menses 
s 
second 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SE 
standard error  
sFlt-1 
soluble fms-like tyrosine kinase 1 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TSH 
thyroid-stimulating hormone 
TVU 
transvaginal ultrasound 
ULN 
upper limit of normal 
V 
visit 
VEGF 
vascular endothelial growth factor 
VFA 
variable flip angle 
βhCG 
beta unit of human chorionic gonadotropin 
µg 
microgram 
 


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Definition of Terms  
Definitions of pharmacokinetic parameters 
AUC 
area under curve  
Cmax 
maximum concentration 
Tmax 
time to maximum concentration  
 
 
Definitions (units) of MRI-derived perfusion imaging biomarkers 
AUC 
area under curve (mmol·kg-1·s) 
kep 
rate constant (min-1) 
Ktrans 
transfer constant rate (min-1) 
ve 
fractional volume of the extravascular-extracellular space (%) 
vp 
fractional volume of the plasma space (%) 
 
 
Definitions (units) of MRI-derived diffusion imaging biomarkers 
ADC 
apparent diffusion coefficient (mm2/s) 
D 
pure diffusion coefficient of cellular component (mm2/s) 
D* 
pseudo-perfusion coefficient of vascular component (mm2/s) 
f 
vascular fraction coefficient (%) 
 
 


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1 
INTRODUCTION 
1.1 
Background 
Endometriosis is an estrogen-dependent disease, pathologically characterised by the presence of 
endometrial-like tissue abnormally implanted outside the uterus and primarily located on the pelvic 
peritoneum, ovaries, and rectovaginal septum.1 By anatomical locations of the lesions, there are 
three sub-types of endometriosis, i.e. superficial peritoneal endometriosis, endometrioma (or 
ovarian endometriosis) and deep infiltrating endometriosis (DIE, defined by the invasion of 
endometriotic lesions >5 mm beneath the peritoneal surface).2,3 Endometriosis is estimated to affect 
6% to 10% of women of reproductive age and clinical symptoms include pain and infertility.4,5 It 
has been estimated that, in Europe, the average annual direct health care costs of endometriosis are 
€3113 per woman suffering from endometriosis-associated symptoms, and the indirect costs of 
productivity loss are twice as much as the direct health care costs.6  
Adenomyosis, also known as endometriosis interna, is defined as benign invasion of endometrium 
into the myometrium, producing a diffusely enlarged uterus, which microscopically exhibits 
ectopic, endometrial glands and stroma.7,8 Adenomyosis and endometriosis are considered similar 
diseases and are often coexisting, because both diseases are characterised by the presence of 
endometrial glands and stroma outside their normal locations and share a common pathophysiology 
of tissue changes.9  
Surgical confirmation of endometriosis and adenomyosis through e.g. laparoscopy / hysterectomy 
is the gold standard of diagnosis. However, the invasive nature of surgery often leads to a delay in 
diagnosis of up to 10 years.6 As a non-invasive diagnostic tool, high-resolution magnetic resonance 
imaging (MRI) is very useful in mapping endometriosis and preoperative surgical planning by 
providing information on the sub-peritoneal extent that can be overseen by laparoscopy. In general, 
the MRI sensitivity and specificity for the identification of endometriosis are relatively high (71% 
and 82%, respectively) and are sometimes even higher for endometrioma and DIE, the two sub-
types of endometriosis selected in this trial.10 Similarly, MRI is highly predictive of adenomyosis.11 
In addition, MRI can provide valuable information on tissue characterisation.  
Treatment of endometriosis and adenomyosis currently involves repeated courses of medical 
therapy, surgical therapy, or both. Empirical treatment with analgesics and combined oral 
contraceptives to relieve dysmenorrhea, without prior definitive diagnosis by surgery, is usually the 
first line treatment especially in adolescents.12 All established hormonal therapies (progestogen, 
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 associated 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.13,14 Long-term treatment of endometriosis or adenomyosis 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 


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agonists have been suggested to inhibit the angiogenesis process that is essential for the initiation, 
growth, invasion and recurrence 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 and is 
approved in Europe as oral tablets under tradename NORPROLAC for the treatment of 
hyperprolactinaemia. In addition, it has been formulated into an extended-release vaginal ring for 
the treatment of endometriosis. 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 on quinagolide vaginal ring, please refer to the Investigator’s Brochure.15 
 
1.2 
Scientific Justification for Conducting the Trial 
As an integral part of the endometriosis pathogenesis, the establishment of 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 and the peritoneal fluid of 
endometriosis patients.16,17,18 A positive correlation between the severity of endometriosis and the 
level of VEGF concentration in peritoneal fluid has been observed.18  
Dopamine 2 receptors are present in ectopic endometrium.19 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.20 In addition, it has been shown that dopamine receptor 2 
agonists diminish nerve fibre density in experimental endometriotic lesions.21  
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 high oral doses of quinagolide (50 or 200 μg/kg per day during a 14-day period) 
versus vehicle.22 In a clinical trial involving 9 hyperprolactinaemic 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.23 Another clinical study in endometrioma patients demonstrated that 
cabergoline, a dopamine receptor 2 agonist, was significantly more effective in decreasing the size 
of endometrioma assessed by transvaginal ultrasound (TVU), compared to GnRH agonist triptorelin 
acetate after 3 months’ treatment.24  


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As part of the clinical development programme of quinagolide for endometriosis, three phase 1 
trials have been conducted with intravaginal administration of quinagolide in healthy volunteers in 
Germany and in United Kingdom. Based on the results of phase 1 trials, quinagolide administered 
as a vaginal ring avoids daily fluctuations of quinagolide levels as seen with oral administration and 
thereby has improved its tolerability. 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. Key results of each phase 1 trial are summarised below.  
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, no impact on ovarian functions or menstrual cyclicity were observed following 
sequential administration of quinagolide vaginal rings for two menstrual cycles (Trial 000207).  
To provide supportive data on the mechanism of action of quinagolide, the present trial intends to 
evaluate the effect of quinagolide vaginal ring on the reduction of endometriotic lesions assessed by 
MRI. Since adenomyotic lesions are similar to endometriotic lesions and can be clearly identified 
by MRI, the effect of quinagolide vaginal ring on the reduction of adenomyotic lesions will also be 
evaluated in this trial. 
MRI is considered the best imaging technique for mapping endometriosis.25 Compared with 
ultrasound, MRI is less observer-dependent and more reproducible. A few studies have also shown 
that MRI is more accurate than TVU when correlating with histopathological findings of 
endometriosis / adenomyosis.26,27 However, due to its high costs, MRI is often used in more 
complicated cases and is considered as a second-line imaging technique after ultrasound.25 In the 
present trial, MRI is used as the primary imaging tool to assess endometrioma, DIE, and 
adenomyosis and TVU is used to assess endometrioma.  
Of the three sub-types of endometriosis, endometrioma and DIE can be visualised by MRI with a 
fairly high sensitivity (82%-90% for endometrioma and 67%-83% for DIE) and specificity (91%-
98% for endometrioma and >89% for DIE).10,28 Due to its high concentration of blood and proteins, 
endometrioma demonstrates high signal intensity on T1-weighted images and low signal intensity 
on T2-weighted images.29 Deep infiltrating endometriosis can involve the pelvic ligaments, anterior 
rectosigmoid colon, bladder, uterus, and cul-de-sac, as well as surgical scars; the lesions often have 
 
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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poorly defined margins and T2 signal hypointensity as a result of fibrosis.29 The presence of sub-
centimetre foci with T2 hyperintensity representing ectopic endometrial glands within these 
infiltrating fibrotic masses may help establish the diagnosis.29  
The accuracy of MRI in the diagnosis of adenomyosis has long been established with a sensitivity 
of 88%-93% and a specificity of 67%-91%.11 On T2-weighted images, adenomyosis appears as a 
poorly-marginated low-signal-intensity area and additional small high-signal-intensity areas 
referring to ectopic endometrium.27 These MRI findings are related to the thickening or hyperplasia 
of the junctional zone and a maximum junction zone thickness of ≥12 mm has been widely used as 
the major criterion for the diagnosis of adenomyosis.8,27,30  
With its high spatial resolution, MRI can also provide additional information on tissue structure and 
functionality. The use of dynamic, contrast-enhanced (DCE) perfusion imaging biomarkers can 
highlight endometriotic tissues with high angiogenesis expression and thereby evaluate the anti-
angiogenic effect of quinagolide through the assessment of tissue vascularisation and vessel 
permeability before and after the treatment.10 Diffusion imaging biomarkers can capture changes in 
water molecules behaviour within tissue microarchitectures, allowing to quantify the diffusion 
coefficient associated with cell density and interstitial space disruption, both of which may help 
define the nature of lesions, especially for endometrioma and adenomyosis.10  
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 and/or adenomyosis. The 
present phase 2 trial aims at assessing the effect of quinagolide vaginal ring on the reduction of 
lesions in women with endometrioma, DIE and adenomyosis. The results of the present trial will 
provide further evidence on the mechanism of action of quinagolide, help identify subgroups of 
endometriosis patients that might benefit from quinagolide, and support the sponsor’s decisions on 
further development of the clinical programme on quinagolide.  
 
1.3 
Benefit / Risk Aspects 
Benefits 
In each subgroup, subjects will be randomised in a 2:1 ratio to quinagolide vaginal ring or placebo 
vaginal ring and may benefit from relief of their symptoms if the treatment is effective. Subjects 
participating in this trial may also benefit from a comprehensive survey of their diseases by the 
MRI examination, which is not routinely performed in standard clinical practices. Subjects will also 
be reimbursed for travel expenses and for the analgesic use for the management of endometriosis or 
adenomyosis pain in line with local reimbursement policies and regulations. 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. If a 3-month wash-out is 
required for participation in the trial, subjects can be compensated for resuming their original 
treatment after the end-of-trial in line with local reimbursement policies and regulations. 
 


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Risks 
The risks associated with this clinical trial, including the risks of the investigational medicinal 
product (IMP), clinical and laboratory procedures, are explained to subjects as part of the 
counselling prior to start of the trial.  
Risks – Investigational Medicinal Product 
In the clinical development programme 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 
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 ovarian function 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, haematology or urinalysis parameters, nor on vital signs, electrocardiography 
recordings, physical or gynaecological 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-moulded rings instead of glued 
rings) will be used in the present trial.    
Quinagolide is approved as an oral tablet formulation under tradename NORPROLAC for the 
treatment of hyperprolactinaemia in Europe and in some other countries. 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 characterised by adverse events involving the gastrointestinal tract and central nervous system. 
The most frequent adverse events (all reported as very common, i.e. at a frequency of ≥10%) in 


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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 secondary to orthostatic hypotension. Orthostatic hypotension occurs at a frequency of 1-10% 
among patients treated with quinagolide oral tablets. As a risk mitigation, subjects should be 
instructed to lie down when experiencing dizziness or light-headedness during the initiation of the 
treatment. 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.31 Impulse control disorders involving pathological gambling, 
increased libido, hypersexuality, 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.32 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 
is not known to have any 5-HT-receptor activity at clinically relevant doses.33,34 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.15 Based on 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. Single-
barrier contraception is considered to be adequate in the present trial. Condoms and contraception 
counselling will be offered throughout the trial and condoms will be provided to all subjects at 
almost every visit to avoid occurrence of pregnancy during participation of the trial. As a 
precautionary measure, a urine pregnancy test will be performed 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.  
Procedures in this trial are mainly MRI, TVU and blood sampling, which are non-invasive or 
minimally invasive. The MRI is a painless radiology technique that has the advantage of avoiding 
the harmful effects of ionizing radiation. Due to the use of the strong magnet, MRI is 
contraindicated in patients with internal or external metallic objects such as implanted devices or 
leg braces. Adverse events associated with MRI are very rare (<0.01%).35 The majority of those 
adverse events are body temperature increase from the radio-frequency energy and hearing 
problems due to the noises of the gradient magnetic fields.35 The use of contrast media in MRI may 
carry a risk of allergic reaction to the contrast media, with an incidence of acute adverse reactions 
varying from 0.17% to 2.4%.36 Fasting may cause dizziness, headache, stomach discomfort or 
fainting, but fasting is required for only 3-4 hours before the MRI examination. The TVU 


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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. 
For further information on quinagolide vaginal ring, please refer to the Investigator’s Brochure.15  


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2 
TRIAL OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
Primary Objective 
• To evaluate the effect of quinagolide vaginal ring compared to placebo on reduction of 
lesions for endometrioma, deep infiltrating endometriosis (DIE) and adenomyosis assessed 
by high-resolution magnetic resonance imaging (MRI) 
 
Secondary Objectives  
• To evaluate the effect of quinagolide vaginal ring compared to placebo on reducing the sizes 
of endometrioma assessed by transvaginal ultrasound (TVU) 
• To evaluate the effect of quinagolide vaginal ring on patient reported outcomes (PROs) 
• To evaluate the plasma concentrations of quinagolide and its metabolites 
• To evaluate the effect of quinagolide vaginal ring on serum endocrine parameters 
• To evaluate the effect of quinagolide vaginal ring on menstrual bleeding pattern 
• To evaluate the safety profile of quinagolide vaginal ring including adverse events and 
routine safety laboratory parameters 
 
Exploratory Objectives  
• To explore the effect of quinagolide vaginal ring on the MRI-derived perfusion imaging 
biomarkers of angiogenesis and on the MRI-derived diffusion imaging biomarkers of lesion 
tissue structure  
• To explore the effect of quinagolide vaginal ring on reducing the size of uterine fibroids 
assessed by both MRI and TVU 
• To explore the effect of quinagolide vaginal ring on endometriosis biomarkers 
 
2.2 
Endpoints 
Primary Endpoint 
• Changes in the sizes (mm) of endometrioma, DIE and adenomyosis lesions summed by type 
on MR images at cycle 4 
 
Secondary Endpoints 
• Percentage of changes in the sizes of endometrioma, DIE and adenomyosis lesions summed 
by type on MR images at cycle 4 
• Proportion of lesions by type with a decrease in a size of ≥5 mm on MR images at cycle 4 


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• Proportion of subjects with a lesion of any type decreased in a size of ≥5 mm on MR images 
at cycle 4 
• Number of new or disappearing endometrioma, DIE and adenomyosis lesions summed by 
type on MR images at cycle 4 
• Changes in the volumes (mm3) of endometrioma and DIE lesions summed by type on MR 
images at cycle 4 
• Changes in the sizes of endometrioma assessed by TVU at cycle 4 
• Changes in the mean individual and total symptom and sign severity of scores of the 
Biberoglu and Behrman (B&B) scale at cycle 4  
• Changes in the Numerical Rating Scale (NRS) pain scores per cycle at cycles 1, 2, 3 and 4 
• Changes in the Endometriosis Health Profile-30 (EHP-30) scores at cycles 2 and 4 
• Changes in the menstrual bleeding pattern over 4 cycles 
• Serum levels of prolactin, thyroid-stimulating hormone (TSH), insulin-like growth factor-1 
(IGF-1) during cycle 1, at cycles 2 and 4 
• Plasma concentrations of quinagolide and its metabolites during cycles 1 to 4  
• Changes in clinical chemistry and haematology parameters and proportion of subjects with 
markedly abnormal changes 
• Frequency and intensity of adverse events  
 
Exploratory Endpoints 
• Changes in the MRI-derived perfusion imaging biomarkers of AUC, Ktrans, kep, ve, vp at 
cycle 4  
• Changes in the MRI-derived diffusion imaging biomarkers of ADC, D, D* and f at cycle 4  
• Changes in the sizes of uterine fibroids on MR images at cycle 4  
• Changes in the sizes of uterine fibroids assessed by TVU at cycle 4 
• Changes in circulating levels of VEGF, placental growth factor (PlGF), interleukin 6 (IL-6), 
cancer antigen 125 (CA125) 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 diagram illustrating the trial design is shown in Figure 3-1.  
 
Abbreviations: B&B=Biberoglu and Behrman Scale, d=day(s), DIE=deep infiltrating endometriosis, EHP-30=Endometriosis Health Profile 30 
Questionnaire, Mens. pattern=menstrual bleeding pattern, MRI=magnetic resonance imaging, NRS=Numerical Rating Scale, 
PK=pharmacokinetic(s), RM=return of menses, RM+7=day 7 after return of menses, TVU=transvaginal ultrasound, V=visit 
 
Figure 3-1 Trial Diagram – Trial Period 
 
3.1.2 
Overall Design and Control Methods 
This is a randomised, double-blind, placebo-controlled, phase 2 trial investigating the effect of 
quinagolide extended-release vaginal ring on reduction of lesions, assessed by high-resolution MRI, 
in women with endometrioma, DIE and/or adenomyosis.  
In this trial, quinagolide vaginal ring or placebo vaginal ring will be administered sequentially for 
four menstrual cycles, where a menstrual cycle is considered the period between day 7 after return 
of menses (RM+7) in a cycle until the following day 7 after return of menses of the next cycle. The 
RM+7 visits in this trial can be scheduled within the period of 6-10 days after return of menses 
(RM+6-10).  
Screening 
Placebo vaginal ring for 4 cycles
Quinagolide vaginal ring for 4 cycles
Treatment
DIE  
Adenomyosis
Endometrioma
MRI
TVU
PK
PK
PK
PK
PK
MRI
B&B
NRS
NRS
B&B
RM+7
Randomisation / V2
Informed consent
NRS
Safety lab
Biomarker
PK
Safety lab
Biomarker
RM+7 / V5
RM+7 / V6
RM+7 / V7
RM+7 / V8
End of treatment
Cycle 4
Cycle 1
Cycle 2
Cycle 3
1-3 months
1-5d of randomisation / V3
7-14d of randomisation / V4
Endocrine
Endocrine
Endocrine
TVU
NRS
NRS
EHP-30
EHP-30
EHP-30
Endocrine
Wash-out
RM+7
Screening visit / V1
Follow-up
Phoe call at 1 month 
after end-of-treatment
1 month
Cycle -1
Mens. pattern
Mens. pattern
Mens. pattern
Mens. pattern
Mens. pattern


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The trial consists of the following periods: 
1) Screening: starting from the signing of informed consent to randomisation (approximately 
4 months) and including a wash-out period (only applicable to subjects using some hormonal 
products) and a screening cycle (cycle -1, applicable to all subjects) 
2) Treatment: double-blind, placebo-controlled treatment with quinagolide vaginal ring or placebo 
vaginal ring administered sequentially for four menstrual cycles (cycles 1, 2, 3 and 4) 
3) Follow-up: about 1 month after end-of-treatment 
Screening: Subjects should be screened for eligibility within approximately 4 months of 
randomisation. Subjects who are currently using some hormonal products (e.g. combined oral 
contraceptive pill, progestogen and levonorgestrel-releasing intrauterine device (IUD)) may be 
eligible for the trial if they have completed the wash-out period and have return of menses. In this 
case, subjects need to sign the informed consent before they discontinue those products. 
Discontinuation of the products should follow their labelling (e.g. completing the current cycle of 
contraceptives before discontinuation). Subjects who are not using exclusionary hormonal products 
can enter the screening cycle directly. Prescriptions of analgesics for pain management are allowed 
in this trial. 
After having completed the wash-out period (if applicable) and having return of menses, subjects 
will attend the screening RM+7 visit to undergo initial screening assessments, including a MRI 
examination by a high resolution 3-tesla (3T) machine. Depending on facilities at sites, MRI may 
not necessarily be scheduled at the same screening visit, but it must be scheduled on a day without 
bleeding to avoid biases and to ensure the availability of the central MRI reading report prior to 
randomisation. The MRI at screening, used as baseline, should not be obtained more than 1 
menstrual cycle before randomisation.  
Eligible subjects must have at least one of the following three types of lesions with the following 
sizes identified by MRI: endometrioma (≥20 mm), DIE (≥15 mm), and/or adenomyosis (maximum 
junctional zone thickness ≥12 mm or focal lesion ≥15 mm). If a subject has more than one type of 
lesions, she will be grouped under the more rare type in the ranking of DIE, adenomyosis and 
endometrioma. For example, a subject with both DIE and endometrioma will be included in the 
DIE sub-group but both types of lesions should be measured. Every measurable lesion (defined as 
≥10 mm in size) of any type should be recorded and should be summed up by type for primary 
analysis. For DIE and endometrioma, lesions will be measured both in size and in volume. For 
uterine fibroid, only size will be measured. Size will be recorded in mm as the longest diameter in 
the plane of measurement. Volume will be recorded in mm3 using a semi-automated method based 
on 3D region-growing algorithm, adjusted with manual correction. For adenomyosis, the maximum 
junctional zone thickness (applicable to diffuse adenomyosis) or the size of the largest focal lesion 
(applicable to focal adenomyosis) will be measured. All MRIs should be uploaded into a specific 
image repository allocated for this trial within 2 business days for central reading and analyses by a 
specialised imaging laboratory. Subject eligibility with regard to inclusion criterion no. 6 must be 
determined based on the central MRI reading report.  


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Subjects are required to fast for 3-4 hours before the MRI examination. The preparations for MRI 
examination should follow the trial-specific MRI manual. The MRI procedures will include the 
following main sequences:  
• Fast spin echo – T2-weighted images (FSE-T2)  
• Diffusion weighted (DW-IVIM) images with more than 2 b-values 
• Gradient echo (GRE) – T1-weighted images with varying flip angles (GRE-T1-VFA)  
• Dynamic, contrast-enhanced, spoiled GRE T1-weighted images (DCE-PKM-Gd)  
• Late gadolinium enhancement spoiled GRE T1-weighted images (GRE-T1-LATEGd)   
Other details for the MRI examination will be specified in the MRI manual. Prior to the start of the 
trial, site radiologists will be trained on the MRI manual. Site radiologists must follow the MRI 
manual for the preparation and the execution of the MRI assessment.  
In addition to MRI, a TVU should be performed at the screening RM+7 visit to assess uterus, 
endometrium, and ovaries and to measure the size(s) of any endometrioma and/or fibroid. 
Subjects will be required to use a non-hormonal single-barrier method for contraception (i.e. 
condom) from screening to end-of-treatment. 
Treatment: Eligible subjects in each sub-group will be randomised at the end of cycle -1 in a 2:1 
ratio to receive quinagolide vaginal ring or placebo vaginal ring for four menstrual cycles (cycles 1, 
2, 3 and 4). Approximately 24 subjects will be randomised in each sub-group, adding up to a total 
of 72 subjects in this trial. Quinagolide vaginal ring contains a dose load of quinagolide 1080 µg at 
a target daily release rate of quinagolide 13.5 µg. 
After randomisation, subjects will self-insert the assigned ring in the upper part of the vagina at 
sites 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 by the next ring at RM+7 visit of the next cycle.  
Subjects who have discontinued during or after cycle 2 should come for an end-of-treatment visit 
with MRI, scheduled within 2 weeks of discontinuation. Subjects who have completed the 
scheduled treatment should come for an MRI examination at or close to the RM+7 visit of cycle 4. 
The MRI at end-of-treatment / cycle 4 must be performed using the same machine, following the 
same procedures and sequences as at screening (detailed in the MRI manual).  
To measure permeability, perfusion imaging biomarkers of the one-compartmental metric (AUC) 
and the two-compartmental metrics (Ktrans, kep, ve, vp) will be derived from the dynamic perfusion 
series. In addition, diffusion metrics (ADC, D, D* and f) of lesion tissue structure will be obtained 
using the intra-voxel incoherent motion (IVIM) model. All perfusion and diffusion parameters at 
screening and at end-of-treatment will be assessed and analysed by the central imaging laboratory. 
All lesions will be segmented in 3D by two radiologists for the analyses of imaging biomarkers.  


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Transvaginal ultrasound will be performed at end-of-treatment / cycle 4, preferably by the same 
sonographer as at screening, to measure the sizes of endometrioma and/or uterine fibroid.  
B&B will be administered at randomisation and at end-of-treatment / cycle 4, with trial 
coordinators completing the first part based on subjects’ verbal response and investigators 
completing the second part based on findings of a pelvic examination. At each RM+7 visit from 
randomisation to cycle 4, subjects will score the worst pain they experienced during the past 
menstrual cycle on a self-administered NRS, with 0 indicating no pain and 10 indicating worst 
imaginable pain. In addition, they will complete the EHP-30 questionnaire at randomisation, at 
cycle 2 and at end-of-treatment / cycle 4. All PROs will be administered on paper at sites.    
At each RM+7 visit from randomisation to end-of-treatment / cycle 4, the site staff should inquire 
about the bleeding pattern of the subject’s immediate past menstrual period, including the start and 
stop dates (if available) of menstrual bleeding and the amount of menstrual flow.  
Blood samples are collected throughout the trial for the purpose of evaluating endocrine profile, 
plasma concentrations of quinagolide and its metabolites, routine safety laboratory parameters as 
well as endometriosis biomarkers. Endocrine parameters, consisting of prolactin, TSH and IGF-1, 
will be assessed at randomisation, within 1-5 days of randomisation, at cycle 2 and at end-of-
treatment / cycle 4. To measure the plasma concentrations of quinagolide and its metabolites, blood 
samples will be taken within 1-5 days of randomisation, within 7-14 days of randomisation and 
prior to ring removal at RM+7 visits of cycles 1 to 4. Routine safety laboratory tests for clinical 
chemistry and haematology parameters will be performed at screening and at end-of-treatment / 
cycle 4. Blood samples for serum and plasma endometriosis biomarkers of VEGF, PlGF, IL-6, 
CA125 and sFlt-1 will be collected at randomisation and at end-of-treatment. 
A follow-up telephone call will be made to all subjects at about 1 month after the end-of-treatment / 
cycle 4 visit to collect information about adverse events and concomitant medications since the 
visit, and reasons for resuming medications indicated for endometriosis / adenomyosis.  
 
3.1.3 
Trial Schedule 
First patient first visit (FPFV) 
 
 
Q3 2019 
Last patient last visit (LPLV)  
 
 
Q2 2021 
 
3.2 
Planned Number of Trial Sites and Subjects 
It is planned to randomise approximately 72 subjects, with approximately 24 subjects in each sub-
group, from 8-12 sites in Europe. It is estimated that 100 subjects will be screened in this trial.  
If the drop-out rate in any of the sub-group is larger than 10%, the sample size of randomised 
subjects may be increased to up to 30 for that sub-group. 
 


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3.3 
Interim Analysis 
No interim analysis is planned for this trial. 
 
3.4 
Data Monitoring Committee  
No Data Monitoring Committee is planned for this trial. During the trial, the internal Safety 
Management Team at Ferring will evaluate blinded safety data at least quarterly. 
 
3.5 
Discussion of Overall Trial Design and Choice of Control Groups 
3.5.1 
Trial Design 
The primary objective of the trial is to evaluate the effect of quinagolide administered as an 
extended-release vaginal ring compared to placebo vaginal ring on reduction of lesions in women 
with endometrioma, DIE and/or adenomyosis. 
This is a randomised, double-blind, placebo-controlled trial. The double-blind, placebo-controlled 
clinical trial has a long history as the standard for investigations of new drugs and is commonly 
used in clinical trials of endometriosis (e.g. ClinicalTrials.gov NCT00225199, NCT01931670). 
Currently, there is no approved non-hormonal treatment of endometriosis. Moreover, the placebo 
response has not been rigorously characterised with respect to endometriotic/adenomyotic lesion 
reduction. A placebo group is justified for this trial in order to properly evaluate the absolute 
treatment effect of quinagolide on lesion reduction. Furthermore, there is a need to account for the 
placebo effect beyond lesion sizes, such as pain reduction and vessel permeability, for a proper and 
comprehensive evaluation of the anti-angiogenic treatment effect of quinagolide. In this trial, 
ethical concerns of using placebo controls have been addressed by allowing subjects to use 
analgesics for pain relief as needed. In addition, the use of analgesics can help prevent dropouts due 
to lack of efficacy. With a randomisation ratio of 2:1, the chance for a subject being randomised to 
the placebo group is decreased, compared to a randomisation ratio of 1:1.  
A double-blind design will ensure blinding and thereby unbiased evaluations of the primary 
endpoint and the secondary endpoints related to MRI findings assessed by the central imaging 
laboratory. Similarly, the blinding of investigators and subjects can guarantee unbiased evaluations 
of the secondary endpoints related to the PROs. Precautions and measures taken to ensure double-
blinding of the trial are described in detail in section 3.5.3.  
In this trial, there are three sub-groups of subjects, with each sub-group representing one sub-type 
of lesions, i.e. endometrioma, DIE and adenomyosis. Epidemiology studies have shown that 
endometriosis and adenomyosis can often coexist in the same subject.37,38 Since MRI can assess all 
pelvic compartments comprehensively at one time, it is feasible and convenient to examine any of 
the three sub-types of lesions presented in the subject in one MRI examination. The design of three 
separate sub-groups, with subjects on placebo in each sub-group, can ensure changes in each sub-


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type of lesions are assessed against placebo and thereby help identify the sub-type of lesions that 
responds best to the treatment.  
Although a multi-centre setting can help guarantee that the required number of subjects can be 
recruited within a reasonable time and also support the subsequent generalisation of the results, this 
trial is limited to a few trial centres with machines of high field strength (3T) and of limited brands 
to minimise variability of results. In addition, the standardisation of the MRI preparations, 
sequences and procedures in the trial-specific MRI manual, cross calibration among sites as well as 
the central reading and analyses of images by the same specialised laboratory have to a great extent 
been incorporated in the design of this trial to minimise variations across sites.  
The treatment period of the trial lasts for four menstrual cycles, which approximately corresponds 
to the active treatment duration of 18-20 weeks in the second-look laparoscopy study, where 
significant reductions in endometriotic lesions were observed following oral administration of 
quinagolide up to 75 µg. 
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 such as oral contraceptives and intrauterine devices (IUDs) can 
potentially interfere with the assessment of lesions. Throughout the trial, contraception counselling 
and condoms will be offered to avoid occurrence of pregnancy during treatment. As a precautionary 
measure, a urine pregnancy test will be performed once per menstrual cycle in the present trial. If 
the test result is positive and is confirmed by a serum βhCG test, the subject will be discontinued 
from the trial immediately.   
 
3.5.2 
Selection of Endpoints 
The primary endpoint of the present trial is the change in the size of endometrioma, DIE and 
adenomyosis lesions summed by type on MR images compared to placebo at cycle 4.  
It is considered clinically sufficient to evaluate changes in the endometriotic / adenomyotic lesion 
sizes after four menstrual cycles, because MRI may not be able to detect minimal changes within a 
short period and endometriotic / adenomyotic lesions are much less aggressive than solid tumours, 
the latter of which are usually evaluated only every 3 months per standard clinical practices. In a 
similar trial assessing adenomyotic lesions by MRI, lesion sizes were evaluated after 6 months of 
treatment with levonorgestrel-releasing IUDs, indicating a mean (±SE) maximal junction zone 
thickness of 17.7 (±0.9) mm at baseline and of 13.1 (±0.8) mm at 6 months (p<0.001).39  
The primary endpoint and primary analysis focus on lesions of ≥10 mm at baseline, which are 
considered “measurable” lesions that are subject to “reproducible repeated measurements” at both 
baseline and at cycle 4. This approach is similar to the selection of target lesions in solid tumours 
and follows the revised Response Evaluation Criteria in Solid Tumours (RECIST) guideline 
(version 1.1).40   


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A relatively strict timing of the MRI assessment, i.e. on a day without bleeding, is required in the 
trial to avoid biases and errors due to the mucosal and myometrial physiological changes during 
bleeding. This practice is in line with the recommendations of radiologists.3,41  
To address measurement limitations of MRI, lesions with a clinically relevant size reduction of 
≥5 mm at cycle 4 are further investigated as part of secondary endpoints. Number of new lesions 
and disappearing lesions (defined in section 7.1) are evaluated to capture lesion progression and 
regression, even if their sizes may not necessarily be measurable. In addition to lesion size, volume 
of endometrioma and DIE lesions are also measured as a complementary metric of lesions by MRI. 
Since TVU is commonly used in clinical practices and can also measure endometrioma, the sizes of 
endometrioma will be evaluated by TVU as a secondary endpoint.  
Other secondary endpoints include B&B, NRS and EHP-30, which are all widely used PROs on 
symptoms and quality of life of endometriosis patients. The B&B scale42 has been widely used for 
endometriosis patients in other endometriosis trials and is selected in the present trial for historical 
comparison. Likewise, the validated 11-point NRS is commonly used in clinical trials to quantify 
pain intensity and is administered on a monthly basis in this trial. Since endometriosis patients can 
also have a compromised quality of life, the EHP-30 questionnaire43 will be administered to assess 
any changes in quality of life associated with treatment.  
Plasma concentrations of quinagolide and its active metabolites (M1 and M2) will be assessed to 
allow estimation of population pharmacokinetic (PK) parameters and investigation of the exposure-
response relationship with lesion reduction being the response in the present trial. Endocrine 
parameters related to the effect of quinagolide will be evaluated. Safety endpoints cover the 
monitoring of adverse events and routine safety laboratory parameters. 
Exploratory endpoints include perfusion imaging biomarkers to assess the angiogenesis expression 
of tissues and diffusion imaging biomarkers to evaluate cell density, thereby providing evidence on 
the mechanism of action of quinagolide. Similarly, plasma and serum endometriosis biomarkers of 
VEGF, PlGF, IL-6, CA125 and sFlt-1 can help monitor the treatment response to quinagolide. The 
treatment effect on uterine fibroids will also be explored. 
 
3.5.3 
Blinding 
The present trial is double-blind. Subjects, investigators, radiologists, other trial staff and MRI 
analysers at the central imaging laboratory will be blinded to treatment allocation during the 
conduct of the trial. Blinding is achieved by randomising subjects in a 2:1 ratio to a vaginal ring 
containing quinagolide dose load 1080 µg or placebo, both 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 


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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.  
Central laboratory analysis results of some endocrine parameters (prolactin, TSH and IGF-1) after 
randomisation and results of endometriosis biomarkers throughout the trial will not be available to 
site or sponsor staff until breaking of the blind. To avoid potential speculation of treatment 
allocation by comparing current pain scores against previous scores, subjects are not given access 
to historically reported data. 
 
3.5.4 
Selection of Dose in the Trial 
Selection of quinagolide vaginal ring dose is based on safety, tolerability and pharmacokinetics data 
obtained from the completed 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 with hyperprolactinaemia.23 The repeated oral 
administration and intravaginal administration of 75 µg quinagolide tablets once daily for 5 days in 
the first phase 1 trial (Trial 000076) showed that intravaginal administration of quinagolide tablets 
was associated with higher exposure of quinagolide and reduced levels of metabolites, 
demonstrating that intravaginal administration circumvents the first pass metabolism. However, it 
was well tolerated with lower incidences of treatment-related adverse events, compared with oral 
administration. In addition, intravaginal administration had a slow absorption with approximately 
8 hours to reach the Cmax of quinagolide, compared with oral administration (Tmax about 1 hour).  
In the subsequent trial (Trial 000155), following administration of the highest dose of quinagolide 
vaginal ring, the mean quinagolide 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 concentrations are 
similar to the mean Cmax of 8 pg/mL observed with the 75 µg oral tablet. In addition, quinagolide 
administered as a vaginal ring avoids daily fluctuations of quinagolide levels as seen with oral 
administration.  
Based on the above data, the highest dose load of quinagolide vaginal ring at a target release rate of 
13.5 µg/day seems to have the most favourable pharmacokinetic profile associated with reduction 
in the size of endometriotic lesions while being well-tolerated and is therefore selected for this trial. 
 
3.5.5 
Selection and Timing of Dose for Each Subject 
In the present 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 after return of menses 
(RM+7) in a cycle until the following day 7 after return of menses of the next cycle.  


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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 or the end 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 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 / adenomyotic lesions prior to 
return of the menses in the next cycle, when most of the severe pain occurs. 
 
3.5.6 
Selection of the Trial Population 
The trial population consists of subjects presenting endometrioma, DIE and/or adenomyosis 
confirmed by the MRI examination. As mentioned in section 1.2, these are the three sub-types of 
lesions that can be visualised by MRI with a fairly high sensitivity and specificity and therefore the 
selected trial population is considered suitable for using MRI to evaluate lesion changes. As 
supplementary information, prior surgeries of eligible subjects will be recorded in medical history.  
To be eligible for this trial, subjects should have at least one of the following sizes of lesions 
identified by MRI: endometrioma (≥20 mm), DIE (≥15 mm), and/or adenomyosis (junctional zone 
thickness ≥12 mm or focal lesion ≥15 mm). The selected thresholds of lesions sizes ensures that 
eligible subjects present relatively large lesions, whose sizes and whose changes in sizes can be 
well captured by MRI, although every lesion ≥10 mm will be measured at baseline.  
The trial will include pre-menopausal women aged between 18 and 45 years and thereby cover the 
age span of the most endometriosis and adenomyosis patients. Eligible women are required to have 
menstrual cycles of 24 to 35 days, covering the release duration of quinagolide vaginal ring.  
The exclusion criteria incorporate the contraindications to NORPROLAC and to MRI examination.  
 
3.5.7 
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 signed and dated prior to any trial-related procedures.  
2. In good physical and mental health to participate in the trial. 
3. Pre-menopausal females between the ages of 18-45 years (both inclusive) at the time of 
signing the informed consent. 
4. A menstrual cycle of 24-35 days (both inclusive) based on observation made in the absence 
of drugs that can affect the cycle length (e.g. oral contraceptives) prior to the screening visit.  
5. Body mass index (BMI) of 18-35 kg/m2 (both inclusive) at screening. 
6. Confirmation of deep infiltrating endometriosis (DIE) (lesion size ≥15 mm), endometrioma 
(≥20 mm) or adenomyosis (maximum junctional zone thickness ≥12 mm or focal lesion 
≥15 mm) by high-resolution MRI at screening. 
7. Transvaginal ultrasound documenting a uterus with no abnormalities of endometrium and 
presence of at least one ovary with no clinically significant abnormalities at screening. Note 
that presence of uterine fibroids are not exclusionary but presence of any submucosal 
fibroids or polyps are exclusionary.  
8. Willing and able to use a non-hormonal single-barrier method (i.e. condom) for 
contraception from the start of screening to the end-of-treatment. This is not required if 
adequate contraception is achieved by vasectomy of the male sexual partner, surgical 
sterilisation (e.g. tubal ligation and blockage methods such as ESSURE) of the subject, or 
true abstinence of the subject (sporadic sexual intercourse with men requiring condom use).  
9. Willing to avoid the use of vaginal douches or any other intravaginally administered 
medications or devices (except for tampons) from randomisation to the end of treatment. 
10. Documentation of normal cervical cytology, or negative human papilloma virus (HPV) 
results for high-risk viral subtypes upon presence of atypical squamous cells of undetermined 
significance, based on test(s) performed within 24 months of randomisation.  
11. Willing and able to comply with trial procedures, including attending scheduled visits and 
adherence to treatment plan. 
 
4.1.2 
Exclusion Criteria 
1. Use of depot medroxyprogesterone acetate (MPA) within 10 months prior to the screening 
visit. 
2. Use of gonadotropin-releasing (GnRH) agonists (3-month depot) or dopamine agonists 
within 6 months prior to the screening visit. 
3. Use of GnRH agonists (1-month depot or nasal spray), GnRH antagonists, aromatase 
inhibitors, danazol, birth control implants (e.g. NEXPLANON), progestogen or 
levonorgestrel-releasing IUD within 3 months prior to the screening visit. 


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4. Use of hormonal contraceptives (including combined oral contraceptive pill, transdermal 
patch, and contraceptive ring) and copper IUDs within 1 menstrual cycle prior to the 
screening visit.  
5. Undiagnosed abnormal vaginal bleeding within the last 3 months of the screening visit. 
6. History of recurrent bacterial, fungal or viral vaginal infection (i.e. ≥4 episodes within a 
year). 
7. History of malignancy within 5 years prior to the screening visit, except for adequately 
managed basal cell carcinoma and squamous cell carcinoma of the skin. 
8. History of orthostatic hypotension or recurrent syncope. 
9. History of mental illness including occurrence of acute psychosis, bipolar disorder and 
schizophrenia (except for well-controlled mild or moderate anxiety and/or depression with 
no changes to interventions for 3 months prior to the screening visit). 
10. History of sudden sleep onset episodes.  
11. Known diagnosis of impulse control disorders including pathological gambling, compulsive 
buying, hypersexuality, and binge eating. 
12. Known positive results of Human Immunodeficiency Virus (HIV) antibody tests.  
13. Any other incidental, clinically significant abnormal findings than endometriotic / 
adenomyotic lesions identified at the screening MRI assessment (e.g. suspected tumour).  
14. Any clinically significant abnormal findings from vital signs, blood tests of haematology and 
clinical chemistry at screening, including alanine aminotransferase (ALT) >2.5 times upper 
limit of normal (ULN) or bilirubin >1.5 times ULN or creatinine >1.5 times ULN.  
15. Any clinically significant abnormal findings at physical examination at screening.  
16. Any vaginal or vulvar lesions that would interfere with vaginal ring usage. 
17. Current pregnancy as confirmed by a positive serum pregnancy test at screening or planning 
a pregnancy within the duration of the trial, or currently breast-feeding or less than 6 months 
post-partum prior to the screening visit. 
18. Planned surgical treatment of endometriosis or adenomyosis during the duration of the trial. 
19. Continuous use of strong opioids (e.g. morphine) and/or illicit drugs (e.g. marijuana and 
amphetamine) for more than 2 weeks within 6 months prior to the screening visit.  
20. Alcohol abuse (>14 units of alcohol a week) within 2 years prior to the screening visit.  
21. Previous or current participation in a clinical trial involving a non-registered investigational 
medicinal product within 1 month of screening. If the trial involves a hormonal drug, the 
exclusion criteria 1-4 shall apply. 
22. Contraindications to MRI such as having internal/external metallic devices and/or 
accessories (e.g. cardiac pacemakers and leg braces). 
23. Hypersensitivity to any active ingredients, excipients or other components of medicinal 
products used in the trial, including quinagolide vaginal ring, placebo vaginal ring and any 
products used for MRI examination. 
 


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4.2 
Method of Assigning Subjects to Treatment Groups 
4.2.1 
Recruitment 
The participating subjects will be recruited from sites included in the trial. Advertisements may be 
used if approved by relevant Independent Ethic Committees (IECs) in line with 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 
Randomisation 
At the RM+7 visit (visit 2) of cycle -1, eligible subjects will be randomised in a 2:1 ratio to 
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).  
An independent statistician will create a computer-generated randomisation list and randomisation 
is performed centrally through the Interactive Response Technology (IRT) system prior to the 
insertion of the first vaginal ring. Thereby each subject will receive a unique randomisation number 
generated in the IRT system. Randomisation is stratified by site. 
 
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 from the following period 
indicated before the screening visit until the end-of-treatment: 


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Prohibited medications / therapies 
Examples 
Minimum prohibited period 
before the screening visit 
Depot MPA  
DEPO-PROVERA 
10 months  
GnRH agonist (3-month depot injection)  
LUPRON, ZOLADEX 
6 months 
Dopamine agonist 
bromocriptine  
cabergoline (DOSTINEX) 
6 months 
GnRH agonist (1-month depot injection or 
nasal spray) 
LUPRON, ZOLADEX, 
SYNAREL 
3 months 
Progestogen and levonorgestrel-releasing IUD 
MIRENA 
3 months 
GnRH antagonist  
 
3 months 
Aromatase inhibitor 
 
3 months 
Danazol 
CYCLOMEN 
3 months 
Birth control implants  
NEXPLANON 
3 months 
Hormonal contraceptives* and copper IUDs 
combined oral contraceptive pill, 
transdermal patch and 
contraceptive ring (NuvaRing) 
1 menstrual cycle 
Prohibited medications / therapies from randomisation to the end-of treatment 
Vaginal douches or any other intravaginally administered medications or devices 
*Discontinuation of hormonal contraceptives should follow the labelling of the product (e.g. completing the current cycle of 
contraceptives before wash-out). Emergency contraceptives are allowed from randomisation to the end-of-trial. 
 
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 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 sterilisation (e.g. tubal ligation or blockage methods such as ESSURE) of the 
subject  
• True abstinence of the subject (sporadic sexual intercourse with men requiring condom use) 
 
4.4 
Withdrawal Criteria 
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 has the right to withdraw a subject from the trial if: 
• The subject requires a medical or surgical treatment that is prohibited by the protocol 


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• The subject becomes pregnant as confirmed by urine and serum βhCG pregnancy tests 
• The subject becomes menopausal as confirmed by blood tests for endocrine parameters 
• There are other medical or safety reasons at the discretion of the investigator 
 
Since it is important to collect efficacy and safety data of all randomised subjects, unnecessary 
withdrawal of subjects should be avoided.  
Every effort should be made to invite withdrawn subjects to complete the end-of-trial assessments 
including the end-of-trial MRI as applicable. For any discontinuation, the investigator will obtain 
all the required details and document the date of the premature termination and the main reason in 
the e-CRF.  
Withdrawal of Consent  
If the subject withdraws her consent, no further data will be obtained. However, already obtained 
samples may be analysed. This will be described in the informed consent form. The subject can 
request destruction of samples, which would otherwise have been kept in storage. 
 
4.5 
Subject Replacement 
A subject can only be assigned one screening number and one randomisation number. The 
screening and randomisation number are unique and cannot be re-used. Subjects who discontinue 
prematurely from the trial after randomisation are not to be replaced.  


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5 
TREATMENTS 
5.1 
Treatments Administered 
5.1.1 
Investigational Medicinal Products  
The investigational medicinal products (IMPs) in the present trial will be supplied as vaginal rings 
containing quinagolide 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 
strength of quinagolide vaginal ring investigated in the present trial has a target release rate of 
quinagolide 13.5 µg/day. Quinagolide or placebo vaginal ring is inserted at the RM+7 visit at the 
site and is kept in the vagina continuously until being replaced by a new ring at the RM+7 visit of 
the next cycle.  
At the RM+7 visit (visit 2) of cycle -1, eligible subjects will be randomised in a 2:1 ratio to 
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 instruction for use, irrespective of whether the subject is still experiencing 
menstrual bleeding. If needed, supervision by site staff can be provided and lubricants 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. Any incidents of ring out of the body for more than 24 hours should be captured in the 
e-CRF. 
 
5.1.2 
Non-Investigational Medicinal Product  
No non-investigational medicinal product will be provided in this trial. 
 
5.2 
Characteristics and Source of Supply 
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. 
An illustration of the vaginal ring is provided in Figure 5-1.  


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The content of the quinagolide and placebo vaginal ring is provided in Table 5-1. 
 
5.3 
Packaging and Labelling 
Packaging and labelling of the IMPs 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.  
Quinagolide vaginal ring and placebo vaginal ring will be packaged in an individual foil moisture 
barrier pouch with re-closable gripper and tear notches in identical appearances. The IMPs will be 
labelled with trial-specific labels in accordance with applicable requirements. 
 
5.4 
Conditions for Storage and Use 
The site staff 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 


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the temperature shall be documented in accordance with the instructions provided by the sponsor. 
Quinagolide and placebo vaginal rings must be stored frozen (-25°C to -10°C). The rings will be 
taken out from the freezer at least 30 minutes but not more than 24 hours prior to insertion. 
Deviations in storage temperature must be reported to the sponsor as instructed in the IMP handling 
guideline.  
For information on warnings, precautions and treatment of overdose, please refer to the 
Investigator’s Brochure for the IMP.15 
 
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 randomisation 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 randomisation number in the IRT system, site staff can 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, radiologists, other trial staff as well as in-field monitors and MRI analysers at the 
central imaging laboratory will be blinded to treatment allocation throughout the trial.  
The personnel at the central laboratory analysing blood samples for quinagolide and its metabolite 
concentration will be unblinded to treatment allocation but the personnel at the other central 
laboratory analysing other blood samples will be blinded to treatment allocation throughout the 
trial. 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 randomisation 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 locked. Likewise, the treatment allocation 
information will not be accessible to investigators, trial staff at the site or central laboratory 
personnel during the trial. 
 


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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 IRT system. 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 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. If possible, the investigator should inform the sponsor before 
unblinding. If this is not possible and the event requires immediate unblinding by the investigator, 
the investigator must inform the sponsor of the unblinding as soon as possible afterwards and 
provided the rationale for unblinding.  
The investigator/person who unblinds a subject’s treatment will use the unblinding module of the 
IRT system, in which he/she is required to enter a password before the treatment code can be 
broken. The IRT 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. 
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 IRT, while the 
IRT records when and by whom the code is broken.  
If Ferring needs to unblind a subject’s treatment, the same unblinding module of the IRT system 
will be used for unblinding. It is required to enter a password before the treatment code can be 
broken. The IRT 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 IECs. 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 will be transferred to the e-CRF. 
In case of emergency or accidental unblinding, information on when and by whom the code is 
broken will be transferred to the e-CRF and the reason for unblinding will also be recorded in the 
e-CRF. All information about emergency or accidental unblinding must be collected before the 
database is declared clean and is released to the responsible statistician. 
In case the IRT cannot be accessed and hence the emergency unblinding cannot be performed 
within the IRT system, the investigator should contact Ferring Global Pharmacovigilance using the 


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contact details given below: 
Global Pharmacovigilance, Ferring Pharmaceuticals A/S 
 
If Ferring Global Pharmacovigilance cannot access the IRT, a back-up procedure involving the IRT 
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 randomised in the trial. The site staff will use the IRT system to assign and dispense IMPs. The 
investigator (or his/her delegated personnel) will also record the dates and quantities of IMPs 
dispensed to and returned by each subject, as well as manage the overall drug accountability for 
each subject within the IRT system. The in-field monitor will review and verify the drug 
accountability of the IMPs 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 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) until being returned. 
The used vaginal rings, returned under temperature controlled shipment, may be analysed for 
aspects such as residual quinagolide content. 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.  
All unused medicinal products will be accounted for and must be destructed in a certified way.  
 
5.8 
Auxiliary Supplies 
Sites will be provided 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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6 
TRIAL PROCEDURES 
6.1 
Trial Flow Chart 
Table 6-1 
Trial Flow Chart – Procedures at Clinic Visits 
 
Screening a,b  
Treatment Period b 
Follow-up 
Wash- 
out a 
Cycle -1 
start 
Cycle -1 
end 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
 
Screening 
visit (V1) 
Randomi-
sation (V2) 
V3 
V4 
V5 
V6 
V7 
V8 
Phone call 
 
~1-3 moths 
before V1 
RM+7 
RM+7 
1-5 days 
of V2 
7-14 days 
of V2 
RM+7 RM+7 RM+7 RM+7 / 
EOT 
~1 month 
after V8 
Written informed consent 
  Xa 
Xa 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
 Xa 
X 
Xc 
 
 
 
 
 
 
 
Demographics  
 
X 
 
 
 
 
 
 
 
 
Medical/menstrual/repro history 
 
X 
 
 
 
 
 
 
 
 
Body measurements 
 
X 
 
 
 
 
 
 
 
 
Vital signs  
 
X 
Xc 
X 
 
 
 
 
X 
 
Physical examination 
 
X 
 
 
 
 
 
 
X 
 
Gynaecological examination  
 
X 
 
 
 
 
 
 
X 
 
Cervical cytology d 
 
X 
 
 
 
 
 
 
 
 
Transvaginal ultrasound (TVU) f 
 
X 
 
 
 
 
 
 
X 
 
Urine pregnancy test g 
 
X 
Xc 
 
 
Xh 
Xh 
Xh 
Xh 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
Blood sample (safety) 
 
X 
 
 
 
 
 
 
X 
 
Blood samples (endocrine) 
 
 
Xh 
X 
 
 
Xh 
 
Xh 
 
Blood samples (biomarkers) 
 
 
Xh 
 
 
 
 
 
Xh 
 
Blood sample (PK)  
 
 
 
X 
X 
Xh 
Xh 
Xh 
Xh 
 
MRI 
 
 Xe 
 
 
 
 
 
 
Xe 
 
B&B scale  
 
 
Xh 
 
 
 
 
 
Xh 
 
NRS  
 
 
Xh 
 
 
Xh 
Xh 
Xh 
Xh 
 
EHP-30 questionnaire 
 
 
Xh 
 
 
 
Xh 
 
Xh 
 
Vaginal ring dispensing 
 
 
X 
 
 
X 
X 
X 
 
 
Insertion (i) / removal (r) of ring 
 
 
i 
 
 
i,r 
i,r 
i,r 
r 
 
Drug accountability 
 
 
 
 
 
X 
X 
X 
X 
 
Menstrual bleeding pattern 
 
 
X 
 
 
X 
X 
X 
X 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Condom dispensing / reminder 
 
X 
X 
X 
X 
X 
X 
X 
 
 
End-of-treatment form 
 
 
 
 
 
 
 
 
X 
 
B&B=Biberoglu and Behrman Scale, EHP-30=Endometriosis Health Profile 30 Questionnaire, EOT=end-of-treatment, i=insertion, NRS=Numerical 
Rating Scale, PK=pharmacokinetic(s), r=removal, RM+7=day 7 after return of menses, V=visit.  
a 
Subjects who are currently using some hormonal products (e.g. combined oral contraceptive pill, progestogen and levonorgestrel-releasing IUD) 
may be eligible for the trial if they have completed the wash-out period (if applicable) and have return of menses. In this case, subjects need to 
sign the informed consent before the wash-out. Subjects not requiring wash-out will sign the informed consent at the screening visit. 
b 
A menstrual cycle in this trial is considered the period between RM+7 in a cycle until the following RM+7 in the next cycle. The RM+7 visit can 
be scheduled 6-10 days after return of menses (RM+6-10) and is always at the end of each cycle. An exception is cycle -1 which starts with 
RM+7 of a prior cycle.  
c 
Performed before randomisation.     
d 
Performed only for subjects who do not have a cervical cytology test result within 24 months of the screening visit. 
e 
Performed at or close to the RM+7 visit at screening and at cycle 4 when the subject has no bleeding and no ring. Performed using the same 
machine, following the same procedures and sequences (see MRI manual). Fasting for 3-4 hours in advance. Subjects prematurely discontinued 
during or after cycle 2 should also come for an end-of-treatment visit with MRI, scheduled within 2 weeks of discontinuation. 
f 
Performed preferably by the same sonographer. Size(s) of endometrioma and/or uterine fibroid, if any, should also be measured.   
g 
If the urine pregnancy test is positive, blood collection for a serum βhCG test at the local laboratory must be performed.  
h 
Performed before ring insertion and/or removal, with PROs performed prior to other non-PRO procedures. 


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6.2 
Screening 
Potential participants will be scheduled to come to the clinic for the screening assessments. The 
screening period should not exceed 5 months. A menstrual cycle in this trial is considered the 
period between RM+7 in a cycle until the following RM+7 in the next cycle. The RM+7 visit can 
be scheduled 6-10 days after return of menses (RM+6-10).  
6.2.1 
Wash-out (As Applicable) 
Subjects who are currently using some hormonal products (e.g. combined oral contraceptive pill, 
progestogen and levonorgestrel-releasing IUD) may be eligible for the trial if they have completed 
the wash-out period and have return of menses. In this case, subjects need to sign the informed 
consent before they discontinue those products. Discontinuation of the products should follow their 
labelling (e.g. completing the current cycle of contraceptives before discontinuation). The wash-out 
period will be approximately 1 to 3 months, depending on the applicable requirements for different 
hormonal products (see section 4.3.1). 
The following must take place if a wash-out period is required, prior to initiating the wash-out: 
• Signed and dated written informed consent, obtained prior to any trial-related procedures  
• Check of inclusion and exclusion criteria (those which are possible to check at this stage) 
• Recording of use of concomitant medications (any hormonal treatment of endometriosis / 
adenomyosis within the last 6 months prior to the signed informed consent for participation 
in the trial and any other concomitant medications within the last 3 months prior to the 
signed informed consent for participation in the trial) 
• Recording of adverse events (from the date of signed informed consent) 
• Reminding the subject to contact trial staff as soon as having return of menses and to attend 
the RM+7 visit (visit 1) 
 
6.2.2 
Screening Visit / Visit 1 (Start of Cycle -1) 
Subjects will attend the screening visit (visit 1), scheduled on 6-10 days after return of menses 
(RM+6-10). This is also the start of the screening cycle (cycle -1).  
The following must take place for those subjects who do NOT require a wash-out period: 
• Signed and dated written informed consent, obtained prior to any trial-related procedures 
 
The following procedures must be performed for all subjects: 
• 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] 


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• Vital signs  
• Physical examination 
• Gynaecological examination  
• Cervical cytology test [note: performed only for subjects who do not have a cervical 
cytology test result within 24 months of the screening visit] 
• Transvaginal ultrasound (record the sizes of endometrioma / uterine fibroids, if any) 
• Urine pregnancy test [note: results must be negative] 
• Blood collection for central laboratory analysis of:  
− 
Safety laboratory tests of clinical chemistry and haematology parameters 
[note: the results of both tests must be available prior to randomisation] 
• Recording of use of concomitant medications (any hormonal treatment of endometriosis / 
adenomyosis within the last 6 months prior to the signed informed consent for participation 
in the trial and any other concomitant medications within the last 3 months prior to the 
signed informed consent for participation in the trial; or from last visit) 
• Recording of adverse events (from the date of signed informed consent; or from last visit) 
• Dispensing of condoms and reminding the subject to use proper contraception 
• Reminding the subject of the MRI examination and the RM+7 visit at the end of cycle -1 
 
The following procedures will be performed at the site’s affiliated radiology department, if subjects 
are considered eligible for the trial based on the inclusion and exclusion criteria assessed at this 
time point: 
• MRI examination [note: performed at or close to this visit when the subject has no bleeding. 
Fasting (no food or drink) for 3-4 hours in advance] 
 
6.2.3 
Randomisation / Visit 2 (RM+7 of Cycle -1) 
Subjects will attend visit 2, scheduled on RM+6-10 of cycle -1 (i.e. the end of cycle -1). 
The following must take place prior to randomisation:  
• Urine pregnancy test [note: results must be negative] 
• Vital signs 
• Check those inclusion and exclusion criteria that were not possible during screening 
 
If the subject fulfils all inclusion and exclusion criteria, she will proceed to randomisation: 
• Randomisation, i.e. assignment to a unique randomisation number in the IRT system and 
thereby allocated to placebo vaginal ring or quinagolide vaginal ring dose load 1080 µg  
 
The following will be performed for eligible subjects before insertion of the ring:  
• Ensuring the completion and legibility of NRS by the subject  
• Ensuring the completion and legibility of the EHP-30 questionnaire by the subject   
• Completing the first part of B&B scale based on the subject’s verbal responses  


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• 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) 
• Blood collection for central laboratory analysis of:  
− 
Endocrine parameters (prolactin, TSH and IGF-1)  
− 
Endometriosis biomarkers (VEGF, PlGF, IL-6, CA125 and sFlt-1) 
Once the above has been completed, the following must be performed: 
• 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 
  
Finally, the following must be done before the subject leaves the clinic:  
• Inquiring bleeding pattern of the immediate past menstrual period (start / stop dates, amount)  
• Recording of use of any concomitant medications including analgesics 
• Recording of adverse events  
• Dispensing of condoms and reminding the subject to use proper contraception  
• Reminding the subject to attend the next visit, scheduled within 1-5 days of ring insertion 
 
6.3 
Treatment Period 
If subjects do not have menstrual bleeding or have delayed menstrual bleeding in a cycle during the 
treatment period, a visit must be arranged within 35 days of the last ring replacement visit. 
6.3.1 
Visit 3 (Within 1-5 days of Visit 2) 
Subjects will attend visit 3, scheduled within 1-5 days of visit 2. 
The following must take place at the visit: 
• Vital signs 
• Blood collection for central laboratory analysis of 
− 
Endocrine parameters (prolactin, TSH and IGF-1)  
− 
Plasma concentrations of quinagolide and its metabolites   
• Recording of use of any concomitant medications including analgesics 
• Recording of adverse events  
• Dispensing of condoms and reminding the subject to use proper contraception  
• Reminding the subject to attend the next visit, scheduled within 7-14 days of ring insertion 
 
6.3.2 
Visit 4 (Within 7-14 days of Visit 2) 
Subjects will attend visit 4, scheduled within 7-14 days of visit 2. 


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The following must take place at the visit: 
• Blood collection for central laboratory analysis of 
− 
Plasma concentrations of quinagolide and its metabolites   
• Recording of use of any concomitant medications including analgesics  
• Recording of adverse events  
• Dispensing of condoms and reminding the subject to use proper contraception  
• Reminding the subject to attend the RM+7 visit of cycle 1 
 
6.3.3 
Cycle 1 Visit / Visit 5 (RM+7 of Cycle 1) 
Subjects will attend visit 5, scheduled on RM+6-10 of cycle 1. 
The following must take place before removal of the used ring and insertion of new ring: 
• Ensuring the completion and legibility of NRS by the subject  
• Urine pregnancy test [note: results must be negative] 
• Blood collection for central laboratory analysis of: 
- 
Plasma concentrations of quinagolide and its metabolites 
Once the above has been completed, the following must be performed: 
• 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  
• Drug accountability of the ring 
• Inquiring bleeding pattern of the immediate past menstrual period (start / stop dates, amount)  
• Recording of use of any concomitant medications including analgesics 
• Recording of adverse events  
• Dispensing of condoms and reminding the subject to use proper contraception 
• Reminding the subject to attend the RM+7 visit of cycle 2 
 
6.3.4 
Cycle 2 Visit / Visit 6 (RM+7 of Cycle 2) 
Subjects will attend visit 6, scheduled on RM+6-10 of cycle 2. 
The following must take place before removal of the used ring and insertion of new ring: 
• Ensuring the completion and legibility of NRS by the subject  
• Ensuring the completion and legibility of the EHP-30 questionnaire by the subject 
• Urine pregnancy test [note: results must be negative. If positive, a serum βhCG test must be 
performed at the local laboratory] 
• Blood collection for central laboratory analysis of:  
− 
Endocrine parameters (prolactin, TSH and IGF-1)  
− 
Plasma concentrations of quinagolide and its metabolites   


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Once the above has been completed, the following must be performed: 
• 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  
• Drug accountability of the ring 
• Inquiring bleeding pattern of the immediate past menstrual period (start / stop dates, amount)  
• Recording of use of any concomitant medications including analgesics 
• Recording of adverse events  
• Dispensing of condoms and reminding the subject to use proper contraception 
• Reminding the subject to attend the RM+7 visit of cycle 3 
 
6.3.5 
Cycle 3 Visit / Visit 7 (RM+7 of Cycle 3) 
Subjects will attend cycle 3 visit (visit 7), scheduled on RM+6-10 of cycle 3. 
The following must take place before removal of the used ring and insertion of new ring: 
• Ensuring the completion and legibility of NRS by the subject  
• Urine pregnancy test [note: results must be negative] 
• Blood collection for central laboratory analysis of: 
- 
Plasma concentrations of quinagolide and its metabolites 
 
Once the above has been completed, the following must be performed: 
• 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  
• Drug accountability of the ring 
• Inquiring bleeding pattern of the immediate past menstrual period (start / stop dates, amount)  
• Recording of use of any concomitant medications including analgesics 
• Recording of adverse events  
• Dispensing of condoms and reminding the subject to use proper contraception 
• Reminding the subject to attend the RM+7 visit of cycle 4 
 
6.3.6 
End-of-Treatment / Cycle 4 Visit / Visit 8 (RM+7 of Cycle 4) 
If subjects attend all scheduled visits and complete the treatment, an end-of-treatment visit (visit 8) 
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 within 2 weeks of discontinuation.  


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The following must take place first for all subjects:  
• Ensuring the completion and legibility of NRS by the subject  
• Ensuring the completion and legibility of the EHP-30 questionnaire by the subject   
• Completing the first part of B&B scale based on the subject’s verbal responses  
• Urine pregnancy test [note: results must be negative] 
• Blood collection for central laboratory analysis of:  
− 
Safety laboratory tests of clinical chemistry and haematology parameters 
− 
Endocrine parameters (prolactin, TSH and IGF-1)  
− 
Endometriosis biomarkers (VEGF, PlGF, IL-6, CA125 and sFlt-1) 
− 
Plasma concentrations of quinagolide and its metabolites 
 
The subject will proceed to the following procedures after the above has been completed: 
• Vital signs 
• Physical examination 
• Gynaecological examination  
• Transvaginal ultrasound, preferably performed by the same sonographer as at screening 
(record the sizes of endometrioma / uterine fibroids, if any) 
• 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) 
• Removal of the used ring by the subject. Supervision by site staff can be provided if needed 
• Drug accountability of the ring 
• Inquiring bleeding pattern of the immediate past menstrual period (start / stop dates, amount)  
• Recording of use of any concomitant medications including analgesics 
• Recording of adverse events  
• Completion of end-of-treatment form 
 
Finally, for subjects who complete the treatment and subjects who are prematurely discontinued 
during or after cycle 2, the following must be performed at the site’s affiliated radiology 
department:  
• MRI examination [note: performed at or close to this visit when the subject has no bleeding 
and no ring. Fasting (no food or drink) for 3-4 hours in advance] 
 
6.4 
Follow-up 
6.4.1 
Follow-up Phone Call (About 1 Month after Visit 8) 
A follow-up telephone call will be made to all subjects at about 1 month after the end-of-treatment / 
cycle 4 visit to collect information about adverse events and concomitant medications since the 
visit, and reasons for resuming medications indicated for endometriosis / adenomyosis. 


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7 
TRIAL ASSESSMENTS 
7.1 
Assessments Related to Primary Endpoint 
7.1.1 
Magnetic Resonance Imaging (MRI)  
The MRI examination will be performed on a high resolution 3T machine at screening and at end-
of-treatment / cycle 4. Depending on facilities at sites, MRI may not necessarily be scheduled at the 
RM+7 visit at screening or at cycle 4, but it must be scheduled on a day without bleeding close to 
the corresponding visits to avoid biases. Subjects who have discontinued during or after cycle 2 
should come for an end-of-treatment visit with MRI, scheduled within 2 weeks of discontinuation. 
The MRI at end-of-treatment / cycle 4 must be performed using the same machine, following the 
same procedures and sequences as at screening (detailed in the MRI manual).  
All the MRI machines will be cross-calibrated by a phantom to calibrate T1-T2 parameters for the 
DCE-MRI quantification. Calibration will be performed both prior to the trial initiation and in case 
of any software and hardware updates.  
Subjects are required to fast for 3-4 hours before the MRI examination. The preparations for MRI 
examination should follow the MRI manual. The MRI procedures will include the following main 
sequences: 
• Fast spin echo – T2 weighted images (FSE – T2) 
• Diffusion weighted (DW-IVIM) images with more than 2 b-values 
• Gradient echo – T1-weighted images with varying flip angles (GRE-T1-VFA)  
• Dynamic contrast enhanced, spoiled GRE T1-weighted images (DCE-PKM-Gd)  
• Late gadolinium enhancement spoiled GRE T1-weighted images (GRE-T1-LATEGd)  
 
Other details for the MRI examination will be specified in the MRI manual. Prior to the start of the 
trial, site radiologists will be trained on the MRI manual. Site radiologists must follow the MRI 
manual for the preparation and the execution of the MRI assessment. All images should be 
uploaded into a specific image repository allocated for this trial within 2 business days for central 
reading and analyses by the imaging laboratory. During image uploading, subjects’ personal 
information (e.g. name) will be pseudonymised. 
At screening, every measurable lesion (defined as ≥10 mm in size) of any type should be recorded 
and should be summed up by type for primary analysis. For DIE and endometrioma, lesions will be 
measured both in size and in volume. For uterine fibroid, only size will be measured. Size will be 
recorded in mm as the longest diameter in the plane of measurement. Volume will be recorded in 
mm3 using a semi-automated method based on 3D region-growing algorithm, adjusted with manual 
correction. For adenomyosis, the maximum junctional zone thickness (applicable to diffuse 
adenomyosis) or the size of the largest focal lesion (applicable to focal adenomyosis) will be 


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measured. The MRI used as baseline at screening should not be obtained more than 1 menstrual 
cycle before randomisation.  
The central reading of MR images will be performed by two radiologists independently. In case of 
disagreement with regard to inclusion criterion no. 6, the opinion of a third radiologist will be 
sought and will determine the subject’s eligibility. Based on the results of the central reading report, 
the investigators can decide which sub-group subjects belong to by allocating subjects to the more 
rare type in the ranking of DIE, adenomyosis and endometrioma. If one of the sub-groups has been 
fully enrolled, subjects will be allocated to the next rarer group. 
The primary analyses will be based on measurable lesions (i.e. lesions with a size ≥10 mm) at 
baseline. All lesions with a size <10 mm will be identified as non-measurable lesions and the 
existence of such lesions will be recorded at baseline. All lesions, however, will be measured for 
the segmentation required in the analyses of the exploratory endpoints related to imaging 
biomarkers (section 7.3.1). 
At end-of-treatment / cycle 4, all lesions will be compared to baseline to distinguish new lesion or 
disappearing lesion, defined as:  
• New lesion: a lesion detected at end-of-treatment, regardless of its size, which is not 
detectable at baseline even during retrospective evaluations  
• Disappearing lesion: a lesion detected at baseline, regardless of its size, which is not 
detectable at end-of-treatment 
In case of any other incidental, clinically significant abnormal findings (e.g. suspected tumour) 
from MRI, it is the investigator’s responsibility to inform subjects of the findings and to refer them 
to further examination and/or treatment. Such findings at end-of-treatment / cycle 4 should be 
reported as adverse events (section 8). If findings are serious (e.g. suspected malignant tumour), 
local radiologists and investigators are entitled to take prompt actions without waiting for central 
reading reports.  
 
7.2 
Assessments Related to Secondary Endpoints 
7.2.1 
Transvaginal Ultrasound (TVU) 
Transvaginal ultrasound (TVU) will be performed, preferably by the same sonographer, at the 
screening visit and at end-of-treatment / cycle 4.  
One purpose of TVU is to assess the general health status of uterus, endometrium and ovaries in 
order to identify any abnormal findings. The other purpose of TVU is to evaluate endometrial 
thickness, number and size of endometrioma if presented, number and size of fibroids if presented 
as well as number and size of ovarian cysts 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 


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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 and/or fibroids will be recorded as observed or not. If observed, the number and size 
of endometrioma and/or fibroids should be recorded.  
Ovarian cysts will also be recorded as observed or not. If observed, the number and size of ovarian 
cysts should be recorded. 
 
7.2.2 
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 (i.e. different types of pain) and the second part evaluating physical signs.  
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.  
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.  
B&B will be administered on paper at randomisation and at end-of-treatment / cycle 4. Trial 
coordinators will complete the first part based on subjects’ verbal response and the first part of the 
B&B should always be completed prior to ring insertion at randomisation and prior to other non-
PRO procedures at end-of-treatment / cycle 4. Investigators will complete the second part of the 
B&B based on findings of a pelvic examination. The scores obtained at randomisation will be used 
as baseline. 
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. The responses must be 
reviewed for legibility and completeness by the trial coordinator before the subject leaves the clinic. 
The B&B scale should be completed independently from the other PROs in this trial, i.e. without 
prior review of the NRS and EHP-30 scores completed by the subject.  
 


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7.2.3 
Numerical Rating Scale (NRS) 
NRS is a self-administered 11-point pain scale, with 0 indicating no pain and 10 indicating worst 
imaginable pain. At each RM+7 visits from randomisation to end-of-treatment / cycle 4, subjects 
will be asked to score the worst pain in relation to endometriosis / adenomyosis on the NRS based 
on a recall of their experiences during the following timeframes: 
• during the last menstrual cycle  
• during the menstrual period of the last menstrual cycle 
• during the non-menstrual period of the last menstrual cycle 
 
The NRS will be completed by subjects on paper prior to ring insertion at randomisation and prior 
to other non-PRO procedures at each RM+7 visit from cycle 1 to end-of-treatment / cycle 4. The 
responses must be reviewed for legibility and completeness by the trial coordinator before the 
subject leaves the clinic. The scores obtained at randomisation will be used as baseline.  
 
7.2.4 
Endometriosis Health Profile-30 (EHP-30) Questionnaire 
The EHP-30 is a quality-of-life questionnaire specifically developed for endometriosis patients and 
is used in this trial for all subjects. 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 four weeks, with five options of never, rarely, sometimes, often and always.  
EHP-30 will be completed on paper by subjects prior to ring insertion at randomisation, prior to 
other non-PRO procedures at cycle 2 and at end-of-treatment / cycle 4. The responses must be 
reviewed for legibility and completeness by the trial coordinator before the subject leaves the clinic. 
The scores obtained at randomisation will be used as baseline.  
 
7.2.5 
Menstrual Bleeding Pattern 
At each RM+7 visit from randomisation to end-of-treatment / cycle 4, the site staff should inquire 
about the subject’s immediate past menstrual period, including the start and stop dates (if available) 
of menstrual bleeding and the amount of menstrual flow. The amount of menstrual flow will be 
graded as none (no bleeding), mild (less than normal flow), moderate (normal flow) and heavy 
(more than normal flow). 
 
7.2.6 
Endocrine Parameters 
Blood samples for measuring serum concentrations of prolactin, TSH and IGF-1 will be collected at 
randomisation, within 1-5 days of randomisation, at cycle 2 and at end-of-treatment / cycle 4.  
The samples will be analysed at a central laboratory. However, the results of prolactin, TSH and 
IGF-1 after randomisation will be blinded to investigators, site staff and Ferring clinical team.  
 


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7.2.7 
Plasma Concentrations of Quinagolide and Its Metabolites 
Blood samples for measurement of plasma concentrations of quinagolide and its metabolites M1 
and M2 will be collected within 1-5 days of randomisation, within 7-14 days of randomisation and 
at RM+7 visits of cycles 1 to 4. Blood samples should be taken prior to removal of the ring at 
RM+7 visits. The analysis of plasma concentrations of quinagolide and its metabolites will be 
performed by means of a validated tandem mass spectrometry method at a central laboratory.  
 
7.2.8 
Clinical Chemistry and Haematology Parameters 
Blood samples for routine safety laboratory tests of clinical chemistry and haematology parameters 
(see lists below) will be drawn at the screening visit and at end-of-treatment / cycle 4. The samples 
will be analysed 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: red blood cells, red blood cell morphology, white blood cells, white blood 
cell morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular 
haemoglobin, mean corpuscular haemoglobin concentration, platelets. 
The investigator will review the laboratory results and evaluate and document whether the results 
are clinically significant or not. The laboratory report will be signed and dated by the investigator.  
 
7.2.9 
Adverse Events 
Adverse events will be recorded from the signing of informed consent for participation in the trial 
until the end-of-trial. 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. See section 8. 
 
7.3 
Assessments Related to Exploratory Endpoints 
7.3.1 
MRI-Derived Perfusion and Diffusion Imaging Biomarkers 
To measure permeability, perfusion imaging biomarkers of the one-compartmental metric (AUC) 
and the two-compartmental metrics (Ktrans, kep, ve, vp) will be derived from the dynamic perfusion 
series obtained at screening and at end-of-treatment / cycle 4. In order to convert the signal 
intensity to contrast concentration in every voxel, the GRE-T1 sequences acquired with different 
angles will be used to calculate the T1 value at every voxel by curve fitting. For the perfusion 
analysis, the different contrast enhancement curves will be obtained voxel-wise and a non-linear 


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least mean squares algorithm (Levenberg-Marquardt) will be used to extract the parameters of the 
model by curve fitting.  
In addition, diffusion metrics (ADC, D, D* and f) of lesion tissue structure will be obtained using 
the IVIM model at screening and at end-of-treatment / cycle 4. For this purpose, the different 
curves of the signal intensity versus b-values will be obtained voxel-wise and a non-linear least 
mean squares algorithm (Levenberg-Marquardt) will be used to extract the parameters of the model 
by curve fitting. All perfusion and diffusion parameters at screening and at end-of-treatment will be 
assessed and analysed by the central imaging laboratory. All lesions will be measured for the 
analyses of the imaging biomarkers. Since the extraction of the parameters is performed voxel-
wise, parametric maps will be generated in order to represent the parameters distribution in the 
different lesion regions. 
 
7.3.2 
Serum and Plasma Endometriosis Biomarkers 
Blood samples will be taken at randomisation and at end-of-treatment / cycle 4 for the analysis of 
serum and plasma endometriosis biomarkers of VEGF, PlGF, IL-6, CA125 and sFlt-1. The samples 
will be analysed at a central laboratory.  
All of the blood samples should be processed and stored in accordance with instructions provided 
in a separate laboratory manual. These exploratory data will be transferred to trial database directly. 
  
7.4 
Other Assessments 
7.4.1 
Demographics 
Demographic information will be obtained at screening, including the following: date of birth (or 
partial date of birth per local regulations), 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). 
  
7.4.2 
Medical History 
Any relevant medical history will be recorded at screening. This includes the year and method (e.g. 
laparoscopy) of endometriosis / adenomyosis diagnosis, documentation of a biopsy (if performed), 
stage of endometriosis at diagnosis (if available), anatomic location of lesions (if available), history 
of previous surgical interventions (including method [e.g. laparoscopy], year and type of surgery 
[ablation of lesions, excision of lesions, lysis of adhesions or other]), and any surgical intervention 
for other gynaecological conditions. 
 
7.4.3 
Menstrual History  
Information about the menstrual history (average cycle length, average number of days with 


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menstrual bleeding and amount of menstrual flow) will be obtained at screening. In addition, the 
start and stop dates (if available) of the immediate past menstrual period should be noted. Any 
history of irregular vaginal bleeding outside menstrual period will also be recorded.  
 
7.4.4 
Reproductive History 
Information about the reproductive history will be obtained at screening. This includes number of 
pregnancies, number of live births and history of infertility (yes/no and if yes, reason for infertility). 
 
7.4.5 
Body Measurement 
Body weight and height will be measured without shoes at screening. The results obtained will be 
used to calculate BMI. 
 
7.4.6 
Urine Pregnancy Test 
A urine pregnancy test will be performed at each clinic visit (except for visits 3 and 4) throughout 
the trial. The test should always be performed before ring insertion / removal at RM+7 visits of the 
treatment periods. If the urine test result is positive, blood collection for βhCG test at the local 
laboratory must be performed. If both test results are positive, the subject will be discontinued from 
the trial.  
 
7.4.7 
Vital Signs 
Systolic and diastolic blood pressure as well as pulse will be measured at the screening visit, prior 
to randomisation at the randomisation visit, within 1-5 days of the first ring insertion (i.e. visit 3) 
and at end-of-treatment / cycle 4. Vital signs at randomisation will be baseline. Blood pressure and 
pulse should be measured 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. 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. 
The investigator will review the results of vital signs and evaluate and document whether the 
finding is clinically significant or not. Any clinically significant finding will be reported as medical 
history (if reported at screening) or as adverse events (if reported during the treatment).  
 
7.4.8 
Physical Examination 
A complete physical examination will be performed at the screening visit and at end-of-treatment / 
cycle 4. Information will be recorded for general appearance, central and peripheral nervous 


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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.  
Each category will be evaluated as normal, abnormal not clinically significant or abnormal 
clinically significant. Abnormal clinically significant findings at the screening visit (baseline) must 
be reported on the Medical History Log. 
At end-of-treatment / cycle 4, potential changes from baseline to end-of-treatment or to cycle 4 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. 
 
7.4.9 
Gynaecological Examination 
A gynaecological examination will be performed by the investigator at the screening visit and at 
end-of-treatment / cycle 4. Information will be recorded for breast, external genitalia, vagina, 
cervix, uterus, uterine adnexa (including ovaries and fallopian tubes) and cul-de-sac.  
Each category will be evaluated as normal, abnormal not clinically significant or abnormal 
clinically significant. Abnormal clinically significant findings at the screening visit (baseline) must 
be reported on the Medical History Log. 
At end-of-treatment / cycle 4, potential changes from baseline to end-of-treatment or to cycle 4 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. 
 
7.4.10 
Cervical Cytology Test 
As part of eligibility check, a cervical cytology test using a liquid-based method will be performed 
at the screening visit for subjects who do not have a cervical cytology test within 24 months of the 
visit. If there is any presence of atypical squamous cells of undetermined significance, a reflex 
testing for HPV must be performed. Subjects with positive HPV test results must be excluded. In 
case of positive findings, it is the investigator’s responsibility to ensure that standard reporting and 
referral procedures at the sites are followed in line with local regulations. 
 
7.4.11 
Concomitant Medications 
The use of any hormonal treatment of endometriosis and/or adenomyosis within the last 6 months 
prior to the signing of the informed consent for participation in the trial will be recorded. The use of 
any other concomitant medications within the last 3 months prior to informed consent for 


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participation in the trial and throughout the trial will be recorded. Recording of concomitant 
medications will be performed at all visits.  
Any use of analgesics, including the dose and the frequency, will be collected in the e-CRF.  
 
7.4.12 
Drug Accountability 
For all vaginal rings, date and time of insertion and removal at the clinics will be recorded in the 
IRT system. Any incidents of ring out of the body for more than 24 hours should be captured in the 
e-CRF. 
 
7.4.13 
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.  
 
7.4.14 
Follow-up Phone Call 
A follow-up telephone call will be made to all subjects at about 1 month after the end-of-treatment / 
cycle 4 visit to collect information about adverse events and concomitant medications since the 
visit, and reasons for resuming medications indicated for endometriosis / adenomyosis. 
 
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 analysed at central laboratories and will be destroyed within 
2 years after reporting of the trial. 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 form, 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 unfavourable 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 sign or finding from physical or gynaecological 
examination assessed as clinically significant by the investigator [note: pre-existing 
conditions diagnosed through assessments and examinations at the screening visit or 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 Medical Dictionary for 
Regulatory Activities (MedDRA).  
Medication errors of IMP will be captured in the e-CRF and will be reviewed by Ferring 
Pharmacovigilance on an ongoing basis. 
 
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 last 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. 
hospitalisation). 
 


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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  
• Intensity 
• Causal relationship to IMP 
• Action taken to IMP 
• Other action taken 
• Date and time of outcome  
• 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.b 
Note: A procedure is not an adverse event; the reason for conducting the procedure is. 
Hospitalisation is not an adverse event; the reason for hospitalisation 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 
date is the date the sample was taken or the examination was performed.  
 
b Exception: if an adverse event with onset before the first IMP administration (i.e. a pre-treatment adverse event) 
worsens in intensity, 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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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 recognised 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 
Dysmenorrhea, Pelvic Pain and Dyspareunia 
Presence of dysmenorrhea, pelvic pain and dyspareunia related to endometriosis / adenomyosis will 
be assessed by B&B and NRS as part of the secondary endpoints and therefore is not to be reported 
as an adverse event unless it fulfils the criteria for a serious adverse event (SAE). 
 


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8.3.2 
Menstrual Bleeding 
Presence of abnormal menstrual bleeding (e.g. amenorrhea, oligomenorrhea and menorrhagia) will 
be assessed by menstrual pattern at each RM+7 visit from randomisation to end-of-treatment / 
cycle 4 as part of the secondary endpoints and therefore is not to be reported as an adverse event 
unless it fulfils the criteria for an SAE.  
 
8.4 
Pregnancy and Pregnancy Outcome 
If a pregnancy occurs, the IMP should be immediately stopped and Ferring Global 
Pharmacovigilance must be informed by mail to 
 within 3 calendar 
days on a specified Pregnancy Form or SAE Report Form. Note that pregnancy itself is not an SAE. 
If a subject becomes pregnant during treatment or follow-up periods and the conception date cannot 
be determined, an ultrasound will be performed during the first trimester of the pregnancy 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 Global 
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 
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 
hospitalisation or 
prolongation of existing 
hospitalisation 
The term hospitalisation means that the subject was admitted to hospital or that 
existing hospitalisation was extended as a result of an event. Hospitalisation 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 hospitalisation. 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). 
Hospitalisations 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 hospitalisation but might 
jeopardise 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 hospitalisation, 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 Global 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 Global Pharmacovigilance using the contact details below. 
Global Pharmacovigilance, Ferring Pharmaceuticals A/S 
E-mail: 
 
Fax: 
 
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 
Global 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 Global 
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 IEC with any additional requested information such as 
results of post-mortem examinations and hospital records. 
Expedited Reporting by Ferring 
Ferring will report all adverse events that are serious, unexpected and with a reasonable possible 
causality to the IMP as judged by either the investigator or Ferring to the relevant parties within 
the stipulated timelines.  
The expectedness is assessed by Ferring according to the Investigator’s Brochure.15  


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SAEs will be considered reportable regardless of whether or not the IMP was used in accordance 
with the provisions in the protocol, Investigator’s Brochure15 and labelling. 
 
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, 
regardless how long after the end of the trial this takes place. 


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9 
STATISTICAL METHODS 
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.  
 
9.1 
Determination of Sample Size 
The sample size calculation is based on demonstrating superiority of quinagolide vaginal ring 
compared to placebo vaginal ring on the primary endpoint of changes in the sizes of endometrioma, 
DIE and adenomyosis lesions summed by type on MRI at cycle 4. An important assumption behind 
the sample size calculation is an equal magnitude of treatment effect for all three types of lesions. 
For example, for adenomyosis, by assuming an average baseline lesion size of 18 mm and a 
standard deviation of 4.5 mm,39 a sample size of 24 randomised subjects (16 on active treatment 
and 8 on placebo) will have 83% power to detect a treatment effect difference of 6 mm 
(corresponding to a 33% reduction in lesion size) using a two-sample t-test at a 5% two-sided 
significance level. A similar assumption, i.e. the ratio between treatment effect and standard 
deviation is 4 to 3, is made for DIE and endometrioma to conclude 24 subjects to be randomised 
per sub-group. In total, 72 subjects will be randomised in this trial.  
Table 9-1 summarises the required sample size in total for different assumptions of treatment effect 
difference and power.  
Table 9-1 
Sample Size by Treatment Effect Difference 
Difference in the sum of lesion size reduction between 
quinagolide vaginal ring group and placebo vaginal ring group 
Number of subjects in total a 
 
Absolute difference (mm) 
Relative difference b (%) 
Power 80% 
Power 90% 
4.5 
25 
39 
51 
5.0 
28 
33 
42 
5.5 
31 
27 
36 
6.0 
33 
24 
30 
6.5 
36 
21 
27 
7.0 
39 
18 
24 
7.5 
42 
15 
21 
a 
Using a 2:1 randomisation and assuming a standard deviation of 4.5 mm. 
b 
Assuming an average baseline lesion size of 18 mm. 
 
If the drop-out rate in any of the sub-groups are larger than 10%, the sample size of randomised 
subjects for that sub-group may be increased to up to 30.  
 


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9.2 
Subject Disposition 
All subjects screened and randomised will be accounted for. Screened subjects who discontinue 
from the trial prior to randomisation are regarded as screening failures. The number of screened but 
not randomised subjects will be summarised by primary reason for screening failure. 
Subject disposition with respect to analysis set will be tabulated by treatment group for all 
randomised subjects.  
All premature discontinuations will be summarised and listed by time of and reason for 
discontinuation. The treatment group difference in the proportion of subjects who discontinue will 
be tested using the Fishers exact 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 randomisation 
• Non-compliance with IMP treatment regimen for >20% of days during the non-menstrual 
period  
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.  
The list of major protocol deviations will be detailed and documented in the clean file document 
prior to database release.  
 
9.4 
Analysis Sets 
9.4.1 
Full Analysis Set (FAS) 
The FAS comprises all randomised and treated subjects and is analysed according to the planned 
treatment.  
 
9.4.2 
Per Protocol (PP) Analysis Set 
The PP analysis set is defined as all randomised subjects except those with a major protocol 
deviations as described in section 9.3. 
 


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9.4.3 
Safety Analysis Set 
The safety analysis set comprises all treated subjects and is analysed according to the actual 
treatment received. 
 
9.5 
Trial Population 
9.5.1 
Demographics and other Baseline Characteristics 
All relevant baseline data will be summarised in tables by treatment groups and in total. In addition 
summary tables will be presented by trial site. 
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 FAS.  
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 summarised by System Organ Class (SOC) and 
preferred term.  
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 FAS population, 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 all the secondary and exploratory endpoints except the safety endpoints (i.e. adverse 
events, clinical chemistry and haematology parameters) will be performed for the FAS population. 
The safety endpoints will be analysed for the safety analysis set unless otherwise noted.  


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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”. 
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 from the MRI 
If a subject is prematurely discontinued during or after cycle 2, an end-of-treatment MRI 
examination will be performed. The results from this end-of-treatment MRI will be used.  
If the end-of-treatment MRI examination is not performed or is missing, the missing measurement 
will be imputed using a multiple imputation strategy. The imputation will be based on a missing-at-
random assumption using baseline MRI results and some other measurements. The precise 
imputation strategy will be described in the SAP.   
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 
For each type of lesion (endometrioma, DIE and adenomyosis), the primary endpoint is the change 
in the sum of the lesion sizes at cycle 4, i.e. the difference between the active treatment group and 
the placebo group in the change from baseline in the sum of the lesion sizes of the same type at the 
end of cycle 4. The baseline is defined as the sum of the sizes of all lesions of the same type 
≥10 mm obtained from the MRI examination at screening. At end-of-treatment / cycle 4, the sizes 
of all lesions included at baseline of the same type will be summed. For each type of lesions, 
subjects with at least one lesion of that type ≥10 mm at baseline will be included.  
For each type of lesions, the primary endpoint will be analysed using an analysis of covariance 
(ANCOVA) model, with the change in the sum of lesion sizes from baseline measured at cycle 4 as 
the dependent variable, the baseline sum of lesions as covariate, the treatment group and site as 
fixed effect. The treatment difference between active treatment versus placebo will be reported with 
95% confidence interval and corresponding p-value for each of the three types of lesions:  




=
1
1
1
1
1
1
1
0
:
:
Placebo
QVR
P
Placebo
QVR
P
H
H




 


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



=
2
2
2
1
2
2
2
0
:
:
Placebo
QVR
P
Placebo
QVR
P
H
H




 




=
3
3
3
1
3
3
3
0
:
:
Placebo
QVR
P
Placebo
QVR
P
H
H




 
Where (
)
1
0
P
H
,(
)
2
0
P
H
,(
)
3
0
P
H
 are the null hypotheses for each of the 3 types of lesions, (
)
1
1
P
H
,(
)
2
1
P
H
,
(
)
3
1
P
H
 are the alternative hypotheses for each of the 3 types of lesions, and 
 
In order to control the overall type I error at 5%, the Hochberg procedure is implemented by 
ranking the 3 p-values in a decreasing order. If the largest p-value is ≤0.05, superiority is 
established for all 3 types of lesions. If the largest p-value is >0.05, but the middle p-value is 
≤0.025, superiority is established for the two types of lesions with the smaller p-values. If the 
largest p-value is >0.05 and the middle p-value is >0.025, but the smallest p-value is ≤0.0125, 
superiority is established for only the type of the lesion with the smallest p-value. If the largest p-
value is >0.05, the middle p-value is >0.025, and the smallest p-value is >0.0125, superiority is not 
established for any of the 3 types of lesions.  
The primary analysis is based on the FAS including those missing the end-of-treatment MRI 
results. As described above, missing values will be imputed using a multiple imputation strategy.  
Sensitivity Analyses 
The following sensitivity analyses will be conducted:  
1. To test efficacy in more perfect conditions:  
• The primary analysis in the PP population  
2. To test sensitivity to missing data: 
• The primary analysis performed on completers (defined as subjects who have completed 
the scheduled treatment and have both a baseline and a cycle 4 MRI)  
• The primary analysis performed on subjects with both a baseline and an end-of-
treatment MRI 
• The FAS using multiple imputation for missing data in a placebo-based pattern mixture 
model (based on a missing-not-at-random condition) as described by Ratitch 


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3. The primary analysis using the actual treatment rather than the planned treatment  
4. The primary analysis using also lesions that are <10 mm at baseline 
5.  The primary analysis adjusted for the type of previous hormonal treatment  
 
9.6.3 
Secondary Endpoints 
The percentage change in the sum of lesion sizes by type, will be analysed using a similar 
ANCOVA model as the primary endpoint, but both the baseline and the cycle 4 / end-of-treatment 
results will be log transformed prior to analysis. The estimated difference between treatment groups 
will be back transformed to ease interpretation.  
Secondary endpoints related to proportion of lesions and proportion of subjects with a decrease in a 
size of ≥5 mm at cycle 4 will be based on all lesions ≥10 mm at baseline and will be analysed using 
logistic regression for binary data with logit link function. The generalised estimating equation 
(GEE) approach will be used to account for correlated data where appropriate.  
Count data related to the number of new / disappearing lesions by type, based on all lesions, will be 
analysed with repeated measures negative-binomial regression using a GEE approach. The 
regression analysis will be performed with log link function using the appropriate off-set.  
Changes from baseline in the volume of endometrioma/DIE lesions assessed by MRI at cycle 4 and 
in the sizes of endometrioma assessed by TVU at cycle 4 will be analysed similarly to the primary 
endpoint, but sensitivity analyses will not be performed for these secondary endpoints. 
Secondary endpoints related to PROs (B&B, NRS and EHP-30) and endocrine parameters will be 
analysed using a repeated measures ANCOVA model, with the change from baseline at each post-
baseline time point as the dependent variable, the baseline value as a covariate, and the treatment 
group and treatment by time as fixed effect. The error-covariance matrix will be unstructured. 
Changes in the menstrual bleeding pattern will be analysed by investigating the time to first event 
of change in bleeding pattern using the proportional odds regression model. 
Plasma concentration of quinagolide and its metabolites will be analysed descriptively. A 
population pharmacokinetic 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. 
All analyses and respective definitions of the endpoints will be further detailed in the SAP. 
 
9.6.4 
Exploratory Endpoints 
The exploratory endpoints related to the MRI-derived perfusion and diffusion imaging biomarkers 
will be analysed by the central imaging laboratory and will be reported separately.  


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Changes in the sizes of uterine fibroids assessed by MRI / TVU and changes in the plasma and 
serum endometriosis biomarkers will be analysed in a similar way as the primary endpoint but 
without sensitivity analyses.  
  
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 summarised by cycle and treatment group. The total extent of exposure (across 
all cycles) will be summarised by treatment group and overall. This will be done both including and 
excluding known periods of intermittent removals of the vaginal ring if applicable. 
 
9.8 
Safety  
General Considerations 
This section describes the descriptive analyses of safety endpoints and routine safety assessments. 
The safety endpoints described in this section will be analysed for the safety analysis set.  
Clinical Chemistry and Haematology Parameters 
Safety laboratory variables will be grouped under “haematology” and “clinical chemistry”. 
Adverse Events 
Treatment-emergent adverse eventsc will be summarized overall, by treatment 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.d 
The circulating levels of clinical chemistry and haematology parameters, including changes from 
baseline, will be tabulated for each laboratory variable. 
 
c 
A treatment-emergent adverse event is any adverse event occurring after start of IMP and before the follow-up phone 
call, or a pre-treatment adverse event or pre-existing medical condition that worsens in intensity after start of IMP and 
before the follow-up phone call. 
d 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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Shift tables will be prepared to compare baseline values to the values at the post-baseline visit, 
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 a post-baseline markedly abnormal value. The denominator will be the number 
of subjects with baseline and 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. 
 
Other Safety Variables 
Vital Signs 
Vital signs and the changes in vital signs will be analysed similarly to routine safety laboratory 
variables. Reference ranges for vital signs will be specified in the SAP.  
Physical and Gynaecological Examination 
Physical and gynaecological examination findings at cycle 4 / end-of-treatment compared to 
screening will be summarised 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 cycle 4 / end-of-treatment 
assessment for comparison. 
 
9.9 
Interim Analysis 
No interim analysis is planned for this trial.  


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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 the subject is a screening failure and the 
reason for screening failure if applicable. For each subject randomised, the investigator / radiologist 
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 (date and time of oral information, date and time of handing out informed 
consent form, date and time of obtaining signed informed consent) 
• Eligibility for participation in the trial (documenting all inclusion / exclusion criteria) 
• Relevant medical history  
• Visit dates 
• MR images 
• Dates of insertion/removal of the ring 
• Dates and indication of concomitant medications 
• PROs (B&B, NRS and EHP-30) 
• 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 the MRI evaluation will be located at the central imaging laboratory. The 
source data for the endocrine parameters, clinical chemistry and haematology parameters will be 


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available at the central laboratory during the trial.  
 
10.2 
e-CRF 
An e-CRF system provided by an independent third-party contract research organisation (CRO), 
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 / authorise 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 the e-CRF vendor. 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 and electronic signature) as write-protected PDF-files produced by the e-CRF 
vendor. 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. 
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 
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, cleaning and validation. 
 
10.4 
Provision of Additional Information 
On request, the investigator will provide Ferring with additional data relating to the trial, duly 
pseudonymised 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 / radiologist will permit the monitor direct access to all source data, including MR 
images, 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. When 
the first subject is randomised at the trial site, a monitoring visit will take place shortly afterwards. 
For this trial, the frequency of the monitoring visits per site will be determined through a risk-based 
approach depending on recruitment rate, observed data quality and overall site performance.  
The source data for central evaluation of MR images will also be verified, and monitoring visits to 
the central reading laboratory will take place on a regular basis during the trial. 
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 IECs who may audit/inspect the trial. 
The main purposes of an audit or inspection are to assess compliance with the trial protocol and the 
principles of ICH-GCP including the Declaration of Helsinki,44 and all other relevant regulations. 
The subjects must be informed by the investigator and in the informed consent form that authorised 
Ferring representatives and representatives from regulatory authorities and IECs 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 / randomisation 
number will appear on these copies. 
The investigator should notify Ferring without any delay of any inspection by a regulatory authority 
or IEC. 
 


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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. 
Documents that are not for submission to Ferring, e.g. the confidential subject identification code 
and the signed informed consent form, 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, if 
applicable, agreed upon by the investigator and Ferring prior to its implementation. Amendments 
may be submitted for consideration to the approving IECs 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 IECs’ approval or favourable opinion. 
 
12.2 
Deviations from the Protocol 
Deviations from the protocol should not occur. If deviations occur, the investigator must inform the 
monitor, and the implications of the deviation must be reviewed and discussed. Any deviation must 
be documented, either as answer to a query in the e-CRF, in a protocol deviation report or a 
combination of both. A log of protocol deviation reports will be maintained by Ferring. Protocol 
deviation reports and supporting documentation must be kept in the Investigator’s File and in the 
Trial Master File. 
 
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 IECs 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).45 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 trials-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. The trial will also be made publicly available at the EU 
Clinical Trials Register at www.clinicaltrialsregister.eu. Trial registration may occur in other 
registries in accordance with local regulatory requirements. 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 
Independent Ethics Committee (IEC)  
An IEC will review the protocol and any amendments and advertisements used for recruitment. The 
IEC will review the Informed Consent Form, their updates (if any), and any written materials given 
to the subjects. A list of all IECs 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’ Notification 
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 and End-of-Trial Notification 
The end of the trial is defined as the date of approximately 1 month after LPLV, i.e. when the 
follow-up phone call is made. 
At the end of the trial, the sponsor shall notify the regulatory authorities and the IECs in the 
participating countries about the completion of the clinical trial within 90 days when the trial has 
ended in all countries. 
In the case of early termination, Ferring must notify the end of the trial to the national regulatory 
authorities and the IECs immediately and at the latest within 15 days after the trial is halted, clearly 
explain the reasons, and describe follow-up measures, if any, taken for safety reasons. 
Within one year of the end of the trial, Ferring shall send a summary of the final Clinical Trial 
Report to the national regulatory authorities and the IECs. 
 
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,44 in compliance with the approved protocol, ICH-GCP and applicable 
regulatory requirements. 
 
14.5 
Informed Consent 
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 
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 


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informed consent form 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 signed copy of the Informed Consent Form 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 Informed Consent Form will be forwarded to the IECs (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, IEC 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 European regulations and with local/national regulations. 
 
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 / adenomyosis 
• 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 and to return it at the last trial visit.  
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. 
 
14.7 
Compliance Reference Documents 
The Declaration of Helsinki,44 the consolidated ICH-GCP, the EU Clinical Trials Directive and 
other national laws in the countries 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 country 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 
pseudonymous e-CRF data for Ferring. The investigator must arrange for the retention of this 
Subject Identification Log and signed Informed Consent Form 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 
 
1 
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Bulun SE. Endometriosis. N Engl J Med 2009; 360: 268-279. 
3  
de Venecia C, Ascher SM. Pelvic endometriosis: spectrum of magnetic resonance imaging 
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4 
Eskenazi B,Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am 
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5 
Meuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D and D’Hooghe T. 
High prevalence of endometriosis in infertile women with normal ovulation and 
normospermic partners. Fertil Steril 2009; 92: 68-74. 
6 
Simoens S, Dunselman G, Dirksen C, Hummelshoj L, Bokor A, Brandes I, et al. The burden 
of endometriosis: costs and quality of life of women with endometriosis and treated in 
referral centres. Hum Reprod 2012; 27:1292-1299. 
7  
Bird C, McElin T, Manalo-Estrella P. The elusive adenomyosis of the uterus revisited. Am J 
Obstet Gynecol. 1972; 111: 583-593. 
8  
Alabiso G, Alio L, Arena S, Barbasetti di Prun A, Bergamini V, Berlanda N, et. al. 
Adenomyosis: What the Patient Needs. J Minim Invasive Gynecol. 2016; 23: 476-488. 
9  
Garcia L, Isaacson K. Adenomyosis: Review of the literature. J Minimally Invasive 
Gynecology 2011; 18 (4): 428-437. 
10  
Montoliu-Fornas G, Marti-Bonmati L. Magnetic resonance imaging structured reporting in 
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11  
Bazot M, Cortez A, Darai E, Rouger J, Chopier J, Antoine JM, et al. Ultrasonography 
compared with magnetic resonance imaging for the diagnosis of adenomyosis: correlation 
with histopathology. Hum Reprod. 2001; 16: 2427–2433. 
12  
Vercellini P, Giudice LC, Evers JL, Abrao MS. Reducing low-value care in endometriosis 
between limited evidence and unresolved issues: a proposal. Hum Reprod 2015; 30: 1996-
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13  
Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. 
Nat Rev Endocrinol 2014; 10: 261-275. 
14  
Olive DL. Endometriosis in clinical practice. London: Taylor & Francis; 2005. pp.173-188. 
15  
Quinagolide (FE 999051) Investigator’s Brochure. Edition 8, May 2018. 
16 
Donnez J, Smoes P, Gillerot S, Casanas-Roux F, Nisolle M. Vascular endothelial growth 
factor (VEGF) in endometriosis. Hum Reprod 1998; 13: 1686-1690. 
17  
Shifren JL, Tseng JF, Zaloudek CJ, Ryan IP, Meng YG, et al. Ovarian steroid regulation of 
vascular endothelial growth factor in the human endometrium: implications for angiogenesis 
during the menstrual cycle and in the pathogenesis of endometriosis. J Clin Endocrinol 
Metab 1996; 81: 3112-3118. 


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18  
McLaren J, Prentice A, Charnock-Jones DS, Millican SA, Müller KH, Sharkey AM, Smith 
SK. Vascular endothelial growth factor is produced by peritoneal fluid macrophages in 
endometriosis and is regulated by ovarian steroids. J Clin Invest 1996; 98: 482-489. 
19  
Novella-Maestre E, Carda C, Ruiz-Sauri A, Garcia-Velasco JA, Simon C, Pellicer A. 
Identification and quantification of dopamine receptor 2 in human eutopic and ectopic 
endometrium: a novel molecular target for endometriosis therapy. Biol Reprod 2010; 83: 
866-873. 
20  
Gómez R, Gonzalez-Izquierdo M, Zimmermann RC, Novella-Maestre E, Alonso-Muriel I, 
Sanchez-Criado J, Remohi J, Simon C, Pellicer A. Low dose dopamine agonist 
administration blocks VEGF mediated vascular permeability without altering VEGFR-2 
dependent luteal angiogenesis in a rat ovarian hyperstimulation model. Endocrinology 2006; 
147: 5400-5411. 
21  
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 
2012; 98: 1209-1217. 
22  
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 
model of endometriosis. Reproduction 2011; 142: 745-755. 
23  
Gómez R, Abad A, Delgado F, Tamarit S, Simón C, Pellicer A. Effects of 
hyperprolactinemia treatment with the dopamine agonist quinagolide on endometriotic 
lesions in patients with endometriosis-associated hyperprolactinemia. Fertil Steril 2011; 95: 
882-888. 
24  
Hamid AM, Madkour WA, Moawad A, Elzaher MA, Roberts MP. Does cabergoline help in 
decreasing endometrioma size compared to LHRH agonist? A prospective randomized 
study. Arch Gynecol Obstet. 2014; 290: 677-682. 
25  
Foti PV, Farina R, Palmucci S, Vizzini IAA, Libertini N, Coronella M, et al. Endometriosis: 
clinical features, MR imaging findings and pathologic correlation. Insights Imaging. 2018 
Feb 15.  
26  
Di Paola V, Manfredi R, Castelli F, Negrelli R, Mehrabi S, Pozzi Mucelli R. Detection and 
localization of deep endometriosis by means of MRI and correlation with the ENZIAN 
score. Eur J Radiol. 2015; 84: 568-574. 
27  
Reinhold C, Tafazoli F, Mehio A, Wang L, Atri M, Siegelman ES, et al. Uterine 
adenomyosis: endovaginal US and MR imaging features with histopathologic correlation. 
RadioGraphics 1999; 19 (Spec Issue): S147-S160. 
28  
Grasso RF, Di Giacomo V, Sedati P, Sizzi O, Florio G, Faiella E, et al. Diagnosis of deep 
infiltrating endometriosis: accuracy of magnetic resonance imaging and transvaginal 3D 
ultrasonography. Abdom Imaging. 2010; 35: 716-725. 
29  
Siegelman ES, Oliver ER. MR imaging of endometriosis: ten imaging pearls. 
Radiographics. 2012; 32: 1675-1691.  


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30  
Kissler S, Zangos S, Kohl J, Wiegratz I, Rody A, Gätje R, et al. Duration of dysmenorrhoea 
and extent of adenomyosis visualised by magnetic resonance imaging. Eur J Obstet Gynecol 
Reprod Biol. 2008; 137: 204-209. 
31  
NORPROLAC, Summary of Product Characteristics, October 2015.   
32  
Moore TJ, Glenmullen J, Mattison DR. Reports of pathological gambling, hypersexuality, 
and compulsive shopping associated with dopamine receptor agonist drugs. JAMA Intern 
Med. 2014; 174: 1930-1933. 
33  
Steiger M, Jost W, Grandas F, Van Camp G. Risk of valvular heart disease associated with 
the use of dopamine agonists in Parkinson's disease: a systematic review. J Neural Transm 
2009; 116: 179-191.  
34  
Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E. Dopamine agonists and the risk 
of cardiac-valve regurgitation. N Engl J Med 2007; 356: 29-38. 
35  
Food and Drug Administration of the United States. Benefits and risks of magnetic 
resonance imaging. https://www.fda.gov/Radiation-
EmittingProducts/RadiationEmittingProductsandProcedures/MedicalImaging/MRI/ucm482
765.htm  [accessed on 28 May 2018] 
36  
Li A, Wong CS, Wong MK, Lee CM, Au Yeung MC. Acute adverse reactions to magnetic 
resonance contrast media – gadolinium chelates. Br J Radiol. 2006; 79: 368-371. 
37  
Di Donato N, Montanari G, Benfenati A, Leonardi D, Bertoldo V, Monti G, et al. 
Prevalence of adenomyosis in women undergoing surgery for endometriosis. Eur J Obstet 
Gynecol Reprod Biol. 2014; 181: 289-293. 
38  
Chapron C, Tosti C, Marcellin L, Bourdon M, Lafay-Pillet MC, Millischer AE, et al. 
Relationship between the magnetic resonance imaging appearance of adenomyosis and 
endometriosis phenotypes. Hum Reprod. 2017; 32: 1393-1401. 
39  
Bragheto A, Caserta N, Bahamondes L, Petta CA. Effectiveness of the levonorgestrel-
releasing intrauterine system in the treatment of adenomyosis diagnosed and monitored by 
magnetic resonance imaging. Contraception 2007; 76: 195-199. 
40  
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009; 45: 228-247.  
41  
Schneider C, Oehmke F, Tinneberg HR, Krombach GA. MRI technique for the preoperative 
evaluation of deep infiltrating endometriosis: current status and protocol recommendation. 
Clin Radiol. 2016; 71: 179-194. 
42  
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. 
43  
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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44  
World Medical Association Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects. 64th WMA General Assembly, Fortaleza, Brazil, 
October 2013. 
45 
International Committee of Medical Journal Editors (ICMJE). Uniform requirements for 
manuscripts submitted to biomedical journals: ethical considerations in the conduct and 
reporting of research: authorship and contributorship. www.ICMJE.org  

SAP_001.pdf: 
 
 
 
Cover page for Statistical Analysis Plan 
 
Sponsor name 
Ferring Pharmaceuticals A/S 
NCT Number 
NCT03749109 
Sponsor trial ID:  
000295 
Official title of study 
A randomised, double-blind, placebo-controlled, 
proof-of-mechanism phase 2 trial investigating 
the effect of quinagolide extended-release 
vaginal ring on reduction of lesions assessed by 
high-resolution magnetic resonance imaging in 
women with endometrioma, deep infiltrating 
endometriosis, and/or adenomyosis 
Document Date 
26 August 2021 
 


Date: 26 Aug 2021 
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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
QLARITY 
Quinagolide Vaginal Ring on Lesion Reduction Assessed by MRI in Women with 
Endometriosis/Adenomyosis  
A randomised, double-blind, placebo-controlled, proof-of-mechanism phase 2 trial 
investigating the effect of quinagolide extended-release vaginal ring on reduction of lesions 
assessed by high-resolution magnetic resonance imaging in women with endometrioma, deep 
infiltrating endometriosis, and/or adenomyosis 
 
Trial 000295 
 
 
Investigational Medicinal Product: FE 999051, Quinagolide Vaginal Ring  
 
Indication: 
Endometriosis 
 
 
Phase: 
2 
 
Author: 
 
 
Date of issue: 
26AUG2021 
 
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 


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CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
TABLE OF CONTENTS 
Page 
1 
Introduction .............................................................................................................................................. 5 
1.1 
Definitions/ Abbreviations ............................................................................................................... 5 
1.1.1 
Definition of Terms ............................................................................................................. 5 
1.1.2 
Abbreviations....................................................................................................................... 5 
2 
Trial Objectives and Endpoints .............................................................................................................. 6 
2.1 
Objectives ........................................................................................................................................ 6 
2.1.1 
Primary Objective ................................................................................................................ 6 
2.1.2 
Secondary Objectives .......................................................................................................... 6 
2.1.3 
Exploratory Objectives ........................................................................................................ 6 
2.2 
Endpoints ......................................................................................................................................... 6 
2.2.1 
Primary Endpoint ................................................................................................................. 6 
2.2.2 
Secondary Endpoints ........................................................................................................... 7 
2.2.3 
Exploratory Endpoints ......................................................................................................... 7 
3 
Trial design ............................................................................................................................................... 8 
3.1 
Overall Trial Design ........................................................................................................................ 8 
3.1.1 
Trial Diagram .................................................................................................................... 11 
3.1.2 
Trial Flow Chart ................................................................................................................ 12 
3.2 
Data presentation ........................................................................................................................... 13 
3.3 
Determination of Sample Size ....................................................................................................... 13 
4 
Subject Disposition ................................................................................................................................. 15 
4.1 
Screened Subjects .......................................................................................................................... 15 
4.2 
Subject Disposition ........................................................................................................................ 15 
4.3 
Subject Completion/Discontinuation ............................................................................................. 15 
4.4 
Subject Disposition and Completion by Trial Site ......................................................................... 15 
4.5 
Time to treatment discontinuation ................................................................................................. 16 
4.6 
Listing ............................................................................................................................................ 16 
5 
Protocol Deviations ................................................................................................................................ 17 
5.1 
Major protocol deviations .............................................................................................................. 17 
5.2 
Listing ............................................................................................................................................ 17 
6 
Analysis Sets ........................................................................................................................................... 18 
6.1 
Full Analysis Sets .......................................................................................................................... 18 
6.2 
Per Protocol Analysis Sets ............................................................................................................. 18 
6.3 
Safety Analysis Sets ....................................................................................................................... 18 
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 
Endometriosis History ....................................................................................................... 20 
7.1.4 
Endometriosis/adenomyosis lesions at baseline ................................................................ 21 
7.2 
Medical History ............................................................................................................................. 21 
7.3 
Prior and Concomitant Medication ................................................................................................ 21 
7.4 
Physical and Gynaecological Examination .................................................................................... 21 
7.5 
TVU at baseline ............................................................................................................................. 22 
7.6 
Listings ........................................................................................................................................... 22 
8 
Exposure and Treatment Compliance .................................................................................................. 23 


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Statistical Analysis Plan 
8.1 
Extent of Exposure ......................................................................................................................... 23 
8.2 
Treatment Compliance ................................................................................................................... 23 
8.3 
Listings ........................................................................................................................................... 24 
9 
Efficacy .................................................................................................................................................... 25 
9.1 
General Considerations .................................................................................................................. 25 
9.2 
Primary Endpoint ........................................................................................................................... 25 
9.2.1 
Primary Analyses ............................................................................................................... 25 
9.2.2 
Sensitivity Analyses .......................................................................................................... 27 
9.2.2.1 
Per Protocol Analysis ........................................................................................ 27 
9.2.2.2 
Missing Data ..................................................................................................... 27 
9.2.2.3 
Actual Treatment ............................................................................................... 28 
9.2.2.4 
Including Small Lesions at Baseline ................................................................. 28 
9.2.2.5 
Adjusting for Previous Hormonal Treatment .................................................... 28 
9.2.3 
Additional Analyses .......................................................................................................... 28 
9.2.4 
Figures ............................................................................................................................... 28 
9.3 
Secondary and Exploratory Endpoints ........................................................................................... 29 
9.3.1 
Percentage of Lesion Size Changes by Type on MRI ....................................................... 29 
9.3.2 
Endometrioma and DIE Changes in Volume on MRI ....................................................... 29 
9.3.3 
Endometrioma Size Changes by TVU ............................................................................... 29 
9.3.4 
Other Secondary and Exploratory Endpoints .................................................................... 29 
9.3.4.1 
Binary Endpoints ............................................................................................... 30 
9.3.4.2 
Count Data ........................................................................................................ 31 
9.3.4.3 
Continuous Endpoints ....................................................................................... 32 
9.4 
Pharmacokinetics ........................................................................................................................... 32 
9.5 
MRI-derived Imaging Biomarkers ................................................................................................. 33 
9.6 
Listings ........................................................................................................................................... 33 
10 Safety ....................................................................................................................................................... 34 
10.1 General Considerations .................................................................................................................. 34 
10.2 Adverse Events .............................................................................................................................. 34 
10.2.1 Overview of Treatment-Emergent Adverse Events ........................................................... 35 
10.2.2 Incidence of Adverse Events ............................................................................................. 35 
10.3 Safety Laboratory Variables .......................................................................................................... 36 
10.3.1 Summary Statistics ............................................................................................................ 36 
10.3.2 Laboratory Variable Changes Relative to Normal Range ................................................. 37 
10.3.3 Markedly Abnormal Changes ............................................................................................ 37 
10.3.4 Data Listings ...................................................................................................................... 37 
10.4 Vital Signs ...................................................................................................................................... 37 
10.4.1 Summary Statistics ............................................................................................................ 37 
10.4.2 Markedly Abnormal Changes ............................................................................................ 38 
10.4.3 Data Listings ...................................................................................................................... 38 
10.5 Physical and gynaecological examinations .................................................................................... 38 
10.5.1 Summary Statistics ............................................................................................................ 38 
10.5.2 Data listings ....................................................................................................................... 38 
10.6 TVU ............................................................................................................................................... 39 
10.6.1 Summary Statistics ............................................................................................................ 39 
10.6.2 Data listings ....................................................................................................................... 39 
11 Interim Analyses ..................................................................................................................................... 40 
12 Deviations from Protocol Analysis ........................................................................................................ 41 
13 References ............................................................................................................................................... 42 


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Trial Code: 000295 
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Statistical Analysis Plan 
Appendix 1 
Markedly Abnormal Laboratory Safety Values, Vital Signs and ECGs .................... 43 
Appendix 2 
Impulse Control Disorder Search String ....................................................................... 45 
 
List of Tables 
Table 3-1 
Trial Flow Chart – Procedures at Clinic Visits ................................................................. 12 
Table 3-2 
Sample Size by Treatment Effect Difference .................................................................... 14 
Table 9-1  
Analyses of Other Secondary and Exploratory Endpoints .............................................. 30 
 
List of Figures 
Figure 3-1 
Trial Diagram – Trial Period .............................................................................................. 11 
 
 


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Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
1 
Introduction 
This document describes the planned statistical analyses for Trial 000295, and is based on version 
4.0 of the clinical trial protocol dated 12th of November 2019.  
1.1 
Definitions/ Abbreviations 
1.1.1 Definition of Terms 
Terms 
Definitions 
Randomised 
Subject randomised to trial treatment 
Screened 
Subject who enters the screening phase 
1.1.2 Abbreviations 
 Abbreviations 
Meaning of abbreviations in document 
 
 
FAS 
Full analysis set 
PP 
IMP 
Per-Protocol 
Investigational Medicinal Product 
DIE 
deep infiltrating endometriosis 
MRI 
magnetic resonance imaging 
TVU 
transvaginal ultrasound  
NRS 
Numerical Rating Scale  
EHP-30 
Endometriosis Health Profile-30  
B&B 
Biberoglu and Behrman  
MedDRA 
Medical Dictionary for Regulatory Activities 
RM 
Return of menses 
ANCOVA 
Analysis of covariance 
GEE 
Generalized estimating equation 
SOC 
System organ class 
PT 
Preferred term 
PROs 
Patient reported outcomes  
TSH 
Thyroid-stimulating hormone 
MCMC 
Markov chain Monte Carlo  
MNAR 
Missing not at random 
MAR 
Missing at random 
MI 
Multiple imputation  
AE 
Adverse events 
TEAE 
Treatment emergent adverse events 
ADR 
Adverse drug reactions 
RMP 
Risk management plan 
 


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Statistical Analysis Plan 
2 
Trial Objectives and Endpoints 
2.1 
Objectives 
2.1.1 Primary Objective 
• To evaluate the effect of quinagolide vaginal ring compared to placebo on reduction of lesions 
for endometrioma, deep infiltrating endometriosis (DIE) and adenomyosis assessed by high-
resolution magnetic resonance imaging (MRI)  
 
2.1.2 Secondary Objectives  
• To evaluate the effect of quinagolide vaginal ring compared to placebo on reducing the sizes of 
endometrioma assessed by transvaginal ultrasound (TVU) 
• To evaluate the effect of quinagolide vaginal ring on patient reported outcomes (PROs) 
• To evaluate the plasma concentrations of quinagolide and its metabolites 
• To evaluate the effect of quinagolide vaginal ring on serum endocrine parameters 
• To evaluate the effect of quinagolide vaginal ring on menstrual bleeding pattern 
• To evaluate the safety profile of quinagolide vaginal ring including adverse events and routine 
safety laboratory parameters 
 
2.1.3 Exploratory Objectives  
• To explore the effect of quinagolide vaginal ring on the MRI-derived perfusion imaging 
biomarkers of angiogenesis and on the MRI-derived diffusion imaging biomarkers of lesion 
tissue structure  
• To explore the effect of quinagolide vaginal ring on reducing the size of uterine fibroids 
assessed by both MRI and TVU 
• To explore the effect of quinagolide vaginal ring on endometriosis biomarkers 
 
2.2 
Endpoints 
2.2.1 Primary Endpoint  
• Changes in the sizes (mm) of endometrioma, DIE and adenomyosis lesions summed by type on 
MR images at cycle 4   


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Statistical Analysis Plan 
2.2.2 Secondary Endpoints  
• Percentage of changes in the sizes of endometrioma, DIE and adenomyosis lesions summed by 
type on MR images at cycle 4 
• Proportion of lesions by type with a decrease in a size of ≥5 mm on MR images at cycle 4 
• Proportion of subjects with a lesion of any type decreased in a size of ≥5 mm on MR images at 
cycle 4 
• Number of new or disappearing endometrioma, DIE and adenomyosis lesions summed by type 
on MR images at cycle 4 
• Changes in the volumes (mm3) of endometrioma and DIE lesions summed by type on MR 
images at cycle 4 
• Changes in the sizes of endometrioma assessed by TVU at cycle 4 
• Changes in the mean individual and total symptom and sign severity of scores of the Biberoglu 
and Behrman (B&B) scale at cycle 4  
• Changes in the Numerical Rating Scale (NRS) pain scores per cycle at cycles 1, 2, 3 and 4 
• Changes in the Endometriosis Health Profile-30 (EHP-30) scores at cycles 2 and 4 
• Changes in the menstrual bleeding pattern over 4 cycles 
• Serum levels of prolactin, thyroid-stimulating hormone (TSH), insulin-like growth factor-1 
(IGF-1) during cycle 1, at cycles 2 and 4 
• Plasma concentrations of quinagolide and its metabolites during cycles 1 to 4  
• Changes in clinical chemistry and haematology parameters and proportion of subjects with 
markedly abnormal changes 
• Frequency and intensity of adverse events  
2.2.3 Exploratory Endpoints 
• Changes in the MRI-derived perfusion imaging biomarkers of AUC, Ktrans, kep, ve, vp at cycle 4 
(The analysis of these endpoints will not be described in this SAP, as it will be reported 
separately) 
• Changes in the MRI-derived diffusion imaging biomarkers of ADC, D, D* and f at cycle 4 (The 
analysis of these endpoints will not be described in this SAP, as it will be reported separately) 
• Changes in the sizes of uterine fibroids on MRI at cycle 4  
• Changes in the sizes of uterine fibroids assessed by TVU at cycle 4 
• Changes in circulating levels of vascular endothelial growth factor (VEGF), placental growth 
factor (PlGF), interleukin 6 (IL-6), cancer antigen 125 (CA125) and soluble fms-like tyrosine 
kinase 1 (sFlt-1) at cycle 4 


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
3 
Trial design 
This is a randomised, double-blind, placebo-controlled, phase 2 trial investigating the effect of 
quinagolide extended-release vaginal ring on reduction of lesions, assessed by high-resolution MRI, 
in women with endometrioma, DIE and/or adenomyosis.  
3.1 
Overall Trial Design 
In this trial, quinagolide vaginal ring or placebo vaginal ring will be administered sequentially for 
four menstrual cycles, where a menstrual cycle is considered the period between day 7 after return 
of menses (RM+7) in a cycle until the following day 7 after return of menses of the next cycle. The 
RM+7 visits in this trial can be scheduled within the period of 6-10 days after return of menses 
(RM+6-10).  
The trial consists of the following periods: 
1) Screening: starting from the signing of informed consent to randomisation (≤3 cycles) and 
including a wash-out period (only applicable to subjects using some hormonal contraceptives) 
and a screening cycle (cycle -1, applicable to all subjects) 
2) Treatment: double-blind, placebo-controlled treatment with quinagolide vaginal ring or placebo 
vaginal ring administered sequentially for four menstrual cycles (cycles 1, 2, 3 and 4) 
3) Follow-up: about 1 month after end-of-treatment 
 
Screening: Subjects should be screened for eligibility within approximately 4 months of 
randomisation. Subjects who are currently using some hormonal products (e.g. combined oral 
contraceptive pill, progestogen and levonorgestrel-releasing intrauterine device (IUD)) may be 
eligible for the trial if they have completed the wash-out period and have return of menses.. In this 
case, subjects need to sign the informed consent before they discontinue those products. 
Discontinuation of the products should follow their labelling (e.g. completing the current cycle of 
contraceptives before discontinuation). Subjects who are not using exclusionary hormonal products 
can enter the screening cycle directly. Prescriptions of analgesics for pain management are allowed 
in this trial. 
After having completed the wash-out period (if applicable) and having RM, subjects will attend the 
screening RM+7 visit to undergo initial screening assessments, including a MRI examination by a 
high resolution 3-tesla (3T) machine. Depending on facilities at sites, MRI may not necessarily be 
scheduled at the same screening visit, but it must be scheduled on a day without bleeding to avoid 
biases and to ensure the availability of the central MRI reading report prior to randomisation. The 
MRI at screening, used as baseline, should not be obtained more than 1 menstrual cycle before 
randomisation.  


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
Eligible subjects must have at least one of the following three types of lesions with the following 
sizes identified by MRI: endometrioma (≥20 mm), DIE (≥15 mm), and/or adenomyosis (maximum 
junctional zone thickness ≥12 mm or focal lesion ≥15 mm). If a subject has more than one type of 
lesions, she will be grouped under the more rare type in the ranking of DIE, adenomyosis and 
endometrioma. For example, a subject with both DIE and endometrioma will be included in the DIE 
sub-group but both types of lesions should be measured. Every measurable lesion (defined as ≥10 
mm in size) of any type should be recorded and should be summed up by type for primary analysis. 
For DIE and endometrioma, lesions will be measured both in size and in volume. For uterine 
fibroid, only size will be measured. Size will be recorded in mm as the longest diameter in the plane 
of measurement. Volume will be recorded in mm3 using a semi-automated method based on 3D 
region-growing algorithm, adjusted with manual correction. For adenomyosis, the maximum 
junctional zone thickness (applicable to diffuse adenomyosis) or the size of the largest focal lesion 
(applicable to focal adenomyosis) will be measured. All MRIs should be uploaded into a specific 
image repository allocated for this trial within 2 business days for central reading and analyses by a 
specialised imaging laboratory. Subject eligibility with regard to inclusion criterion no. 6 must be 
determined based on the central MRI reading report.  
Subjects are required to fast for 3-4 hours before the MRI examination. The preparations for MRI 
examination should follow the trial-specific MRI manual. The MRI procedures will include the 
following main sequences:  
• Fast spin echo – T2-weighted images (FSE-T2)  
• Diffusion weighted (DW-IVIM) images with more than 2 b-values 
• Gradient echo (GRE) – T1-weighted images with varying flip angles (GRE-T1-VFA)  
• Dynamic, contrast-enhanced, spoiled GRE T1-weighted images (DCE-PKM-Gd)  
• Late gadolinium enhancement spoiled GRE T1-weighted images (GRE-T1-LATEGd)   
Other details for the MRI examination will be specified in the MRI manual. Prior to the start of the 
trial, site radiologists will be trained on the MRI manual. Site radiologists must follow the MRI 
manual for the preparation and the execution of the MRI assessment.  
In addition to MRI, a TVU should be performed at the screening RM+7 visit to assess uterus, 
endometrium, and ovaries and to measure the size(s) of any endometrioma and/or fibroid. 
Subjects will be required to use a non-hormonal single-barrier method for contraception (i.e. 
condom) from screening to end-of-treatment.  
Treatment: Eligible subjects in each sub-group will be randomised at the end of cycle -1 in to 
receive quinagolide vaginal ring or placebo vaginal ring for four menstrual cycles (cycles 1, 2, 3 
and 4). The study was planned to be have a randomisation ratio of 2:1 with 2 subjects receiving 
quinagolide vaginal ring for each subject receiving placebo vaginal ring, however it was discovered, 
after LPLV but before database lock, that the randomisation list used during the study had a 1:1 
ratio between quinagolide vaginal ring and placebo vaginal ring. Approximately 24 subjects will be 


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
randomised in each sub-group, adding up to a total of 72 subjects in this trial. Quinagolide vaginal 
ring contains a dose load of quinagolide 1080 µg at a target daily release rate of quinagolide 
13.5 µg. 
After randomisation, subjects will self-insert the assigned ring in the upper part of the vagina at 
sites 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 by the next ring at RM+7 visit of the next cycle.  
Subjects who have discontinued during or after cycle 2 should come for an end-of-treatment visit 
with MRI, scheduled within 2 weeks of discontinuation. Subjects who have completed the 
scheduled treatment should come for an MRI examination at or close to the RM+7 visit of cycle 4. 
The MRI at end-of-treatment / cycle 4 must be performed using the same machine, following the 
same procedures and sequences as at screening (detailed in the MRI manual).  
To measure permeability, perfusion imaging biomarkers of the one-compartmental metric (AUC) 
and the two-compartmental metrics (Ktrans, kep, ve, vp) will be derived from the dynamic perfusion 
series. In addition, diffusion metrics (ADC, D, D* and f) of lesion tissue structure will be obtained 
using the intra-voxel incoherent motion (IVIM) model. All perfusion and diffusion parameters at 
screening and at end-of-treatment will be assessed and analysed by the central imaging laboratory. 
All lesions will be segmented in 3D by two radiologists for the analyses of imaging biomarkers.  
TVU will be performed at end-of-treatment / cycle 4, preferably by the same sonographer as at 
screening, to measure the sizes of endometrioma and/or uterine fibroid.  
B&B will be administered at baseline and at end-of-treatment / cycle 4, with trial coordinators 
completing the first part based on subjects’ verbal response and investigators completing the second 
part based on findings of a pelvic examination. At each RM+7 visit from randomisation to cycle 4, 
subjects will score the worst pain they experienced during the past menstrual cycle on a self-
administered NRS, with 0 indicating no pain and 10 indicating worst imaginable pain. In addition, 
they will complete the EHP-30 questionnaire at randomisation, at cycle 2 and at end-of-treatment / 
cycle 4. All PROs will be administered on paper at sites.    
At each RM+7 visit from randomisation to end-of-treatment / cycle 4, the site staff should inquire 
about the bleeding pattern of the subject’s immediate past menstrual period, including the start and 
stop dates (if available) of menstrual bleeding and the amount of menstrual flow.  
Blood samples are collected throughout the trial for the purpose of evaluating endocrine profile, 
plasma concentrations of quinagolide and its metabolites, routine safety laboratory parameters as 
well as endometriosis biomarkers. Endocrine parameters, consisting of prolactin, TSH and IGF-1, 
will be assessed at randomisation, within 1-5 days of randomisation, at cycle 2 and at end-of-
treatment / cycle 4. To measure the plasma concentrations of quinagolide and its metabolites, blood 
samples will be taken within 1-5 days of randomisation, within 7-14 days of randomisation and 
prior to ring removal at RM+7 visits of cycles 1 to 4. Routine safety laboratory tests for clinical 


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
chemistry and haematology parameters will be performed at screening and at end-of-treatment / 
cycle 4. Blood samples for serum and plasma endometriosis biomarkers of VEGF, PlGF, IL-6, 
CA125 and sFlt-1 will be collected at randomisation and at end-of-treatment. 
Follow-up: A telephone call will be made to all subjects at about 1 month after the end-of-
treatment / cycle 4 visit to collect information about adverse events and concomitant medications 
since the visit, and reasons for resuming medications indicated for endometriosis / adenomyosis.  
3.1.1 Trial Diagram  
Screening 
Placebo vaginal ring for 4 cycles
Quinagolide vaginal ring for 4 cycles
Treatment
DIE  
Adenomyosis
Endometrioma
MRI
TVU
PK
PK
PK
PK
PK
MRI
B&B
NRS
NRS
B&B
RM+7
Randomisation / V2
Informed consent
NRS
Safety lab
Biomarker
PK
Safety lab
Biomarker
RM+7 / V5
RM+7 / V6
RM+7 / V7
RM+7 / V8
End of treatment
Cycle 4
Cycle 1
Cycle 2
Cycle 3
1-3 months
1-5d of randomisation / V3
7-14d of randomisation / V4
Endocrine
Endocrine
Endocrine
TVU
NRS
NRS
EHP-30
EHP-30
EHP-30
Endocrine
Wash-out
RM+7
Screening visit / V1
Follow-up
Phoe call at 1 month 
after end-of-treatment
1 month
Cycle -1
Mens. pattern
Mens. pattern
Mens. pattern
Mens. pattern
Mens. pattern
 
Abbreviations: B&B=Biberoglu and Behrman Scale, d=day(s), DIE=deep infiltrating endometriosis, EHP-30=Endometriosis Health Profile 30 
Questionnaire, Mens. pattern=menstrual bleeding pattern, MRI=magnetic resonance imaging, NRS=Numerical Rating Scale, PK=pharmacokinetic(s), 
RM=return of menses, RM+7=day 7 after return of menses, TVU=transvaginal ultrasound, V=visit 
Figure 3-1 
Trial Diagram – Trial Period 


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CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
3.1.2 Trial Flow Chart 
Table 3-1 
Trial Flow Chart – Procedures at Clinic Visits 
 
Screening a,b  
Treatment Period b 
Follow-up 
Wash- 
out a 
Cycle -1 
start 
Cycle -1 
end 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
 
Screening 
visit (V1) 
Randomi-
sation (V2) 
V3 
V4 
V5 
V6 
V7 
V8 
Phone call 
 
~1-3 months 
before V1 
RM+7 
RM+7 
1-5 days 
of V2 
7-14 days 
of V2 
RM+7 RM+7 RM+7 RM+7 / 
EOT 
~1 month 
after V8 
Written informed consent 
  Xa 
Xa 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
 Xa 
X 
Xc 
 
 
 
 
 
 
 
Demographics  
 
X 
 
 
 
 
 
 
 
 
Medical/menstrual/repro history 
 
X 
 
 
 
 
 
 
 
 
Body measurements 
 
X 
 
 
 
 
 
 
 
 
Vital signs  
 
X 
Xc 
X 
 
 
 
 
X 
 
Physical examination 
 
X 
 
 
 
 
 
 
X 
 
Gynaecological examination  
 
X 
 
 
 
 
 
 
X 
 
Cervical cytology d 
 
X 
 
 
 
 
 
 
 
 
Transvaginal ultrasound (TVU) f 
 
X 
 
 
 
 
 
 
X 
 
Urine pregnancy test g 
 
X 
Xc 
 
 
Xh 
Xh 
Xh 
Xh 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
Blood sample (safety) 
 
X 
 
 
 
Xi 
 
 
X 
 
Blood samples (endocrine) 
 
 
Xh 
X 
 
 
Xh 
 
Xh 
 
Blood samples (biomarkers) 
 
 
Xh 
 
 
 
 
 
Xh 
 
Blood sample (PK)  
 
 
 
X 
X 
Xh 
Xh 
Xh 
Xh 
 
MRI 
 
 Xe 
 
 
 
 
 
 
Xe 
 
B&B scale  
 
 
Xh 
 
 
 
 
 
Xh 
 
NRS  
 
 
Xh 
 
 
Xh 
Xh 
Xh 
Xh 
 
EHP-30 questionnaire 
 
 
Xh 
 
 
 
Xh 
 
Xh 
 
Vaginal ring dispensing 
 
 
X 
 
 
X 
X 
X 
 
 
Insertion (i) / removal (r) of ring 
 
 
i 
 
 
i,r 
i,r 
i,r 
r 
 
Drug accountability 
 
 
 
 
 
X 
X 
X 
X 
 
Menstrual bleeding pattern 
 
 
X 
 
 
X 
X 
X 
X 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Condom dispensing / reminder 
 
X 
X 
X 
X 
X 
X 
X 
 
 
End-of-treatment form 
 
 
 
 
 
 
 
 
X 
 
B&B=Biberoglu and Behrman Scale, EHP-30=Endometriosis Health Profile 30 Questionnaire, EOT=end-of-treatment, i=insertion, NRS=Numerical 
Rating Scale, PK=pharmacokinetic(s), r=removal, RM+7=day 7 after return of menses, V=visit.  
a 
Subjects who are currently using some hormonal contraceptives (including combined oral contraceptive pill, transdermal patch and contraceptive 
ring) may be eligible for the trial if they have completed the wash-out period (if applicable) and have return of menses. In this case, subjects need 
to sign the informed consent before the wash-out. Subjects not requiring wash-out will sign the informed consent at the screening visit. 
b 
A menstrual cycle in this trial is considered the period between RM+7 in a cycle until the following RM+7 in the next cycle. The RM+7 visit can 
be scheduled 6-10 days after return of menses (RM+6-10) and is always at the end of each cycle. An exception is cycle -1 which starts with 
RM+7 of a prior cycle.  
c 
Performed before randomisation.     
d 
Performed only for subjects who do not have a cervical cytology test result within 24 months of the screening visit. 
e 
Performed at or close to the RM+7 visit at screening and at cycle 4 when the subject has no bleeding and no ring. Performed using the same 
machine, following the same procedures and sequences (see MRI manual). Fasting for 3-4 hours in advance. Subjects prematurely discontinued 
during or after cycle 2 should also come for an end-of-treatment visit with MRI, scheduled within 2 weeks of discontinuation. 
f 
Performed preferably by the same sonographer. Size(s) of endometrioma and/or uterine fibroid, if any, should also be measured.   


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CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
g 
If the urine pregnancy test is positive, blood collection for a serum βhCG test at the local laboratory must be performed.  
h 
Performed before ring insertion and/or removal, with PROs performed prior to other non-PRO procedures. 
i 
Performed only at Italian sites. 
 
3.2 
Data presentation  
Due to the trial design including separate analysis of the primary endpoint for each of the three 
types of lesion (endometrioma, DIE and adenomyosis), some presentations will be performed by 
type of lesion, some will be performed for the three types of lesions combined, and some will be 
performed both by type and combined. Additionally, some presentations are also prepared by type 
of disease (i.e. endometriosis and adenomyosis), where the category of endometriosis combines 
endometrioma and DIE.   
A subject will be included in the by type analysis if she has at least one lesion of that type ≥10 mm 
at baseline. Notice that a subject can be included in the analysis of more than one type of lesions.  
3.3 
Determination of Sample Size 
The sample size calculation is based on demonstrating superiority of quinagolide vaginal ring 
compared to placebo vaginal ring on the primary endpoint of changes in the sizes of endometrioma, 
DIE and adenomyosis lesions summed by type on MRI at cycle 4. An important assumption behind 
the sample size calculation is an equal magnitude of treatment effect for all three types of lesions. 
For example, for adenomyosis, by assuming an average baseline lesion size of 18 mm and a 
standard deviation of 4.5 mm [1], a sample size of 24 randomised subjects (16 on active treatment 
and 8 on placebo) will have 83% power to detect a treatment effect difference of 6 mm 
(corresponding to a 33% reduction in lesion size) using a two-sample t-test at a 5% two-sided 
significance level. A similar assumption, i.e. the ratio between treatment effect and standard 
deviation is 4 to 3, is made for DIE and endometrioma to conclude 24 subjects to be randomised per 
sub-group. In total, 72 subjects will be randomised in this trial.  


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
Table 3-2 
Sample Size by Treatment Effect Difference 
Difference in the sum of lesion size reduction between 
quinagolide vaginal ring group and placebo vaginal ring 
group 
Number of subjects in total a 
 
Absolute difference 
(mm) 
Relative difference b (%) 
Power 80% 
Power 90% 
4.5 
25 
39 
51 
5.0 
28 
33 
42 
5.5 
31 
27 
36 
6.0 
33 
24 
30 
6.5 
36 
21 
27 
7.0 
39 
18 
24 
7.5 
42 
15 
21 
a 
Using a 2:1 randomisation and assuming a standard deviation of 4.5 mm. 
b 
Assuming an average baseline lesion size of 18 mm. 
 
If the drop-out rate in any of the sub-groups are larger than 10%, the sample size of randomised 
subjects for that sub-group may be increased to up to 30.  
The study was planned to be have a randomisation ratio of 2:1 with 2 subjects receiving quinagolide 
vaginal ring for each subject receiving placebo vaginal, however it was discovered, after LPLV but 
before database lock, that the randomisation list used during the study had a 1:1 ratio between 
quinagolide vaginal ring placebo vaginal ring. The use of a 1:1 ratio instead of a 2:1 ratio will 
increase the power to detect a difference between quinagolide vaginal ring and placebo vaginal ring.  
 


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
4 
Subject Disposition 
4.1 
Screened Subjects 
Screened subjects who discontinue prior to randomisation 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 summarised for the three types of lesions combined (n and % of total number of 
screened subjects) by: randomised, reason for failure and all. 
4.2 
 Subject Disposition 
Subject disposition with respect to analysis sets (Safety, FAS, PP) will be summarised for each of 
the three types of lesion (endometrioma, DIE and adenomyosis) by treatment and in total. If 
applicable a row will be added to the table counting the number of subjects that are randomised but 
not treated. 
4.3 
Subject Completion/Discontinuation  
Completion of treatment will be based on the study completion/early withdrawal form, attendance 
to end-of-treatment MRI will be based on the MRI form for visit 8, and completion of follow-up 
will be based in the follow-up call form. 
Based on the FAS, subjects completion of treatment and attendance to follow-up MRI, will be 
summarised (n and %): completed and attending follow-up MRI, completed and not attending 
follow-up MRI, discontinued and attending follow-up MRI (with information on primary reason for 
discontinuation according to study completion/early withdrawal form), discontinued and not 
attending follow-up MRI (with information on primary reason for discontinuation according to 
study completion/early withdrawal form). The summaries will be performed by treatment and in 
total for each of the three types of lesion (endometrioma, DIE and adenomyosis) and for the three 
types of lesions combined. For each of these four summaries the treatment group difference in the 
proportion of subjects who discontinue treatment will be tested using Fishers exact test. 
Based on the FAS, subjects completion of follow-up will be summarised (n and %). The summaries 
will be performed by treatment and in total for each of the three types of lesion (endometrioma, DIE 
and adenomyosis), for endometriosis (endometrioma and DIE), and for the three types of lesions 
combined.  
4.4 
Subject Disposition and Completion by Trial Site 
The summaries described in section 4.2 and 4.3 will also be performed by trial site.  


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
4.5 
Time to treatment discontinuation  
Based on the FAS five Kaplan-Meier plots for time to treatment discontinuation (from the study 
completion form) will be used to compare treatment groups. One plot for each of the three types of 
lesion (endometrioma, DIE, and adenomyosis), one for endometriosis (endometrioma and DIE), and 
one for the three types of lesions combined. 
The Kaplan-Meier plots will compare the 2 treatment groups, log rank tests will be performed 
comparing the two treatment groups.  
4.6 
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 combined FAS, subject disposition with respect to analysis sets will be listed by site, 
treatment and subject number, this listing will include information on in which subgroup the subject 
was allocated to at randomisation. Subjects who discontinued from the trial will be listed by site, 
treatment, and subject number including information on timing of and reason for discontinuation. 


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
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 be rated as major. Major 
protocol deviations will lead to exclusion of data from the per protocol (PP) analysis sets. 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 randomisation 
• Non-compliance with investigational medicinal product (IMP) treatment regimen for >20% of 
days during the non-menstrual period. The non-menstrual period of each cycle (cycle 1 to 4) is 
defined as the period from stop date of menstrual bleeding (excluding the stop day) to start of 
menstrual bleeding (excluding the start date). For a given cycle the stop date is based on the 
menstrual bleeding pattern form obtained at the beginning of the cycle, and the start date of 
menstrual bleeding is based on the menstrual bleeding pattern form obtained at the end of the 
cycle. The calculation of non-compliance percent is based on the combined non-menstrual 
period for cycle 1 to 4. In case of missing information on start and/or stop dates, the entire cycle 
in question will be considered as non-menstrual.        
Unforeseen deviations deemed to impact the primary endpoint of the trial may additionally be rated 
as major protocol deviations by the Ferring clinical team, with support from the Syneos 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 lock.  
5.1 
Major protocol deviations 
Based on the FAS analysis sets major protocol deviations will be summarised (n and %) for each 
category of protocol deviation, by treatment and in total for each of the three types of lesion 
(endometrioma, DIE and adenomyosis), for endometriosis (endometrioma and DIE), and for the 
three types of lesions combined. 
5.2 
Listing  
Based on the combined FAS 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. All major protocol deviation will also be listed separately. 


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
6 
Analysis Sets 
6.1 
Full Analysis Sets 
For this trial five full analysis sets (FAS) will be defined. One for each of the three types of lesions, 
one for endometriosis (endometrioma and DIE combined) and one for all three types of lesions 
combined (referred to as the combined FAS).  
For the analysis of endometrioma, the FAS comprises of all randomised and treated subjects with at 
least one endometrioma lesion ≥10 mm at baseline.  
For the analysis of DIE, the FAS comprises of all randomised and treated subjects with at least one 
DIE lesion ≥10 mm at baseline.   
For the analysis of adenomyosis, the FAS comprises of all randomised and treated subjects with a 
maximum junctional thickness ≥12 mm at baseline or the size of another adenomyosis lesion ≥10 
mm at baseline.   
For the analysis of endometriosis, the FAS comprises of all randomised and treated subjects with at 
least one endometrioma lesion ≥10 mm at baseline and/or at least one DIE lesion ≥10 mm at 
baseline (referred to as the endometriosis FAS). 
For the analysis of the three types combined, the FAS comprises of all randomised and treated 
subjects.  
Treatment assignment for summaries and analyses are according to planned treatment. The study 
was planned to be have a randomisation ratio of 2:1 with 2 subjects receiving quinagolide vaginal 
ring for each subject receiving placebo vaginal ring, however the randomisation list used during the 
study had a 1:1 ratio between quinagolide placebo and placebo vaginal ring. The planned treatment 
used in the FAS is the treatment according to the actually used randomisation list.  
6.2 
Per Protocol Analysis Sets 
For each of the lesion types the corresponding PP analysis set comprises all subjects from the 
corresponding FAS except those excluded due to major protocol deviations as defined in section 5.  
6.3 
Safety Analysis Sets  
The combined safety analysis set (SAS) comprises all treated subjects and are analysed according to 
the actual treatment received. If a subject receives both treatments during the trial, quinagolide 
treatment will be considered as the actual treatment for the safety analysis.  


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
Four additional SAS will be defined. One for each of the three types of lesions, one for 
endometriosis (endometrioma and DIE).  
For the analysis of endometrioma, the SAS comprises of all treated subjects with at least one 
endometrioma lesion ≥10 mm at baseline.  
For the analysis of DIE, the SAS comprises of all treated subjects with at least one DIE lesion ≥10 
mm at baseline.   
For the analysis of adenomyosis, the SAS comprises of all treated subjects with a maximum 
junctional thickness ≥12 mm at baseline or the size of another adenomyosis lesion ≥10 mm at 
baseline.   
For the analysis of endometriosis, the SAS comprises of all treated subjects with at least one 
endometrioma lesion ≥10 mm at baseline and/or at least one DIE lesion ≥10 mm at baseline 
(referred to as the endometriosis SAS). 
 


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CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
7 
Trial Population 
Unless otherwise specified all tables and listing in this section will be based on the FAS.  
All summaries in this section will be performed by treatment and in total for each of the three types 
of lesion (endometrioma, DIE and adenomyosis), for endometriosis (endometrioma and DIE), and 
for the three types of lesions combined. In addition, summaries of the three types of lesions 
combined will be performed by treatment and in total for each site. Listings will be based on the 
combined FAS only. 
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 and body measurements (age (calculated using date of visit 1 and time of 
birth), race and ethnicity, height, weight and BMI) will be summarised. 
7.1.2 Vital Signs at Baseline 
Baseline vital signs will be summarised as described in section 10.4. 
7.1.3 Endometriosis History 
Endometriosis initial diagnosis (time since initial diagnosis, method, stage and anatomic location) 
will be summarised. In case of partial missing date of initial diagnosis, following imputation will be 
used: If both day and month are missing 01JAN will be used, if only the day is missing 01 will be 
used as the day. 
Endometriosis surgical history since the initial diagnosis (Any history (yes/no), time since, method 
and type of surgery) will be summarised. In case of partial missing date of initial diagnosis, 
following imputation will be used: If both day and month are missing 01JAN will be used, if only 
the day is missing 01 will be used as the day.   
Menstrual history and reproductive history will be summarised.  


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
7.1.4 Endometriosis/adenomyosis lesions at baseline 
The number of lesions per subject, the size the lesions and the sum of the sizes of the lesion will be 
summarised.   
The occurrence of subjects having more than one lesion type will be summarised for the three types 
of lesions combined in the following way: The subjects will be categorised in the following groups: 
Endometrioma lesions only, DIE lesions only, adenomyosis lesions only, endometrioma and DIE 
lesions, endometrioma and adenomyosis lesions, DIE and adenomyosis lesions, endometrioma, DIE 
and adenomyosis lesions. This will be based on the occurrence of lesions ≥10 mm at the baseline 
MRI.   
7.2 
Medical History 
Medical history recorded at screening visit will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) version 21.0. 
Medical history will be summarised by system organ class (SOC) sorted alphabetically and 
preferred term (PT) sorted in decreasing frequency of occurrence.  
Ongoing (ongoing at time of screening) 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 
Medications will be coded using the World Health Organization Drug Reference List and 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).  
 
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 and Gynaecological Examination 
The results of the physical and gynaecological examinations at baseline will be summarised.  


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
7.5 
TVU at baseline 
Baseline TVU results will be summarised as described in section 9.3.3 and 10.6.  
7.6 
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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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
8 
Exposure and Treatment Compliance 
Unless otherwise specified all summaries in this section will be based on the FAS, and will be 
performed by treatment and in total for each of the three types of lesion (endometrioma, DIE and 
adenomyosis), for endometriosis (endometrioma and DIE), and for the three types of lesions 
combined. 
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 
Extent of Exposure  
Total extent of exposure will be summarised. Total extent of exposure will be based on information 
from the vaginal ring administration form.  
The total extent of exposure will be the date of the last ring removal minus the date of first ring 
insertion. 
Extent of exposure for each cycle (cycle 1 to 4) will also be summarised, but only for the three 
types of lesions combined. Extent of exposure for each cycle will as above be calculated as the 
difference in ring removal dates and insertion dates.  
Additionally the extent of exposure counted in cycles will be summarised as a categorical variable. 
A subject is considered exposed in a given cycle if a ring is inserted at visit 2, visit 5, visit 6, or visit 
7 respectively.   
8.2 
Treatment Compliance  
The treatment compliance in percent will be summarised. Treatment compliance will be based on 
information about missed dose from the medication errors form and the vaginal ring administration 
form.  
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.  
The expected number of days exposed to the ring is; if the subjects completes treatment, the date of 
visit 8 minus the date of visit 2; and if the subject discontinues treatment the date of withdrawal 
minus the date of visit 2. The number of days exposed to the ring is based on the vaginal ring 
administration form and taking information on the number of days with missed dose >24 hours 
from the medication errors form into account.   


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
Non-compliance with IMP treatment regimen for >20% of days during a non-menstrual period, 
defined as a major protocol deviation in section 5 will be summarised. 
8.3 
Listings 
Based on the safety analysis set the exposure data from the vaginal ring administration form and the 
medication errors form will be listed and the list will be sorted by site, treatment, subject number, 
and date. The listing will include information on, dates of insertion and removals, and type and 
timing of medication error. 


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
9 
Efficacy 
9.1 
General Considerations 
All efficacy endpoints will be summarised using descriptive statistics and will be performed by 
treatment and in total for each of the three types of lesion (endometrioma, DIE and adenomyosis), 
for endometriosis (endometrioma and DIE), and for the three types of lesions combined. 
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, unless otherwise specified.  
All 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”.  
9.2 
Primary Endpoint 
The primary endpoint consists of the following three evaluations, all based on the MRI 
examinations at baseline and at end-of-treatment: 
• The changes from baseline to end-of-treatment in the sum of sizes (mm) of all 
endometrioma lesions ≥10 mm at baseline   
• The changes from baseline to end-of-treatment in the sum of sizes (mm) of all DIE lesions 
≥10 mm at baseline  
• The changes from baseline to end-of-treatment in the sum of sizes (mm) of the maximum 
junctional thickness  (if ≥ 12 mm) and all other adenomyosis lesions ≥10 mm at baseline 
Based on the FAS and the PP analysis sets the absolute sum of sizes at baseline and at end-of-
treatment, and the change in the sum of sizes from baseline to end-of-treatment will be summarised. 
The summaries will be performed by treatment and in total for each of the three types of lesions 
(endometrioma, DIE, and adenomyosis).  
9.2.1 Primary Analyses 
The primary analyses are based on the FAS. 
For each type of lesion (endometrioma, DIE and adenomyosis), the primary endpoint is the change 
in the sum of the lesion sizes at end-of-treatment, i.e. the difference between the active treatment 


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
group and the placebo group in the change from baseline in the sum of the lesion sizes of the same 
type at the end-of-treatment. The baseline is defined as the sum of the sizes of all lesions of the 
same type ≥10 mm obtained from the MRI examination at screening. At end-of-treatment / cycle 4, 
the sizes of all lesions included at baseline of the same type will be summed. For each type of 
lesions, subjects with at least one lesion of that type ≥10 mm at baseline will be included.  
If a subject is prematurely discontinued during or after cycle 2, an end-of-treatment MRI 
examination will be performed. The results from this end-of-treatment MRI will be used to 
calculate the primary endpoints. 
If the end-of-treatment MRI examination results in an assessment of a lesion size as <5 mm without 
a precise value (or categorised as detectable), the size of this lesion will be imputed as 2.5 mm. If 
the end-of-treatment MRI examination results in a lesion assessed as being truly not detectable, the 
size of this lesion will be imputed as 0 mm. 
If the end-of-treatment MRI examination is not performed or is missing, the missing measurement 
will be imputed using a multiple imputation (MI) strategy. The imputation will be based on a 
missing a random assumption (MAR). The missing sum of lesion sizes at end-of-treatment will be 
imputed by regression-based imputation models using treatment group, baseline sum of lesion sizes, 
and the overall NRS score (at visit 2, 5, 6, 7, 8) as the predictors. The imputation procedure will be 
repeated 100 times. For technical reasons, the imputation is implemented in two steps as described 
below. 
Firstly any non-monotone missingness of the predictors mentioned above is imputed using the 
Markov chain Monte Carlo (MCMC) method, assumptions underlying this partial imputation step 
are such that subjects with missing data follow the same model as other subjects with the same 
value of the observed predictors that have complete data, and this is a reasonable assumption for 
this partial imputation, because subjects tend to miss intermediate visits due to scheduling conflicts 
or other reasons unrelated to their medical condition under study. 
Secondly all monotone missingness is imputed, using a standard MAR based MI approach for 
monotone missingness, which imputes variables one at a time in the following order: the overall 
NRS score at visit 2, at visit 5, at visit 6, at visit 7, and at visit 8, and finally the sum of lesion sizes 
at end-of-treatment.  
For each type of lesion and each imputation, the primary endpoint will be analysed using an 
analysis of covariance (ANCOVA) model, with the change in the sum of lesion sizes from baseline 
measured at end-of-treatment as the dependent variable, the baseline sum of lesions as covariate, 
and the treatment group as fixed effect. The treatment difference between active treatment versus 
placebo will be estimated for each of the three types of lesions.  
Finally, the 100 different imputations are combined to an estimate of the treatment difference 
between active treatment versus placebo and its 95% confidence interval and corresponding p-value 
using SAS Proc Mianalyze. 


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
In order to control the overall type I error at 5%, the Hochberg procedure is implemented by 
ranking the 3 p-values in a decreasing order. If the largest p-value is ≤0.05, superiority is 
established for all 3 types of lesions. If the largest p-value is >0.05, but the middle p-value is 
≤0.025, superiority is established for the two types of lesions with the smaller p-values. If the 
largest p-value is >0.05 and the middle p-value is >0.025, but the smallest p-value is ≤0.0125, 
superiority is established for only the type of the lesion with the smallest p-value. If the largest p-
value is >0.05, the middle p-value is >0.025, and the smallest p-value is >0.0125, superiority is not 
established for any of the 3 types of lesions. 
9.2.2 Sensitivity Analyses  
A number of sensitivity analyses are planned to establish robustness of the primary analysis, 
including summary statistics (expect for the placebo based MI in section 9.2.2.2). All sensitivity 
analysis except the PP analysis will be performed on the FAS.  
9.2.2.1 
Per Protocol Analysis  
To test efficacy in more perfect conditions. For each type of lesion an analysis similar to the 
primary analysis will be performed using the PP population. 
9.2.2.2 
Missing Data 
For each type of lesion three sensitivity analyses will be performed to investigate the impact of 
missing data, two completer analyses and one MI analysis: 
Firstly, an ANCOVA analysis similar to the primary analysis, but without doing any imputation, 
and using only data from subject that have completed the scheduled treatment and have information 
from both the baseline and the cycle 4 MRI.  
Secondly, a similar ANCOVA without imputation, using data from all subjects that have 
information from both the baseline and the end-of-treatment MRI.  
Thirdly, a MI analysis will be performed using MI for missing data in a placebo-based pattern 
mixture model (based on a missing not at random (MNAR) condition). A MNAR assumption will 
be used as the primary analysis gives an unbiased estimation of the treatment effect under the MAR 
assumption.   
This is done in 3 steps firstly initiating the process by imputing any non-monotone missingness 
using the MCMC method, just as in the primary analysis, the non-monotone missingness (missing 
at intermediate visits) is assumed to be MAR opposed to missingness due to drop-out which is 
assumed to MNAR. That is the non-monotone missingness is assumed to be unrelated to the 
medical condition, whereas the monotone missingness is allowed to depend on the medical 
condition. Secondly all monotone missingness is imputed, an approach, which imputes variables 
one at a time in the following order: NRS score at visit 2, at visit 5, at visit 6, at visit 7, and at visit 
8, and finally the sum of lesion sizes at end-of-treatment, similar to the primary analysis, however 
this imputation will be based on only the placebo group. So the mean of the imputed values will be 
based on the mean of the placebo subjects with the same predictors as the subject that has missing 


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Ferring Pharmaceuticals 
 
 
 
CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
information. Thirdly the 100 imputations are analysed and combined similarly to the primary 
analysis.  
9.2.2.3 
Actual Treatment 
For each type of lesion, the primary analysis will be performed using the actual treatment rather 
than the planned treatment. If a subject receives both treatments, then the treatment that the subject 
received for the longest period is used as the actual treatment for this sensitivity analysis. 
9.2.2.4 
Including Small Lesions at Baseline  
For each type of lesion, the primary analysis performed on a redefined outcome. The outcome will 
be the change from baseline to end-of-treatment in the sum of all lesions of that type including the 
lesions below <10 mm in size at baseline, as opposed to the primary analysis focusing on all lesion 
of that type that are ≥10 mm at baseline. 
9.2.2.5 
Adjusting for Previous Hormonal Treatment  
For each type of lesion the primary analysis will be performed adjusting for previous hormonal 
treatment as a fixed factor. Previous hormonal treatment will be defined as a Yes/No variable and 
will take the value yes if the subject has any prior medication with a stop date less than 6 month 
prior to first us of IMP, with ATC classification 1st level equal to “Genito urinary system and sex 
hormones” and  ATC classification 2nd level equal to “sex hormones and modulators of the genital 
system” or “other gynaecologicals” and the value no otherwise.  
9.2.3 Additional Analyses   
Based on the endometriosis FAS (endometrioma and DIE). The changes from baseline to end-of-
treatment in the sum of sizes (mm) of all endometriosis (endometrioma and DIE) lesions ≥10 mm at 
baseline will be analysed using a similar ANCOVA model and a similar imputation scheme as the 
primary analysis.  
9.2.4 Figures   
Figures based on the FAS for each of the three types of lesion (endometrioma, DIE and 
adenomyosis), for endometriosis (endometrioma and DIE), and for the three types of lesions 
combined will be prepared. The mean of the primary outcome (with 95% confidence interval) will 
be graphed as a function time (Baseline and End-of-treatment) for the two treatment groups in the 
same figure. No imputations will be used for the figures.  


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CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
9.3 
Secondary and Exploratory Endpoints  
The summaries and analysis of the secondary efficacy endpoints will be performed for the FAS. No 
sensitivity analysis will be performed for any of the secondary or exploratory outcomes. 
9.3.1 Percentage of Lesion Size Changes by Type on MRI 
For each type of lesion (endometrioma, DIE and adenomyosis), the percentage change in the sum of 
lesion sizes, will be analysed using a similar ANCOVA model and a similar imputation scheme as 
the primary endpoint, but both the baseline sum of sizes and the cycle 4 / end-of-treatment sum of 
sizes will be log transformed prior to analysis. The estimated difference between treatment groups 
will be back transformed to ease interpretation.  
If the end-of-treatment MRI examination results in that all lesions of the same type are assessed as 
truly not detectable the sum will be imputed as 1 mm, in order to facilitate the log-transformation. 
9.3.2 Endometrioma and DIE Changes in Volume on MRI 
The absolute sum of volumes at baseline and at end-of-treatment, and the change in the sum of 
volumes from baseline to end-of-treatment will be summarised. The summaries will be performed 
by treatment and in total for each of the two types of lesions (endometrioma and for the two types 
combined and DIE). 
For each of the two types of lesions (endometrioma and DIE) and for the two types combined, the 
change in the sum of lesion volumes, will be analysed using a similar ANCOVA model and a 
similar imputation scheme as the primary endpoint. 
9.3.3 Endometrioma Size Changes by TVU 
The absolute sum of sizes of endometrioma lesions assessed by TVU at baseline and at end-of-
treatment, and the change in the sum of sizes from baseline to end-of-treatment will be summarised. 
The summaries will be performed by treatment and in total only for endometrioma lesions. 
The change in the sum of lesion sizes assessed by TVU, will be analysed using a similar ANCOVA 
model and a similar imputation scheme as in the primary endpoint.  
9.3.4 Other Secondary and Exploratory Endpoints  
All summaries in this section will be performed by treatment and in total. As indicated in Table 9-1 
some endpoints will be summarised and analysed for each of the three types of lesion 
(endometrioma, DIE and adenomyosis) and for endometriosis (endometrioma and DIE), some for 
all types of lesion combined, and some for both.  


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CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
No imputation will be done for the analysis of these other secondary and exploratory endpoints. The 
endpoint derived from the MRI will, however, use the end-of-treatment assessment even if the end-
of-treatment assessment is performed before end of cycle 4.  
Table 9-1  
Analyses of Other Secondary and Exploratory Endpoints 
Endpoint 
Analysis method  
Presentation 
ANCOVA 
Repeated 
measures 
ANCOVA 
Logistic 
regression 
Negative 
Binomial 
regression  
Proportional 
odds  
By type 
of lesion 
and 
disease  
All types 
of lesions 
combined 
Proportion of lesions by type with a 
decrease in a size of ≥5 mm on MR images 
at cycle 4 
 
 
X 
 
 
X 
 
Proportion of subjects with a lesion of any 
type decreased in a size of ≥5 mm on MR 
images at cycle 4 
 
 
X 
 
 
 
X 
Number of new endometrioma, DIE and 
adenomyosis lesions by type on MR 
images at cycle 4 
 
 
 
X 
 
X 
 
Number of disappearing endometrioma, 
DIE and adenomyosis lesions by type on 
MR images at cycle 4 
 
 
 
X 
 
X 
 
Changes in the total physical sign pain 
score and change in the total symptom and 
sign severity score of the Biberoglu and 
Behrman (B&B) scale at cycle 4 
X 
 
 
 
 
X 
X 
Changes in the Numerical Rating Scale 
(NRS) pain scores at cycles 1, 2, 3 and 4 
 
X 
 
 
 
X 
X 
Changes in each of the five  EHP-30 scores 
and the total EHP-30 score per cycle at 
cycles 2 and 4 
 
X 
 
 
 
X 
X 
Changes in the menstrual bleeding pattern 
over 4 cycles 
 
X 
 
 
X 
X 
X 
Change in serum levels of prolactin, TSH, 
IGF-1 during cycle 1, at cycles 2 and 4 
 
X 
 
 
 
X 
X 
Changes in the sizes of uterine fibroids on 
MR images at cycle 4 
X 
 
 
 
 
 
 
Changes in the sizes of uterine fibroids 
assessed by TVU at cycle 4 
X 
 
 
 
 
 
 
Changes in circulating levels of VEGF, 
PlGF, IL-6, CA125 and sFlt-1 at cycle 4 
X 
 
 
 
 
X 
X 
Note: Exploratory endpoints are shaded in grey.  
9.3.4.1 
Binary Endpoints  
Secondary endpoints related to proportion of lesions with a decrease in a size of ≥5 mm at cycle 4 
and proportion of subjects with a lesion of any type that decreased in a size of ≥5 mm at cycle 4 will 
be based on all lesions ≥10 mm at baseline. 


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Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
The proportion of lesions with a decrease as defined above and the proportions of subjects with at 
least one lesion decreased as defined above will be summarised  
The proportion of lesions will be analysed using logistic regression for binary data with logit link 
function, the generalised estimating equation (GEE) approach will be used to account for correlated 
data (multiple lesions in one subject), and the analysis will be adjusted for baseline lesion size. The 
analyses will be performed for each of the three types of lesions, and for endometriosis 
(endometrioma and DIE).  
The proportion of subjects will be analysed using logistic regression for binary data with logit link 
function, and the analysis will be adjusted for the number of lesions ≥10 mm at baseline. The 
analyses will be performed for the three types of lesions combined.  
Menstrual bleeding pattern will be analysed by looking at the first occurrence of change from 
baseline (visit 2) in the amount of menstrual flow (either to a more heavy flow or to a more mild 
flow). This will be analysed using the proportional odds regression model. The analyses will be 
performed for each of the three types of lesions, and for endometriosis (endometrioma and DIE). 
The treatment differences between active treatment versus placebo will be reported as odds ratios 
with 95% confidence intervals and corresponding p-values for each of these endpoints. 
9.3.4.2 
Count Data 
The number of new lesions of each of the three types of lesions will be counted for all subject, 
regardless of which types of lesions the subject had at baseline. The definition of a new lesion is a 
lesion that is > 0 mm at the end-of-treatment MRI, but was non-detectable at baseline.  
The number of disappearing lesions of each of the three types of lesions will be counted for all 
subject with at least one lesion of that type that is > 0 mm at baseline. The definition of a 
disappearing lesion is a lesion that is detectable at baseline, but is non-detectable at end-of-
treatment.  
The number of new and disappearing lesions will, for each type of lesion, be summarised as 
categorical variables.  
The analysis of the number of new lesions will be performed for each of the three types of lesion 
and for endometriosis (endometrioma and DIE). It will be analysed using a negative-binomial 
regression with log link function.  
The analysis of the number of disappearing lesions will be performed for each of the three types of 
lesion and for endometriosis (endometrioma and DIE). It will be analysed using a negative-binomial 
regression with log link function, using the number of lesions of that type as off-set.  


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Trial Code: 000295 
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Statistical Analysis Plan 
The treatment differences between active treatment versus placebo will be reported as rate ratios 
with 95% confidence intervals and corresponding p-values for each of these endpoints. 
9.3.4.3 
Continuous Endpoints 
The analysis of the secondary endpoints related to PROs (B&B, NRS, and EHP-30), endocrine 
parameters (prolactin, TSH, and IGF-1), serum endometriosis biomarkers (VEGF, PlGF, IL-6, 
CA125, and sFlt-1), sizes of uterine fibroids (the sum of the size of all fibroids) assessed by MRI 
and TVU, will be described in this subsection.  
The absolute value at baseline and the absolute value at each post baseline measurement, and the 
change from baseline to each post baseline measurement will be summarised. These endpoints will 
be analysed using a repeated measures ANCOVA model, with the change from baseline at each 
post-baseline time point as the dependent variable, the baseline value as a covariate, and the 
treatment group and treatment group by time as fixed effects. The error-covariance matrix will be 
unstructured. For the endpoints only measured once post baseline, an ordinary ANCOVA similar to 
the one used in the primary analysis will be applied (without imputations). The analyses will be 
performed for each of the three types of lesions, and for endometriosis (endometrioma and DIE). 
The treatment difference between active treatment versus placebo will be reported with 95% 
confidence interval and corresponding p-value for each post baseline of these endpoints. 
  
As an additional analysis the menstrual bleeding pattern will be investigated by analysing the 
number days with menstrual bleeding (calculated as the stop date of menstrual bleeding minus start 
day plus 1) for each of the four cycles under treatment and the length of the menstrual cycle 
(calculated as the difference between two consecutive start of menstrual bleeding dates) for each of 
the four cycles under treatment. The baseline values for these two variables will be the number of 
bleeding days and the length of the menstrual period of the last pre-treatment cycle, respectively. If 
the stop date of a menstrual bleeding is missing due to the subject still bleeding at the RM+7 visit, 
the visit date plus 1 is used for calculating the length of the bleeding period. If the start date of 
menstrual bleeding is missing due to the subject having delayed or skipped menstrual bleeding, both 
of the two length of menstrual cycles will be considered missing, and the length of the bleeding 
period will be set to 0. To summarise the occurrence of delayed or skipped menstrual bleeding 
descriptive tables summarising the number of delayed or skipped menstrual bleedings and the 
number of subjects that experience at least one delayed or skipped menstrual bleeding will be 
prepared. 
9.4 
Pharmacokinetics 
Plasma concentration of quinagolide and its metabolites will be analysed descriptively, by 
summarising (N, mean (SD), geometric mean (CV%), min, and max) by visit, for all subjects that 
received active quinagolide. A population pharmacokinetic modelling method will be outlined in a 


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CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
modelling analysis plan under the responsibility of the Translational Medicine Department of 
Ferring Pharmaceuticals A/S and the results will be reported separately.  
9.5 
MRI-derived Imaging Biomarkers  
The exploratory endpoints related to the MRI-derived perfusion and diffusion imaging biomarkers 
will be analysed by the central imaging laboratory and will be reported separately 
9.6 
Listings  
All observed endpoints will be listed by site, treatment, and subject number. For the laboratory 
endpoints values outside the reference range (with information on clinically significance) and 
markedly abnormal values will be flagged. 


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CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
10 Safety 
10.1 General Considerations 
Safety parameters will be evaluated for the combined safety analysis data set for all types of lesions 
combined, for each of the three types of lesions separately, and for endometriosis (endometrioma 
and DIE), See section 6.3 for the definition of the safety analysis sets. All summaries will be 
performed by treatment. For adverse events (AE) the following rules will apply: 
Treatment period 
AE to be included 
Pre-treatment period 
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 
Treatment emergent AE 
A treatment-emergent adverse event is any adverse event occurring 
after start of IMP and before the follow-up phone call, or a pre-
treatment adverse event or pre-existing medical condition that worsens 
in intensity after start of IMP and before the follow-up phone call. 
 
For safety data where only a partial date has been reported, the following rules will be applied: 
• Year and month given: for start dates, starting first day in the month and for stop dates, 
stopped last day in the month 
• Only year given: for start dates, starting 1st of January and for stop dates, stopped 31st of 
December   
10.2 Adverse Events 
AEs are classified according to MedDRA version 21.0. 
An AE which occurs between signing informed consent and the first dose of the IMP or a pre-
existing condition that worsens in intensity after signing of informed consent is defined as a pre-
treatment AE. A treatment-emergent adverse event is any adverse event occurring after start of IMP 
and before the follow-up phone call, or a pre-treatment adverse event or pre-existing medical 
condition that worsens in intensity after start of IMP and before the follow-up phone call. If the 
timing of an AE cannot be established in relation to the administration of IMP, it will be considered 
as a treatment emergent AE. Pre-treatment AEs will be presented in a separate data listing only. AE 
in connection with screening safety lab values are considered pre-treatment if the blood is sampled 
prior to treatment.  


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Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
 
If causality for an AE is missing then the AE will be considered related. If intensity for an AE is 
missing then the AE will be considered severe. If seriousness for an AE is missing then the AE will 
be considered serious. If outcome for an AE is missing then the AE will be considered not 
recovered. 
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 
• TEAEs by intensity  
• All adverse drug reactions (ADR) (i.e. an AE judged by the investigator and/or sponsor 
to have a reasonable possible causality to the IMP) 
• ADR by intensity 
• TEAEs leading to death  
• Serious TEAEs  
• Serious ADR 
• TEAEs leading to discontinuations  
• ADR leading to discontinuations 
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 TEAEs 
• Mild TEAE  
• Moderate TEAE  
• Severe TEAE  
• All ADR  
• Mild ADR 
• Moderate ADR 
• Severe ADR 
• Treatment emergent unrelated adverse events 
• TEAEs leading to death 


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CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
• ADRs leading to death  
• Serious TEAE  
• Serious ADR  
• Non- serious ADR  
• TEAEs leading to discontinuation  
• ADRs leading to discontinuation 
• TEAEs for impulse control disorder search string (see appendix 2) 
• ADRs for impulse control disorder search string (see appendix 2) 
• TEAEs with an incidence ≥5% of subjects in any treatment group 
• Non-serious TEAEs with an incidence ≥5% of subjects in any treatment group 
 
Supporting data listings will be provided for all adverse events sorted by centre and subject number 
and date of onset. Further, data listings by MedDRA SOC sorted alphabetically and Preferred Term 
sorted in decreasing frequency of occurrence will be provided for: 
• All TEAE 
• Severe TEAE  
• Serious TEAE  
• TEAE leading to death 
• TEAE leading to discontinuation 
• Treatment emergent adverse events to be followed up after end-of-trial 
  
10.3 Safety Laboratory Variables 
Safety lab values are planned to be measured twice, at baseline (visit 1), at end-of-treatment (visit 
8). If multiple blood samples are obtained prior to first dose of IMP the last blood sampling 
performed prior to the first dose of IMP is used as baseline.  
Laboratory variables will be grouped under “Haematology” and “Clinical Chemistry”.  
10.3.1 Summary Statistics 
Mean change and mean percentage (%) change from baseline at end-of-treatment 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 both 
baseline and end-of-treatment as well as for changes from baseline to end-of-treatment (both 
absolute change and relative change).  


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Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
10.3.2 Laboratory Variable Changes Relative to Normal Range 
Changes relative to normal ranges are presented with shift tables with total number of subjects, and 
number and percent of subjects who experienced a shift from baseline to end-of-treatment. The 
laboratory reference ranges are provided by the central laboratory. The following categories for 
shift tables are defined: 
• Low:   
Values which are below the lower reference range limit; 
• Normal:  
Values which are within the lower and upper reference range; 
• High:   
Values which are above the upper reference range limit. 
 
For all haematology and clinical chemistry variables, shift tables will be prepared to compare 
baseline values to the end-of-treatment value. More specifically, for haematology and clinical 
chemistry, tables presenting the changes from Low or Normal to High and from High or Normal to 
Low will be provided.   
10.3.3 Markedly Abnormal Changes 
For each laboratory variable, a summary tables will be prepared displaying the number and 
percentage of subjects in each treatment group with normal baseline values but having at least one 
pre-specified markedly abnormal value any time after first dose of IMP. Pre-specified markedly 
abnormal criteria for laboratory tests are given in Appendix 1.   
10.3.4 Data Listings 
All laboratory values will be listed by subject number and time point. Values outside the reference 
range (with information on clinically significance) and markedly abnormal values will be flagged.  
10.4 Vital Signs 
Vital signs (pulse rate, systolic blood pressure, and diastolic blood pressure) are planned to be 
measured 4 times during the trial, at visit 1, at visit 2 prior to first dose of IMP, at visit 3 and at end-
of-treatment (visit 8), for each of the 4 visits vital signs will be measured 4 times; in supine 
position, in seated position, at 1 minute after standing, and at 3 minutes after standing. For each 
visit changes in systolic and diastolic blood pressure will be calculated using the minimum standing 
measurement minus the seated measurement and the minimum standing measurement minus the 
supine measurement. Baseline for all vital signs analyses will be the values obtained at the last 
assessment prior to the first dose of IMP.  
10.4.1 Summary Statistics 
Mean change and mean percentage (%) change from baseline to visit 3 and to end-of-treatment will 
be presented for each vital signs variable (including change from sitting to standing and from supine 


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Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
to standing as described above). In addition, descriptive statistics, i.e., the number of subjects with 
data, mean (standard deviation), median, minimum, and maximum values, will be presented for the 
observed values (at screening, at baseline, at visit 3, and at end-of treatment) and for change from 
baseline (both absolute change and relative change) to visit 3 and at end-of-treatment for each vital 
signs variable(including change from sitting to standing and from supine to standing as described 
above).  
10.4.2 Markedly Abnormal Changes 
Summary tables will be prepared displaying the number and percentage of subjects with normal 
baselines who had one or more pre-specified markedly abnormal treatment-emergent values, 
according to the definition in Appendix 1. 
10.4.3 Data Listings 
All vital signs values (including change from sitting to standing and from supine to standing as 
described above) will be listed by subject number and time point. Markedly abnormal values and 
clinically significant changes or values will be flagged. 
10.5 Physical and gynaecological examinations 
Physical and gynaecological examinations are planned at baseline and at end-of-treatment. At the 
physical examination a number of body systems will be assessed, and at gynaecological 
examination a number of categories will be assessed. Each resulting in a result of normal, not 
clinically significant abnormal, or clinically significant abnormal. If multiple examinations are 
performed after first dose of IMP, then at worst case approach will be used for reporting, such that 
if any post baseline examination are judged as clinically significant abnormal, this result will be 
used as the end-of treatment value, and only if all post baseline examinations are judged as normal 
the end-of-treatment value will be normal.        
10.5.1 Summary Statistics 
Shift tables summarising the number (%) of subjects that shifted between all combinations of 
baseline and end-of-treatment values for each body system examined at the physical examination 
and each category examined at the gynaecological examination will be produced. The number of 
subjects with baseline values will be used as denominator when percentages are calculated (e.g. the 
percentage of subjects going from normal to not clinically significant abnormal will be using the 
number of subjects being normal at baseline as denominator).     
10.5.2 Data listings 
All subjects with any abnormalities at any visit will be listed with all physical and gynaecological 
examination evaluations.  


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CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
10.6 TVU 
TVU is planned at baseline and at end-of-treatment. The overall interpretation of TVU results in a 
result of normal, not clinically significant abnormal, or clinically significant abnormal. If multiple 
examinations are performed after first dose of IMP, then a worst case approach will be used for 
reporting, such that if any post baseline examination are judged as clinical significant abnormal, this 
result will be used as the end-of treatment value, and only if all post baseline examinations are 
judged as normal the end-of-treatment value will be normal.  
10.6.1 Summary Statistics 
Shift tables summarising the number (%) of subjects that shifted between all combinations of 
baseline and end-of-treatment values for the overall interpretation will be produced. The number of 
subjects with that baseline values will be used as denominator when percentages are calculated (e.g. 
the percentage of subjects going from normal to not clinically significant abnormal will be using the 
number of subjects being normal at baseline as denominator).  
The number of subjects with ovarian cyst will be summarised at baseline and at end-of-treatment.  
The endometrial thickness at baseline, at end-of-treatment and the change from baseline to end-of-
treatment will be summaries by time point.  
10.6.2 Data listings 
All subjects with any abnormalities at any visit and/or any ovarian cyst at any visit will be listed 
with all TVU evaluations.  


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CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
11 Interim Analyses 
No interim analysis is planned for this trial. 


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Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
12 Deviations from Protocol Analysis 
The Study Protocol stated that the primary analysis should be adjusted for site. In this SAP the 
primary analysis is not adjusted for site, this change has been made because of the actual 
distribution of subjects on sites. We have 4 out of 6 sites with 4 or less subjects. Adjustment for site 
leads to a high risk of noninformative sites.  
The study was planned to be have a randomisation ratio of 2:1 with 2 subjects receiving quinagolide 
for each subject receiving placebo, however it was discovered, after LPLV and before database 
lock, that the randomisation list used during the study had a 1:1 ratio between quinagolide placebo. 
The use of a 1:1 ratio instead of a 2:1 ratio will increase the power to detect a difference between 
quinagolide vaginal ring and placebo vaginal ring. 
The use of the 1:1 randomization ratio, have not led to any change of the planned analysis in this 
SAP.  
 


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Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
13 References 
[1] 
Bragheto A, Caserta N, Bahamondes L, Petta CA. Effectiveness of the levonorgestrel-
releasing intrauterine system in the treatment of adenomyosis diagnosed and monitored by 
magnetic resonance imaging. Contraception 2007; 76: 195-199 
[2] 
Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York, John Wiley 
and sons.  


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CONFIDENTIAL 
Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
Appendix 1 
Markedly Abnormal Laboratory Safety Values, Vital 
Signs and ECGs  
Table 1: 
Markedly abnormal Criteria for Laboratory Tests 
 
 
Markedly abnormal Criteria 
Variable 
Units 
Low 
High 
Haematology 
Haemoglobin 
g/L 
 80 
Not applicable 
Haematocrit 
Ratio 
>0.20 
>0.60 
Total WBC 
109/L 
<2.0 
>35.0 
Platelets 
109/L 
<50 
>999 
Total RBC 
1012/L 
 
Not applicable 
Clinical Chemistry 
AST  
IU/L 
Not applicable 
> 155 
ALT  
IU/L 
Not applicable 
> 165 
Alkaline 
phosphatase 
IU/L 
Not applicable 
> 520 
GGT 
IU/L 
Not applicable 
> 180 
Total bilirubin 
μmol/L 
Not applicable 
 1.5xULN 
Creatinine 
μmol/L 
Not applicable 
>252 
Albumin 
g/L 
<20 
 
Sodium 
mmol/L 
 130 
 155 
Potassium 
mmol/L 
 3.0 
>6.0 
Phosphorus 
mmol/L 
>0.65 
 
Calcium 
mmol/L 
<1.75 
>3.13 
Glucose 
mmol/L 
 
>13.9 
Total cholesterol 
mmol/L 
Not applicable 
>10.36 
 


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Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
Table 2: 
Markedly abnormal Criteria for Vital Signs* 
Variable 
Criterion Value 
Change from Baseline 
Systolic blood pressure 
 180 mmHg 
 90 mmHg 
A drop of 20 mmHg from changing 
position 
Increase of  20 mmHg  
Decrease of  20 mmHg 
Diastolic blood pressure 
 105 mmHg  
 50 mmHg 
A drop of 10 mmHg from changing 
position 
Increase of  15 mmHg  
Decrease of  15 mmHg 
Pulse rate 
 120 bpm 
 50 bpm 
Increase of  15 bpm 
Decrease of  15 bpm 
Body weight 
None 
 
Increase of  7% 
Decrease of  7% 
Body temperature 
> 38.3 C 
Increase to  39.4C 
* To be identified as markedly abnormal, a treatment value must meet the criterion value and also the specified change 
from baseline. 
 
Table 3: 
Abnormal Criteria for Quantitative ECG Data 
Variable 
Baseline  
Abnormal Treatment-Emergent Value 
ECG heart rate 
Normal 
 50 bpm and decrease from baseline of  15 bpm 
 120 bpm and increase from baseline of  15 bpm 
Duration of PR interval 
Normal 
≥ 220 msec 
Duration of QRS interval 
Normal 
≥ 120 msec 
Duration of QTc interval 
Normal 
≥ 450 msec 
Duration of QTc interval 
Normal 
≥ 480 msec 
Duration of QTc interval 
Normal 
≥ 500 msec 
Duration of QTc interval* 
Not applicable 
Increase from baseline of ≥ 30 msec 
Duration of QTc interval 
Not applicable 
Increase from baseline of ≥ 60 msec 
 
* QTc will be calculated both using Bazett’s and Fridericia’s correction formulae. 
 
 


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Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
Appendix 2 
Impulse Control Disorder Search String  
The adverse events summary table for all AEs for impulse control disorder search string mentioned 
in section 10.2.2 of this SAP will include all AEs with the below mentioned preferred terms. 
All preferred terms under the SMQ hostility/aggression (broad) that is: 
Aggression 
Amygdalotomy 
Anger 
Antisocial behaviour 
Antisocial personality disorder 
Belligerence 
Borderline personality disorder 
Child abuse 
Conduct disorder 
Defiant behaviour 
Homicidal ideation 
Homicide 
Hostility 
Incest 
Intermittent explosive disorder 
Physical abuse 
Physical assault 
Psychopathic personality 
Sexual abuse 
Violence-related symptom 
Abnormal behaviour 
Activation syndrome 
Affect lability 
Agitated depression 
Agitation 
Agitation postoperative 
Asphyxia 
Attention-seeking behaviour 
Bipolar disorder 
Bipolar I disorder 
Bipolar II disorder 
Bite 
Delinquency 
Delusional disorder, jealous type 
Delusional disorder, persecutory type 
Disinhibition 
Disruptive mood dysregulation disorder 
Disturbance in social behaviour 
Drowning 


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Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
Elder abuse 
Fight in school 
Gun shot wound 
Hanging 
Human bite 
Hypomania 
Impatience 
Imprisonment 
Imprisonment of relative 
Impulse-control disorder 
Impulsive behaviour 
Injury 
Irritability 
Irritability postvaccinal 
Jealous delusion 
Laceration 
Mania 
Oppositional defiant disorder 
Paedophilia 
Paranoia 
Paranoid personality disorder 
Paraphilia 
Personality change 
Personality disorder 
Psychological abuse 
Psychomotor hyperactivity 
Psychotic behaviour 
Psychotic disorder 
Pyromania 
Sadism 
Screaming 
Spousal abuse 
Stab wound 
Substance-induced psychotic disorder 
Spousal abuse 
Stab wound 
Substance-induced psychotic disorder 
Theft 
Verbal abuse 
 
And additionally, the following preferred terms: 
 
Alcohol abuse  
Alcohol problem  
Alcohol use  


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Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
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 


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Quinagolide, FE 999051 
Trial Code: 000295 
Vaginal Delivery System 
Statistical Analysis Plan 
Stereotypy 
Thinking abnormal 
Weight increased