Clinical trial NCT03201419
Conditions: Nocturia
Sponsor: Ferring Pharmaceuticals
Start date: 2017-07-27; Completion date: 2019-10-31
Enrollment: 302 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial was to investigate the efficacy, safety and tolerability of different oral doses of FE 201836, with desmopressin as a benchmark, during 12 weeks of treatment for nocturia due to nocturnal polyuria in adults

Detailed description:

Arms: arm 1: FE 201836 500 μg oral solution and placebo orally disintegrating tablet (ODT), administered once daily arm 2: FE 201836 350 μg oral solution and placebo ODT, administered once daily arm 3: FE 201836 250 μg oral solution and placebo ODT, administered once daily arm 4: FE 201836 150 μg oral solution and placebo ODT, administered once daily arm 5: FE 201836 100 μg oral solution and placebo ODT, administered once daily arm 6: FE 201836 50 μg oral solution and placebo ODT, administered once daily arm 7: Placebo oral solution and placebo ODT, administered once daily arm 8: Desmopressin 25 μg ODT and placebo oral solution, administered once daily (female subjects) arm 9: Desmopressin 50 μg ODT and placebo oral solution, administered once daily (male subjects)
Interventions: intervention 1: FE 201836 intervention 2: Desmopressin intervention 3: Placebo oral solution intervention 4: Placebo ODT
Intervention descriptions: intervention 1: Oral solution for daily intake intervention 2: Desmopressin Orally Disintegrating Tablet (ODT) intervention 3: Manufactured to mimic experimental drug intervention 4: Manufactured to mimic experimental drug

Protocol documents:
Prot_000.pdf: 
Protocol 
Title of trial: 
A Randomised, Double-blind, Placebo-controlled, Response-adaptive Dose- 
finding Trial Investigating the Efficacy, Safety and Tolerability of Oral Doses 
of FE 201836, with Desmopressin Orally Disintegrating Tablet as a 
Benchmark, During 12 Weeks of Treatment for Nocturia due to Nocturnal 
Polyuria in Adults 
NCT number: 
NCT03201419 
Sponsor trial code: 
000233  
Date:  
05 Jul 2018 


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FE 201836 
Trial Code: 000233 
Oral Solution  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
CLINICAL TRIAL PROTOCOL 
A Randomised, Double-blind, Placebo-controlled, Response-adaptive Dose-finding Trial 
Investigating the Efficacy, Safety and Tolerability of Oral Doses of FE 201836, with 
Desmopressin Orally Disintegrating Tablet as a Benchmark, During 12 Weeks of Treatment 
for Nocturia due to Nocturnal Polyuria in Adults 
000233 
DAWN 
EudraCT Number: 
2016-003851-31 
IND Number: 
129355 
Investigational Medicinal Product: 
FE 201836 
Indication: 
Nocturia due to Nocturnal Polyuria 
Phase: 
2 
Name and Address of Sponsor: 
Ferring Pharmaceuticals A/S 
Global Clinical R&D 
Kay Fiskers Plads 11 
2300 Copenhagen S, Denmark 
Tel: +45 8833 8834 
Version: 
5.0 (consolidated protocol; changes introduced with global 
amendments #01, #02, and #03 implemented) 
GCP Statement: 
This trial will be performed in compliance with GCP. 
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in 
any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or another company 
within the Ferring Group. 


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FE 201836 
Trial Code: 000233 
Oral Solution  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
SYNOPSIS 
TITLE OF TRIAL 
A Randomised, Double-blind, Placebo-controlled, Response-adaptive, Dose-finding Trial 
Investigating the Efficacy, Safety and Tolerability of Oral Doses of FE 201836, with Desmopressin 
Orally Disintegrating Tablet as a Benchmark, During 12 Weeks of Treatment for Nocturia due to 
Nocturnal Polyuria in Adults 
SIGNATORY INVESTIGATORS 
Department of Urology, 
UZ Gent.
 Gent, Belgium 
Consultant in Urology 
New York, 
, USA 
TRIAL SITES 
Approximately 70 sites in Europe and North America. 
PLANNED TRIAL PERIOD 
First subject first visit: Q3 2017 
Last subject last visit: Q3 2019 
CLINICAL PHASE 
Phase 2 
BACKGROUND AND SCIENTIFIC JUSTIFICATION FOR CONDUCTING THE TRIAL 
Nocturia is defined by the International Continence Society (ICS) as waking from sleep (during the 
night) at least once to urinate. This may occur when there is an excessive urine production during 
the night (nocturnal polyuria [NP]). The antidiuretic hormone arginine vasopressin (AVP) plays a 
key role in the control of urine production during the night. Desmopressin, a synthetic analogue of 
AVP developed by Ferring Pharmaceuticals, is approved and used for the treatment of nocturia due 
to NP in more than 80 countries, including Canada and European countries. However, 
desmopressin has not yet been approved for this indication in the USA.  
Low doses of desmopressin (25 µg for women and 50 µg for men) are approved to date in Canada, 
Australia and European countries under the trade name NOCDURNA (desmopressin Orally 
Disintegrating Tablet [ODT]). These gender specific minimum effective low doses are approved for 
use in all adult ages and are indicated for treatment of nocturia due to NP in adults, who awaken 
two or more times each night to void. The global cumulative patient exposure of NOCDURNA by 
end-2016 is 1,389 patient years based on a dose of 25 μg for women and 50 μg for men (women: 
779 patient years; men: 610 patient years). Analysis of the combined data from three trials of 
low-dose desmopressin ODT, comprising >1400 patients with nocturia, shows that desmopressin 
dose, patient age, baseline serum sodium levels, and kidney function according to estimated 


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glomerular filtration rate clearance were significant risk factors for hyponatraemia in both sexes. 
Ferring Pharmceuticals is currently developing FE 201836, another synthetic analogue of AVP and 
a potent and highly selective short-acting vasopressin-2 (V2)-receptor agonist with an antidiuretic 
action profile suitable for treating nocturia due to NP in adults. FE 201836 exerts its antidiuretic 
effect by increasing the water permeability of the luminal membrane of the renal cortical and 
medullary collecting ducts, and thereby reducing free water excretion. 
Hyponatraemia may develop over time if excessive drinking occurs during the period of 
antidiuretic drug effect. Therefore, the ideal V2-receptor agonist should provide an antidiuretic 
duration of action not exceeding 6-8 hours i.e., corresponding to the night-time sleep period when 
drinking does not occur or is limited to a minimum (to satisfy thirst). The oral half-life should be 
shorter than that of desmopressin and the key route of metabolism non-renal, since the clinical 
promise of a short-acting V2-receptor agonist is based on an improved safety profile without a 
prolonged duration of action leading to hyponatraemia. A shorter and more predictable duration of 
antidiuretic action would minimise the risk of hyponatraemia and may reduce the need for serum 
sodium monitoring. 
In the present clinical trial, 6 doses of FE 201836 (50-500 µg) will be evaluated for estimation of 
the dose-response curve, where the response is the change in the number of nocturnal voids. The 
choice of FE 201836 doses is based on the data regarding the antidiuretic effect of FE 201836 in 
healthy subjects and by the antidiuretic effects of desmopressin in healthy subjects and in patients 
with NP. 
In phase 1 trial 000195 in young healthy men and women oral doses of FE 201836 up to 4800 µg 
(i.e., 9.6 times higher than the suggested maximum dose in the present phase 2 trial) were 
administered and found to be safe and well tolerated. The exposure after intravenous infusion of 
0.5 µg FE 201836, comparable to the exposure after an oral dose of approximately 900 µg 
FE 201836, resulted in approximately 8 hours of antidiuretic effect.  
The present trial is powered for detecting differences in treatment effects between FE 201836 and 
placebo. Desmopressin is included as benchmark treatment. There is no prospectively planned 
power for conclusive inference with regards to differences between desmopressin and placebo (or 
FE 201836). 
In order to select trial subjects with nocturia primarily due to the underlying condition of NP driven 
with increased Free Water Clearance (FWC), who will benefit the most from treatment with an 
antidiuretic agent, a 1-week active run-in period followed by a 1-week washout period (referred to 
as the ‘enrichment period’) will be applied to ensure that drug-responders (defined as a reduction of 
nocturnal diuresis [mL/min]of 20% or more) are identified. The ≥20% decrease in the nocturnal 
diuresis rate has been established as a relevant marker of antidiurectic responsiveness in previous 
nocturia trials with an active run-in. The majority of fluid output occurs via the urine, 
approximately 1,500 mL/day, therefore there is no evidence in adult nocturia patients that the 


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relative change over the time in nocturnal diuresis rate (mL/min normalised to time in bed) should 
be adjusted for body weight and or/body surface area which are both assumed to be constant over a 
short period of just 1 week. An analysis of individual nocturia subject data found that reducing 
Nocturnal Urine Volume (NUV) and increasing the duration of antidiuretic action of a V2-receptor 
agonist (desmopressin) was a significant predictor for subsequent decrease from baseline in the 
number of nocturnal voids. 
The underlying pathophysiologic mechanism of NP can be driven by either increased FWC, which 
based on mode of action will be responsive to antidiuretic treatment, or by increased sodium 
clearance, which differs substantially in mode of action and is governed by Atrial Natriuretic 
Peptide (ANP) which again is directly and indirectly influenced by the Renin-Angiotensin-
Aldosterone System (RAAS).  
The aim of the active run-in is (after excluding all other medical causes of NP) to identify subjects 
with increased FWC which is responsive to V2-receptor agonism. In addition, safety will be 
assessed in this period with special emphasis on hyponatraemia. 
OBJECTIVES 
Primary Objective 
• 
To establish the dose-response of FE 201836 with respect to the number of nocturnal voids 
in subjects with nocturia due to NP. 
Secondary Objectives 
• 
To evaluate responder rates with regards to changes in number of nocturnal voids. 
• 
To psychometrically validate the Nocturia Impact Diary© (NI Diary). 
• 
To evaluate the patient benefit of FE 201836 based on the NI Diary data. 
• 
To evaluate the clinical benefit of FE 201836 based on reduction in nocturnal voiding. 
• 
To evaluate FE 201836 with respect to sleep benefit, i.e., duration of the First Undisturbed 
Sleep Period (FUSP) and sleep related Patient Reported Outcomes (PROs). 
• 
To evaluate the pharmacodynamic (PD) effect of FE 201836 with respect to nocturnal 
diuresis rate and NP. 
Safety Objective 
• 
To evaluate the safety profile of FE 201836. 
Exploratory Objectives 
• 
To explore the biomarker copeptin, an AVP surrogate, to identify low nocturnal vasopressin 
levels in plasma. 
• 
To explore the dose-response of FE 201836 with respect to total sleep time. 
• 
To explore the association between total sleep time and FUSP. 
• 
To explore the effect of FE 201836 with respect to Nocturnal Polyuria index (NPi). 


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• 
To benchmark the efficacy of FE 201836 in relation to desmopressin. 
ENDPOINTS 
Primary Endpoint 
• 
Change from baseline in number of nocturnal voids during 12 weeks of treatment. 
Secondary Endpoints 
• 
Change from baseline in number of nocturnal voids at Weeks 1, 4, 8 and 12. 
• 
Responder rate defined as 50% reduction in nocturnal voids from baseline at Weeks 1, 4, 8 
and 12 and during 12 weeks of treatment. 
• 
Change from baseline in NI Diary Total Score at Weeks 1, 4, 8 and 12 and during 12 weeks 
of treatment. 
• 
Percentage of nights during the treatment period with at most one nocturnal void. 
• 
Percentage of nights during the treatment period with complete response, i.e., with no 
nocturnal voids. 
• 
Change from baseline in NI Diary Overall Impact Score at Weeks 1, 4, 8 and 12 and during 
12 weeks of treatment. 
• 
Patient Global Impression of Improvement (PGI-I) urinary symptoms scores at Weeks 1, 4, 
8 and 12. 
• 
Change from baseline in Patient Global Impression of Severity (PGI-S) scores at Weeks 1, 
4, 8 and 12. 
• 
Change from baseline in Bother as measured by the Hsu 5-point Likert Bother scale at 
Weeks 1, 4, 8 and 12. 
• 
Change from baseline in Insomnia Severity Index (ISI) at Weeks 4, 8 and 12. 
• 
Change from baseline in FUSP at 1, 4, 8 and 12 weeks of treatment and during 12 weeks. 
• 
Change from baseline in nocturnal diuresis rate (hourly) profiles at Week 1 and Week 12. 
• 
Change from baseline in NUV at Week 1 and Week 12. 
Safety Endpoints 
• 
Incidence and severity of adverse events. 
• 
Incidence of hyponatraemia as measured by serum sodium level throughout the trial. 
• 
Change from baseline in mean 24-hour urine volume at Week 1 and Week 12. 
• 
Clinically significant changes in vital signs and laboratory values. 
Exploratory Endpoints 
• 
Responder rates defined as 33%, 60%, 70%, 80%, 90% and 100% reduction from baseline 
in number of nocturnal voids at Weeks 1, 4, 8 and 12. 
• 
Responder rates defined as 1, 2, and 3 voids reduction from baseline in number of nocturnal 
voids at Weeks 1, 4, 8 and 12. 


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• 
The correlation of copeptin levels to NPi at Visit 2. 
• 
Change from baseline in copeptin levels at Week 12. 
• 
Change from baseline in total sleep time per night at Weeks 1, 4, 8 and 12 and during 
12 weeks of treatment.  
• 
Correlation between change from baseline in total sleep time and FUSP at Weeks 1, 4, 8 
and 12. 
• 
Change from baseline in NPi at Week 1 and Week 12. 
METHODOLOGY 
This is a randomised, double-blind, placebo-controlled, response-adaptive, dose-finding trial 
investigating the efficacy, safety and tolerability of 6 different oral doses (50-500 µg) of 
FE 201836, with desmopressin as a benchmark, during 12 weeks of treatment for nocturia due to 
NP in adults. 
The trial will comprise 8 visits to the clinic and will consist of a 2-week screening/lifestyle changes 
period where no Investigational Medicinal Product (IMP) will be given, an enrichment period 
consisting of a 1-week single-blind (to subjects) active run-in period and a 1-week washout period, 
and a 12-week double-blind randomised treatment period for each subject. During the active run-in 
period the trial subjects will receive 500 µg FE 201836 and placebo to assess safety and establish 
that subjects who respond to treatment with FE 201836 are included in the trial (i.e., an enrichment 
design). 
The 12-week double-blind randomised treatment period of the trial will follow a response-adaptive 
Bayesian top-down design. Initially subjects will be randomised to: placebo, 500 µg FE 201836 or 
desmopressin (for benchmarking only). When approximately 125 subjects have been randomised to 
the trial, an interim analysis will be conducted to investigate the efficacy of 500 µg FE 201836. If 
500 µg FE 201836 is not sufficiently efficacious compared to placebo the trial will be stopped for 
futility. If 500 µg FE 201836 is efficacious additional doses of FE 201836 (doses 50-350 µg) will 
be opened up for randomisation of new subjects in order to identify the Minimum Effective Dose 
(MED) and near maximal Effective Dose (ED85). The ED85 is the lowest dose that achieves at least 
85% of the effect of the maximum dose (500 µg). After the first interim analysis, subsequent 
interim analyses will take place every 8 weeks to reassess the randomisation allocation probabilities 
to 50-500 µg FE 201836, based on observed responses at the respective interim locks. 
After the first interim analysis eligible subjects will be randomised to one of 8 treatment groups 
(Table S-1). Each subject will be instructed to take the IMP every night at bedtime with the 
intention to sleep. In order to keep the treatment blinded each subject will receive two medications 
throughout the trial; an oral solution and an Orally Disintegrating Tablet (ODT), i.e., a double-
dummy design will be applied because desmopressin is available in an ODT formulation and 
FE 201836 is an oral solution. 
Subjects will be asked to follow lifestyle changes (e.g., limiting fluid intake) throughout the entire 


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duration of the trial. In addition, subjects will be asked to complete electronic diary (e-Diary) 
assessments  and Patient Reported Outcome (PRO) questionnaires before and after randomisation. 
One objective of the present trial is to further validate the NI Diary. Therefore, a sample of subjects 
(from trial sites in the USA) who have completed the trial will be invited to participate in an exit 
interview within 14 days of attending the end-of-trial visit (Visit 8), to record the subjects’ 
perception of what constitutes a meaningful change in the NI Diary Total Score. 
Safety, including serum sodium levels, adverse events and clinically significant changes in vital 
signs and laboratory values will be monitored throughout the trial and reviewed on an ongoing 
basis by a Safety Review Committee (SRC). 
Furthermore, the risk for subjects developing hyponatraemia will be mitigated by a serum sodium 
monitoring plan, including a 1-week active run-in period to identify subjects at increased risk for 
developing acute hyponatraemia prior to randomisation. If the incidence of serum sodium levels 
<130 mmol/L is statistically significantly >10% during the active run-in, the Data Monitoring 
Committee (DMC) will be notified and further action will be discussed, e.g., the DMC may 
recommend that the highest dose of FE 201836 may be replaced by a lower dose. The trial is 
designed so the dose may be lowered from 500 µg to 350 µg, if recommended by the DMC. 
NUMBER OF SUBJECTS 
A maximum of 300 subjects (males and females) will be randomised into the trial. At least 50% of 
subjects should be randomised at trial sites in the USA. 
CRITERIA FOR INCLUSION / EXCLUSION 
Inclusion Criteria 
Each subject must meet the following inclusion criteria between Visit 1 (screening) through Visit 4 
(randomisation): 
1. Written informed consent prior to performance of any trial-related activity 
2. Adults ≥18 years of age (at the time of written consent) 
3. Female subjects of child-bearing potential must be willing and able to use adequate 
contraception throughout the trial. Documentation of an acceptable effective method of 
contraception must be available. All pre- and perimenopausal subjects have to perform 
pregnancy tests. Amenorrhea of more than 12 months duration based on the reported date of the 
last menstrual period is sufficient documentation of post-menopausal status and does not require 
a pregnancy test 
4. Medical history of, or subject reported nocturia symptoms during the 6 months prior to Visit 1 
5. ≥2 nocturnal voids (an average over 3 days) as documented in the 3-day e-Diary prior to Visit 2 
6. The largest single voided volume must be ≥200 mL (at least 1 void ≥200 mL) as documented in 
the 3-day e-Diary prior to Visit 2 


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7. Nocturnal polyuria, defined as NPi >33%, a ratio of NUV in excess of 33% of total daily (24-
hour) urine volume as documented in the 3-day e-Diary prior to Visit 2 
8. b 
9. ≥20% decrease in the nocturnal diuresis rate (mL/min) (that was recorded at Visit 2) as 
documented in the 3-day e-Diary prior to Visit 3 
10. Additionally to be randomised into the trial at Visit 4 subjects must have ≥2 nocturnal voids (an 
average over 3 days) as documented in the 3-day e-Diary prior to Visit 4 
Exclusion Criteria 
Any subject meeting one or more of the following exclusion criteria between Visit 1 (screening) 
through Visit 4 (randomisation) will be considered as a screening failure: 
1. Current diagnosis of Obstructive Sleep Apnoea (OSA) 
2. Restless Legs Syndrome (RLS) 
3. Suspicion of Bladder Outlet Obstruction (BOO) or urine flow <5 mL/s, as confirmed by 
uroflowmetry during screening prior to Visit 2  
4. Urinary incontinence defined as an average of >1 episode/day in the 3-day e-Diary prior to 
Visit 2 (occasional urge incontinence during daytime or at night on the way to void is not 
necessarily exclusionary)  
5. c 
6. Any pelvic or lower urinary tract surgery and/or radio therapy or previous pelvic irradiation 
within the past 6 months prior to Visit 1. Including e.g., transurethral resection for BOO or 
Benign Prostatic Hyperplasia (BPH), hysterectomy or female incontinence procedures 
7. Genito-urinary tract pathology that can in the investigator’s opinion be responsible for urgency 
or urinary incontinence e.g., symptomatic or recurrent urinary tract infections, interstitial 
cystitis, bladder-related pain, chronic pelvic pain syndrome, or stone in the bladder or urethra 
causing symptoms 
8. A history of cancer with the last date of disease activity/prescence of malignancy within the last 
12 months prior to Visit 1, except for adequately treated basal cell carcinoma of the skin 
9. History of any neurological disease affecting bladder function or muscle strength (e.g., Multiple 
Sclerosis, Parkinson’s, spinal cord injury, spina bifida) 
10. Habitual (fluid intake >3L per day) or psychogenic polydipsia 
11. Uncontrolled hypertension, as judged by the investigator 
                                              
b Original inclusion criterion omitted as per Clinical Trial Protocol Amendment 02 (applicable for all trial sites). 
c Original exclusion criterion omitted as per Clinical Trial Protocol Amendment 03 (applicable for all trial sites). 


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12. a 
13. Uncontrolled diabetes mellitus, as judged by the investigator 
14. Central or nephrogenic diabetes insipidus 
15. Known history of Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion 
16. History of gastric retention 
17. Suspicion or evidence of congestive heart failure, (New York Heart Association [NYHA] class 
II, III, IV) 
18. Hyponatraemia: 
• 
Serum sodium level <135 mmol/L at Visit 1(re-tested, with results available within 7 days) 
• 
Serum sodium level <130 mmol/L at Visit 3 (re-tested, with results available within 7 days) 
19. Hepatic and/or biliary diseases:  
• 
Child-Pugh Class A, B, or C 
or 
• 
Aspartate aminotransferase and/or alanine aminotransferase levels >3x the upper limit of 
normal range as well as total bilirubin level >2x the upper limit of normal range 
20. Known history of hypersensitivity to desmopressin ODT 
21. Pregnancy, breastfeeding, or a planning to become pregnant during the period of the trial  
22. Known alcohol or substance abuse 
23. Work or lifestyle that may interfere with regular night-time sleep e.g., shift workers 
24. Any other medical condition, laboratory abnormality, psychiatric condition, mental incapacity, 
or language barrier that, in the judgment of the investigator, would impair participation in the 
trial 
25. d 
26. Previous participation in a nocturia, Benign Prostatic Obstruction (BPO), or OAB clinical trial 
within the past 6 months prior to Visit 1 
27. The subject is in a state of dependence of the sponsor, or is directly or indirectly involved in the 
conduct of this trial as an investigator, sub-investigator, trial coordinator or other trial staff 
member, or the subject is a first degree family member, significant other or relative residing 
with one of the above persons involved directly or indirectly with the trial 
                                              
a Original exclusion criterion omitted as per Clinical Trial Protocol Amendment 01 (applicable for all trial sites). 
d Original exclusion criterion omitted as per Clinical Trial Protocol Amendment 03 (applicable for all trial sites). 


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28. Use of any restricted therapy not in accordance with the protocol 
29. Use of any prohibited therapy listed below: 
• 
Current or former (within 3 months prior to screening) treatment with any other IMP 
• 
Unstable electrostimulation or behavioural bladder training program less than 3 months 
prior to screening (stable electrostimulation or behavioural bladder training program started 
at least 3 months before screening are acceptable)  
• 
Thiazide diuretics 
• 
Antiarrhythmic agents 
• 
V2-receptor antagonists/agonists (e.g., vaptans/desmopressin, vasopressin) 
• 
Loperamide 
• 
Botulinum toxin (cosmetic non-urological use is acceptable) 
• 
Valproate 
INVESTIGATIONAL MEDICINAL PRODUCTS 
In order to maintain the treatment blinding each subject will receive 2 medications (a 
double-dummy design), an oral solution and an ODT formulation, during every treatment period of 
the trial, as outlined in Table S-1. 
Table S-1 Treatment During the Trial 
Treatment 
Investigational Medicinal Product 
 
Active Substance 
Placebo 
Active Run-in 
 
 
500 µg FE 201836 
500 µg FE 201836 oral solution 
Placebo ODT 
Washout 
 
 
- 
- 
- 
Randomised Trial Period 
 
 
Up to First Interim Analysis 
 
 
500 µg FE 201836 
500 µg FE 201836 oral solution  
Placebo ODT 
Desmopressin 
Desmopressin ODT (25µg for 
females and 50 µg for males) 
Placebo oral solution 
Placebo 
- 
Placebo oral solution and Placebo ODT 
After First Interim Analysis 
 
 
50 µg FE 201836  
50 µg FE 201836 oral solution  
Placebo ODT 
100 µg FE 201836 
100 µg FE 201836 oral solution 
Placebo ODT 
150 µg FE 201836  
150 µg FE 201836 oral solution  
Placebo ODT 
250 µg FE 201836 
250 µg FE 201836 oral solution  
Placebo ODT 
350 µg FE 201836  
350 µg FE 201836 oral solution  
Placebo ODT 
500 µg FE 201836  
500 µg FE 201836 oral solution  
Placebo ODT 
Desmopressin 
Desmopressin ODT (25µg for 
females and 50 µg for males) 
Placebo oral solution 
Placebo 
- 
Placebo oral solution and Placebo ODT 
 


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DURATION OF TREATMENT 
The duration of the trial is approximately 16 weeks. Subjects will be screened, enter a 2-week 
lifestyle changes period followed by a 1-week single-blind active run-in and 1-week washout prior 
to randomisation. Following randomisation, the first 125 subjects will be treated daily with placebo, 
500 µg FE 201836 or desmopressin (25 µg for females and 50 µg for males) for up to 12 weeks. 
When the first 125 subjects have been randomised an interim analysis will be conducted and a 
decision taken on whether to continue the trial as planned or stop the trial for futility. 
If the decision is to continue the trial as planned, subjects may be randomised to one of 8 treatment 
groups for 12 weeks: placebo, 50 µg FE 201836, 100 µg FE 201836, 150 µg FE 201836, 250 µg FE 
201836, 350 µg FE 201836, 500 µg FE 201836, or desmopressin (25 µg for females and 50 µg for 
males). 
STATISTICAL METHODS 
Primary Analysis Model used in the Response-adaptive Trial Design 
The primary analysis is based on a time-course hierarchical longitudinal model, i.e., 
𝑌𝑡,𝑖= 𝑒𝛾𝑡(𝜇𝑑,𝑖+ 𝛿𝑖) + 𝜀𝑡 
where Yt,i is the change from baseline in number of nocturnal voids at visit t for subject i, d is the 
dose, 𝑒𝛾𝑡 the fraction of the effect at Visit t (Week 1, Week 4 or Week 8) as compared to the Month 
3 visit (𝛾t=0 at Month 3), δi the random subject effect and εt the independent N(0, 𝜆𝑡
2) distributed 
error term. The dose-response for subject 𝑖, 𝜇𝑑,𝑖, is adjusted for the number of baseline voids (𝑥0,𝑖) 
and modelled using the sigmoidal E-max model, i.e., 
𝜇𝑑,𝑖= 𝛽𝑥0,𝑖+ 𝛼1 +
(𝛼2 −𝛼1) 𝑑𝛼4
𝑑𝛼4 + 𝛼3𝛼4
= 𝛽𝑥0,𝑖+ 𝜇𝑑  
Inference will be based on a Bayesian analysis using sufficiently non-informative priors on 
respective parameters. The trial will be considered successful if the maximum dose has a greater 
than 97.5% posterior probability of being better than placebo, i.e., if Pr(μMAX < μPlb) > 97.5%.  
Response-adaptive Decision Rules 
The double-blind treatment period is based on a response-adaptive Bayesian top-down design. 
After an initial 125 subjects have been randomised to placebo, 500 µg FE 201836 (the highest dose) 
or desmopressin in a 2:2:1 ratio an interim analysis will take place to stop for futility if the Pr (μMAX 
– μPlb < -0.3) <10%, where Pr (.) denotes posterior probability (under the assumed monotonic dose-
response relation, i.e. smaller doses will be less effective). 
If not stopped for futility, all treatment arms will be opened up for randomisation, subjects can be 
randomised to placebo, desmopressin or to any FE 201836 dose (50-500 µg) in a 2:1:7 ratio. When 
allocated to a FE 201836 dose (7/10), unrestricted randomisation will be used to allocate a subject 


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to a specific FE 201836 dose using an allocation probability that is the average of I(dose is MED) 
and I(dose is ED85), where I(target) is the probability that “dose is target” scaled by the squared 
standard error at that dose. The MED is the lowest dose that has at least a ∆=0.3 larger reduction in 
mean nocturnal voids as compared to placebo and the ED85 is the lowest dose that achieves at least 
85% of the effect of the maximum dose (500 µg).  
After the first interim analysis, subsequent interims will take place every 8 weeks where the 
randomisation allocation probabilities to FE 201836 doses are being updated. Futility stopping will 
remain to take place if Pr (μMAX – μPlb < -0.3) <5.  
Operating Characteristics  
Under the assumptions (based on previous desmopressin trials and feasibility) that: 
• 
Response fractions of 0.8142, 0.9328 and 0.9874 at Weeks 1, 4 and 8, respectively, as 
compared to the averaged dose-response at Week 12 
• 
Variance fractions of 0.8481, 0.8329 and 0.8900 at Weeks 1, 4 and 8, respectively, as 
compared to the averaged dose-response at Week 12 
• 
A constant drop-out rate of 15% during the randomised treatment period 
• 
A between to total variance (σ2) ratio of 0.90 and a true underlying σ of 0.95 
• 
During the initial 17 weeks the recruitment rate will increase linearly from 0 to 8.2 subjects 
per week 
• 
After 17 weeks, when all trial sites have been initiated, the recruitment rate is assumed to 
remain constant at 8.2 subjects per week 
and  
• 
Considering six dose-response scenarios for the mean change from baseline to a large extent 
is characterised by the response of the maximum dose (500 µg FE 201836)  
Given these assumptions the operating characteristics presented in Table S-2 apply: 
Table S-2 Operating Characterisitics 
Dose-Response 
Scenario 
Maximum 
response 
(𝛼2) 
ED50 
(𝛼3) 
Average 
Number of 
Subjects 
Futility 
Stopping at 
First Interim 
Total  
Futility 
stopping 
Power 
(Total  
Success) 
Null 
0 
0 µg 
200 
75.8% 
97.0% 
3.0% 
I 
-0.3 
150 µg 
277 
15.7% 
47.9% 
52.1% 
II 
-0.4 
200 µg 
288 
7.9% 
25.1% 
74.9% 
III 
-0.5 
200 µg 
296 
2.8% 
9.6% 
90.4% 
IV 
-0.5 
350 µg 
295 
3.4% 
15.4% 
84.6% 
V 
-0.6 
300 µg 
298 
1.4% 
2.7% 
97.3% 
 
For each dose-response scenario, 1,000 trials were simulated in order to estimate the operating 
characteristics presented in Table S-2. Assuming a maximum reduction versus placebo of 0.5 voids 


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the power (probability of success) reaches approximately 85 to 90%, while the probability of 
making a false positive conclusion is 3.0%. 
Randomisation if the Maximum Dose is Lowered 
The trial has been designed with the option to decrease the maximum dose of FE 201836 from 
500 µg to 350 µg if recommended by the DMC. If this decision is made, randomisation to the 
500 µg FE 201836 treatment group will be closed, the trial will continue with 350 µg FE 201836 as 
the highest dose for the active run-in and the highest dose of FE 201836 that any subject can be 
randomised to. In the case where subjects have already been randomised to 500 µg FE 201836 and 
have not completed the trial the DMC will recommend whether or not, these subjects may be 
permitted to remain on 500 µg FE 201836 treatment for the remainder of the trial. In case subjects 
randomised to treatment with 500 µg FE 201836 prematurely discontinue the trial due to DMC 
decision they may be replaced by subjects randomised to treatment with a lower dose of 
FE 201836. No other prematurely discontinued subjects will be replaced. 
If the decision to close randomisation to 500 µg FE 201836 occurs prior to the first interim analysis 
(when the first 125 subjects are randomised) the remaining subjects will be randomised to the 
following treatment groups: placebo, desmopressin (25 µg for females and 50 µg for males) or 
350 µg FE 201836. After the first interim analysis the dose-response adaptive randomisation will 
allocate subjects to the remaining open doses, i.e., one of 7 treatment groups: placebo, 50 µg FE 
201836, 100 µg FE 201836, 150 µg FE 201836, 250 µg FE 201836, 350 µg FE 201836, or 
desmopressin (25 µg for females and 50 µg for males). 
The dose-response model will be fitted across all doses, i.e., 0-500 µg, but inference will be made 
only on the doses that remain open to randomisation e.g., 0-350 µg. That is, the MED and ED85 
doses and the inferences with regards to proof-of-concept and futility are limited to the dose range 
(i.e, with a maximum dose of 350 µg FE 201836).  


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................. 2 
LIST OF TABLES ......................................................................................................................18 
LIST OF FIGURES.....................................................................................................................18 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................19 
1 
INTRODUCTION .............................................................................................................22 
1.1 
Background.............................................................................................................22 
1.2 
Scientific Justification for Conducting the Trial ............................................................24 
1.3 
Benefit / Risk Aspects...............................................................................................24 
2 
TRIAL OBJECTIVES AND ENDPOINTS ..........................................................................26 
2.1 
Objectives...............................................................................................................26 
2.2 
Endpoints ...............................................................................................................26 
3 
INVESTIGATIONAL PLAN..............................................................................................28 
3.1 
Overall Trial Design .................................................................................................28 
3.1.1 
Trial Design Diagrams...................................................................................28 
3.1.2 
Overall Design and Control Methods ...............................................................31 
3.1.3 
Trial Schedule ..............................................................................................32 
3.2 
Planned Number of Trial Sites and Subjects .................................................................32 
3.3 
Interim Analyses ......................................................................................................32 
3.4 
Safety Review and Data Monitoring Committees ..........................................................32 
3.5 
Discussion of Overall Trial Design and Choice of Control Groups ...................................33 
3.5.1 
Trial Design .................................................................................................33 
3.5.2 
Selection of Endpoints ...................................................................................34 
4 
SELECTION OF TRIAL POPULATION ...........................................................................36 
4.1 
Trial Population .......................................................................................................36 
4.1.1 
Inclusion Criteria ..........................................................................................36 
4.1.2 
Exclusion Criteria .........................................................................................37 
4.2 
Method of Assigning Subjects to Treatment Groups ......................................................39 
4.2.1 
Recruitment .................................................................................................39 
4.2.2 
Randomisation .............................................................................................40 
4.2.2.1 
Randomisation if Maximum Dose is Lowered .....................................40 
4.3 
Restrictions .............................................................................................................41 
4.3.1 
Prior and Concomitant Therapies ....................................................................41 
4.3.2 
Prohibited Therapy .......................................................................................42 
4.3.3 
Lifestyle Changes and Other Restrictions .........................................................43 
4.3.4 
Contraception...............................................................................................43 
4.4 
Withdrawal Criteria ..................................................................................................44 
5 
TREATMENTS.................................................................................................................45 
5.1 
Treatments Administered ..........................................................................................45 
5.2 
Characteristics and Source of Supply ..........................................................................46 
5.2.1 
Investigational Medicinal Products ..................................................................46 
5.3 
Packaging and Labelling ...........................................................................................46 
5.4 
Conditions for Storage and Use ..................................................................................46 
5.5 
Blinding/Unblinding.................................................................................................47 


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5.5.1 
Blinding ......................................................................................................47 
5.5.2 
Unblinding of Individual Subject Treatment......................................................47 
5.6 
Treatment Compliance ..............................................................................................48 
5.6.1 
Dispensing and Accountability........................................................................48 
5.6.2 
Assessment of Compliance.............................................................................48 
5.7 
Return and Destruction of Investigational Medicinal Products.........................................48 
6 
TRIAL PROCEDURES .....................................................................................................49 
6.1 
Trial Flow Chart ......................................................................................................49 
6.2 
Visit 1 Screening......................................................................................................51 
6.3 
Visit 2 Active Run-in Period ......................................................................................52 
6.4 
Visit 3 Washout Period .............................................................................................52 
6.5 
Visit 4 ....................................................................................................................53 
6.6 
Visit 5 to Visit 7 ......................................................................................................53 
6.7 
Visit 8 – End-of-Trial Visit ........................................................................................54 
6.8 
Unscheduled Visits...................................................................................................54 
7 
TRIAL ASSESSMENTS ....................................................................................................56 
7.1 
Assessments Related to Endpoints ..............................................................................56 
7.1.1 
e-Diary........................................................................................................56 
7.1.1.1 
3-Day Voiding Diary.......................................................................56 
7.1.1.2 
Nocturia Impact Diary .....................................................................58 
7.1.1.3 
Patient Reported Outcomes ..............................................................59 
7.1.1.3.1 
Patient Global Impression of Severity and Patient 
Global Impression of Disease Improvement ......................59 
7.1.1.3.2 
Insomnia Severity Index.................................................59 
7.1.1.3.3 
Bother .........................................................................60 
7.1.2 
Adverse Events ............................................................................................61 
7.1.3 
Clinical Laboratory Variables .........................................................................61 
7.1.3.1 
Serum Sodium................................................................................62 
7.1.3.2 
von Willebrand Factor and Factor VIII ...............................................63 
7.1.3.3 
Copeptin........................................................................................64 
7.1.4 
Vital Signs ...................................................................................................64 
7.1.5 
24-Hour Urine Volume and Nocturnal Urine Volume .........................................64 
7.2 
Other Assessments ...................................................................................................64 
7.2.1 
Demographics ..............................................................................................64 
7.2.2 
Medical History............................................................................................64 
7.2.3 
Concomitant Medication ................................................................................64 
7.2.4 
Body Weight and Height................................................................................64 
7.2.5 
Physical Examination ....................................................................................65 
7.2.6 
Pregnancy Test .............................................................................................65 
7.2.7 
Electrocardiogram.........................................................................................65 
7.3 
Handling of Biological Samples .................................................................................65 
8 
ADVERSE EVENTS..........................................................................................................66 
8.1 
Adverse Event Definition ..........................................................................................66 
8.2 
Collection and Recording of Adverse Events ................................................................66 
8.2.1 
Collection of Adverse Events..........................................................................66 
8.2.2 
Recording of Adverse Events..........................................................................66 


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8.3 
Adverse Events of Special Interest ..............................................................................69 
8.4 
Pregnancy and Pregnancy Outcome ............................................................................69 
8.5 
Serious Adverse Events.............................................................................................70 
8.5.1 
Serious Adverse Event Definition....................................................................70 
8.5.2 
Collection, Recording and Reporting of Serious Adverse Events ..........................71 
8.6 
Follow-up of Adverse Events and Serious Adverse Events .............................................72 
8.6.1 
Follow-up of Adverse Events with Onset during the Trial ...................................72 
8.6.2 
Collection of Serious Adverse Events with Onset after Last Visit in the Trial .........72 
9 
STATISTICAL METHODS ...............................................................................................73 
9.1 
Operating Characteristics ..........................................................................................73 
9.2 
Protocol Deviations ..................................................................................................75 
9.3 
Analysis Sets ...........................................................................................................76 
9.3.1 
Intention-to-Treat Analysis Set for the Enrichment (ITT-ENR) Period ..................76 
9.3.2 
Safety Analysis Set for the Enrichment Period...................................................76 
9.3.3 
Intention-to-Treat (ITT) Analysis Set for the Randomised Treatment Period ..........76 
9.3.4 
Full Analysis Set (FAS) .................................................................................76 
9.3.5 
Per Protocol (PP) Analysis Set ........................................................................76 
9.3.6 
Safety Analysis Set for the Randomised Treatment Period ..................................76 
9.4 
Subject Disposition ..................................................................................................76 
9.5 
Enrichment Period Assessments and Analysis Sets ........................................................77 
9.6 
Trial Population .......................................................................................................77 
9.6.1 
Medical History, Concomitant Medication and Other Safety Evaluations ..............77 
9.7 
Endpoint Assessments ..............................................................................................77 
9.7.1 
General Considerations ..................................................................................77 
9.7.2 
Primary Analysis ..........................................................................................78 
9.7.2.1 
Statistical Dose-Response Model ......................................................78 
9.7.2.2 
Overall Trial Outcome .....................................................................80 
9.7.2.3 
Dose-Response...............................................................................80 
9.7.2.4 
Sensitivity Analyses ........................................................................80 
9.7.2.5 
Descriptive Analysis .......................................................................80 
9.7.3 
Secondary and Explorative Analyses ...............................................................81 
9.7.3.1 
Therapeutic Window .......................................................................83 
9.8 
Explorative Benchmarking Analysis ...........................................................................83 
9.9 
Extent of Exposure and Treatment Compliance.............................................................83 
9.10 
Safety.....................................................................................................................83 
9.10.1 General Considerations ..................................................................................83 
9.10.2 Adverse Events ............................................................................................84 
9.10.3 Adverse Events of Special Interest: Hyponatraemia Episodes ..............................84 
9.10.3.1 Hyponatraemia during the Randomised Treatment Period .....................85 
9.10.4 Safety Laboratory Variables ...........................................................................85 
9.11 
Interim Analyses ......................................................................................................85 
9.11.1 Serum Sodium Monitoring during the Active Run-In Period................................86 
9.11.2 Interim Efficacy Analyses ..............................................................................87 
10 
DATA HANDLING ...........................................................................................................89 
10.1 
Source Data and Source Documents............................................................................89 
10.2 
Electronic Case Report Form .....................................................................................90 


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10.3 
Use of Patient Reported Outcomes..............................................................................90 
10.3.1 Validation of the Nocturia Impact Diary ...........................................................91 
10.3.1.1 Psychometric Validation ..................................................................91 
10.3.1.2 Validation through Exit Interviews ....................................................91 
10.4 
Data Management ....................................................................................................92 
10.5 
Provision of Additional Information............................................................................92 
11 
MONITORING PROCEDURES ........................................................................................93 
11.1 
Periodic Monitoring .................................................................................................93 
11.2 
Audit and Inspection.................................................................................................93 
11.3 
Confidentiality of Subject Data ..................................................................................94 
11.4 
Centralised Statistical Monitoring ...............................................................................94 
12 
CHANGES IN THE CONDUCT OF THE TRIAL ...............................................................95 
12.1 
Protocol Amendments...............................................................................................95 
12.2 
Deviations from the Protocol .....................................................................................95 
12.3 
Premature Trial Termination ......................................................................................95 
13 
REPORTING AND PUBLICATION ..................................................................................96 
13.1 
Clinical Trial Report.................................................................................................96 
13.2 
Confidentiality and Ownership of Trial Data ................................................................96 
13.3 
Publications and Public Disclosure .............................................................................96 
13.3.1 Publication Policy .........................................................................................96 
13.3.2 Public Disclosure Policy ................................................................................97 
14 
ETHICAL AND REGULATORY ASPECTS.......................................................................98 
14.1 
Independent Ethics Committee / Institutional Review Board / Research Ethics Board .........98 
14.2 
Regulatory Authorities Approval ................................................................................98 
14.3 
End-of-Trial and End-of-Trial Notification ..................................................................98 
14.4 
Ethical Conduct of the Trial .......................................................................................98 
14.5 
Subject Information and Consent ................................................................................98 
14.6 
Subject Participation Card .........................................................................................99 
14.7 
Compliance Reference Documents .............................................................................99 
15 
LIABILITIES AND INSURANCE .................................................................................... 100 
15.1 
ICH-GCP Responsibilities ....................................................................................... 100 
15.2 
Liabilities and Insurance ......................................................................................... 100 
16 
ARCHIVING .................................................................................................................. 101 
16.1 
Investigator File..................................................................................................... 101 
16.2 
Trial Master File .................................................................................................... 101 
17 
REFERENCES................................................................................................................ 102 
18 
APPENDICES................................................................................................................. 105 
Appendix 1 ...................................................................................................................... 105 
Appendix 2 ...................................................................................................................... 140 
 


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LIST OF TABLES 
Table 5-1 
Treatment during the Trial ..........................................................................................45 
Table 6-1 
Trial Flow Chart........................................................................................................50 
Table 7-1 
Timing of Voiding Diary Assessments..........................................................................57 
Table 7-2 
Example of Voiding Diary Completion When Visit Planned for Friday..............................57 
Table 7-3 
Safety Laboratory Variables........................................................................................61 
Table 8-1 
Serious Adverse Events during the Trial .......................................................................70 
Table 9-1 
Operating Characteristics............................................................................................75 
Table 9-2 
Quantities of Interest..................................................................................................79 
Table 9-3 
Overall Trial Criteria .................................................................................................80 
Table 9-4 
Analysis of Endpoints ................................................................................................82 
Table 9-5 
Tabulations of Adverse Events ....................................................................................84 
Table 9-6 
Definition of Hyponatraemic Episodes by Serum Sodium Range during the Randomised 
Treatment Period.......................................................................................................85 
Table 9-7 
Examples of Incidence Rates that are Statistically Significantly >10% ...............................86 
LIST OF FIGURES 
Figure 3-1 
Trial Overview..........................................................................................................28 
Figure 3-2 
e-Diary Assessments and Questionnaires to be Completed by the Subject Prior to
Randomisation ..........................................................................................................29 
Figure 3-3 
e-Diary Assessments and Questionnaires to be Completed by the Subject During the
Randomised Treatment Period.....................................................................................30 
Figure 9-1 
Dose-Response Scenarios ...........................................................................................73 
Figure 9-2 
Interim Analysis Decision Tree (2nd Interim Analysis and Onwards) ................................88 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
List of Abbreviations 
ADR 
Adverse Drug Reaction 
ANCOVA 
Analysis of Covariance 
ANP 
Atrial Natriuretic Peptide 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUA 
American Urology Association 
BOO 
Bladder Outlet Obstruction 
BPO 
Benign Prostatic Obstruction 
BPH 
Benign Prostatic Hyperplasia 
CRO 
Contract Research Organisation 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
e-Diary 
Electronic Diary 
ED85 
The near (≥85%) maximal Effective Dose 
EU 
European Union 
FACTS 
Fixed and Adaptive Clinical Trial Simulator 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FWC 
Free Water Clearance 
FUSP 
First Undisturbed Sleep Period 
GCP 
Good Clinical Practice 
GEE 
Generalized Estimating Equation 
GMP 
Good Manufacturing Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ISI 
Insomnia Severity Index 
ITT 
Intention-to-Treat analysis set for the randomised treatment period 
ITT-ENR 
Intention-to-Treat analysis set for the enrichment period 


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IUD 
Intrauterine Device 
IUS 
Intrauterine System 
KM 
Kaplan-Meier 
LAM 
Lactational Amenorrhoea Method 
LUTS 
Lower Urinary Tract Symptoms 
MED  
Minimum Effective Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNAR 
Missing Not At Random 
NLM 
National Library of Medicine 
NP 
Nocturnal Polyuria 
NPi 
Nocturnal Polyuria index 
NYHA 
New York Heart Association 
NI Diary 
Nocturia Impact Diary© 
NUV 
Nocturnal Urine Volume 
OAB 
Overactive Bladder 
ODT 
Orally Disintegrating Tablet 
OSA 
Obstructive Sleep Apnoea 
PAP 
Psychometric Analysis Plan 
PD 
Pharmacodynamic 
PGI-I 
Patient Global Impression of Improvement 
PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PRO 
Patient Reported Outcome 
RAAS 
Renin-Angiotensin-Aldosterone System 
REB 
Research Ethics Board 
RLS 
Restless Legs Syndrome 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SIADH 
Syndrome of Inappropriate Antidiuretic Hormone 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
SSRI 
Selective Serotonin Reuptake Inhibitors 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 


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Definition of Terms 
Hyponatraemia 
Hyponatraemia is categorised by severity based on serum sodium 
concentrations: 
• 
Normal lower limit of serum sodium >135 mmol/L 
• 
Mild hyponatraemia: serum sodium 134-130 mmol/L 
• 
Moderate* hyponatraemia: serum sodium <130 mmol/L 
• 
Severe hyponatraemia: serum sodium <125 mmol/L 
* Moderate hyponatraemia is equivalent to the term ‘clinically significant 
hyponatraemia‘ (Verbalis, 2013) 
Nocturnal diuresis 
The nocturnal diuresis rate is calculated from the mean of 3 days 
Nocturnal Urine Volume (NUV) and total time in bed: 
𝑁𝑜𝑐𝑡𝑢𝑟𝑛𝑎𝑙 𝑑𝑖𝑢𝑟𝑒𝑠𝑖𝑠 𝑟𝑎𝑡𝑒 (𝑚𝐿/𝑚𝑖𝑛) =
NUV (mL)
Total Time in Bed (min) 
 
FUSP 
First Undisturbed Sleep Period (FUSP) is defined as the time in minutes 
from the time of going to bed to the time of first nocturnal void, or time of 
awakening if no void occurred. 
MED 
The lowest dose that has at least a ∆=0.3 larger reduction in mean 
nocturnal voids as compared to placebo. 
ED85 
The lowest dose that achieves at least 85% of the effect of the maximum 
dose. 
NPi 
Nocturnal Polyuria index (NPi) is calculated by dividing the nocturnal 
urine volume (NUV) by the 24-hour urine volume (van Kerrebroeck, 
2002; Gormley, 2014). 
In this clinical trial the NPi definition >33% is used for all ages to define 
presence of Nocturnal Polyuria (NP). 
NUV 
Nocturnal Urine Volume (NUV) is the total urine volume from 5 minutes 
after bedtime with the intention to sleep until the first void within 
30 minutes of rising (in the morning). 
Enrichment 
period 
The enrichment period consists of 1 week active run-in followed by 
1 week washout. The enrichment ensures that subjects respond to the drug 
(reduction in nocturna diureis by ≥20% from Visit 2 to Visit 3) and have a 
stable condition of ≥2 voids at Visit 2 and Visit 4. 


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1 
INTRODUCTION 
1.1 
Background 
Nocturia is defined by the International Continence Society (ICS) as waking from sleep (during the 
night) at least once to urinate. Nocturia is a symptom complex associated with several underlying 
medical and urological causes and pathologies (van Kerrebroeck, 2002; Wein, 2002). It is common 
in the elderly, occurring in up to 50% of men and women older than 75 years (Bosch, 2010). 
Nocturia is associated with a variety of clinical syndromes and disorders, which may result from 
(van Kerrebroeck, 2002): 
• 
Disorders that cause frequent low volume voids (e.g., Overactive Bladder [OAB], Bladder 
Outlet Obstruction [BOO], stiffer/less-compliant/functionally-smaller bladder associated 
with aging) 
or 
• 
frequent high volume voids (e.g., Nocturnal Polyuria [NP], global polyuria [diabetes 
insipidus or mellitus]) 
or 
• 
a combination of both, which is common. 
As described above, NP is a subset of nocturia defined as excessive volume of urine produced at 
night. The human body typically produces less urine while asleep. People with NP produce larger 
volumes of urine when asleep, causing them to awaken multiple times in the night to void. Thus, 
the diagnosis nocturia may be applied when there is an excessive urine production during the night. 
Nocturnal polyuria has been attributed to: 
• 
Abnormalities in diurnal variation in vasopressin secretion (a condition also coined as NP 
syndrome) (Asplund, 1991) 
• 
Abnormalities in the diuresis of solutes (e.g., urea, sodium, potassium) 
• 
Night time mobilisation of oedematous fluid in conditions such as congestive heart failure, 
nephrotic syndrome, or venous insufficiency 
However, as described above, patients often have more than one symptom presenting as nocturia 
(or NP); e.g., high volume of urine at night in combination with low volume bladder (perhaps 
associated with ageing) and BOO. 
Taken together, these facts make the clinical situation complicated since patients may have NP 
overlaid symptoms associated with frequent, low-volume voids, including OAB and Benign 
Prostatic Hyperplasia (BPH). 
The antidiuretic hormone arginine vasopressin (AVP) plays a key role in the control of urine 
production during the night. Desmopressin, a synthetic analogue of AVP developed by Ferring 
Pharmaceuticals, is approved and used for the treatment of nocturia due to NP in more than 


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80 countries, including Canada and European countries. However, desmopressin has not yet been 
approved for this indication in the USA. 
Low doses of desmopressin (25 µg for women and 50 µg for men) are approved to date in Canada, 
Australia and European countries under the trade name NOCDURNA (desmopressin Orally 
Disintegrating Tablet [ODT]). These gender specific minimum effective low doses are approved for 
use in all adult ages and are indicated for treatment of nocturia due to NP in adults, who awaken 
two or more times each night to void. The global cumulative patient exposure of NOCDURNA by 
end-2016 is 1,389 patient years based on a dose of 25 μg for women and 50 μg for men (women: 
779 patient years; men: 610 patient years). Analysis of the combined data from three trials of 
low-dose desmopressin ODT, comprising >1400 patients with nocturia, shows that desmopressin 
dose, patient age, baseline serum sodium levels, and kidney function according to estimated 
glomerular filtration rate clearance were significant risk factors for hyponatraemia in both sexes 
(Juul, 2016). 
Ferring Pharmaceuticals is currently developing FE 201836, another synthetic analogue of AVP 
and a potent and highly selective short-acting vasopressin-2 (V2)-receptor agonist with an 
antidiuretic action profile suitable for treating nocturia due to NP in adults. FE 201836 exerts its 
antidiuretic effect by increasing the water permeability of the luminal membrane of the renal 
cortical and medullary collecting ducts, and thereby reducing free water excretion. 
Hyponatraemia may develop over time if drinking occurs during the period of antidiuretic drug 
effect. Therefore, the ideal V2-receptor agonist should provide an antidiuretic duration of action not 
exceeding 6-8 hours i.e., corresponding to the night-time sleep period when drinking does not occur 
or is limited to a minimum (to satisfy thirst only). The oral half-life should be shorter than that of 
desmopressin and the key route of metabolism non-renal, since the clinical promise of a short-
acting V2-receptor agonist is based on an improved safety profile without a prolonged duration of 
action potentially leading to hyponatraemia. A shorter and more predictable duration of antidiuretic 
action would minimise the risk of hyponatraemia and may reduce the need for serum sodium 
monitoring. 
In the present clinical trial, 6 doses of FE 201836 (50-500 µg) will be evaluated for estimation of 
the dose-response curve, where the response is the change in the number of nocturnal voids. The 
selection of FE 201836 doses in the trial is based on data regarding the antidiuretic effect of 
FE 201836 in healthy subjects and by the antidiuretic effects of desmopressin in healthy subjects 
and in patients with NP. In a phase 1 trial (000195) in young healthy men and women, oral doses of 
FE 201836 of up to 4,800 µg were administered and found to be safe and well tolerated. The 
exposure after intravenous infusion of 0.5 µg FE 201836, comparable to the exposure after an oral 
dose of approximately 900 µg FE 201836, resulted in approximately 8 hours of antidiuretic effect. 
The present trial is powered for detecting differences in treatment effects between FE 201836 and 
placebo. Desmopressin is included as benchmark treatment. There is no prospectively planned 
power for conclusive inference with regards to differences between desmopressin and placebo (or 
FE 201836). 


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1.2 
Scientific Justification for Conducting the Trial 
Concern over hyponatraemia and the risk-benefit ratio has limited the use of desmopressin to 
younger patients and recently allowing treatment in elderly nocturia patients only under serum 
sodium monitoring. Renal impairment has also limited the use due to a risk of prolonging duration 
of action. FE 201836, a novel short-acting V2-receptor agonist, now under development, is 
designed to preserve potency at the V2-receptor at the same level as desmopressin, with a shorter 
half-life, increased selectivity, faster clearance and greater extra-renal clearance compared to 
desmopressin. 
The present phase 2 trial will establish the dose-response of FE 201836 with respect to the number 
of nocturnal voids in subjects with nocturia due to NP, allowing the development to proceed for a 
novel agonist at the V2-receptor for treatment of nocturia due to NP. 
1.3 
Benefit / Risk Aspects 
Benefits 
Subjects enrolled in the present trial will be closely monitored and they will have the same or more 
frequent visits to the hospital compared to routine treatment, depending on local practice. During 
these visits the subjects will be given instructions regarding lifestyle changes (including limiting 
fluid intake). For some subjects the implementation of lifestyle changes might be enough to reduce 
bothersome nocturia, defined as 2 or more nocturnal voids. 
Risks 
Treatment of nocturia due to NP with desmopressin implies a prolonged antidiuretic effect that may 
be associated with an increased risk of developing hyponatraemia, especially in elderly patients. 
FE 201836 is designed to preserve potency at the V2-receptor at the same level as desmopressin, 
with a shorter half-life, increased selectivity, faster clearance and greater extra-renal clearance 
compared to desmopressin. Based on the low degree of unchanged renal excretion of FE 201836, 
renal impairment is not expected to have any clinically relevant impact on the duration of the 
antidiuretic effect. 
An improved safety profile is expected to result from this combination of characteristics. The short 
half-life of FE 201836 (approximately 2 hours) and low degree of unchanged renal excretion 
(approximately 5%) are designed to limit the antidiuretic effect to the night-time sleep period, when 
subjects do not drink or their fluid intake is limited to a minimum (to satisfy thirst only). Therefore, 
the risk for dilutional hyponatraemia that may occur after the subject starts drinking in the morning 
is expected to be low. 
Subjects in the phase 1 clinical trial 000195 were dosed with up to 4800 µg (i.e., 9.6 times higher 
than the suggested maximum dose in the present phase 2 trial) orally without any subject being 
hyponatraemic. Pharmacokinetic/pharmacodynamic (PK/PD) modelling suggests that the duration 
of antidiuretic effect at 500 µg will be approximately 6 hours, limiting the potential for daytime 
antidiuresis.  


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In the present trial, the risk of subjects developing hyponatraemia will be mitigated by a serum 
sodium monitoring plan, as described in Section 7.1.3.1. The plan includes a 1-week active run-in 
period to identify subjects at increased risk for developing acute hyponatraemia prior to 
randomisation, as well as serum sodium sampling at Week 1, Week 4, Week 8 and Week 12, to 
identify any subject developing hyponatraemia while on treatment with Investigational Medicinal 
Product (IMP). Moreover, safety including the occurrence of adverse events and clinically 
significant changes in laboratory values (including serum sodium values) will be monitored 
throughout the trial. 


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2 
TRIAL OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
Primary Objective 
• 
To establish the dose-response of FE 201836 with respect to the number of nocturnal voids 
in subjects with nocturia due to NP. 
Secondary Objectives 
• 
To evaluate responder rates with regards to changes in number of nocturnal voids. 
• 
To psychometrically validate the Nocturia Impact Diary© (NI Diary). 
• 
To evaluate the patient benefit of FE 201836 based on the NI Diary data. 
• 
To evaluate the clinical benefit of FE 201836 based on reduction in nocturnal voiding. 
• 
To evaluate FE 201836 with respect to sleep benefit, i.e., duration of the First Undisturbed 
Sleep Period (FUSP) and sleep related Patient Reported Outcomes (PROs). 
• 
To evaluate the PD effect of FE 201836 with respect to nocturnal diuresis rate and NP. 
Safety Objective 
• 
To evaluate the safety profile of FE 201836. 
Exploratory Objectives 
• 
To explore the biomarker copeptin, an AVP surrogate, to identify low nocturnal vasopressin 
levels in plasma. 
• 
To explore the dose-response of FE 201836 with respect to total sleep time. 
• 
To explore the association between total sleep time and FUSP. 
• 
To explore the effect of FE 201836 with respect to Nocturnal Polyuria index (NPi). 
• 
To benchmark the efficacy of FE 201836 in relation to desmopressin. 
2.2 
Endpoints 
Primary Endpoint 
• 
Change from baseline in number of nocturnal voids during 12 weeks of treatment. 
Secondary Endpoints 
• 
Change from baseline in number of nocturnal voids at Weeks 1, 4, 8 and 12. 
• 
Responder rate defined as 50% reduction in nocturnal voids from baseline at Weeks 1, 4, 8 
and 12 during 12 weeks of treatment. 
• 
Change from baseline in NI Diary Total Score at Weeks 1, 4, 8 and 12 and during 12 weeks 
of treatment. 
• 
Percentage of nights during the treatment period with at most one nocturnal void. 
• 
Percentage of nights during the treatment period with complete response, i.e., with no 
nocturnal voids. 


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• 
Change from baseline in NI Diary Overall Impact Score at Weeks 1, 4, 8 and 12 and during 
12 weeks of treatment. 
• 
Patient Global Impression of Improvement (PGI-I) urinary symptoms scores at Weeks 1, 4, 
8 and 12. 
• 
Change from baseline in Patient Global Impression of Severity (PGI-S) scores at Weeks 1, 
4, 8 and 12. 
• 
Change from baseline in Bother as measured by the Hsu 5-point Likert Bother scale 
(Hsu, 2015) at Weeks 1, 4, 8 and 12. 
• 
Change from baseline in Insomnia Severity Index (ISI) at Weeks 4, 8 and 12. 
• 
Change from baseline in FUSP at 1, 4, 8 and 12 weeks of treatment and during 12 weeks. 
• 
Change from baseline in nocturnal diuresis rate (hourly) profiles at Week 1 and Week 12. 
• 
Change from baseline in Nocturnal Urine Volume (NUV) at Week 1 and Week 12. 
Safety Endpoints 
• 
Incidence and severity of adverse events. 
• 
Incidence of hyponatraemia as measured by serum sodium level throughout the trial. 
• 
Change from baseline in mean 24-hour urine volume at Week 1 and Week 12. 
• 
Clinically significant changes in vital signs and laboratory values. 
Exploratory Endpoints 
• 
Responder rates defined as 33%, 60%, 70%, 80%, 90% and 100% reduction from baseline 
in number of nocturnal voids at Weeks 1, 4, 8 and 12. 
• 
Responder rates defined as 1, 2, and 3 voids reduction from baseline in number of nocturnal 
voids at Weeks 1, 4, 8 and 12. 
• 
The correlation of copeptin levels to NPi at Visit 2. 
• 
Change from baseline in copeptin levels at Week 12. 
• 
Change from baseline in total sleep time per night at Weeks 1, 4, 8 and 12 and during 
12 weeks of treatment.  
• 
Correlation between change from baseline in total sleep time and FUSP at Weeks 1, 4, 8 
and 12. 
• 
Change from baseline in NPi at Week 1 and Week 12. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Trial Design 
3.1.1 
Trial Design Diagrams 
A trial overview is presented in Figure 3-1. Overviews of trial visits and electronic diary (e-Diary) 
assessments and questionnaires to be completed by the subjects before and after randomisation are 
presented in Figure 3-2 and Figure 3-3. 
 
a 
A sample of subjects (from trial sites in the USA) who have completed the trial will participate, by telephone, in an exit interview within 
14 days of attending Visit 8. 
Figure 3-1 Trial Overview 
 
Screening (1 Day)
Lifestyle Changes 
2 weeks
Visit 1
Active Run-in
1 week
Visit 2
Washout
1 week
Visit 3
Randomised 
Treatment
12 weeks
Visits
4-7
End-of-Trial
Exit Interviewa
Visit 8


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Figure 3-2 e-Diary Assessments and Questionnaires to be Completed by the Subject Prior to Randomisation 
 
 
V1
Reminder
Call
Diary Training 5 Days
Minimum 2 weeks Lifestyle Changes
Screening
7 Days Active Run-in
7 Days Washout
V: Visit
*R*: Randomisation
ISI: Insomnia Severity Index
PGI-S: Patient Global Impression of Disease Severity
IMP: Investigational Medicinal Product
NI Diary: Nocturia Impact Diary©
Bother: Hsu 5-point Likert Bother Scale
Enrichment Period
Void
Diary
V2
-3
Days
to V2
-2
Days
to V2
-1
Days
to V2
NI
Diary
NI
Diary
NI
Diary
IMP
IMP
ISI
IMP
-4
Days
to V2
PGI-S
V3
-3
Days
to V3
-2
Days
to V3
-1
Days
to V3
IMP
IMP
IMP
IMP
-4
Days
to V3
V4
-3
Days
to V4
-2
Days
to V4
-1
Days
to V4
Day 1
PGI-S
*R*
IMP
ISI
-4
Days
to V4
NI
Diary
NI
Diary
NI
Diary
Bother
Void
Diary
Void
Diary
Void
Diary
Void
Diary
Void
Diary
Void
Diary
Void
Diary
Void
Diary
Void
Diary
Void
Diary
Void
Diary
Void
Diary


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Figure 3-3 e-Diary Assessments and Questionnaires to be Completed by the Subject During the Randomised Treatment Period 
 


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3.1.2 
Overall Design and Control Methods 
This is a randomised, double-blind, placebo-controlled, response-adaptive, dose-finding trial 
investigating the efficacy, safety and tolerability of 6 different oral doses (50-500 µg) of 
FE 201836, with desmopressin as a benchmark, during 12 weeks of treatment for nocturia due to 
NP in adults. 
The trial will comprise 8 visits (Section 3.1.1) to the clinic and will consist of a 2-week 
screening/lifestyle changes period where no IMP will be given, an enrichment period consisting of 
a 1-week single-blind (to subjects) active run-in period and a 1-week washout period, and a 
12-week double-blind randomised treatment period for each subject (Figure 3-1). During the active 
run-in period the trial subjects will receive 500 µg FE 201836 and placebo to assess safety and 
establish that subjects who respond to treatment with FE 201836 are included in the trial (i.e., an 
enrichment design). 
The 12-week double-blind randomised treatment period of the trial will follow a response-adaptive 
Bayesian top-down design. Initially subjects will be randomised to: placebo, 500 µg FE 201836 or 
desmopressin (for benchmarking only). When approximately 125 subjects have been randomised to 
the trial, an interim analysis will be conducted to investigate the efficacy of 500 µg FE 201836. If 
500 µg FE 201836 is not sufficiently efficacious compared to placebo the trial will be stopped for 
futility. If 500 µg FE 201836 is efficacious additional doses of FE 201836 (doses 50-350 µg) will 
be opened up for randomisation of new subjects in order to identify the Minimum Effective Dose 
(MED) and near maximal Effective Dose (ED85). The ED85 is the lowest dose that achieves at least 
85% of the effect of the maximum dose (500 µg). After the first interim analysis, subsequent 
interim analyses will take place every 8 weeks to reassess the randomisation allocation probabilities 
to 50-500 µg FE 201836, based on observed responses at the respective interim locks. For more 
information regarding the interim analyses, please refer to Section 3.3 and Section 9.11.2. 
After the first interim analysis eligible subjects will be randomised to one of 8 treatment groups 
(Table 5-1). Each subject will be instructed to take the IMP every night at bedtime with the 
intention to sleep. In order to keep the treatment blinded each subject will receive two medications 
throughout the trial; an oral solution and an ODT, i.e., a double-dummy design will be applied 
because desmopressin is available in an ODT formulation and FE 201836 is an oral solution (Table 
5-1). 
Subjects will be asked to follow lifestyle changes (e.g., limiting fluid intake) throughout the entire 
duration of the trial. In addition, subjects will be asked to complete e-Diary assessments 
(Section 7.1.1) and PRO questionnaires (Section 7.1.1.3) before and after randomisation  
(Figure 3-2 and Figure 3-3). One objective of the present trial is to further validate the NI Diary. 
Therefore, a sample of subjects (from trial sites in the USA) who have completed the trial will be 
invited to participate in an exit interview within 14 days of attending the end-of-trial visit (Visit 8), 
to record the subjects’ perception of what constitutes a meaningful change in the NI Diary Total 
Score (Section 10.3.1). 


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Safety, including serum sodium levels (Section 7.1.3.1), adverse events and clinically significant 
changes in vital signs and laboratory values will be monitored throughout the trial and reviewed on 
an ongoing basis by a Safety Review Committee (SRC) (Section 3.4).  
Furthermore, the risk for subjects developing hyponatraemia will be mitigated by a serum sodium 
monitoring plan (Section 7.1.3.1), including a 1-week active run-in to identify subjects at increased 
risk for developing acute hyponatraemia prior to randomisation. If the incidence of serum sodium 
levels <130 mmol/L is statistically significantly >10% during the active run-in, the Data Monitoring 
Committee (DMC) established for the trial (Section 3.4) will be notified and further action will be 
discussed, e.g., the DMC may recommend that the highest dose of FE 201836 may be replaced by a 
lower dose. The trial is designed so the dose may be lowered from 500 µg to 350 µg if 
recommended by the DMC, as described in Section 9.11.1. 
3.1.3 
Trial Schedule 
The first trial visit (Visit 1, screening) for the first subject is expected in Q3 2017 and the last trial 
visit for the last subject is expected in Q3 2019. The total duration of the trial (for a subject) is 
expected to be approximately 18 weeks (including the exit interview). 
Trial completion is defined as when the last subject has completed the last visit in the randomised 
trial period (Visit 8). 
3.2 
Planned Number of Trial Sites and Subjects 
The trial will be conducted at approximately 70 sites in Europe and North America. A maximum of 
300 subjects will be included (Section 9.1). 
3.3 
Interim Analyses 
Interim analyses will be performed by an internal DMC established for the trial. 
The first interim analysis will be conducted after an initial 125 subjects have been randomised in a 
2:2:1 ratio to placebo, 500 µg FE 201836 or desmopressin. 
After the first 125 randomised subjects, the allocation ratio is 2:7:1 for placebo, active treatment 
and desmopressin, respectively. Subsequent interim analyses will be performed every 8 weeks, 
where the randomisation allocation probabilities to FE 201836 doses will be adjusted. 
The interim analyses are detailed in Section 9.11. 
3.4 
Safety Review and Data Monitoring Committees 
Trial data will be reviewed on an ongoing basis by the sponsor SRC. 
In addition, an internal DMC will be established for the trial. The main purpose of the DMC is to 
perform pre-planned interim analyses (Section 3.3) and make recommendations based on review of 
the efficacy and safety data. An additional purpose of the DMC is to address any potential safety 
concerns raised by the SRC. The responsibilities and the composition of the DMC are provided in a 
separate charter document. 


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3.5 
Discussion of Overall Trial Design and Choice of Control Groups 
3.5.1 
Trial Design 
The present clinical trial includes a 2-week period of lifestyle changes. Lifestyle changes (e.g., 
limiting fluid intake) are recommended as an initial treatment in most clinical guidelines, e.g., the 
updated American Urology Association (AUA) guideline on the management of BPH 
(McVary, 2011), despite the relative paucity of supporting data (Weiss, 2013). Excluding pelvic 
floor exercises for bladder-related Lower Urinary Tract Symptoms (LUTS), which are not part of 
the present trial, there seems to be no evidence that prolonged lifestyle changes, versus the 
proposed 2 weeks in the present trial, will result in additional benefit on NP related to excessive 
nocturnal fluid intake. From a practical point of view, the total of 4 weeks during the 
pre-randomisation period in the present trial is considered adequate for subject compliance. 
In order to select subjects with nocturia primarily due to the underlying condition of NP driven with 
increased Free Water Clearance (FWC), who will benefit the most from treatment with an 
antidiuretic agent, a 1-week active run-in period followed by a 1-week washout period will be 
applied to ensure that drug-responders (defined as subjects with a reduction of nocturnal diuresis 
rate [mL/min] of 20% or more) are identified. 
The ≥20% decrease in the nocturnal diuresis rate has been established as a relevant marker of 
antidiurectic responsivenes in previous nocturia trials with an active run-in (Lose, 2003; 
Mattiasson, 2002). The NUV is defined as the total urine volume from 5 minutes after bedtime with 
the intention to sleep until the first void within 30 minutes of rising in the morning. Total time in 
bed is a proxy for the time the subject is in nocturnal diuresis. The nocturnal diuresis rate is 
calculated from the mean of 3 days NUV and total time in bed: 
𝑁𝑜𝑐𝑡𝑢𝑟𝑛𝑎𝑙 𝑑𝑖𝑢𝑟𝑒𝑠𝑖𝑠 𝑟𝑎𝑡𝑒 (𝑚𝐿/𝑚𝑖𝑛) =
NUV (mL)
Total Time in Bed (min) 
The majority of fluid output occurs via the urine, approximately 1500 mL/day, therefore threre is 
no evidence in adult nocturia subjects that the relative change over the time in nocturnal diuresis 
rate (mL/min normalised to time in bed) should be adjusted for body weight and or/body surface 
area which are both assumed to be constant over a short period of 1 week only. An analysis of 
individual nocturia subject data found that reducing NUV and increasing the duration of 
antidiuretic action of a V2-receptor agonist (desmopressin) was a significant predictor for 
subsequent decrease from baseline in the number of nocturnal voids (Yamaguchi, 2013). 
The underlying pathophysiologic mechanism of NP can be driven by either increased FWC, which 
based on mode of action will be responsive to antidiuretic treatment, or by increased sodium 
clearance, which differs substantially in mode of action and is governed by Atrial Natriuretic 
Peptide (ANP) which is directly and indirectly influenced by the Renin-Angiotensin-Aldosterone 
System (RAAS).  
The aim of the active run-in is (after excluding all other medical causes of NP) to identify subjects 
with increased FWC, which is responsive to V2-receptor agonism. In addition, safety will be 
assessed in this period with special emphasis on hyponatraemia. 


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Treatment group allocation will be determined by central randomisation to eliminate selection bias 
and ensure that any difference in treatment groups at baseline is a result of random chance. 
Following randomisation at Visit 4, a double-blind design has been chosen to minimise both 
investigator and subject ascertainment bias. In order to keep the treatment blinded each subject will 
receive two medications throughout the trial; an oral solution and an ODT, i.e., a double-dummy 
design will be applied because desmopressin is available in an ODT formulation and FE 201836 is 
an oral solution. The blinding is further described in Section 5.5. 
Interim analyses will be conducted throughout the trial in order to investigate the efficacy of 
FE 201836 and to reassess the randomisation probabilities for each dose of FE 201836 based on 
observed responses at the respective interim locks. In addition, serum sodium will be monitored 
during the active run-in in order to identify subjects at increased risk of developing acute 
hyponatraemia. The interim analyses are further described in Section 3.3 and Section 9.11. 
3.5.2 
Selection of Endpoints 
The change in mean number of nocturnal voids has become a standard primary clinical trial 
endpoint in nocturia trials since the first overseas trials (with desmopressin) in early 2000 
(Lose, 2003; Mattiasson, 2002; van Kerrebroeck, 2007). It is therefore reasonable and appropriate 
to use reduction in number of nocturnal voids from baseline as the primary endpoint in this trial.  
Nocturia is one of the primary causes of sleep disturbance and has been shown to impair 
functioning, quality of life, health and productivity, with those experiencing 2 or more voids per 
night reporting significant bother (Ancoli-Israel, 2011). Awakening during the first 3-4 hours of the 
night during the deep and slow-wave restorative sleep is more likely to contribute to daytime 
fatigue (Chartier-Kastler, 2006). The clinically relevant benefit (for the subject) of desmopressin 
treatment may be demonstrated further by measuring the time to first awakening to void (FUSP), 
which reduces the time spent in slow wave (deep) sleep (Bliwise, 2015). Therefore it is reasonable 
to include FUSP as an endpoint in the present trial. To further evaluate the clinical benefit of 
FE 201836 endpoints relating to percentage of nights with at most one nocturnal void or with 
complete response are included for analysis. 
The significant impact of nocturia and its treatment on subjects’ quality of life and daily lives will 
be documented by the use of an e-Diary which contains a 3-day voiding diary, NI Diary and PRO 
questionnaires. Voiding diaries are standard tools used within the urology area 
(Holm-Larsen, 2009) and are among the best possible means of obtaining objective data on 
subjective symptoms (Abrams, 1983). A voiding diary therefore represents a self-monitoring daily 
record of the individual’s voiding behaviour. The ICS recommends inclusion of voiding diaries in 
clinical assessment of subjects with LUTS (Abrams, 2002). The subjects will be asked to complete 
voiding diaries over 3 consecutive 24-hour periods just prior to scheduled visits throughout the 
trial. Three-day voiding diaries have been shown to be as effective as 7-day diaries with the 
potential for better accuracy (Dmochowski, 2005). 
The NI Diary, is a 12-item PRO measure assessing the impact burden associated with nocturia 
(Holm-Larsen, 2014). The NI Diary has been developed and psychometrically evaluated in patients 
with nocturia, in line with published International Society for Quality of Life Research (ISOQOL) 


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and International Society for Pharmacoeconomic and Outcomes Research (ISPOR) guidance 
(Patrick, 2011; Reeve, 2013), as well as the Food and Drug Administration (FDA) Guidance for 
Industry, Patient-Reported Outcome Measures, 2009 (FDA, 2009). 
The PGI-S and PGI-I questionnaires, developed for use in populations with urinary tract conditions 
(Viktrup, 2012; Yalcin, 2003), are included to support anchor-based analysis of the NI Diary, as 
described in Section 10.3.1. 
To further assess the change in subjective bothersomeness of nocturia, trial participants will be 
asked, “How much has this frequency of night-time urination bothered you?” with response options 
including “not at all,” “slightly,” “moderately,” “quite a bit,” and “extremely.” This 5 point Likert 
scale has previously been used in a large epidemiological study (Hsu, 2015). 
The ISI is a PRO instrument to quantify the subject's perception of his/her insomnia severity, it is 
included as a measure of sleep quality. The ISI targets the subjective symptoms and consequences 
of insomnia as well as the degree of concern or distress caused by those difficulties (Bastien, 2001). 


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4 
SELECTION OF TRIAL POPULATION 
4.1 
Trial Population 
The trial population will be adult male and female subjects with nocturia due to NP, approximately 
50% of each gender, who fulfil the eligibility criteria listed below. 
4.1.1 
Inclusion Criteria 
Each subject must meet the following inclusion criteria between Visit 1 (screening) through Visit 4 
(randomisation): 
1. Written informed consent prior to performance of any trial-related activity 
2. Adults ≥18 years of age (at the time of written consent) 
3. Female subjects of child-bearing potential must be willing and able to use adequate 
contraception throughout the trial. Documentation of an acceptable effective method of 
contraception must be available. All pre- and perimenopausal subjects have to perform 
pregnancy tests. Amenorrhea of more than 12 months duration based on the reported date of the 
last menstrual period is sufficient documentation of post-menopausal status and does not require 
a pregnancy test 
4. Medical history of, or subject reported nocturia symptoms during the 6 months prior to Visit 1 
5. ≥2 nocturnal voids (an average over 3 days) as documented in the 3-day e-Diary prior to Visit 2 
6. The largest single voided volume must be ≥200 mL (at least 1 void ≥200 mL) as documented in 
the 3-day e-Diary prior to Visit 2 
7. Nocturnal polyuria, defined as NPi >33%, a ratio of NUV in excess of 33% of total daily 
(24-hour) urine volume as documented in the 3-day e-Diary prior to Visit 2 
8. b 
9. ≥20% decrease in the nocturnal diuresis rate (mL/min) (that was recorded at Visit 2) as 
documented in the 3-day e-Diary prior to Visit 3 
10. Additionally to be randomised into the trial at Visit 4 subjects must have ≥2 nocturnal voids (an 
average over 3 days) as documented in the 3-day e-Diary prior to Visit 4 
                                              
b Original inclusion criterion omitted as per Clinical Trial Protocol Amendment 02 (applicable for all trial sites). 


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4.1.2 
Exclusion Criteria 
Any subject meeting one or more of the following exclusion criteria between Visit 1 (screening) 
through Visit 4 (randomisation) will be considered as a screening failure: 
1. Current diagnosis of Obstructive Sleep Apnoea (OSA) 
2. Restless Legs Syndrome (RLS) 
3. Bladder Outlet Obstruction (BOO) or urine flow <5 mL/s, as confirmed by uroflowmetry upon 
suspicion during screening prior to Visit 2  
4. Urinary incontinence defined as an average of >1 episode/day in the 3-day e-Diary prior to 
Visit 2 (occasional urge incontinence during daytime or at night on the way to void is not 
necessarily exclusionary)  
5. c 
6. Any pelvic or lower urinary tract surgery and/or radio therapy or previous pelvic irradiation 
within the past 6 months prior to Visit 1. Including e.g., transurethral resection for BOO or 
BPH, hysterectomy or female incontinence procedures 
7. Genito-urinary tract pathology that can in the investigator’s opinion be responsible for urgency 
or urinary incontinence e.g., symptomatic or recurrent urinary tract infections, interstitial 
cystitis, bladder-related pain, chronic pelvic pain syndrome, or stone in the bladder or urethra 
causing symptoms 
8. A history of cancer with the last date of disease activity/prescence of malignancy within the last 
12 months prior to Visit 1, except for adequately treated basal cell carcinoma of the skin 
9. History of any neurological disease affecting bladder function or muscle strength (e.g., Multiple 
Sclerosis, Parkinson’s, spinal cord injury, spina bifida) 
10. Habitual (fluid intake >3L per day) or psychogenic polydipsia 
11. Uncontrolled hypertension, as judged by the investigator 
12. a 
13. Uncontrolled diabetes mellitus, as judged by the investigator 
14. Central or nephrogenic diabetes insipidus 
15. Known history of Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion 
16. History of gastric retention 
17. Suspicion or evidence of congestive heart failure, (New York Heart Association [NYHA] class 
II, III, IV) 
                                              
c Original exclusion criterion omitted as per Clinical Trial Protocol Amendment 03 (applicable for all trial sites). 
a Original exclusion criterion omitted as per Clinical Trial Protocol Amendment 01 (applicable for all trial sites). 


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18. Hyponatraemia: 
• 
Serum sodium level <135 mmol/L at Visit 1(re-tested, with results available within 7 days) 
• 
Serum sodium level <130 mmol/L at Visit 3 (re-tested, with results available within 7 days) 
19. Hepatic and/or biliary diseases:  
• 
Child-Pugh Class A, B, or C 
or 
• 
Aspartate aminotransferase and/or alanine aminotransferase levels >3x the upper limit of 
normal range as well as total bilirubin level >2x the upper limit of normal range 
20. Known history of hypersensitivity to desmopressin ODT 
21. Pregnancy, breastfeeding, or a planning to become pregnant during the period of the trial  
22. Known alcohol or substance abuse 
23. Work or lifestyle that may interfere with regular night-time sleep e.g., shift workers 
24. Any other medical condition, laboratory abnormality, psychiatric condition, mental incapacity, 
or language barrier that, in the judgment of the investigator, would impair participation in the 
trial 
25. d 
26. Previous participation in a nocturia, Benign Prostatic Obstruction (BPO), or OAB clinical trial 
within the past 6 months prior to Visit 1 
27. The subject is in a state of dependence of the sponsor, or is directly or indirectly involved in the 
conduct of this trial as an investigator, sub-investigator, trial coordinator or other trial staff 
member, or the subject is a first degree family member, significant other or relative residing 
with one of the above persons involved directly or indirectly with the trial 
28. Use of any restricted therapy not in accordance with the protocol 
29. Use of any prohibited therapy listed below: 
• 
Current or former (within 3 months prior to screening) treatment with any other IMP 
• 
Unstable electrostimulation or behavioural bladder training program less than 3 months 
prior to screening (stable electrostimulation or behavioural bladder training program started 
at least 3 months before screening are acceptable)  
• 
Thiazide diuretics 
• 
Antiarrhythmic agents 
• 
V2-receptor antagonists/agonists (e.g., vaptans/desmopressin, vasopressin) 
• 
Loperamide 
                                              
d Original exclusion criterion omitted as per Clinical Trial Protocol Amendment 03 (applicable for all trial sites). 


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• 
Botulinum toxin (cosmetic non-urological use is acceptable) 
• 
Valproate 
4.2 
Method of Assigning Subjects to Treatment Groups 
4.2.1 
Recruitment 
Subjects who have given written informed consent will receive a unique (site-specific) screening 
number and be invited to perform a screening visit (Visit 1). 
All screening assessments must be completed and evaluated to confirm that all eligibility criteria 
are met by the subject. A site-specific Screening Log, for recording of details of all subjects 
screened and confirmation of eligibility or recording of reasons for screening failure, as applicable, 
must be maintained at the trial site. The screening number, which will be allocated sequentially in 
the order in which the subjects are screened, must be entered into the Screening Log. 
It is permitted to re-screen a subject in this trial in case a subject has been considered a screening 
failure due to one or more of the following reasons: 
• 
not fulfilling the inclusion criterion number 6 as defined in Clinical Trial Protocol versions 
2.0 (>250 mL), 3.0 (>250 mL), or 4.0 (≥250 mL) but had at least 1 single voided volume 
≥200 mL prior to Visit 2 
• 
not fulfilling the inclusion criterion of an NI Diary Total Score of ≥10 points (raw score) 
prior to Visit 2 (inclusion criterion number 8) as defined in Clinical Trial Protocol versions 
2.0 and 3.0 
• 
fulfilling the exclusion criterion of a serum triglyceride level >400 mg/dL (exclusion 
criterion number 12) as defined in Clinical Trial Protocol version 2.0 
• 
fulfilling the exclusion criterion of aspartate aminotransferase and/or alanine 
aminotransferase levels >2x the upper limit of normal range and a total bilirubin level 
>1.5 mg/dL (second part of exclusion criterion number 19) as defined in Clinical Trial 
Protocol version 2.0 
• 
fulfilling exclusion criterion number 3 as defined in Clinical Trial Protocol versions 2.0, 3.0, 
and 4.0 
• 
fulfilling exclusion criterion number 5 as defined in Clinical Trial Protocol versions 2.0, 3.0, 
and 4.0 
• 
fulfilling exclusion criterion number 25 as defined in Clinical Trial Protocol versions 2.0, 
3.0, and 4.0 
• 
technical issues with the e-Diary device prior to Visit 2 
If a subject has failed screening due to any other reason the subject must not be re-screened for 
participation in the trial at a later time. 


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4.2.2 
Randomisation 
A computer-generated randomisation list will be prepared prior to enrolment of the first subject into 
the trial. The randomisation list will be adjusted during the course of the trial via a response-
adaptive randomisation procedure. At least 50% of subjects should be randomised at trial sites in 
the USA to allow for an optimised validation of the NI Diary. Therefore, a cap of maximum 
150 subjects will need to be set for countries other than the USA. 
Subject-specific randomisation numbers will be allocated in the order at which the subjects are 
being randomised into the trial. The subject randomisation number will be recorded in the 
Screening Log. It is not permitted for a subject to be randomised in the trial twice. 
The first 125 subjects will be randomised to treatment in a fixed manner. The allocation ratio is 
2:2:1 for placebo, 500 µg FE 201836 and desmopressin. At the first interim analysis, after 
125 subjects being randomised, the allocation ratio is 2:7:1 for placebo, active treatment and 
desmopressin, respectively. Subjects will be randomised to the active treatment groups of 
FE 201836 in a response-adaptive randomisation manner. A pre-defined algorithm will be used to 
determine the relative randomisation to each of the FE 201836 groups. Subsequent interim analyses 
will be conducted every 8 weeks to adjust the adaptive randomisation probabilities. The enrolment 
of subjects will continue without any stop at the interim analyses. For more information regarding 
the interim analyses, please refer to Section 3.3 and Section 9.11. 
The screening rate will be monitored such that the accrual of randomised subjects does not 
overshoot the operating characteristics described in Section 9.1, which could potentially result in a 
loss of statistical power. 
4.2.2.1 
Randomisation if Maximum Dose is Lowered 
The trial has been designed with the option to decrease the maximum dose of FE 201836 from 
500 µg to 350 µg if recommended by the DMC (Section 9.11.1). If this decision is made, 
randomisation to the 500 µg FE 201836 treatment group will be closed, the trial will continue with 
350 µg FE 201836 as the highest dose for the active run-in and the highest dose of FE 201836 that 
any subject can be randomised to. In case subjects have already been randomised to the 500 µg 
FE 201836 treatment group and have not completed the trial, the DMC will recommend whether or 
not these subjects may be permitted to remain on treatment with 500 µg FE 201836 for the 
remainder of the trial. Subjects randomised to treatment with 500 µg FE 201836 who prematurely 
discontinue the trial due to DMC decision (Section 4.4) may be replaced by subjects randomised to 
treatment with a lower dose of FE 201836. 
If the decision to close randomisation to 500 µg FE 201836 is taken prior to the first interim 
analysis, i.e., when the first 125 subjects have been randomised, the remaining subjects will be 
randomised to the following treatment groups: placebo, desmopressin (25 µg for females and 50 µg 
for males) or 350 µg FE 201836. After the first interim analysis the dose-response adaptive 
randomisation will allocate subjects to the remaining 7 open treatment groups: placebo, 50 µg 
FE 201836, 100 µg FE 201836, 150 µg FE 201836, 250 µg FE 201836, 350 µg FE 201836, or 
desmopressin (25 µg for females and 50 µg for males). 


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4.3 
Restrictions 
4.3.1 
Prior and Concomitant Therapies 
Details of all concomitant medications/therapies and the main reason for the prescription must be 
recorded in the medical source record and in the Electronic Case Report Form (eCRF) at screening 
(Visit 1). Any changes (including new therapies) must be recorded at each subsequent visit. 
Any therapy for treatment of nocturia or sleep disorders (e.g., guidance for lifestyle changes, pelvic 
floor muscle training, electrostimulation, biofeedback treatment) that a subject received before trial 
initiation should be continued without any change throughout the trial period. All subjects must 
have normal serum sodium (≥135 mmol/L) at screening and serum sodium levels will be monitored 
throughout the trial as described in Section 6.1 (Table 6-1) and Section 7.1.3.1. 
The following medications will be permitted, provided that the subject has been on a stable dose for 
the 3 months prior to the screening visit (Visit 1) (i.e., treatment has not been initiated or 
discontinued and there has been no change in dose): 
• 
Sedative/hypnotic medications for sleep disorders 
• 
Selective Serotonin Reuptake Inhibitors (SSRIs): citalopram, duloxetine, venlafaxine, 
escitalopram, paroxetine, fluoxetine, sertraline 
• 
Chronic use of Non-steroidal Anti-inflammatory Drugs (NSAIDs) 
• 
Chlorpromazine 
• 
Medicines used for treatment of BPH such as alpha-blockers (doxazosin, tamsulosin, 
terazosin and alfuzosin) and 5-alpha-reductase inhibitors (e.g., dutasteride and finasteride) 
and phosphodiesterase-5 inhibitors (e.g., tadalafil)  
• 
Medicines used for treatment of OAB such as antimuscarinic therapy (tolterodine, 
fesoterodine, oxybutynin, darifenacin, hyoscyamine, trospium, solifenacin) and beta-3 
adrenergic receptor agonists (mirabegron) 
• 
Sulfonylurea, including chlorpropamide 
• 
Loop diuretics (furosemide, torsemide, ethacrynic acid) and other classes of diuretics 
(triamterene, chlorthalidone, amiloride, indapamide) are permitted, either as monotherapy or 
combination therapy if the subject takes the loop diuretic prior to 4 pm (the timing of this 
treatment regimen must have been in place for at least 1 week prior to the screening visit 
[Visit 1]) 
• 
Systemic corticosteroids 
• 
Carbamazepine  
• 
Lithium  
• 
Opioids  
• 
Lamotrigine  
• 
Tricyclic antidepressants 


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Additional serum sodium monitoring should be performed as described in Section 7.1.3.1 if 
treatment with the following medications is initiated or dosing is increased during the trial: 
• 
SSRIs: citalopram, duloxetine, venlafaxine, escitalopram, paroxetine, fluoxetine, sertraline  
• 
Chronic use of NSAIDs  
• 
Chlorpromazine 
• 
Sulfonylurea, including chlorpropamide   
• 
Loop diuretics (furosemide, torsemide, ethacrynic acid) and other classes of diuretics 
(triamterene, chlorthalidone, amiloride, indapamide)  
• 
Systemic corticosteroids  
• 
Carbamazepine 
• 
Lithium 
• 
Opioids 
• 
Lamotrigine  
• 
Tricyclic antidepressants  
• 
Any other drug that increases the risk of hyponatraemia 
4.3.2 
Prohibited Therapy 
The following medications are prohibited throughout the duration of the trial (exclusion criterion 
number 29, Section 4.1.2): 
• 
Current or former (within 3 months prior to the screening visit [Visit 1]) treatment with any 
other IMP 
• 
Unstable electrostimulation or behavioural bladder training program less than 3 months 
prior to the screening visit (Visit 1) (stable electrostimulation or behavioural bladder 
training program started at least 3 months prior to the screening visit are acceptable)  
• 
Thiazide diuretics 
• 
Antiarrhythmic agents 
• 
V2-receptor antagonists/agonists 
• 
Loperamide 
• 
Botulinum toxin (non-urological use is acceptable) 
• 
Valporate 
Any new therapy for treatment of nocturia or sleep disorders must not be initiated throughout the 
duration of the trial. 


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4.3.3 
Lifestyle Changes and Other Restrictions 
In order to prevent hyponatraemia and to avoid interference with efficacy assessment of the 
treatment: 
• 
The fluid intake must be limited to a minimum (to satisfy thirst only) during the time 
interval of 1 hour before, until 8 hours after administration of IMP 
• 
The subject should empty the bladder before going to bed with the intention to sleep 
• 
The treatment should be interrupted during acute intercurrent illnesses characterised by fluid 
and/or electrolyte imbalance (such as systemic infections, fever, gastroenteritis) until the 
subject has fully recovered. The treatment can be re-started at the discretion of the 
investigator once the condition of the subject is stabilised 
Subjects will be reminded to follow instructions regarding lifestyle changes throughout the duration 
of the trial. 
Subjects participating in the present trial should refrain from donating blood or sperm throughout 
the trial period. 
4.3.4 
Contraception 
Female subjects of child-bearing potential must be willing and able to use an acceptable effective 
contraceptive method throughout the trial. Documentation of the method used must be available. A 
female subject is considered to be of child-bearing potential following menarche and until 
becoming post-menopauseal, unless permanently sterile. Post-menopausal is defined as amenorrhea 
of >12 months duration based on the reported date of the last menstrual period. 
In the context of this trial, acceptable effective methods include: 
• Transdermal patch 
• Established use of oral, injected or implanted hormonal methods of contraception 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository 
• Male sterilisation (with the appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate) 
• True abstinence: When this is in line with the preferred and usual lifestyle of the subject 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable 
methods of contraception. Female condom and male condom should not be used together. 
Contraceptive measures will not be required for male subjects participating in the trial based on 
genotoxicity data obtained in animal studies with FE 201836, as detailed in the Investigator’s 
Brochure. 


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4.4 
Withdrawal Criteria 
A subject must be withdrawn from the trial in case of: 
• 
Serum sodium level is ≤125 mmol/L at any time point during the trial 
• 
Significant non-compliance with the trial protocol, as judged by the investigator and/or the 
sponsor 
• 
Other medical or safety reasons, as judged by the investigator and/or the sponsor 
• 
The subject wishes to discontinue for any reason 
A subject has the right to withdraw from the trial at any time for any reason, without the need to 
justify his/her decision. However, the investigator should record the reason for the subject’s 
withdrawal, if possible. The investigator also has the right to withdraw a subject. Since an excessive 
rate of withdrawals can render the trial devoid of meaning, unnecessary withdrawal of subjects 
should be avoided. 
Every effort should be made to invite subjects withdrawn/discontinued from the trial to an end-of-
trial visit (Visit 8) as soon as possible after a decision of withdrawal/discontinuation has been taken. 
For any discontinuation, the investigator should obtain the required information and document the 
date and reason for the premature discontinuation in the eCRF. 
In case the subject has withdrawn consent, no new data can be recorded in the eCRF. Correction of 
previous data and/or recording data related to visits/procedures done prior to but made available 
after withdrawal of consent (e.g., laboratory results) will be allowed unless the subject disapproves 
it. 
If the reason for withdrawal is an adverse event, the specific event or the main laboratory 
abnormality must be recorded in the eCRF. The investigator should make thorough efforts to 
document the outcome. 
Subjects discontinued from the trial will not be replaced, except for subjects randomised to 
treatment with 500 µg FE 201836 in case a decision is taken to decrease the maximum dose of 
FE 201836 from 500 µg to 350 µg (Section 4.2.2.1). 


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5 
TREATMENTS 
5.1 
Treatments Administered 
In order to maintain the treatment blinding each subject will receive 2 medications (double-dummy 
design), an oral solution and an ODT formulation, during every treatment period of the trial, as 
outlined in Table 5-1. 
During the active run-in period all subjects will receive 500 µg FE 201836 oral solution (and 
placebo ODT) for 1 week. 
After the lifestyle changes/screening, active run-in and washout periods, eligible subjects will be 
randomised to a treatment group as follows: 
• Prior to the first interim analysis, the first 125 subjects will be randomised to the following 
treatment groups: placebo, desmopressin or 500 µg FE 201836. 
• After the first interim analysis, subjects may be randomised to one of 8 treatment groups: 
placebo, 50 µg FE 201836, 100 µg FE 201836, 150 µg FE 201836, 250 µg FE 201836, 
350 µg FE 201836, 500 µg FE 201836 or desmopressin (25 µg for females and 50 µg for 
males). 
After randomisation, the duration of treatment is 12 weeks. 
Table 5-1 
Treatment during the Trial 
Treatment 
Investigational Medicinal Product 
 
Active Substance 
Placebo 
Active Run-in 
 
 
500 µg FE 201836 
500 µg FE 201836 oral solution 
Placebo ODT 
Washout 
 
 
- 
- 
- 
Randomised Treatment Period 
 
 
Up to First Interim Analysis  
 
 
500 µg FE 201836 
500 µg FE 201836 oral solution  
Placebo ODT 
Desmopressin 
Desmopressin ODT (25µg for females 
and 50 µg for males) 
Placebo oral solution 
Placebo 
- 
Placebo oral solution and Placebo ODT 
After First Interim Analysis 
 
 
50 µg FE 201836  
50 µg FE 201836 oral solution  
Placebo ODT 
100 µg FE 201836 
100 µg FE 201836 oral solution 
Placebo ODT 
150 µg FE 201836  
150 µg FE 201836 oral solution  
Placebo ODT 
250 µg FE 201836 
250 µg FE 201836 oral solution  
Placebo ODT 
350 µg FE 201836  
350 µg FE 201836 oral solution  
Placebo ODT 
500 µg FE 201836  
500 µg FE 201836 oral solution  
Placebo ODT 
Desmopressin 
Desmopressin ODT (25µg for females 
and 50 µg for males) 
Placebo oral solution 
Placebo 
- 
Placebo oral solution and Placebo ODT 
 
Each subject will be instructed to take the IMP every night at bedtime with the intention to sleep. In 
addition, as potential food interaction cannot be ruled out at this point in the development of 


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FE 201836, subjects participating in the present trial will be instructed to wait for a minimum of 
2 hours after eating the main evening meal before taking the IMP. 
5.2 
Characteristics and Source of Supply 
All IMP is provided by Ferring Pharmaceuticals A/S and will be handled according to the 
principles of Good Manufacturing Practice (GMP). Ferring Pharmaceuticals A/S will provide the 
trial sites with IMP in amounts sufficient for the trial. 
5.2.1 
Investigational Medicinal Products 
The following IMP will be used in the trial: 
IMP:  
 
 
FE 201836 
Strength: 
 
 
50, 100, 150, 250, 350 and 500 µg 
Formulation: 
 
 
Oral solution, bottle of 5 mL 
Administration method 
For oral use 
IMP:  
 
 
Desmopressin 
Strength: 
 
 
25 µg and 50 µg 
Formulation: 
 
 
ODT 
Administration method:  
To be placed under the subject’s tongue, without water 
IMP:  
 
 
Placebo 
Strength: 
 
 
- 
Formulation: 
 
 
Oral solution, bottle of 5 mL 
Administration method:  
For oral use 
IMP:  
 
 
Placebo 
Strength: 
 
 
- 
Formulation: 
 
 
ODT 
Administration method:  
To be placed under the subject’s tongue, without water 
5.3 
Packaging and Labelling 
Packaging and labelling of the IMP will be performed under the responsibility of the IMP 
department at Ferring Pharmaceuticals A/S in accordance with GMP and national regulatory 
requirements. 
The IMP will be labelled in a manner that ensures the treatment blinding of the trial is maintained. 
The active drug and placebo are visually identical. 
The label of the IMP will contain one self-adhesive tear-off portion to be affixed to the Drug 
Dispensing Log maintained at the trial site. 
5.4 
Conditions for Storage and Use 
The investigator will ensure that the IMP is stored under appropriate conditions in a secure location 
with controlled access. The storage compartment shall be monitored regularly and the temperature 
shall be documented. 


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FE 201836 and placebo oral solution must be stored at 2-8°C (36-46°F) before dispensing. After 
dispensing, the products should be stored at room temperature. 
Desmopressin and placebo ODT should be stored at 25°C (77ºF); excursions permitted to 15-30°C 
(59-86°F). The product should be kept in the original package to be protected from moisture and 
light. The product should be used immediately upon opening of the individual tablet blister. 
The investigator will ensure that the IMP is stored under appropriate conditions in a secure location 
with controlled access. The storage temperature shall be monitored regularly and documented in 
accordance with the instructions provided by the sponsor. Deviations in storage temperature must 
be reported to the sponsor as instructed in the IMP handling instruction. 
Returned IMP from the subjects (used/partly used or unused, including empty packaging material) 
must be stored separately from non-allocated IMP. 
The subjects will be instructed to store the IMP in accordance with the above-mentioned 
conditions. 
5.5 
Blinding/Unblinding 
5.5.1 
Blinding 
The IMP will be supplied by the sponsor in individually packed containers.  
The IMP for the randomised treatment period will be packaged according to a computer-generated 
randomisation list prepared for all trial sites. The randomisation list will not be available to any 
person involved in the conduct and evaluation of the trial until the trial database is declared clean 
and is released to the trial statistician. 
5.5.2 
Unblinding of Individual Subject Treatment  
An emergency unblinding procedure will be available for the investigator and designated personnel 
at the sponsor through the eCRF. It is the investigator’s responsibility to decide whether it is 
medically necessary to know which IMP the subject receives (i.e., unblinding) to ensure the 
subject’s welfare and safety. Breaking of the blind for individual subjects in emergency situations is 
only permitted in case of a Suspected Unexpected Serious Adverse Reaction (SUSAR), or in case 
of an adverse event where the knowledge of the IMP administered is required for medical 
management of the subject. 
As far as the emergency permits, the need to break the blind will be agreed by the investigator and 
the sponsor. The investigator who unblinds a treatment will use the eCRF and is required to enter a 
password and must record the reason for unblinding before the treatment code can be broken. It 
must also be recorded in the eCRF when, and by whom, the code was broken. The investigator 
must record the event of unblinding in the subject’s medical record, including the reason for 
unblinding. 
If the sponsor needs to unblind a treatment, the eCRF will be used for unblinding. It is a 
requirement to enter a password and the reason for unblinding before the treatment code can be 
broken. It must also be recorded in the eCRF when and by whom the code was broken. 


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It may be necessary to unblind an individual subject’s treatment schedule for the purposes of 
expedited reporting to the authorities and/or Independent Ethics Committees (IECs)/Institutional 
Review Boards (IRBs)/Research Ethics Boards (REBs). In that situation, every effort should be 
made to maintain blinding of the sponsor personnel involved in data analysis and interpretation. 
Other personnel may be unblinded for SUSARs, including trial site personnel as well as personnel 
acting on behalf of the sponsor. 
Information on whether the blind has been broken for any subjects is available in the eCRF and 
must be collected before the database is declared clean and is released to the trial statistician. 
In case the eCRF cannot be accessed, and hence the emergency unblinding cannot be performed 
within the eCRF system, the investigator should contact Ferring Global Pharmacovigilance using 
the contact details below: 
Global Pharmacovigilance, Ferring Pharmaceuticals A/S 
Tel: 
 
5.6 
Treatment Compliance 
5.6.1 
Dispensing and Accountability 
The IMP will be handled by authorised personnel at the trial site according to instructions provided 
by the sponsor. 
The IMP for the active run-in will only be dispensed to subjects who meet the eligibility criteria at 
Visit 2. 
The IMP for the randomised treatment period will only be dispensed to subjects who meet the 
eligibility criteria at Visit 4 and are randomised into the trial.  
The investigator (or his/her designee) will maintain a Drug Dispensing Log detailing the dates and 
quantities of IMP dispensed to, and used by each subject, as well as the batch number(s).  
Each subject should return all unused and used IMP bottles and ODT blister sheets (empty foils) to 
the trial site. The delegated designee at each trial site will reconcile all used and unused IMP and 
maintain all IMP (including empty bottles and ODT blister/foils) for drug accountability. The 
monitor will verify the drug accountability during the trial. 
5.6.2 
Assessment of Compliance 
Treatment compliance will be verified at Visits 3, 5, 6, 7 and 8, by reviewing the used, partly used 
and unused IMP and/or subject’s statements documented in the source documents in case the IMP 
is lost. 
5.7 
Return and Destruction of Investigational Medicinal Products 
Subjects will be asked to return unused and used IMP bottles and ODT blister sheets. Used and 
partly used IMP bottles and blisters (foils) will be destroyed at the trial site according to local 
regulations and standard procedures at the site, after the drug accountability has been verified by 


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the monitor. Any unused IMP will be returned for destruction, as instructed by the IMP department 
at Ferring Pharmaceuticals A/S and in accordance with local requirements. 
Documentation on destruction will be forwarded to the sponsor. 
6 
TRIAL PROCEDURES 
The investigator is obliged to keep logs of all screened and randomised subjects. Each subject will 
receive a unique screening number available at each trial site. Prior to, or at Visit 1, all subjects 
must receive a detailed explanation (verbal and written information) of the trial and must sign an 
Informed Consent Form (ICF) after having had sufficient time to consider the participation in the 
trial. No trial-related procedures must be performed on the subject prior to signing the ICF. 
6.1 
Trial Flow Chart 
The overall trial design is shown in Section 3.1. The assessments scheduled for each visit are 
presented in the flow chart in Section 6.1, listed in Sections 6.2
 
to
 
6.7 and further described in 
Section 7. 


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Table 6-1 
Trial Flow Chart 
Assessment 
Screening/ 
Lifestyle Changes 
Active Run-in 
Period 
Washout 
Period 
Randomised Trial Period 
Visit (V) 
V1 
Reminder 
V2 
Telephone 
Follow-up 
V3 
V4 L 
V5 
V6 
V7 
V8 O 
Week 
 
 
 
 
 
 
1 
4 
8 
12 
Day/Visit window 
S1 
 
-14 
-10±1 m 
-7 n 
1 
8±2 
28±3 
56±3 
84±7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
X 
 
X 
X 
 
 
 
 
Lifestyle Changes a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomisation 
 
 
 
 
 
X 
 
 
 
 
Dispense e-Diary 
X 
 
 
 
 
 
 
 
 
 
e-Diary Training 
X 
 b 
 
 
 
 
 
 
 
 
e-Diary Compliance 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Dispense IMP 
 
 
X 
 
 
X 
X 
X 
X 
 
Accountability of IMP 
 
 
 
 
X 
 
X 
X 
X 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
X 
 
 
 
X 
Body weight 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Vital Signs c 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Electrocardiogram (ECG) 
X 
 
 
 
 
 
 
 
 
X 
Pregnancy test - serum d  
X 
 
 
 
 
X 
 
 
 
X 
Pregnancy test - urine d 
X 
 
 
 
 
 
 
 
 
 
Clinical chemistry, 
haematology, urinalysis 
X 
 
 
 
 
X 
X 
X 
X 
X 
Coagulation factors 
X 
 
 
 
 
X 
 
X 
 
X 
Copeptin 
 
 
X 
 
 
X 
 
 
 
X 
OSA assessment e 
X 
 
 
 
 
 
 
 
 
 
Serum sodium p 
X j 
 
 
 
 X k, n 
 
X 
X 
X 
X 
Voiding Diary f 
 
 
X 
 
X 
X 
X 
X 
X 
X 
NI Diary f 
 
 
X 
 
 
X 
X 
X 
X 
X 
PGI-S g 
 
 
X 
 
 
X 
X 
X 
X 
X 
PGI-I g 
 
 
 
 
 
 
X 
X 
X 
X 
ISI h 
 
 
X 
 
 
X 
 
X 
X 
X 
Bother h 
 
 
 
 
 
X 
X 
X 
X 
X 
Exit Interview i  
 
 
 
 
 
 
 
 
 
X 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
a. 
Subjects will be reminded about lifestyle changes throughout the trial. 
b. 
Original footnote omitted as per Clinical Trial Protocol Amendment 03 (applicable for all trial sites).  
c. 
Vital signs (blood pressure and heart rate) measured after resting for 5 minutes in a sitting position. 
d. 
Applicable to all pre- and perimenopausal female subjects. 
e. 
Original footnote omitted as per Clinical Trial Protocol Amendment 03 (applicable for all trial sites). 
f. 
Completed by the subjects at home over 3 consecutive days just prior to scheduled visits. 
g. 
Completed at home 1 day prior to scheduled visits. 
h. 
Completed at the site visit before any consultation with the trial site personnel takes place. 
i. 
A sample of subjects (at trial sites in the USA) who completed the trial will be invited to participate, by telephone, in an exit interview within 
14 days of attending Visit 8. 
j. 
If serum sodium is <135mmol/L the test should be repeated within 7 days, if the second result is <135mmol/L the subject must be discontinued 
from the trial as a ‘screening failure’. If more than 21 days elapse between the serum sodium measurement at Visit 1 and Visit 2, the serum 
sodium measurement must be re-tested, with results available prior to Visit 2. 
k. 
If serum sodium is <130mmol/L the investigator must immediately contact the subject and schedule visits for further evaluation , if the serum 
sodium is <130mmol/L (results confirmed within 7 days) the subject will not be randomised to the trial and must be discontinued from the trial 
as a ‘screening failure’. 
l. 
Baseline efficacy. 
m. 
During the 1 week active run in period, 4 days (±1 day) after the planned start of IMP treatment, the subject will be telephoned to follow up on 
safety. 
n. 
If the subject cannot attend Visit 3 as planned, arrangements must be made to test the serum sodium level at Day 6-8 from the IMP start date. 
o. 
The end-of-trial visit (Visit 8) should be performed if the subject discontinues the trial prior to Visit 8. 
p. 
Sample to be taken preferably in the morning.  


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6.2 
Visit 1 Screening 
Potential participants will be scheduled to come to the clinic for the screening assessments.  
The following must take place during the screening period: 
• 
Signing of informed consent 
• 
Allocation of a screening number 
• 
Inclusion and exclusion criteria will be evaluated. 
• 
Demographic data will be recorded. 
• 
Information on medical history will be recorded based on review of the medical records and 
interview of the subject. 
• 
Information on concomitant medication will be recorded. 
• 
Physical examination, including body weight and height, will be performed. 
• 
Vital signs (blood pressure and heart rate) will be measured. 
• 
Blood samples will be drawn for analysis of haematology, clinical chemistry (including 
serum sodium) and coagulation factors. 
• 
Urine samples will be collected for urinalysis. 
• 
Serum and urine pregnancy tests will be performed in all pre- and perimenopausal female 
subjects. 
• 
Assessment of OSA.  
• 
12-lead electrocardiogram (ECG) will be measured. 
• 
The e-Diary will be dispensed. Subjects will be trained to complete the e-Diary and will be 
encouraged to complete the diary at home during 5 days for training purposes. 
• 
The subject will be given instructions about lifestyle changes and will be requested to 
maintain these lifestyle changes throughout the trial (Section 4.3.3). 
The e-Diary training will be followed by the trial site personnel (via the web-portal).  
Prior to Visit 2 the subject will be reminded to complete the e-Diary (Section 7.1.1) for 
3 consecutive days just prior to the visit. 


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6.3 
Visit 2 Active Run-in Period  
All assessments and procedures to be performed at Visit 2 are listed below. 
• 
The subject will complete the questionnaire (ISI), in the e-Diary (Section 7.1.1.3.2), at the 
trial site before any consultation with the trial site personnel takes place. 
• 
Inclusion and exclusion criteria will be evaluated. 
• 
Body weight will be measured. 
• 
Vital signs (blood pressure and heart rate) will be measured. 
• 
The subject will be interviewed about any changes in concomitant medication and about any 
adverse events since the last visit. 
• 
Blood samples will be drawn for assessment of copeptin. 
• 
The subject will be reminded about lifestyle changes (Section 4.3.3). 
• 
Instructions for start and use of IMP will be given. 
• 
IMP will be dispensed to eligible subjects for the 1-week active run-in (Table 5-1). 
Prior to Visit 3 the subject will be reminded to complete the e-Diary (Section 7.1.1) for 
3 consecutive days prior to the visit. The e-Diary will be reviewed for completeness (via the 
web-portal) by the trial site personnel.  
Four days after the planned start of IMP treatment the subject will be telephoned to follow-up on 
safety.  
6.4 
Visit 3 Washout Period  
All assessments and procedures to be performed at Visit 3 are listed below. 
• 
Inclusion and exclusion criteria will be evaluated (specifically inclusion criterion number 9, 
Section 4.1.1). 
• 
Eligible subjects will enter the 1-week Washout-period.  
• 
The subject will be interviewed about any changes in concomitant medication and about any 
adverse events since the last visit. 
• 
Body weight will be measured. 
• 
Vital signs (blood pressure and heart rate) will be measured. 
• 
A blood sample will be collected for analysis of serum sodium. 
• 
Used IMP bottles, ODT blister sheets and unused IMP will be collected for drug 
accountability. 
• 
The subject will be reminded about lifestyle changes (Section 4.3.3). 
If the subject cannot attend Visit 3 as planned, arrangements must be made to test the serum sodium 
level at Day 6-8 from the IMP start date. 


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Prior to Visit 4 the subject will be reminded to complete the e-Diary (Section 7.1.1) for 
3 consecutive days prior to the visit. The e-Diary will be reviewed for completeness (via the 
web-portal) by the trial site personnel.  
6.5 
Visit 4 
All assessments/procedures to be performed at Visit 4 are listed below. 
• 
The subject will complete the questionnaires (ISI and Bother), in the e-Diary 
(Section 7.1.1), at the trial, site before any consultation with the trial site personnel takes 
place. 
• 
Inclusion and exclusion criteria will be evaluated (specifically inclusion criterion 
number 10, Section 4.1.1). 
• 
The subject will be interviewed about any changes in concomitant medication and about any 
adverse events since the last visit. 
• 
A physical examination including body weight, will be performed. 
• 
Vital signs (blood pressure and heart rate) will be measured. 
• 
Blood samples will be drawn for analysis of haematology, clinical chemistry, coagulation 
factors and copeptin. 
• 
Urine samples will be collected for urinalysis. 
• 
Serum pregnancy test will be performed in all pre- and perimenopausal female subjects. 
• 
Eligible subjects will be randomised to a treatment group (placebo, 500 µg FE 201836 or 
desmopressin up until the first interim analysis and placebo, 50-500 µg FE 201836 or 
desmopressin after the first interim analysis). 
• 
The subject will be reminded about lifestyle changes (Section 4.3.3) and to wait for a 
minimum of 2 hours after eating their evening meal before taking the IMP. 
• 
IMP will be dispensed (Table 5-1). 
Prior to Visit 5 the subject will be reminded to complete the e-Diary (Section 7.1.1) for 
3 consecutive days prior to the visit. The e-Diary will be reviewed for completeness (via the 
web-portal) by the trial site personnel.  
6.6 
Visit 5 to Visit 7 
All assessments/procedures to be performed at Visits 5 to 7 are listed below. 
• 
The subject will complete the questionnaires (Bother [Visits 5, 6 and 7] and ISI [Visit 6 
and 7]), in the e-Diary (Section 7.1.1), at the trial site before any consultation with the trial 
site personnel takes place. 
• 
The subject will be interviewed about any changes in concomitant medication and about any 
adverse events since the last visit. 
• 
Body weight will be measured. 
• 
Vital signs (blood pressure and heart rate) will be measured. 


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• 
Blood samples will be drawn for analysis of haematology, clinical chemistry (including 
serum sodium) and coagulation factors (Visit 6). 
• 
Urine samples will be collected for urinalysis. 
• 
Used IMP bottles, blister sheets and unused IMP will be collected for drug accountability. 
• 
IMP will be dispensed. 
• 
The subject will be reminded about lifestyle changes (Section 4.3.3) and to wait for a 
minimum of 2 hours after eating their evening meal before taking the IMP. 
Prior to the next visit (Visits 6, 7 and 8) the subject will be reminded to complete the e-Diary 
(Section 7.1.1) for 3 consecutive days prior to the visit. The e-Diary will be reviewed for 
completeness (via the web-portal) by the trial site personnel. 
6.7 
Visit 8 – End-of-Trial Visit 
All assessments/procedures to be performed at Visit 8 are listed below. 
• 
The subject will complete the questionnaires (ISI and Bother), in the e-Diary 
(Section 7.1.1), at the trial, site before any consultation with the trial site personnel takes 
place. 
• 
The subject will be interviewed about any changes in concomitant medication and about any 
adverse events since the last visit. 
• 
Physical examination including body weight will be performed. 
• 
12-lead ECG will be measured. 
• 
Vital signs (blood pressure and heart rate) will be measured. 
• 
Blood samples will be drawn for analysis of haematology, clinical chemistry (including 
serum sodium), coagulation factors and copeptin. 
• 
Urine samples will be collected for urinalysis. 
• 
Serum pregnancy test will be performed in all pre- and perimenopausal female subjects. 
• 
Used IMP bottles, blister sheets and unused IMP will be collected for drug accountability. 
In addition to the above, a sample of subjects (from trial sites in the USA) who have completed the 
trial, will be invited to participate in an exit interview (Section 10.3.1.2), by telephone, within 
14 days of attending the end-of-trial visit (Visit 8) to record the subjects’ perception of what 
constitutes a meaningful change in the NI Diary Total Score. 
6.8 
Unscheduled Visits 
The subject may be called in for additional unscheduled visits due to safety reasons at the discretion 
of the investigator or the sponsor, unless the subject has withdrawn his/her consent. The subject 
may also contact the trial site due to safety reasons for an unscheduled visit. The unscheduled visit 
may include additional collection of blood samples for safety reasons. The unscheduled visit may 
also include additional assessments deemed necessary by the investigator such as laboratory 
samples, ECGs, or other procedures which were missed at a previous visit. All unscheduled visits 


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should be described (including the reason for the visit) and documented in the medical/source 
record, and in the eCRF. 


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7 
TRIAL ASSESSMENTS 
7.1 
Assessments Related to Endpoints 
7.1.1 
e-Diary 
Subjects will receive an e-Diary for completion containing: a 3-day voiding diary (Section 7.1.1.1), 
the NI Diary and PRO questionnaires as described in Section 7.1.1.2. The following items are 
included in the e-Diary: 
• 
Time of daily IMP administration 
• 
3-Day Voiding Diary 
• 
Nocturia Impact (NI) Diary© 
• 
PRO questionnaires 
o Patient Global Impression of Severity (PGI-S) 
o Patient Global Impression of Improvement (PGI-I) 
o Insomnia Severity Index (ISI) 
o Hsu 5-point Likert Bother Scale 
At Visit 1, the subjects will be trained to complete the e-Diary, which they will be encouraged to 
complete at home for 5 days (Figure 3-2).  
If the subject is not able to complete the e-Diary assessments, due to technical issues, prior to 
Visit 2 (only), it is permitted that the subject repeats the e-Diary assessments. 
The e-Diary will be reviewed for completeness by the trial site personnel, via the web portal, 
throughout the trial. 
7.1.1.1 
3-Day Voiding Diary 
A 3-day voiding diary (included in the e-Diary, Section 7.1.1) will be used to collect information 
regarding: time of voiding episodes, urine volume, with or without urgency, with or without 
incontinence and other related information, including time of going to bed and time of awakening 
in the morning. The subjects will be asked to complete voiding diaries over 3 consecutive 24-hour 
periods just prior to scheduled visits, as outlined in Table 7-1 and shown in Figure 3-2 and 
Figure 3-3. 


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Table 7-1 
Timing of Voiding Diary Assessments 
Voiding Diary Assessment 
3 Consecutive Days Prior to Visit(s) 
Time of Going to Bed with the Intention to Sleep 
2, 3, 4, 5, 6, 7, 8  
Time of Awakening in the Morning 
2, 3, 4, 5, 6, 7, 8 
Assessment of Urgency and Incontinence Episodes 
2 
Number and Timing of Nocturnal Voids 
6, 7 
Number and Timing of Voids during 24-hours 
2, 3, 4, 5, 8 
Nocturnal Urine Volume 
3* 
24-hour Urine Volume 
2, 4, 5, 8 
* Includes collection of total urine volume within 30 minutes of rising (in the morning) 
 
Effort should be made to ensure that the subject fills out the voiding diary (in the e-Diary) on the 
same weekdays throughout the trial for consistency, e.g., if the first voiding diary (in the e-Diary) is 
started on a Monday, the subsequent e-Diary should also be started on a Monday (Table 7-2). 
During the night (the sleep period) before the visit no measurements will be recorded. 
Table 7-2 
Example of Voiding Diary Completion When Visit Planned for Friday 
 
Monday 
Day-4 
Tuesday 
Day -3 
Wednesday 
Day-2 
Thursday 
Day-1 
Friday 
Visit Day 
Saturday 
Sunday 
Morning 
 
X 
X 
X 
 
 
 
Afternoon/ 
Evening 
 
X 
X 
Finish 
voiding 
diary 
(in e-Diary) 
X 
 
 
 
Night 
Start 
voiding 
diary 
(in e-Diary) 
X 
X 
X 
 
 
 
 
During the screening period, each subject must complete the 3-day voiding diary to document the 
severity of nocturia and to confirm the eligibility for the active run-in period. The voiding diary 
should be completed over 3 consecutive 24-hour periods just prior to Visit 2. 
During the 1-week active run-in period, each subject must complete a 3-day voiding diary to 
document treatment response of ≥20% decrease in the nocturnal diuresis (mL/min) that was 
recorded at Visit 2 and confirm the eligibility. The voiding diary should be completed over 
3 consecutive 24-hour periods just prior to Visit 3.  


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During the 1-week washout period, each subject must complete a 3-day voiding diary to confirm 
the eligibility for the trial. The voiding diary should be completed over 3 consecutive 24-hour 
periods just prior to Visit 4. 
After randomisation (Visit 4) each subject has to complete four 3-day voiding diaries prior to the 
scheduled trial visits.  
Nocturnal voids are defined as the voids occurring from 5 minutes after bedtime, with the intention 
to sleep at night, until rising in the morning. The first morning void will not be counted as a 
nocturnal void even though its volume is included as part of the NUV. The time to first void is 
defined as the time from bedtime with the intention to sleep until first nocturnal void. 
The sponsor will provide the subjects with cups for measuring the urine volume. 
Prior to each visit the subjects will receive reminders to complete the e-Diary.  
7.1.1.2 
Nocturia Impact Diary 
Nocturia has wide-ranging implications for patients’ quality of life, mainly through persistent, 
repeated sleep interruptions. Valid patient self-reported assessments of disease burden and benefit 
of therapy are essential to evaluate the full clinical value of treatment for the patient.  
The NI Diary is a validated, nocturia-specific tool available in multiple languages and consists of a 
12-item questionnaire with 11 core items (Q1-Q11) and an overall QoL impact question (Q12) 
(Holm-Larsen, 2014). It is used in conjunction with a voiding diary to capture patient reported 
consequences of nocturia and its treatment. It has a recall period of one night and day. Responses 
are scored from 0 to 4 (lowest to highest impact). For Question 12, response options range from 
0 (not at all) to 4 (a great deal). The NI Diary total scores are calculated by summing the 11 core 
items. The NI Diary total and overall impact scores are standardised from 0 to 100 (lowest to 
highest impact).  
The NI Diary will be included in the e-Diary (Section 7.1.1), which will be completed by the 
subjects at home, for the 3 consecutive days just prior to scheduled visits as outlined in Figure 3-2 
and Figure 3-3. The NI Diary should be completed in the evening and before completing the PGI-S 
and PGI-I questionnaires. 
One objective of this trial is to further validate the NI Diary, as well as to establish what constitutes 
a meaningful change in the NI Diary Total Score. Thus, the disease-specific NI Diary will be 
further tested and validated in connection with this trial. This will be done through pshychometric 
validation, as described in Section 10.3.1.1, and through exit interviews, as described in 
Section 10.3.1.2. 


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7.1.1.3 
Patient Reported Outcomes 
The PRO instruments (questionnaires) that will be used in the trial are listed below. They should be 
completed in the following order: 
• At home in the evening (after completion of the NI Diary): 
o Patient Global Impression of Severity (PGI-S) 
o Patient Global Impression of Improvement (PGI-I) 
• At the trial site: 
o Insomnia Severity Index (ISI) 
o Bother (Hsu 5-point Likert Bother Scale) 
The two PRO questionnaires that will be completed at the trial site (ISI and Hsu 5-point Likert 
Bother Scale) are recommended to be completed before any other assessments are performed, by 
the subject in a quiet place without influence from the trial personnel or accompanying family or 
friends. It is not permitted to help the subject choose an answer or interpret or rephrase questions 
which the subject does not understand. The subjects should be informed that there are no right or 
wrong answers and that all of the subjects’ responses will remain confidential. 
7.1.1.3.1 Patient Global Impression of Severity and Patient Global Impression of Disease 
Improvement 
Patient Global Impression of Disease scales are commonly used measures of symptom severity, 
treatment response and the efficacy of treatments (Yalcin, 2003). The PGI-I and PGI-S will be 
included in the trial to indicate change or stability in global health status for anchor-based analyses 
to identify thresholds for clinically important changes in, e.g., NI Diary scores and number of 
nocturnal voids, as described in a separate Psychometric Analysis Plan (PAP). Moreover, both 
scales will be analysed for treatment effect, as described in Section 9.7.3. To better reflect the 
current condition, the revised and patient-tested versions of PGI-I and PGI-S will refer to ‘night-
time voiding’, as compared to ‘LUTS’ (Viktrup, 2012). 
The PGI-S is a prospective measure that measures a patient’s current severity reported as “None,” 
“Mild,” “Moderate,” or “Severe” (coded as 1-4). Scores on this measure will provide a patient-rated 
summary of the severity of the patient’s nocturia symptoms. 
The PGI-I is a retrospective measure. It will provide a patient-rated summary of change in nocturia 
since the start of trial treatment, reported as “Very much better,” “Much better,” “A little better,” 
“No change,” “A little worse,” “Much worse,” or “Very much worse,” (coded as 1-7). 
PGI-S followed by PGI-I will be completed by the subjects at home in the evening immediately 
after completing the NI Diary, as outlined in Figure 3-2 and Figure 3-3. 
7.1.1.3.2 Insomnia Severity Index 
Chronic disruptions of sleep will have consequences for daytime performance and well-being. 
Nocturia patients often report excessive daytime sleepiness, with some experiencing more severe 
symptoms, including increased rates of mood disorders and decrease of physical health. Fatigue is a 


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commonly reported symptom by individuals and causes a great amount of interferences with daily 
life. Sleepiness has also been linked to increased risks for accidents, such as falling asleep while 
driving or work-related accidents (Asplund, 2005; Ancoli-Israel, 2011).  
Nocturia is characterised by shortening the FUSP. The first sleep period is of high importance due 
to that deepest stages of sleep (most restorative sleep) typically occur within the first few hours of 
the sleeping and once these stages are interrupted by wakening (e.g., to void) patients are not able 
to make up for this during the rest of the night (Bliwise, 2015). FUSP will be a secondary endpoint 
in the trial. 
Sleep quality will be measured through the ISI, which is an instrument to quantify the subject's 
perception of his/her insomnia severity. The ISI targets the subjective symptoms and consequences 
of insomnia as well as the degree of concern or distress caused by those difficulties (Bastien, 2001). 
The ISI comprises of four `sleep-related' items and three `wake-related' items assessing the severity 
of sleep-onset and sleep maintenance difficulties (both nocturnal and early morning awakenings), 
satisfaction with current sleep pattern, interference with daily functioning, noticeability of 
impairment attributed to the sleep problem and degree of distress or concern caused by the sleep 
problem. Each item is rated on a 0-4 scale and the total score ranges from 0 to 28. A higher score 
suggests more severe insomnia. 
The self-administered ISI questionnaire will be completed at the trial site by the subject before 
active run-in period (Visit 2), at the randomisation visit (Visit 4), after 4 weeks (Visit 6), after 
8 weeks (Visit 7) and at the last trial visit after 12 weeks of treatment (Visit 8) as illustrated in 
Figure 3-2 and Figure 3-3. Since the ISI has a two-week recall, a reminder to think back two weeks 
will appear on the screen upon start of completion, in order to improve on quality of the 
information captured. The ISI will be completed at Visit 2 in order to compare insomnia severity to 
other diseases presenting with insomnia, as recorded by the ISI. The ISI completed at the remaining 
visits (Visits 4, 6, 7 and 8) will be used to measure treatment effect. 
7.1.1.3.3 Bother 
Patient bother is a broad concept covering aspects such as impact on sleep, daily life, social life, 
mental health, fatigue, etc. (Tikkinen, 2010). It has been shown that most nocturia patients are not 
very bothered by one nightly void, but that there is clearly a bother threshold at two voids or more. 
Moreover, comparing two adjacent voiding categories at a time, the increase was statistically 
significant with each increment in number of nightly voids. To further assess the change in 
subjective bothersomeness of nocturia, trial participants will be asked, “How much has this 
frequency of night-time urination bothered you?” with response options including “not at all,” 
“slightly,” “moderately,” “quite a bit,” and “extremely.” This 5-point Likert scale has previously 
been used in a large epidemiological study (Hsu, 2015). 
The Hsu 5-point Likert Bother Scale will be completed by the subject at the trial site at 
randomisation (Visit 4), after 1 week (Visit 5), after 4 weeks (Visit 6), after 8 weeks (Visit 7) and at 
the last trial visit after 12 weeks of treatment (Visit 8), as illustrated in Figure 3-2 and Figure 3-3. 


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7.1.2 
Adverse Events 
The procedures for collection and recording of adverse events are described in Sections 8 (Adverse 
Events) and 8.5 (Serious Adverse Events). 
7.1.3 
Clinical Laboratory Variables 
Urine and blood samples for assessment of safety laboratory values (urinalysis, haematology, 
coagulation factors and clinical chemistry parameters including serum sodium) will be collected as 
presented in Table 6-1. A central laboratory will be used for the analyses (Section 7.3). Evaluation 
of the laboratory-based eligibility criteria will be determined by the central laboratory results. The 
analytical parameters are listed in Table 7-3. 
Details for handling of serum sodium samples are given in Section 7.1.3.1. 
Laboratory values will be reported to the investigator. Laboratory reports from the screening visit 
(Visit 1) must be available for evaluating the inclusion and exclusion criteria prior to the active run-
in period (Visit 2) and before randomisation (Visit 4). Measurements outside normal ranges will be 
assessed by the investigator as ‘abnormal, not clinically significant’ or ‘abnormal, clinically 
significant’. Any abnormal, clinically significant changes should be reported as adverse events 
(Section 8.2). The laboratory reports will be signed and dated by the investigator. 
Table 7-3 
Safety Laboratory Variables 
Clinical Chemistry 
Haematology 
Coagulation 
Urinalysis 
Alanine aminotransferase 
Haemoglobin 
von Willebrand Factor 
Blood 
Albumin 
Haematocrit 
Factor VIII 
Glucose 
Albumin/Globulin ratio 
Platelet count  
 
Ketones 
Alkaline phosphatase 
Red blood cell count 
 
Urinary sediment 
(erythrocytes, leukocytes) 
Aspartate aminotransferase 
White blood cell count with 
differential count 
(eosinophils, monocytes, 
basophils, neutrophils, 
lymphocytes) 
 
Calcium 
 
pH 
Chloride 
 
Protein 
Creatinine 
 
Urobilinogen 
Creatine phosphokinase 
 
 
Gamma-glutamyl 
transferase 
 
 
Dipstick assessment and 
microscopic examination 
will be performed. A 
culture will be performed 
in case of abnormal values. 
Glucose 
 
 
HbA1c 
 
 
Potassium 
 
 
Sodium  
 
 
Total bilirubin 
 
 
Direct bilirubin 
 
 
Total protein 
 
 
Blood urea nitrogen 
 
 
Uric acid 
Triglycerides 
 
 
 


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7.1.3.1 
Serum Sodium 
Serum sodium levels will be monitored throughout the trial as hyponatraemia is a potentially 
serious adverse drug reaction (ADR) associated with desmopressin treatment and may potentially 
be associated with FE 201836 treatment. 
A central laboratory will be used. However, a local laboratory may be used in addition to the 
central laboratory if a quick turn-around time of the result is needed. In such case a sample must 
also be sent to the central laboratory. Evaluation of the laboratory-based eligibility criteria will be 
determined by the central laboratory results. All serum sodium values must be reviewed as soon as 
possible after the results are available. Any unexpected low serum sodium value must be re-tested. 
Any significant changes in serum sodium, judged by the investigator as clinically significant must 
be reported as adverse events, as described in Section 8.2. 
Blood samples for analysis of serum sodium will be collected, preferably in the morning, at 
Visits 1, 3, 5, 6, 7 and 8, as presented in Table 6-1. The risk for subjects developing hyponatraemia 
during the trial period will be mitigated as follows (serum monitoring plan): 
Screening (Visit 1) 
All subjects must have normal serum sodium (≥135 mmol/L) at screening (Visit 1). If the serum 
sodium value is <135 mmol/L (re-tested and confirmed, with results available within 7 days) the 
subject must be discontinued from the trial as a ‘screening failure’. 
Active Run-in Period 
During the 1-week active run-in period, 4 days (±1 day) after the planned start of IMP treatment, 
the subject will be telephoned to follow-up on safety. 
Visit 3 
At Visit 3 (after the active run-in), if the serum sodium value is <130 mmol/L the investigator must 
immediately contact the subject and schedule visits for further evaluation. If the serum sodium 
value is <130 mmol/L (re-tested and confirmed, with results available within 7 days) the subject 
will not be randomised to the trial and must be discontinued from the trial as a ‘screening failure’. 
The subject will be followed (by the investigator) for safety until the serum sodium level is stable 
and not clinically significant, preferably until at least ≥135 mmol/L. 
If the subject cannot attend Visit 3 as planned, arrangements must be made to test the serum sodium 
level at Day 6-8 from the IMP start date to ensure the serum sodium level is measured while the 
subject is taking IMP. 
12-week Randomised Treatment Period 
During the 12 weeks randomised treatment period, any unexpected low serum sodium value 
(<135 mmol/L or a drop in serum sodium level >10 mmol/L) must be re-tested with at least 
2 additional consecutive tests to identify the nadir and duration of the hyponatraemic episode. The 
serum sodium level should be re-tested within 5 (±2 days) since the previous test. The subject will 
be followed (by the investigator) for safety until the serum sodium level is stable and not clinically 
significant, preferably until at least ≥135 mmol/L. 


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Any Time Point during the Trial 
If the serum sodium value is ≤125 mmol/L at any time point during the trial, the treatment with the 
IMP must be stopped immediately and the subject must be withdrawn from the trial. All cases of 
serum sodium values ≤125 mmol/L will be reported as Serious Adverse Event (SAEs) 
(Section 8.5). The subject will be followed (by the investigator) for safety until the serum sodium 
level is stable and not clinically significant, preferably until at least ≥135 mmol/L. 
Acute Intercurrent Illness 
In case of acute intercurrent illnesses characterised by fluid and/or electrolyte imbalance (such as 
systemic infections, fever, gastroenteritis), the treatment with IMP should be interrupted until the 
subject has fully recovered. The treatment can be re-started at the discretion of the investigator once 
the condition of the subject is stabilised. 
In addition, subjects may be called in for additional unscheduled visits due to safety reason, as 
described in Section 6.8. 
Additional Serum Sodium Testing 
Events that will trigger additional serum sodium testing include, but are not limited to, the 
following: 
• If more than 21 days elapse from the serum sodium measurement at Visit 1 and the visit 
date of Visit 2, the serum sodium measurement must be re-tested, with results available 
prior to Visit 2. 
• A subject is presenting with signs or symptoms of hyponatraemia (e.g., headache, dizziness) 
• A subject has gained more than 2 kilograms in body weight between visits (Section 7.2.4) 
• If concomitant treatment with therapy that may induce hyponatraemia (Section 4.3.1) is 
initiated or dosing of an existing therapy is increased during the trial, additional serum 
sodium monitoring should be performed in the first week (4-8 days) after initiation and 
again with follow-up as judged by the investigator, at least at 4 weeks. 
7.1.3.2 
von Willebrand Factor and Factor VIII 
Blood samples for assessment of coagulation factors will be collected at Visits 1, 4, 6 and 8. 
The concentrations of the coagulation factors von Willebrand Factor (vWF) and Factor VIII (FVIII) 
were assessed in the phase 1 clinical trial, 000195, after both oral and intravenous administration of 
FE 201836. The results indicated that both vWF and FVIII were increased at high plasma 
concentrations of FE 201836. vWF started to increase at a plasma concentration of approximately 
150 pg/mL FE 201836 and FVIII at a plasma concentration of approximately 200 pg/mL. Such high 
plasma concentrations are unlikely to be reached in the urological doses proposed for the present 
trial, however, vWF and FVIII will be measured as a safety precaution, and to ensure that these 
coagulation factors are not released in clinically significant amounts. 


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7.1.3.3 
Copeptin 
Blood samples for exploratory analysis of copeptin levels in plasma will be collected at Visit 2, 
Visit 4 and Visit 8. The biomarker copeptin can be easily tested for, and is therefore used as an 
AVP surrogate to potentially identify low nocturnal vasopressin levels in plasma. In patients with 
NP, an inverse circadian rhythm of vasopressin is suspected, resulting in low nocturnal 
concentrations, which may be the root cause of NP. Copeptin may be a useful biomarker to 
diagnose NP due to low levels of endogenous AVP, thereby identifying the ideal candidate for 
antidiuretic therapy (Brunell, 2016) and consequently treatment with FE 201836. 
7.1.4 
Vital Signs 
Diastolic and systolic blood pressure (mm Hg) and heart rate (beats per minute) will be measured 
after resting for 5 minutes in a sitting position, according to usual clinical practice at all trial visits. 
Measurements outside normal ranges will be assessed by the investigator as ‘abnormal, not 
clinically significant’ or ‘abnormal, clinically significant’. Any abnormal, clinically significant 
changes should be reported as adverse events. 
7.1.5 
24-Hour Urine Volume and Nocturnal Urine Volume 
Data on 24-hour urine volume, i.e., including NUV, will be obtained from the 3-day voiding diary 
(Section 7.1.1.1) completed prior to Visits 2, 4, 5 and 8. In addition, NUV data will be obtained 
from the 3-day voiding diary completed prior to Visit 3 (Table 7-1). 
7.2 
Other Assessments 
7.2.1 
Demographics 
Demographic data, including date of birth and race, will be collected at screening (Visit 1). 
7.2.2 
Medical History 
Information on clinically significant previous and concomitant illnesses, signs or findings from 
assessments and examinations during the screening, including surgical history, will be recorded as 
medical history at the screening visit (Visit 1). 
7.2.3 
Concomitant Medication 
Information on concomitant medications will be collected at each visit throughout the trial, as 
described in Section 4.3.1. Concomitant medications are defined as any medication, other than the 
IMP, taken by the subject at entry and during the trial. Prohibited medications/therapies are listed in 
Section 4.3.2. 
7.2.4 
Body Weight and Height 
Body weight and height will be measured to calculate the body mass index (BMI). The eCRF will 
be configured to automatically calculate the BMI. Height (without shoes) will be measured at 
screening (Visit 1). 


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Body weight (without overcoat and shoes) will be measured at all visits. The same scale should 
preferably be used on the subject during the course of the trial for consistency in readings. 
If the subject has gained more than 2 kilograms between trial visits, the serum sodium level must be 
measured, as described in Section 7.1.3.1. 
7.2.5 
Physical Examination 
Physical examinations will be performed at Visits 1, 4 and 8 by the investigator or a delegated 
sub-investigator (MD, Medical Doctor; DO, Doctor of Osteopathic Medicine; PA, Physician 
Assistant; NP, Nurse Practitioner) and must not be delegated to any other trial site personnel. The 
same individual should preferably perform the physical examinations for a subject for consistency 
in evaluation.  
A complete physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, urological and neurological systems. Any abnormal, clinically 
significant changes should be reported as adverse events. 
7.2.6 
Pregnancy Test 
A serum pregnancy test will be performed in all pre- and peri-menopausal female subjects at 
screening (Visit 1), Visit 4 and at the end-of-trial visit (Visit 8). A urine pregnancy test will also be 
performed at screening (Visit 1). 
Female subjects of childbearing potential must have documentation of an acceptable effective 
method of contraception, as described in Section 4.3.4. Amenorrhea of >12 months duration based 
on the reported date of the last menstrual period is sufficient documentation of post-menopausal 
status and does not require a pregnancy test. 
7.2.7 
Electrocardiogram 
A 12-lead ECG will be performed by the investigator or appropriate designee at the screening visit 
(Visit 1) and at the end-of-trial visit (Visit 8). The ECG should be taken after resting for 5 minutes. 
The ECG print-out should be reviewed, signed and dated by the investigator. Any abnormal, 
clinically significant changes should be reported as adverse events. 
7.3 
Handling of Biological Samples 
A trial-specific laboratory manual will be provided to the participating sites, describing in detail 
how to handle, store and transport the biological samples in this trial. All biological samples will be 
analysed at central laboratories and will be destroyed after the results are available. For all 
biological samples collected in the trial, analyses beyond those described in the protocol can only 
be performed after obtaining the required approvals. The processes related to handling biological 
samples will be described in the informed consent documents and data protection legislation 
including local legislation will be adhered to. 
In addition to the central laboratory, a local laboratory may be used for analysis of serum sodium if 
a quick turn-around time of the result is needed (Section 7.1.3.1). 


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8 
ADVERSE EVENTS 
8.1 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a subject participating in a clinical trial. It 
includes: 
• 
Any unfavourable and unintended sign, symptom or disease temporally associated with the 
use of the IMP, whether or not considered to be caused by the IMP. 
• 
Adverse events commonly observed and adverse events anticipated based on the 
pharmacological effect of the IMP. 
• 
Any laboratory abnormality, vital sign or finding from physical examination assessed as 
clinically significant by the investigator (note: pre-existing conditions diagnosed through 
assessments and examinations at the screening visit or during the screening period are not 
adverse events, but are recorded as medical history). 
• 
Accidental injuries, reasons for any change in medication (drug and/or dose), reasons for 
any medical, nursing or pharmacy consultation, or reasons for admission to hospital or 
surgical procedures. 
• 
Overdoses and medication errors with and without clinical consequences. 
8.2 
Collection and Recording of Adverse Events 
8.2.1 
Collection of Adverse Events 
The investigator must monitor the condition of the subject throughout the trial from the time of 
obtaining informed consent until the last visit. 
The sources of adverse events cover: 
• 
The subject’s response to questions about his/her health (a standard non-leading question 
such as “How have you been feeling since your last visit?” is asked at each visit). 
• 
Symptoms spontaneously reported by the subject. 
• 
Investigations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities. 
• 
Other information relating to the subject’s health becoming known to the investigator (e.g., 
hospitalisation). 
8.2.2 
Recording of Adverse Events 
The investigator must record all adverse events in the Adverse Event Log provided in each 
subject’s eCRF with information about: 
• 
Adverse event 
• 
Date and time of onset (time can be omitted, if applicable) 
• 
Intensity 
• 
Causal relationship to IMP 


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• 
Action taken to IMP 
• 
Other action taken 
• 
Date and time of outcome (time can be omitted, if applicable) 
• 
Outcome 
• 
Seriousness. 
Each of the items in the Adverse Event Log is described in detail in the following sections. 
Adverse Event 
Adverse events should be recorded as diagnoses, if available. If not, separate signs and symptoms 
should be recorded. One diagnosis/symptom should be entered per record. 
If a subject suffers from the same adverse event more than once and the subject recovers in between 
the events, the adverse events should be recorded separately. If an adverse event changes in 
intensity, a worst-case approach should be used when recording the event, i.e. the highest intensity 
and the longest duration of the event.a 
Note the following: A procedure is not an adverse event; the reason for conducting the procedure is. 
Hospitalisation is not an adverse event; the reason for hospitalisation is. Death is not an adverse 
event, but the cause of death is (an exception is sudden death of unknown cause, which is an 
adverse event). 
Date and Time of Onset 
The date of onset is the date when the first sign(s) or symptom(s) were first noted. If the adverse 
event is an abnormal clinically significant laboratory test or outcome of an examination, the onset 
date is the date the sample was taken or the examination was performed.  
Intensity 
The intensity of an adverse event must be classified using the following 3-point scale: 
Mild: 
Awareness of signs or symptoms, but no disruption of usual activity. 
Moderate: 
Event sufficient to affect usual activity (disturbing). 
Severe: 
Inability to work or perform usual activities (unacceptable). 
                                              
a  
Exception: if an adverse event with onset before the first IMP administration (i.e., a pre-treatment adverse 
event) worsens in intensity, this must be recorded as two separate events. The initial adverse event should be 
recorded with outcome “not recovered” and the date and time of outcome is when the intensity changed. The 
second adverse event should be recorded with date and time of onset when the intensity changed.  
 


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Causal Relationship to IMP 
The possibility of whether the IMP caused the adverse event must be classified as one of the 
following: 
Reasonable possibility:  
There is evidence or argument to suggest a causal relationship between the IMP and the adverse 
event, i.e., it is an ADR. The ADR may occur as part of the pharmacological action of the IMP or 
may be unpredictable in its occurrence. 
No reasonable possibility: 
There is no reasonable evidence or argument to suggest a causal relationship between the IMP and 
the adverse event. 
Action Taken to IMP 
The action taken to the IMP in response to an adverse event must be classified as one of the 
following: 
• 
No change (medication schedule maintained or no action taken) 
• 
Withdrawn 
• 
Interrupted 
Other Action Taken 
Adverse events requiring therapy must be treated with recognised standards of medical care to 
protect the health and well-being of the subject. Appropriate resuscitation equipment and medicines 
must be available to ensure the best possible treatment of an emergency situation. 
If medication is administered to treat the adverse event, this medication should be entered in the 
Concomitant Medication Log. 
Date and Time of Outcome 
The date and time the subject recovered or died. 
Outcome 
The outcome of an adverse event must be classified as one of the following: 
• 
Recovered (fully recovered or the condition has returned to the level observed at initiation 
of trial treatment) 
• 
Recovered with sequelae (resulted in persistent or significant disability/incapacity) 
• 
Recovering (the event is improving) 
• 
Not recovered 
• 
Fatal 


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8.3 
Adverse Events of Special Interest 
Hyponatraemia 
Serum sodium levels will be monitored throughout the trial as hyponatraemia is a well-known ADR 
associated with desmopressin treatment (Section 7.1.3.1) and may potentially be associated with 
FE 201836 treatment. Serum sodium levels should be tested in subjects presenting with signs or 
symptoms of hyponatraemia. Any significant changes in serum sodium, judged by the investigator 
as clinically significant must be reported as adverse events, as described in Section 8.2. 
All cases of serum sodium values ≤125 mmol/L are considered important medical events and must 
be reported as SAEs, as described in Section 8.5.2. 
8.4 
Pregnancy and Pregnancy Outcome 
If a pregnancy occurs, the IMP should be immediately stopped for the pregnant subject and Global 
Pharmacovigilance at Ferring Pharmaceuticals A/S must be informed. The pregnancy should be 
reported via the pregnancy Report Form included in the eCRF system. In case the eCRF cannot be 
accessed and hence the Pregnancy Report Form cannot be filled in within the eCRF system, a paper 
Pregnancy Report Form available in the investigator’s file should be used and sent to Ferring 
Global Pharmacovigilance. Contact details to Ferring Global Pharmacovigilance are provided in 
Section 8.5.2. 
A pregnant participant or the partner of a male participant should be followed until termination or 
until term to ensure absence of congenital anomaly or birth defect that may have resulted from 
maternal exposure or transmission of the study drug via semen following paternal exposure. The 
pregnancy should be followed-up at least until the birth of the infant and 4-6 weeks after the birth 
of the infant. In general, the follow-up will include the course; duration and the outcome of the 
pregnancy as well as neonatal health. 
If a pregnancy results in an abnormal outcome (birth defect/congenital anomaly) this must be 
reported as an SAE to Global Pharmacovigilance at Ferring Pharmaceuticals A/S. 


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8.5 
Serious Adverse Events 
8.5.1 
Serious Adverse Event Definition 
Table 8-1 
Serious Adverse Events during the Trial 
An event is defined a serious 
adverse event if it: 
Guidance 
results in death 
Any event resulting in a fatal outcome must be fully documented and reported, 
including deaths occurring within 4 weeks after the treatment ends and irrespective of 
the causal relationship to the IMP. The death of a subject enrolled in a trial is per se 
not an event, but an outcome. 
is life-threatening 
The term life-threatening refers to an adverse event in which the subject was at 
immediate risk of death at the time of the event. It does not refer to an event, which 
may have caused death if it were more severe. 
requires in-patient 
hospitalisation or 
prolongation of existing 
hospitalisation 
The term hospitalisation means that the subject was admitted to hospital or that 
existing hospitalisation was extended as a result of an event. Hospitalisation describes 
a period of at least 24 hours. Over-night stay for observation, stay at emergency room 
or treatment on an out-patient basis do not constitute a hospitalisation. However, 
medical judgement must always be exercised and when in doubt the case should be 
considered serious (i.e., if case fulfils the criterion for a medically important event). 
Hospitalisations for administrative or social purposes do not constitute an SAE. 
Hospital admissions and/or surgical operations planned before trial inclusion are not 
considered adverse events, if the illness or disease existed before the subject was 
enrolled in the trial, provided that the condition did not deteriorate during the trial. 
results in persistent or 
significant 
disability/incapacity 
Disability/incapacity means a substantial disruption of a person’s ability to conduct 
normal life functions. In doubt, the decision should be left to medical judgement by 
the investigator. 
is a congenital anomaly/birth 
defect 
Congenital anomaly/birth defect observed in any offspring of the subject conceived 
during treatment with the IMP. 
is an important medical 
event 
Important medical events are events that may not be immediately life-threatening or 
result in death or hospitalisation but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. 
Examples of important medical events include adverse events that suggest a 
significant hazard, contraindication or precaution, occurrence of malignancy or 
development of drug dependency or drug abuse. Medical and scientific judgement 
should be exercised in deciding whether events qualify as medically important. 
Important medical events include any suspected transmission of an infectious agent 
via a medicinal product. Any organism virus or infectious particle (e.g., prion protein 
transmitting Transmissible Spongiform Encephalopathy), pathogenic or non-
pathogenic, is considered an infectious agent. A transmission of an infectious agent 
may be suspected from clinical symptoms or laboratory findings indicating an 
infection in a subject exposed to a medicinal product. 
 


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8.5.2 
Collection, Recording and Reporting of Serious Adverse Events 
SAE Reporting by the Investigator 
An SAE must be reported immediately to Ferring Global Pharmacovigilance as soon as it becomes 
known to the investigator and not later than within 24 hours of their knowledge of the occurrence of 
an SAE. 
The investigator is responsible for submitting the completed SAE Report Form with the fullest 
possible details within 3 calendar days of his/her knowledge of the SAE. 
The SAE Report Form is included in the eCRF system and must be completed. In case the eCRF 
cannot be accessed and hence the SAE Report Form cannot be filled in within the eCRF system, a 
paper SAE Report Form available in the investigator’s file should be used and sent to Ferring 
Global Pharmacovigilance using the contact details below: 
Global Pharmacovigilance, Ferring Pharmaceuticals A/S 
E-mail: 
 
Fax: 
 
eCRF information regarding demographics, adverse events, medical history and concomitant 
medication is mandatory for initial reports and for follow-up reports if any changes have been 
made since the initial report. 
Additional information relevant to the SAE such as hospital records, results from investigations, 
e.g. laboratory parameters (that are not already uploaded in the eCRF), invasive procedures, scans 
and x-rays and autopsy results can be faxed or scanned and e-mailed to Ferring Global 
Pharmacovigilance using the contact details in the section above. In any case this information must 
be supplied by the investigator upon request from the sponsor. On any copies provided, such details 
such as subject’s name, address and hospital ID number should be concealed and instead subject 
number should be provided. 
The investigator will supply the sponsor and the IEC/IRB/REB with any additional requested 
information such as results of post-mortem examinations and hospital records. 
Expedited Reporting by the Sponsor 
The sponsor will report all adverse events that are serious, unexpected and with a reasonable 
possible causality to the IMP (referred to as suspected unexpected serious adverse reactions 
[SUSARs]) as judged by either the investigator or the sponsor to the relevant parties (i.e., 
investigators, IECs/IRBs/REBs and regulatory authorities) within the stipulated timelines. The 
expectedness is assessed by the sponsor according to the current Investigator’s Brochure for 
FE 201836. Unblinded SAEs will be assessed using the current relevant reference safety 
information, which for FE 201836 is in the Investigator’s Brochure and for desmopressin in the 
Decentralised Procedure NOCDURNA Summary of Product Characteristics. 
SAEs will be considered reportable regardless of whether or not the IMP was used in accordance 
with the provisions in the protocol and the applicable reference safety information document. 


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


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9 
STATISTICAL METHODS 
The Global Biometrics Department at Ferring Pharmaceuticals A/S will be responsible for data 
management, the Statistical Analysis Plan (SAP) and the statistical analyses, production of tables, 
listings and figures. This section outlines the planned statistical analysis of the primary endpoint 
and the planned statistical analyses for the secondary endpoints. All analyses and further 
description of the statistical methodology for primary as well as secondary endpoints will be 
detailed in the SAP. The SAP will be available before the first interim analysis. 
The analysis concerning the psychometric validation of the NI Diary is provided in a separate PAP.  
9.1 
Operating Characteristics 
The operating characteristics and associated power are estimated for different dose-response 
scenarios by computer simulations using the Fixed and Adaptive Clinical Trial Simulator (FACTS) 
version 5.6. The five sigmoidal dose-response profiles that were used to simulate trial data are 
illustrated in Figure 9-1. Further details on the dose-response model and the associated primary 
analysis are given in Section 9.7.2 and Appendix 2. 
 
Figure 9-1 Dose-Response Scenarios 
 


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The longitudinal data profile used in the simulations is based on pooled data from desmopressin 
clinical trials FE 992026 CS40 and FE 992026 CS41 (planned treatment group). The following 
estimates and assumptions were used: 
• 
Dose-response standard deviation 𝜎= 0.95 voids 
• 
A between to total variance (σ2) ratio of 0.90 and a true underlying σ of 0.95 
• 
Response fractions of 0.8142, 0.9328 and 0.9874 at Weeks 1, 4 and 8, respectively, as 
compared to the averaged dose-response at Week 12 
• 
Variance fractions of 0.8481, 0.8329 and 0.8900 at Weeks 1, 4 and 8, respectively, as 
compared to the averaged dose-response at Week 12 
Further design specifications were: 
• 
During the initial 17 weeks the recruitment rate will increase linearly from 0 to 8.2 subjects 
per week 
• 
After 17 weeks, when all trial sites have been initiated, the recruitment rate is assumed to 
remain constant at 8.2 subjects per week 
• 
Constant dropout rate of 15% during the randomised treatment period 
• 
First interim analysis when 125 subjects are randomised, thereafter interim analyses every 
8 weeks  
• 
Up to the first interim analysis the allocation ratio is 2:2:1 for placebo, 500 µg FE 201836 
and desmopressin 
• 
After the first interim analysis the allocation ratios are 2:7:1, for placebo, 50-500 µg 
FE 201836 and desmopressin  
o Subjects randomised to FE 201836 will be dynamically allotted to 
50 µg FE 201836, 100 µg FE 201836, 150 µg FE 201836, 250 µg FE 201836, 
350 µg FE 201836 or 500 µg FE 201836 using response-adaptive allocation as 
outlined in Section 9.11. 
• 
Maximum of 300 randomised subjects 
These settings were shared for all treatment groups. The average number of subjects and 
probabilities for futility and success are presented in Table 9-1. 


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Table 9-1 
Operating Characteristics 
Dose-Response 
Scenario 
Maximum 
response 
(𝛼2) 
ED50 
(𝛼3) 
Average 
Number of 
Subjects 
Futility 
Stopping at 
First Interim 
Total  
Futility 
stopping 
Power 
(Total  
Success) 
Null 
0 
0 µg 
200 
75.8% 
97.0% 
3.0% 
I 
-0.3 
150 µg 
277 
15.7% 
47.9% 
52.1% 
II 
-0.4 
200 µg 
288 
7.9% 
25.1% 
74.9% 
III 
-0.5 
200 µg 
296 
2.8% 
9.6% 
90.4% 
IV 
-0.5 
350 µg 
295 
3.4% 
15.4% 
84.6% 
V 
-0.6 
300 µg 
298 
1.4% 
2.7% 
97.3% 
 
For each dose-response scenario, 1,000 trials were simulated in order to estimate the operating 
characteristics presented in Table 9-1. The simulations under the null-hypothesis (no effect) 
demonstrate that assuming a maximum reduction versus placebo of 0.5 voids, the power 
(probability of success) reaches approximately 85 to 90%, while the probability of making a false 
positive conclusion is 3.0%. 
9.2 
Protocol Deviations 
Protocol deviations will be rated as either minor or major. Protocol deviations deemed to impact the 
primary endpoint and possibly affect the conclusions of the trial will be rated as major. Major 
protocol deviations will lead to exclusion of data from the Per Protocol (PP) analysis set 
(Section 9.3.5). Data up to the point where the violation occurs will be used in the evaluations.  
Major protocol deviations include, but are not restricted to, the following: 
• 
<2 nocturnal voids (average over 3 diaries) prior to Visit 2 or Visit 4 
• 
NPi ≤33% prior to Visit 2 
• 
<20% decrease in nocturnal diuresis rate (mL/min) from during active run-in (Visit 2 to 
Visit 3) 
• 
Maximum voided volume <200 mL prior to Visit 2 
• 
Actual treatment not in accordance with randomised treatment 
• 
Significant non-compliant treatment administration and e-Diary completion  
Serious unforeseen deviations deemed to impact the primary endpoint of the trial may additionally 
be rated as major protocol deviations by the sponsor on the basis of a blinded review of data before 
declaration of clean-file and lock of database. The list of major protocol deviations will be detailed 
and documented in the clean file document prior to database release to the trial statistician. 


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9.3 
Analysis Sets 
9.3.1 
Intention-to-Treat Analysis Set for the Enrichment (ITT-ENR) Period 
The Intention-to-Treat analysis set for the enrichment period (ITT-ENR) will be comprised of all 
subjects found to be eligible to enter the enrichment period (1 week active run-in and 1 week 
washout) at Visit 2. All analyses will be conducted with respect to the planned treatment allocation.  
9.3.2 
Safety Analysis Set for the Enrichment Period 
The safety analysis set for the enrichment period will be comprised of all subjects who received at 
least one dose of IMP after Visit 2 i.e., during the 1 week active run-in and 1 week washout. The 
safety analysis set also includes any subject who was found not eligible at Visit 2, but who had at 
least one administration of IMP after Visit 2. All analyses will be with respect to actual treatment 
received. 
9.3.3 
Intention-to-Treat (ITT) Analysis Set for the Randomised Treatment Period 
The Intention-to-Treat (ITT) analysis set for the randomised treatment period will be comprised of 
all subjects randomised at Visit 4. All analyses will be conducted with respect to the planned 
treatment allocation.  
9.3.4 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) will be comprised of all subjects in the ITT analysis set with at least 
one post-baseline record of the number of nocturnal voids (primary endpoint). All analyses will be 
conducted with respect to the planned treatment allocation. 
9.3.5 
Per Protocol (PP) Analysis Set 
The PP analysis set will be defined as all subjects included in the FAS except those for whom all 
data are excluded as a result of major protocol deviations as described in Section 9.2.  
9.3.6 
Safety Analysis Set for the Randomised Treatment Period 
The safety analysis set for the randomised treatment period will be comprised of all subjects who 
have received at least one dose of IMP (placebo, FE 201836, or desmopressin) and have had at least 
one safety assessment after randomisation (Visit 4). This also includes any subject who was found 
not eligible at Visit 4, but who had at least one dose of IMP after Visit 4. All analysis will be 
conducted with respect to the actual treatment received. 
9.4 
Subject Disposition 
Subject disposition with respect to the number of subjects screened, ITT-ENR and ITT analysis sets 
(Section 9.3.1 and 9.3.3) will be tabulated by treatment group for all subjects. Reasons for not being 
randomised at Visit 4 will be categorised and summarised for the ITT-ENR analysis set. Subject 
disposition, with respect to the number of subjects in the safety analysis sets (Section 9.3.2 and 
9.3.6), will be presented separately. 


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1-Kaplan–Meier (1-KM) plots of time to early discontinuation per treatment group will be 
displayed for the ITT analysis set and the treatment group difference will be tested using the 
Log-Rank test. In addition, time to early discontinuation by reason for discontinuation and 
treatment group will be presented using cumulative incidence functions. All premature 
discontinuations will be summarised and listed by time of and reason for, discontinuation. 
Presentations of subject dispositions will be produced for the overall trial population and by gender. 
9.5 
Enrichment Period Assessments and Analysis Sets 
Descriptive statistics for demographics and other pre-baseline characteristics (e.g., number of 
nocturnal voids, NPi, serum sodium levels, etc.) obtained at Visit 2 (latest) will be summarised for 
the ITT-ENR and the safety analysis set defined for the enrichment period. Continuous variables 
will be presented with number of subjects, mean, standard deviation, median, minimum and 
maximum. Categorical variables will be presented with number and percentage of subjects within 
each specific category.  
Treatment compliance, efficacy and safety pertaining to the enrichment period (Visits 2 through 4) 
will be summarised by visit for the ITT-ENR and Safety Analysis Set (as defined for the 
Enrichment period). Tables will be produced for the overall trial population and by gender. 
Analyses of hyponatraemia during the enrichment period are further described in Section 9.10.3.  
9.6 
Trial Population 
Descriptive statistics for demographics and other baseline characteristics obtained at Visit 4 (latest) 
will be summarised for the ITT and safety analysis set as outlined above. All data will be listed per 
subject for the ITT analysis set. Gender specific tabulations will be provided. 
9.6.1 
Medical History, Concomitant Medication and Other Safety Evaluations 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA). The 
version of MedDRA will be documented. Medical history will be listed by subject and summarised 
by System Organ Class (SOC) and preferred term. 
Prior and concomitant medication will be summarised by Anatomical Therapeutic Chemical 
Classification System (ATC) classification first level (alphabetically), ATC classification second 
level (in decreasing order of frequency) and treatment group.  
9.7 
Endpoint Assessments 
9.7.1 
General Considerations 
Unless stated otherwise the efficacy analysis will be presented for the ITT analysis set.  
Continuous variables will be presented with number of subjects, mean, standard deviation, median, 
inter-quartile range, minimum and maximum. Categorical variables will be presented with number 
and percentage of subjects within each specific category. 


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For endpoints obtained in the e-Diary prior to a visit, the 3-day e-Diary data will be averaged and 
interpreted as the observation of the endpoint in question. 
If nothing else is stated the Bayesian dose-response analyses are conducted with respect to the time-
averaged treatment effect. The posterior means estimates, 95% credibility interval of the estimates 
and posterior probabilities of quantities of interest will be reported.  
Frequentist inferences will rely on the appropriate choice of model and report p-values 
corresponding to the statistical test of the hypothesis of “equal effect” against the alternative of 
“different effect”. The level of significance is set at 5% (two-sided).  
Treatment comparison refers to the pair-wise comparison between active doses and placebo. There 
are no planned adjustments for multiplicity when pair-wise testing any active dose of FE 201836 
versus placebo. Desmopressin is included as a benchmark treatment only. None of the primary, 
secondary or explorative analyses will include desmopressin. Explorative benchmarking analyses 
are furher described in Section 9.8. 
9.7.2 
Primary Analysis 
The objectives of the primary analysis are to establish Proof-of-Concept of FE 201836 and to 
estimate the dose-response profile of FE 201836. The dose-response is the average reduction from 
baseline in nocturnal voids during the randomised period. Proof-of-concept will be evaluated by the 
posterior probability that FE 201836 has superior efficacy as compared to placebo. Similarly, 
interim analysis futility criteria will be evaluated by pre-defined quantities of interest.  
This section provides a brief background on the statistical Bayesian model that is utilised.  
9.7.2.1 
Statistical Dose-Response Model  
Let 𝑥𝑡,𝑖 denote the observed cross-sectional change from baseline in nocturnal voids (averaged 
across three consecutive nights) and let 𝑦𝑡,𝑖 denote the time-averaged change from baseline for 
subject 𝑖 up to time 𝑡: 
𝑦𝑡,𝑖=
∑
𝑥𝑘,𝑖 
𝑡
𝑘=1
𝑡
, 𝑡= 1,2,3,4, 
where 𝑡 denotes the nominal post-baseline time-point reflecting data observed at Weeks 1, 4, 8 
and 12 (Visits 5, 6, 7 and 8, respectively). The final endpoint, 𝑦4,𝑖, is modelled as being an 
observation of 𝑌4,𝑖~𝑁(𝜇𝑑,𝑖,𝜎2) where the dose-response at dose 𝑑 for subject 𝑖 is adjusted for the 
number of baseline voids (𝑥0,𝑖) and assumed to follow a sigmoidal model: 
𝜇𝑑,𝑖= 𝛽𝑥0,𝑖+ 𝛼1 +
(𝛼2−𝛼1)𝑑𝛼4
𝑑𝛼4+𝛼3𝑎4 = 𝛽𝑥0,𝑖+ 𝜇𝑑, 
 


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and 𝜎2 represents the (total error) variance of the dose-response. The interpretation of the 
parameters are: 𝛼1 is the placebo response; 𝛼2 is the maximum response; 𝛼3 is the dose (ED50) at 
which 50% of the maximum effect is obtained; 𝛼4 is the slope parameter.  
The longitudinal aspect of the average change from baseline is captured by the following model: 
𝑌𝑡,𝑖~𝑁(𝑒𝛾𝑡(𝜇𝑑,𝑖+ 𝛿𝑖),𝜆𝑡
2), 
where the per-subject offset from the mean dose-response is 𝛿𝑖~𝑁(0, 𝜏2) and 𝜆𝑡
2 represents the 
within subject variance. The model is constrained such that 𝛼4 = 0 and the intermediate values of 𝑦. 
can thus be thought of as being fractions of final value.  
Missing data (missing due to drop-out or final visit has not occurred yet) will be imputed using the 
longitudinal model, assuming missing at random. This implies that also data from subjects who 
have not yet been observed at Week 12 are used in the primary efficacy analysis, as described in 
Appendix 2. 
All parameters in the models are given sufficiently non-informative prior distributions as specified 
in Appendix 2. By application of Bayes’ theorem and Markov chain Monte Carlo sampling 
techniques the posterior probabilities (or the quantities of interest) given in Table 9-2 can be 
estimated. 
Table 9-2 
Quantities of Interest 
Quantity of Interest 
Probability Within the Trial That: 
Objective 
Pr(𝜇𝑀𝐴𝑋< 𝜇𝑃𝑙𝑏) 
the dose with the maximum effect (i.e. the dose 
that is most likely to have the maximum effect) is 
superior to placebo  
Proof-of-Concept 
Pr(𝜇𝑀𝐴𝑋−𝜇𝑃𝑙𝑏< −0.3) 
the dose with the maximum effect (i.e. the dose 
that is most likely to have the maximum effect) has 
>0.3 voids reduction in nocturnal voids as 
compared to placebo  
Futility 
Pr(dose d is MED) 
dose d is the minimum dose that has >0.3 voids 
reduction in nocturnal voids as compared to 
placebo 
Establish the 
MED 
Pr (dose 𝑑 is 𝐸𝐷85) 
dose d is the minimum dose that has > 85% of the 
treatment effect of the maximum effective dose 
Establish ED85 
 


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The final two quantities are also used to characterise the dose-response curve (as they are calculated 
for each dose d) and to assign weights for the adaptive dose allocation. 
9.7.2.2 
Overall Trial Outcome 
The overall trial outcome will be presented in terms of the quantities of interest in Table 9-3. 
Tabulated are also their criteria against which the overall trial success will be judged. 
Table 9-3 
Overall Trial Criteria 
 
Quantity of Interest 
Criteria 
At the First 
Interim 
Analysis 
At Intermediate 
Interim Analyses 
At the Final 
Analysis 
Futility 
Pr(𝜇𝑀𝐴𝑋−𝜇𝑃𝑙𝑏< −0.3) 
<10% 
<5% 
 
Success 
Pr(𝜇𝑀𝐴𝑋< 𝜇𝑃𝑙𝑏) 
 
 
>97.5% 
 
9.7.2.3 
Dose-Response 
The dose-response will be characterised by the posterior estimates of the mean dose-response at 
each dose, 𝜇𝑑 and the mean dose-response contrast versus placebo, their associated 95% credibility 
intervals and the posterior probability Pr(𝜇𝑑< 𝜇𝑃𝑙𝑏) will be tabulated. Associated with these, the 
following (posterior) probabilities will also be tabulated: Pr(𝜇𝑑−𝜇𝑃𝑙𝑏< −0.3), 
Pr(dose 𝑑 is MED), Pr (dose 𝑑 is 𝐸𝐷85) and Pr (dose d achieves 𝜇𝑀𝐴𝑋).  
The mean dose-response will also be presented graphically with its 95% credible interval. 
9.7.2.4 
Sensitivity Analyses 
The following sensitivity analyses will be conducted: 
• 
The primary analysis will be carried out using the PP analysis sets. 
• 
A completer analysis will be run testing the sensitivity of the imputation method applied in 
the primary analysis. 
• 
The primary analysis using different priors specified in the SAP. 
• 
Repeated measures Analysis of Covariance (ANCOVA) using a Missing Not At Random 
(MNAR) placebo-based pattern mixture model (Ratitch, 2011). 
9.7.2.5 
Descriptive Analysis 
The raw average and raw average change from baseline at each dose will be tabulated together with 
95% confidence intervals. No imputations will be done for this analysis which will be based on the 
observed cases only.  


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9.7.3 
Secondary and Explorative Analyses 
The following main categories of inferential analyses will be performed for the secondary 
endpoints: 
• 
Bayesian estimation of the Sigmoidal dose-response curve will follow the analysis 
described in Section 9.7.2.3. Prior distributions for primary analysis are specified in 
Appendix 2, while prior distributions for secondary analyses will be specified in the SAP. 
The dose-response model for the 50% responder rates will also be further detailed in the 
SAP. 
• 
Continuous treatment effects at a certain visit will be analysed using SAS PROC MIXED 
assuming a repeated measures ANCOVA. (A non-parametric dose-response curve is 
assumed.) The changes from baseline per visit will be regressed upon the baseline 
observation as covariate and treatment, visit and treatment-by-visit interaction as factors. An 
unstructured covariance structure will be used for the random subject effect. Least square 
mean estimates of the changes from baseline and the treatment contrasts (with associated 
95% confidence intervals) versus placebo will be tabulated and the changes from baseline 
will be graphically illustrated. Should only one post-baseline visit be obtained for an 
endpoint, an ANCOVA will be performed without the visit and treatment-by-visit 
interaction terms. 
• 
Correlation between endpoints will be reported using Pearson correlation coefficients and 
partial correlation where applicable. 
• 
Binary endpoints such as “responder status” at a certain visit will be analysed using SAS 
PROC GENMOD with the logit as link function for the responder probability. An 
unstructured covariance matrix will be assumed for the repeated responder status which will 
be adjusted for baseline value as covariate and treatment, visit and treatment-by-visit 
interaction as factors. (Associated with e.g., responder analysis in terms of reduction in 
number of voids, cumulative distritubtion function plots of percentage change from baseline 
by treatment may be produced.)  
Table 9-4 presents the planned analyses. 
Illustration of the therapeutic window is described separately in Section 9.7.3.1 and safety related 
endpoints are further described in Section 9.10. 
Explorative gender analyses are planned for all endpoints. For these the following are noted: 
• 
Estimates of the gender specific dose-response during 12 weeks of treatment will follow the 
analysis described in Section 9.7.2.3 by conducting separate analysis for each gender. 
Possible differences between the gender specific models will be investigated. 
• 
Regression models will include gender and gender-by-treatment as factors. (Possible 
differences between the treatment effects on gender will be evaluated by the interaction term 
gender-by-treatment.)  
Correlation analyses will be done separately for each gender. 


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Table 9-4 
Analysis of Endpoints 
Efficacy Endpoint 
Analysis category 
Bayesian 
Estimation 
of Dose-
response 
Curve 
Repeated 
measures 
ANCOVA 
Correlation 
Analysis 
Repeated 
logistic 
regression 
(Generalized 
Estimating 
Equation 
[GEE]) 
ANCOVA 
Change from baseline in number of nocturnal voids a 
Primary 
Secondary e 
 
 
 
Responder rate defined as 50% reduction in nocturnal voids 
from baseline a 
Secondary 
 
 
Secondary 
 
Change from baseline in NI Diary Total Score a 
Secondary 
Secondary  
 
 
 
Percentage of nights during treatment period with at most one 
nocturnal void i 
 
 
 
 
Secondary 
Percentage of nights during treatment period with complete 
response i 
 
 
 
 
Secondary 
Change from baseline in NI Diary Overall Impact Score a 
Secondary 
Secondary 
 
 
 
PGI-I urinary symptoms score a,b 
 
Secondary 
 
 
 
Change from baseline in PGI-S score a 
 
Secondary 
 
 
 
Change from baseline in Bother as measured by the Hsu 
5-point Likert Bother Scale a 
 
Secondary 
 
 
 
Change from baseline in ISI f 
 
Secondary 
 
 
 
Change from baseline in FUSP a  
Secondary 
Secondary Explorative h 
 
 
Change from baseline in nocturnal diuresis rate (hourly) c 
 
Secondary  
 
 
 
Change from baseline in NUV c 
Secondary  
Secondary  
 
 
 
Responder rates defined as 33%, 60%, 70%, 80%, 90% and 
100% reduction from baseline in number of nocturnal voids a 
 
 
 
Explorative 
 
Responder rates defined as 1, 2, and 3 voids reduction from 
baseline in number of nocturnal voids a 
 
 
 
Explorative 
 
Copeptin levels at Visit 2 
 
 
Explorative g 
 
 
Change from baseline in copeptin levels d 
 
 
 
 
Explorative 
Change from baseline in total sleep time per night a 
 
Explorative 
 
 
 
Change from baseline in NPi c 
 
Explorative 
 
 
 
Safety Endpoints 
 
 
 
 
 
Change from baseline in mean 24-hour urine volume c 
 
Safety 
 
 
 
Incidence and severity of Adverse Events 
Section 9.10.2 
Adverse Event of Special Interest: Hyponatraemia Episodes 
Section 9.10.3 
Clinically significant changes in vital signs and laboratory 
values 
Sections 9.10.1 and 9.10.4 
a. 
Endpoint assessed at Weeks 1, 4, 8 and 12 weeks of treatment. 
b. 
This questionnaire is retrospective and raw scores will be used in the 
analysis (not changes from baseline) and the ANCOVA model will 
not be adjusted for baseline value. 
c. 
Endpoint assessed at Week 1 and 12 weeks of treatment. 
d. 
Endpoint assessed at 12 weeks of treatment. 
e. 
Sensitivity analysis placebo pattern-mixture models. 
f. 
Endpoint assessed at Week 4, 8 and 12. 
g. 
Correlation with NPi at Visit 2. 
h. 
Correlation between changes in FUSP and total sleep time at Visits 
1, 4, 8 and 12. 
i. 
Endpoints are derived using all diary data collected during the 
treatment period. 
 
 


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9.7.3.1 
Therapeutic Window 
The estimated dose-response curve (left-sided y-axis) will be illustrated together with the (3 month) 
incidences of serum sodium <130 mmol/L and ≤125 mmol/L (both on right-sided y-axis). The 
horizontal x-axis will represent the dose range of FE201836. The therapeutic window is defined as 
the dose range where FE 201836 is deemed efficacious while the incidence of hyponatraemia is 
acceptable. Corresponding efficacy and safety of desmopressin will be illustrated in a side panel for 
comparison. Two illustrations will be made, one using the ITT and one using the Safety Analysis 
Set.  
The gender-specific therapeutic windows will also be illustrated similarly. 
The therapeutic window of nocturnal volume will be presented similarly. 
9.8 
Explorative Benchmarking Analysis 
The explorative benchmarking analysis will descriptively summarise the changes from baseline and 
percentage changes from baseline in number of nocturnal voids by all treatment groups, including 
desmopressin. Tables and figures will be produced as appropriate. This analysis will also be 
repeated by gender 
9.9 
Extent of Exposure and Treatment Compliance 
Treatment compliance will be summarised by treatment group and visit period for the ITT and 
safety analysis set.  
9.10 
Safety 
9.10.1 
General Considerations 
Safety analyses with respect to the enrichment period will be based on the Safety Analysis Set 
defined for the enrichment period, while analysis with respect to the randomised period will be 
performed using the safety analysis set. 
Safety will be assessed by analysis of adverse events, vital signs, clinical chemistry, haematology, 
urinalysis and physical examination. 
Missing values will be treated as missing, except for causality, intensity, seriousness and outcome 
of adverse events. A worst-case approach will be used: if causality is missing, the adverse event 
will be regarded as related to the IMP; if the intensity of an adverse event is missing, the adverse 
event will be regarded as severe; if seriousness is missing the adverse event will be regarded as 
serious; if onset date is missing it will be assumed to be the first day of dosing; if outcome is 
missing and no date of outcome is present the outcome is regarded as ‘ongoing’. 
Data will be presented in summary tables and listings. Categorical data will be summarised by 
treatment group using the number and percentage of subjects in each category. For calculation of 
percentages, the denominator will be the total number of subjects in the respective treatment group 


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in the safety analysis set. Continuous data will be summarised by treatment group using number of 
subjects, mean, standard deviation, median, minimum and maximum. 
All individual subject data will be listed per subject and treatment as observed including any 
derived values. 
9.10.2 
Adverse Events 
Adverse events will be summarised overall and tabulated by SOC and preferred term using 
MedDRA. The version of MedDRA will be documented. The total number of subjects reporting an 
adverse event, the percentage of subjects (%) with an adverse event and the number of events 
reported will be presented. 
Tables will be prepared for the enrichment period and randomised treatment period as outlined in 
Table 9-5. 
Table 9-5 
Tabulations of Adverse Events 
 
Enrichment Period 
Enrichment 
period-emergent 
Adverse Events 
(Safety Analysis Set 
Defined for the 
Enrichment Period) 
Randomised Period 
Treatment-emergent 
Adverse Events 
(Safety Analysis 
Data Set) 
Gender-Specific 
Tabulations 
Overview of Adverse Events 
X 
X 
Both 
Adverse Events by causality (related/unrelated) 
X 
X 
X 
Adverse Events leading to death 
X 
X 
Both 
Adverse Events by intensity 
 
X 
X 
SAEs 
X 
X 
Both 
Adverse Events leading to discontinuation 
X 
X 
Both 
Adverse Events with an incidence of at least 5% in 
any treatment group 
 
X 
X 
Non-serious Adverse Events with an incidence of 
at least 5% in any treatment group 
 
X 
X 
 
9.10.3 
Adverse Events of Special Interest: Hyponatraemia Episodes 
Observed serum sodium levels and the change from baseline will be tabulated by (planned) visit 
and treatment group. Similar tables will be produced for both trial periods (enrichment and 
randomised). 
The prevalence of worst-case hyponatraemic episodes, as defined in Table 9-6 will be presented by 
treatment group and visit for the randomised treatment period.  
During the enrichment period (active run-in and washout) hyponatraemic episodes will be 
presented in the same ranges, but here the definition requires only one observation below the upper 
limit (≥135 mmol/L) to yield a hyponatraemic episode.  


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Table 9-6 
Definition of Hyponatraemic Episodes by Serum Sodium Range during the 
Randomised Treatment Period 
Serum Sodium Range 
(mmol/L) 
Number of Serum Sodium Observations  
≥135 
Not applicable (normal serum sodium level) 
≥130 to <135 
3 Consecutive Observations a 
>125 to <130 
2 Consecutive Observations a 
≤125 
1 Observation 
a 
Below upper threshold 
All subjects with a serum sodium value <130 mmol/L will be listed by treatment group, including 
all serum sodium assessments by time-point and including respective demographical data. 
Presentations will be done for the overall trial population and by gender. 
9.10.3.1 
Hyponatraemia during the Randomised Treatment Period 
These analyses are restricted to the Safety Analysis Set only. 
The incidence of the post-baseline worst-case hyponataemia episode for each subject will be 
summarised as described in Table 9-6.  
Graphs will plot the serum sodium levels by treatment group and the profiles of the subjects who at 
any time (Visit 1 and onwards) have a serum sodium level <135 mmol/L will be highlighted.  
Kaplan-Meier plots of time from randomisation (Visit 4) to hyponatraemic serum sodium levels 
(<135, <130 and ≤125 mmol/L) per treatment group will be produced. For the thresholds <135 and 
<130 mmol/L at least 3 and 2 consecutive observations, respectively, have to be below the 
threshold to yield a hyponatraemic event (Table 9-6). For both cases the time is from randomisation 
until first observation below the respective limit that counts. 
The associated relative hazards of treatment and gender will be analysed using Cox proportional 
hazards model adjusting for baseline serum sodium and age (<65, ≥65 years). Possible 
heterogeneity between the genders in the relative treatment hazards will be explored by the 
inclusion of a treatment-by-gender interaction term. 
9.10.4 
Safety Laboratory Variables 
Laboratory test results and their change from baseline to end-of-trial will be summarised by 
treatment group for the Safety Analysis Set. The number and percent of subjects with clinically 
significant laboratory abnormalities will be presented. Shift tables from baseline to end-of-trial visit 
(categorised as low, normal and high) will be presented by treatment group. 
9.11 
Interim Analyses 
Two kinds of interim analyses are planned in the trial. One is safety-oriented and concerns the 
monitoring of the serum sodium levels observed during the active run-in period. As described in 


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Section 3.4, a DMC will be established for the trial and make recommendations based on review of 
safety data, e.g., increased rates of clinically significant serums sodium levels observed during the 
active run-in period, as described in Section 9.11.1. The second kind concerns the pre-planned 
efficacy analyses upon which the trial may be stopped due to futility, or allocation probabilities to 
FE201836 doses may be adjusted based on estimated dose-response curve, as described in 
Section 9.11.2. 
9.11.1 
Serum Sodium Monitoring during the Active Run-In Period 
The risk of subjects developing hyponatraemia will be mitigated by a serum sodium monitoring 
plan (Section 7.1.3.1), including a 1-week active run-in period to identify subjects at increased risk 
for developing acute hyponatraemia prior to randomisation. If the incidence of serum sodium levels 
<130 mmol/L is statistically significantly >10% during the active run-in, the DMC (Section 3.4) 
will be notified and further action will be discussed, e.g., the DMC may recommend that the highest 
dose of FE 201836 may be replaced by a lower dose. 
The number of cases of serum sodium levels <130 mmol/L resulting in an estimated rate that is 
statistically significantly >10% depends on the number of subjects who have completed the active 
run-in, examples are presented in Table 9-7. 
Table 9-7 
Examples of Incidence Rates that are Statistically Significantly >10% 
Number of Subjects who 
have Completed 1-week 
Active-run in 
Number of Cases 
Observed with Serum 
Sodium levels 
<130 mmol/L 
Estimate of Incidence 
Rate 
Lower Limit of 95% 
Confidence Interval 
10 
4 
40% 
12.2% 
20 
6 
30% 
11.9% 
50 
10 
20% 
10.0% 
100 
17 
17% 
10.2% 
200 
30 
15% 
10.4% 
 
Thus, the present trial has been designed with the option to decrease the maximal dose of 
FE 201836 from 500 µg to 350 µg if recommended by the DMC. If this decision is made, 
randomisation to the 500 µg FE 201836 treatment group will be closed, the trial will continue with 
350 µg FE 201836 as the highest dose for the active run-in and the highest dose of FE 201836 that 
any subject can be randomised to. In the case where subjects have already been randomised to 
500 µg FE 201836 and have not completed the trial the DMC will recommend whether or not, these 
subjects may be permitted to remain on 500 µg FE 201836 treatment for the remainder of the trial. 
If the decision to close randomisation to 500 µg FE 201836 occurs prior to the first interim analysis 
(when the first 125 subjects are randomised) the remaining subjects will be randomised to the 
following treatment groups: placebo, desmopressin (25 µg for females and 50 µg for males) or 
350 µg FE 201836. After the interim analysis subjects may be randomised to one of 7 treatment 
groups: placebo, 50 µg FE 201836, 100 µg FE 201836, 150 µg FE 201836, 250 µg FE 201836, 
350 µg FE 201836, or desmopressin (25 µg for females and 50 µg for males).  


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The dose-response model will be fitted across all doses, i.e., 0-500 µg, but inference will be made 
only on the doses that remain open to randomisation e.g., 0-350 µg. That is, the MED and ED85 
doses and the inferences with regards to proof-of-concept and futility will be limited to the dose 
range (i.e., with a maximum dose of 350 µg FE 201836).  
9.11.2 
Interim Efficacy Analyses 
The planned interim analyses will be conducted by an internal DMC (Section 3.4) according to a 
separate DMC charter, which will be established before the first interim analysis. The interim 
analyses will use unblinded efficacy data to infer whether to stop early for futility or to continue the 
trial as planned.  
At the first interim analysis the trial may be stopped due to futility if there is a low probability (less 
than 10%) that 500 µg FE 201836 is at least 0.3 voids more efficacious than placebo:  
Pr(𝜇𝑀𝐴𝑋−𝜇𝑃𝑙𝑏< −0.3) < 10%. 
Up to the first interim analysis (conducted when 125 subjects have been randomised) the allocation 
ratio is 2:2:1 for placebo, 500 µg FE 201836 and desmopressin. Should the trial continue, the 
allocation ratios will be changed to 2:7:1, where all doses of FE 201836 (50-500 µg) are opened for 
response-adaptive allocation. The randomisation probabilities for each dose of FE 201836 will be 
proportional to the average of I(dose is MED) and I(dose is ED85), where I(target) is the square root 
of the probability that “dose is target” scaled by the standard error at that dose. 
The remaining interim analyses are planned to occur every 8 weeks as depicted in the decision 
tree (Figure 9-2).  
These interim analyses will re-iterate the (overall) futility criteria at the 5% threshold: 
Pr(𝜇𝑀𝐴𝑋−𝜇𝑃𝑙𝑏< −0.3) < 5% (see Table 9-2 for interpretation). 
At the final analysis (when all subjects have had their 12-week visit, or discontinued prior to this 
visit) Proof-of-Concept is established if Pr(𝜇𝑀𝐴𝑋< 𝜇𝑃𝑙𝑏) > 97.5%.  
 


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Figure 9-2 Interim Analysis Decision Tree (2nd Interim Analysis and Onwards) 


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10 
DATA HANDLING 
10.1 
Source Data and Source Documents 
Source Data – International Conference on Harmonisation (ICH) Definition 
Source data are defined as all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies). 
Source Documents - ICH Definition 
Source documents are defined as original documents, data and records (e.g., hospital records, 
clinical and office charts, laboratory notes, memoranda, subject diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files and records kept at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical trial). 
Trial-specific Source Data Requirements - The Sponsor 
No specific protocol data can be recorded directly in the e-CRF without a prior written or electronic 
record. The data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The e-Diary data is part of a 
process where the subject uses the e-Diary to transmit data to the service provider’s database, hence 
the service provider’s database is considered to be the source data. The investigator may need to 
request previous medical records or transfer records, current medical records must also be 
available.  
For each subject enrolled, the investigator must document in the subject’s medical record, that the 
subject participates in this trial and at least the following information must be recorded: 
• 
Documentation of signed and dated informed consent 
• 
Subject’s name and date of birth 
• 
Confirmation of participation in the trial (trial identification, screening/randomisation 
[subject] number) 
• 
Eligibility of participation in the trial (inclusion/exclusion) 
• 
Relevant medical history 
• 
Nocturia medical history or subject-reported nocturia symptoms  
• 
Visit Dates 
• 
Results of any examinations/tests and assessment performed 
• 
Details of any concomitant medication/therapy 


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• 
Details of any adverse events/SAEs (including description and duration) 
• 
Date IMP is dispensed and returned 
• 
Reason for discontinuation/withdrawal, if applicable 
• 
Event of unblinding, including the reason for unblinding, if applicable 
The following documents collected during the trial should be stored and archived together with the 
subject’s hospital/medical records or in the investigator file as agreed upon prior to the trial start: 
• 
Laboratory print-outs from central laboratory (and local laboratory, if used) – evaluated, 
signed and dated by the investigator 
• 
ECG print-outs/reports - evaluated, signed and dated by the investigator 
• 
Subject dispensing logs of IMP 
• 
Relevant records for collection of laboratory samples 
• 
Evaluations of physical examinations 
• 
Demographics 
10.2 
Electronic Case Report Form 
An eCRF system provided by 
 an independent third-party Contract Research 
Organisation (CRO) will be used for data capture. The system is validated and access at all levels to 
the system is granted/revoked following sponsor and vendor procedures, in accordance with 
regulatory and system requirements. 
Trial data should be entered into the eCRF in a timely manner preferably within 3 working days 
after the subject visit.  
The investigator will approve/authorise the eCRF entries for each subject with an electronic 
signature which is equivalent to a handwritten signature.  
The eCRF system and the database will be hosted at 
. After the trial database is 
declared clean and released to the statistician, a final copy of the database will be stored at the 
sponsor. The investigator will also receive a copy of the trial site’s final and locked data (including 
audit trail, electronic signature and queries) as write-protected PDF-files produced by 
 
. The PDF-files will be stored electronically and will be provided by 
 to the 
investigator before access to the eCRF is revoked. 
Entry errors occurring in the eCRF will be corrected electronically. Such corrections/modifications 
will be automatically tracked by an audit trail detailing the date and time of the correction, the name 
of the person making the correction and the reason for the correction. 
10.3 
Use of Patient Reported Outcomes 
The PRO questionnaires to be used in the trial are described in Section 7.1.1.3. 


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All PROs will be captured in the 3-day e-Diary and completed by the subject, either at the trial site 
(ISI, Bother) or at home just prior to the trial visit (PGI-I, PGI-S), as outlined in Figure 3-2 and 
Figure 3-3. For PROs completed at home, subjects will be reminded in due time. The 3-day 
e-Diary, including the PROs will be reviewed for completeness (via the web-portal) by the trial site 
personnel throughout the trial (Section 6). 
In case of missing ISI and Bother assessments, the reason(s) should be recorded by the trial 
personnel in the eCRF, e.g., subject refusal, lack of time from subject or functional limitation from 
subject to complete the questionnaire. Handling of missing assessments and missing data will be 
detailed in the SAP. 
10.3.1 
Validation of the Nocturia Impact Diary 
10.3.1.1 
Psychometric Validation 
In connection with this trial, the NI Diary will be further tested and validated through anchor-based 
analyses including the PRO questionnaires PGI-I and PGI-S (Section 7.1.1.3.1) and subjects’ 
perception of change in NI Diary Total Score as captured in exit interviews (Section 10.3.1.2). 
Details of these analyses are described in a separate PAP. The order of these three e-Diary 
assessments, all completed at home, should therefore be NI Diary first, PGI-S second and PGI-I 
last, as described in Section 7.1.1.3. 
10.3.1.2 
Validation through Exit Interviews 
A sample of subjects (from trial sites in the USA) who have completed the trial will be invited to 
participate in an exit interview within 14 days of attending the end-of-trial visit (Visit 8). Signed 
informed consent must have been obtained through the ICF for the trial, as appropriate, before 
participation in the exit interview. 
The exact size of the sample will depend on when saturation has been reached. The subjects 
included will be proportionate to the clinical trial sample distribution with respect to demographic 
and clinical characteristics. The investigator at the trial site will be asked to complete a Case Report 
Form that includes specific requirements for recruiting subjects to ensure the correct mix of 
subjects. 
The exit interview is designed to examine the impact of living with nocturia and to assess what a 
meaningful positive change would be from the subject’s perspective in terms of this impact. In the 
exit interviews, subjects’ ratings and perceptions of changes will be collected using qualitative and 
quantitative methods. These data will be used to aid in understanding what is, from a subject’s 
perspective, a meaningful change threshold for indicating positive improvement in the impact of 
nocturia on a subject’s life, as measured by the NI Diary. 
A detailed description of the exit interview is provided in the Exit Interview Protocol, enclosed in 
Appendix 1. 
All exit interviews will be conducted over the telephone by a trained interviewer from
. 


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10.4 
Data Management 
A data management plan will be prepared under the responsibility of the Global Biometrics 
Department at Ferring Pharmaceuticals A/S. The data management plan will be issued before data 
collection begins and will describe all functions, processes and specifications for data collection, 
cleaning and validation. 
10.5 
Provision of Additional Information 
On request, the investigator will provide the sponsor with additional data relating to the trial, duly 
anonymised and protected in accordance with applicable requirements. 


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11 
MONITORING PROCEDURES 
11.1 
Periodic Monitoring 
The monitor will contact and visit the investigator periodically to ensure adherence to the protocol, 
International Conference of Harmonisation-Good Clinical Practice (ICH-GCP), standard operating 
procedures and applicable regulatory requirements, maintenance of trial-related source records, 
completeness, accuracy and verifiability of eCRF entries compared to source data, verification of 
drug accountability and compliance to safety reporting instructions.  
The investigator will permit the monitor direct access to all source data, including electronic 
medical records and/or documents in order to facilitate data verification. The investigator will co-
operate with the monitor to ensure that any discrepancies that may be identified are resolved. The 
investigator is expected to be able to meet the monitor during these visits.  
Risk based monitoring will be applied for this trial. The frequency of the on-site monitoring visits 
will be adapted depending on the risk level of the site and workload. Site risk is based on multiple 
factors including, but not limited to, the quantity of data generated, quality of the source 
documents, unreported adverse events or SAEs and number of protocol deviations. 
The risk-based monitoring and adaptive monitoring strategy, source data verification process and 
definition of key variables to be monitored will be described in detail in the Monitoring Plan for the 
trial.  
11.2 
Audit and Inspection 
The investigator will make all the trial-related source data and records available at any time to 
quality assurance auditor(s) mandated by the sponsor, or to domestic/foreign regulatory inspectors 
or representatives from IECs/IRBs/REBs who may audit/inspect the trial. 
The main purposes of an audit or inspection are to assess compliance with the trial protocol and the 
principles of ICH-GCP including the Declaration of Helsinki (World Medical Association 
Declaration of Helsinki, 2013) and all other relevant regulations. 
The subjects must be informed by the investigator and in the Informed Consent Documents that 
authorised sponsor representatives and representatives from regulatory authorities and 
IECs/IRBs/REBs may wish to inspect their medical records. During audits/inspections the 
auditors/inspectors may copy relevant parts of the medical records. No personal identification apart 
from the screening/randomisation number will appear on these copies. 
The investigator should notify the sponsor without any delay of any inspection by a regulatory 
authority or IEC/IRB/REB. 


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11.3 
Confidentiality of Subject Data 
The investigator will ensure that the confidentiality of the subjects’ data will be preserved. In the 
eCRF or any other documents submitted to the sponsor, the subjects will not be identified by their 
names, but by an identification system, which consists of an assigned number in the trial. 
Documents that are not for submission to the sponsor, e.g., the confidential subject identification 
code and the signed Informed Consent Documents, will be maintained by the investigator in strict 
confidence. 
11.4 
Centralised Statistical Monitoring 
Centralised statistical monitoring will be conducted on (but not limited to) the following key 
aspects of the trial: 
• 
The incidence rate of hyponatraemia throughout the trial 
• 
Key inclusion criteria (number of voids, voided volumes, NI Diary and Bother)  
• 
The number of voids and NI Diary data as collected in the e-Diary throughout the trial 
• 
Monitoring at trial site level will focus on the accumulated trial site data and comparisons 
across trial sites will be performed 


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


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13 
REPORTING AND PUBLICATION 
13.1 
Clinical Trial Report 
The data and information collected during this trial will be reported in a clinical trial report 
prepared by the sponsor and submitted for comments and signature to the signatory investigators. 
13.2 
Confidentiality and Ownership of Trial Data 
Any confidential information relating to the IMP or the trial, including any data and results from 
the trial will be the exclusive property of the sponsor. The investigator and any other persons 
involved in the trial will protect the confidentiality of this proprietary information belonging to the 
sponsor. 
13.3 
Publications and Public Disclosure 
13.3.1 
Publication Policy 
At the end of the trial, one or more manuscripts for joint publication may be prepared in 
collaboration between the investigator(s) offered authorship and the sponsor. In a multi-site trial 
based on the collaboration of many sites, any publication of results must acknowledge all sites. 
Results from multi-site trials must be reported in entirety in a responsible and coherent manner and 
results from subsets should not be published in advance or without clear reference to the primary 
publication of the entire trial. 
Authorship is granted based on the International Committee of Medical Journal Editors (ICMJE) 
criteria (see current official version: http://www.icmje.org). The total number of authors is based on 
the guideline from the relevant journal or congress. In the event of any disagreement in the content 
of a publication, both the investigator’s and the sponsor’s opinion will be fairly and sufficiently 
represented in the publication. 
Any external CRO or laboratory involved in the conduct of this trial has no publication rights 
regarding this trial. 
If the investigator wishes to independently publish/present any results from the trial, the draft 
manuscript/presentation must be submitted in writing to the sponsor for comments prior to 
submission. Comments will be given within 4 weeks from receipt of the draft manuscript. This 
statement does not give the sponsor any editorial rights over the content of a publication, other than 
to restrict the disclosure of the sponsor’s intellectual property. If the matter considered for 
publication is deemed patentable by the sponsor, scientific publication will not be allowed until 
after a filed patent application is published. Under such conditions the publication will be modified 
or delayed at the investigator’s discretion, to allow sufficient time for the sponsor to seek patent 
protection of the invention. 


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13.3.2 
Public Disclosure Policy  
ICMJE member journals have adopted a trials-registration policy as a condition for publication. 
This policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is 
the responsibility of the sponsor to register the trial in an appropriate public registry, i.e. 
www.ClinicalTrials.gov; a website maintained by the National Library of Medicine (NLM) at the 
U.S. National Institutes of Health (NIH). The trial will also be made publicly available at the 
European Union (EU) Clinical Trials Register at www.clinicaltrialsregister.eu. Trial registration 
may occur in other registries in accordance with local regulatory requirements. A summary of the 
trial results is made publicly available in accordance with applicable regulatory requirements. 


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14 
ETHICAL AND REGULATORY ASPECTS 
14.1 
Independent Ethics Committee / Institutional Review Board / Research Ethics Board 
An IEC/IRB/REB will review the protocol and any amendments and advertisements used for 
recruitment. The IEC/IRB/REB will review the subject information sheet and the ICF, their updates 
(if any) and any written materials given to the subjects. A list of all IECs/IRBs/REBs to which the 
protocol has been submitted and the name of the committee chairmen will be included in the 
clinical trial report. 
14.2 
Regulatory Authorities Approval 
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available before a subject is 
exposed to any trial-related procedure, including screening tests for eligibility. 
14.3 
End-of-Trial and End-of-Trial Notification 
The end of this trial is defined as the date of the last visit (Visit 8) of the last subject undergoing the 
trial. An end-of-trial declaration will be prepared when the trial has ended and will be submitted to 
the IECs/IRBs/REBs and regulatory authorities. 
14.4 
Ethical Conduct of the Trial 
This trial will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki (World Medical Association Declaration of Helsinki, 2013), in compliance 
with the approved protocol, ICH-GCP and applicable regulatory requirements. 
14.5 
Subject Information and Consent 
The investigator (or the person delegated by the investigator) will obtain a freely given written 
consent from each subject after an appropriate explanation of the aims, methods, sources of 
funding, any possible conflicts of interest, anticipated benefits, potential risks of the trial and the 
discomfort it may entail, post-trial provisions and any other aspects of the trial which are relevant to 
the subject’s decision to participate. The trial subject must be given ample time to consider 
participation in the trial, before the consent is obtained. The Informed Consent Documents must be 
signed and dated by the subject and the investigator who has provided information to the subject 
regarding the trial before the subject is exposed to any trial-related procedure, including screening 
tests for eligibility. Subjects must be given the option of being informed about the general outcome 
and the results of the trial. 
The investigator (or the person delegated by the investigator) will explain that the subject is 
completely free to refuse to enter the trial or to withdraw from it at any time, without any 
consequences for his/her further care and without the need to justify his/her decision. 
The subject will receive a copy of the subject information and his/her signed ICF. 


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If new information becomes available that may be relevant to the trial subject’s willingness to 
continue participation in the trial, a new subject information and ICF will be forwarded to the 
IECs/IRBs/REBs (and regulatory authorities, if required). The trial subjects will be informed about 
this new information and re-consent will be obtained. 
Each subject will be informed that the monitor(s), quality assurance auditor(s) mandated by the 
sponsor, IRB/IEC/REB representatives or regulatory authority inspector(s), in accordance with 
applicable regulatory requirements, may review his/her source records and data. Data protection 
will be handled in compliance with national/local regulations. 
14.6 
Subject Participation Card 
The subject will be provided with a Subject Participation Card bearing the following information: 
• 
That he/she is participating in a clinical trial 
• 
That he/she is treated with FE 201836 / Desmopressin / Placebo 
• 
The name and phone number of the investigator 
• 
The name, address and phone number of the sponsor 
The subject will be asked to keep the Subject Participation Card in their possession at all times 
during the trial and to return it at the last trial visit, if applicable. 
Each subject’s primary care physician will be notified of their participation in the trial by the 
investigator, if the subject agrees and if applicable. 
14.7 
Compliance Reference Documents 
The Declaration of Helsinki (World Medical Association Declaration of Helsinki, 2013), the 
consolidated ICH-GCP, the EU Clinical Trials Directive and other national laws in the countries 
where the trial takes place shall constitute the main reference guidelines for ethical and regulatory 
conduct. 


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


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


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17 
REFERENCES 
Abrams P, Feneley R, Torrens M. Urodynamics. New York: Springer-Verlag Berlin 
Heidelberg;1983. Chapter 2; Patient assessment; p.6-27. 
Abrams P, Mattiasson A, Lose GR, Robertson GL. The role of desmopressin in the treatment of 
adult nocturia. BJU Int. 2002; 90(suppl 3):32-36. 
Ancoli-Israel S, Bliwise DL, Nørgaard JP. The effect of nocturia on sleep. Sleep Med Rev. 2011 
Apr;15(2):91-7. 
Asplund R, Aberg H. Diurnal variation in the levels of antidiuretic hormone in the elderly. J Intern 
Med. 1991 Feb;229(2):131-4. 
Asplund R. Nocturia: consequences for sleep and daytime activities and associated risks. Eur Urol 
Suppl. 2005;3(6):24-32. 
Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome 
measure for insomnia research. Sleep Med. 2001 Jul;2(4):297-307. 
Bliwise DL, Dijk DJ, Juul KV. Nocturia is associated with loss of deep sleep independently from 
sleep apnea. Neurourol Urodyn. 2015;34:392. 
Bosch JL, Weiss JP. The Prevalence and Causes of Nocturia. J Urol. 2010;184(2):440-6. 
Brunell E, Goessaert AS, Denys MA, Vande Walle J, Juul KV, Rittig S, Nørgaard JP, Everaert K. 
Copeptin in nocturics: A posthoc explorative analysis. Eur Urol Suppl 2016; 15: e539. 
Chartier-Kastler E, Tubaro A. The measurement of nocturia and its impact on quality of sleep and 
quality of life in LUTS/BPH. Eur Urol Suppl. 2006;5:3-11. 
Dmochowski RR, Sanders SW, Appell RA, Nitti VW, Davila GW. Bladder health diaries: an 
assessment of 3-day vs 7 day entries. BJU Int. 2005;96:1049-54. 
U.S. Department of Health and Human Services Food and Drug Administration (FDA). Guidance 
for Industry, Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims [Internet]. 2009 [cited 2016 Nov 30]. Available from: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf 
Gormley EA, Lightner DJ, Burgio KL, Chai TC, Clemens JQ, Culkin DJ et al. Diagnosis and 
treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline [Internet]. 2014 
[cited 2016 Nov 30]. Available from: https://www.auanet.org/common/pdf/education/clinical-
guidance/Overactive-Bladder.pdf 
Holm-Larsen T, Klein B, Weiss J. Correlation between voiding/sleep diaries, and nocturia and 


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sleep quality of life questionnaires. J Urol. 2009;181(suppl 4):538-539. 
Holm-Larsen T, Andersson F, van der Meulen E, Yankov V, Rosen RC, Nørgaard JP. The nocturia 
impact diary: a self-reported impact measure to complement the voiding diary. Value Health. 2014 
Sept;17(6):696-706. 
Hsu A, Nakagawa S, Walter LC, Van Den Eeden SK, Brown JS, Thom DH, et al. The Burden of 
Nocturia Among Middle-Aged and Older Women. Obstet Gynecol. 2015;125(1):35-43. 
Juul KV, Malmberg A, van der Meulen E, Walle JV, Nørgaard JP. Low-dose desmopressin 
combined with serum sodium monitoring can prevent clinically significant hyponatraemia in 
patients treated for nocturia. BJU Int. 2016 Nov 15. [Epub ahead of print] 
Lose G, Lalos O, Freeman RM, van Kerrebroeck P; Nocturia Study Group. Efficacy of 
desmopressin (Minirin) in the treatment of nocturia: a double-blind placebo-controlled study in 
women. Am J Obstet Gynecol. 2003 Oct;189(4):1106-13. 
McVary KT, Roehrborn CG, Avins AL, Barry MJ, Bruskewitz RC, Donnell RF, et al. Update on 
AUA guideline on the management of benign prostatic hyperplasia. J Urol. 2011 May;185(5):1793-
803.doi:10.1016/j.juro.2011.01.074. 
Mattiasson A. Efficacy of desmopressin in the treatment of nocturia: a double-blind placebo-
controlled study in men. BJU Int. 2002;89(9):855-62. 
Patrick DL, Burke LB, Gwaltney CJ, Leidy NK, Martin ML, Molsen E, et al. Content validity--
establishing and reporting the evidence in newly developed patient-reported outcomes (PRO) 
instruments for medical product evaluation: ISPOR PRO Good Research Practices Task Force 
report: part 2 -assessing respondent understanding. Value Health. 2011;14(8):978-88. 
Ratitch B, O’Kelly M. Implementation of Pattern-Mixture Models Using Standard SAS/STAT 
Procedures. Proceedings of PharmaSUG 2011 (Pharmaceutical Industry SAS Users Group), SP04, 
Nashville. 
Reeve BB, Wyrwich KW, Wu AW, Velikova G, Terwee CB, Snyder CF et al. ISOQOL 
recommends minimum standards for patient-reported outcome measures used in patient-centered 
outcomes and comparative effectiveness research. Qual Life Res. 2013;22(8):1889-905. 
Tikkinen KA, Johnson TM 2nd, Tammela TL, Sintonen H, Haukka J, Huhtala H, et al. Nocturia 
frequency, bother, and quality of life: how often is too often? A population-based study in Finland. 
Eur Urol. 2010;57(3):488-96. 
van Kerrebroeck P, Abrams P, Chaikin D, Donovan J, Fonda D, Jackson S, et al. The 
standardisation of terminology in nocturia: report from the Standardisation Sub-committee of the 
International Continence Society. Neurourol Urodyn. 2002;21(2):179-83. 


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van Kerrebroeck P. Desmopressin in the Treatment of Nocturia: A Double-Blind, Placebo-
Controlled Study. Eur Urol. 2007;52(1):221–229. 
Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, et al. Diagnosis, 
evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013 
Oct;126(10 Suppl 1):1-42. 
Viktrup L, Hayes RP, Wang P, Shen W. Construct validation of patient global impression of 
severity (PGI-S) and improvement (PGI-I) questionnaires in the treatment of men with lower 
urinary tract symptoms secondary to benign prostatic hyperplasia. BMC Urology. 2012;12(1):1-8. 
Wein A, Lose GR, Fonda D. Nocturia in men, women and the elderly: a practical approach. BJU 
Int. 2002 Dec;90(Suppl 3):28-31. 
Weiss JP, Blaivas JG, Blanker MH, Bliwise DL, Dmochowski RR, Drake M, et al. The New 
England Research Institutes, Inc. (NERI) Nocturia Advisory Conference 2012: focus on outcomes 
of therapy. BJU Int. 2013 May;111(5):700-16. 
World Medical Association Declaration of Helsinki. Ethical Principles for Medical Research 
Involving Human Subjects. 64th WMA General Assembly, Fortaleza, Brazil, October 2013. 
Yalcin I, Bump RC. Validation of two global impression questionnaires for incontinence. Am J 
Obstet Gynecol. 2003;189(1):98-101.  
Yamaguchi O, Nishizawa O, Juul KV, Nørgaard JP. Gender difference in efficacy and dose 
response in Japanese patients with nocturia treated with 4 different doses of desmopressin orally 
disintegrating tablet in a randomized, placebo-controlled trial. BJU Int. 2013 Mar;111(3):474-84. 


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18 
APPENDICES 
Appendix 1 
 
Exit Interview Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2 
 
Statistical Design and Operating Characteristics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SAP_001.pdf: 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
Title of trial:  
A Randomised, Double-blind, Placebo-controlled, Response-adaptive Dose- 
finding Trial Investigating the Efficacy, Safety and Tolerability of Oral Doses 
of FE 201836, with Desmopressin Orally Disintegrating Tablet as a 
Benchmark, During 12 Weeks of Treatment for Nocturia due to Nocturnal 
Polyuria in Adults 
NCT number: 
NCT03201419 
Sponsor trial code: 
000233  
Date:  
12 Dec 2019  
 
 
 
 
 


Date: 12 Dec 2019
E-Statistical Analysis Plan-23946; Ver. 1.0
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Page 1 of 53
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CONFIDENTIAL 
FE 201836 
Trial Code: 000233  
Statistical Analysis Plan 
STATISTICAL ANALYSIS PLAN 
A Randomised, Double-blind, Placebo-controlled, Response-adaptive Dose-finding Trial 
Investigating the Efficacy, Safety and Tolerability of Oral Doses of FE 201836, with 
Desmopressin Orally Disintegrating Tablet as a Benchmark, During 12 Weeks of Treatment 
for Nocturia due to Nocturnal Polyuria in Adults  
000233 (DAWN) 
Investigational Product: 
FE 201836 Oral Solution 
Indication: 
Nocturia due to Nocturnal Polyuria 
Phase: 
2 
Author: 
 
Date of issue: 
Version: 
1.0 
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in 
any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or another company 
within the Ferring Group 


Date: 12 Dec 2019
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FE 201836 
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Statistical Analysis Plan 
 
 
Change log 
 
Version 
No. 
 
Effective 
Date 
 
Reason for the Change / Revision 
 
Supersedes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Date: 12 Dec 2019
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FE 201836 
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Statistical Analysis Plan 
Review and Approval of Statistical Analysis Plan 
 
 
Author 
   
 
___________________________________________________ 
 
 Statistician, Global Biometrics 
Ferring Pharmaceuticals A/S 
 
Reviewers 
 
 
__________________________________________________ 
 
 
 
Statistical Programmer, Global Biometrics 
Ferring Pharmaceuticals A/S 
 
__________________________________________________ 
 
 
 
 Pharmacovigilance physician, Global Pharmacovigilance,
 
Ferring Pharmaceuticals A/S 
 
__________________________________________________ 
 
 
 
 
 
 
Medical writer, Medical Writing 
Ferring Pharmaceuticals A/S 
 
__________________________________________________ 
 
  
 Statistician, Global Biometrics 
Ferring Pharmaceuticals A/S 
 
__________________________________________________ 
 
 
Ferring Pharmaceuticals A/S 
 
 
Approval by 
   
__________________________________________________ 
  
 
 
 
, Biometrics 
Ferring Pharmaceuticals A/S 
 


Date: 12 Dec 2019
E-Statistical Analysis Plan-23946; Ver. 1.0
Supersedes: None
Page 4 of 53
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
FE 201836 
Trial Code: 000233  
Statistical Analysis Plan 
 
TABLE OF CONTENTS 
1 
Introduction ....................................................................................................................... 7 
1.1 
General Considerations .............................................................................................. 7 
1.2 
Definitions/ Abbreviations .......................................................................................... 7 
1.2.1 
Definition of Terms ..................................................................................... 7 
1.2.2 
Abbreviations ............................................................................................. 8 
1.3 
Presentation of Results ............................................................................................... 9 
1.3.1 
Presentation of Descriptive Results ................................................................ 9 
1.3.2 
Presentation of Inferential Results .................................................................. 9 
1.3.3 
Subject Data Listings by Domain ................................................................... 9 
1.3.4 
Subject Profiles ........................................................................................... 9 
2 
Trial Objectives and Endpoints.......................................................................................... 10 
2.1 
Objectives .............................................................................................................. 10 
2.2 
Endpoints............................................................................................................... 10 
3 
Trial design ...................................................................................................................... 12 
3.1 
Design Considerations ............................................................................................. 12 
3.1.1 
General Considerations .............................................................................. 12 
3.1.2 
Sample Size.............................................................................................. 13 
3.1.3 
Trial Stages .............................................................................................. 13 
3.1.4 
Trial Epochs ............................................................................................. 14 
3.1.5 
Visits and Visit Windows ........................................................................... 14 
4 
Major Protocol Deviations ................................................................................................. 17 
5 
Analysis sets ..................................................................................................................... 18 
5.1 
Enrichment-Period Analysis Sets ............................................................................... 18 
5.1.1 
Intention-To-Treat Analysis Set for the Enrichment Period (ITT-ENR).............. 18 
5.1.2 
Safety Analysis Set for the Enrichment Period (Safety-ENR) ........................... 18 
5.2 
Randomized-Treatment-Period Analysis Sets .............................................................. 18 
5.2.1 
Intention-To-Treat Analysis Set for the Randomized-Treatment Period (ITT-
RT) ......................................................................................................... 18 
5.2.2 
Per Protocol (PP) Analysis Set for the Randomized-Treatment Period ............... 18 
5.2.3 
Safety Analysis Set for the Randomized-Treatment Period (Safety-RT) ............. 18 
6 
Trial population................................................................................................................ 19 
6.1 
Demographics and Other Baseline Characteristics ........................................................ 19 
6.1.1 
General Considerations .............................................................................. 19 
6.1.2 
Demographics........................................................................................... 19 
6.1.3 
Vital Signs at Baseline ............................................................................... 19 
6.1.4 
Physical Examination at Baseline................................................................. 19 
6.1.5 
Laboratory Efficacy Parameters at Baseline................................................... 19 
6.1.6 
e-Diary Assessments at Baseline.................................................................. 19 
6.2 
Medical History ...................................................................................................... 19 
7 
Subject Disposition............................................................................................................ 20 
8 
Prior and Concomitant Medication .................................................................................... 21 


Date: 12 Dec 2019
E-Statistical Analysis Plan-23946; Ver. 1.0
Supersedes: None
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Ferring Pharmaceuticals 
CONFIDENTIAL 
FE 201836 
Trial Code: 000233  
Statistical Analysis Plan 
9 
Exposure and Treatment Compliance................................................................................. 22 
9.1.1 
Extent of Exposure .................................................................................... 22 
9.1.1.1 
General Considerations ............................................................. 22 
9.1.1.2 
Extent of Exposure Based on the Investigator-Assessed Amount 
of IMP Dispensed and Returned ................................................. 22 
9.1.1.3 
Extent of Exposure Based on the Subject’s e-Diary Registration ..... 23 
9.1.1.4 
Agreement of the Two Sources .................................................. 23 
9.1.2 
Treatment Compliance ............................................................................... 24 
10 
Efficacy ............................................................................................................................ 25 
10.1 
General Considerations ............................................................................................ 25 
10.2 
Primary Efficacy Endpoint........................................................................................ 25 
10.2.1 
Primary Analysis....................................................................................... 25 
10.2.2 
Sensitivity Analyses .................................................................................. 27 
10.2.3 
Descriptive analysis ................................................................................... 28 
10.3 
Secondary Efficacy and Exploratory Analyses ............................................................. 28 
10.3.1 
General Considerations .............................................................................. 28 
10.3.2 
Scoring of Patient-Reported Outcomes ......................................................... 31 
10.3.3 
Bayesian estimation of the sigmoidal dose-response curve ............................... 33 
10.3.4 
Treatment effects on cross-sectional change from baseline for quantitative 
variables and PGI-I.................................................................................... 34 
10.3.5 
Treatment effects on cross-sectional binary variables ...................................... 34 
10.3.6 
Treatment effects on single-time-point quantitative variables ........................... 35 
10.4 
Therapeutic Window................................................................................................ 35 
10.5 
Explorative Benchmarking Analysis........................................................................... 36 
11 
Safety............................................................................................................................... 37 
11.1 
General Considerations ............................................................................................ 37 
11.1.1 
Analysis Sets ............................................................................................ 37 
11.1.2 
Imputation Rules ....................................................................................... 37 
11.1.3 
Visit and Visit Windows............................................................................. 37 
11.2 
Safety Endpoints of Special Interest ........................................................................... 37 
11.2.1 
Hyponatraemia Episodes Based on Observed Serum Sodium Levels ................. 37 
11.2.1.1 
General Considerations ............................................................. 37 
11.2.1.2 
Observed Serum Sodium Levels................................................. 38 
11.2.1.3 
Hyponatraemia Episodes During the Randomized-Treatment 
Period based on Observed Serum Sodium Levels.......................... 38 
11.2.2 
24-hour Urine Volume ............................................................................... 39 
11.3 
Routine Safety Assessments...................................................................................... 39 
11.3.1 
Adverse Events ......................................................................................... 39 
11.3.1.1 
General Considerations ............................................................. 39 
11.3.1.2 
Tabulations of Treatment-Emergent Adverse Events ..................... 40 
11.3.2 
Safety Laboratory Variables........................................................................ 41 
11.3.2.1 
General Considerations ............................................................. 41 
11.3.2.2 
Visits and Visit Windows.......................................................... 41 
11.3.2.3 
Summary Statistics .................................................................. 41 
11.3.2.4 
Laboratory Variable Changes Relative to Normal Range................ 42 
11.3.3 
Vital Signs ............................................................................................... 42 


Date: 12 Dec 2019
E-Statistical Analysis Plan-23946; Ver. 1.0
Supersedes: None
Page 6 of 53
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
FE 201836 
Trial Code: 000233  
Statistical Analysis Plan 
11.3.3.1 
Visits and Visit Windows.......................................................... 42 
11.3.3.2 
Summary Statistics .................................................................. 42 
11.3.4 
ECGs ...................................................................................................... 42 
11.3.5 
Other Safety Variables ............................................................................... 42 
11.3.5.1 
Weight Changes ...................................................................... 42 
11.3.5.2 
Physical examination................................................................ 43 
12 
Interim analyses................................................................................................................ 44 
13 
Risk-benefit assessment ..................................................................................................... 45 
14 
Deviations From the Trial Protocol .................................................................................... 46 
15 
Tables, Listings and Figures .............................................................................................. 49 
16 
References ........................................................................................................................ 50 
Appendices ................................................................................................................................ 51 
Appendix 1 
Markedly Abnormal Laboratory Safety Values, Vital Signs and ECGs.............. 51 
 
List of Tables 
Table 1 
Posterior Probabilities of Interest ................................................................................... 12 
Table 2 
Operating Characteristics.............................................................................................. 13 
Table 3 
Schedule for Assessments of Endpoints According to the Flow Chart in the Protocol. ............ 14 
Table 4 
Visit Windows Using Analysis Day Calculated as Site Visit Date – Date of Visit 4. .............. 16 
Table 5 
Analysis of Endpoints .................................................................................................. 29 
Table 6 
Constant to be subtracted from baseline, mean in the prior distributions of α1 and α2, and 
scaling factor used in the Bayesian analyses .................................................................... 33 
Table 7 
Definition of Hyponatraemia Episodes by Serum Sodium Range: Number of Consecutive 
Measurements of Serum Sodium below Upper Threshold Needed to Start Episode ................ 37 
Table 8 
Tabulations of Treatment-Emergent Adverse Events......................................................... 40 
 


Date: 12 Dec 2019
E-Statistical Analysis Plan-23946; Ver. 1.0
Supersedes: None
Page 7 of 53
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
FE 201836 
Trial Code: 000233  
Statistical Analysis Plan 
1 
Introduction 
1.1 
General Considerations 
This document describes the planned statistical analyses for 000233 DAWN.  This SAP is based on 
the consolidated protocol Ver.5.0, dated 05 July 2018, with changes according to Global 
Amendments #01, #02, and #03 implemented. 
1.2 
Definitions/ Abbreviations 
1.2.1 
Definition of Terms 
Terms 
Definitions 
Aggregated Average 
Average over post-randomization visits up to and including the current visit 
Baseline-ENR 
Baseline measurement for the enrichment period, assessed at Visit 2 
Baseline-RT 
Baseline measurement for the randomized-treatment period, assessed at Visit 4 
Δd 
Effect of dose d of FE 201836 compared to placebo 
e-Diary 
Electronic diary filled out by the participant at home, covering Insomnia Severity Index 
(ISI), Nocturia Impact Diary (NI diary), Patient Global Impression of Severity (PGI-S), 
Patient Global Impression of Improvement (PGI-I), HSU 5 point Likert bother scale 
(Bother), Voiding Diary, and IMP intake 
ED85 
The minimum dose most likely to have more than 85% of the effect of the maximum dose 
Enrichment Period 
Period between dispense of single-blind treatment and randomization 
FUSP 
First Undisturbed Sleep Period (FUSP) is defined as the time in minutes from the time of 
going to bed to the time of first nocturnal void, or time of awakening if no void occurred 
MED 
The minimally effective dose defined as the lowest dose that has at least a 0.3 larger 
reduction in mean nocturnal voids compared to placebo 
µd 
The mean dose-response at dose d of FE 201836 corresponding to two nocturnal voids at 
baseline-RT 
Nocturnal diuresis rate 
The nocturnal diuresis rate is the ratio of Nocturnal Urine Volume (NUV, mL) to tot al time 
in bed (min) 
NPi 
Nocturnal Polyuria index (NPi) is calculated as the ratio of  the nocturnal urine volume 
(NUV) by the 24-hour urine volume 
NUV 
Nocturnal Urine Volume (NUV) is the total urine volume from 5 minutes after bedtime with 
the intention to sleep until the first void within 30 minutes of rising in the morning 
Pr(dose d is ED85) 
Posterior probability that the dose d is the ED85 
Pr(dose d is MED) 
Posterior probability that the dose d is the MED 
Pr(Δd<−0.3) 
Posterior probability that the dose d has at least a 0.3 larger reduction in mean nocturnal 
voids compared to placebo 
Pr(µ500<µPlb) 
Posterior probability that 500 µg FE 201836 is superior to placebo  
Safety-ENR 
Safety analysis set for the enrichment period 
Safety-RT 
Safety analysis set for the randomized-treatment period 
 


Date: 12 Dec 2019
E-Statistical Analysis Plan-23946; Ver. 1.0
Supersedes: None
Page 8 of 53
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
FE 201836 
Trial Code: 000233  
Statistical Analysis Plan 
1.2.2 
Abbreviations 
Abbreviations 
Meaning of abbreviations in document 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC  
Anatomic Therapeutic Chemical  
CV  
Coefficient of Variation 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ENR 
Enrichment Period 
FUSP 
First Undisturbed Sleep Period 
HLGT 
High Level Group Term 
HLT 
High Level Term 
IMP 
Investigational Medicinal Product 
ISI 
Insomnia Severity Index 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measurements (repeated-measurements ANCOVA) 
NI 
Nocturia Impact 
NPi 
Nocturnal Polyuria index  
NUV 
Nocturnal Urine Volume  
ODT 
Orally Disintegrating Tablet 
PP 
Per-Protocol 
PT 
Preferred Term 
RT 
Randomized-treatment Period 
SAE 
Serious Adverse Event 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 


Date: 12 Dec 2019
E-Statistical Analysis Plan-23946; Ver. 1.0
Supersedes: None
Page 9 of 53
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
FE 201836 
Trial Code: 000233  
Statistical Analysis Plan 
1.3 
Presentation of Results 
1.3.1 
Presentation of Descriptive Results 
Categorical data will be summarized, unless otherwise stated, using frequency (n) and relative 
frequencies as percentage (i.e. n/N*100). 
Continuous data will be presented for observed values and change form baseline for each visit and 
at last visit, unless otherwise stated, using the number of subjects (N), mean, standard deviation 
(SD), median, lower and upper quartiles, minimum, and maximum. 
Only table shells for inferential statistics will be provided.  End-of-Text and In-Text tables of 
descriptive statistics follow in-house standards. 
1.3.2 
Presentation of Inferential Results 
Frequentist inferential results will be presented using the respective point estimates with two-sided 
95% confidence intervals unless otherwise stated.  Bayesian inferential results are expressed in 
terms of posterior means and medians and 95% credibility intervals, unless otherwise stated.     
Generic table shells per type of analysis will be provided. 
1.3.3 
Subject Data Listings by Domain  
All subject data will be presented by listings organized in accordance to ICH –E3. More precisely 
the following listings will be provided: 
• Discontinued subjects  
• Major protocol deviations  
• Subjects (and observations) excluded from the efficacy analysis  
• Demographic data  
• Compliance  
• Individual efficacy response data  
• Adverse event listings (each subject)  
• Listing of individual laboratory measurements by subject, when required by regulatory 
authorities 
1.3.4 
Subject Profiles  
Subject profiles will be created using in-house standard SAS macros. 


Date: 12 Dec 2019
E-Statistical Analysis Plan-23946; Ver. 1.0
Supersedes: None
Page 10 of 53
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
FE 201836 
Trial Code: 000233  
Statistical Analysis Plan 
2 
Trial Objectives and Endpoints 
2.1 
Objectives 
Primary Objective 
• To establish the dose-response of FE 201836 with respect to the number of nocturnal voids 
in subjects with nocturia due to NP. 
Secondary Objectives 
• To evaluate responder rates with regards to changes in number of nocturnal voids. 
• To psychometrically validate the Nocturia Impact Diary© (NI Diary). 
• To evaluate the subject benefit of FE 201836 based on the NI Diary data. 
• To evaluate the clinical benefit of FE 201836 based on reduction in nocturnal voiding. 
• To evaluate FE 201836 with respect to sleep benefit, i.e., duration of the First Undisturbed 
Sleep Period (FUSP) and sleep related Patient Reported Outcomes (PROs). 
• To evaluate the PD effect of FE 201836 with respect to nocturnal diuresis rate and NP. 
Safety Objective 
• To evaluate the safety profile of FE 201836. 
Exploratory Objectives 
• To explore the biomarker copeptin, an AVP surrogate, to identify low nocturnal vasopressin 
levels in plasma. 
• To explore the dose-response of FE 201836 with respect to total sleep time. 
• To explore the association between total sleep time and FUSP. 
• To explore the effect of FE 201836 with respect to Nocturnal Polyuria index (NPi). 
• To benchmark the efficacy of FE 201836 in relation to desmopressin. 
2.2 
Endpoints 
Primary Endpoint 
• Change from baseline in number of nocturnal voids during 12 weeks of treatment. 
Secondary Endpoints 
• Change from baseline in number of nocturnal voids at Weeks 1, 4, 8 and 12. 
• Responder rate defined as 50% reduction in nocturnal voids from baseline at Weeks 1, 4, 8 
and 12 during 12 weeks of treatment. 
• Change from baseline in NI Diary Total Score at Weeks 1, 4, 8 and 12 and during 12 weeks 
of treatment. 
• Percentage of nights during the treatment period with at most one nocturnal void. 


Date: 12 Dec 2019
E-Statistical Analysis Plan-23946; Ver. 1.0
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Ferring Pharmaceuticals 
CONFIDENTIAL 
FE 201836 
Trial Code: 000233  
Statistical Analysis Plan 
• Percentage of nights during the treatment period with complete response, i.e., with no 
nocturnal voids. 
• Change from baseline in NI Diary Overall Impact Score at Weeks 1, 4, 8 and 12 and during 
12 weeks of treatment. 
• Patient Global Impression of Improvement (PGI-I) urinary symptoms scores at Weeks 1, 4, 
8 and 12. 
• Change from baseline in Patient Global Impression of Severity (PGI-S) scores at Weeks 1, 
4, 8 and 12. 
• Change from baseline in Bother as measured by the Hsu 5-point Likert Bother scale 
(Hsu, 2015) at Weeks 1, 4, 8 and 12. 
• Change from baseline in Insomnia Severity Index (ISI) at Weeks 4, 8 and 12. 
• Change from baseline in FUSP at 1, 4, 8 and 12 weeks of treatment and during 12 weeks. 
• Change from baseline in nocturnal diuresis rate (hourly) profiles at Week 1 and Week 12. 
• Change from baseline in Nocturnal Urine Volume (NUV) at Week 1 and Week 12. 
Safety Endpoints 
• Incidence and severity of adverse events. 
• Incidence of hyponatraemia as measured by serum sodium level throughout the trial. 
• Change from baseline in mean 24-hour urine volume at Week 1 and Week 12. 
• Clinically significant changes in vital signs and laboratory values. 
Exploratory Endpoints 
• Responder rates defined as 33%, 60%, 70%, 80%, 90% and 100% reduction from baseline 
in number of nocturnal voids at Weeks 1, 4, 8 and 12. 
• Responder rates defined as 1, 2, and 3 voids reduction from baseline in number of nocturnal 
voids at Weeks 1, 4, 8 and 12. 
• The correlation of copeptin levels to NPi at Visit 2. 
• Change from baseline in copeptin levels at Week 12. 
• Change from baseline in total sleep time per night at Weeks 1, 4, 8 and 12 and during 
12 weeks of treatment.  
• Correlation between change from baseline in total sleep time and FUSP at Weeks 1, 4, 8 
and 12. 
• Change from baseline in NPi at Week 1 and Week 12. 


Date: 12 Dec 2019
E-Statistical Analysis Plan-23946; Ver. 1.0
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Ferring Pharmaceuticals 
CONFIDENTIAL 
FE 201836 
Trial Code: 000233  
Statistical Analysis Plan 
3 
Trial design 
3.1 
Design Considerations 
3.1.1 
General Considerations 
DAWN is a randomized, double-blind, placebo-controlled, response-adaptive, dose-finding trial 
with Desmopressin Orally Disintegrating Tablet (ODT) as a benchmark.  The trial has a screening 
period with a 2-week life-style intervention period and an enrichment phase with a 1-week single-
blind treatment with the highest dose of FE 201836 and a 1-week washout period, followed by a 
randomization to double-blind, double-placebo treatment with placebo, different doses of 
FE 201836, or desmopressin.  
The trial is designed with two stages:   
In the first stage of the trial, 125 subjects are randomized in a 2:2:1 allocation ratio to placebo, 
500 µg FE 201836, or desmopressin, and an interim analysis for futility is performed.  
In the second stage, the subjects are randomized with the allocation ratio 2:7:1 for placebo, active 
treatment with FE 201836, or desmopressin, respectively.  Subjects allocated to FE 201836 are 
randomized to 50 µg FE 201836, 100 µg FE 201836, 150 µg FE 201836, 250 µg FE 201836, 
350 µg FE 201836, or 500 µg FE 201836 according to allocation probabilities determined in the 
interim analyses according to pre-specified rules.  Subsequent interim analyses will be performed 
every 8 weeks, where futility analyses will be performed and the randomization allocation 
probabilities to the different FE 201836 doses will be adjusted. 
Based on the Bayesian analysis of a baseline-adjusted dose-response curve, the minimum dose most 
likely to have more than 85% of the effect of the maximum dose (ED85), and the dose most likely to 
be the minimally effective dose (MED, defined as the minimum dose that has more than 0.3 voids 
reduction in nocturnal voids as compared to placebo) will be identified during the reporting of the 
trial.  There are four posterior probabilities of interest as presented in Table 1:  
Table 1 
Posterior Probabilities of Interest 
Quantity of Interest Posterior Probability within the Trial that: 
Objective 
Pr(𝜇500 < 𝜇𝑃𝑙𝑏) 
the effect of 500 µg FE 201836 during the 12 weeks 
of randomized treatment is superior to placebo  
Proof-of-Concept 
Pr(𝛥500 < −0.3) 
500 µg FE 201836 has more than 0.3 voids 
reduction in nocturnal voids as compared to placebo  Futility 
Pr(dose d is MED) 
dose d is the MED 
Establish the MED 
Pr(dose 𝑑 is 𝐸𝐷85) 
dose d is the ED85 
Establish ED85 
 


Date: 12 Dec 2019
E-Statistical Analysis Plan-23946; Ver. 1.0
Supersedes: None
Page 13 of 53
 
 
Ferring Pharmaceuticals 
CONFIDENTIAL 
FE 201836 
Trial Code: 000233  
Statistical Analysis Plan 
In the trial updates of the allocation probabilities, the two posterior probabilities: Pr(dose d is MED) 
and Pr(dose d is ED85), are used in the updated allocation probability for dose d.  The trial updates 
are performed as analyses without baseline adjustment, thus, they are not based on the model used 
for the primary analysis in the reporting of the trial.  For additional information, see Section 12. 
3.1.2 
Sample Size 
A maximum of 300 subjects (males and females) will be randomized into the trial.  The sample size 
was based on computer simulations under five sigmoidal dose-response profiles without baseline 
adjustment.  The operating characteristics and associated power were estimated for the different 
dose-response scenarios by computer simulations using the Fixed and Adaptive Clinical Trial 
Simulator (FACTS) version 5.6.  
The average number of subjects and probabilities for futility and success are presented in Table 2. 
Table 2 
Operating Characteristics 
Dose-Response 
Scenario 
Maximum 
response 
(𝛼2) 
ED50 
(𝛼3) 
Average 
Number of 
Subjects 
Futility 
Stopping at 
First Interim 
Total  
Futility 
stopping 
Power 
(Total  
Success) 
Null 
0 
0 µg 
200 
75.8% 
97.0% 
3.0% 
I 
-0.3 
150 µg 
277 
15.7% 
47.9% 
52.1% 
II 
-0.4 
200 µg 
288 
7.9% 
25.1% 
74.9% 
III 
-0.5 
200 µg 
296 
2.8% 
9.6% 
90.4% 
IV 
-0.5 
350 µg 
295 
3.4% 
15.4% 
84.6% 
V 
-0.6 
300 µg 
298 
1.4% 
2.7% 
97.3% 
 
For each dose-response scenario, 1,000 trials were simulated in order to estimate the operating 
characteristics presented in Table 2. The simulations under the null-hypothesis (no effect) 
demonstrate that the probability of making a false positive conclusion is 3.0%, while under the 
assumption of a maximum reduction versus placebo of 0.5 voids, the power (probability of success) 
reaches approximately 85 to 90%. 
3.1.3 
Trial Stages 
In the first of the two trial stages, an interim Bayesian analysis for futility is performed after 125 
subjects have been randomized.  The futility stopping rule in the first stage is that a less than 10% 
posterior probability that 500 µg FE 201836 has >0.3 voids reduction in nocturnal voids as 
compared to placebo (Pr(𝜇500 −𝜇𝑃𝑙𝑏< −0.3)<10%).   
The futility stopping rule in the second stage is a less than 5% posterior probability that 500 µg 
FE 201836 has >0.3 voids reduction in nocturnal voids as compared to placebo (Pr(𝜇500 −𝜇𝑃𝑙𝑏<
−0.3)<5%). 
Bayesian estimates based in the dose-response curve without baseline adjustment will be used to 
update the allocation probabilities for the different doses of FE 201836 (see Section 12). 


Date: 12 Dec 2019
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Ferring Pharmaceuticals 
CONFIDENTIAL 
FE 201836 
Trial Code: 000233  
Statistical Analysis Plan 
3.1.4 
Trial Epochs  
During the screening period, the trial has a 2-week lifestyle-changes period followed by an 
enrichment phase consisting of a 1-week single-blind active run-in period and a 1-week washout 
period.  The screening period is followed by a 12-week randomized, double-blind treatment period. 
Thus, the trial has 4 epochs, a lifestyle-changes epoch, a single-blind, active run-in epoch, a 
washout epoch, and a randomized, double-blind treatment epoch. 
3.1.5 
Visits and Visit Windows 
The scheduled measurement time points are presented in Table 3 for primary, secondary, safety, 
and exploratory endpoints in the order they occur in Section 2.2.  
Table 3 
Schedule for Assessments of Endpoints According to the Flow Chart in the 
Protocol.  
Capital X Shows Endpoint-Analyses Time Points, Lowercase x Shows Trial Assessments Not 
Considered as Endpoints.  
Trial Epoch 
Life-style 
Changes 
(Start of) Active 
Run-in 
(Start of) 
Washout 
Randomized Trial Period 
Visit  
V1 
V2 
V3 
V4 
(baseline-RT) 
V5 
V6 
V7 
V8 
Week 
 
 
 
 
1 
4 
8 
12 
Planned Day 
 
−14 
−7 
1 
8±2 
28±3 
56±3 
84±7 
Endpoints 
 
 
 
 
 
 
 
 
Primary Endpoint 
 
 
 
 
 
 
 
 
Number of nocturnal voids 
 
x 
x 
x 
X 
X 
X 
X 
Secondary Endpoints 
 
 
 
 
 
 
 
 
Responder rates derived from 
number of nocturnal voids 
 
 
 
 
X 
X 
X 
X 
NI Diary Total Score 
 
x 
 
x 
X 
X 
X 
X 
NI Diary Overall Impact Score 
 
x 
 
x 
X 
X 
X 
X 
PGI-I 
 
 
 
 
X 
X 
X 
X 
PGI-S 
 
x 
 
x 
X 
X 
X 
X 
Bother 
 
 
 
x 
X 
X 
X 
X 
ISI 
 
x 
 
x 
 
X 
X 
X 
FUSP 
 
x 
x 
x 
X 
X 
X 
X 
Nocturnal diuresis rate (=NUV 
/ Total sleep) 
 
x 
x 
x 
X 
 
 
X 
NUV 
 
x 
x 
x 
X 
 
 
X 
Safety Endpoints  
 
 
 
 
 
 
 
 
Adverse events a 
 
X 
X 
X 
X 
X 
X 
X 
Hyponatremia serum sodium 
level 
X 
 
X 
b 
X 
X 
X 
X 
Total daily urine volume 
 
x 
 
x 
X 
 
 
X 
Vital signs 
x 
X 
X 
X 
X 
X 
X 
X 
Laboratory values: 
Clinical chemistry, 
haematology, urinalysis 
x 
 
 
X 
X 
X 
X 
X 
Laboratory values: 
Coagulation factors 
x 
 
 
X 
 
X 
 
X 


Date: 12 Dec 2019
E-Statistical Analysis Plan-23946; Ver. 1.0
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Ferring Pharmaceuticals 
CONFIDENTIAL 
FE 201836 
Trial Code: 000233  
Statistical Analysis Plan 
Trial Epoch 
Life-style 
Changes 
(Start of) Active 
Run-in 
(Start of) 
Washout 
Randomized Trial Period 
Visit  
V1 
V2 
V3 
V4 
(baseline-RT) 
V5 
V6 
V7 
V8 
Week 
 
 
 
 
1 
4 
8 
12 
Planned Day 
 
−14 
−7 
1 
8±2 
28±3 
56±3 
84±7 
Endpoints 
 
 
 
 
 
 
 
 
Exploratory Endpoints 
 
 
 
 
 
 
 
 
NPi (=NUV / Total daily urine 
volume) 
 
X 
 
x 
X 
 
 
X 
Copeptin 
 
X 
 
x 
 
 
 
X 
Total sleep 
 
x 
x 
x 
X 
X 
X 
X 
 
a AEs are also recorded at a telephone follow-up scheduled at Day  −10±1 
b Serum Sodium is also measured at Visit 4 as a part of the standard laboratory measurments 
                                              
For post-randomization Voiding Diary endpoints, the date of completion of the diary (Night 3), will 
be used for the allocation of the data according to the visit windows.  For all other endpoints 
including pre-randomization Voiding Diary data, the corresponding actual site visit day will be used 
for the allocation of the data according to the visit windows.  The analysis day (ADY) is defined as 
date of corresponding site visit (Night 3 for post-randomization Voiding Diary data) – date of Visit 
4 (day of randomization / baseline of the double-blind treatment period).  Visit 4 is defined as 
Analysis Day 0 and has no visit window for the corresponding site visit date. 
For the screening period (the lifestyle-changes epoch, the active run-in epoch, and the washout 
epoch), the visit windows for all endpoints are linked to the start of the active run-in epoch (the 
baseline for the enrichment period), that is, the date of the scheduled Visit 2 (VISITNUM=2):  All 
visits before the date of VISITNUM=2 are allocated to the Visit 1 window.  All visits after the date 
of VISITNUM=2 and before the date of VISITNUM=4 are allocated to the Visit 3 window. 
Prioritization between multiple visits with non-missing assessment of the endpoint within the same 
visit window for the screening period will be performed according the following rules, unless 
otherwise specified: 
1. If the assessment is non-missing at the scheduled visit, the assessment at the scheduled visit 
is used.  
2. If the assessment is missing at the scheduled visit, the non-missing assessment closest to the 
scheduled visit is used. 
3. If the assessment is missing at the scheduled visit and the two closest, non-missing 
assessments from unscheduled visits in the same visit window have equal distances from the 
date of the scheduled visit, then the latest one will be selected (only relevant for Visit 3). 
For the randomized, double-blind treatment epoch, different visit windows will be used for different 
endpoints.  The endpoints fall mainly into two major categories according to when the endpoint is 
assessed.   


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Statistical Analysis Plan 
Category I comprises efficacy and safety endpoints assessed at all visits during the randomized-
treatment period. Efficacy endpoints are Number of Nocturnal Voids and Responder outcomes 
derived from number of nocturnal voids, NI Diary Total Score, NI Diary Overall Impact Score, 
PGI-I. PGI-S, Bother, FUSP, and Total Sleep. Safety endpoints are Hyponatremia Serum Sodium 
Level, Clinical Chemistry, Haematology, Urinalysis, Weight, and Vital Signs. 
Category II comprises the efficacy endpoints assessed only at Visits 5 and 8: Nocturnal Diuresis 
Rate, NUV, and NPi; and the safety endpoint: Total Daily Urine Volume.  
The remaining endpoints, the efficacy endpoints ISI and Copeptin and the safety endpoint 
Coagulation factors, are assessed at different visits. All visit windows for the randomized-treatment 
period are specified below (Table 4): 
Table 4 
Visit Windows Using Analysis Day Calculated as Site Visit Date – Date of Visit 4. 
 
Visit windows a 
Visit Number 
5 
6 
7 
8 
Visit Week 
Week 1 Week 4 
Week 8 Week 12 
Planned Day According to Protocol 8 
28 
56 
84 
Target day b 
7 
28 
56 
84 
Category I Endpoints 
[1, 17] 
[18, 42] 
[43, 70] 
[71, ∞[ 
Category II Endpoints 
[1, 45] 
NA 
NA 
[46, ∞[ 
ISI 
NA 
[1, 42] 
[43, 70] 
[71, ∞[ 
Copeptin 
NA 
NA 
NA 
[1, ∞[ 
Coagulation factors 
NA 
[1, 55] 
NA 
[56, ∞[ 
a using analysis day derived from the corresponding site visit date 
b to be used when prioritizing multiple assessments of an endpoint within the visit window 
                                              
Prioritization between multiple visits with non-missing assessment of the endpoint within the same 
visit window will be performed according the following rules, unless otherwise specified: 
1. If more than one non-missing assessment of an endpoint fall within the same visit window, 
the one closest to the target day will be used for that endpoint.   
2. If two non-missing assessments in the same visit window have equal distances from the 
target day, the latest one will be used. 
For the first safety interim analysis, the actual visit (VISITNUM) will be used.  For the futility 
interim analyses, the site visit date and the visit windows specified in Table 4 will be used. 


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Trial Code: 000233  
Statistical Analysis Plan 
4 
Major Protocol Deviations 
The following protocol deviations are considered major in the sense that they lead to exclusion of 
subject or subject data from the Per Protocol Set (see Section 5.2.2):  
• The subject is excluded in case of  <2 nocturnal voids (average over 3 diary nights) prior to 
Visit 2 or Visit 4 
• The subject is excluded in case of NPi ≤33% prior to Visit 2 
• The subject is excluded in case of  <20% decrease in nocturnal diuresis rate (mL/min) from 
during active run-in (Visit 2 to Visit 3) 
• The subject is excluded in case of maximum voided volume <200 mL prior to Visit 2 
• The subject is excluded in case of actual treatment not in accordance with randomized 
treatment 
• Visit-specific data are excluded in case of significant non-compliant treatment 
administration for the visit. For each visit, this is defined as e-Diary-registered intake of trial 
medication for less than half of the nights for which number of nocturnal voids could be 
derived 
• The subject is excluded in case of significant non-compliant e-Diary completion at Visit 4 
defined as the Voiding Diary filled out more than 1 week before the site visit for Visit 4 
• For Visits◦6, 7 and 8, visit-specific data are excluded in case of significant non-compliant 
e-Diary completion at the visit defined as the Voiding Diary completed more than 2 weeks 
before or after the planned day according to the protocol (28, 56, and 84 days after Visit 4, 
respectively). For Visit 5, significant non-compliance is defined as the Voiding Diary 
completed more than 14 days after Visit 4 
• Visit-specific data are excluded in case of current treatment with any of the following 
prohibited medications: 
o Thiazide diuretics [ATC code: C03AA] 
o V2-receptor antagonists/agonists (e.g., vaptans/desmopressin, vasopressin) 
[ATC code: C03XA/H01BA] 
o Loperamide [ATC code: A07DA03] 
o Botulinum toxin (cosmetic non-urological use is acceptable) [ATC code: J06AA04] 
o Valproate [ATC code: N03AG01]  
Serious unforeseen deviations deemed to impact the primary endpoint of the trial may additionally 
be rated as major protocol deviations by the sponsor on the basis of a blinded review of data before 
declaration of clean-file and lock of database. The list of major protocol deviations will be detailed 
and documented in the clean file document prior to database release to the trial statistician. 


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Trial Code: 000233  
Statistical Analysis Plan 
5 
Analysis sets 
5.1 
Enrichment-Period Analysis Sets 
5.1.1 
Intention-To-Treat Analysis Set for the Enrichment Period (ITT-ENR) 
The Intention-to-Treat analysis set for the enrichment period (ITT-ENR) comprises all subjects 
found to be eligible to enter the enrichment period (comprising 1 week of active run-in and 1 week 
of washout) at Visit 2.  All ITT-ENR analyses will be according to the planned treatment allocation. 
5.1.2 
Safety Analysis Set for the Enrichment Period (Safety-ENR) 
The safety analysis set for the enrichment period (Safety-ENR) comprises all subjects who received 
investigational medicinal product (IMP) at Visit 2 and did not return all IMP unused at or before 
Visit 4, based on the drug accountability.  This also includes any subject who was found not eligible 
at Visit 2 but received at least one dose of IMP at or after Visit 2 and before Visit 4 and did not 
return all IMP unused at or before Visit 4.  All safety analyses will be according to actual treatment 
received.   
5.2 
Randomized-Treatment-Period Analysis Sets 
5.2.1 
Intention-To-Treat Analysis Set for the Randomized-Treatment Period (ITT-RT) 
The Intention-to-Treat analysis set for the randomized-treatment period (ITT-RT) comprises all 
subjects randomized at Visit 4.   
5.2.2 
Per Protocol (PP) Analysis Set for the Randomized-Treatment Period 
The Per Protocol analysis set comprises all subject data (that is, all combinations of subject and 
visit) in the ITT-RT analysis set excluding subject data that meet any of the major protocol 
deviations as defined in Section 4.  Subjects for whom all post-baseline data are excluded are not 
included in the Per Protocol Set.   
5.2.3 
Safety Analysis Set for the Randomized-Treatment Period (Safety-RT) 
The safety analysis set for the randomized-treatment period (Safety-RT) comprises all subjects who 
received IMP at Visit 4 and did not return all IMP unused, based on the drug accountability, and 
have had at least one safety assessment after randomization (Visit 4).  This also includes any subject 
who was found not eligible at Visit 4 but who received at least one dose of IMP at or after Visit 4 
and did not return all IMP unused.  All safety analyses will be according to actual treatment 
received. 
 


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Trial Code: 000233  
Statistical Analysis Plan 
6 
Trial population 
6.1 
Demographics and Other Baseline Characteristics 
6.1.1 
General Considerations 
The trial has two baselines, one for the enrichment period (denoted baseline-ENR) including the 
latest data obtained before or at Visit 2, and one for the randomized-treatment period (denoted 
baseline-RT) including the latest data obtained before or at Visit 4 unless otherwise specified. 
6.1.2 
Demographics 
Baseline-ENR values of the demographics variables: age, sex, race, and ethnic origin, height, 
weight and BMI will be summarized overall for the ITT-ENR and the Safety-ENR analysis sets. 
Baseline-RT demographics will be summarized overall and by treatment group for the ITT-RT 
analysis set.  
6.1.3 
Vital Signs at Baseline 
Baseline-ENR vital signs will be summarized overall for the ITT-ENR analysis set. Baseline-RT 
vital signs will be summarized overall and by treatment group for the ITT-RT analysis set.  
6.1.4 
Physical Examination at Baseline  
Physical examination at baseline-ENR will be summarized overall for the ITT-ENR analysis set, 
and physical examination at baseline-RT will be summarized overall and by treatment group for the 
ITT-RT analysis set.  
6.1.5 
Laboratory Efficacy Parameters at Baseline 
Baseline-ENR copeptin will be summarized for the ITT-ENR analysis set. Baseline-RT copeptin 
will be summarized overall and by treatment group for the ITT-RT analysis set. 
6.1.6 
e-Diary Assessments at Baseline 
The baseline registrations in the e-Diary include a Voiding Diary, a Nocturia Impact Diary, PGI-S, 
ISI, and Bother. Based on the baseline registrations in the Voiding Diary, baseline values for several 
variables are derived: number of nocturnal voids, nocturnal urine volume, NPi, nocturnal diuresis 
rate, FUSP, and total sleep. The Nocturia Impact Diary is used to derive the baseline values of the 
two NI Diary endpoints, NI Diary Total Score and the overall QoL impact question. 
Baseline-ENR values of the e-Diary variables will be summarized overall for the ITT-ENR analysis 
set. Baseline-RT values of the e-Diary variables will be summarized overall and by treatment group 
for the ITT-RT analysis set. 
6.2 
Medical History 
Medical history recorded at the screening visit will be coded using the latest version of MedDRA 
and tabulated by System Organ Class (SOC) and preferred term (PT) and randomized-treatment 
group (including non-randomized subjects as a separate treatment group) for the Safety-ENR 
analysis set. 


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Statistical Analysis Plan 
7 
Subject Disposition 
Presentations of subject dispositions will be produced for the overall trial population and by sex. 
All subjects screened will be accounted for.  All screening failures, protocol violations, and 
discontinuations from trial will be summarized with frequency and percentage for each category of 
screening failure reason, protocol violation, and reason for discontinuation, respectively.  
All screening failures will be listed in a data listing including the reason(s) for screening failure. 
Subject disposition for the ITT-RT analysis set (Section 5.2.1) will be tabulated by treatment group.  
Reasons for not being randomized at Visit 4 will be categorized and summarized for the ITT-ENR 
(Section 5.1.1) analysis set.  Subject disposition for the safety analysis sets (Sections 5.1.2 and 
5.2.3), will be presented separately. 
For the ITT-RT analysis set, the treatment-arm (placebo, FE 201836 pooled, desmopressin pooled) 
differences in time to early discontinuation will be tested using the Log-Rank test, and, for each 
treatment arm separately, the one-minus-Kaplan–Meier (1-KM) plots of time to early 
discontinuation will be displayed differentiated by reason for discontinuation.  In these analyses, 
completers will be censored at the maximum of 84 days and the latest observed day of early 
discontinuation.  All early discontinuations will be summarized by time of and reason for 
discontinuation. 


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Trial Code: 000233  
Statistical Analysis Plan 
8 
Prior and Concomitant Medication 
Prior and concomitant medication will be summarized by the Anatomical Therapeutic Chemical 
Classification System (ATC) classification 1st level (alphabetically), ATC classification 2nd level (in 
decreasing order of frequency) and treatment group.  These medications will be tabulated for the 
Safety-ENR analysis set according to 
1) Prior medication taken exclusively prior to any treatment with IMP, i.e., with stop date 
before the date of dispense of first single-blind IMP; 
2) Concomitant medication taken during the enrichment period, i.e., medication that was not 
stopped before the date of first single-blind IMP administration and not started after the date 
of first double-blind IMP administration;  
3) Concomitant medication taken during the randomized-treatment period, i.e., medication that 
was not stopped before the date of first double-blind IMP administration and not started 
after the End-of-Trial Visit. 
If the timing of the dose of a concomitant medication cannot be established in relation to the 
administration of randomized IMP, it will be considered as concomitant medication in both the 
enrichment period and the randomized-treatment period. 


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Trial Code: 000233  
Statistical Analysis Plan 
9 
Exposure and Treatment Compliance 
9.1.1 
Extent of Exposure  
9.1.1.1 
General Considerations 
There are two independent sources for assessment of the extent of exposure: investigator’s 
registration of amount of IMP dispensed and amount of IMP returned, and the subject’s e-Diary 
registrations.  
The subjects are always dispensed two sets of IMP, one set of bottles and one set of ODT. 
Therefore, there are two sets of registrations of IMP accountability at each visit, one for the number 
of bottles dispensed and returned, and one for the number of ODT dispensed and returned. The 
investigator registers the amount of IMP dispensed in number of bottles and number of ODT at the 
scheduled Visits 2, 4, 5, 6, and 7 with dispense of IMP; and the amount of IMP returned in number 
of bottles and number of ODT at the scheduled Visits 3, 5, 6, 7, and End-of-Trial visit with 
accountability of IMP.   
The subject registers whether he/she took the trial medication in the e-Diary on a daily basis 
between Visits 2 and 3, and from Visit 4 to End-of-Trial Visit. 
The two sources will be summarized separately, and in addition, the agreement between the two 
sources will be quantified and summarized.   
9.1.1.2 
Extent of Exposure Based on the Investigator-Assessed Amount of IMP Dispensed 
and Returned 
Extent of exposure is measured both as duration of treatment in number of days and as number of 
doses.  The exposure in number of bottles and the exposure in number of ODT will be summarized 
separately. 
Duration for the active run-in period is derived as the date of the earliest of Visit 3 and End-of-Trial 
Visit minus the date of Visit 2.  Number of doses for the active run-in period is derived as number 
of doses dispensed at Visit 2 minus number of doses returned at the earliest of Visit 3 and End-of-
Trial Visit.  Duration and number of doses during the active run-in period will be summarized 
overall and by sex for the ITT-ENR analysis set and for the Safety-ENR analysis set. 
For each of the post-randomization visits with registration of amount of IMP returned, the duration 
in the preceding period between visits will be derived as the difference between the date of the 
current visit and the date of the previous visit with IMP accountability.  The number of doses will 
be calculated as the number of doses dispensed at the previous visit with IMP accountability minus 
the number of doses returned at the current visit.  If two or more visits with IMP accountability fall 
into the same visit window, the duration will be summed across the visits and the number of doses 
will be summed across the visits.   


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Statistical Analysis Plan 
The duration and the number of doses will be summarized by treatment group and visit, overall and 
by sex, for the ITT-RT analysis set and for the Safety-RT analysis set. 
Duration for the whole randomized-treatment period is derived as the date of the End-of-Trial Visit 
minus the date of Visit 4 and will be summarized by treatment group for the ITT-RT analysis set 
and for the Safety-RT analysis set.  Number of doses for the whole randomized-treatment period is 
derived as the sum of the doses across the post-randomization visits and will be summarized by 
treatment group for the ITT-RT analysis set and for the Safety-RT analysis set. 
Total duration will be derived as the difference between the date of the End-of-Trial Visit and the 
date of Visit 2.  Total extent of exposure in number of doses will be derived as the sum of the doses 
in the enrichment period and the doses in the randomized-treatment period. Total duration and total 
extent of exposure in number of doses will be summarized by treatment group for the ITT-RT 
analysis set and for the Safety-RT analysis set. 
9.1.1.3 
Extent of Exposure Based on the Subject’s e-Diary Registration 
When deriving extent of exposure based on the e-Diary, days with Voiding Diary assessments as 
well as days without Voiding Diary assessments will be considered. 
For each visit with an e-Diary assessment of IMP intake, the duration of exposure in days is derived 
as 1 + the difference between the date of the latest intake of IMP after the previous visit and the date 
of the earliest intake of IMP after the previous visit, and the extent of exposure in number of doses 
will be derived as the number of days where the subject answered Yes to “Did you take your study 
medication [during this diary day]?”.  In case two or more visits with an e-Diary assessment of 
IMP intake fall into the same visit window, the duration will be derived as the difference between 
the latest date of intake of IMP in any of the diaries and the earliest date of intake of IMP in any of 
the diaries, and the number of doses will be derived as the sum of doses across the diaries. 
Duration and number of doses at Visit 3 will be summarized overall and by sex for the ITT-ENR 
analysis set and for the Safety-ENR analysis set. 
Duration and number of doses will be summarized by treatment group and visit, overall and by sex, 
for the ITT-RT analysis set and for the Safety-RT analysis set. 
9.1.1.4 
Agreement of the Two Sources 
For each visit with e-Diary assessments of the exposure (scheduled Visits 3, 5, 6, 7, and 8), the 
number of doses according to the e-Diary in Section 9.1.1.3 will be subtracted from the 
investigator-assessed number of doses of bottles and ODT, respectively, derived for the same period 
according to Section 9.1.1.2.  The differences will be summarized by treatment group, sex, and 
visit; Visit 3 will be summarized for the ITT-ENR analysis set and for the Safety-ENR analysis set; 
the post-randomization visits will be summarized for the ITT-RT analysis set and for the Safety-RT 
analysis set.   


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Statistical Analysis Plan 
9.1.2 
Treatment Compliance  
Compliance will be derived separately for each of the three exposure measures of number of doses: 
the number of bottles and the number of ODT (Section 9.1.1.2), and the number of doses according 
to the e-Diary (Section 9.1.1.3).  For each exposure measure of number of doses, compliance in % 
during a specific period (that is, a period between two visits, the active run-in period, the 
randomized-treatment period, or total exposure duration) will be derived as the exposure measure of 
number of doses for the period divided by the corresponding exposure duration in days for the same 
period calculated in Section 9.1.1.2 as the end date minus the start date of the period, and multiplied 
by 100 to obtain a percentage. 
Compliance during the active run-in period will be summarized as overall and by sex for the ITT-
ENR analysis set and for the Safety-ENR analysis set. 
Compliance will be summarized by treatment group and visit, overall and by sex, for the ITT-RT 
analysis set and for the Safety-RT analysis set.  
In addition, for each visit with Voiding Diary assessments, treatment compliance will be derived for 
the nights where the number of nocturnal voids can be derived.  The treatment compliance in % 
during Voiding Diary assessment will be derived as the number of nights where the number of 
nocturnal voids can be derived and the subject answered Yes to “Did you take your study 
medication during this diary day?” divided by the total number of nights where the number of 
nocturnal voids can be derived in the Voiding Diary for the visit, and multiplied by 100 to obtain a 
percentage.  Treatment compliance during Voiding Diary assessment will be summarized as a 
categorical variable by treatment group and visit for the ITT-RT analysis set and for the PP analysis 
data set. 


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Statistical Analysis Plan 
10 
Efficacy 
10.1 
General Considerations 
For endpoints obtained from the Voiding Diary prior to a visit, the average of the endpoint across 
the 3 days will be interpreted as the cross-sectional observation of the endpoint in question at the 
specific visit, with the exception of the two endpoints, “Percentage of nights during the treatment 
period with at most one nocturnal void” and “Percentage of nights during the treatment period with 
complete response, i.e., with no nocturnal voids”.  
If the baseline number of nocturnal voids is missing for a reason that can be considered to be 
missing completely at random (e.g., missing due to technical problems of the eDiary), the subject 
will not included in any analyses that involves baseline measurements of nocturnal voids or other 
variables derived using baseline measurements of nocturnal voids. 
The Bayesian dose-response analyses are conducted on aggregated averages, that is, outcomes 
averaged across preceding post-randomization visits.  The posterior mean, median, and 95% 
credibility interval (2.5 and 97.5 percentiles of the posterior distribution) of quantities of interest as 
well as posterior probabilities of interest will be reported.  
Frequentist inferences will rely on the appropriate choice of model and report p-values 
corresponding to the statistical test of the hypothesis of “no difference / no association” against the 
alternative of “any difference / any (linear) association”.  The level of significance is set at 5% 
(two-sided).  
Treatment comparison refers to the pair-wise comparison between each of the different doses of 
active treatment with FE 201836 and placebo.  There are no planned adjustments for multiplicity 
when pair-wise testing the active treatment with different doses of FE 201836 versus 
placebo.  Desmopressin is included as a benchmark treatment only.  None of the primary, secondary 
or explorative analyses will include data from subjects treated with desmopressin.  Explorative 
benchmarking analyses are further described in Section 10.5. 
10.2 
Primary Efficacy Endpoint 
10.2.1 
Primary Analysis  
The primary endpoint is the aggregated average of change from baseline-RT in number of nocturnal 
voids after 12 weeks of treatment, that is, averaged across all post-randomization visits. The 
objectives of the primary analysis are to establish Proof-of-Concept of FE 201836 and to estimate 
the dose-response profile of FE 201836.  The analyses will be performed on the ITT-RT analysis 
set.  
The overall trial outcome is proof-of-concept evaluated by the posterior probability that 500 µg 
FE 201836 has superior efficacy as compared to placebo (Pr(µ500<µPlb)>97.5%) based on a 
Bayesian analysis of the dose-response profile at Week 12 for the ITT-RT analysis set not including 
the active comparator desmopressin. 


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Statistical Analysis Plan 
The dose-response profile will be characterized by the posterior estimates of the mean dose-
response at each dose, µd, corresponding to two nocturnal voids at baseline and the mean dose-
response contrast versus placebo, Δd, with their associated 95% credibility intervals.  The posterior 
probabilities Pr(Δd<−0.3), Pr(dose d is MED), and Pr(dose d is ED85), will be tabulated.  The 
dose-response curve relative to placebo will also be presented graphically with its 95% credible 
interval in the plots illustrating the therapeutic window (Section 10.4).  No multiplicity adjustment 
will be performed. 
The dose-response profiles are determined using the following model:  Let  xt,i  denote the observed 
cross-sectional change from baseline-RT in nocturnal voids (averaged across the nights in the 
Voiding diary corresponding to the visit) and let  yt,i  denote the aggregated average change from 
baseline for subject 𝑖, averaged across post-randomization visits up to time t (for visit windows see 
Section 3.1.5): 
𝑦𝑡,𝑖=
∑
𝑥𝑘,𝑖 
𝑡
𝑘=1
𝑡
, 𝑡= 1,2,3,4, 
where 𝑡 denotes the nominal post-randomization time points reflecting Visits 5, 6, 7 and 8, 
corresponding to Weeks 1, 4, 8, and 12, respectively.  The final endpoint,  y4,i  is modelled as being 
an observation of 
Y4,i ~ N(β∙(x0,i – 2) + µd, σ2),  
 
 
 
( 1 ) 
where  x0,i  is the baseline-RT number of nocturnal voids,  σ2  is the error variance, and  µd  
describes the dose-response relationship.  µd  is assumed to follow a four-parameter sigmoidal 
model:  
𝝁𝒅= 𝜶𝟏+
(𝜶𝟐−𝜶𝟏)𝒅𝜶𝟒
𝒅𝜶𝟒+𝜶𝟑𝜶𝟒, 
 
 
 
 
( 2 ) 
where d is the dose measured in 100 µg (so d=0, 0.5, 1, 1.5, 2.5, 3.5, or 5), and the interpretation of 
the parameters are:  α1  is the placebo response for a subject with 2 nocturnal voids at baseline;  α2  
is the maximum response for a subject with 2 nocturnal voids at baseline;  α3  is the dose (ED50) at 
which 50% of the maximum effect is obtained; and  α4  is the slope parameter.  In the primary 
analysis of  y4,i,  the model parameters  θ = (β, α1, α2, α3, α4, σ2)  are modelled with the prior 
distributions  β~N(0, 102);  α1~N(−1, 32);  α2~N(−0.5, 22);  α3~N+(2, 22);  α4~N+(5, 3.52); and  
σ2~IG(0.5, 0.605), where the notation N+(η, ζ2) refers to a positive truncated normal distribution, 
and the IG(a, b) is the inverse gamma distribution.  
Missing data due to drop out or insufficient Voiding Diary data at Visit 8 will be imputed using a 
longitudinal model applied to the observed data including all visits, corresponding to a missing-at-
random assumption.  The longitudinal model of  yt,i  is modelled conditional on an individual 
parameter,  δi,  modelling  yt,i  as 


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Statistical Analysis Plan 
𝒚𝒕,𝒊= 𝒆𝝃𝒕(𝜷(𝒙𝟎,𝒊−𝟐) + 𝝁𝒅+ 𝜹𝒊) + 𝜺𝒕,𝒊 
 
 
 
( 3 ) 
where  ξ4=0.  Bayesian analysis will be based on the same priors as in the primary analysis 
described above for the β and the α parameters, while the remaining parameters are modelled with 
the priors:  ξt~N(0, 1);  δi~N(0, τ2)  with  τ2~IG(0.5, 0.36125),  and  εt,i~N(0, λt2)  with  
λt2~IG(0.5, 0.125).   
A total of 1000 imputations of the missing  y4,i  will be performed.  In the multiple imputation of the 
missing  y4,i  for the primary analysis, a sample of size 1000 of the model parameters,  
π = (ξ1, ξ2 , ξ3, β, α1, α2, α3, α4, δi (i=1,…,300), λ12, λ22, λ32, λ42),  is first sampled from the posterior 
for the Bayesian analysis of the longitudinal model, using the seed=2720, a burn-in of 10 000 and a 
thinning factor of 50.  Then for each set of model parameters,  πs,  the imputed value of a missing  
y4,i  is obtained by adding a normally distributed error,  ε4,i,s,  with seed=152 to the conditional mean 
of  y4,i  (conditional on  δi,s),  giving a single imputation,  y4,i,s,  thereby capturing all the variability 
in each imputed  y4,i,s.   
For each of the imputed data sets, the Bayesian analysis of the (possibly imputed)  y4,i  will be 
performed with a seed=10000+s using a burn-in of 10 000, and a single set of the model parameters  
θs  is obtained as number  50∙s  after the burn-in of the generated posterior values of  θ.  The set 
{θs; s=1,…,1000} will be used to derive the  µd  and  Δd  with 95% credibility intervals and the 
posterior probabilities, Pr(Δd<−0.3), Pr(dose d is MED), and Pr(dose d is ED85).  
10.2.2 
Sensitivity Analyses  
The following sensitivity analyses will be conducted: 
1. The mean, the median, and the 95% credibility intervals for  µd,  Δd,  exp(ξ1),  exp(ξ2),  and  
exp(ξ3);  as well as the posterior probabilities,  Pr(Δd<−0.3),  Pr(dose d is MED),  and  
Pr(dose d is ED85),  will be presented for the longitudinal analysis used in the imputation of  
y4,i. 
2. The primary-analysis approach according to the planned treatment allocation will be carried 
out on the PP analysis set. 
3. The primary-analysis approach according to the planned treatment allocation will be carried 
out on the ITT-RT analysis set, replacing  µd  by  α1  in the conditional mean of missing  y4,i  
when imputing from the longitudinal model, that is, using a Missing Not At Random 
(MNAR) placebo model for the imputation of subjects who drop out. 
4. The primary analysis according to the planned treatment allocation will be carried out on the 
ITT-RT analysis set using priors with twice as large scale parameters (standard deviations 
for normal distributions) than used for the primary analysis. 
5. A Bayesian analysis will be performed for the observed value at Week 12 for completers, 
using a seed=10 000 and the same burn-in and thinning factor as specified for the 
longitudinal analysis, obtaining a final posterior sample size equal to the posterior sample 
size obtained in the primary analysis. 


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6.  The primary-analysis approach but using the actual treatment allocation will be carried out 
on the Safety-RT analysis sets. 
7. A mixed-effect model for repeated measurements (MMRM) analysis according to the 
planned treatment allocation will be performed on the ITT-RT analysis set using Markov 
chain Monte Carlo (MCMC) to impute intermediate missing 1000 times with seed=742738, 
and an MNAR placebo-based pattern mixture model (see Ratitch 2011) to impute after drop 
out for each of the 1000 imputed data set with monotone missing pattern, using the seeds 
841621, 745274, 830367, and 995004 for the imputation of missing at Week 1, Week 4, 
Week 8, and Week 12, respectively.  The systematic effects will comprise visit number and 
treatment-by-visit as categorical variables, and baseline-RT number of nocturnal voids 
minus 2 as a linear covariate interacting with visit number.  An unstructured covariance 
matrix will be used.  The estimated contrasts to placebo at Week 12 will be presented with 
95% confidence intervals.  Based on the same sets of imputed data, the log-linear trend 
across active doses (replacing the categorical treatment variable with an indicator variable 
for treatment with Placebo and a linear variable, log2(d/0.5)) and the linear trend across all 
doses (replacing the categorical treatment variable with the linear variable, d) will be 
estimated with 95% confidence limits. 
10.2.3 
Descriptive analysis 
The mean aggregated average and mean aggregated average change from baseline for each dose at 
each visit will be tabulated together with 95% confidence intervals as a part of the explorative 
benchmarking analyses described in Section 10.5. 
10.3 
Secondary Efficacy and Exploratory Analyses 
10.3.1 
General Considerations  
The following main categories of inferential analyses will be performed for the secondary efficacy 
endpoints: 
• Bayesian estimation of the sigmoidal dose-response curve will be used for aggregated 
averages and for the aggregated responder variable, 50% reduction from baseline-RT in 
number of nocturnal voids, defined as the aggregated average change from baseline being 
less or equal to 50% of the baseline-RT number of nocturnal voids.  For details, see 
Section 10.3.3. 
• MMRM will be used to evaluate treatment effects on cross-sectional change from baseline 
for quantitative variables.  For details, see Section 10.3.4.  
• General Estimating Equations with the logit as link function will be used for cross-sectional 
binary responder variables.  For details, see Section 10.3.5.  
• Analysis of covariance (ANCOVA) will be used for the single-time-point quantitative 
variables: percentage of nights during treatment period with at most 1 nocturnal void and 
with a complete response, respectively, and change from baseline in copeptin levels.  For 
details, see Section 10.3.6.   


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• Correlation between endpoints will be reported using Pearson correlation coefficients and 
linear regression coefficients, regressing total sleep on FUSP and NPi on copeptin.  
Table 5 presents the planned analyses for all endpoints.  All analyses will be performed on the 
observed data in the ITT-RT analysis set unless otherwise specified. Visit windows for each 
endpoint will be as described in Section 3.1.5. 
Table 5 
Analysis of Endpoints 
Endpoint 
Analysis category 
Bayesian 
Estimation 
of Dose-
response 
Curve for 
Aggregated 
Averages 
MMRM 
Repeated 
logistic 
regression 
(Generalized 
Estimating 
Equation 
[GEE]) 
ANCOVA Correlation 
Analysis 
Efficacy Endpoints 
 
 
 
 
 
Aggregated average change from baseline during the 
12 weeks randomized-treatment period for number of 
nocturnal voids 
Primary 
Sensitivity, 
Therapeutic 
Window 
 
 
 
Change from baseline in number of nocturnal voids at 
the visit a 
 
Secondary 
 
 
 
Rate of response defined as 50% reduction in 
nocturnal voids from baseline based on aggregated 
average change from baseline  
Secondary 
 
Secondary 
 
 
Rate of response defined as 50% reduction in 
nocturnal voids from baseline a 
 
 
Secondary 
 
 
Rate of response defined as 33%, 60%, 70%, 80%, 
90% and 100% reduction from baseline in number of 
nocturnal voids a  
 
 
Explorative 
 
 
Rate of response defined as 1, 2, and 3 voids reduction 
from baseline in number of nocturnal voids a   
 
 
Explorative 
 
 
Percentage of nights during treatment period with at 
most one nocturnal void b 
 
 
 
Secondary 
 
Percentage of nights during treatment period with 
complete response b 
 
 
 
Secondary 
 
Change from baseline in NUV c 
Secondary  Secondary  
 
 
 
Change from baseline in FUSP a 
Secondary Secondary 
 
 
Explorative d 
Change from baseline in total sleep time per night a   
 
Explorative 
 
 
 
Change from baseline in nocturnal diuresis rate 
(hourly) c 
 
Secondary  
 
 
 
Change from baseline in NPi c 
 
Explorative 
 
 
 
Change from baseline in NI Diary Total Score a  
Secondary Secondary  
 
 
 
Change from baseline in NI Diary Overall Impact 
Score a 
Secondary Secondary 
 
 
 


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Statistical Analysis Plan 
Endpoint 
Analysis category 
Bayesian 
Estimation 
of Dose-
response 
Curve for 
Aggregated 
Averages 
MMRM 
Repeated 
logistic 
regression 
(Generalized 
Estimating 
Equation 
[GEE]) 
ANCOVA Correlation 
Analysis 
PGI-I urinary symptoms score a, e 
 
Secondary 
 
 
 
Change from baseline in PGI-S score a  
 
Secondary 
 
 
 
Change from baseline in Bother as measured by the 
Hsu 5-point Likert Bother Scale a 
 
Secondary 
 
 
 
Change from baseline in ISI f 
 
Secondary 
 
 
 
Copeptin levels at Visit 2 g 
 
 
 
 
Explorative 
Change from baseline in copeptin levels h 
 
 
 
Explorative 
 
Safety Endpoints 
 
 
 
 
 
Change from baseline in mean 24-hour urine volume c 
 
Safety 
 
 
 
Lowest observed change from baseline-RT in Serum 
Sodium 
 
 
 
Alternative 
safety 
indicator for 
therapeutic 
window  
 
Incidence and severity of Adverse Events 
Section 11.3.1 
Adverse Event of Special Interest: Hyponatraemia 
Episodes 
Section 11.2.1 
Clinically significant changes in laboratory values and 
vital signs 
Sections 11.3.2 and 11.3.3 
a Endpoint assessed at Weeks 1, 4, 8 and 12. 
b Endpoints are derived using all diary data collected during the treatment period. 
c Endpoint assessed at Weeks 1 and 12. 
d Correlation between changes in FUSP and total sleep time at Weeks 1, 4, 8 and 12. 
e This questionnaire is retrospective and raw scores will be used in the analysis (not changes from baseline) and the ANCOVA mo del 
will not be adjusted for baseline value. 
f Endpoint assessed at Weeks 4, 8 and 12. 
g Correlation with NPi  at Visit 2. 
h Endpoint assessed at Week 12. 
                                              
Illustration of the therapeutic window is described separately in Section 10.4 and safety related 
endpoints are further described in Section 11. 
Explorative analyses by sex are planned for all endpoints, including correlation analyses. For these 
the following are noted: 


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• Estimates of the sex-specific dose-response for the aggregated averages after 12 weeks of 
treatment will follow the Bayesian analysis described in Sections 10.2.1 and 10.3.3 by 
conducting a separate analysis for each sex.  Possible differences between the sex-specific 
models will be investigated. 
• The regression models will be supplemented with an analysis considering sex as well as all 
interactions between sex and the effects specified in the all-subjects analysis, including any 
interaction terms specified in the all-subject analysis.  Possible differences between the 
treatment effects for men and women will be evaluated by the  treatment-by-visit-by-sex 
(treatment-by-sex for single-visit outcomes) interaction term with the effect of treatment-by-
visit (treatment for single-visit outcomes) included in the model.   
10.3.2 
Scoring of Patient-Reported Outcomes 
The post-randomization, visit-specific, cross-sectional change from baseline-RT,  xt,i,  in number of 
nocturnal voids is defined as the average across the nights in the Voiding Diary corresponding to 
the single visit.  Regarding assigning number of voids for a single night, the following rules are 
used: 
1. Voids less than 5 minutes apart will be collapsed into a single void and the corresponding 
volumes will be summed to a total volume.  Voids on different sides of a time threshold 
(5 minutes after bed time with the intention to sleep at night, rising in the morning, and 
30 minutes after rising in the morning) will not be collapsed.  
2.  If day/night cannot be assigned due to missing go-to-bed or got-up time, number of 
nocturnal voids and NUV for that 24-hour period is set to missing.   
3. If day/night can be assigned and there are no voids during the night period, number of 
nocturnal voids is set to 0 for that 24-hour period and NUV is set to 0 plus the volume of the 
first void within 30 minutes of rising in the morning. 
4. If day/night can be assigned, and there are a positive number of voids during both the night 
period, the number of voids during the night period is used, whether or not the volume of 
every void is registered. If at least one volume is not registered, NUV is set to missing for 
that 24-hour period. 
The post-randomization aggregated average change from baseline-RT,  yt,i,  in number of nocturnal 
voids is defined as the average of the cross-sectional changes from baseline-RT,  xs,i,  across the 
post-randomization visits up to and including the current visit.  If the cross-sectional change from 
baseline-RT,  xt,i,  is missing at a single visit, the corresponding aggregated average change from 
baseline-RT,  yt,i,  will be set to missing. 
The aggregated average change from baseline being less or equal to 50% of the baseline-RT 
number of nocturnal voids,  z50% ,t,i,  is derived from the corresponding aggregated average change 
from baseline in number of nocturnal voids,  yt,i,  as  z50% ,t,i = 1 if  yt,i/x0,i ≤ −0.5,  and  z50% ,t, = 0  
otherwise. 


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The visit-specific, cross-sectional responder variables related to number of nocturnal voids (33%, 
50%, 60%, 70%, 80%, and 90% reduction from baseline; and 1, 2, and 3 voids reduction from 
baseline) are derived by categorization of the corresponding  xt,i  divided by the baseline-RT number 
of nocturnal voids,  x0,i.  
The percentages of nights with response defined as at most one nocturnal void and complete 
response (no nocturnal voids), respectively, are derived as the percentage of nights with the specific 
response among all single, post-randomization nights in the Voiding Diary for which number of 
nocturnal voids can be derived.   
The NUV for a single night is the total urine volume in mL from 5 minutes after bedtime with the 
intention to sleep including the first void within 30 minutes of rising in the morning.  The NUV for 
a visit is calculated as the average of the single-night values.  Aggregated values are derived 
similarly to the derivation of the aggregated values for number of nocturnal voids. 
The FUSP for a single night is calculated as the time in minutes from the time of going to bed to the 
time of first nocturnal void, or time of awakening if no void occurred.  The FUSP for a visit is 
calculated as the average of the single-night values.  Aggregated values are derived similarly to the 
derivation of the aggregated values for number of nocturnal voids. 
The total sleep for a single night is calculated as the time in minutes from the time of going to bed 
to the time of awakening.  The total sleep for a visit is calculated as the average of the single-night 
values. 
The diuresis rate measured in mL/min for a single night is calculated as NUV/total sleep.  The 
diuresis rate for a visit is calculated as the average of the single-night values. 
The NPi for a single night is calculated as 100%∙NUV/24-hours urine volume.  The NPi for a visit 
is calculated as the average of the single-night values. 
The NI Diary outcomes will be scored as described in Holm-Larsen (2014): 
The NI Diary Total Score for a single night will be calculated as the sum of the scores for the first 
11 questions divided by 44 and multiplied by 100.  If any of the single-item scores is missing, the 
NI Diary Total Score is missing for that single night.  The NI Diary Total Score for a visit is 
calculated as the average of the single-night values.  The number of nights on which the NI Diary 
Total Score for a visit is based will be provided. 
The NI Diary Overall Impact Score for a single night will be calculated as the score for the 12th 
question divided by 4 and multiplied by 100.  The NI Diary Overall Impact Score for a visit is 
calculated as the average of the single-night values.  The number of nights on which the NI Diary 
Overall Impact Score for a visit is based will be provided. 
Aggregated values for NI Diary Total Score as well as NI Diary Overall Impact Score are derived 
similarly to the derivation of the aggregated values for number of nocturnal voids. 


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The PGI-S and the PGI-I are scored as described in Viktrup (2012): 
The PGI-I is scored from 1 (Very much better) to 7 (Very much worse). 
The PGI-S is scored from 1 (None) to 4 (Severe). 
The Hsu 5-point Likert Bother scale is scored as described in Hsu (2015): 
The Hsu Bother scale is scored from 0 (Not at all) to 4 (Extremely). 
The ISI will be scored as described in Bastien (2001): 
For the ISI, each item is scored from 0 (None/Very satisfied/Not interfering at all/Not at all 
noticeable/Not at all) to 4 (Very severe/Very dissatisfied/Very much interfering/Very much 
noticeable/Very much) and ISI is calculated as the sum of the single-item scores.  ISI is missing if 
any single item is missing. 
10.3.3 
Bayesian estimation of the sigmoidal dose-response curve 
Bayesian estimation of the sigmoidal dose-response curve for aggregated, quantitative outcomes 
will follow the approach described for the primary analysis in Section 10.2.1 using the priors 
β~N(0, 102);  α1, α2~N(ā, 52) with the outcome-specific mean ā presented in Table 6;  α3~N+(2, 102);  
α4~N+(5, 102);  ξt~N(0, 1);  δi~N(0, τ2);  and  σ2, τ2, λt2~IG(0.5, 0.01);  after rescaling the variables 
using the outcome-specific scaling factors presented in Table 6.  The baseline will be subtracted by 
the constant presented in Table 6.  
Table 6 
Constant to be subtracted from baseline, mean in the prior distributions of α1 and 
α2, and scaling factor used in the Bayesian analyses 
Efficacy outcome 
Constant to be 
subtracted from baseline 
Mean ā of the prior 
distributions of  
α1 and α2 
Scaling factor 
NUV 
750 (mL) 
−1 
250 (~¼ L) 
FUSP 
180 (minutes) 
1.5 
60 (~1 hour) 
NI Diary Total Score 
50 (percentage points) 
−2 
10 
(~10 percentage points) 
NI Diary Overall Impact Score 
 
For each efficacy outcome, the posterior probability that FE 201836 performs better than placebo 
will be presented together with the difference to placebo with 95% credibility intervals for each 
dose of FE 201836. 
Bayesian estimation of the sigmoidal dose-response curve for the aggregated responder variable 
corresponding to 50% reduction from baseline-RT in number of nocturnal voids,  z50% ,4,i,  will 
follow the primary analysis approach with imputed outcomes derived from the imputed values of  
y4,i  from the primary analysis.  The dose-response model for  z50% ,4,i  will be modelled as a binary 
variable with mean  
Mean(z50% ,4,i) = expit( (–0.5∙x0,i – Mean(y4,i))/SD(y4,i) ), 


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where expit is the function expit(x)=exp(x)/(1+exp(x)),  Mean(y4,i)=β∙(x0,i – 2) + µd,  and  SD(y4,i)=σ  
as specified in ( 1 ).  The model parameters are modelled with the same prior distributions as used 
in the primary analysis.  The posterior probability that FE 201836 performs better than placebo will 
be presented together with the odds ratio of at least 50% reduction from baseline-RT in number of 
nocturnal voids during 12 weeks of treatment for each dose of FE 201836 relative to placebo with 
95% credibility intervals. 
10.3.4 
Treatment effects on cross-sectional change from baseline for quantitative variables 
and PGI-I 
Treatment effects on cross-sectional change from baseline for quantitative variables will be 
analysed using SAS PROC MIXED assuming a MMRM (a non-parametric dose-response curve is 
assumed).  The systematic effects will comprise visit number and treatment-by-visit as categorical 
variables, and the baseline-RT value as a linear covariate interacting with visit number.  An 
unstructured covariance matrix will be used if technically possible, alternatively a Toeplitz, a 
compound-symmetry, or if necessary, an independent covariance matrix will be used.  The 
treatment contrasts (with associated 95% confidence intervals without multiplicity adjustment) 
versus placebo will be tabulated and graphically illustrated.  The analyses will be applied to the 
observed data on the ITT-RT analysis set. 
The same approach will be applied to the aggregated average change from baseline in number of 
nocturnal voids. 
For PGI-I there is no baseline so the systematic effects will comprise only visit number and 
treatment-by-visit as categorical variables. 
10.3.5 
Treatment effects on cross-sectional binary variables 
Binary endpoints such as the cross-sectional “responder status” at a visit will be analysed using 
SAS PROC GENMOD with logit as the link function for the responder probability.  An 
unstructured correlation matrix will be used as working correlation matrix if technically possible, 
alternatively an autoregressive, a compound-symmetry, or if necessary, an independent working 
correlation matrix will be used.  The systematic effects will include visit and treatment-by-visit 
interaction as factors and will be adjusted for the log2-transformed number of nocturnal voids at 
baseline-RT, subtracted by 1, as a covariate interacting with visit number.  Odds ratios relative to 
placebo with associated 95% confidence intervals (without multiplicity adjustment) will be 
presented.  The analyses will be applied to the observed data for the ITT-RT analysis set.  
Combinations of visit and dose of FE 201836 where all or none of the subjects respond will be 
omitted from the analysis since this corresponds to estimates of infinity in a logistic regression 
model.   
For the investigation of interaction with sex, combinations of sex, visit and dose of FE 201836 
where all or none of the subjects respond will be omitted from the analyses, and an autoregressive 
correlation matrix will be used, if technically possible, alternatively, a compound-symmetry, or if 
necessary, an independent working correlation matrix will be used. 


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In the analysis of the responder variable corresponding to one nocturnal void decrease from 
baseline, only subjects with at least one nocturnal void at baseline will be included.  In the analysis 
of the responder variable corresponding to two nocturnal voids decrease from baseline, only 
subjects with at least two nocturnal voids at baseline will be included.  In the analysis of the 
responder variable corresponding to three nocturnal voids decrease from baseline, only subjects 
with at least three nocturnal voids at baseline will be included.   
10.3.6 
Treatment effects on single-time-point quantitative variables 
Treatment effects on single-time-point quantitative variables will be analysed using SAS PROC 
MIXED to perform an ANCOVA (a non-parametric dose-response curve is assumed).  For the 
percentages of nights with response, the systematic effects will comprise treatment as a categorical 
variable and baseline-RT number of nocturnal voids minus 2 as a linear covariate.  For change from 
baseline-RT in copeptin, the systematic effects will comprise treatment as a categorical variable and 
the baseline-RT level minus 13.1 as a linear covariate.  For change from baseline-RT to lowest 
observed serum sodium, the systematic effects will comprise treatment as a categorical variable and 
the baseline-RT level minus 135 as a linear covariate.  The treatment contrasts (with associated 95% 
confidence intervals without multiplicity adjustment) versus placebo will be tabulated and  
graphically illustrated.  The analyses will be applied to the observed data on the ITT-RT analysis 
set.  For change from baseline-RT to lowest observed serum sodium, the analyses will be performed 
both using randomized treatment for the observed data on the ITT-RT analysis set for comparability 
with the results for the efficacy variables and using actual treatment for the Safety-RT analysis set 
for comparability with the analyses of episodes of hyponatraemia based on observed serum sodium. 
10.4 
Therapeutic Window 
The estimated sigmoidal dose-response curve with 95% credibility limits compared to placebo (left-
sided y-axis) will be illustrated together with the incidence per 100 person-weeks with 95% 
confidence limits of observation of serum sodium <130 mmol/L and ≤125 mmol/L, respectively, at 
or before 12 weeks (both on the right-sided y-axis).  The estimated treatment effects with 95% 
confidence limits compared to placebo for the groups treated with FE 201836 based on the MMRM 
model described in Section 10.3.4 will also be presented in the graph.  The horizontal x-axis will 
represent the dose range of FE 201836.  The therapeutic window is defined as the dose range where 
FE 201836 is deemed efficacious while the incidence of hyponatraemia is acceptable.  Two 
illustrations will be made with different estimated dose-response curves for the efficacy of 
FE 201836: one using the results from the primary analysis and one using Sensitivity Analysis 6 
based on the actual treatment received.  
The sex-specific therapeutic windows will be illustrated similarly. 
The therapeutic window of nocturnal volume will be presented similarly. 
In addition, similar illustrations of the therapeutic window will be produced using the estimated 
treatment contrast compared to placebo for the change from baseline-ENR to lowest post-baseline 
measurement of serum sodium as the safety indicator.  To make the results for the efficacy indicator 


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and the safety indicator comparable in each of these figures, the same treatment definition and the 
same analysis set will be used for both indicators in each figure. 
10.5 
Explorative Benchmarking Analysis 
The explorative benchmarking analysis will descriptively summarize aggregated as well as visit-
specific changes from baseline and percentage changes from baseline in number of nocturnal voids 
by all treatment groups, including desmopressin, for each visit in the randomized-treatment period.  
The summary statistics will include 95% confidence limits for simple means.  No imputations will 
be done for this analysis which will be based on the observed cases only.  Tables and figures will be 
produced as appropriate. This analysis will also be repeated by sex. 
Similar tables will be produced for the quantitative, secondary endpoints: percentage of nights 
during treatment period with at most one nocturnal void, percentage of nights during treatment 
period with complete response, change from baseline in NUV, change from baseline in FUSP, 
change from baseline in nocturnal diuresis rate, change from baseline in NI Diary Total Score, 
change from baseline in NI Diary Overall Impact Score, PGI-I urinary symptoms score, change 
from baseline in PGI-S score, change from baseline in Bother as measured by the Hsu 5-point 
Likert Bother Scale, change from baseline in ISI. 
Frequency tables by treatment for each visit will be produced for the categorical, secondary 
endpoints: response defined as 50% reduction in nocturnal voids from baseline based on aggregated 
average change from baseline, and response defined as 50% reduction in nocturnal voids from 
baseline based on visit-specific change from baseline.  


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11 
Safety 
11.1 
General Considerations 
11.1.1 
Analysis Sets 
Safety analyses with respect to the enrichment period will be based on the Safety-ENR analysis set, 
while analysis with respect to the randomized-treatment period will be performed using the Safety-
RT analysis set.  For calculation of percentages, the denominator will be the total number of 
subjects in the treatment group in the corresponding safety analysis set. 
All analyses will be based on the actual treatment received. 
11.1.2 
Imputation Rules  
Missing values will be treated as missing, except for the causality, intensity, seriousness and 
outcome of adverse events and for the definition of treatment emergent.  For adverse events (AEs), 
a worst-case approach will be used: if causality is missing, the adverse event will be regarded as 
related to the IMP; if the intensity of an adverse event is missing, the adverse event will be regarded 
as severe; if seriousness is missing, the adverse event will be regarded as serious; if onset date is 
missing, it will be assumed to be at the date of Visit 2; if outcome is missing and no date of 
outcome is present, the outcome is regarded as ‘ongoing’ at the End-of-Trial Visit. 
11.1.3 
Visit and Visit Windows  
See Section 3.1.5 for visit windows. 
11.2 
Safety Endpoints of Special Interest 
11.2.1 
Hyponatraemia Episodes Based on Observed Serum Sodium Levels 
11.2.1.1 
General Considerations 
All tables and figures will be done for the overall trial population and by gender. 
Observed serum sodium levels will both be summarized as a continuous variable and be used to 
define worst-case hyponatraemia episodes using the definitions specified in Table 7.   
Table 7 
Definition of Hyponatraemia Episodes by Serum Sodium Range: Number of 
Consecutive Measurements of Serum Sodium below Upper Threshold Needed to 
Start Episode 
Degree 
Serum Sodium 
Range 
(mmol/L) 
Enrichment Period 
Randomized-Treatment Period 
Hyponatraemia Episode 
Hyponatraemia Episode 
‘Confirmed’ 
Hyponatraemia Episode 
None 
≥135 
Not applicable (normal serum sodium level) 
Mild 
≥130 to <135 
1st observation  
1st observation  
3rd consecutive observation  
Moderate >125 to <130 
1st observation  
1st observation  
2nd consecutive observation  
Severe 
≤125 
1st observation  
1st observation  
1st observation 


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Trial Code: 000233  
Statistical Analysis Plan 
11.2.1.2 
Observed Serum Sodium Levels 
Observed serum sodium levels and the change from baseline-ENR will be summarized by visit for 
the Safety-ENR analysis set.  Observed serum sodium levels and the change from baseline-RT will 
be summarized by visit and treatment group for the Safety-RT analysis set.   
All subjects in the Safety-ENR analysis set with a serum sodium value <130 mmol/L at any time 
point will be listed by actual treatment group for the randomized period (non-randomized will be 
listed as a separate treatment group), including all serum sodium assessments by time point and 
including demographic data. 
Graphs will present the serum sodium levels against analysis day (ADY) by treatment group and the 
subject profiles with a serum sodium level <135 mmol/L at any time point during the trial will be 
highlighted.  In addition, lowest observed serum sodium against age will be presented in two 
figures, one figure using plot symbols showing sex and one figure using plot symbols showing 
actual treatment group. 
11.2.1.3 
Hyponatraemia Episodes During the Randomized-Treatment Period based on 
Observed Serum Sodium Levels 
When presenting occurrence (measured as number of subjects) by visit of worst-case hyponatraemia 
episodes as defined in Table 7, all visits within the same visit window will be combined to define 
the worst-case hyponatraemia episode observed for the subject within the visit window.  The 
occurrence of worst-case hyponatraemia episodes will be presented by treatment group and visit for 
the randomized-treatment period for the Safety-RT analysis set. 
The number of the post-baseline-ENR ‘worst-case’ hyponatraemia episodes for each subject will be 
summarized overall and by visit as a categorical variable; here ‘worst-case’ for each episode is 
defined as the worst-case serum sodium level observed during the hyponatraemia episode.   
In addition, the incidence of “Hyponatraemia Episode” (Table 7) per 1000 person-years at risk 
counting all events for a subject will be presented overall and by visit using the upper end of the 
visit window specified for Category I endpoints in Table 4 as cut-points for the categorization of the 
at-risk time. 
For each of the thresholds (<135, <130, and ≤125 mmol/L), graphs presenting treatment-stratified 
Kaplan-Meier curves of time from randomization (Visit 4) to first serum sodium level below the 
threshold will be produced for the Safety-RT analysis set.  The time to event is calculated as the 
date of the first serum sodium level below the threshold minus the date of randomization. 
In addition, for the thresholds <135 (mild to severe) and <130 mmol/L (moderate to severe), 
treatment-stratified Kaplan-Meier plots corresponding to first ‘confirmed’ hyponatraemia episode 
will be produced.  Here the date of confirmation is used as the date of the event.  For mild to severe, 
the date of confirmation is the first of the dates of ‘3rd consecutive observation <135 mmol/L’,  ‘2nd 
consecutive observation <130 mmol/L’,  and  ‘1st observation  ≤125 mmol/L’.  For moderate to 


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Statistical Analysis Plan 
severe, the date of confirmation is the first of the dates of ‘2nd consecutive observation 
<130 mmol/L’  and  ‘1st observation  ≤125 mmol/L’.   
In Kaplan-Meier plots, all subjects are censored at the earliest of End-of-Trial Visit and 85 days 
after randomization. 
Since the event times are interval censored (the true time of crossing the threshold was after the 
time of the preceding serum sodium measurement and before or at the time of the current serum 
sodium measurement) and essentially grouped by the planned visits, the Kaplan-Meier plots are not 
quite appropriate. Therefore, event-free-time curves will also be produced based on life table 
methods using interval cut points derived as 1 + the largest observed event time within each of the 
visit windows specified for Category I endpoints in Table 4.   
Duration of the hyponatraemia episode will be derived as  1  + end date of episode – date of start of 
episode.  For each threshold separately, the duration will be listed for serum sodium episodes 
defined as one or more observed serum sodium levels below the threshold.  The listings will contain 
the duration, demographics, the day of stop of treatment relative to the start of the hyponatraemia 
episode, and the serum sodium values observed during the episode including the serum sodium 
value above 135 mmol/L defining the end of the hyponatraemia episode.  For episodes starting 
before randomization, duration will be listed by sex for all subjects in the Safety-ENR analysis set.  
For episodes starting after randomization, duration will be listed by sex and treatment group for all 
subjects in the Safety-RT analysis set experiencing an episode of hyponatraemia based on observed 
serum sodium levels.   
Nadir of observed serum sodium during hyponatramia episodes will be illustrated by a 
graph including all hyponatraemia episodes and showing observed serum sodium levels against 
time since start of the hyponatraemia episode (time zero for an episode is defined as first time point 
with observed serum sodium below 135 mmol/L in the current episode). 
11.2.2 
24-hour Urine Volume 
Observed 24-hour urine volume and the change from baseline-RT will be summarized by visit and 
treatment group for the Safety-RT analysis set.  In addition, change from baseline-RT will be 
analysed for the using the MMRM approach described in Section 10.3.4.   
11.3 
Routine Safety Assessments 
11.3.1 
Adverse Events 
11.3.1.1 
General Considerations 
Adverse events (AEs) are classified according to the latest version of the MedDRA dictionary.  The 
version of MedDRA will be documented. 
Written narratives will be issued for all serious AEs (SAE, including deaths) and AEs leading to 
discontinuation. 


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Statistical Analysis Plan 
Regarding definition of treatment emergent, there are three levels for treatment emergent because of 
the single-blind enrichment period: pre-treatment, enrichment-treatment emergent, and randomized-
treatment emergent. The rules for classification are the following: 
• Any AE starting before date of Visit 2 is considered pre-treatment. 
• Any AE starting on date of Visit 2 as well as any AE starting after Visit 2, but before date-
time for randomization at Visit 4, are considered enrichment-treatment emergent. 
• If the subject is not randomized, any AE starting on date of Visit 2 as well as any AE 
starting after Visit 2 are considered enrichment-treatment emergent. 
• Any AE starting after the date-time of randomization at Visit 4 is randomized-treatment 
emergent.  
• AEs with missing start time but starting on date of Visit 4 are considered randomized-
treatment emergent.  
• AEs with missing start date are considered enrichment emergent. 
The total number of subjects reporting an AE, and the percentage of subjects (%) reporting an AE 
(denominator: number of subjects screened for pre-treatment; number of subjects in the Safety-ENR 
analysis set for enrichment-treatment emergent; and number of subjects in the Safety-RT analysis 
set for randomized-treatment emergent) will be presented. 
11.3.1.2 
Tabulations of Treatment-Emergent Adverse Events 
Treatment-emergent adverse events will be summarized by system organ class (SOC) and preferred 
term (PT) and by treatment group. The tables will display the total number of subjects reporting an 
AE, the percentage of subjects (%) with an AE, and the number of events reported. AEs will be 
presented by SOC sorted alphabetically and PT sorted in decreasing frequency of occurrence. 
Summary tables will be prepared for the enrichment period and randomized-treatment period as 
outlined in Table 8. 
Table 8 
Tabulations of Treatment-Emergent Adverse Events 
 
Enrichment Period 
Enrichment 
Period-Emergent 
Adverse Events 
(Safety-ENR 
Analysis Set) 
Randomized Period 
Randomized-
Treatment-Emergent 
Adverse Events 
(Safety-RT Analysis 
Data Set) 
Gender-Specific 
Tabulations 
Overview of Adverse Events by treatment group 
X 
X 
  
Adverse Events by causality (related/unrelated) 
X 
X 
X 
Adverse Events leading to death 
X 
X 
 
Adverse Events by intensity 
 
X 
X 
SAEs 
X 
X 
 
Adverse Events leading to discontinuation 
X 
X 
 
Adverse Events with an incidence of at least 10% 
in any treatment group 
 
X 
X 


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Statistical Analysis Plan 
 
Enrichment Period 
Enrichment 
Period-Emergent 
Adverse Events 
(Safety-ENR 
Analysis Set) 
Randomized Period 
Randomized-
Treatment-Emergent 
Adverse Events 
(Safety-RT Analysis 
Data Set) 
Gender-Specific 
Tabulations 
Adverse drug reactions with an incidence of at 
least 10% in any treatment group 
 
X 
X 
 
Supporting data listings will be provided for: 
• All adverse events sorted by site and subject number 
• All adverse events sorted by MedDRA Preferred Term 
• Serious adverse events  
• Adverse events leading to death 
• Adverse events leading to discontinuation  
11.3.2 
Safety Laboratory Variables 
11.3.2.1 
General Considerations 
Laboratory variables will be grouped under “Haematology”, “Clinical Chemistry”, “Urinalysis”, or 
“Coagulation Factors”.  
The reference ranges for laboratory values are presented in Appendix 1. 
11.3.2.2 
Visits and Visit Windows  
• Baseline for all laboratory analyses will be the values obtained at the last assessment before the 
subject received the first dose of the IMP.  
• Treatment-emergent for laboratory data will be defined as specified for AEs in Section 11.3.1.1.  
• End of trial will include the last post-baseline-ENR observation during the trial.  
• Data will be analysed by planned visit using the visit-window structure as described in 
Section 3.1.5. 
11.3.2.3 
Summary Statistics 
For each laboratory variable, summary statistics (see Section 1.3.1) by treatment group will be 
provided for test results and their change from baseline-ENR (quantitative variables only) at each 
visit up to and including the End-of-Trial Visit for the Safety-ENR analysis set; and for test results 
and their change from baseline-RT (quantitative variables only) at each visit up to and including the 
End-of-Trial Visit for the Safety-RT Analysis Set.  The number and percent of subjects with 
clinically significant laboratory abnormalities according to the investigator’s assessment of the 
categories ‘normal’, ‘abnormal, not clinically significant’, and ‘abnormal, clinically significant’ will 
be presented.  For Visits 2, 3, and 4, the Safety-ENR analysis set will be used; for post-
randomization visits, the Safety-RT analysis set will be used. 


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Trial Code: 000233  
Statistical Analysis Plan 
11.3.2.4 
Laboratory Variable Changes Relative to Normal Range 
Shift tables will be presented on an as-needed basis only. 
11.3.3 
Vital Signs  
11.3.3.1 
Visits and Visit Windows  
• Baseline for all vital signs analyses will be the values obtained at the last assessment before the 
subject received the first dose of the IMP during the enrichment period.  
• Treatment-emergent vital signs data will be defined as specified for AEs in Section 11.3.1.1. 
• End of trial will include the last post-baseline observation during the trial.  
• Data will be analysed by planned visit using the visit-window structure as described in 
Section 3.1.5. 
11.3.3.2 
Summary Statistics 
For each vital sign variable, summary statistics (see Section 1.3.1) will be presented for observed 
values as well as the investigator’s assessment of the categories ‘normal’, ‘abnormal, not clinically 
significant’ and ‘abnormal, clinically significant’.  For Visits 2, 3, and 4, the Safety-ENR analysis 
set will be used; for post-randomization visits, the Safety-RT analysis set will be used. 
11.3.4 
ECGs  
• ECG will be categorized as ‘normal’, ‘abnormal, not clinically significant’, and ‘abnormal, 
clinically significant’.   
• Baseline for ECG is the assessment at the Screening Visit. 
• Randomized-treatment-emergent ECG is the ECG at the End-of-Trial Visit. 
The ECG variable will be summarized overall for the Safety-ENR analysis set and by treatment for 
the Safety-RT analysis set.  Shift tables will be presented on an as-needed basis only. 
11.3.5 
Other Safety Variables 
11.3.5.1 
Weight Changes 
• Weight Change will be derived as weight at the current visit minus weight at the previous visit 
using the visit-window structure described in Section 3.1.5.  
• Data will be analysed by planned visit using the visit-window structure as described in 
Section 3.1.5. 
• Enrichment-treatment-emergent weight changes comprise weight changes from Visit 2 to Visit 
3 and weight changes from Visit 3 to Visit 4.  Post-randomization weight changes are 
considered randomized-treatment-emergent weight changes  
• The end of trial value for a subject will include the last post-baseline-ENR observation for the 
subject during the trial.  


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Statistical Analysis Plan 
Summary tables will be presented by visit displaying the number and percentage of subjects with a 
weight change of more than 2 kg since the previous visit.  
11.3.5.2 
Physical examination 
• Physical examination findings will be categorized according to ‘normal’, ‘abnormal, not 
clinically significant’, and ‘abnormal, clinically significant’.   
• Baseline-ENR for the physical examination is the assessment at the Screening Visit, 
baseline-RT is the assessment at Visit 4, and End of Trial will include the last post-baseline-RT 
assessment during the trial. 
Summary tables will be prepared by visit for the Safety-ENR analysis set, and by visit and 
treatment for the Safety-RT analysis set.  Shift tables will be presented on an as-needed basis only. 


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Statistical Analysis Plan 
12 
Interim analyses 
The safety data will be reviewed on a regular basis by a Data Monitoring Committee (DMC) as 
described in a separate DMC charter. 
After 125 subjects have been randomized and every 8 weeks thereafter, an interim analysis is 
performed by 
.  Each of these interim analyses comprises a futility analysis and, 
until end of recruitment, an update of allocation probabilities for the FE 201836 doses based on a 
Bayesian analysis of the dose-response relation.  The updating of the allocation probabilities is 
focused on improving the design with regard to the identification of the MED and the ED85.   
In contrast to the primary analysis, the interim analyses will not be adjusted for baseline number of 
nocturnal voids. 
In the first interim, the futility stopping rule is to stop for futility if Pr(μ500 – μPlb < −0.3) < 10%.  In 
the later interim analyses, the futility rule is to stop for futility if Pr(μ500 – μPlb < −0.3) < 5%.  At all 
these trial updates, Bayesian estimates will be used to update the allocation probabilities for the 
doses of FE 201836.  The allocation probability for each dose d of FE 201836 is proportional to the 
posterior variance of µd multiplied by the average of Pr(d is the MED) and Pr(d is the ED85), and 
divided by nd + 1. 
The power and the probability of making a false positive conclusion using the adaptive design was 
investigated based on simulations as described in the trial protocol. 


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Statistical Analysis Plan 
13 
Risk-benefit assessment 
Risk-benefit will be evaluated based on the graphical illustrations of the therapeutic window 
(Section 10.4). 


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14 
Deviations From the Trial Protocol 
A Full Analysis Set was defined in the protocol. However, none of the analyses specified in the trial 
protocol were based on the Full Analysis Set, so no Full Analysis Set has been defined in this SAP. 
Pr(µd<µPlb) will presented only for the 500 µg FE 201836 dose (Proof of Concept) since all doses 
will have the same probability because of the monotone dose-response curve parameterization; and 
Pr(µd=µMAX) will not be displayed since it always equals 1 for the 500 µg dose, and 
probabilistically almost surely (that is, with probability 1) equals 0 for all other doses, again 
because of the monotone dose-response curve parameterization. 
For some subjects, the baseline voiding diary is missing due to technical problems in the beginning 
of the study.  The change from baseline in voiding data are considered missing completely at 
random for these subjects, and the subjects are not included in any analyses involving baseline 
measurements of voiding data. 
Two sensitivity analyses have been added:   
• Estimates of all quantities of interest based on the Bayesian analysis of the longitudinal 
model will be presented.   
• A Bayesian analysis of the primary outcome with imputation using the level corresponding 
to placebo for drop-out. 
The first sensitivity analysis presents the result for the model used for imputation.  The second 
analysis is the Bayesian equivalent to the frequentist approach specified in the trial protocol based 
on a mixed model for repeated measurement (repeated-measurements ANCOVA) using MNAR 
placebo-based pattern mixture model.   
Linear trend estimates have been added to the above mentioned protocol-specified frequentist 
approach as supplements to the description of the association with dose in case there are difficulties 
with the convergence for the primary analysis or very large uncertainties on the estimated α 
parameters.   
A secondary analysis of aggregated average change from baseline in nocturnal urine volume has 
been added.  This outcome variable was added to comply with the Bayesian analysis mentioned in 
Table 9-4 in the trial protocol.   
The ITT-RT data set will be used for all secondary analyses as stated in the protocol; but only 
observed data will be used.  This is considered a clarification of the protocol. 
For all baseline-adjusted analyses of more than one visit at a time, the interaction between visit and 
baseline has been added as a systematic effect.  This is done because it is unlikely that the baseline 
value has the exact same influence on measurements 1 week after baseline and 12 weeks after 
baseline.  Furthermore, this leads to a frequentist approach more similar to the Bayesian model in 
which the association with baseline depends on the visit.  For all analyses estimating the interaction 
between treatment and sex, interactions have been added between sex and each of the systematic 


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Statistical Analysis Plan 
effects.  This is done to prevent potentially contradictory results from separate analyses of the two 
sexes and the evaluation of the interaction between treatment and sex (overall or visit-specific, as 
appropriate) caused by non-comparable statistical models. 
The protocol states in Section 9.7.3 Secondary and Exploratory Analyses: 
Binary endpoints such as “responder status” at a certain visit will be analysed using SAS PROC 
GENMOD with the logit as link function for the responder probability. An unstructured covariance 
matrix will be assumed for the repeated responder status which will be adjusted for baseline value 
as covariate and treatment, visit and treatment-by-visit interaction as factors. (Associated with e.g., 
responder analysis in terms of reduction in number of voids, cumulative distritubtion function plots 
of percentage change from baseline by treatment may be produced.) 
This has been clarified to the following: 
Binary endpoints such as the cross-sectional “responder status” at a visit will be analysed using 
SAS PROC GENMOD with logit as the link function for the responder probability.  An 
unstructured correlation matrix will be used as working correlation matrix.  The systematic effects 
will include treatment, visit, and treatment-by-visit interaction as factors, and will be adjusted for 
the log2-transformed number of nocturnal voids at baseline-RT, subtracted by 1, as a covariate 
interacting with treatment.  Odds ratios relative to placebo with associated 95% confidence intervals 
(without multiplicity adjustment) will be presented.  The analyses will be applied to the observed 
data for the ITT-RT analysis set.  
In addition to the illustrations of the therapeutic window specified in the protocol, illustrations of 
the therapeutic window will be produced using the estimated treatment contrast compared to 
placebo for the change from baseline-RT to lowest post-baseline measurement of serum sodium as 
the safety indicator.  The inclusion of desmopressin in the plots illustrating the therapeutic window 
(“Corresponding efficacy and safety of desmopressin will be illustrated in a side panel for 
comparison.”) has been deleted to comply with “None of the primary, secondary or explorative 
analyses will include desmopressin.” (Section 10.1).   
In the analyses of time to ‘confirmed’ hyponatraemia episodes, the time to event is defined as the 
time of confirmation in stead of the time to first measurement below the threshold to avoid 
conditioning on the future.  The protocol states “The associated relative hazards of treatment and 
gender will be analysed using Cox proportional hazards model adjusting for baseline serum sodium 
and age (<65, ≥65 years). Possible heterogeneity between the genders in the relative treatment 
hazards will be explored by the inclusion of a treatment-by-gender interaction term”.  These 
analyses will not be performed since the trial is too small to perform Cox regression analyses of the 
occurrence of hyponatraemia events with 9 treatment groups and 2 covariates. 
The adverse events tables presenting incidences of least 5% have been changed to presenting at 
incidences of at least 10% because it is expected that for several of the FE 201836 treatment groups, 
20 subjects or less are allocated to the group. 


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Statistical Analysis Plan 
According to 
, the interim analyses will deviate from the Appendix 2 in the 
protocol regarding the derivation of the allocation probabilities by the factor 1/( nd + 1) before the 
normalization to sum to 1.  
Remaining changes are all considered clarifications of presentations specified in the protocol. 


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Statistical Analysis Plan 
15 
Tables, Listings and Figures 
Non-standard table and listing shells and figure specifications will be provided in a separate 
document on an as-needed basis. 
Standard tables and listing are according to the end-of-text and in-text specifications specified at 
O:\GB_Prog\05_Data Standard\Standardisation of output.  
 


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16 
References 
Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome 
measure for insomnia research. Sleep Med. 2001 Jul; 2 (4):297-307. 
Holm-Larsen T, Andersson F, van der Meulen E, Yankov V, Rosen RC, Nørgaard JP. The nocturia 
impact diary: a self-reported impact measure to complement the voiding diary. Value Health. 2014 
Sept; 17 (6): 696-706. 
Hsu A, Nakagawa S, Walter LC, Van Den Eeden SK, Brown JS, Thom DH, et al. The Burden of 
Nocturia Among Middle-Aged and Older Women. Obstet Gynecol. 2015; 125 (1): 35-43. 
Ratitch B, O’Kelly M.  Implementation of Pattern Mixture Models Using Standard SAS/STAT 
Procedures, PharmaSUG2011 – Paper SP04 
Viktrup L, Hayes RP, Wang P, Shen W. Construct validation of patient global impression of 
severity (PGI-S) and improvement (PGI-I) questionnaires in the treatment of men with lower 
urinary tract symptoms secondary to benign prostatic hyperplasia. BMC Urology. 2012; 12 (1): 1-8. 


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Statistical Analysis Plan 
Appendices 
Appendix 1 
Markedly Abnormal Laboratory Safety Values, Vital Signs and ECGs 
Table A: Criteria for Markedly Abnormal Laboratory Test Results (Haematology) 
 
 
Criteria for Markedly Abnormal 
Variable 
Units 
Low 
High 
Haemoglobin 
g/L 
 80 
 200 
Haematocrit 
Ratio 
≤ 0.30 
≥ 0.54 
Total WBC 
109/L 
 2.0 
 35.0 
Total RBC 
1012/L 
 3.0 
 6.2 
MCV 
fL 
 75 
 105 
MCH 
pg 
 25 
 35 
MCHC 
mmol/L  
 18.62 
 22.96 
Basophils   
% 
 0 
 1.5 
Absolute Basophils   
109/L 
 0 
 2.0 
Eosinophils   
109/L 
< 3.0 
Not applicable 
Leucocytes 
109/L 
< 2.5 
> 15.0 
Lymphocytes 
109/L 
< 0.50 
> 20.00 
Monocytes 
% 
< 3.4  
> 9.0 
Absolute Neutrophil Count 
109/L 
< 1 
Not applicable 
Platelets 
109/L 
< 50 
> 999 
  
MCH: Mean corpuscular haemoglobin 
MCHC: Mean corpuscular haemoglobin concentration 
MCV: Mean corpuscular volume 
RBC: Red blood cells 
WBC: White blood cells 


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Table B: Criteria for Markedly Abnormal Laboratory Test Results (Clinical Chemistry) 
 
 
Criteria for Markedly Abnormal 
Variable 
Units 
Low 
High 
AST (SGOT) 
IU/L 
Not applicable 
> 5 x ULN 
AST(female): >155 
AST(Male): >185 
ALT (SGPT) 
IU/L 
Not applicable 
> 5 x ULN 
ALT (female): >165 
ALT(Male): >205 
Alkaline 
phosphatase 
IU/L 
Not applicable 
5 x ULN 
ALP (female): > 520 
ALP(Male): >645 
GGT 
IU/L 
Not applicable 
> 3 x ULN 
LDH 
IU/L 
Not applicable 
> 3 x ULN 
Globulin  
g/dL 
 
 
Total bilirubin 
mg/dL 
Not applicable 
 1.5 x ULN 
Direct bilirubin 
mg/dL 
Not applicable 
 8.55 
Urea nitrogen 
mmol/L 
Not applicable 
 10.7   
Creatinine 
umol/L 
Not applicable 
Female: >168 
Male: > 206 
Glomerular 
Filtration Rate 
mL/min 
 60 
Not applicable 
Total protein 
g/L 
 45 
 90 
Albumin 
g/L 
 20 
 65 
Potassium 
mmol/L 
 2.5 
 6.5 
Sodium 
mmol/L 
 125 
> 155 
Chloride 
mmol/L 
 90 
 115 
Phosphorus 
mmol/L 
 0.5 
 1.9 
Calcium 
mmol/L 
 1.75 
 3.13 
Bicarbonate 
mmol/L 
 15 
 34 
Glucose 
mmol/L 
 2.8 
> 13.9  
Magnesium 
mmol/L 
 0.6 
 1.1 
Total cholesterol 
mmol/L 
Not applicable 
 10.36  
Triglycerides 
mmol/L 
Not applicable 
> 5.65 
CPK 
U/L 
 
> 850 
ALT: Alanine transaminase 
ALP: Alkaline phosphatase 


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AST: Aspartate transaminase 
CPK: Creatine phosphokinase 
GGT: Gamma glutamyl transferase 
IU: 
LDH: Lactate dehydrogenase 
SGOT: Serum glutamic oxaloacetic transaminase 
SGPT: Serum glutamic pyruvic transaminase 
ULN: Upper Limit Normal 
 
 
 
 
 
Table C. 
Criteria for Markedly Abnormal Vital Sign Values* and Body Weight 
Variable 
Values 
Change from Baseline 
Systolic blood pressure 
 180 mmHg                            
 90 mmHg 
Increase of  20 mmHg  
Decrease of  20 mmHg 
Diastolic blood pressure 
 105 mmHg    
 50 mmHg 
Increase of  15 mmHg  
Decrease of  15 mmHg 
Pulse rate 
 120 bpm                                
 50 bpm 
Increase of  15 bpm     
Decrease of  15 bpm 
Body Weight 
None 
Increase of  7%  or 2 kg 
between trial visits 
Decrease of  7% 
Bmp: beats per minute 
 
* To be considered as markedly abnormal, a value must be above or below the specified 
values and fulfill one of the criteria for change from baseline (increase or decrease).