An Adaptive Phase 2, Open-Label, Multicentre Study Investigating the Pharmacokinetics, Pharmacodynamics, Efficacy and Safety of Teverelix Trifluoroacetate, a GnRH Antagonist, in Participants With Advanced Prostate Cancer
Phase: PHASE2
Conditions: Prostatic Adenoma
Sponsor: Antev Ltd.

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Study Protocol
An Adaptive Phase 2, Open-Label, Multicentre Study Investigating the Pharmacokinetics, 
Pharmacodynamics, Efficacy and Safety of Teverelix Trifluoroacetate, a Gonadotropin-
releasing Hormone (GnRH) Antagonist, in Participants with Advanced Prostate Cancer
TEACh (Teverelix Evaluated in Advanced prostate Cancer)
EudraCT No.: 2020-000543-31
Trial No.: ANT-1111-02
Original Protocol (Version 1.0), dated 22 April 2020
Final Version 2.0, dated 21 September 2020
Final Version 3.0, dated 27 November 2020
Final Version 4.0, dated 21 July 2021
DRAFT Version 5.0, dated 31 May 2022
Antev Ltd
106 New Bond Street
London
W1S 1DN
Confidentiality Statement
The information in this document is confidential and proprietary to Antev Ltd. It is 
understood that the information will not be disclosed to any person or institution other than 
investigators or consultants for review, their staff, applicable Ethics 
Committee(s)/Institutional Review Board(s), regulatory authorities and study participants 
without express authorisation by Antev Ltd.

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Protocol Synopsis
Title
An Adaptive Phase 2, Open-Label, Multicentre Study Investigating the 
Pharmacokinetics, Pharmacodynamics, Efficacy and Safety of Teverelix 
Trifluoroacetate, a Gonadotropin-releasing Hormone (GnRH) Antagonist, 
in Participants with Advanced Prostate Cancer
Study No.
ANT-1111-02
EudraCT No.
2020-000543-31
Clinical Phase
Phase 2
Investigational 
Product
Teverelix trifluoroacetate (TFA)
Number of 
Participants
Group 1: Twenty participants will be needed to complete the first period 
of 28 days (Stage 1)
Group 2: Sixty participants will be needed to complete the first period of 
28 days (Stage 1) 
Group 2 subjects who are enrolled onto protocol version V4.0 dated 21 
July 2021, and, are ongoing on the trial when protocol version V5.0 dated 
16 May 2022 is implemented, will have the option to transfer to protocol 
version V5.0.  They may also choose to continue on protocol version V4.0 
dated 21 July 2021.
Number of 
Centres
Up to 7
Countries
Lithuania (Groups 1 and 2) and (potentially) Netherlands and/or Belgium 
(Group 2 only)
Study 
Duration
Screening Period: Up to 6 days
Treatment Period:
Core Study:
Stage 1 (loading-dose period): 28 days
Stage 2 (maintenance-dose period): Up to 168 days
Stage 3 (follow up period): Up to 84 days (or until local lab T 
levels are > 1 ng/mL, whichever occurs first).  Final assessment is 
done 7 days later.
Study 
Objective(s)
Primary Objective
To assess the efficacy of teverelix TFA in terms of ability to suppress 
serum testosterone (T) levels to below castration level (<0.5 ng/mL or 

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1.73 nmol/L) at Day 28
Secondary Objective(s)

To assess the efficacy of teverelix TFA in terms of ability to 
suppress serum T levels to below castration level (<0.2 ng/mL or 
0.6934 nmol/L) at Day 28

To assess the efficacy of teverelix TFA in terms of ability to 
suppress serum T levels to below castration level (<0.5 ng/mL or 
1.73 nmol/L) at Day 42

To assess the efficacy of teverelix TFA in terms of ability to 
suppress serum T levels to below castration level (<0.2 ng/mL or 
0.6934 nmol/L) at Day 42

To assess the efficacy of teverelix TFA in terms of ability to 
suppress serum T levels to below castration level (<0.5 ng/mL or 
1.73 nmol/L) at Day 168

To assess the efficacy of teverelix TFA in terms of ability to 
suppress serum T levels to below castration level (<0.2 ng/mL or 
0.6934 nmol/L) at Day 168

To assess the efficacy of teverelix TFA in terms of ability to 
maintain suppression of serum T levels below castration level 
(<0.5 ng/mL or 1.73 nmol/L) over time during Stage 2 
(maintenance-dose period)

To assess the efficacy of teverelix TFA in terms of ability to 
maintain suppression of serum T levels below castration level 
(<0.2 ng/mL or 0.6934 nmol/L) over time during Stage 2 
(maintenance-dose period)

To assess the time taken to achieve serum T levels below castration 
level (<0.5 ng/mL or 1.73 nmol/L)

To assess the time taken to achieve serum T levels below castration 
level (<0.2 ng/mL or 0.6934 nmol/L)

To assess the time taken for serum T levels to increase to >0.5 
ng/mL following the final, Day 168 injection

To delineate the pharmacokinetics (PK) profile of teverelix TFA

To assess the effects of teverelix TFA on:
-
prostate-specific antigen (PSA)
-
T
-
follicle stimulating hormone (FSH)
-
luteinising hormone (LH)

To assess the predictive effect for new cardiovascular (CV) events 
of cardiac biomarkers
o
N-terminal pro-B-type natriuretic peptide (NTproBNP)
o
D-dimer
o
C-reactive protein (CRP)
o
high-sensitivity troponin (hsTn)

To assess the safety of teverelix TFA in terms of:
-
local tolerability (injection site reactions [ISR])
-
systemic tolerability (adverse events, vital signs, 
electrocardiograms (ECG), Holter monitoring (subset of 30 

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subjects in Group 2 only) and laboratory parameters)
Design and 
Methodology
This adaptive Phase 2 study will be performed as a prospective, open-
label, multicentre, non-controlled study based on within-group comparison 
in participants with advanced prostate cancer.
The study consists of the following periods/visits:
Screening Period: Days -6 to -1
Treatment Period:
Core Study:
1. Stage 1: Loading dose administered at baseline (Day 0) with 
follow-up visits until Day 28
2. Stage 2: Maintenance treatment administered every 6 weeks 
(Groups 1 and 2) with visits from Day 28 up to Day 168 or until 
treatment ceases to be effective
3. Stage 3: Follow up period.  After final, Day 168 injection, subjects 
will return on Day 203 and weekly thereafter until Day 252 or until 
serum T levels are >1 ng/mL (local lab result), whichever occurs 
first
4. Follow-up Visit: Day 259 or 7 days after serum T levels > 1 
ng/mL (local lab result), whichever occurs first
Treatments Administered:
The study is designed to evaluate up to 2 dosing regimens:
Grou
p
Loading Dose
Maintenance Dose
Dosing 
Interval
1
120 mg IM+120 mg 
SC
120 mg SC
6 weekly
2
180 mg IM+180 mg 
SC
180 mg SC
6 weekly
IM=intramuscular; SC=subcutaneous
Participants will receive different doses depending on whether they join 
Group 1 or Group 2. The study will enrol participants into Group 1 first.
On Day 0, participants in Group 1 will receive a single loading dose 
consisting of 2 injections, each of which will contain 120 mg of teverelix 
TFA. The first injection will be administered as an intramuscular (IM) 
injection and the other as a subcutaneous (SC) injection (Stage 1).
After Stage 1, participants in Group 1 will receive a maintenance dose, 
which will consist of a single 120 mg SC injection administered every 42 
days.
If 3 or more participants have a total T (local laboratory) value of 
>2 ng/mL at Day 21 or at any subsequent study visit, the dosing regimen 
will have failed to meet its 90% efficacy target and, if applicable, further 
enrolment into Group 1 will cease.
Total T (central laboratory) samples will be frozen, and batch shipped to 
SGS (formerly Synlab), Münich for analysis every 3 months. Ad hoc 
shipments may be triggered if data review milestones require. 
If the serum T value (measured by the local laboratory) at the Day 35 visit 
is >2 ng/mL, the participant will be withdrawn from the study without 

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receiving any IMP in Stage 2.
If treatment of Group 1 has been terminated early due to a low therapeutic 
response rate, recruitment of participants into Group 2 will start.
On Day 0, participants in Group 2 will receive a single loading dose 
consisting of 2 injections, each of which will contain 180 mg of teverelix 
TFA. The first injection will be administered as an intramuscular (IM) 
injection and the other as a subcutaneous (SC) injection (Stage 1).
After Stage 1, participants in Group 2 will receive a maintenance dose, 
which will consist of a single 180 mg SC injection administered every 42 
days.
If the serum T value (measured by the local laboratory) at the Day 21 visit 
is >2 ng/mL, the participant will then be withdrawn from the study.
Participants will have their serum T measured by the local laboratory 
1 week prior to each maintenance dose during Stage 2 of the study. If, at 
any point the local laboratory serum T result is >2 ng/mL the participant 
will be withdrawn from the study. Local laboratory serum T values ≤2 
ng/mL allow the participants to continue in the study.
Total T (central laboratory) samples will be frozen and batch shipped to 
SGS (formerly Synlab), Münich for analysis every 3 months. Ad hoc 
shipments may be triggered if data review milestones require.
Study Procedures
The first IMP administration will be performed on an inpatient basis. IMP 
administration at consecutive visits may be performed on an outpatient 
basis. Study visits will be held as described below.
Screening Examination
The screening examination consists of the following assessments and 
procedures which will be performed within the 6 days prior to baseline 
assessments conducted on Day 0: determination of provision of informed 
consent; eligibility; medical and surgical history, especially for prostate 
cancer; previous medication; demographics; physical examination; body 
weight and height; serology (human immunodeficiency virus [HIV] and 
hepatitis); fasted (>8 hours) safety laboratory tests; glycated haemoglobin 
(HbA1c); total T (local laboratory), triplicate 12-lead ECGs; and vital 
signs.  As fasting is considered a study procedure informed consent must 
be obtained prior to asking the subjects to fast.  Therefore, it may be 
necessary to conduct the screening visit over more than one day.
Stage 1 Visits for Group 1 and Group 2
Participants will attend study visits on Days 0, 1, 2, 3, 4, 7, 10, 12, 14, 21 
and 28. At Day 0 (baseline visit), the loading dose of teverelix TFA will be 
administered.
Participants will attend weekly study visits from Day 14 to Day 28.
Baseline (Day 0) Visit
A check of eligibility, as well as pre-dose blood sampling for PK and 
pharmacodynamics (PD) analyses,and fasted (>8 hours) safety laboratory 
testing will be conducted. Samples will be collected for urine analysis. A 
pre-dose adverse events (AE) assessment, physical examination, triplicate 

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12-lead ECG and assessment of vital signs (including sitting blood 
pressure and heart rate) will be performed.
For a subset of 30 Group 2 subjects only (first 30 enrolled subjects with no 
more than 8 subjects at any one site), 24 hour continuous Holter 
monitoring will be performed.  For analysis of the continuous 12-lead 
ECG data, triplicate 10 second 12-lead ECGs will be extracted at time 
points matching PK sampling times after at least 5 minutes rest in order to 
facilitate concentration-QTc effect modelling. Data will be analysed for 
arrhythmias following completion of the entire study to investigate the 
potential effect of teverelix on QTc interval. 
All participants will start Stage 1 with the administration of the loading 
dose of teverelix TFA IM followed by SC injection.
After the administration of the IMP, participants will be monitored for 24 
hours for the occurrence of ISR and AEs.
If, in the opinion of the investigator, no safety concerns exist, participants 
will be discharged from the centre.
Day 1 to Day 14 Visits
On Days 1 to 14, blood sampling for PK and PD analysis will be 
performed. In addition, blood sampling for assessment of PSA will be 
performed on Days 7 and 14.
Day 21 Visit
On Day 21, local testing of T levels will be performed to guide decision 
making at the Day 28 visit. PK, total T, LH, FSH and PSA (total and 
high-sensitivity [hs]) samples will also be collected for central laboratory 
analysis.
Day 28 Visit
Before the participant is able to continue into Stage 2, laboratory results 
that confirm serum T levels will be checked.
For participants in Group 1, the following actions will be taken at the Day 
28 visit based on the results of the locally analysed T level determined 
from the Day 21 visit:
[T] 
(ng/mL)
Action Taken
Dose Administered
≤2
Continue with 
Stage 2 of Group 1
No dose on Day 28. Maintenance 
dose of 120 mg SC teverelix TFA 
every 42 days
>2
Withdraw from 
study, safety 
follow-up visit on 
Day 28 
None
SC=subcutaneous; T=testosterone; TFA=Trifluoroacetate
For participants in Group 2, the following actions will be taken at the Day 
28 visit based on the results of the locally analysed T level determined 
from the Day 21 visit:

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[T] 
(ng/mL)
Action Taken
Dose Administered
≤2
Continue with 
Stage 2 of Group 2
No dose on Day 28. Maintenance 
dose of 180 mg SC teverelix TFA 
every 42 days
>2
Withdraw from 
study; safety 
follow-up visit on 
Day 28 
None
SC=subcutaneous; T=testosterone; TFA=Trifluoroacetate
Day 35 Visit
On Day 35, local testing of T levels will be performed to guide decision 
making at the Day 42 visit. PK, total T, LH, FSH and PSA (total and 
high-sensitivity [hs]) samples will also be collected for central laboratory 
analysis.
Stage 2 Visits in Groups 1 and 2
Day 28 Visit
Stage 2 will start at the Day 28 visit. However, participants will receive 
their first maintenance dose at the Day 42 visit and participants will visit 
the clinic at Day 35 to provide a blood sample for local laboratory testing 
of T levels.
Blood samples for PK and PD analyses (T, LH, FSH, PSA), and fasted (>8 
hours) safety laboratory testing will be collected. Samples will also be 
collected for urine analysis. AE assessment, physical examination, 
triplicate 12-lead ECG and assessment of vital signs (including sitting 
blood pressure and heart rate) will be performed.
If, in the opinion of the investigator, no safety concerns exist, participants 
will be discharged from the centre.
Visits at Day 42, Day 84, Day 126, and Day 168
On Day 42 the first maintenance dose will be administered.
Before administration of the maintenance dose, blood samples for PK and 
PD analyses as well as fasted (>8 hours) safety laboratory testing will be 
collected. Samples will also be collected for urine analysis. Pre-dose AE 
assessment (including ISR), physical examination, triplicate 12-lead ECG 
and assessment of vital signs (including sitting blood pressure and heart 
rate) will be performed.
Participants will attend the clinic 1 week before each maintenance dose is 
given (i.e. at Days 35, 77, 119 and 161) to provide a blood sample for local 
laboratory assessment of T levels. At the Day 35 visit (only) PK, total T, 
LH, FSH and PSA (total and hs) samples will also be collected for central 
laboratory analysis. Based on the results of the local analysis of T level 
from 7 days prior to the scheduled visit, participants will receive:

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[T] 
(ng/mL)
Action Taken
Dose Administered
≤2
Continue in Stage 
2 of Group 1
Maintenance dose of 120 mg SC 
teverelix TFA
>2
Withdraw from 
study, safety 
follow-up visit
None
SC=subcutaneous; T=testosterone; TFA=Trifluoroacetate
After the administration of the IMP the participants will be monitored for 
30 minutes for the occurrence of ISRs and AEs.
If, in the opinion of the investigator, no safety concerns exist, participants 
will be discharged from the centre.
At each of the maintenance dose visits, the procedures carried out at the 
Day 42 visit will be repeated.
Safety Follow-up Visit (28 days after last dose)(Group 1 and Group 2 
subjects without Stage 3)
Blood samples will be collected for fasted (>8 hours) safety laboratory 
testing. Physical examination and assessments of vital signs (including 
sitting blood pressure and heart rate), height/weight, and triplicate 12-lead 
ECG will be performed
Stage 3 Visits (Group 2 only)
After final, Day 168 injection subjects will return on Day 203 and weekly 
thereafter until Day 252 or until serum T levels >1 ng/mL (local lab 
result), whichever occurs first
Safety Follow-up Visit (Day 259 or 7 days after serum T levels are >1 
ng/mL (local lab result), whichever occurs first)
Blood samples will be collected for fasted (>8 hours) safety laboratory 
testing. Physical examination and assessments of vital signs (including 
sitting blood pressure and heart rate), height/weight, and triplicate 12-lead 
ECG will be performed
Pharmacokinetic and Pharmacodynamic Samplings
Stage 1:
Post-dose PK blood sampling on Day 0 is scheduled at the following 
timepoints: 1, 1.5, 2, 2.5, 3, 4, 8, 12, 18, and 24 hours.
Blood samples for PD analysis (total T, LH, FSH) will be initiated at 
24 hours post-dose.
The participant will return to the study site for additional post-dose PK and 
PD blood sampling at 48 hours (Day 2) and 72 hours (Day 3), and on Days 
4, 7, 10, 12, 14, and 21.
On Days 7, 14, and 21, blood sampling for PSA will be performed.
Stage 2:
Post-dose PK and PD (total T, LH, FSH, PSA) blood sampling is 
scheduled on the following days: Days 28, 35, 42, 84, 126 and 168, and 

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follow-up for Group 1 and Group 2
Treatment
Participants will receive different doses depending on whether they join 
Group 1 or Group 2. The study will enrol participants into Group 1 first.
On Day 0 participants will receive a single loading dose consisting of 2 
injections, each of which will contain 120 mg of teverelix TFA (Group 1) 
or 180 mg teverelix TFA (Group 2). The first injection will be 
administered as an IM and the other as an SC injection (Stage 1).
After Stage 1, participants of Group 1 will receive a maintenance dose, 
which will consist of a single 120 mg SC injection administered every 42 
days up to Day 168.
If treatment of Group 1 has been terminated early due to a low therapeutic 
response rate, recruitment of participants into Group 2 will start.
After Stage 1, participants in Group 2 will receive a maintenance dose, 
which will consist of a single 180 mg SC injection administered every 42 
days up to Day 168.
The total treatment period in this study will end when the last maintenance 
dose is administered on Day 168.  
For Group 2 subjects only a follow up period will be followed.  Subjects 
will return on Day 203 (5 weeks after final Day 168 injection) for serum T 
levels to be measured.  Weekly visits will continue until serum T levels are 
> 1 ng/mL (local lab result).
A safety follow-up visit will be done 7days after serum T levels are > 1 
ng/mL (local lab result). Participants withdrawn early from the study will 
be asked to return to the study site for a safety follow-up visit >28 days 
after administration of the last dose.
Population
Inclusion Criteria
The participant must fulfil all of the following criteria:
1. Is male, aged ≤85 years (≥18 years) at the beginning of the treatment 
period (Day 0)
2. Has histologically proven advanced adenocarcinoma of the prostate 
(metastatic or non-metastatic, hormone-sensitive, non-curative), 
suitable for androgen deprivation therapy
3. Is treatment naïve for any of the following:
a.
GnRH analogues,
b. Androgen receptor antagonists, or
c.
Androgen synthesis inhibitors (e.g. abiraterone)
4. Agrees to practice contraception during the entire study treatment 
period and for 3 months after the last dose of IMP is administered:
a. Either by using double barrier contraception,
b. or, is truly sexually abstinent, when this is in line with the 
preferred and usual lifestyle of the participant
Note: Periodic abstinence [e.g. calendar, ovulation, 
symptothermal, postovulation methods for the female partner 
with childbearing potential] and withdrawal are not 

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acceptable methods of contraception.
5. Has provided written (personally signed and dated) informed consent 
before completing any study-related procedure, which means any 
assessment or evaluation that would not have formed a part of his 
normal medical care
Exclusion Criteria
If any of the following criteria apply, the participant MUST NOT be 
admitted to the study. The participant:
1. Has abnormal screening and/or baseline laboratory values that suggest 
a clinically significant underlying disease, or the following laboratory 
values:
a.
Liver function test (aspartate aminotransferase 
[ASAT/SGOT], alanine aminotransferase [ALAT/SGPT]), 
or total bilirubin exceeding twice the upper limit of the 
normal (ULN) range
b. Creatinine twice the ULN range
c.
Uncontrolled diabetes (HbA1c >7.5%) or previously 
undiagnosed diabetes mellitus with HbA1c >6.5%
2. Has any contraindication to the use of teverelix TFA
3. Has a life expectancy of less than 1 year
4. Has T levels <2.0 ng/mL at screening
5. Has a medical history of bilateral orchidectomy
6. Using any of the following prohibited treatments:
a.
Within 25 weeks prior to screening: dutasteride
b. Within 12 weeks prior to screening: finasteride
c.
Current use of any of the following:
i.
Anti-androgen therapy, including T replacement therapy 
and 5α-reductase inhibitor treatment etc. 
(Spironolactone is a permitted concomitant treatment)
ii.
Any other medication or herbal product that may affect 
hormone levels and might, therefore, confound 
interpretation of the study results (e.g. St. John’s wort)
7. Has neurological disease, psychiatric disease, drug or alcohol abuse, 
which could interfere with the participant’s proper compliance
8. Has a history of myocardial infarction, unstable symptomatic 
ischaemic heart disease, any ongoing cardiac arrhythmias of grade >2 
(chronic stable atrial fibrillation on stable anticoagulant therapy is 
allowed), thromboembolic events (e.g. deep vein thrombosis, 
pulmonary embolism, or symptomatic cerebrovascular events), or any 
other significant cardiac condition (e.g. pericardial effusion, restrictive 
cardiomyopathy) within the 6 months prior to screening
9. Has congenital long QT syndrome or ECG abnormalities at screening 
of:
a.
Q-wave infarction, unless identified ≥6 months before 
screening
b. Fridericia corrected QT interval (QTcF interval) >480 msec. If 
QTcF is prolonged in a participant with a pacemaker, the 

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participant may be enrolled in the study upon discussion with 
the project clinician

If the QTcF interval is 450-480 msec, inclusive, in a participant 
with current use of medications with known effects on QT interval, 
the participant may be enrolled in the study following discussion 
with the Medical Lead
Note: Cardiac arrhythmia grading:
o            Bradyarrhythmias (HR <60/min)
o            Tachyarrhythmias (HR >100/min)
o            Supraventricular arrhythmias – arrhythmias that originate 
in the sinoatrial node, atrial myocardium or atrioventricular node 
(regular QRS complex)
o            Ventricular arrhythmias – arrhythmias that originate below 
the atrioventricular node (wide QRS complex)
10. Has known or suspected severe renal impairment
11. Has a medical history of diagnosis of, or treatment for, another 
malignancy within the 2 years prior to administration of the first dose 
of IMP, or previous diagnosis of another malignancy with evidence of 
residual disease. Participants with nonmelanoma skin cancer or 
carcinoma in situ of any type are not excluded if they have undergone 
complete resection
12. Is currently using Class IA (e.g. quinidine, procainamide) or Class III 
(e.g. amiodarone, sotalol) antiarrhythmic medications
13. Has uncontrolled hypertension despite appropriate medical therapy 
(sitting blood pressure [BP] of >180 millimetres of mercury [mmHg] 
systolic and >95 mmHg diastolic at 2 separate measurements taken no 
more than 60 minutes apart during the screening visit). Participants 
with isolated systolic BP measurements >180 mmHg may be 
rescreened. Participants with isolated systolic BP measurements 141 to 
180 mmHg or isolated diastolic BP measurements ≥95 mmHg, 
although eligible, should be referred for further management of 
hypertension if indicated
14. Has known, previously diagnosed HIV infection, active chronic 
hepatitis B or C, life-threatening illness unrelated to prostate cancer, or 
any serious medical condition that could, in the investigator's opinion, 
potentially interfere with participation in this study. Specific screening 
for chronic viral illness is at the discretion of the site and/or local 
Institutional Review Board (IRB)
15. Has been exposed to another investigational drug within the 3 months 
prior to screening
16. Has anticipated non-availability for study visits/procedures
17. Plans to undergo surgery during the study period
18. Known presence of hepatic metastases
Efficacy 
Endpoints
Primary Endpoint:

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Proportion of participants achieving castration level with serum T 
<0.5 ng/mL or 1.73 nmol/L at Day 28.
Secondary Endpoints:
1. Proportion of participants achieving castration level with serum T 
<0.2 ng/mL at Day 28
2. Proportion of participants achieving castration level with serum T 
<0.5 ng/mL at Day 42
3. Proportion of participants achieving castration level with serum T 
<0.2 ng/mL at Day 42
4. Proportion of participants achieving a T castration rate over 
168 days of treatment period
Note: Castration rate is defined as the observed percentage of 
participants who have T concentrations <0.5 ng/mL (1.73 
nmol/L) at all scheduled visits.
5. Proportion of participants achieving profound castration rate (<0.2 
ng/mL) over 168 days of treatment period
6. Mean time to T levels falling below castration level (<0.5 ng/mL 
[1.73 nmol/L]) for the first time
7. Mean time to (first) overstep of T castration level after achieving 
castration
8. Mean time for serum T levels to be > 0.5 ng/mL after final, Day 
168 injection
9. Proportion of participants achieving castration level for LH (LH 
<1.1 U/L) at Day 28
10. Proportion of participants with effective LH castration rate over 
168 days of treatment period
11. Mean time to LH levels falling below castration level (LH <1.1 
U/L) for the first time
12. Mean time to (first) overstep of LH castration level after achieving 
castration
13. Changes from baseline in PD and PK parameters over time
14. Number of participants with a PSA response of ≥50% reduction at 
the Day 168 visit
15. Number of participants with a PSA response of ≥80% reduction at 
the Day 168 visit
16. Percent change from baseline in serum PSA concentration at each 
visit
17. Mean serum PSA concentration at each visit
18. Mean serum LH concentration at each visit
19. Mean serum T concentration at each visit
20. Mean serum FSH concentration at each visit

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Safety 
Endpoints
Safety endpoints for the study include:
1. Number of participants with treatment-emergent AEs (defined as 
any AE occurring or worsening following treatment), summarised 
by system organ class (SOC) and preferred term (PT)
Note: Occurrence of ISRs will be included.
2. Mean changes in vital signs, triplicate 12-lead ECG and laboratory 
data parameters at each visit during the 168-day treatment period, 
compared to baseline.
3. Continuous 12-lead, 24 hour Holter monitoring (subset of 30 Group 
2 subjects only)
4. Predictive effect of cardiac biomarkers (terminal pro-B-type 
natriuretic peptide (NTproBNP, D-dimer, C-reactive protein 
(CRP), high-sensitivity troponin (hsTn)) for CV events
5. Percentage of participants with ISRs at each visit during the 168 
days treatment period
Note: Photography of injection sites will be performed at each 
dosing visit, and ISRs will be scored based on a specific scoring 
matrix.
Statistical 
Methods
Analysis Populations
Screening population: All participants who signed the informed consent 
form.
Safety population: All participants who received any dose of the IMP.
Intention-to-treat (ITT) analysis set: All participants included in the 
safety population for whom the primary endpoint is evaluable.
Per protocol (PP) analysis set: All participants included in the ITT 
analysis set who complete the study without major protocol violation.
The analysis will be done in 2 stages. Stage 1 will only include the analysis 
of the primary objective, which investigates the effect of the loading dose 
required to achieve castration levels by Day 28. Stage 2 will include all 
other analyses.
The primary objective will be assessed by determination of the proportion 
of participants achieving castration level T concentrations on Day 28.
The primary result will be the proportion of those participants in the PP 
analysis set, together with its Clopper-Pearson confidence interval (CI) and 
absolute frequencies. The same holds for the proportion of participants 
maintaining castration over 24 weeks at all scheduled visits.
In addition the calculation of the Kaplan-Meier estimate of the proportion of 
patients who achieve and maintain castrate T levels (T level < 50 ng/dL) from 
Day 28 through the end of the treatment period will be done.
All safety and efficacy endpoints will be summarised descriptively, i.e. by 
absolute and relative frequencies (relative to the respective analysis 

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population) for categorical endpoints. The distribution of continuous 
endpoints will be described by standard measures of location and 
dispersion in terms of mean, standard deviation (SD), median, Quartiles 1 
and 3, minimum and maximum, and CIs for the mean.
AEs: All AEs will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) terminology and summarised by PT and SOC. 
Frequencies of AEs will be presented by absolute and relative frequencies 
of (a) the number of AEs and (b) the number of participants experiencing 
an event for each SOC and PT.
AEs will be summarised separately for serious AEs, treatment-emergent 
AEs (defined as any new or worsening pre-existing AE with a date equal 
to or later than the date of IMP administration) and possibly treatment-
related AEs.
PK/PD: Concentrations over time will be described by area under the 
concentration-time curve from time zero to last available measurement 
(AUC0-t), maximum concentration (Cmax), time to reach maximum 
concentration (Tmax), terminal half-life (t1/2), first-order elimination rate and 
graphical representation of the concentrations over time. The geometric 
mean will be calculated additionally for AUCs and Cmax.
Depending on the progression of the concentrations, multiple peaks of 
concentrations can occur. Additional AUC, Tmax and Cmax will be specified 
accordingly (total and separated by each phase of concentration increase) 
for the parameters.
Missing data will not be substituted in general, but in the case of a 
laboratory reporting concentrations as unquantifiably low, they will be set 
to 0.
All study data will be reported in participant data listings.
Detailed statistical methodology, definitions and data handling will be 
described in a separate statistical analysis plan (SAP) prior to analysis.

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Responsibilities
Sponsor's Responsible Representative:
Carol MacLean, PhD
VP Women’s Health & Clinical Operations
Antev Limited
106 New Bond Street (3rd Floor)
London
W1S 1DN
UK
Email: cmaclean@antev.co.uk
Sponsor's Medical Expert:
Dr Finn Larsen
Chief Scientific Officer
Antev Limited
106 New Bond Street (3rd Floor)
London
W1S 1DN
UK
Email: flarsen@antev.co.uk
Medical Lead Insuvia UAB:
Tomas Janusonis, MD
Clinical Research Physician
Jonavos str. 30
Kaunas 44262
Tomas.janusonis@insuvia.com
Biometrician Quanticate International 
Ltd:
Saira Ahmad 
Senior Statistician I 
Bevan House, 9-11 Bancroft, Hitchin SG5 
1LH 
Email: Saira.Ahmad@quanticate.com 
Pharmacokinetic Laboratory:
Rebecca Wright
Senior Scientist Small Molecule Bioanalysis 
Drug Development Solutions
LGC
Newmarket Road
Fordham Cambridgeshire
CB7 5WW
UK
Tel: +44 (0)1638 724 343 | Ext: 1343
Email: rebecca.wright@lgcgroup.com

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Serious Adverse Event Reporting
All serious adverse events (SAEs) must be reported immediately (within 1 working day) to: 
safety@intuvigilance.com
Name and address of drug safety manager:
Nimisha Kotecha
Managing Director/EU QPPV
IntuVigilance Limited
Scotsbridge House,
Scots Hill, Rickmansworth
WD3 3BB,
Hertfordshire,
UK.
Email: nimisha.kotecha@intuvigilance.com
Phone: +44 (0)1923-545474
Fax: 
 +44 (0) 01923 545229
Mobile: +44 (0)7834-766990

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Signatures
The signatories are obliged to comply in all respects with:

This clinical study protocol

The standards of Good Clinical Practice as defined in the "Note for Good Clinical 
Practice" (CPMP/ICH 135/95) and related guidelines

The "Declaration of Helsinki" current valid version according to applicable national 
regulatory and legal requirements

All applicable regulatory requirements including national drug and data protection 
law
Sponsor: Antev
Responsible 
Representative
Carol MacLean, PhD
VP Women’s Health & Clinical Operations
Clinical Research Organisation (CRO): Quality, Regulatory and Clinical Consultancy 
(QRCC)
CRO Project Manager
Alex Gage
Senior PM
Sponsor’s Medical 
Expert

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Finn Larsen, MD
Chief Scientific Officer
Biometrician
Saira Ahmad 
Senior Statistician I 

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Declaration by the Investigator
I have read this study protocol and agree that it contains all the information required to 
conduct the study. I agree to conduct the study as set out in this protocol. In particular, I agree 
to adhere to the moral, ethical and scientific principles governing clinical research as set out 
in the current versions of the "Declaration of Helsinki" current valid version according to 
applicable national regulatory and legal requirements and the guidelines on Good Clinical 
Practice.
I understand that all documentation supplied to me by the Sponsor and the Clinical Research 
Organisation (CRO) concerning this study which has not been previously published will be 
kept in the strictest confidence. This documentation includes the study protocol, investigator's 
brochure, case report forms, and other scientific data.
Responsible Investigator at 
the Study Centre
Name/address printed
Place / date
Signature

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Abbreviations
ADR
Adverse drug reaction
ADT
Androgen deprivation therapy
AE
Adverse event
ALAT
Alanine aminotransferase
APC
Advanced prostate cancer
ASAT
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical Classification
AUC0-∞
Area under the concentration-time-curve from time zero up to 
infinity (∞)
AUC0-t
Area under the concentration-time-curve from time zero up to 
the last measurable concentration at timepoint t
AUC0-t1
Area under the concentration-time-curve from time zero up to 
concentration at timepoint t1 after which the concentrations 
start to rise again towards a second peak
AUCt1-t
Area under the concentration-time-curve from timepoint t1 up 
to timepoint t (slow release component of total observed 
AUC)
BMI
Body mass index
BP
Blood pressure
BPH
Benign prostatic hyperplasia
CI
Confidence interval
Cmax
Maximum plasma concentration
Cmax,0-t1
Maximum plasma concentration after administration from 
zero up to timepoint t1
Cmax,t1-t
Maximum plasma concentration after administration from 
timepoint t1 up to timepoint t
CRA
Clinical research associate
CRO
Clinical Research Organisation
CTCAE
Common Terminology Criteria for Adverse Events
ECG
Electrocardiogram(s)
eCRF
Electronic case report form
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GnRH
Gonadotropin-releasing hormone
HbA1c
glycated haemoglobin
HIV
hsTn
Human immunodeficiency virus
High sensitivity troponin
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IM
Intramuscular
IMP
Investigational medicinal product

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I-PSS
International Prostate Symptom Score
IRB
Institutional Review Board
ISI
Injection site inspection
ISR
Injection site reaction(s)
ITT
Intention-to-treat
IV
Intravenous
L
Litre
LH
Luteinising hormone
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mL
Millilitre
mmHg
Millimetre of mercury
msec
Millisecond
ng
Nanogram
nmol
Nanomole
NT proBNP
B-type natriuretic peptide
PD
Pharmacodynamic
PK
Pharmacokinetic
PP
Per protocol
PSA
Prostate-specific antigen
PT
Preferred term
QoL
Quality of Life
QTcF
Fridericia corrected QT interval
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
SD
Standard deviation
SOC
System organ class
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse drug reaction
T
Testosterone
t½
Apparent terminal plasma half-life
TFA
Trifluoroacetate
Tmax
Time to reach Cmax after dosing
Tmax,0-t1
Time to reach Cmax,0-t1 after dosing
Tmax,t1-t
Time to reach Cmax,t1-t after dosing
TNM
Primary Tumor, Lymph Node and Metastasis
TURP
Transurethral Resection of The Prostate
U
Unit
ULN
Upper limit of normal
λz
Apparent terminal rate constant

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Table of Contents
Study Protocol
1
Protocol Synopsis
2
Responsibilities
13
Serious Adverse Event Reporting 14
Signatures 15
Declaration by the Investigator
17
Abbreviations
18
Table of Contents
20
List of In-Text Tables
23
List of In-Text Figures
23
1
Introduction
24
1.1
Background
24
1.1.1
Epidemiology of Advanced Prostate Cancer24
1.1.2
Presentation of Advanced Prostate Cancer 24
1.1.3
Treatment Overview 25
1.2
Background Information on Investigational Medicinal Product
25
1.2.1
Preclinical Studies
26
1.2.2
Clinical Studies
27
1.2.3
Risk-benefit Assessment
28
1.3
Study Rationale
28
2
Study Objectives and Purpose28
3
Overall Study Design and Plan Description 29
3.1
Core Study
29
3.2
Discussion of Study Design 31
4
Selection of Study Population 31
4.1
Participant Inclusion Criteria 32
4.2
Participant Exclusion Criteria
32
4.3
Participant Withdrawal Criteria
33
5
Study Treatments
34
5.1
Treatments Administered
34

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5.2
Identity of Investigational Product(s)
35
5.3
Method of Assigning Participants to Treatment Groups
35
5.4
Selection of Doses in the Study
35
5.5
Selection and Timing of Dose for Each Participant 36
5.6
Supply, Packaging and Labelling
37
5.6.2
Storage
37
5.6.3
Shipment
37
5.6.4
Packaging
37
5.6.5
Labelling
38
5.7
Blinding and Randomisation 38
5.8
Prior and Concomitant Therapy
38
5.8.1
Prohibited Previous and Concomitant Treatments
38
5.8.2
Admissible Concomitant Treatments
38
5.9
Treatment Compliance and Drug Accountability
38
5.10
Safety Monitoring for Allergic Reactions
39
5.11
Management of Drug Overdose
39
6
Variables and Methods39
6.1
Population Characteristics
39
6.1.1
Demography 39
6.1.2
Medical History
39
6.1.3
Prostate Cancer Diagnosis
40
6.1.3.1 Primary Tumor, Lymph Node and Metastasis Classification of Prostate Cancer
40
6.1.3.2 Gleason Score41
6.2
Efficacy
42
6.2.1
Primary Efficacy Variable
42
6.2.2
Secondary Efficacy Variables
42
6.3
Safety 43
6.3.1
Vital Signs
43
6.3.2
Physical Examination44
6.3.3
Triplicate 12-Lead Electrocardiogram
44
6.3.4
Injection Site Inspection
45
6.3.4.1 Photographic Documentation of Injection Site
45
6.3.5
Safety Laboratory Variables 46
6.3.6
Additional Safety Assessments
46
6.3.7
Adverse Events
46
6.3.7.1 Definition of Adverse Events46
6.3.7.2 Assessment of Adverse Events
47
6.3.7.3 Follow-up of Adverse Events
50
6.3.7.4 Documentation and Reporting of Adverse Events
50
6.4
Pharmacokinetics
50

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6.4.1
Pharmacokinetic Variables
50
6.4.2
Blood Sampling Time Points, Handling and Labelling of Blood Samples 51
6.5
Pharmacodynamics
52
7
Study Conduct 54
7.1
Study Schedule
54
7.2
Observations by Visit59
7.2.2
Baseline Examination (Day 0), Stage 1
59
7.2.3
Treatment (Maintenance Dose) Period Visits (Day 28 to Day 168), Stage 2
60
7.2.4
Follow-up Visit (28 Days after Last Dose) 60
7.3
Duration of the Study60
7.3.1
Planned Duration for the Individual Participant
60
7.3.2
Premature Termination
61
8
Statistics 62
8.1
Statistical and Analytical Plans
62
8.1.1
Analysis Populations 62
8.1.2
Adaptive Study Design
62
8.1.3
Primary Efficacy Analysis
63
8.1.4
Secondary Endpoint Analyses
63
8.1.5
Analysis of Safety Data
64
8.1.6
Missing Data 65
8.1.7
Multicentre Study
65
8.1.8
Participant Data Listings
65
8.1.9
Deviations from the Planned Statistical Analysis
65
8.1.10 Interim Analysis
65
8.1.11 Software used for Statistical Analysis
66
8.1.12 Determination of Sample Size
66
8.2
Data Management
66
9
Data Handling and Data Quality Assurance 67
9.1
Data Management
67
9.2
Documentation
67
9.2.1
Pre-screening List and Participant Identification List
67
9.2.2
Source Data and Participant Records
67
9.2.3
Electronic Case Report Form67
9.3
Direct Access to Source Data/Documents
68
9.4
Monitoring
68
9.5
Quality Assurance
69
10
Ethical, Legal and Administrative Aspects 70
10.1
Approval Procedures 70
10.2
Protocol Amendments
70

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10.3
Informed Consent
70
10.4
Confidentiality and Data Protection 71
10.5
Liability, Insurance and Finances
71
10.6
Clinical Study Report, Publication and Use of Study Findings
71
10.7
Archiving of Study Records 72
11
List of References
73
List of In-Text Tables
Table 1: Dosing Regimens under Evaluation
29
Table 2: Investigational Medicinal Product Details
33
Table 3: Decision-making in Relation to Serum Testosterone Levels
35
Table 4: Testosterone Testing in Groups 1 and 2
35
Table 6: TNM Classification of Primary Tumours [13]
38
Table 7: TNM Classification of Regional Lymph Nodes (N) [14]
39
Table 8: TNM Classification of Distant Metastasis (M)a [14]
39
Table 9: Gleason Scoring System
40
Table 10: Timepoints for Efficacy Variables
41
Table 11: Food and Drug Administration Local Toxicity Scale
43
Table 12: Clinical Safety Laboratory Tests
44
Table 13: Pharmacokinetic Parameters
49
Table 14: Pharmacokinetic Timepoints
50
Table 15: Pharmacodynamic Blood Sampling Schedulea
51
Table 16: Schedule of Assessments for Groups 1 and 2
53
List of In-Text Figures
Figure 1: Study Design
30
Figure 2: Gleason Score
41

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1
Introduction
The procedures set out in this study protocol are designed to ensure that the conduct, 
evaluation and documentation of this study take place according to the guidelines for Good 
Clinical Practice for Trials on Medical Products for Human Use (GCP) of the International 
Conference on Harmonisation (ICH) and the current version of the Declaration of Helsinki 
according to applicable national regulatory and legal requirements. The study will also be 
carried out in keeping with national legal requirements which will be described in the 
national supplement to the protocol.
1.1
Background
Prostate cancer is the most commonly diagnosed cancer in men, and the second leading cause 
of cancer-related deaths [1]. Most prostate cancer-related deaths are due to advanced disease, 
which results from any combination of lymphatic, haematogenous, or contiguous local 
spread.
1.1.1
Epidemiology of Advanced Prostate Cancer
Approximately 11.6% of men will develop prostate cancer in their lifetime, with the likelihood 
increasing with age. Prostate cancer is most often diagnosed in men aged between 55 and 
74 years, with a median age at diagnosis of 66 years [2]. Since the advent of prostate
 
 - specific 
 
 
antigen (PSA) screening, prostate cancer is being detected and treated earlier.
Overall, incidence rates of prostate cancer began declining in 2000. Acceleration in the decline 
began in 2008, when health organisations started to argue against routine PSA screening. From 
2009 to 2013, the incidence rate decreased by approximately 8% per year [1].
A review of almost 800,000 cases of prostate cancer diagnosed from 2004 to 2013 found that 
although the incidence of low-risk prostate cancer decreased between 2007 to 2013 to 37% less 
than that of 2004, the annual incidence of metastatic prostate cancer during those years increased 
to 72% more than that of 2004. The increase in metastatic prostate cancer was greatest (92%) in 
men aged 55 to 69 years [3].
At diagnosis, 79% of prostate cancer cases are localised; in 12%, the cancer has spread to 
regional lymph nodes, and in 5% there are distant metastasis. The 5-year relative survival rate 
for localised and regional prostate cancer is 100%, compared with 29.8% for metastatic cases 
[2].
Since the early 1990s, prostate cancer death rates have been decreasing in men of all races and 
ethnicities. However, they remain more than twice as high in black men as in any other group 
[1]. Prostate cancer tends to not only be more aggressive and progressive in black men, leading 
to advanced disease, but to also be of a higher grade at diagnosis [4, 5]. Death rates are also 
higher in men who have advanced-stage cancer, and in men who are 75 to 84 years of age [2].
The mortality rate associated with prostate cancer continues to increase in Europe and in 
countries such as Australia, Japan, and Russia.
1.1.2
Presentation of Advanced Prostate Cancer
Advanced prostate cancer results from any combination of lymphatic, blood, or contiguous local 
spread. Manifestations of metastatic and advanced disease may include the following:

Anaemia

Bone marrow suppression

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
Weight loss

Pathologic fractures

Spinal cord compression

Pain

Haematuria

Ureteral and/or bladder outlet obstruction

Urinary retention

Chronic renal failure

Urinary incontinence

Symptoms related to bony or soft-tissue metastases
Treatment-related symptoms (sometimes associated with radiation therapy), such as rectal 
bleeding, gross haematuria, and urethrorectal fistula, need to be differentiated from the 
disease-specific symptoms.
Physical examination findings of adenopathy, lower-extremity oedema, and bony tenderness 
may indicate metastatic disease. In addition, obliteration of the lateral sulcus or seminal vesical 
involvement found during rectal examination often indicates locally advanced disease.
Neurologic examination, including determination of external anal sphincter tone, should be 
performed to help detect possible spinal cord compression.
1.1.3
Treatment Overview
Several treatment options exist for different stages of prostate cancer, including observation, 
prostatectomy, radiation therapy, chemotherapy, and hormone therapy. Hormone therapy has 
evolved from the use of oestrogens to gonadotropin-releasing hormone (GnRH) agonists and 
recently, investigational GnRH antagonists [6].
Androgen deprivation therapy (ADT) is the backbone of treatment for participants with 
advanced prostate cancer, and it is indicated for use in multiple clinical settings of prostate 
cancer. Chemical castration consists of GnRH agonists and antagonists administered 
intramuscularly (IM), subcutaneously (SC), or orally. One of the main concerns when using 
GnRH agonists is a surge in testosterone (T) caused by the medication’s initial effect on the 
pituitary gland. This T surge could lead to a tumour flare, which is characterised by a rapid 
expansion of the prostate cancer, leading to pain and potential debilitation, particularly in 
participants with spinal metastases. This concern of tumour flare led to the development of the 
GnRH antagonists, which do not cause a T surge, since there is no initial stimulation of the 
pituitary gland by the medication. The GnRH antagonist degarelix is currently approved by the 
US Food and Drug Administration (FDA) for the treatment of participants with advanced 
prostate cancer [7].
GnRH antagonists are analogues of GnRH, and act as a competitive inhibitor of GnRH [8]. 
GnRH mediates stimulation of gonadotropin (i.e., follicle stimulating hormone [FSH] and 
luteinising hormone [LH]) secretion [9]). Unlike GnRH agonists, the GnRH antagonists do not 
cause an initial surge of gonadotropins. They rapidly decrease the secretion of LH and FSH from 
the pituitary gland, thereby leading to an immediate decrease in T secretion from the Leydig 
cells of the testicles [10].
1.2
Background Information on Investigational Medicinal Product
The investigational medicinal product (IMP) to be tested in this study is teverelix 
trifluoroacetate (TFA), a depot formulation of a GnRH antagonist used for the treatment of 
advanced prostate cancer. Treatment with the IMP will start with a loading dose administered 

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through 2 injections, one of which will be given IM and the other of which will be given SC, 
followed by a maintenance SC injection every 4 or 6 weeks. Two treatment regimens will be 
tested in this study: 120 mg of teverelix TFA administered, after the loading dose, every 42 
days and 180 mg of teverelix TFA administered, after the loading dose, every 42 days.
1.2.1
Preclinical Studies
In preclinical studies, teverelix has been shown to exert anti-ovulatory activity and to inhibit 
LH, FSH and T secretion.
No target organ toxicity was observed from subacute and chronic toxicity studies in rats and 
dogs following SC administration of teverelix and no adverse systemic effects have been 
demonstrated. In general, treatment-related effects were considered to be either physiological 
changes arising as a result of the pharmacological response to administration of a GnRH 
antagonist, or foreign body inflammatory reactions at the injection site arising as a result of 
the physical nature of the test material, rather than a direct toxic response to teverelix.
The most notable finding across species and studies was the clear reduction in reproductive 
organ and accessory gland weight, confirmed pathologically as arrested development or 
degeneration. Notable findings in males were spermatogenic arrest within the testes, 
ductal/tubular atrophy, absence of spermatozoa within the epididymides, and prostate gland 
atrophy. In females, atrophy of the vagina, cervix and uterus, maturation arrest within the 
ovaries, and atrophy of mammary gland tissue were apparent.
Injection site reactions (ISR) were noted during dose range finding studies and were cited as 
the limiting factor in the selection of high doses for the definitive repeat dose toxicity studies. 
In the rat and dog, daily SC administration of teverelix at a concentration of 10 mg/mL (doses 
of up to 50 mg/kg in the rat and 20 mg/kg in the dog) was unsuitable and led to unacceptable 
ISRs, which were considered to be a function of the physical characteristics of the test 
substance, the dosing regime, and the dose volume. SC doses of up to 20 mg/kg/day using a 
concentration of 75 mg/mL were tolerated, demonstrating that reducing the dose volume and 
using a higher concentration to achieve the same dose ameliorated the local response. Weekly 
dosing for up to 6 months in rats and 9 months in dogs using a 75 mg/mL (in 5% mannitol) 
formulation was associated with some evidence of clinical ISRs, but overall, dosing was 
tolerated. Pathologically, signs of an inflammatory response within the SC tissue, 
predominantly consisting of an infiltration of macrophages (foreign body-type response), was 
apparent.
Early screening studies indicated that teverelix acetate was devoid of anaphylactoid reactions 
when administered intravenously in rats (single dose 5 mg/kg) or other species including 
mice, rabbits, and dogs. Teverelix also had very modest histamine-releasing properties on rat 
mast cells. When intravenous (IV) teverelix acetate was administered to rats and cynomolgus 
monkeys in toxicity studies, clinical signs indicative of release of vasoactive chemical 
modulators were seen and some animals were found dead following administration of the 
highest dose. Subsequent studies with teverelix TFA administered by the SC route, which is 
relevant to the clinical situation, did not identify any signs of anaphylaxis or histamine 
release, and no effects on blood pressure [BP] were apparent. Even a single and repeat dose 
of 50 mg/kg administered by the SC route to rats did not induce adverse clinical signs and 
teverelix showed no mutagenic or clastogenic potential.
Given the pharmacological effect of teverelix on pituitary gonadotrophic hormones, a 
reduction in fertility is anticipated. However, studies have been conducted to determine 
whether restoration of fertility is seen post-dosing. A single dose of 2 mg/kg administered to 
male rats resulted in reduced plasma T concentrations for 5 weeks after dosing, but there was 

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no subsequent effect on mating performance or pregnancy outcome 11-, 14- or 17-weeks 
post-dosing. A single dose of 2 mg/kg administered to female rats had no effect on oestrous 
cyclicity 5/6 weeks post-dosing, and no effect on the capability of the females to become 
pregnant 12 weeks post-dosing. Lower numbers of corpora lutea, implantations, and live 
foetuses and a higher number of early intra-uterine deaths were consistent with the known 
pharmacological effect.
In embryofoetal/teratogenicity studies, an increase in post-implantation loss was noted 
following administration of 15 μg/kg in the rabbit but no embryotoxicity was seen up to a 
dose of 10 μg/kg in the rat. No evidence of teratogenicity was found in either species [11].
1.2.2
Clinical Studies
In Phase 1 clinical studies conducted in healthy men, teverelix produced a rapid, marked 
suppression of serum levels of LH, T, and to a lesser extent FSH. In the first Phase 1 studies, 
the teverelix-induced T suppression was fully reversible within 1 week. In higher dose 
Phase 1 studies, some patients had persistent T suppression for several months. A Phase 1 
clinical study conducted in healthy women demonstrated that teverelix TFA reduced the 
serum levels of LH, FSH, oestradiol, and progesterone in a dose-dependent manner.
As early as 2 weeks after administration of two 60 mg teverelix TFA injections in 
participants with benign prostatic hyperplasia (BPH), a statistically significant decrease was 
observed in prostatic symptoms, as measured by the International Prostate Symptom Score (I-
PSS). Symptomatic improvement increased over time,and was most pronounced at study 
completion (16 weeks). A total of 83% of participants who received teverelix TFA were 
classified as responders (defined as a >3 point reduction in symptom score from baseline). In 
addition, statistically significant improvements were observed in maximum urine flow rate, 
Quality of Life (QoL) and prostate size when compared to baseline. In a subsequent study, 
where participants were administered a single injection of 30 mg teverelix TFA, 60 mg 
teverelix TFA or placebo, a larger increase in maximum urinary flow rate occurred in both 
the 30 mg and 60 mg teverelix TFA treatment groups compared to placebo. In addition, a 
significant increase from baseline for mean urinary flow rate was observed in the 60 mg 
teverelix TFA treatment group, and the 30 mg teverelix TFA group was more than 3 times as 
likely to give a favourable QoL response compared to placebo. In the extension study, 
participants administered a second dose of either 30 mg or 60 mg teverelix TFA experienced 
an increase in mean and maximum urinary flow rate, compared to the placebo treated group, 
and were more likely to give a favourable response with respect to QoL.
In the case of advanced prostate cancer, suppression of T to castration levels (<0.5 ng/mL) 
was achieved within 3 days in the majority of the participants and this was maintained for 4 
to 8 weeks. Some participants experienced transient castration breakthrough, where 
T concentrations temporarily increased to ≥0.5 ng/mL. Teverelix TFA was also shown to 
rapidly reduce and normalise PSA levels.
Pharmacokinetic (PK) and pharmacodynamic (PD) data from 2 studies indicate that the SC 
route of administration for teverelix TFA produces a more sustained suppression of T levels 
than the IM route. No safety concerns were identified in any of the conducted clinical studies. 
The most frequently reported adverse events (AEs) were mild ISRs and reversible symptoms 
characteristic of T and oestrogen deprivation, such as hot flushes, decrease in libido and 
potency, and reduction in testis size. No serious adverse events (SAEs), considered to be at 
least possibly related to the administration of teverelix TFA, have been reported [11].

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1.2.3
Risk-benefit Assessment
No SAEs assessed as attributable to the administration of teverelix TFA have been reported. 
Three SAEs have been reported for teverelix TFA participants to date and none of these was 
thought to be related to IMP (SAE 1, jaundice cholestatic/cholelithiasis/bile duct 
stone/pancreatitis; SAE 2, worsening ischaemic heart disease/atrial fibrillation; SAE 3, 
nephrolithiasis).
The most frequently reported AEs were mild ISR and reversible symptoms characteristic of T 
and oestrogen deprivation, such as hot flushes, decrease in libido, erectile disorder, and 
reduced testes size. No signs indicative of allergic reactions have been noted in the clinical 
participants dosed with teverelix TFA to date.
The studies conducted so far have demonstrated no safety concerns and, in the later studies, 
castration levels of sex hormones in men were obtained within a few days. Teverelix TFA 
reduced the serum levels of LH, FSH, oestradiol, and progesterone in a dose-dependent 
manner in healthy women. Statistically significant improvements in symptoms were achieved 
in participants with BPH, and PSA levels were normalised in participants with advanced 
prostate cancer [11].
1.3
Study Rationale
As an GnRH antagonist, teverelix antagonises the GnRH by reversibly binding to GnRH 
receptors in the pituitary gland. This subsequently blocks the action of GnRH in the body and 
the release of both LH and FSH from the pituitary gland, which leads to a rapid suppression of T 
release from the testes. 
Antev Ltd has conducted a Phase 1, open-label, single centre study investigating the PK, safety, 
and PD of a single dose of teverelix TFA administered either SC or IM to healthy male 
volunteers. The doses and administration schedule of teverelix TFA used in this Phase 2 study 
are based on the PK and PD results of the above-mentioned Phase 1 study.
The study population planned for this Phase 2 study is comparable to that of the previously 
conducted Phase 2 study for the development of degarelix, which has been approved by the 
FDA and the European Medicines Agency in 2008 based on the data from the pivotal study [2].
2
Study Objectives and Purpose
Primary Objective
To assess the efficacy of teverelix TFA in terms of ability to suppress serum T levels to 
below castration level (<0.5 ng/mL or 1.73 nmol/L) at Day 28.
Secondary Objective(s)

To assess the efficacy of teverelix TFA in terms of ability to suppress serum T levels 
to below castration level (<0.2 ng/mL or 0.6934 nmol/L) at Day 28

To assess the efficacy of teverelix TFA in terms of ability to suppress serum T levels 
to below castration level (<0.5 ng/mL or 1.73 nmol/L) at Day 42

To assess the efficacy of teverelix TFA in terms of ability to suppress serum T levels 
to below castration level (<0.2 ng/mL or 0.6934 nmol/L) at Day 42

To assess the efficacy of teverelix TFA in terms of ability to suppress serum T levels 
to below castration level (<0.5 ng/mL or 1.73 nmol/L) at Day 168

To assess the efficacy of teverelix TFA in terms of ability to suppress serum T levels 
to below castration level (<0.2 ng/mL or 0.6934 nmol/L) at Day 168

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
To assess the efficacy of teverelix TFA in terms of ability to maintain suppression of 
serum T levels below castration level (<0.5 ng/mL or 1.73 nmol/L) over time during 
Stage 2 (maintenance-dose period) of the study

To assess the efficacy of teverelix TFA in terms of ability to maintain suppression of 
serum T levels below castration level (<0.2 ng/mL or 0.6934 nmol/L) over time 
during Stage 2 (maintenance-dose period) of the study

To assess the time taken to achieve serum T levels below castration level (<0.5 ng/mL 
or 1.73 nmol/L)

To assess the time taken to achieve serum T levels below castration level (<0.2 ng/mL 
or 0.6934 nmol/L)

To assess the time taken to achieve serum T levels above castration level (>0.5 ng/mL 
or or 1.73 nmol/L)) following the final, Day 168 injection of teverelix TFA

To delineate the PK profile of teverelix TFA

To assess the effects of teverelix TFA on:
-
PSA
-
T
-
FSH
-
LH

To assess the predictive effect for new cardiovascular (CV) events of cardiac 
biomarkers:
-
N-terminal pro-B-type natriuretic peptide (NTproBNP)
-
D-dimer
-
C-reactive protein (CRP)
-
high-sensitivity troponin (hsTn)

To assess the safety of teverelix TFA in terms of:
-
local tolerability (injection site reactions [ISR])
-
systemic tolerability (adverse events, vital signs, electrocardiograms (ECG), 
Holter monitoring (subset of 30 subjects in Group 2 only) and laboratory 
parameters)
3
Overall Study Design and Plan Description
3.1
Core Study
This is an adaptive Phase 2, open-label, multicentre study to evaluate the PK, PD, efficacy 
and safety of teverelix TFA, a GnRH antagonist in participants with advanced prostate 
cancer.
For Group 1, it is planned to enrol approximately 24 participants from 3 investigational sites 
in Lithuania to obtain 20 evaluable participants with prostate advanced cancer.  For Group 2, 
it is planned to enrol approximately 60 participants from up to 7 investigational sites in 
Lithuania and (potentially) Netherlands/Belgium in order to obtain 50 evaluable participants 
with advanced prostate cancer, for the assessment of treatment response on Day 28 and 
throughout the study up to Day 168. 
Figure 1 displays the study design.
The study consists of the following periods/visits:

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Screening Period: Day -6 to -1
Groups 1 & 2 Treatment Period:
Stage 1: Loading dose administered at baseline (Day 0) with follow-up visits until 
Day 28
Stage 2: Maintenance treatment administered every 6 weeks with visits from Day 28 up 
to Day 168, or until treatment ceases to become effective
Follow-up Visit: 28 days after the last dose of IMP
Group 2 (Stage 3 subjects only) Treatment Period:
Stage 1: Loading dose administered at baseline (Day 0) with follow-up visits until 
Day 28
Stage 2: Maintenance treatment administered every 6 weeks with visits from Day 28 up 
to Day 168, or until treatment ceases to become effective
Stage 3: Follow up period.  Day 203 visit followed by weekly visits until Day 252 or 
until serum T levels are > 1 ng/mL (local lab result), whichever occurs first
Follow-up Visit: Day 259 or >7 days after serum T levels are > 1 ng/mL (local lab 
result), whichever occurs first
An overview of the Schedule of Assessments is provided in Section 7.1. After signing the 
informed consent for the core study, participants will undergo a screening examination within 
6 days prior to the administration of teverelix TFA to verify the participants’ eligibility, and 
to document participant characteristics, including medical and surgical history, and disease 
characteristics.
Table 1 presents the 2 dosing regimens to be evaluated in this study.
Figure 1: Study Design
D0=Day 0; IM=intramuscular; SC=subcutaneous

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Table 1: Dosing Regimens under Evaluation
Group
Loading Dose
Maintenance Dose
Dosing Interval
1
120 mg IM +120 mg SC
120 mg SC
6 weekly
2
180 mg IM +180 mg SC
180 mg SC
6 weekly
IM=intramuscular; SC=subcutaneous
Initially enrolment will open for Group 1 only. If, after Day 28, a participant’s serum T value 
(as tested by the local laboratory on Day 21) is >2 ng/mL, the participant will be withdrawn 
from the study.
Enrolment will continue for Group 1 until 20 participants have completed the Day 28 visit 
with no more than 2 participants being classified as a treatment failure. Treatment failure is 
defined as having a T level >2 ng/mL at Day 28 (as tested by the local laboratory on Day 21) 
or requiring to be withdrawn at any later timepoint during the study.
If 3 or more participants fail treatment in Group 1 then further enrolment into that group will 
stop due to statistical confidence that a 90% responder rate cannot be achieved with that 
dosing regimen. All future participants will be enrolled into Group 2.
If in Group 2 at Day 28, a participant’s serum T value (as tested by the local laboratory on 
Day 21) is >2 ng/mL, the participant will be withdrawn from the study.
If 7 or more participants fail in Group 2 then all further enrolment will be stopped and the 
study will be terminated.
3.2
Discussion of Study Design
Teverelix is currently being developed for chemical castration in participants with advanced 
prostate cancer. Five previous Phase 1 clinical studies of teverelix have been conducted in 
healthy male volunteers as well as 5 Phase 2 clinical studies in prostate cancer patients.
In these studies, teverelix TFA depot formulation has been tested following administration by 
single and multiple (2) SC injection(s) at doses of 10 mg, 30 mg, 60 mg, 120 mg or 180 mg. 
Teverelix produced a rapid, marked suppression of serum levels of LH, T and, to a lesser 
extent, FSH. The teverelix TFA-induced hormone suppression demonstrated in these studies 
was fully reversible within 1 week and exhibited no signs of a weight effect. Overall, 
teverelix TFA was safe and well tolerated.
Three Phase 2 studies in participants with BPH have been conducted as well. In participants 
with BPH, a statistically significant decrease was observed in prostatic symptoms as early as 
2 weeks after administration of teverelix TFA. Symptomatic improvement increased over 
time and was most pronounced at study completion (after 16 weeks). A total of 76% of 
participants on teverelix TFA were classified as responders.
For participants with APC suppression of T below castration level, this was achieved within 
3 days and was maintained for 4 to 8 weeks. Teverelix TFA was also shown to rapidly reduce 
and normalise PSA levels. In the Phase 1 and 2 studies a small number of study subjects (0.6 
to1.5%) experienced transient elevated liver function enzymes. Standard monitoring of liver 
function enzymes is recommended for future clinical studies.
PK and PD data from 2 different studies indicate that the SC route of administration of 
teverelix TFA produces a more sustained suppression of T levels than the IM route. This 
appears to be due to the fact that the SC route is more effective at maintaining adequate 
systemic levels of teverelix TFA.
In this study, teverelix TFA is being tested in participants with APC with a loading dose 
regimen administered as 2 doses of 120 mg each, given IM and SC, followed by SC 
injections of 120 mg of teverelix TFA every 6 weeks thereafter, as the preferred treatment 
regimen. If this treatment schedule fails to induce castration levels of T (≤2 ng/mL), an 

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alternative treatment option will be tested: 180 mg each of teverelix TFA, given IM and SC, 
followed by SC injections of 180 mg of teverelix TFA every 6 weeks thereafter, for a total 
duration of 168 days. As this is a Phase 2 study to evaluate the dosage and effectiveness of 
teverelix TFA in the suppression and maintenance of serum T concentrations below 
castration levels, an open-label, non-controlled study design has been chosen.
4
Selection of Study Population
In this study, approximately 24 participants from Group 1, or 60 participants from Group 2 
will be recruited from 7 up to study centres in Lithuania and potentially Netherlands and/or 
Belgium in order to provide a sample size of 20 participants from Group 1, or 50 participants 
from Group 2. These participants will comprise the per-protocol (PP) analysis set for 
evaluation of treatment response at Day 28 and throughout the study up to Day 168. As soon 
as this number of enrolled participants is reached, no more participants will be recruited. 
Enrolled participants who cannot be analysed in the PP analysis set will not be replaced.
The participants for this study will be recruited from inpatient/outpatient departments of 
clinics/hospitals and/or general practitioners/specialists. If inpatients are included in the 
study, they will receive further treatment as inpatients.
4.1
Participant Inclusion Criteria
The participant is allowed to participate in the study if ALL of the following criteria are 
fulfilled:
1. Is male, aged ≤85 years (≥18 years) at the beginning of the treatment period (Day 0)
2. Has histologically proven advanced adenocarcinoma of the prostate (metastatic or 
non-metastatic hormone-sensitive non-curative), suitable for ADT
3. Is treatment naïve for any of the following:
a.
GnRH analogues
b. Androgen receptor antagonists, or
c.
Androgen synthesis inhibitors (e.g. abiraterone)
4. Agrees to practice contraception during the entire study treatment period and for 
3 months after the last dose of IMP is administered:
a.
Either by using double barrier contraception,
b. or, is truly sexually abstinent, when this is in line with the preferred and usual 
lifestyle of the participant
Note: Periodic abstinence [e.g. calendar, ovulation, symptothermal, 
postovulation methods for the female partner with childbearing potential] 
and withdrawal are not acceptable methods of contraception.
5. Has provided written (personally signed and dated) informed consent before 
completing any study-related procedure, which means any assessment or evaluation 
that would not have formed a part of his normal medical care
4.2
Participant Exclusion Criteria
If any of the following criteria apply, the participant MUST NOT be admitted to the study.
The participant:
1. Has abnormal screening and/or baseline laboratory values that suggest a clinically 
significant underlying disease, or the following laboratory values:

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a.
Liver function test (aspartate aminotransferase [ASAT/SGOT], alanine 
aminotransferase [ALAT/SGPT]), or total bilirubin exceeding twice the upper 
limit of the normal (ULN) range
b. Creatinine twice the ULN range
c.
Uncontrolled diabetes (HbA1c >7.5%) or previously undiagnosed diabetes 
mellitus with HbA1c >6.5%
2. Has any contraindication to the use of teverelix TFA
3. Has a life expectancy of less than 1 year
4. Has T levels <2.0 ng/mL at screening
5. Has a medical history of bilateral orchidectomy
6. Using any of the following prohibited treatments:
a.
Within 25 weeks prior to screening: dutasteride
b. Within 12 weeks prior to screening: finasteride
c.
Current use of any of the following:
i.
Anti-androgen therapy, including T replacement therapy and 5α-
reductase inhibitor treatment etc. (Spironolactone is a permitted 
concomitant treatment)
ii.
Any other medication or herbal product that may affect hormone 
levels and might, therefore, confound interpretation of the study 
results (e.g. St. John’s wort)
7. Has neurological disease, psychiatric disease, drug or alcohol abuse, which could 
interfere with the participant’s proper compliance
8. Has a history of myocardial infarction, unstable symptomatic ischaemic heart disease, 
any ongoing cardiac arrhythmias of grade >2 (chronic stable atrial fibrillation on 
stable anticoagulant therapy is allowed), thromboembolic events (e.g. deep vein 
thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any 
other significant cardiac condition (e.g. pericardial effusion, restrictive 
cardiomyopathy) within 6 months before screening
9. Has congenital long QT syndrome or ECG abnormalities at screening of:
a.
Q-wave infarction, unless identified ≥6 months before screening
b. Fridericia corrected QT interval (QTcF interval) >480 msec. If QTcF is 
prolonged in a participant with a pacemaker, the participant may be enrolled in 
the study upon discussion with the project clinician

If the QTcF interval is 450-480 msec, inclusive, in a participant with current use of 
medications with known effects on QT interval, the participant may be enrolled in the 
study following discussion with the Medical Lead
Note: Cardiac arrhythmia grading:
o            Bradyarrhythmias (HR <60/min)
o            Tachyarrhythmias (HR >100/min)
o            Supraventricular arrhythmias – arrhythmias that originate in the sinoatrial 
node, atrial myocardium or atrioventricular node (regular QRS complex)
o            Ventricular arrhythmias – arrhythmias that originate below the 
atrioventricular node (wide QRS complex)
10. Has known or suspected severe renal impairment
11. Has a medical history of diagnosis of, or treatment for, another malignancy within 
2 years before the first dose of IMP, or previous diagnosis of another malignancy with 

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evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma 
in situ of any type are not excluded if they have undergone complete resection
12. Is currently using Class IA (e.g. quinidine, procainamide) or Class III (e.g. 
amiodarone, sotalol) antiarrhythmic medications
13. Has uncontrolled hypertension despite appropriate medical therapy (sitting BP of 
>180 millimetres of mercury [mmHg] systolic and >95 mmHg diastolic at 2 separate 
measurements taken no more than 60 minutes apart during the screening visit). 
Participants with isolated systolic BP measurements >180 mmHg may be rescreened. 
Participants with isolated systolic BP measurements 141 to 180 mmHg or isolated 
diastolic BP measurements ≥95 mmHg, although eligible, should be referred for 
further management of hypertension if indicated
14. Has known, previously diagnosed human immunodeficiency virus (HIV) infection, 
active chronic hepatitis B or C, life-threatening illness unrelated to prostate cancer, or 
any serious medical condition that could, in the investigator's opinion, potentially 
interfere with participation in this study. Specific screening for chronic viral illness is 
at the discretion of the site and/or local Institutional Review Board (IRB)
15. Has been exposed to another investigational drug within the 3 months prior to 
screening
16. Has anticipated non-availability for study visits/procedures
17. Plans to undergo surgery during the study period
18. Known presence of hepatic metastases
4.3
Participant Withdrawal Criteria
Premature study termination for an individual participant should be taken into consideration 
under the following circumstances:

An illness/AE occurs during the study that influences the use, or the assessment of, 
the investigational medication

He/she requires a forbidden concomitant medication (see Section 5.8.1)

Adequate cooperation is not guaranteed
Decisions concerning study termination for individual participants will be made in 
accordance with the Medical Lead of the study and the Sponsor.
Premature study termination for an individual participant is mandatory under the following 
circumstances:

Lack of efficacy and progressive disease (e.g. T levels >2 ng/mL)

Lost to follow-up (the participant did not show up for the examination and the study 
personnel were unable to contact the participant)

Death of the participant
The study must be terminated for an individual participant if the participant withdraws his/her 
consent or it is, in the investigator's opinion, necessary from a medical point of view (e.g. 
allergic reactions to the study medication).
If possible, a complete final examination, as planned for the visit that takes place on Day 168, 
should be carried out and documented on the corresponding pages of the electronic case 
report form (eCRF) for all participants who stop taking part in the study. If possible, the 
participant will also be asked to return to the site for a safety follow-up visit 28 days after the 
last administration of teverelix TFA.
Although participants may withdraw from the study at any time without giving any reasons, 
efforts should be made to find out the cause and document it.
For follow-up of participants' withdrawal because of an AE please see Section 6.3.7.3.

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Participants who terminate the study prematurely will not be replaced.
For criteria concerning the termination of the whole study please refer to Section 7.3.2.
5
Study Treatments
The IMP to be tested in this study is teverelix TFA, which is administered on Day 0 as a 
loading dose, followed by a maintenance dose as per the schedule below.
5.1
Treatments Administered
Participants will receive different doses depending on whether they join Group 1 or Group 2. 
The study will enrol participants into Group 1 first.
On Day 0, participants will receive a single loading dose consisting of 2 injections, each of 
which will contain 120 mg of teverelix TFA (Group 1). The first injection will be 
administered as an IM injection and the second as an SC injection (Stage 1). After Stage 1, 
participants will receive a maintenance dose, which in Group 1 will consist of a single 120 
mg SC injection administered every 42 days, and in Group 2, will consist of a single 180 mg 
SC injection administered every 42 days (see Table 1).
If treatment of Group 1 has been terminated early due to a low therapeutic response rate, 
recruitment into Group 2 will start.
The total treatment period will be up to 168 days (24 weeks) in the core study, or until 
treatment ceases to be effective (serum T >2 ng/mL). 
Participants withdrawn early from the study will be asked to return to the study site 28 days 
after the last dosing for a safety follow-up visit.
Depending on the safety and efficacy of the study drug observed during the core study, 
participants who complete the core study and who maintain serum T levels (local laboratory) 
≤2 ng/mL at the end of the core study (at the Day 168 visit) may be offered the opportunity to 
continue in an extension study, during which the maintenance treatment will be continued up 
to D336.  The decision to extend the treatment period for eligible subjects will be made when 
5 or more subjects have reached D28 with D21 local laboratory T levels < 2 ng/mL.   
5.2
Identity of Investigational Product(s)
Table 2 presents the details of the IMP.
Table 2: Investigational Medicinal Product Details
Active Ingredient
Teverelix TFA
Brand name
-
Dosage form
Powder presented in glass vials (powder weight is 250 mg net 
weight with 200 mg base weight) 
Strength
120 mg (Group 1) and 180 mg (Group 2) injection
Frequency
Every 6 weeks (Groups 1 and 2)
Route of 
administration
Loading dose: IM injection followed by SC injection
Maintenance dose: SC injections
Supplied by
Antev Ltd.
IM=intramuscular; IMP=investigational medicinal product; SC=subcutaneous

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5.3
Method of Assigning Participants to Treatment Groups
All enrolled participants will be identifiable throughout the study. The investigator will 
maintain a personal list of participant numbers and participant names to enable records to be 
found at a later date.
Upon enrolment each participant receives a 5-digit screening number, which is sufficient for 
unambiguous identification:
Digits 1 and 2:
Study centre (11, 12, 13, etc.)
Digits 3, 4 and 5: Individual participant number within the centre (consecutively in 
the order of enrolment within the centre: 001, 002, etc.)
Enrolled participants who drop out of the study before their baseline visit will retain their 
screening number.
On completion of the screening phase, the participant's eligibility will be confirmed.
Eligible participants will receive treatment on Day 0. All participants will receive the same 
dose per treatment group (Group 1 or Group 2) of teverelix TFA as defined in Section 5.1.
Medication will be dispensed in numerical order, starting with the smallest number available 
in the centre.
5.4
Selection of Doses in the Study
The goal of this study is the selection of an optimal treatment regime, which allows 
achievement of the highest level of efficacy with an acceptable safety profile and optimal 
convenience for patients and physicians. For this reason, 2 treatment regimens will be 
evaluated.
The treatment regimen for Group 1 comprises a dose of 120 mg administered SC and IM as a 
loading dose and SC as a maintenance dose every 6 weeks. For Group 2, the dose will be 180 
mg administered SC and IM as a loading dose and SC as a maintenance dose every 6 weeks. 
The 180 mg dosage has been administered in 4 Phase 1 studies conducted in healthy male 
volunteers and 2 Phase 2 studies conducted in participants with APC. No severe or serious 
AEs were noted in these studies. The dosing regimen and treatment period will be according 
to the details described in Section 5.1.
5.5
Selection and Timing of Dose for Each Participant
Participants will receive different doses depending on whether they join Group 1 or Group 2. 
The study will enrol participants into Group 1 first.
On Day 0 participants will receive a single loading dose consisting of 2 injections, each of 
which will contain 120 mg of teverelix TFA (Group 1) or 180 mg (Group 2). The first 
injection will be administered as an IM injection and the other as an SC injection (Stage 1).
After Stage 1, participants in Group 1 will receive a maintenance dose, which will consist of 
a single 120 mg SC injection administered every 42 days.
If the serum T value (measured by the local laboratory) at the Day 35 visit is >2 ng/mL, the 
participant will be withdrawn from the study.
If 3 or more participants have a total T (local laboratory) value of >2 ng/mL at Day 21 or at 
any subsequent study visit, the dosing regimen will have failed to meet its 90% efficacy 
target and, if applicable, further enrolment into Group 1 will cease.
If treatment of Group 1 has been terminated early due to a low therapeutic response rate, 
recruitment of participants into Group 2 will start.
After Stage 1, participants in Group 2 will receive a maintenance dose, which will consist of 
a single 180 mg SC injection administered every 42 days.

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If the serum T value (measured by the local laboratory) at the Day 21 visit is >2 ng/mL, the 
participant will be withdrawn from the study.
Participants will have their serum T measured by the local laboratory 1 week prior to each 
maintenance dose during Stage 2 of the study. If, at any point the local laboratory serum 
T result is >2 ng/mL the participant will be withdrawn from the study. Local laboratory 
serum T values ≤2 ng/mL allow the subjects to continue in the study.
Table 3 describes the decision-making process for doses participants will receive based on 
the results of the locally analysed T level from 7 days prior to the scheduled dosing visit.
Table 3: Decision-making in Relation to Serum Testosterone Levels
[T] (ng/mL)
Action Taken
Dose Administered
≤2
Continue in Stage 2
Group 1: Maintenance dose 120 mg 
SC teverelix TFA
Group 2: Maintenance dose 180 mg 
SC teverelix TFA
>2
Withdrawal from study, safety 
follow-up visit
None
SC=subcutaneous; T=testosterone; TFA=Trifluoroacetate
Depending on the level of T prior to dosing, a decision will be made regarding whether to 
continue the participant in the study, request a re-test 7 days prior to the next scheduled 
dosing visit, or initiate early study withdrawal. If T levels are ≥2 ng/mL, the participant will 
be withdrawn from the study.
In the event that a participant of Group 1 will be continued during Stage 2, each dose will be 
administered according to Table 4: Testosterone Testing in Groups 1 and 2 every 6 weeks.
Table 4: Testosterone Testing in Groups 1 and 2
Local [T] Testing
Teverelix TFA Dose
DAY 21 [T]
DAY 28: No teverelix TFA dose
DAY 35 [T]
DAY 42: Maintenance dose 120 or 180 mg SC
DAY 77 [T]
DAY 84: Maintenance dose 120 or 180 mg SC
DAY 119 [T]
DAY 126: Maintenance dose 120 or 180 mg SC
DAY 161 [T]
*DAY 203 [T]
*DAY 210 [T]
*DAY 217 [T]
*DAY 224 [T]
*DAY 231 [T]
*DAY 238 [T]
*DAY 245 [T]
*DAY 252 [T]
DAY 168: Maintenance dose 120 or 180 mg SC
No dose
No dose
No dose
No dose
No dose
No dose
No dose
No dose
SC=subcutaneous; T=testosterone
*Group 2 subjects with Stage 3 only

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5.6
Supply, Packaging and Labelling
5.6.1
Supply
The study medication teverelix TFA will be provided by the Sponsor. The IMP will be 
manufactured, packed, labelled, and released by a qualified person and distributed under the 
responsibility of the Sponsor in accordance with the principle of Good Manufacturing 
Practice (GMP) and the applicable local regulations.
Teverelix TFA is supplied as a white powder to be reconstituted with 5% mannitol (w/v) in 
water for injection.
5.6.2
Storage
The study medication teverelix TFA has to be stored at -20°C±5°C. The diluent, mannitol, 
shall be stored at +20°C±5°C.
5.6.3
Shipment
The IMP will be shipped according to local regulations. The responsible 
investigator/responsible study personnel at the study site will confirm correct receipt of the 
IMP in writing and ensure it is stored safely and correctly. The investigator will document the 
distribution date and the amount used on the forms provided for this purpose.
5.6.4
Packaging
The packaging will be performed by the Sponsor according to GMP and all local legal 
requirements.
5.6.5
Labelling
The labelling will be performed by the Sponsor according to GMP and all local legal 
requirements. The labels will be written in the local language.
5.7
Blinding and Randomisation
Not applicable as this is an open-label study with regards to the administration of IMP.
5.8
Prior and Concomitant Therapy
Any concomitant therapies and medications administered during the study have to be 
documented. This also includes any non-medicinal treatment and hormonal contraception. 
The following details must be given: nature of the disease (indication), date of diagnosis, 
name of medicine (including active ingredient[s]) or specification of measures, dosage, route 
of administration and the dates of the start and end of the treatment.
5.8.1
Prohibited Previous and Concomitant Treatments
In line with the inclusion and exclusion criteria, during the study the use of the following 
drugs is prohibited:

Antiarrhythmic medications
-
Class IA (e.g. quinidine, procainamide)
-
Class III (e.g. amiodarone, sotalol)

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
Anti-androgen therapy (e.g. T replacement therapy, and 5α-reductase inhibitor 
treatment etc.) (Spironolactone is a permitted concomitant treatment)

GnRH analogue or antagonists

Androgen receptor antagonist

Androgen synthesis inhibitors (e.g. abiraterone)

Any other medication (e.g. 5-alpha reductase inhibitors) or herbal product (e.g. 
St. John’s wort) that may affect hormone levels and might, therefore, confound 
interpretation of study results

Finasteride and dutasteride within 12 weeks and 25 weeks, respectively, prior to 
screening
5.8.2
Admissible Concomitant Treatments
All other medicines, as well as over-the-counter medicines, apart from those mentioned in the 
prohibited treatments are allowed provided they do not affect the primary endpoint or 
integrity of this study.
This applies also specifically to following treatment options for prostate cancer:

Prostate surgery

Radiation therapy (discuss with Antev medical monitor prior to inclusion)

Chemotherapy

Cryotherapy

Immunotherapy
5.9
Treatment Compliance and Drug Accountability
The reconstitution of the IMP will be prepared by the investigator or by study personnel as­
signed by the investigator. The IMP will be administered by the investigator to the participants 
according to the study protocol.
The investigator will ensure that the provided IMP will only be used within the framework of 
this study and as directed by the study protocol.
IMP accountability must be documented at each site and will be checked by a study monitor. 
All used and unused IMP will be collected by the study monitor and returned to the Sponsor 
upon completion of the study. Receipt, distribution, and return of the IMP must be 
documented according to study-specific instructions provided separately.
5.10
Safety Monitoring for Allergic Reactions
To  ensure  subject  safety,  investigators  must  be  able  to  diagnose  and  treat  immediate 
hypersensitivity reactions, including anaphylaxis.  Medication and equipment necessary to 
treat immediate hypersensitivity reactions, including anaphylaxis must be available at the 
study  centre.   Subjects  will  be  observed  during  drug  administration  and  for  at  least 
30 minutes following the injection for fever, chills, or other administration-related reactions. 
Should an immediate hypersensitivity reaction associated with hypotension and/or syncope 
occur,  appropriate  supportive  measures  (e.g.,  leg  elevation;  oxygen  administration; 
intravenous fluids; and, medications such as epinephrine, antihistamines and corticosteroids, 
alone  or  in  combination)  will  be  employed,  in  accordance  with  standard  emergency 
procedures of the study centre.
5.11
Management of Drug Overdose
No consequences are to be expected in case of drug overdose.

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6
Variables and Methods
6.1
Population Characteristics
6.1.1
Demography
The following demographic characteristics will be documented in the eCRF:

Year of birth

Age

Weight and height

Body mass index (BMI)
6.1.2
Medical History
General medical history findings in the past 5 years, considered relevant to the study by the 
investigator, will be documented in the eCRF together with the respective dates and periods 
(it should be indicated whether the condition is a past or an ongoing disease/illness at study 
entry). Relevant findings include, but may not be limited to, major surgeries, heart diseases, 
respiratory diseases, central nervous system and neurological diseases, psychiatric disorders, 
blood disorders, hepatorenal disorders, genitourinary disorders, and known allergies.
6.1.3
Prostate Cancer Diagnosis
Details of the underlying condition will be documented in the eCRF, including:

Type of adenocarcinoma of the prostate
-
Metastatic
-
Non-metastatic
-
Hormone-sensitive
-
Non-curative

Date of first diagnosis

Presence of metastases (body region)

Clinical signs and symptoms
6.1.3.1
Primary Tumor, Lymph Node and Metastasis Classification of Prostate Cancer
Table 5 presents the Primary Tumor, Lymph Node and Metastasis (TNM) classification of 
primary tumours.

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Table 5: TNM Classification of Primary Tumours [13]
Clinical (cT) 
TX
Primary tumour cannot be assessed
T0
No evidence of primary tumour
T1
Clinically inapparent tumour not palpable or visible by imaging
T1
a
Tumour incidental histologic finding in ≤5% of tissue resected (at time of 
transurethral resection of the prostate [TURP])
T1
b
Tumour incidental histologic finding in >5% of tissue resected (at time of TURP)
T1c
Tumour identified by needle biopsy (because of elevated PSA level)
T2
Tumour confined within prostate
Note: Tumours found in 1 or both lobes by needle biopsy but not palpable on 
digital rectal examination or reliably visible by imaging are classified as T1c)
T2
a
Tumour involves one-half of 1 lobe or less
T2
b
Tumour involves more than one-half of 1 lobe but not both lobes
T2c
Tumour involves both lobes
T3
Tumour extends through the prostatic capsule
Note: invasion into the prostatic apex, or into—but not beyond—the prostatic 
capsule is classified as T2
T3
a
Extracapsular extension (unilateral or bilateral)
T3
b
Tumour invading seminal vesicle(s)
T4
Tumour fixed or invades adjacent structures other than seminal vesicles (e.g. 
bladder, levator muscles, and/or pelvic wall)
TNM= Primary Tumor, Lymph Node and Metastasis
Table 6 presents TNM classification of regional lymph nodes.
Table 6: TNM Classification of Regional Lymph Nodes (N) [13]
Clinical (cN)
NX
Regional lymph nodes were not assessed
N0
No regional lymph node metastasis
N1
Metastasis in regional lymph node(s)
TNM= Primary Tumor, Lymph Node and Metastasis
Table 7 presents TNM classification of distant metastasis.
Table 7: TNM Classification of Distant Metastasis (M)a [13]
Clinical (cM)
M0
No distant metastasis
M1
Distant metastasis
M1a
Non-regional lymph nodes(s)
M1b
Bone(s)
M1c
Other site(s) with or without bone disease

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TNM= Primary Tumor, Lymph Node and Metastasis
a If more than 1 site of metastasis is present, use the most advanced category
6.1.3.2
Gleason Score
The Gleason score is the grading system used to determine the aggressiveness of prostate 
cancer. Gleason grades range from 1 to 5 and describe how much of the cancer from a biopsy 
looks like healthy tissue (lower score) or abnormal tissue (higher score). Most cancers score a 
Grade 3 or higher [14].
Since prostate tumours are often made up of cancerous cells that have different grades, 
2 grades are assigned for each participant. A primary grade is given to describe the cells that 
make up the largest area of the tumour and a secondary grade is given to describe the cells of 
the next largest area. These numerical values are added to calculate the Gleason score (see 
Table 8 and Figure 2).
For instance, if the Gleason score is written as 3 + 4 = 7, it means most of the tumour is 
Grade 3 and the next largest section of the tumour is Grade 4, together they make up the total 
Gleason score. If the cancer is almost entirely made up of cells with the same score, the grade 
for that area is counted twice to calculate the total Gleason score.
Typical Gleason scores range from 6–10 (Table 8) The higher the Gleason score, the more 
likely that the cancer will grow and spread quickly. Each specimen is assigned 2 grades based 
on the most common and second most common pattern.
Figure 2: Gleason Score

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Table 8: Gleason Scoring System
Grade Group
Gleason Score
Gleason Pattern(s)
1
≤6
≤3 + 3
2
7
3 + 4
3
7
4 + 3
4
8
4 + 4 (3 + 5/5 + 3)
5
9 or 10
4 + 5, 5 + 4, 5 + 5
6.2
Efficacy
6.2.1
Primary Efficacy Variable
The primary efficacy analysis is the evaluation of serum T concentration at Day 28.
6.2.2
Secondary Efficacy Variables
Secondary efficacy analyses include the evaluation of the following variables:

T (Total)

LH

FSH

PSA
All these variables will be assessed at the timepoints shown in Table 9.

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Table 9: Timepoints for Efficacy Variables
Stage
Group
Timepoint
Variables
Local 
T
Central 
T
LH
FSH
PSA
Stage 1
1 and 2
Baseline (pre-dose)




24 hours post-dose



48 hours post-dose



72 hours post-dose



Day 4 



Day 7 




Day 14




Day 21a





Stage 2
1 and 2
Day 28




Day 35





Day 42




Day 77

Day 84




Day 119

Day 126




Day 161

Day 168




Stage 3
2 only
Day 203





Day 210





Day 217





Day 224b





Day 231b





Day 238b





Day 245b





Day 252





Follow up visit





FSH=follicle stimulating hormone; LH=luteinising hormone; PSA=prostate-specific antigen; 
T=testosterone
a If PSA is <0.06 ng/mL, hs PSA will be measured and reported. If PSA is ≥0.06 ng/mL then 
hs PSA will not be measured and reported.
bWeekly assessments from Day 203 until Day 252 or until serum T levels are >1 ng/mL 
(local lab result), whichever occurs first

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6.3
Safety
6.3.1
Vital Signs
Vital signs parameters will be measured at screening, baseline (Day 0), and Day 28 for both 
Groups 1 and 2. During Stage 2 these assessments will be performed on the day of the 
maintenance dose. In both groups this will occur at Days 42, 84, 126, and168 and follow-up. 
These vital signs will be measured with the participant in sitting position for at least 5 
minutes.
In the clinic, measurements of the vital signs described below will be made by a trained and 
authorised person:

Systolic BP (mmHg)

Diastolic BP (mmHg)

Heart rate (bpm)

Respiratory rate (breaths per minute)

Body temperature (°C)
The investigator will evaluate any worsening in vital signs for its clinical relevance as to 
whether it meets the definition of an AE (see Section 6.3.7). All changes in vital signs that 
meet the definition of an AE must be documented as an AE in the eCRF.
A manual or automated sphygmomanometer will be used to measure systolic and diastolic 
BP. BP results will be recorded in mmHg. Pulse rate will be measured in the radial artery for 
60 seconds and will be recorded as beats per minute. If possible, BP and pulse rate should 
preferably be measured in the same arm at each visit.
Weight will be measured while the participant is clothed with shoes off and recorded in 
kilograms (kg).
Height will be measured in centimetres at the screening visit (Visit 1) only.
6.3.2
Physical Examination
A physical examination will be performed at the timepoints specified in Table 15, Error: 
Reference source not found, and Error: Reference source not found. Any abnormalities must 
be specified in the eCRF and, if observed after administration of teverelix TFA, the 
abnormality must also be documented as an AE (see Section 6.3.7).
The complete physical examination will consist of evaluation of general appearance, the skin, 
head, eyes (including size and reactivity of the pupils), ears, nose, throat, neck, thyroid, lungs, 
heart, lymph nodes, abdomen, and extremities (to include deep tendon reflexes, clonus, and 
muscle rigidity). Any abnormalities noted should be described.
6.3.3
Triplicate 12-Lead Electrocardiogram
At screening (Visit 1), 12-lead ECG recordings will be obtained in triplicate (within an 
approximate 2- to 5-minute window) with the participant in a supine position, suitably rested 
(for at least 5 minutes). At baseline (Visit 2), 12-lead ECGs will be performed in triplicate 
before administration of the first dose of the IMP; the results should be reviewed by the 
cardiologist at the site delegated to review all study ECGs (ie the rater) to confirm that 
the participant may be dosed (see Exclusion Criterion Number 8).
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Subsequently, triplicate 12-lead ECGs (within an approximate 5-minute window) will be 
obtained at each dosing visit and at the follow-up visit.
All 12-lead ECGs, including those performed at screening, will be of at least 10-second 
duration.
The confirmation of the decision regarding the participant’s eligibility for the study and all 
ECGs are to be based on local readings. For evaluation of participants with left bundle branch 
block, a cardiology consultation is strongly recommended.
At a minimum, interval data (QTcF), ventricular rate, and overall interpretation will be 
reported for each ECG.
The investigator will record on the eCRF whether the results are normal or abnormal (not 
clinically significant or clinically significant). If recorded as abnormal and clinically 
significant, the machine-read results and any clinical interpretations must be incorporated into 
the eCRF, and, if observed after administration of teverelix TFA, the abnormality must also 
be documented as an AE (see Section 6.3.7).
6.3.4 Continuous 12-lead Holter Electrocardiogram  (Subset of 30 Group 2 subjects)
Continuous 12-lead Holter ECGs will be performed in a subset of 30 Group 2 subjects only 
(first 30 enrolled subjects with no more than 8 subjects at any one site). Continuous 12-lead 
Holter data will be obtained from subjects in accordance with time points detailed in the 
Schedule of Assessments (Table 16). 
For analysis of the continuous 12-lead ECG data, triplicate 10 second 12-lead ECGs will be 
extracted at time points matching certain PK sampling times after at least 5 minutes rest in 
order to facilitate concentration-QTc effect modelling. 
6.3.4
Injection Site Inspection
Each injection site will be visually inspected at each visit for local reactions such as pain, 
tenderness, erythema/redness and swelling. If the only reaction is induration, this should be 
indicated on the eCRF and reported as an AE. Any other local reactions will be graded 
according to the grades mentioned as specified in Table 10 [15] and reported as an AE. Upon 
complete resolution of an injection site reaction, injection site inspections of that injection site 
can cease.
During the first administration of the injection, an injection site inspection (ISI) will be 
performed to ensure that the injection site is free from blemishes, tattoos, or other marks that 
may make subsequent ISIs difficult. ISIs will also be performed at 30 minutes, 4, 12, and 24 
hours post-dose. The ISI will be performed at 30 minutes post-dose for all other IMP 
administration. ISRs will be reported as AEs.
At maintenance dose visits ALL injection sites must be inspected unless an injection site 
reaction has fully resolved (including induration).  For example, at Day 42 the following 
injection sites should be inspected: D0 SC; D0 IM; D42 SC.  And at Day 84 the injection sites 
for D0 SC; D0 IM; D42 SC; D84 SC should be inspected.  Only when an injection site 
reaction (including induration) has fully resolved can inspection of that injection site stop.
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Table 10: Food and Drug Administration Local Toxicity Scale
Local Reaction to 
Injectable Product
Mild
(Grade 1)
Moderate 
(Grade 2)
Severe
(Grade 3)
Potentially 
Life-
threatening 
(Grade 4)
Pain
Does not 
interfere with 
activity
Interferes with 
activity or 
repeated use of 
non-narcotic 
pain reliever
Prevents daily 
activity or 
repeated use of 
narcotic pain 
reliever
ER visit or 
hospitalisation
Tenderness
Mild pain to 
touch
Pain with 
movement
Significant 
pain at rest
ER visit or 
hospitalisation
Erythema/Rednessa
2.5–5 cm
5.1–10 cm
>10 cm
Necrosis or 
exfoliative 
dermatitis
Swellingb
2.5–5 cm and 
does not 
interfere with 
activity
5.1–10 cm or 
interferes with 
activity
>10 cm or 
prevents daily 
activity
Necrosis
ER=emergency room
a In addition to grading the measured local reaction at the greatest single diameter, the 
measurement should be recorded as a continuous variable.
b Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement.
6.3.4.1
Photographic Documentation of Injection Site
The investigator should photograph the injection site (abdomen or buttock, as applicable) at 
the time the injection is given.  This is to provide a pre-reaction/baseline photograph in the 
event that a reaction does occur.
If a visible ISR (i.e. one that could be observed in a photograph) subsequently develops, a 
digital photograph of the injection site will be taken by the investigator. The picture must be 
uploaded into the eCRF. Prior to the photograph being taken, a label will be placed close to 
the injection site. This label will display a centimetre ruler and contain space for the entry of 
participant number, visit number, date of visit and time of photograph. The photograph must 
be taken with the camera at an angle 90 degrees perpendicular to the injection site wherever 
possible. The details regarding the instructions for taking the photograph will be documented 
in the photography manual.
ISRs at the abdominal site should be monitored and photographed at each study visit until 
complete absence/resolution. ISRs at the buttock site should be monitored and photographed 
at each study visit until Day 42 or until complete absence/resolution, whichever is later.
6.3.5
Safety Laboratory Variables
Fasted (>8 hours) blood samples for haematology and biochemistry tests, as well as a urine 
sample for urinalysis, will be collected for safety monitoring at screening, baseline, Day 28, 
all dosing visits of Stage 2 and the follow-up visit. For safety analysis, a blood volume of 
approximately 8 mL will be drawn per timepoint. Full details of blood volumes drawn during 
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the study are documented in the Laboratory Manual. An overview of measured parameters is 
given in Table 11.
Table 11: Clinical Safety Laboratory Tests
Haematology:
Haemoglobin
Erythrocytes
Leucocytes
Thrombocytes
Neutrophils
Eosinophils
Basophils
Lymphocytes
Monocytes
Biochemistry:
Alkaline phosphatase
ASAT
ALAT
-
GT
Creatinine
Fasting glucose
Fasting insulin
Urea
Total Bilirubin
Total protein
Sodium
Potassium
Total cholesterol
LDL
HDL
VLDL
Triglycerides
HbA1c (screening visit only)
Urinalysis:
Leucocytes
Erythrocytes
Epithelial cells
pH
Protein
Glucose
Urobilinogen
Ketones
Bilirubin
Nitrite
Specific density 
ALAT=alanine aminotransferase; ASAT=aspartate aminotransferase; HDL=high-density 
lipoprotein; LDL=low-density lipoprotein; VLDL=very low-density lipoprotein; -
GT=gamma-glutamyl transpeptidase
6.3.6
Additional Safety Assessments
It will be left to the investigators' discretion to perform safety assessments in addition to those 
outlined above. Unless useful for specific purposes (e.g. individual SAEs), the data from these 
additional safety assessments will not form part of the database of the present study.
6.3.7
Adverse Events
All AEs, including intercurrent illnesses or pathological changes in laboratory values, must be 
reported and documented in detail including the time of start and end of onset and the 
outcome. The measures taken will be documented in the eCRF as well as intensity, 
relationship to study medication and seriousness of the AE.
6.3.7.1
Definition of Adverse Events
An AE is any untoward medical occurrence in a participant or clinical investigation 
participant who is administered a pharmaceutical product. This untoward medical occurrence 
does not necessarily have a causal relationship with the administered treatment. An AE can, 
therefore, be defined as any unfavourable and unintended sign (including abnormal laboratory 
findings), symptom, or disease that is temporally associated with the use of a medicinal 
(investigational) product, whether or not related to that medicinal (investigational) product.
If, during treatment with an investigational product, pathological laboratory values occur 
which were not present before the treatment started, further clinical or laboratory tests must be 
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carried out until the values return to the normal range or until a plausible explanation is found 
(e.g. concomitant disease) for the change in the laboratory values.
Symptoms  or  clinically significant  laboratory  or  instrumental  (e.g.  electrocardiographic) 
abnormalities of a pre-existing condition, such as cancer or other diseases, should not be 
considered an AE. However, occurrence of new  symptoms,  laboratory,  or  instrumental 
abnormalities, as well as worsening of pre-existing ones, are considered AEs.
Laboratory values outside the normal laboratory-specific reference range, which make an 
intervention necessary and/or are considered clinically significant by the investigator must be 
reported as AEs. If the abnormal laboratory value is a sign of a disease, only this diagnosis 
should be reported as an AE.
An AE is considered to be an adverse drug reaction (ADR) if a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility.
6.3.7.2
Assessment of Adverse Events
The  investigator  will  identify  the  occurrence  of  pre-dose  events  and/or  AEs  through 
non-leading questioning and examination of the participant.
For each AE, the investigator will document the following:

Signs and symptoms of the event (if a specific disease can be diagnosed, this disease 
should be the reported AE; if only signs and symptoms can be evaluated, each sign or 
symptom should be reported as a separate AE)

Onset date and time (if a change from pre-dose in a laboratory test is reported as an 
AE, the start date is the date of collection of the first laboratory sample that shows the 
change)

End date and time (if a change from pre-dose in a laboratory test is reported as an 
AE, the end date is the date of collection of the first laboratory sample that shows a 
return to pre-dose level)

Measure  taken  (none,  drug  treatment  required,  hospitalisation  or  prolonged 
hospitalisation, study discontinuation, other measures [specification])

Outcome
 (recovered/resolved,  recovering/resolving,  recovered/resolved  with 
sequelae, not recovered/not resolved, fatal, unknown)
In addition, each AE will be rated by the investigator according to the following categories 
(the Sponsor has to carry out a separate assessment for causal relationship, seriousness, and 
expectedness):
Relationship to Study Medication
If the AE is a deterioration in the study disease and, therefore, indicates a lack of efficacy of 
the study medication, the causality assessment "no relationship" will be made, as the 
impairment of health is not caused by a intolerability of the study medication. "Deterioration 
of study disease" is to be given as the cause of the AE.
Assessments of relationship to study medication will be made by the investigator first.
For the evaluation of the relationship between AEs and IMP the following definitions will be 
used:
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Related
This category applies to those AEs which the investigator feels are 
incontrovertibly related to the IMP. The relationship between the IMP and an 
AE is considered definite if the AE:

follows a reasonable temporal sequence after administration of the IMP or 
after achieving effective levels in body fluids and tissues, respectively

is already known as side effect in relation to the IMP

disappears or decreases on cessation of the IMP

recurs with re-exposure to the IMP
Probable
This category applies to those AEs which, after careful medical consideration 
at the time they are evaluated, are felt with a high degree of certainty by the 
investigator to be related to the IMP. The relationship between the IMP and an 
AE is considered probable if the AE:

follows a reasonable temporal sequence after administration of the IMP

has already been described as a side effect of the IMP

disappears or decreases on cessation of the IMP

cannot be reasonably explained by the participant’s clinical state
Possible
This category applies to those AEs for which, after careful medical 
consideration at the time they are evaluated, a connection with the IMP 
appears improbable but cannot be ruled out with certainty. The relationship 
between the IMP and an AE is considered possible if the AE:

follows a reasonable temporal sequence after administration of the IMP

has already been described as an AE in connection with the IMP

could also be reasonably explained by a number of other causes
Unlikely
In general, this category can be considered applicable to those AEs which, 
after careful medical consideration at the time they are evaluated, are judged 
with a high degree of certainty to be unrelated to the IMP. The relationship 
between the IMP and an AE is considered unlikely if the AE:

does not follow a reasonable temporal sequence after administration of the 
IMP

could also be reasonably explained by a number of other causes

does not follow a known pattern of response to the IMP
Not related
This category applies to those AEs which, after careful consideration, are 
clearly and incontrovertibly due to causes other than the IMP (intercurrent 
disease, worsening of study indication/lack of efficacy, concomitant disease, 
concomitant therapy, other).
Intensity
Regardless of the classification of an AE as serious or non-serious (see below), its intensity 
must be assessed according to medical criteria alone using the Common Terminology Criteria 
for Adverse Events (CTCAE) classification (v5.0):
Grade 1 (mild):
asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
Grade 2 (moderate):
minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (e.g. 
preparing meals, shopping, using the telephone, managing 
money, etc.)
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Grade 3 (severe):
severe or medically significant but not immediately life-
threatening; hospitalisation or prolongation of hospitalisation 
indicated; disabling; limiting self-care activities of daily living 
(e.g. bathing, dressing, undressing feeding self, using toilet, 
taking medications, and not bedridden, etc.)
Grade 4 (life-threatening): life-threatening consequences; urgent intervention indicated
Grade 5 (death):
death related to AE (death is reported as an outcome of an AE)
It should be noted that a severe AE does not necessarily have to be serious in nature and that a 
serious AE need not be severe.
Seriousness
An SAE is an untoward medical occurrence that at any dose:

results in death

is life-threatening

requires in-participant hospitalisation or prolongation of existing hospitalisation

results in persistent or significant disability/incapacity

is a congenital anomaly or birth defect
or

is an important medical event that does not have to be immediately life-threatening or 
result in death or hospitalisation, but which may jeopardise the participant or may 
require medical intervention to prevent 1 of the outcomes listed above.
All SAEs must be reported immediately (within 1 working day) to the drug safety 
department at IntuVigilance Limited, by the investigator.
All AEs that do not fall into any of the above categories are defined as non-serious.
Expectedness
At the drug safety department at IntuVigilance Limited an additional rating for expectedness 
of AEs will be given:
Expected:
The event is judged expected if its description agrees in nature, severity, 
frequency, and specificity with the description of events in the Investigator's 
Brochure.
Unexpected: SAEs which do not fall into the expected category are assessed to be 
unexpected.
A suspected unexpected serious adverse drug reaction (SUSAR) is defined as an untoward 
and unintended response to an IMP, which is not listed in the applicable product information, 
and meets 1 of the above-mentioned serious criteria. The drug safety department at 
IntuVigilance Limited, acting on behalf of the Sponsor, will ensure that all SUSARs 
associated with the IMP will be reported to the applicable regulatory authority/competent 
authorities and the relevant independent ethics committees(IECs)/IRBs in accordance with the 
applicable national/local regulations (usually within 7 calendar days for life-threatening and 
fatal SUSARs or within 15 calendar days for all other SUSARs). The drug safety department 
at IntuVigilance Limited will also promptly notify all investigators about any SUSAR.
6.3.7.3
Follow-up of Adverse Events
Regardless of the duration of the study, each AE must be followed-up until it subsides or until 
the cause is known or an adequate final assessment can be given. The maximum follow-up 
period will be 6 weeks after the participant’s study termination. If after 6 weeks no final 
outcome can be acquired, the outcome of the AE is ‘unresolved’.
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6.3.7.4
Documentation and Reporting of Adverse Events
Any AE has to be documented in the eCRF with the specifications made in Section 6.3.7.2. 
All SAEs must be reported immediately (within 1 working day) to the drug safety manager or 
the responsible person and/or the clinical research associate (CRA) by the investigator (see 
Responsibilities).
All SAEs must be reported by the investigator immediately (within 24 hours) to the drug 
safety department at IntuVigilance Limited via the eCRF (see below).
A specific SAE form for immediate reporting will be provided to the investigators as part of 
the eCRF. In case of a SAE, this form should be completed and checked immediately within 
the eCRF. These data entries will be used to automatically create the corresponding SAE 
reporting form. Furthermore, any other requested data (like concomitant medications) already 
present in the eCRF will be used to populate the respective fields of the SAE reporting form. 
A trigger mechanism implemented in the eCRF will ensure that the form will be sent 
automatically via email to the drug safety department at IntuVigilance Limited within 24 
hours.
Note: Any changes in fields being part of these reports will create a new (follow-up) 
report, which will also be sent automatically.
If due to any reason the electronic completion and forwarding of the SAE reporting form via 
the eCRF is not possible, the investigator may fill out the pre-printed Sponsor SAE reporting 
form manually and send the required information via scanned email to both parties mentioned 
above (see Responsibilities for contact details).
Follow-up reports will be provided by the investigator each time new information on the SAE 
becomes available (until the case is solved or the participant has recovered). For reporting of 
follow-up information, a similar procedure as for reporting of initial SAEs will apply.
Notification to the regulatory authorities, the IECs, and the investigator sites about all 
SUSARs will be performed by and to the investigator sites and/or by the investigator (as 
applicable) according to all applicable national/local regulations.
6.4
Pharmacokinetics
6.4.1
Pharmacokinetic Variables
Pharmacokinetic parameters will be generated using Phoenix WinNonlin Version 6.4 or 
higher for evaluation.
The concentrations of all participants who successfully complete the study will be analysed 
and samples of withdrawn or dropout participants will not be analysed. This analysis may 
include the parameters shown in Table 12. Full details will be presented in the statistical 
analysis plan (SAP).
Table 12: Pharmacokinetic Parameters
PK 
Parameter
Description
Unit
AUC0-t
Area under the concentration-time-curve from time zero up to 
the last measurable concentration at timepoint t
ng•h/
mL
AUC0-t1
Area under the concentration-time-curve from time zero up to 
concentration at timepoint t1 after which the concentrations start 
to rise again towards a second peak, t1 will be determined after 
review of the concentration-time profiles (immediate release 
component of total observed AUC)
ng•h/
mL
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PK 
Parameter
Description
Unit
AUCt1-t
Area under the concentration-time-curve from timepoint t1 up to 
timepoint t (slow release component of total observed AUC)
ng•h/
mL
AUC0-∞
Area under the concentration-time-curve from time zero up to 
infinity (∞)
ng•h/
mL
Cmax
Maximum plasma concentration
ng/mL
Cmax,0-t1
Maximum plasma concentration after administration from zero 
up to timepoint t1
ng/mL
Cmax,t1-t
Maximum plasma concentration after administration from 
timepoint t1 up to timepoint t
ng/mL
Tmax
Time to reach Cmax after dosing
h
Tmax,0-t1
Time to reach Cmax,0-t1 after dosing
h
Tmax,t1-t
Time to reach Cmax,t1-t after dosing
h
λz
Apparent terminal rate constant
1/h
t½
Apparent terminal plasma half-life
h
h=hours; PK=pharmacokinetic
6.4.2
Blood Sampling Time Points, Handling and Labelling of Blood Samples
Blood samples for PK evaluation will be collected by venepuncture (or by using an 
indwelling catheter). A blood volume of 5 mL will be drawn per timepoint.
Blood is drawn for PK analysis according to the schedule below, where timepoints are relative 
to IM injection of teverelix TFA at time zero, and the pre-dose PK sample is collected within 
30 minutes prior to IM injection (Table 13).
Handling and labelling of blood samples for PK analysis will be performed according to the 
instructions provided by the central analytical laboratory. Special tubes, labels, packaging, 
and instructions for storage and shipment will also be provided by the analytical laboratory. 
Blood samples should be shipped for analysis on the day of collection.
Blood teverelix TFA concentrations will be determined from all collected samples using a 
validated sensitive analytical procedure (e.g. inductively coupled plasma mass spectrometry) 
at a specialised central analytical laboratory.
After completion of all analyses, any leftover blood or blood samples will be destroyed 
immediately after termination of the study.
Stability data supports the storage of teverelix PK samples:

In a freezer set at nominally -20°C for up to 376 days 

In a freezer set at nominally -80°C for up to 60 days
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Table 13: Pharmacokinetic Timepoints
Timepoi
nt
Pre-
dose
1
h
1.5 
h
2
h
2.5 
h
3
h
4
h
8
h
12
h
18
h
24
ha
48
h
72
h
Window
±0 
day
±1
5 
mi
n
±1
5 
mi
n
±15 
min
±15 
min
±15 
min
±15 
min
±15 
min
±15 
min
±15 
min
±15 
min
±1 
hou
r
±1 
hou
r













Timepoin
t
Da
y 4b
Da
y 7b
Da
y 
10b
Da
y 
12b
Da
y 
14b
Da
y 
21b
Day 
28c
Day 
35
Thereafter at each dosing visit 
and follow up visitsd
Window
±0 
day
±0 
day
±1 
day
±1 
day
±1 
day
±1 
day
±3 
day
s
±3 
day
s
±3 days









PK=pharmacokinetic
a Participants will remain in the clinic as in-participants until after the 24-hour PK blood 
sample has been drawn after which time they will be discharged.
b From Day 4 onwards, when a PK sample is to be drawn on a non-dosing day, the PK sample 
should be drawn at the same time of day as the Day 0 pre-dose PK sample was drawn (+ 1 
hour).
c Before dosing (up to 30 minutes pre-dose). Dosing should be done at the same time of day 
throughout the study (or at least + 1 hour of this timepoint).
dIncluding Day 203 to Final Assessment visits for Group 2 subjects
6.5
Pharmacodynamics
The following parameters will be investigated:

T

LH

FSH

PSA
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Table 14 presents the PD blood sampling schedule for the study.
Table 14: Pharmacodynamic Blood Sampling Schedulea
Day 0
(pre-
dose)
24h
48h
72h
Day 
4
Day 
7
Day 
10
Day 
12
Day 
14
Day 
21b
Day 
28
Day 
35 c
Thereafter 7 
days prior to 
each dosing 
visit
Thereafter 
at each 
dosing visit 
and follow 
up visitsd
T (local)



T 
(central)













LH













FSH













PSA







FSH=follicle stimulating hormone; hs=high-sensitivity; LH=luteinising hormone; PD=pharmacodynamic; PK=pharmacokinetic; 
PSA=prostate-specific antigen; T=testosterone
a PD blood draws should be done at the same time of day as PK blood draws (pre-dose on Day 0)
b If PSA is <0.06 ng/mL hs PSA will be measured and reported. If PSA is ≥0.06 ng/mL then hs PSA will not be measured and reported.
c Group 1 only
dIncluding Day 203 to Final Assessment Visit for Group 2 subjects
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7
Study Conduct
7.1
Study Schedule
Table 15 presents the study schedule for Groups 1 and 2.
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Table 15: Schedule of Assessments for Groups 1 and 2
Visit/
Procedure
Screeni
ng
Treatment Period Groups 1 & 2
Follo
w-up
Unsche
d. Visit
Stage 1
Stage 2
Days/
Weeks
Da
y 0
Da
y 1
Da
y 2
Da
y 3
Da
y 4
Da
y 7
Da
y 
10
Da
y 
12
Da
y 
14
Da
y 
21
Da
y 
28
Da
y 
35
Da
y 
42
Da
y 
77
Da
y 
84
Da
y 
11
9
Da
y 
12
6
Da
y 
16
1
Da
y 
16
8
28 
days 
after 
last 
dose
Visit 
Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V1
0
V1
1
V1
2
V1
3
V1
4
V1
5
V1
6
V1
7
V1
8
V1
9
V2
0
V21
Window
D-6 To -
1
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±1 
D
±1 
D
±1 
D
±1
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 D
Informed 
Consent

Inclusion 
and 
Exclusion 
Criteria


Medical 
History

Physical 
Exam.









12-Lead 
ECGl









Holter 
ECG
(Group 2 
only)


Safety 
Labs1









Vital Signs









Demograp
hy2









1 Safety laboratory tests are detailed in Section 6.3.5.
2 Demographic details include height, weight, year of birth and age; During baseline and other visits including follow up (28 days after last dose) height, weight and BMI only will be measured.
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Visit/
Procedure
Screeni
ng
Treatment Period Groups 1 & 2
Follo
w-up
Unsche
d. Visit
Stage 1
Stage 2
Days/
Weeks
Da
y 0
Da
y 1
Da
y 2
Da
y 3
Da
y 4
Da
y 7
Da
y 
10
Da
y 
12
Da
y 
14
Da
y 
21
Da
y 
28
Da
y 
35
Da
y 
42
Da
y 
77
Da
y 
84
Da
y 
11
9
Da
y 
12
6
Da
y 
16
1
Da
y 
16
8
28 
days 
after 
last 
dose
Visit 
Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V1
0
V1
1
V1
2
V1
3
V1
4
V1
5
V1
6
V1
7
V1
8
V1
9
V2
0
V21
Window
D-6 To -
1
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±1 
D
±1 
D
±1 
D
±1
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 D
Injection of 
teverelix 
TFA IM3

Injection of 
teverelix 
TFA SC





Blood draw 
for pre-
dosing 
local lab T 
testing






3 IM injection and SC injection of teverelix TFA will be given immediately sequentially (within 10 minutes of each other); IM first; all PK time points detailed relative to the IM injection time. Participants to 
be monitored for hypersensitivity reaction for 30 minutes following SC injection.
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Visit/
Procedure
Screeni
ng
Treatment Period Groups 1 & 2
Follo
w-up
Unsche
d. Visit
Stage 1
Stage 2
Days/
Weeks
Da
y 0
Da
y 1
Da
y 2
Da
y 3
Da
y 4
Da
y 7
Da
y 
10
Da
y 
12
Da
y 
14
Da
y 
21
Da
y 
28
Da
y 
35
Da
y 
42
Da
y 
77
Da
y 
84
Da
y 
11
9
Da
y 
12
6
Da
y 
16
1
Da
y 
16
8
28 
days 
after 
last 
dose
Visit 
Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V1
0
V1
1
V1
2
V1
3
V1
4
V1
5
V1
6
V1
7
V1
8
V1
9
V2
0
V21
Window
D-6 To -
1
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±1 
D
±1 
D
±1 
D
±1
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 D
PK/PD 
Blood 
Draw4
5
6
7
8
9
E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f
o
u
n
d
E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f
o
u
n
d
E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f
o
u
n
d
E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f
o
u
n
d
E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f
o
u
n
d
E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f
o
u
n
d
E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f
o
u
n
d
E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f
o
u
n
d
E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f
o
u
n
d
E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f
o
u
n
d
E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f
o
u
n
d

4 On Day of dosing visit, blood samples for PK/PD analysis will be collected before the administration of the Maintenance Dose.
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Visit/
Procedure
Screeni
ng
Treatment Period Groups 1 & 2
Follo
w-up
Unsche
d. Visit
Stage 1
Stage 2
Days/
Weeks
Da
y 0
Da
y 1
Da
y 2
Da
y 3
Da
y 4
Da
y 7
Da
y 
10
Da
y 
12
Da
y 
14
Da
y 
21
Da
y 
28
Da
y 
35
Da
y 
42
Da
y 
77
Da
y 
84
Da
y 
11
9
Da
y 
12
6
Da
y 
16
1
Da
y 
16
8
28 
days 
after 
last 
dose
Visit 
Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V1
0
V1
1
V1
2
V1
3
V1
4
V1
5
V1
6
V1
7
V1
8
V1
9
V2
0
V21
Window
D-6 To -
1
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±1 
D
±1 
D
±1 
D
±1
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 D
PSA/hs 
PSA10











Cardiac 
biomarkers







Injection 
Site 
Inspection
















Injection 
Site 
Photograph
k
















Prior and 
current 
Concomita
nt 
Medication
s


















5 Post-dose PK blood sampling on Day 0 is scheduled at the following time points: at 1, 1.5, 2, 2.5, 3, 4, 8, 12, 18 hours.
6 Post-dose PK blood sampling at 24 hours. At the time point of 24 hours post-dose sampling for PD analysis (T, LH, FSH) will be initiated.
7 Post-dose PK blood sampling at 48 hours.
8 72 hour PK profile: PD testing blood draw to be done at same time of day as the Day 0 pre-dose PK blood draw.
9  PK and PD testing blood draw to be done at same time of day as pre-dose PK blood draw. 
10 If PSA is <0.06 ng/mL hs PSA will be measured and reported. If PSA is ≥0.06 ng/mL then hs PSA will not be measured and reported.
kIf a visible injection site reaction is present, two photographs should be taken and the better photograph uploaded to the eCRF
l ECGs to be done in triplicate at each visit
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Visit/
Procedure
Screeni
ng
Treatment Period Groups 1 & 2
Follo
w-up
Unsche
d. Visit
Stage 1
Stage 2
Days/
Weeks
Da
y 0
Da
y 1
Da
y 2
Da
y 3
Da
y 4
Da
y 7
Da
y 
10
Da
y 
12
Da
y 
14
Da
y 
21
Da
y 
28
Da
y 
35
Da
y 
42
Da
y 
77
Da
y 
84
Da
y 
11
9
Da
y 
12
6
Da
y 
16
1
Da
y 
16
8
28 
days 
after 
last 
dose
Visit 
Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V1
0
V1
1
V1
2
V1
3
V1
4
V1
5
V1
6
V1
7
V1
8
V1
9
V2
0
V21
Window
D-6 To -
1
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±1 
D
±1 
D
±1 
D
±1
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 D
Adverse 
Events


















BMI=body mass index; D=days; ECG=electrocardiogram; hs=high-sensitivity; IM=intramuscular; PD=pharmacodynamic; 
PK=pharmacokinetic; PSA=prostate-specific antigen; SC=subcutaneous; T=testosterone
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Table 17: Schedule of Assessments for Group 2 (subjects with Stage 3 included)
Visit/
Procedure
Screeni
ng
Treatment Period Group 2 (with Stage 3 only)
Unsch
ed. 
Visit
Stage 1
Stage 2
Stage 3
Days/
Weeks
Da
y 0
Da
y 1
Da
y 2
Da
y 3
Da
y 4
Da
y 7
Da
y 
10
Da
y 
12
Da
y 
14
Da
y 
21
Da
y 
28
Da
y 
35
Da
y 
42
Da
y 
77
Da
y 
84
Da
y 
11
9
Da
y 
12
6
Da
y 
16
1
Da
y 
16
8
Day 
203
Follo
w up 
Visit
Visit 
Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V1
0
V1
1
V1
2
V1
3
V1
4
V1
5
V1
6
V1
7
V1
8
V1
9
V2
0
V21
*
FA
Window
D-6 To 
-1
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±1 
D
±1 
D
±1 
D
±1
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 D
Informed 
Consent

Inclusion 
and 
Exclusion 
Criteria


Medical 
History

Physical 
Exam.









12-Lead 
ECGl









Holter 
ECG
(Group 2 
only)


Safety 
Labs11









Vital Signs









11 Safety laboratory tests are detailed in Section 6.3.5.
? Demographic details include height, weight, year of birth and age; During baseline and other visits including follow up (28 days after last dose) height, weight and BMI only will be measured.
*Subjects should attend on Day 203 and every 7 days until serum T levels are >1 ng/mL (local lab result).  A final assessment visit should be conducted 7 days after serum T levels are >1 ng/mL (local lab 
result).
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Visit/
Procedure
Screeni
ng
Treatment Period Group 2 (with Stage 3 only)
Unsch
ed. 
Visit
Stage 1
Stage 2
Stage 3
Days/
Weeks
Da
y 0
Da
y 1
Da
y 2
Da
y 3
Da
y 4
Da
y 7
Da
y 
10
Da
y 
12
Da
y 
14
Da
y 
21
Da
y 
28
Da
y 
35
Da
y 
42
Da
y 
77
Da
y 
84
Da
y 
11
9
Da
y 
12
6
Da
y 
16
1
Da
y 
16
8
Day 
203
Follo
w up 
Visit
Visit 
Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V1
0
V1
1
V1
2
V1
3
V1
4
V1
5
V1
6
V1
7
V1
8
V1
9
V2
0
V21
*
FA
Window
D-6 To 
-1
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±1 
D
±1 
D
±1 
D
±1
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 D
Demograp
hy12









Injection of 
teverelix 
TFA IM13

Injection of 
teverelix 
TFA SC





Blood 
draw for 
pre-dosing 
local lab T 
testing







12 Demographic details include height, weight, year of birth and age; During baseline and other visits including follow up (28 days after last dose) height, weight and BMI only will be measured.
*Subjects should attend on Day 203 and every 7 days until Day 252 or until serum T levels are >1 ng/mL (local lab result).  A final assessment visit should be conducted on Day 259 or 7 days after serum T 
levels are >1 ng/mL (local lab result), Whichever occurs first.
13 IM injection and SC injection of teverelix TFA will be given immediately sequentially (within 10 minutes of each other); IM first; all PK time points detailed relative to the IM injection time. Participants to 
be monitored for hypersensitivity reaction for 30 minutes following SC injection.
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Visit/
Procedure
Screeni
ng
Treatment Period Group 2 (with Stage 3 only)
Unsch
ed. 
Visit
Stage 1
Stage 2
Stage 3
Days/
Weeks
Da
y 0
Da
y 1
Da
y 2
Da
y 3
Da
y 4
Da
y 7
Da
y 
10
Da
y 
12
Da
y 
14
Da
y 
21
Da
y 
28
Da
y 
35
Da
y 
42
Da
y 
77
Da
y 
84
Da
y 
11
9
Da
y 
12
6
Da
y 
16
1
Da
y 
16
8
Day 
203
Follo
w up 
Visit
Visit 
Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V1
0
V1
1
V1
2
V1
3
V1
4
V1
5
V1
6
V1
7
V1
8
V1
9
V2
0
V21
*
FA
Window
D-6 To 
-1
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±1 
D
±1 
D
±1 
D
±1
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 D
PK/PD 
Blood 
Draw14
15
16
17
18
19

E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f

E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f

E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f

E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f
E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f

E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f

E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f

E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f

E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f

E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f

E
r
r
o
r
:
R
e
f
e
r
e
n
c
e
so
u
r
c
e
n
o
t
f


14 On Day of dosing visit, blood samples for PK/PD analysis will be collected before the administration of the Maintenance Dose.
15 Post-dose PK blood sampling on Day 0 is scheduled at the following time points: at 1, 1.5, 2, 2.5, 3, 4, 8, 12, 18 hours.
16 Post-dose PK blood sampling at 24 hours. At the time point of 24 hours post-dose sampling for PD analysis (T, LH, FSH) will be initiated.
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Visit/
Procedure
Screeni
ng
Treatment Period Group 2 (with Stage 3 only)
Unsch
ed. 
Visit
Stage 1
Stage 2
Stage 3
Days/
Weeks
Da
y 0
Da
y 1
Da
y 2
Da
y 3
Da
y 4
Da
y 7
Da
y 
10
Da
y 
12
Da
y 
14
Da
y 
21
Da
y 
28
Da
y 
35
Da
y 
42
Da
y 
77
Da
y 
84
Da
y 
11
9
Da
y 
12
6
Da
y 
16
1
Da
y 
16
8
Day 
203
Follo
w up 
Visit
Visit 
Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
V1
0
V1
1
V1
2
V1
3
V1
4
V1
5
V1
6
V1
7
V1
8
V1
9
V2
0
V21
*
FA
Window
D-6 To 
-1
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±0 
D
±1 
D
±1 
D
±1 
D
±1
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 
D
±3 D
PSA/hs 
PSA20












Cardiac 
biomarkers







Injection 
Site 
Inspection
















Injection 
Site 
Photograph
k
















Prior and 
current 
Concomita
nt 
Medication
s



















Adverse 
Events



















17 Post-dose PK blood sampling at 48 hours.
18 72 hour PK profile: PD testing blood draw to be done at same time of day as the Day 0 pre-dose PK blood draw.
19 PK and PD testing blood draw to be done at same time of day as pre-dose PK blood draw. 
20 If PSA is <0.06 ng/mL hs PSA will be measured and reported. If PSA is ≥0.06 ng/mL then hs PSA will not be measured and reported.
11If a visible injection site reaction is present, two photographs should be taken and the better photograph uploaded to the eCRF
l2 ECGs to be done in triplicate at each visit
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7.2
Observations by Visit
7.2.1
Screening Examination (Day -6 to Day -1)
At the screening examination the following will be carried out and/or documented:

Participant signs ICF as a part of the written participant information including the 
agreement concerning protection of personal data and direct access to source 
documents

Date of visit

Demographic data (height, weight, year of birth, age)

Diagnosis of study indication (specify duration, severity as requested)

Relevant medical history for the past 5 years

Pre-treatment during the past 6 months

Concomitant disease(s) (including date of diagnoses), concomitant therapy(ies)

Physical examination (see Section 6.3.2)

12-Lead ECG (see Section 6.3.3)

Safety laboratory tests (fasted > 8 hours)

Total T (local laboratory)

HbA1c

Vital signs

Check of inclusion and exclusion criteria
Concomitant diseases are to be documented, taking into consideration the medical history of 
the participant for the past 5 years. Findings that are not medically relevant for the study are: 
operation scars, accident scars, and bad sight etc.
7.2.2
Baseline Examination (Day 0), Stage 1
At baseline examination the following will be carried out and/or documented:

Date of visit

Weight, and BMI

Documentation of changes in concomitant diseases and/or concomitant therapies (also 
medication taken only once and any non-prescription medicine)

AEs (for definition see Section 6.2.4)

Check of inclusion and exclusion criteria

Physical examination

12-Lead ECG

Continuous 24 h, 12-lead Holter ECG (Subset of 30 Group 2 subjects only)

Safety laboratory tests (fasted (>8 hours))

Vital signs

Pre-dose blood sampling for PK, PSA and PD analysis

Pre-dose blood sampling for cardiac biomarkers (Group 2 only)

Administration of the loading dose of teverelix TFA, which consists of IM followed 
by SC injection

ISI

Post-dose PK blood sampling
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Additional Visits for Pharmacokinetic and Pharmacodynamic Samplings during Stage 1:

During Stage 1, the participant will return to the study site for additional PK and PD 
blood sampling at 24, 48 and 72 hours post-dose, and on Days 4, 7, 10, 12, 14, and 21

On Day 21 local testing of T levels will be performed

On Days , 7, 14, and 21, blood sampling for PSA will be performed
7.2.3
Treatment (Maintenance Dose) Period Visits (Day 28 to Day 168), Stage 2
At the treatment period visits, the following examinations will be carried out and/or 
documented:

Date of visit

Date and time of day when the medication was administered

Documentation of changes in concomitant diseases and/or concomitant therapies (also 
medication taken only once and any non-prescription medicine)

AEs (for definition see Section 6.3.7)

Physical examination

12-Lead ECG

Safety laboratory tests (fasted (>8 hours))

Vital signs

Blood sampling for PK, PSA, and PD analysis (before administration of teverelix 
TFA) (see Table 15 and Error: Reference source not found)

Pre-dose blood sampling for cardiac biomarkers (Group 2 only)

ISI

Administration of the maintenance dose of teverelix TFA, which consists of an 
SC injection
7.2.4
Follow-up Visit (28 Days after Last Dose)(Group 1 and Group 2 subjects without 
Stage 3)
At the final visit, the following examinations will be carried out and/or documented:

Date of visit

Documentation of changes in concomitant diseases and/or concomitant therapies (also 
medication taken only once and any medicine taken without a prescription)

AEs

Physical examination

12-Lead ECG

Safety laboratory tests (fasted (>8 hours))

Blood sampling for PK, PSA, and PD

Blood sampling for cardiac biomarkers (Group 2 only)

ISI

Vital signs

Demography (only weight)

Final assessment by investigator and participant
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7.2.5
Follow-up Visits (starting 35 days after Last Dose)(Group 2 with Stage 3 subjects 
only)
Five weeks after the Day 168 maintenance dose injections (Day 203), subjects will attend the 
clinic and the following procedures will be done:

Date of visit

Documentation of changes in concomitant diseases and/or concomitant therapies (also 
medication taken only once and any medicine taken without a prescription)

AEs

Blood sampling for PK, PSA, and PD (local AND central lab serum T levels)
Subjects will continue to attend the clinic every 7 days where the above procedures will be 
done.  Weekly visits will continue until Day 252 or until serum T levels (local lab result) are 
> 1 ng/mL (local lab result) when the subject will attend the clinic 7 days later and the 
following procedures will be done:

Date of visit

Documentation of changes in concomitant diseases and/or concomitant therapies (also 
medication taken only once and any medicine taken without a prescription)

AEs

Physical examination

12-Lead ECG

Safety laboratory tests (fasted (>8 hours))

Blood sampling for PK, PSA, and PD

Blood sampling for cardiac biomarkers (Group 2 only)

ISI

Vital signs

Demography (only weight)

Final assessment by investigator and participant
7.3
Duration of the Study
The study will be terminated when all participants have completed the planned investigation 
period.
7.3.1
Planned Duration for the Individual Participant
For the individual participants, the core study lasts for a maximum of 184 days. The study 
duration might be shorter for individual participants in the event that the treatment ceases to 
be effective. 
7.3.2
Premature Termination
Study
At any time, the study as a whole will be terminated prematurely by the Sponsor if:

New toxicological or pharmacological findings or SAEs invalidate the earlier positive 
benefit–risk assessment

The development of the study IMP is discontinued, a market authorisation is no longer 
intended, or the study proves not to meet the expected goal
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
Other important reasons, not named above, call for the premature termination of the 
study
Centre
At any time, an individual centre participating in the study can be excluded from participation 
by a joint decision between Insuvia UAB, QRCC and the Sponsor if the centre fails to:

Comply with the requirements of the protocol

Comply with GCP standards

Recruit the first participant within a reasonable period
Participant
Individual participants are to be withdrawn from the study according to the criteria specified 
in Section 4.3.
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8
Statistics
8.1
Statistical and Analytical Plans
All statistical analyses will be outlined in detail in a SAP which will be prepared and signed 
prior to any study-specific analyses. In general, all continuous measures will be summarised 
descriptively, including number of available values, minimum, Quartiles 1 and 3, median, 
mean, standard deviation (SD), maximum, and 95% confidence interval (CI) for the mean if 
appropriate. Categorical data will be presented by frequency and percentage. Ordinal ratings 
may be handled as continuous data if appropriate. The analysis will be done in 2 stages. 
Stage 1 will include the analysis of the primary objective: the effect of the loading dose on 
achievement of castration levels by Day 28 (primary endpoint analysis). Stage 2 will include 
all other analyses (full analysis).
8.1.1
Analysis Populations
All participants who have received least 1 dose of study medication will be included in the 
safety analysis (safety population). The efficacy analysis will be performed on an “intention-
to-treat (ITT)” basis and a “PP” basis (see definitions below). Participants with major protocol 
violations will be excluded from the latter. For this purpose, protocol violations that could 
interfere with the objectives of the study, incorrect concomitant medications or violation of 
the inclusion/exclusion criteria etc. will be assessed as ‘minor’ or ‘major’ in collaboration 
with the Sponsor. The criteria for this assessment will be defined before analysis. Listings will 
be prepared to show the eligibility of all participants. These listings will be presented in a 
Data Review Meeting.
Definition of Analysis Populations:
Population
Description
Screening 
population
All participants who signed the ICF
Safety 
population
All participants who received any dose of the IMP
Intention-to-
treat (ITT) 
analysis set
All participants included in the safety population for whom the primary 
endpoint is evaluable
Per protocol 
(PP) analysis set 
All participants included in the ITT analysis set who complete the 
study without major protocol violation
The primary analysis will be performed on the PP analysis set. In addition, a sensitivity 
analysis will be performed using the ITT analysis set. All efficacy assessments on the PP 
analysis set will be repeated for the ITT analysis set.
8.1.2
Adaptive Study Design
In this study the decision of whether or not the treatment regimen for Group 2 will be tested is 
based on the treatment effect observed in Group 1 on Day 28. If serum T levels at Day 28 are 
<0.5 ng/mL, the participant is classified as a treatment responder. Participants with serum 
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T levels at Day 28 of >2 ng/mL will be classified as non-responders. The target group 
treatment response is 90%.
Enrolment will continue for Group 1 until 20 participants have completed the Day 28 visit 
with no more than 2 participants being classified as a treatment failure. Treatment failure is 
defined by a serum T concentration >2 ng/mL at Day 28 or requiring to be withdrawn at any 
later timepoint during the study.
If 3 or more participants in Group 1 fail treatment then further enrolment into that group will 
stop due to statistical confidence that a 90% responder rate cannot be achieved with that 
dosing regimen. All future participants will be enrolled into Group 2.
If in Group 2 at Day 28, a participant’s serum T value (as tested by the local laboratory) is 
>2 ng/mL, the participant will be withdrawn from the study.
If 7 or more participants fail in Group 2 then all further enrolment will be stopped and the 
study will be terminated.
The planned Group 1 treatment continuation analysis will be described in greater detail in the 
SAP.
8.1.3
Primary Efficacy Analysis
Primary Endpoint
The primary endpoint of the study is the proportion of participants achieving castration level 
with serum T <0.5 ng/mL or 1.73 nmol/L at Day 28.
The primary parameter analysis will be performed on the PP analysis set. In addition, a 
sensitivity analysis will be performed on the ITT analysis set.
8.1.4
Secondary Endpoint Analyses
Secondary Endpoints
1. Proportion of participants achieving castration level with serum T <0.2 ng/mL at Day 
28
2. Proportion of participants achieving castration level with serum T <0.5 ng/mL at 
Day 42
3. Proportion of participants achieving castration level with serum T <0.2 ng/mL at 
Day 42
4. Proportion of participants achieving a T castration rate over 168 days of treatment 
period
Note: Castration rate is defined as the observed percentage of participants who 
have T concentrations <0.5 ng/mL (1.73 nmol/L) at all scheduled visits.
5. Proportion of participants achieving profound castration rate (<0.2 ng/mL) over 
168 days of treatment period
6. Mean time to T levels falling below castration level (<0.5 ng/mL [1.73 nmol/L]) for 
the first time
7. Mean time to (first) overstep of T castration level after achieving castration
8. Mean time for serum T levels to be > 0.5 ng/mL after final, Day 168 injection
9. Proportion of participants achieving castration level for LH (LH <1.1 U/L) at Day 28
10. Proportion of participants with effective LH castration rate over 168 days of treatment 
period
11. Mean time to LH levels falling below castration level (LH <1.1 U/L) for the first time
12. Mean time to (first) overstep of LH castration level after achieving castration
13. Changes from baseline in PD and PK parameters over time
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14. Number of participants with a PSA response of ≥50% reduction at the Day 168 visit
15. Number of participants with PSA response of ≥80% reduction at the Day 168 visit
16. Percent change from baseline in serum PSA concentration at each visit
17. Mean serum PSA concentration at each visit
18. Mean serum LH concentration at each visit
19. Mean serum T concentration at each visit
20. Mean serum FSH concentration at each visit
The secondary efficacy parameters will be analysed in an exploratory manner using 
descriptive statistics.
Secondary efficacy variables will be summarised by number of available values, minimum, 
Quartiles 1 and 3e, median, mean, SD, maximum, and 95% CI for the mean if appropriate. 
Categorical data will be presented by frequency and percentage.
These parameters are according to the secondary endpoints:

Percentage of participants who have T concentrations <0.2 ng/mL at the end of 
Stage 1 (Day 28)

Percentage of participants who have T concentrations <0.5 ng/mL and < 0.2 ng/mL at 
all scheduled visits

Percentage of participants who have LH concentrations <1.1 U/L at all scheduled 
visits

Time to T levels falling below castration level (<0.5 ng/mL) for the first time

Time to first T concentration ≥0.5 ng/mL after castration has been achieved

Time to LH levels falling below castration level (<1.1 U/L) for the first time

Time to first LH concentration ≥1.1 U/L after castration has been achieved

PD (LH, FSH, PSA, T) and PK (teverelix TFA concentrations) parameters over time 
(see Sections 6.4 and 6.5) and their changes from baseline

Serum PSA concentration at each visit including absolute and relative change from 
baseline

Number of participants with a PSA response of ≥50% reduction at the Day 168 visit 
compared to baseline

Number of participants with a PSA response of ≥90% reduction at the Day 168 visit 
compared to baseline

Serum LH concentration at each visit

Serum FSH concentration at each visit
PK/PD parameters will be analysed by measuring actual times for each concentration. 
Descriptive statistics will be based on the scheduled times. The participants’ concentration-
time curves will be presented graphically per parameter.
Further details regarding PK/PD analyses, including scale transformations, parameter 
formulas and determination of terminal rate will be detailed in the SAP.
8.1.5
Analysis of Safety Data
Safety Endpoints
1. Number of participants with treatment-emergent AEs (defined as any AE occurring or 
worsening following treatment), summarised by system organ class (SOC) and 
preferred term (PT)
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Note: Occurrence of ISRs will be included.
2. Mean changes in vital signs, triplicate 12-lead ECGs and laboratory data parameters at 
each visit during the 168-day treatment period, compared to baseline
3. Continuous 24 hour 12-lead Holter ECG (subset of 30 Group 2 subjects only)
4. Percentage of participants with ISRs at each visit during the 168-day treatment period
Note: Photography of injections sites with visible injection site reactions will be 
performed at each visit, and ISRs will be scored based on a specific scoring matrix
The treatment-emergent AEs (defined as any AE occurring or worsening with the same date 
or later than that of the first application of study treatment) will be coded using the most 
recent version of the Medical Dictionary for Regulatory Activities (MedDRA) available at the 
study start date. This version will be used throughout the entire study. Updates to MedDRA 
will not be applied afterwards. Frequency tables for the preferred terms will be compiled 
based on participants experiencing an AE and on the number of AEs. These frequency tables 
will take the SOC into consideration.
All reported AEs will be listed and ISRs will be summarised.
The vital sign, triplicate 12-lead ECG, and laboratory data parameters will be presented using 
descriptive statistics and shift-tables with respect to normal ranges for each visit including 
changes from baseline.
Concomitant diseases and medical history will also be coded using MedDRA. These data will 
be presented using frequency tables by SOC and PT.
Previous medication and concomitant medication will be coded using the Anatomical 
Therapeutic Chemical Classification (ATC) dictionary. Frequency tables will be compiled 
based on the coding for the medication.
8.1.6
Missing Data
Missing efficacy data will not be replaced in general.
If a laboratory reports concentrations as unquantifiable (too low), the value will be set to 0. 
Values for samples that are not technically evaluable will be set to missing.
In case a start date for an AE is missing or incomplete, so that it is not possible to evaluate if 
it has occurred pre- or post-treatment, this AE will be classified conservatively as 
treatment-emergent. More information on missing data imputation will be described in the 
SAP.
8.1.7
Multicentre Study
This study will be performed as a multicentre study. Count and proportion of participants 
achieving castration level within the first 28 days, and participants maintaining castration over 
the 168-day treatment period will be stratified by site. No other risks are expected.
8.1.8
Participant Data Listings
All recorded data will be presented in-participant data listings.
8.1.9
Deviations from the Planned Statistical Analysis
Any deviations from the planned statistical analysis have to be discussed in the final study 
report and should be defined in the SAP.
Any deviations from the original SAP should be described and justified in the final study 
report.
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8.1.10 Interim Analysis
After completion of Stage 1, i.e. after all participants have completed the visit at Day 28 and 
their T concentration levels are available, an analysis of the primary efficacy parameter will 
be performed analysing the number and proportion of participants reaching castration level by 
Day 28 with the loading dose of teverelix TFA.
The study will proceed during the analysis and all other efficacy, safety and demographic 
parameters will be evaluated at the end of the study (full analysis, Stage 2).
8.1.11 Software used for Statistical Analysis
The SAS® software version 9.2 (SAS® Institute) or higher will be used for the statistical 
analysis and for the reporting of this study. PK/PD analyses will be performed with Phoenix® 
WinNonlin® Version 6.3 or higher (Certara L.P).
8.1.12 Determination of Sample Size
Initially, since no confirmatory analyses were planned, no sample size calculations were 
performed. A total of 24 participants was deemed sufficient for 1 treatment group to obtain at 
least 20 evaluable participants (Day 168 visit completed).
Subsequently the Sponsor undertook a formal sample size calculation so that the Group 2 data 
could be used to support the dose selection for future Phase 3 clinical trials.
A sample size of 60 has been chosen on clinical grounds. This number gives good power to 
detect a minimum proportion of 90% subjects achieving castration with central lab serum T 
<0.5 ng/mL or 1.73 nmol/L at Day 28 from the per protocol population. It is based on the null 
hypothesis that the true response rate is 74.5%, the average response rate in previous 
Teverelix trials not achieving 90% response rate. This is tested using a two-sided test with a 
5% alpha level against the alternative hypothesis that the response rate is 90%, the minimally 
clinically relevant response rate. Based on this, fifty participants give power of 80%. 
Assuming a dropout rate of 16%, sixty patients are recommended.
Sixty patients will ensure acceptable precision for justification for further analysis of this 
regimen in Phase 3. A true 90% response rate in this instance would give a confidence 
interval of (79,96) and if 10 subjects drop out, and interval of (78,97). A true 95% response 
rate with 60 participants would give a confidence interval of (86,99) and if 10 subjects drop 
out, an interval of (85,99).
8.2
Data Management
Data management will be performed using Oracle Clinical Version 3.3 or later running on 
2 Microsoft Windows NT servers. Details will be defined in the data management manual, 
which will be signed by the Sponsor and the Clinical Research Organisation (CRO) prior to 
start of the data entry.
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9
Data Handling and Data Quality Assurance
9.1
Data Management
Data will be captured using the eCRF provided by the designated CRO. The eCRF is 
specifically designed to meet the data recording requirements of the clinical study protocol. 
Only the investigator and his/her authorised staff who are trained appropriately on the eCRF 
system are allowed to fill in the eCRFs or to make corrections, and will have access to the 
data or may change data (however this access will be granted without the possibility to delete 
the original entries). After completion, each eCRF will be electronically signed and dated by 
the investigator. Central laboratory test results will be imported automatically into the eCRF.
The overall procedures for quality assurance of clinical study data are described in the 
respective standard operating procedures (SOPs) of the CRO. A document describing the 
functional specification will be prepared by the CRO in cooperation with the eCRF provider 
and will be approved by the Sponsor prior to the start of the study. This functional 
specification will describe in detail the structure and functionality of the eCRF. In addition, 
the CRO will prepare a data management plan to describe the procedures and processes of 
data collection and data coding.
Electronic validation of the data entered in the eCRFs will take place (e.g. check of ranges, 
consistency, and plausibility). All plausibility checks will be defined in the data validation 
plan to be approved by the Sponsor. Additionally, the eCRFs will be reviewed by qualified 
data management and medically qualified personnel for completeness, consistency, and 
plausibility. Any data anomalies will be communicated to the site(s) for 
clarification/resolution (data query). Procedures of data entry and correction will be tracked 
and appropriately documented in the audit trail of the eCRF.
9.2
Documentation
9.2.1
Pre-screening List and Participant Identification List
A screening log will be kept by the investigator, listing all participants screened for this study. 
Participants will be identified by initials and year of birth. The status of the participant, i.e. 
whether enrolled in this study or not, will be entered on the log.
All participants who have given informed consent to participate in the study – regardless of 
whether the participant has received any investigational product(s) or not – have to be entered 
on the participant identification list by the investigator, giving full name, initials, year of birth, 
and participant identification code. The participant identification list will be kept in the 
investigator's file.
9.2.2
Source Data and Participant Records
In this study, all collected data in the participant file are considered source data. All data 
reported in the eCRF must be supported by appropriately signed identified source documents.
9.2.3
Electronic Case Report Form
An appropriate eCRF in English will be developed by the CRO. An eCRF completion manual 
for the use of the electronic data capture system will be provided prior to the study start, and 
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investigators will be trained on how to enter all study-specific data into the eCRF. 
Investigators must enter the information required by the protocol into the eCRF and should 
complete the eCRF as soon as possible, but on the 3rd working day after a participant visit at 
the latest (or in case of on-site assessment results: within 3 working days after the on-site 
assessment). No questions must be left unanswered.
Note: All SAEs must be reported by the investigator immediately (within 24 hours) via the 
SAE form in the eCRF (see Section 6.3.7.4).
Monitors will review the eCRFs for completeness and accuracy, and instruct site personnel to 
make any required corrections or additions. The eCRFs are saved immediately after entering 
the data by the investigator. All eCRF data are stored in a central database at the eCRF 
provider while the study is ongoing and at the responsible CRO for final analysis after study 
completion.
After study completion, the study site will receive a CD/DVD with a compilation of the eCRF 
study data per site (electronic PDF files) for filing with its study documents. The Sponsor will 
receive electronic, bookmarked PDF files of individual eCRFs (including audit trail). The 
Sponsor will also receive a list of queries and SAE forms after database closure.
9.3
Direct Access to Source Data/Documents
Checking of eCRFs for completeness and clarity, and cross-checking with source documents 
will be required to monitor the progress of the study. The CRAs are entitled to compare eCRF 
entries with source data and to inform the investigator about errors and omissions. The 
investigator will provide direct access to source data/documents for the Sponsors designated 
representatives (CRAs and auditors) as well as IRB/IEC members and regulatory inspections.
Regulatory authorities and/or the Sponsor's Clinical Quality Assurance Group may also carry 
out such source data checks and/or on-site audit inspections. They will be carried out giving 
due consideration to data protection and medical confidentiality. The investigator is to give 
the CRO and the Sponsor whatever support is necessary.
9.4
Monitoring
Monitoring will be done in accordance with the stipulations of Chapter 5.18 of the ICH GCP 
Guideline by Insuvia UAB CRAs.
During the course of the study, a CRA will make site visits to review protocol compliance, 
compare eCRFs and individual participants' medical records, assess drug accounting, and 
ensure that the study is being conducted according to pertinent regulatory requirements and 
the protocol. eCRF entries will be verified against source documentation in accordance with 
the applicable SOPs of the Sponsor/CRO. CRAs of the CRO will maintain confidentiality of 
the personal data of participants.
The investigator will allow the study monitor to make regular visits during the course of the 
study to:

Verify that written informed consent was obtained prior to each participant’s 
participation in the study

Discuss any emergent problem

Check the eCRFs for completeness and plausibility

Review accountability, correct storage, and handling of the IMP

Ensure that the study is being conducted according to pertinent regulatory 
requirements, ICH GCP E6(R2), and the protocol
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A close-out visit will be performed upon the conclusion of the study site’s participation in the 
study.
The Sponsor reserves the right to order special examinations of laboratory samples if there is 
any doubt concerning the validity of individual participant data or the accuracy of data 
generation at an investigational site.
9.5
Quality Assurance
Risk-based quality management will be implemented in this study based on the requirements 
of the Integrated Addendum of the Good Clinical Practice guideline ICH E6(R2). Aspects of 
risk-based quality management will be detailed in a risk management plan.
A member of the Sponsor’s (or designated CRO’s) quality assurance unit may conduct an 
audit at the study site to ensure compliance with the protocol, GCP, and the applicable 
regulatory requirements.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The investigator or his/her designee should notify the Sponsor immediately of any 
such inspection.
The investigator is expected to cooperate with such inspections and to discuss any findings 
with the auditor. The observations and findings of the auditor will be documented and the 
investigator will be informed of the audit outcome.
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10
Ethical, Legal and Administrative Aspects
The study will be carried out in conformity with the ethical principles enunciated in the 
Declaration of Helsinki. The current valid version according to applicable national regulatory 
and legal requirements will be considered.
The study will also be carried out in accordance with the Integrated Addendum of the ICH 
Guideline on Good Clinical Practice E6(R2), the Regulation EU No. 536/2014, which will 
replace the EU Clinical Trial Directive 2001/20/EC, the Commission Directive 2005/28/EC 
(April 8, 2005), and all local laws, regulatory requirements, and guidelines applicable in the 
participating countries.
By signing the Investigator’s Declaration, the investigator agrees to conduct the study as set 
out in this protocol and in accordance with the moral, ethical and scientific principles 
governing clinical research.
Signatures of Sponsor and CRO representatives can be found on the Signature Page.
10.1
Approval Procedures
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the appropriate Ethics Committee.
The relevant authorities, in accordance with local legal requirements will be notified/asked for 
approval of the intended study.
10.2
Protocol Amendments
After initiation of the study, any change in this protocol will require a formal amendment. The 
amendment must be signed by all of the signatories to the original protocol. Once the study 
has started, amendments will be made only in exceptional cases.
If ethically relevant aspects are concerned, the Ethics Committee(s) will be informed of 
amendments and approval will be sought.
All protocol amendments will be submitted to the regulatory authorities as regulated by 
national law.
Changes to the protocol may only be implemented after all appropriate requirements listed 
above (ethics, regulatory approval of all responsible personnel) have been fulfilled.
10.3
Informed Consent
Before participants can be admitted to the study, their informed consent will be obtained 
according to the regulatory and legal requirements. To this end, the investigator or an 
authorised designate will explain the nature, purpose, significance, and scope of the study, 
including its potential risks, to the participant. In addition to this oral information, the 
participant will receive for his/her own records the written participant information sheet 
summarising the relevant information. Sufficient time will be allowed to discuss any 
questions raised. Consent for participation can only be given after this information has been 
provided. The consent form must be personally signed and dated by the participant giving 
consent, and it must be retained by the investigator as part of the study records. A copy of the 
signed ICF will be handed out to the participant.
The investigator will not undertake any investigation required for the clinical study until 
informed consent has been obtained. The terms of the consent and the date when it was 
obtained should also be entered into the eCRF.
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After releasing an amendment to the protocol, the contents of which might influence the 
participant's decision for participation, the participant information sheet and the ICF must be 
amended accordingly. They must be submitted to the relevant Ethics Committee and the 
relevant authority as requested by local law. In addition, any relevant new information on the 
study medication that becomes available during the study will be passed on to the 
investigators and the participants. Depending on the nature of the amendment it might be 
necessary that participants already enrolled must confirm their informed consent on the basis 
of the new information.
10.4
Confidentiality and Data Protection
All relevant provisions of the European General Data Protection Regulation (GDPR [EU] 
2016/679, 27 April 2016) and all local legal requirements regarding protection of personal 
data will be adhered to.
The anonymity of study participants will be maintained. Participants’ names will not be 
supplied to the Sponsor or designated CRO. Participants will be identified on all eCRFs, 
image media (CDs or DVDs) and other documents by a specific participant identification 
(screening) number.
Documents which identify the participant (e.g. the signed informed consent) must be 
maintained in confidence by the investigator. The Sponsor, CRO, central laboratory, and 
off-site readers will only be given pseudonymised data, samples, or images.
The participants will be informed about all media used in this study for documentation, 
storing, and transferring the participants’ study findings and will be assured that all data will 
be handled in the strictest confidence.
This study protocol, any other unpublished documentation (e.g. eCRF), any information 
provided to the investigator regarding the IMP (e.g. investigator’s brochure), and any results 
derived from the study will be regarded as confidential. The investigators and members of 
their research teams will not be allowed to disclose such information without prior written 
approval from the Sponsor.
10.5
Liability, Insurance and Finances
The Sponsor has taken out appropriate 3rd-party liability insurance cover in accordance with 
all local legal requirements in the respective country in which the study is performed. It 
covers the eventuality that personal injury may be caused by using the IMP or by any study-
specific procedure carried out according to this protocol.
The general insurance conditions will be kept in the investigator's file and will be made 
available for participants at any time.
The financial agreements for each site (e.g. clinical study agreement) are addressed in 1 or 
more documents. The parties must sign the agreement before each site is initiated. All the 
investigators, and other relevant site staff participating in this study must complete a financial 
disclosure form.
10.6
Clinical Study Report, Publication and Use of Study Findings
An integrated study report according to the standards of the ICH E3 guideline, covering 
clinical and biometrical aspects, will be prepared by the Sponsor or its designee within 1 year 
of the end of the study (last protocol-defined contact with any enrolled participant). The report 
will be reviewed and approved by the coordinating investigator.
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A publication policy will be prospectively defined before the start of the study. Any results 
derived from this study may be published in a scientific journal or presented at a scientific 
meeting with the Sponsor's consent. The Sponsor will be provided with a copy of the 
manuscript for review and approval prior to any such submission.
The Sponsor will make the results of this study publicly available on the internet at 
www.clinicaltrials.gov and in the European Union Drug Regulating Authorities Clinical 
Trials (EudraCT) database. Upon completion of the study and when the study results are 
available, the participant has the right to be informed by the investigator about the overall 
study results.
10.7
Archiving of Study Records
Essential documents as listed in ICH GCP E6(R2), Chapter 8, shall be archived safely and 
securely in such a way that they are readily available upon authorities’ request.
Copies of the protocol, participant information sheet/ICF, participant identification list, 
printout of eCRF (or a CD with the eCRF), the participant record with all original data and all 
other documents pertaining to this study will be retained for a minimum of 25 years after the 
completion and approval of the integrated study report or for a period that is in accordance 
with national regulatory requirements, whichever is longest.
The Sponsor will inform the investigator when the prescribed period for archiving study 
documents has elapsed and the investigator no longer needs to retain the records relating to 
the study. The investigator site file is not to be destroyed without the Sponsor’s approval.
The final integrated study report must be retained by the Sponsor for 5 years beyond the 
lifetime of the IMP.
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11
List of References
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https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/
annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed 03 
September 2020.
2. Cancer Stat Facts: Prostate Cancer. National Cancer Institute. Available at:
https://seer.cancer.gov/statfacts/html/prost.html. Accessed 03 September 2020.
3. Weiner AB, Matulewicz RS, Eggener SE, Schaeffer EM. Increasing incidence of 
metastatic prostate cancer in the United States (2004–2013). Prostate Cancer Prostatic 
Dis. 2016;19(4):395–7. Available at: https://www.nature.com/articles/pcan201630. 
Accessed 03 September 2020.
4. Fowler JE, Sanders J, Bigler SA, Rigdon J, Kilambi NK, Land SA. Percent free 
prostate specific antigen and cancer detection in black and white men with total 
prostate specific antigen 2.5 to 9.9 ng./mL. J Urol. 2000;163(5):1467
 
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5. Moul JW, Douglas TH, McCarthy WF, McLeod DG. Black race is an adverse 
prognostic factor for prostate cancer recurrence following radical prostatectomy in an 
equal access health care setting. J Urol. 1996;155(5):1667-73
6. Kittai AS, Blank J, Graff JN. Gonadotropin-Releasing Hormone Antagonists in 
Prostate Cancer. Oncology (Williston Park). 2018;32(12):599-602, 604-6
7. Firmagon. Parsippany, NJ. Ferring Pharmaceuticals, 2013 (package insert). Available 
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