Evaluation of the Effects of Neurexan® on Short-Term Insomnia, Daytime Performance and Stress Response by Polysomnography (PSG), Electroencephalogram (EEG), Stress Biomarkers and Patient-Reported Outcomes (PROs)
Phase: PHASE2
Conditions: Insomnia, Stress Reaction
Sponsor: Biologische Heilmittel Heel GmbH

Biologische Heilmittel Heel GmbH 
  
 
CONFIDENTIAL INFORMATION 
Cover Sheet 
Clinical Trial Code: C2104 
 
Cover Sheet -Clinical Trial Protocol, 27 February 2025 final version 4.0 
 
 
 
Evaluation of the Effects of Neurexan® on 
Short-Term Insomnia, Daytime Performance and Stress Response by  
Polysomnography (PSG), Electroencephalogram (EEG),  
Stress Biomarkers and Patient-Reported Outcomes (PROs) 
 
 
 
An Exploratory, Placebo-Controlled Trial in Short-Term Insomnia Patients 
 
 
 
 
 
Protocol:  
  
Approved Version 4.0, dated 27-Feb-2025 
 
 
 
EudraCT Number:  
 
2022-003565-38 
 
 
 
EU CT Number:  
 
2024-514391-41-00 
 
 
 
NCT Number: 
 
 
NCT06278077 
 
 
 

Biologische Heilmittel Heel GmbH 
CONFIDENTIAL INFORMATION 
Clinical Trial Protocol 
Clinical Trial Code: C2104 
Clinical Trial Protocol 27 February 2025 final version 4.0 
Page 1 / 94 
Clinical Trial Protocol 
Evaluation of the Effects of Neurexan® on 
Short-Term Insomnia, Daytime Performance and Stress Response by 
Polysomnography (PSG), Electroencephalogram (EEG),  
Stress Biomarkers and Patient-Reported Outcomes (PROs) 
An Exploratory, Placebo-Controlled Trial in Short-Term Insomnia Patients 
Development Phase: 
II 
EudraCT Number:  
2022-003565-38 
EU CT Number:  
2024-514391-41-00 
Sponsor’s Protocol Code: 
C2104 
Investigational Product:  
Neurexan® 
Indication: 
Short-term insomnia 
Coordinating Investigator: 
Prof Dr. Martin Walter, MD 
Chair of Department of Psychiatry and 
Psychotherapy 
Jena University Hospital 
Philosophenweg 3 
07743 Jena 
Germany 
Sponsor: 
Biologische Heilmittel Heel GmbH 
Dr.-Reckeweg-Straße 2-4 
76532 Baden-Baden 
Germany 
Conduct: In accordance with the ethical principles that originate from the Declaration 
of Helsinki and that are consistent with the Good Clinical Practice guideline of the 
International 
Council 
for 
Harmonisation 
of 
Technical 
Requirements 
for 
Pharmaceuticals for Human Use (ICH) and regulatory requirements as applicable. 
Confidential: The information contained in this protocol is confidential and is 
intended for the use of clinical trial Investigators. It is the property of Biologische 
Heilmittel Heel GmbH and should not be copied by or distributed to persons not 
involved in the clinical investigation of Neurexan®, unless such persons are bound by 
a confidentiality agreement with Biologische Heilmittel Heel GmbH or its subsidiaries.

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Clinical Trial Code: C2104 
 
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REVISION HISTORY 
 
Number 
Date 
Section of 
clinical trial 
protocol 
Amendment or update 
Reason 
0 
V. 1.0 
24 November
 2022  
 
 
 
1 
V. 2.0 
15 February 
2023 
Signature 
page of 
Sponsor’s 
Representati
ves 
 
Head of Medicine & Research 
 
Senior Medical Manager 
Organizational changes 
 
 
In Schedule 
of Trial 
Procedures/ 
and 
accordingly 
in whole 
document 
Daytime/Performance 
Questionnaires, Level of 
Anxiety and Depression  
Paper PROs: BAI, BDI-II, 
WEIMuS, SF-36v2,  
AMS-ePRO®: ESS 
BDI-II questionnaire will be 
used on paper (paper PRO) 
instead of AMS-ePRO®. 
FSS questionnaire was 
replaced by WEIMuS 
questionnaire measuring the 
same construct. WEIMuS will 
be used on paper (paper 
PRO) 
 
 
Whole 
document 
Perceived Stress Scale-10 
(PSS-10) 
PSS questionnaire further 
specified that it is the 10-item 
scale  
 
 
Whole 
document 
Short Form-36 version 2 (SF-
36v2) 
SF-36 questionnaire further 
specified that version 2.0 is 
used 
 
 
Exclusion 
criteria 
(synopsis 
and section 
6.2) 
No. 5. 
History of psychiatric 
disorders within the last 6 
months prior to Screening Visit, 
according to the Structured 
Clinical Interview for DSM-5® 
Disorders – Clinician Version 
(SCID-5-CV) 
Excl. criterion no. 5 further 
specified; SCID-5-CV used to 
screen for psychiatric 
disorders in the last 6 months 
 
 
Whole 
document 
 
Minor corrections of typos 
and commas 
 
 
Section 6.4 
Insufficient treatment 
compliance as specified in the 
protocol (see section 11.3.2) 
Withdrawal criterion no. 3 
further specified 
 
 
Section 9.1.2 
Saliva samples are collected in 
2 ml SaliCap sampling tubes 
(TECAN/ IBL International, 
Hamburg, Germany, ref. no. 
RE69985) using short drinking 
straws 
Further information added 
 
 
Section 9.1.9 
Venous blood for 
transcriptome analysis will be 
collected in PAXgene® Blood 
RNA Tubes (Qiagen/ 
PreAnalytiX, purchased from 
Becton Dickinson, Heidelberg, 
Germany, ref. no. 762165) 
using a BD Vacutainer Safety-
Lok blood collection set 
(Becton Dickinson, ref. no. 
367282) before and after each 
Further information added 

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adaptation PSG night (4 
samples of 2.5 ml/ sample) 
 
 
Section 
9.1.15.4 
Würzburg Fatigue Inventory 
(WEIMuS) 
The WEIMuS is a 17-item 
scale designed to assess 
fatigue as a symptom of a 
variety of different chronic 
conditions and disorders. 
The scale addresses 
fatigue’s effects on daily 
functioning, querying its 
relationship to motivation, 
physical activity, work, family, 
and social life, and asking 
respondents to rate the ease 
with which they are fatigued 
and the degree to which the 
symptom poses a problem 
for them. The WEIMuS will 
be completed on paper at 
Baseline 1 and at Visit 1 
Fatigue questionnaire FSS 
was replaced by WEIMuS 
measuring the same 
construct 
2 
V. 3.0. 
19 July 2023 
Signature 
page of 
Contract 
Research 
Organization 
 
 
Clinical Trial Statistician 
Organizational change 
 
 
Synopsis 
Section 4.1 
 
The primary endpoint of this trial 
is to assess Neurexan® related 
changes in sleep efficiency (SE) 
at Visit 2 compared to Baseline 
2 as revealed by polysomno-
graphy. 
Further clarification which 
Visits are used to assess the 
primary endpoint 
 
 
Synopsis 
Section 4.2 
Added sentence for objective 
sleep parameters: 
To be assessed as change at 
Visit 2 compared to Baseline 2 
 
For subjective sleep pattern 
parameters 
o Insomnia Severity Index 
(ISI): changes in ISI at Visit 1 
compared to Baseline 1 
Further clarification which 
Visits are used to assess the 
secondary endpoints 
 
 
Synopsis 
Section 4.2 
• 
Stress questionnaires 
 Changes in subjective stress 
levels compared to Baseline 
as assessed by 
• Subclinical Stress Symptom 
Questionnaire-25 (SSQ-25) 
• Primary Appraisal 
Secondary Appraisal (PASA) 
• Perceived Stress Scale-10 
(PSS-10) 
• Continuous (over the whole 
trial period) daily stress 
assessment using AMS-
ePRO® functionality. 
Shift of stress questionnaires 
for logic reasons and addition 
of sentence for clarification 
 

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Inclusion 
criteria 
(synopsis 
and 
section 6.1) 
No. 2 
Short-term insomnia with 
moderate symptoms 
according to ISI of at least 8 
and below 22 being present 
for at least one week, but no 
longer than 3 months prior to 
Screening Visit and Baseline 1 
 
Inclusion criterion 2 was 
amended for clarification 
(deleted “and Baseline 1”) 
 
 
Inclusion 
criteria 
(synopsis 
and 
section 6.1), 
Section 10.7 
No. 8 
Females (Women, in section 
10.7) of childbearing 
potential must agree to 
maintain highly effective or 
acceptable birth control 
throughout the trial (CTFG 
2020). 
Highly effective (failure rate 
of less than 1% per year) 
Such methods include: 
 
• 
Oral or intravaginal or 
transdermal cCombined 
(estrogen and 
progestogen containing) 
hormonal contraception 
associated with inhibition 
of ovulation: oral, 
intravaginal, transdermal 
• 
Progestogen-only 
hormonal contraception 
associated with inhibition 
of ovulation: oral, 
injectable, implantable 
• 
Intrauterine device 
• 
oral or injectable or 
implantable hormonal 
contraception associated 
with inhibition of 
ovulation, or 
iIntrauterine hormone-
releasing system (IUS)  
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
(provided partner is sole 
sexual partner and if 
vasectomized partner has 
received medical 
assessment of the 
surgical success) 
• 
Sexual abstinence (only 
if defined as refraining 
from heterosexual 
intercourse during the 
entire period of risk 
associated with the study 
treatments) 
 
Inclusion criterion 8 was 
amended to also allow 
females with medically 
acceptable contraception 
according to CTFG 2020. In 
order to allow enrollment of 
female patients with 
acceptable non-hormonal 
contraception 
 
Section 10.7 on pregnancy 
adapted accordingly 

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Acceptable birth control 
methods which may not be 
considered as highly effective 
(failure rate of more than 1% 
per year) 
• 
Progestogen-only oral 
hormonal contraception, 
where inhibition of 
ovulation is not the 
primary mode of action 
• 
Male or female condom 
with or without 
spermicide 
• 
Cap, diaphragm or 
sponge with spermicide 
• 
Combination of male 
condom with either cap, 
diaphragm or sponge 
with spermicide (double 
barrier methods) 
 
 
 
Exclusion 
criteria 
(synopsis 
and section 
6.2) 
No. 3 
Based on the first 
polysomnographic screening 
night at Baseline 1, insomnia 
due to sleep apnea or 
periodic limb movement 
disorder (PLMD): OSA 
(Apnea Hypopnea Index of 
>5 events/ hour), PLMD 
(Periodic Limb Movement 
Index (PLMI) >15 events/ 
hour 
Exclusion criterion 3: Added 
“the first” and “at Baseline 1” 
for clarification 
 
Adjusted number of Periodic 
Limb Movement Index 
(PLMI) to >15 events/ hour in 
order to avoid screening 
failures due to normal PLMI 
exclusion criterion  
 
 
Exclusion 
criteria 
(synopsis 
and section 
6.2) 
 
No. 8  
Cognitive impairment (age
adapted cut-off of 24 points 
in the Montreal Cognitive 
Assessment [MoCA], 
Thomann, Berres et al. 2020) 
at Screening Visit 
Deleted “age-adapted”, 
addition “of 24 points” and a 
reference for higher 
specificity 
 
 
Exclusion 
criteria 
(synopsis 
and section 
6.2) 
Section 7.6.1 
No. 13 
Excessive consumption of 
xanthine-containing beverages 
(more than 7 cups daily of 
coffee or tea or other 
beverages containing 
xanthines) 
Added “daily” to avoid 
misunderstanding 
 
 
Exclusion 
criteria 
(synopsis 
and section 
6.2) 
No 18. 
Hypertension defined as 
systolic blood pressure >145 
≥140 mmHg (Burnier, 2018) 
Threshold for hypertension 
was amended and reference 
added to align with current 
European hypertension 
guideline  
 
 
Schedule/ 
Flowchart of 
trial 
procedures 
Inclusion and Exclusion 
criteria (except exclusion 
criterion 3) 
Further clarification for in- 
and exclusion criteria that 
eligibility will be assessed at 
Screening Visit, except 

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(following 
synopsis 
section 2.2, 
section 8.1) 
Randomization Exclusion 
Criterion 3 
exclusion criterion 3 which 
will be assessed at first 
polysomnographic screening 
night at Baseline 1. 
 
Harmonized flowchart in 
order to address changes 
made in exclusion criterion 3, 
and which is no longer 
defined as randomization 
criterion 
 
 
Synopsis and 
section 
11.3.2 
Criteria for Evaluation: 
The enrolled screening 
population is defined as all 
patients who signed informed 
consent. 
Wording amended for 
clarification “The screening 
population is defined as all 
patients who signed informed 
consent.” 
 
 
Synopsis and 
section 
11.4.2 
Secondary Efficacy Variables 
Biochemical parameters 
Serum cortisol levels (ug/dl) 
and other stress-related 
parameters in response to 
the stress induction by Cold 
Pressor Test (CPT). 
Units are not given anywhere 
else. Deleted to harmonize 
 
 
Synopsis and 
section 
11.4.2 
Secondary Efficacy Variables 
Exploratory Efficacy 
Variables 
• 
Cognitive performance in 
three attentional 
distraction tasks 
• 
PSG Adaptation sleep 
parameters data of 
derived polysomnography 
from the two adaptation 
nights at Baseline 1 and 
Visit 1 
Wording changed for 
correction and clarification 
reasons 
 
 
Synopsis and 
section 
11.4.2 
Statistical Methods: 
Correlations will may be 
analyzed using Spearman's 
rank correlation coefficient or 
another appropriate method. 
Wording changed to allow 
other methods than 
Spearman’s. 
 
 
Section 4.1  
The primary objective is to 
demonstrate an improvement of 
sleep efficiency (SE) measured 
by polysomnography on daily 
treatment with Neurexan® in 
short-term insomnia. 
The primary endpoint of this trial 
is to assess Neurexan® related 
changes in sleep efficiency SE 
(SE) at Visit 2 compared to 
Baseline 2 as revealed by 
polysomnography (PSG). 
Further clarification which 
Visits are used to assess the 
primary endpoint 

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Section 4.2 
The secondary objectives are 
to assess further PSG-based 
objective as well as subjective 
sleep parameters, daytime 
performance and stress 
processing in patients with 
short-term insomnia treated 
daily with Neurexan® 
compared to placebo.  
Further specified in objective, 
that trial medication is to be 
taken daily 
 
 
Section 6 
An enrollment of 80 patients 
suffering from short-term 
insomnia is planned for the 
trial. If a patient fulfils all of the 
inclusion criteria and none of 
the exclusion criteria, his/her 
eligibility will be assessed 
during the Screening Visit and 
he/she will be randomly 
assigned to Neurexan® or 
placebo treatment with 1:1 
allocation and stratification by 
sex as soon as the 
randomization criterion is 
fulfilled. 
Amended in order to address 
changes made in exclusion/ 
randomization criterion 3 
 
 
Section 6.1 
 
Inclusion criterion 3. 
Reports habitual bedtime, 
defined as the time the 
participant attempts to sleep, 
between 21:00 24:00 and and 
habitual wake time between 
05:00 and 09:00 01:00 
Inclusion criterion 3 was 
accurately stated in the 
synopsis and has now been 
harmonized 
 
 
Section 6.2  
Added sentence regarding 
blood tests taken at 
Screening: 
The eligibility of patients 
based on safety laboratory 
parameters (except CRP) are 
at the discretion of the 
investigator. 
Addition to further clarify that 
it is at the investigator’s 
discretion to decide upon 
eligibility of patients based 
on safety laboratory 
parameters (except CRP, 
because a clear threshold is 
defined in exclusion criterion 
no 17) 
 
 
Section 6.3  
Randomization Criterion 
Only patients who do not meet 
the exclusion criterion number 
3 following Baseline 2 PSG 
night at Day 0 are eligible for 
randomization.  
Randomization criterion is no 
longer needed. Exclusion 
criterion 3 will be assessed 
at first polysomnographic 
screening night at 
Baseline 1. 
 
 
Section 6.4 
Intake of prohibited 
concomitant medication (see 
section 7.6.1) that might 
influence the trial procedures 
or the results  
Included cross-reference to 
section 7.6.1 to increase 
readability 
 
 
Section 7.6.1  Prohibited Medications 
Abuse of alcohol and/or use of 
amphetamines, benzodiaze-
Clarification that not only the 
abuse but also “use of” 
amphetamines, benzodiaze-
pines, cocaine, marijuana, 

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pines, cocaine, marijuana, 
methaqualone, methadone, 
opioids, propoxyphene, 
barbiturates, phencyclidine 
methaqualone, methadone, 
opioids, propoxyphene, 
barbiturates and 
phencyclidine are considered 
as prohibited  
 
 
Section 8.1 
Screening Visit 
Restructuring of assessments; 
Informed consent followed by 
diagnosis of short-term 
insomnia directly after and 
completion of ISI  
• 
Instruction in the use of 
the actigraphy watch, i.e., 
Actiwatch Spectrum Plus, and 
its handing over. 
Restructuring for clarification 
and addition of instruction in 
the use of Actiwatch 
 
 
Section 8.1  
From Screening Visit onwards 
daily until the End of Trial 
(Follow-up Visit/ Day 28+3) 
patients must wear an 
actigraphy watch portable 
actimetric device recording 
their rest sleeping and activity 
cycles, complete a sleep diary 
and answer digital 
questionnaires regarding 
stress level (AMS-ePRO®). 
Wording harmonized 
throughout the document 
 
 
Section 8.1 
Baseline 1 
(…) patients will have their first 
night at the trial site for PSG 
adaptation and screening for 
exclusion criterion 3. 
 
In the evening before the 
second Baseline 1 night urine 
and breath alcohol tests will be 
conducted on drugs and 
alcohol, respectively 
 
PSG for screening of exclusion 
criterion 3 and for adaptation 
to the unfamiliar sleep lab 
environment to measure SOL, 
WASO, TST, NWAK and ARI 
during sleep in the night 
between Day -2 and Day -1 
(section 9.1.1) 
 
Check exclusion criterion 3 at 
Day -1 
Addition of “and screening for 
exclusion criterion 3” to 
reflect changes of evaluation 
timepoint of exclusion 
criterion 3 
 
 
Correction: Baseline 1 night 
 
 
 
 
 
Clarification that PSG at 
Baseline 1 is for screening of 
exclusion criterion 3 and for 
the adaptation of the patients 
to unfamiliar sleep lab 
environment and not to 
measure any endpoint 
parameters 
 
Addition since exclusion 
criterion 3 to be assessed at 
Baseline 1 now 

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Section 8.1 
Baseline 1 
Collection of approximately 
15.112.5 ml blood for 
measuring cortisol, DHEA-S, 
adrenaline, noradrenaline, 
inflammation markers (IL-6 
and TNF-α) prior to CPT, 
20 minutes and 50 minutes 
after CPT at Day -1 (section 
9.1.8) 
Amount of blood to be 
collected reduced from 
approximately “15.1 ml” to 
“12.5 ml” 
 
 
Section 8.1  
Baseline 2 
After fulfilment of the 
randomization criterion 
pPatients will be randomly 
assigned to treatment group 
Neurexan® or placebo with a 
1:1 allocation and stratification 
by sex. 
 
Baseline 2 PSG night 
recording to measure primary, 
i.e., SE and secondary 
endpoints, i.e., SOL, WASO, 
TST, NWAK, and ArI during 
sleep in the night between 
Day -1 and Day 0 (section 
9.1.1)  
Check randomization criterion 
at Day 0 (section 6.3 )  
Changed because there is no 
longer a randomization 
criterion 
 
 
 
 
 
 
 
Clarification of time point and 
endpoints to be measured. 
 
 
 
 
 
 
 
 
 
Deleted, no longer needed 
 
 
Section 8.1 
Visit 1 
PSG night, againto for 
adaptation to the unfamiliar 
sleep lab environment 
measure SOL, WASO, TST, 
NWAK, and ArI during sleep in 
the night between Day 12 and 
Day 13 (section 9.1.1) 
Clarification that PSG 
between Day 12 and Day 13 
night is for the adaptation of 
the patients to unfamiliar 
sleep lab environment and 
not to measure any endpoint 
parameters 
 
 
Section 8.1 
Visit 1 
Collection of approximately 
15.112.5 ml blood for 
measuring cortisol, DHEA-S, 
adrenaline, noradrenaline, 
inflammation markers (IL-6 
and TNF-α) and alpha
amylase prior to CPT, 
20 minutes and 50 minutes 
after CPT at Day 13 (section 
9.1.8) 
Changed “approximately 
15.1 ml” to “approximately 
12.5 ml”, deleted “and alpha-
amylase” 

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Section 9.1.1  Polysomnography (PSG) 
(…) Sleep efficiency (SE) is 
calculated as the ratio of total 
sleep time (TST) to time in bed 
(TIB) (i.e., both sleeping and 
attempting to fall asleep or fall 
back asleep).  
Sentence added to define 
sleep efficiency 
 
 
Section 9.1.2  Salivary samples are stored 
frozen at -80°C (+/- 10°C 
fluctuation) […]. 
Further specified storage 
temperature  
 
 
Section 9.1.5  Actigraphy 
(…), which will continuously 
monitor movement information 
over the whole trial duration 
(Screening Visit/ Day -28 to -8 
until Follow-up Visit/ Day 28) to 
assess time asleep SE, SOL, 
WASO, TST and NWAK sleep 
stages (time spent in REM, 
light sleep, and deep sleep) as 
well as to track daily activity to 
investigate habitual sleep–
wake patterns 
Parameters that will be 
measured by actigraphy are 
further specified 
 
 
Section 9.1.7 
Immediately bBefore 
conduction of the CPT (at 
Baseline) value, 20 minutes 
and 50 minutes after CPT 
blood (15.1 12.5 ml/ blood 
sample) will be taken to 
assess cortisol and DHEA-S, 
adrenalin and noradrenalin 
and inflammatory response 
(IL-6 and TNF-α). 
Wording changed for 
clarification, amount of blood 
changed “15.1 ml” to 
“12.5 ml”, “adrenalin and 
noradrenalin” added 
 
 
Section 9.1.8 
Each blood sample consists of 
15.1 12.5 ml blood that will be 
split up in 4 3 monovettes (all 
from Sarstedt, Nümbrecht, 
Germany) as following: 
Changed “15.1 ml” to 
“12.5 ml”, and “4 
monovettes” to “3 
monovettes” 
 
 
Section 9.1.8 
4.9 ml serum blood will be 
collected in an S-Monovette® 
Serum Gel (ref no 04.1935.001) 
for the analysis of cortisol, 
DHEA-S and TNF-α,  
Replaced “serum” with 
“blood”, added “DHEA-S” 
 
 
Section 9.1.8 
4.9 ml serum will be collected 
in a S-Monovette® Serum Gel 
(ref no 04.1935.001) for the 
analysis of DHEA S, 
Deleted second bullet point 
(DHEA-S will be analyzed 
together with cortisol and 
TNF-α from one S-
Monovette®) 

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Section 9.1.8 
2.6 4.9 ml plasma blood will be 
collected in a S-Monovette® K3 
EDTA (ref no 04.193101.001) 
for the analysis of adrenalin 
and noradrenalin, and  
Replaced “2.6 ml plasma” 
with “4.9 ml blood” and 
adapted ref no 
 
 
Section 9.1.8 
2.7 ml plasma blood will be 
collected in a S-Monovette® 
Lithium-heparin gel (ref no. 
04.1928.001) for the analysis 
of IL-6. 
Replaced “plasma” with 
“blood” 
 
 
Section 9.1.9  (…) interim storage at -80°C 
(+/- 10°C fluctuation) in the 
biobank (…). 
Further specified storage 
temperature  
 
 
Section 
9.1.11 
With neuropsychological tests 
the Investigator assesses the 
patients’ alertness, vigilance 
and sustained attention 
concentration, distraction as 
well as psychomotor speed. 
Correction for consistency 
 
 
Section 9.2.4 
Safety Laboratory 
Safety laboratory blood 
samples will be collected once 
at Screening Visit (and up to 
2 working days later) (...). 
Clarification that screening 
safety lab can be collected 
within 2 working days 
following the Screening Visit 
 
 
Section 11.3 
Definition of Baseline 
For PSG derived parameters 
the baseline is defined as the 
night from Day -1 to Day 0 
(Baseline 2). 
Sentence added for further 
clarification of Baseline 
values for PSG parameters 
 
 
Section 
11.3.1 
Hypothesis 
The null hypothesis will be 
rejected and the superiority of 
a treatment (Neurexan® or 
placebo) will be claimed if the 
p-value will be equal or less 
than 0.05. 
Added “equal or” for 
clarification 
 
 
Section 
11.4.1 
Primary Efficacy 
The primary efficacy variable for 
changes in sleep pattern will be 
sleep efficiency (SE) measured 
by polysomnography at 
Baseline 2 and Visit 2, 
calculated as the ratio of total 
sleep time (TST) to time in bed 
(TIB), as difference at Visit 2 to 
Baseline 2. 
Clarification which Visits are 
used to assess primary 
efficacy endpoint 
 
 
Section 
11.4.2 
Secondary Efficacy 
Specification of exploratory 
instead of descriptive 

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For all secondary variables, 
exploratory descriptive 
statistics comparing the 2 
treatment groups will be 
performed. 
 
Group comparisons of 
continuous numeric 
parameters will be tested using 
an ANCOVA including 
treatment, the stratification 
factor sex, and the baseline 
value of continuous numeric 
parameters at Baseline as 
covariate; (..). 
 
Polysomnography at Baseline 
2 and Visit 2 
 
 
 
 
 
Re-wording for better 
understanding 
 
 
 
 
 
 
 
 
 
Addition to clarify when these 
variables will be assessed 
 
 
Whole 
document 
 
Minor corrections of typos 
and commas 
3 
V. 4.0. 
27 February 
2025 
2.1 Synopsis 
Trial Duration: 
First Patient First Visit 
planned:   March June 2023 
Last Patient Last Visit planned: 
 
January November 
20246 
Updating actual FPFV and 
planned LPLV 
 
 
 
2.1 Synopsis 
Stress Processing 
Further secondary objectives 
are to assess correlations 
between: 
• 
Changes in sleep 
parameters, stress 
parameters and daytime 
performance with whole 
blood transcriptomics. 
 
It was decided to omit the 
analysis of whole blood 
transcriptomics for this trial 
due to the following 
limitations:  
• RNA Stability and 
Degradation RNA: in 
whole blood is prone to 
degradation, especially 
if samples are not 
processed immediately 
or properly. This 
instability can 
compromise data 
quality and 
reproducibility. 
• The WBT blood 
samples taken so far 
are incomplete (based 
on the currently 46 
randomized patients, 
WBT blood samples are 
incomplete for 10 
patients, >20%). 
 
 
2.1 Synopsis 
Subgroup Analyses 
Sex (female/ male) differences 
based on whole blood 
transcriptomics 
See the justification above 
for decision to omit WBT for 
this trial.  
 

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2.2 Schedule 
of Trial 
Procedures 
and  
8.1 Visit 
Schedule  
Table 3 
 
Venous 
Blood 
Samples 
for 
Whole 
Blood 
Transcri
ptomics2 
 
X 
 
X 
 
 
 
2Venous blood sampling (2.5 
ml in PAXgene® Blood RNA 
Tubes) for transcriptome 
analysis before sleep and after 
awakening and additionally 
before and 50 minutes after 
CPT stress induction. 
See the justification above 
for decision to omit WBT for 
this trial.  
 
 
4.2 
Secondary 
Objectives 
and 
Endpoints 
4.2 Secondary Objectives 
and Endpoints  
Daytime Performance by  
• 
Resting state EEG:  
Regional changes in spectral 
characteristics of EEG using 
relative power in delta-theta-
alpha-beta gamma frequency 
ranges at Visit 1 compared to 
Baseline 1 
Further secondary 
objectives are to assess 
correlations between: 
(…) 
• 
Changes in sleep 
parameters, stress 
parameters and 
daytime performance 
with whole blood 
transcriptomics 
 
 
 
 
 
Correction 
 
 
 
 
 
See the justification above 
for decision to omit WBT for 
this trial. 
 
 
5.1 Trial 
Type and 
Design 
Features 
It is planned to randomize 
enroll a total of 80 patients with 
short-term insomnia. 
Substituted “enroll” by 
“randomize” in order to be 
more accurate 
 
 
5.3 Trial 
Duration 
The estimated First Patient 
First Visit (FPFV) is was in 
June March 2023. A total of 
80 patients will be 
randomized recruited within 
approximately 32 21 months. 
The Last Patient Last Visit 
(LPLV) is planned to be in 
January 2026. 
Updating actual FPFV and 
planned LPLV 

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5.5.3 Central 
Laboratories 
(…) (Institut für Klinische 
Chemie und Laboratoriums-
diagnostik IKCL, University 
Hospital Jena) will analyze 
safety laboratory blood 
samples (see section 9.2.4) as 
well as blood biomarker 
samples (see section 9.1.8) 
and will provide frozen interim 
storage of saliva and whole 
blood transcriptomic samples 
in their biobank.  
Saliva biomarker samples 
(9.1.2) will be analyzed at 
Dresden LabService GmbH. 
and whole blood transcriptomic 
samples (section 9.1.9) will be 
analyzed at German Center for 
Neurodegenerative Diseases 
DZNE, Göttingen. 
See the justification above 
for decision to omit WBT for 
this trial. 
 
 
6. Patient 
Enrollment 
Screening, 
Randomizat-
ion, Disconti-
nuation and 
Withdrawal 
An enrollment Randomization 
of 80 patients suffering from 
short-term insomnia is planned 
for the trial.  
Substitution “enrollment” by 
either “screening” or 
“randomization” in order to 
be more accurate 
 
 
6.3 Patient 
Premature 
Withdrawal 
from Trial/ 
Withdrawal 
Criteria 
If possible, a remotely 
prematurely withdrawn patient 
should be invited for a last 
onsite visit to return remaining 
IMP and the Actiwatch. The 
procedures of the Follow-Up 
Visit should be followed. 
Addition for further 
clarification 
 
 
7.2 Dosage 
and  
Administration 
The trial treatment consists of 
2 tablets taken sublingually 3 
times daily (a total of 6 tablets/ 
day) for a period of 
14 consecutive days (+ up to 2 
days allowance, see flow chart 
at section 2.2 and Table 3).  
Insertions for time deviation 
allowance 
 
 
7.3 Blinding 
The unblinding has to be 
documented by the 
Investigator. Details of the 
unblinding procedure will be 
explained in the Safety 
Reporting Management Plan 
for this trial. 
Correction 
 
 
7.4 
Manufacturing
, Packaging 
and Labelling 
(…) Labelling implements the 
use of the computer-generated 
randomization plan in a 
treatment ratio of 1:1 and 
stratification by sex. IMP 
containers for males and for 
females are provided, 
distinguishable by 
randomization numbers and 
IMP label color. 
Insertion of further IMP 
details. 

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8.1 Visit 
Schedule  
Baseline 1 
(…) Before sleep, pPatients 
complete their electronic sleep 
diary (…).Venous blood for 
transcriptome analysis will be 
collected. (…) 
Venous blood for 
transcriptome analysis will be 
collected after awakening as 
well as before and after CPT. 
The following procedures will 
be performed: (…) 
• 
Completion of the 
following questionnaires 
at Day -2:  
o a) on paper: BAI, 
BDI-II, WEIMuS, 
PSQI, PSS-10, SF-
36v2, SSQ-25  
o b) on AMS-ePRO®: 
ESS, ISI, PASA 
(section 9.1.14) 
• 
Collection 
of 
2.5 ml 
venous 
blood 
for 
transcriptome analysis 
before sleep at Day -2 
and at awakening (Day 
-1) (section 9.1.8) 
 
(…) 
• 
Collection of 2.5 ml 
venous blood for 
transcriptome analysis 
before and 50 minutes 
after CPT at Day 1 
(section 9.1.8) 
Extended time frame to 
complete the patient diary at 
Baseline 1. 
 
See the justification above 
for decision to omit WBT for 
this trial.  
 
 
Extended time frame to 
complete the patient 
questionnaires at Baseline 1, 
either at Day -1 or Day -2. 
 
 
 
 
 
 
 
 
See the justification above 
for decision to omit WBT for 
this trial 
 
 
8.1 Visit 
Schedule  
Visit1 
(…)Before sleep, venous blood 
for transcriptome analysis will 
be collected. (…) 
Venous blood for 
transcriptome analysis will be 
collected after awakening and 
before and after CPT. 
The following procedures will 
be performed: (…) 
• 
Collection of 2.5 ml 
venous blood for 
transcriptome analysis, 
before sleep at Day 12 
and at awakening at 
Day 13 (section 9.1.8) 
• 
Collection of 2.5 ml 
venous blood for 
transcriptome analysis 
before and 50 minutes 
after CPT at Day 13 
(section 9) 
See the justification above 
for decision to omit WBT for 
this trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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• 
Completion of the 
following questionnaires 
at Day 12: ESS, ISI, 
PASA (AMS-ePRO®); 
BDI-II and WEIMuS 
(both paper-based; 
section 9.1.14)  
Extended time frame to 
complete the patient 
questionnaires at Visit 1. 
 
 
8.1 Visit 
Schedule  
Visit 2 
The following procedures will 
be performed:  
- 
(…) Last IMP intake in the 
night of Day 13 prior to 
sleep 
Addition to specify when 
exactly the last IMP dose is 
to be taken. 
 
 
9.1.3 
Electroencep
halography 
(EEG) 
In addition to EEG recordings 
during PSG nights, patients 
will undergo continuous EEG 
measurements at Baseline 1 
(Day -1) and Visit 1 (Day 13). 
These include a resting-state 
EEG before the CPT, an EEG 
recording during the CPT, and 
a resting-state EEG after the 
CPT. 
Besides EEG during PSG 
nights patients will have 4 
additional EEG measurements 
during this trial.  
Two EEGs (rsEEG to measure 
the EEG vigilance fluctuations, 
EEG asymmetry index and 
spectral characteristics of EEG 
during resting state at 
Baseline 1 and at Visit 1 and 
two EEGs during stress 
induction by CPT at Baseline 1 
and Visit 1.  
(…) 
Regional changes in spectral 
characteristics of EEG using 
relative power indices in delta-
theta-alpha-beta-gamma 
frequency ranges are 
assessed. 
Insertions to specify EEG 
data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correction 
 
 
9.1.7 Cold 
Pressor Test 
(CPT) 
Before and after CPT a 2.5 ml 
venous blood sample will be 
collected for transcriptome 
analysis.  
See the justification above 
for decision to omit WBT for 
this trial 
 
 
 
9.1.9 Venous 
Blood for 
Whole Blood 
Transcriptom
ics 
 
With whole blood 
transcriptomics a more 
detailed picture of the 
physiological condition of the 
patients can be obtained.  
Venous blood for 
transcriptome analysis will be 
collected in PAXgene® Blood 
RNA Tubes (Qiagen/ 
PreAnalytiX, purchased from 
See the justification above 
for decision to omit WBT for 
this trial 
 

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Becton Dickinson, Heidelberg, 
Germany, ref. no. 762165) 
using a BD Vacutainer Safety
Lok blood collection set 
(Becton Dickinson, ref. no. 
367282) before and after each 
adaptation PSG night 
(4 samples of 2.5 ml/ sample).  
Additionally, 2 venous blood 
samples for transcriptome 
analysis (2.5 ml/ sample) will 
be collected in PAXgene® 
Blood RNA Tubes using BD 
Vacutainer before and 
50 minutes after CPT at Day -1 
and Day 13 (4 samples of 
2.5 ml/ sample).  
Blood tubes will be gently 
inverted 8 to 10 times, stored 
upright for 2 hours at room 
temperature (18-25°C) and 
then transferred to -20°C for 
minimum 24 hours and 
maximum 72 hours followed by 
interim storage at -80°C (+/- 
10°C fluctuation) in the 
biobank of the local laboratory 
of the investigational site 
(Institut für Klinische Chemie 
und Laboratoriumsdiagnostik, 
IKCL, Jena University 
Hospital). Analysis will be 
performed by the German 
Center for Neurodegenerative 
Diseases (DZNE), Göttingen. 
 
 
9.1.154 
Patient 
Question-
naires 
Patient-Reported 
Outcomes(…), at Baseline 1 
(either in the evening prior to 
Baseline 1 PSG night or next 
morning following Baseline 1 
PSG night) and either at Visit 1 
(either in the evening prior to 
Visit 1 PSG night or next 
morning following Visit 1 PSG 
night), or at Follow-up Visit. 
Insertions to specify 
completion timepoints 
 
 
9.1.154.1 
Pittsburgh 
Sleep Quality 
Index (PSQI) 
The PSQI is well suited for 
measuring change in insomnia 
and will be completed on 
paper at Baseline 1 and at 
Follow-up Visit (AMS-ePRO®). 
 
 
 
 
Correction 
 
 
9.1.154.6 
Subclinical 
Stress Symp-
tom Question-
naire-25 
(SSQ-25) 
This questionnaire consists of 
125 questions (…) . 
Correction 
 
 
9.1.154.8 
Perceived 
The English version of the 
PSS-10 comprises 10 items 
that are answered on a five-
Correction of used scale. 

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Stress Scale-
10 (PSS-10) 
point rating scale ranging 
from 01 = ‘never’ to 45 = ‘very 
often’ and will be completed 
on paper at Baseline 1 and at 
Follow-up Visit. A German 
translation of the English 
PSS-10 version is used. 
 
 
10.3 
Recording of 
AEs 
Information dated after the 
end of the trial for the patient 
concerned will not be part of 
the data collection in the 
eCRF. 
Insertion to specify the 
follow-up of AEs after the 
End of Trial documentation 
 
 
11.3 
Statistical 
Planning 
Subgroup Analyses 
The following subgroups will 
be defined: 
• (…)Sex (female/ male) 
differences based on 
whole blood 
transcriptomics 
 
Descriptive Analyses 
For continuous variables the 
number of observations (n), 
arithmetic mean, standard 
deviation (SD), minimum, 
median, 25%-, 75%-quantile, 
maximum, 95% confidence 
interval (CI) (2-sided), and the 
number of missing data will be 
presented.  
 
 
 
See the justification above 
for decision to omit WBT for 
this trial. 
 
 
 
Insertion of 25%- and 75%-
quantile 
 
 
11.4.2 
Secondary 
Efficacy 
Secondary efficacy variables 
are the following: 
(…) 
Whole blood transcriptomics  
 
Correlations between  
• 
(…)Changes in sleep 
parameters, stress 
parameters, and 
daytime performance 
with whole blood 
transcriptomics 
See the justification above 
for decision to omit WBT for 
this trial 
 
 
 
12.2 
Competent 
Authorities 
Irrespective of the outcome of 
the clinical trial, the trial results 
are to be reported within one 
year from the end of the 
clinical trial to regulatory 
authorities and published in 
international databases. 
A summary of the results 
understandable to laypersons 
will be made available in the 
EU database irrespective of 
the outcome of the trial. 
Addition to align with the 
CTR requirements 

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12.3 Ethical 
Conduct of 
the Trial 
The trial will be was originally 
submitted under the EU 
Clinical Trials Directive (EC) 
No. 2001/ 20/EC and 
transitioned in 2024 to the EU 
Clinical Trials Regulation (EU 
CTR No. 536/2014). 
Added information on trial 
transition to CTR 
 
 
12.8 
Serious 
Breaches 
 
A serious breach is any 
deviation of the approved 
protocol version or the Clinical 
Trials Regulation that is likely 
to affect the safety, rights of 
trial participants and/or data 
reliability and robustness to a 
significant degree in a clinical 
trial. 
Serious breaches require 
immediate attention of the 
Investigator. Any suspected 
serious breaches must be 
reported to the Sponsor within 
24 hours after becoming aware 
of it using the following contact 
details: 
Emails: C2104@heel.com, 
drugsafety@heel.com 
Phone +49 160 88 29 373 
Addition of section regarding 
‘serious breaches’ to align 
with the CTR requirements 
 
 
13.4.1 
Investigator 
Site File (ISF) 
(…) The Investigator records in 
the Patient Identification Log 
the following details for all 
persons giving their consent to 
participate in the trial: name 
(first and surname), date of 
birth, sex, postal address and 
the assigned unique 7-digit 
trial patient number. The date 
of enrollment (Screening Visit) 
date into the trial must also be 
documented. 
 
 
 
 
 
 
Correction 
 
Substituted “date of 
enrollment” by “Screening 
Visit date” in order to be 
more accurate 
 
 
Whole 
document 
Minor corrections, typos and 
commas 
Minor corrections, typos and 
commas 
 
 

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TABLE OF CONTENTS 
RESPONSIBILITIES AND SIGNATURES ..................................................................................... 2 
REVISION HISTORY ..................................................................................................................... 7 
TABLE OF CONTENTS ............................................................................................................... 25 
1. 
List of Abbreviations ................................................................................................ 28 
2. 
Overview .................................................................................................................. 31 
 
Protocol Synopsis .................................................................................................... 31 
 
Schedule of Trial Procedures .................................................................................. 39 
3. 
Introduction .............................................................................................................. 42 
3.1 
Background and Rationale ...................................................................................... 42 
3.2 
Investigational Drug ................................................................................................. 44 
3.3 
Risk-Benefit Evaluation ........................................................................................... 46 
4. 
Trial Objectives and Endpoints ................................................................................ 47 
 
Primary Objective and Endpoint .............................................................................. 47 
 
Secondary Objectives and Endpoints ..................................................................... 47 
5. 
Trial Design .............................................................................................................. 50 
 
Trial Type and Design Features .............................................................................. 50 
 
Investigational Treatment ........................................................................................ 50 
 
Trial Duration ........................................................................................................... 50 
 
Discussion of Trial Design ....................................................................................... 50 
 
Trial Administrative Structure .................................................................................. 51 
5.5.1 
Sponsor ................................................................................................................... 51 
5.5.2 
Contract Research Organization (CRO) .................................................................. 51 
5.5.3 
Central Laboratories ................................................................................................ 51 
5.5.4 
Participating Site ...................................................................................................... 51 
5.5.5 
Trial Coordinating Investigator ................................................................................. 51 
5.5.6 
Prerequisites for the Start of the Trial ...................................................................... 51 
6. 
Patient Screening, Randomization, Discontinuation and Withdrawal ..................... 51 
 
Inclusion Criteria ...................................................................................................... 51 
 
Exclusion Criteria ..................................................................................................... 53 
 
Patient Premature Withdrawal from Trial/ Withdrawal Criteria ................................ 54 
 
Premature Termination of the Trial by the Sponsor ................................................ 54 
7. 
Trial Treatment ........................................................................................................ 55 
 
Investigational Medicinal Product (IMP) .................................................................. 55 
 
Dosage and Administration ..................................................................................... 55 
 
Blinding .................................................................................................................... 55 
 
Manufacturing, Packaging and Labelling ................................................................ 56 
 
Storage and Dispensing of Trial Medication(s) ....................................................... 56 
 
Concomitant Medications/ Treatment ...................................................................... 57 
7.6.1 
Prohibited Medications/ Substances/ Treatments During the Trial ......................... 57 
8. 
Trial Procedures ...................................................................................................... 57 
 
Visit Schedule .......................................................................................................... 57 
9. 
Efficacy and Safety Parameters .............................................................................. 65 
 
Efficacy Parameters/ Assessments ......................................................................... 65 
9.1.1 
Polysomnography (PSG) ......................................................................................... 65 
9.1.2 
Resting State Stress Response ............................................................................... 65 
9.1.3 
Electroencephalography (EEG) ............................................................................... 66 

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9.1.4 
Heart Rate (HR), Heart Rate Variability (HRV) and Electrodermal Activity (EDA) .. 66 
9.1.5 
Actigraphy ................................................................................................................ 67 
9.1.6 
ePRO Designed Stress Questionnaires (EMAs) ..................................................... 67 
9.1.7 
Cold Pressor Test (CPT) ......................................................................................... 67 
9.1.8 
Blood Samples for Stress Response ....................................................................... 68 
9.1.9 
Sleep Diary .............................................................................................................. 68 
9.1.10 
Neuropsychological Tests (TAP) ............................................................................. 68 
9.1.11 
Urine Test and Alcohol Breath Test......................................................................... 68 
9.1.12 
Pregnancy Test........................................................................................................ 68 
9.1.13 
Blood Pressure ........................................................................................................ 68 
9.1.14 
Patient Questionnaires ............................................................................................ 69 
 
Pittsburgh Sleep Quality Index (PSQI) .................................................................... 69 
 
Insomnia Severity Index (ISI) .................................................................................. 69 
 
Epworth Sleepiness Scale (ESS) ............................................................................ 69 
 
Würzburg Fatigue Inventory (WEIMuS) .................................................................. 69 
 
Short Form-36 Health Survey Version 2 (SF-36v2) ................................................ 69 
 
Subclinical Stress Symptom Questionnaire-25 (SSQ-25) ....................................... 69 
 
Primary Appraisal Secondary Appraisal (PASA) ..................................................... 69 
 
Perceived Stress Scale-10 (PSS-10) ...................................................................... 70 
 
Beck's Depression Inventory-II (BDI-II) ................................................................... 70 
 
Beck's Anxiety Inventory (BAI) ................................................................................ 70 
 
Safety Parameters ................................................................................................... 70 
9.2.1 
Adverse Events........................................................................................................ 70 
9.2.2 
Vital Signs ................................................................................................................ 70 
9.2.3 
Physical Examination .............................................................................................. 70 
9.2.4 
Safety Laboratory .................................................................................................... 70 
 
Appropriateness of Measurements.......................................................................... 71 
10. 
Safety Reporting ...................................................................................................... 72 
 
Definitions ................................................................................................................ 72 
10.1.1 
Adverse Event (AE) ................................................................................................. 72 
10.1.2 
Treatment-Emergent Adverse Events (TEAE) ........................................................ 72 
10.1.3 
Adverse Drug Reaction (ADR) ................................................................................ 72 
10.1.4 
Serious Adverse Event/ Serious Adverse Drug Reaction (SAE/ SADR)................. 72 
10.1.5 
Medical Events not to be Considered AEs or SAEs ................................................ 73 
10.1.6 
Unexpected Adverse Reaction (UAR) ..................................................................... 73 
10.1.7 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ................................. 73 
 
Criteria for Clinically Relevant Abnormal Findings .................................................. 73 
 
Recording of AEs ..................................................................................................... 73 
 
Evaluation of AEs .................................................................................................... 73 
10.4.1 
AE Intensity .............................................................................................................. 74 
10.4.2 
AE Causality ............................................................................................................ 74 
10.4.3 
Handling of AEs ....................................................................................................... 74 
 
Reporting of Serious Adverse Events (SAEs) ......................................................... 75 
10.5.1 
Responsibility of Investigator ................................................................................... 75 
10.5.2 
Responsibility of Sponsor ........................................................................................ 76 
 
Follow-up of AEs...................................................................................................... 76 
 
Pregnancy ................................................................................................................ 76 
11. 
Statistical Methods and Data Analysis .................................................................... 78 
 
Sample Size Estimation ........................................................................................... 78 
 
Randomization ......................................................................................................... 78 

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Statistical Planning .................................................................................................. 78 
11.3.1 
Hypothesis ............................................................................................................... 79 
11.3.2 
Analysis Populations ............................................................................................... 80 
 
Efficacy Analysis ...................................................................................................... 80 
11.4.1 
Primary Efficacy ....................................................................................................... 80 
11.4.2 
Secondary Efficacy .................................................................................................. 80 
11.4.3 
Handling of Missing Data ......................................................................................... 82 
 
Safety Analysis ........................................................................................................ 82 
12. 
Ethical and Regulatory Requirements ..................................................................... 83 
 
Independent Ethics Committee (IEC) ...................................................................... 83 
 
Competent Authorities ............................................................................................. 83 
 
Ethical Conduct of the Trial ..................................................................................... 83 
 
Patient Information and Consent ............................................................................. 83 
 
Amendments to the Protocol ................................................................................... 84 
 
Patient Insurance ..................................................................................................... 84 
 
Confidentiality .......................................................................................................... 85 
 
Serious Breaches .................................................................................................... 85 
13. 
Data from Patients and Sites: Handling and Record Keeping ................................ 85 
 
Data Handling .......................................................................................................... 85 
 
Monitoring ................................................................................................................ 86 
 
Data Management ................................................................................................... 87 
13.3.1 
Source Data ............................................................................................................. 87 
13.3.2 
Electronic Case Report Form (eCRF) ..................................................................... 87 
13.3.3 
Direct Entries ........................................................................................................... 88 
13.3.4 
Coding ..................................................................................................................... 88 
13.3.5 
Confidentiality of Personal Data .............................................................................. 88 
 
Record Keeping ....................................................................................................... 88 
13.4.1 
Investigator Site File (ISF) ....................................................................................... 89 
14. 
General Regulations, Agreements and Organizational Procedures ....................... 89 
 
Responsibilities of the Investigator (Among Others) ............................................... 89 
 
Audits and Inspections ............................................................................................ 90 
 
Final Report and Publication/ Registry .................................................................... 90 
14.3.1 
Confidentiality .......................................................................................................... 90 
14.3.2 
Data Ownership ....................................................................................................... 90 
14.3.3 
Publications ............................................................................................................. 90 
15. 
References .............................................................................................................. 92 
16. 
Appendices .............................................................................................................. 94 
 
 
 

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1. List of Abbreviations  
Abbreviation 
Term 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALAT (ALT) 
Alanine Transaminase (formerly GPT) 
AMS 
Advanced Medical Services (contract research organization) 
ANCOVA 
Analysis of Covariance (a collection of statistical models used to analyze the 
differences among means) 
ANS 
Autonomic Nervous System 
AR 
Adverse Reaction 
ArI 
Arousal Index 
ASAT 
Aspartate Aminotransferase (also GOT) 
BAI 
Beck’s Anxiety Inventory (paper PRO) 
BDI-II 
Beck’s Depression Inventory revision II (paper PRO) 
BDRM 
Blind Data Review Meeting 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte 
BMI 
Body Mass Index 
CAR 
Cortisol Awakening Response 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CLIA 
ChemiLuminescence Immune Assay 
CONSORT 
CONsolidated Standards Of Reporting Trials guideline 
CPT 
Cold Pressor Test 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CTFG 
(European Union) Clinical Trials Facilitation and Coordination Group 
CTR 
Clinical Trials Regulation (EU CTR No. 536/2014) 
DGSM 
Deutsche Gesellschaft für Schlafforschung und Schlafmedizin 
DHEA-S 
Dehydroepiandrosterone Sulfate 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
DSUR 
Development Safety Update Report 
eCRF 
Electronic Case Report Form 
EDA 
Electrodermal Activity 
EDC 
Electronic Data Capture 
EEG 
Electroencephalogram 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EMA 
Ecological Momentary Assessment (used for daily stress assessment via 
AMS-ePRO®) 
ePRO 
Electronic Patient-Reported Outcome 
ESR 
Erythrocyte Sedimentation Rate 
ESS 
Epworth Sleepiness Scale (AMS-ePRO®) 
EoT 
End of Trial 
FDA 
Food and Drug Administration 
fMRI 
Functional Magnetic Resonance Imaging 
FPFV 
First Patient First Visit 
Gamma GT (GGT) 
Gamma-Glutamyl Transferase 
GAMP 
Good Automated Manufacturing Practice, a risk-based approach to compliant 
GxP computerized systems 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HPA axis 
Hypothalamic-Pituitary-Adrenal axis 
HR 
Heart Rate 
HRV 
Heart Rate Variability 
ICF 
Informed Consent Form 
ICH GCP 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use – Guideline on Good Clinical Practice 
ICMJE 
International Committee of Medical Journal Editors 

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Abbreviation 
Term 
ID 
Identification 
IEC 
Independent Ethics Committee 
IKCL 
Institut für Klinische Chemie und Laboratoriumsdiagnostik, University Hospital 
Jena (local routine laboratory performing safety laboratory and blood 
biomarker analysis) 
IMP 
Investigational Medicinal Product 
ISF 
Investigator Site File 
ISI 
Insomnia Severity Index (AMS-ePRO®) 
ITT 
Intention-To-Treat (analysis population) 
LF/HF 
Low Frequency / High Frequency Power 
LOCF 
Last Observation Carried Forward 
LPLV 
Last Patient Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
Millimeters of mercury (unit of blood pressure) 
MoCA 
Montreal Cognitive Assessment 
MSLT 
Multiple Sleep Latency Test 
NWAK 
Number of Awakenings (by PSG and sleep diary) 
OSA 
Obstructive Sleep Apnea 
PASA 
Primary Appraisal Secondary Appraisal (AMS-ePRO®) 
PK 
Pharmacokinetics 
PLMD 
Periodic Limb Movement Disorder 
PLMI 
Periodic Limb Movement Index 
PP 
Per-Protocol 
PPP 
Per-Protocol Population 
PRO 
Patient-Reported Outcome (e.g., patient questionnaire and sleep diary) 
PSG 
Polysomnography 
PSQI 
Pittsburgh Sleep Quality Index (paper PRO) 
PSS-10 
Perceived Stress Scale-10 (paper PRO) 
QoL 
Quality of Life 
QPPV 
Qualified Person for Pharmacovigilance 
RCT 
Randomized Controlled Trial 
REM 
Rapid Eye Movement sleep 
RLS 
Restless Legs Syndrome 
RMSSD 
Root Mean Square of Successive Differences 
rsEEG 
Resting state electroencephalogram 
S1, S2, S3 
Sleeping states 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SADR 
Serious Adverse Drug Reaction 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus-2 
SBQ 
STOPBang questionnaire 
SCID-5-CV 
Structured Clinical Interview for DSM-5® Disorders – Clinician Version 
SD 
Standard Deviation 
SDV 
Source Data Verification 
SE 
Sleep Efficiency 
SF-36v2 
Short Form-36 Health Survey version 2.0 (QoL questionnaire, paper PRO) 
SI 
Stress Index (Baevsky’s SI) 
SOL 
Sleep Onset Latency (by PSG and sleep diary) 
SOP 
Standard Operating Procedure 
SSL 
Secure Sockets Layer 
SSQ-25 
Subclinical Stress symptom Questionnaire-25 (paper PRO) 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAP 
Tests of Attentional Performance 
TEAE 
Treatment-Emergent Adverse Event 
TIB 
Time In Bed 
TSST 
Trier Social Stress Test 
TST 
Total Sleep Time (by PSG and sleep diary) 

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Clinical Trial Code: C2104 
 
Clinical Trial Protocol, 27 February 2025 final version 4.0 
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Abbreviation 
Term 
UAR 
Unexpected Adverse Reaction 
VIGALL 
Vigilance Algorithm Leipzig software to objectively classify vigilance in resting 
EEG recordings, latest version 2.1 
WASO 
Wake After Sleep Onset (by PSG and sleep diary) 
WHO 
World Health Organization 
WEIMuS 
Würzburg Fatigue Inventory (paper PRO) 
 
 

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Clinical Trial Code: C2104 
 
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2. Overview 
 
Protocol Synopsis  
 
Sponsor: 
Name of Medical Product: 
Active Ingredient(s): 
Biologische Heilmittel Heel 
GmbH 
Neurexan® tablets 
Homeopathic preparation, containing 
herbal and mineral ingredients as 
described in the Clinical Trial Protocol 
EudraCT number: 2022-003565-38 
Indication: Short-Term Insomnia 
Title: 
Evaluation of the Effects of Neurexan® on Short-Term Insomnia, Daytime Performance and Stress 
Response by Polysomnography (PSG), Electroencephalogram (EEG), Stress Biomarkers and Patient-
Reported Outcomes (PROs) 
An Exploratory, Placebo-Controlled Trial in Short-Term Insomnia Patients 
 
Investigational Sites:  
 
Coordinating/ Principal Investigator:  Prof Dr. Martin Walter 
 
 
 
 
Chair of Department of Psychiatry and Psychotherapy 
 
 
 
 
Jena University Hospital 
 
 
 
 
Philosophenweg 3 
 
 
 
 
07743 Jena, Germany 
 
 
 
 
Phone: 
 
Trial Duration: 
First Patient First Visit:  
 
June 2023 
Trial Phase:  
II 
Last Patient Last Visit planned:  
January 2026 
 
Trial Objectives and Endpoints 
The objective of this clinical trial is to demonstrate the effects of daily treatment with Neurexan® on 
improvements of objective and subjective measures of sleep quality, daytime performance and stress 
responsiveness in patients with short-term insomnia according to Diagnostic and Statistical Manual of 
Mental Disorders, 5th edition (DSM-5).  
 
The primary objective is to demonstrate an improvement of sleep efficiency (SE) measured by 
polysomnography (PSG) on daily treatment with Neurexan® in short-term insomnia. 
 
Primary endpoint of this trial is: 
 
Sleep Parameter  
To assess Neurexan® related changes in sleep efficiency (SE) at Visit 2 compared to Baseline 2 as revealed 
by polysomnography. 
 
The secondary endpoints are to assess: 
 
Sleep Pattern 
• 
Further objective sleep parameters revealed by polysomnography (PSG) 
To be assessed as change at Visit 2 compared to Baseline 2 
o 
Sleep Onset Latency (SOL): changes in SOL compared to Baseline 2 
o 
Wake After Sleep Onset (WASO): changes in WASO compared to Baseline 2 
o 
Total Sleep Time (TST): changes in TST compared to Baseline 2 
o 
Number of awakenings (NWAK): changes in NWAK compared to Baseline 2 
o 
Number of arousals during sleep (Arousal Index, ArI): changes in Arousal Index 
compared to Baseline 2 
o 
Latencies to sleeping stages S1, S2, S3, and Rapid Eye Movement (REM): changes in 
these latencies compared to Baseline 2.  

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Clinical Trial Code: C2104 
 
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Sponsor: 
Name of Medical Product: 
Active Ingredient(s): 
Biologische Heilmittel Heel 
GmbH 
Neurexan® tablets 
Homeopathic preparation, containing 
herbal and mineral ingredients as 
described in the Clinical Trial Protocol 
EudraCT number: 2022-003565-38 
Indication: Short-Term Insomnia 
 
• 
Objective in-home assessment of sleep pattern revealed by actigraphy (24/7) 
o 
A portable device, i.e., an actigraphy watch will be used to continuously monitor 
movement information over the whole clinical trial duration for actimetric sleep–wake 
detection to investigate habitual sleep–wake patterns and daily activity. 
 
• 
Subjective sleep pattern assessed using sleep questionnaires and sleep diary (adapted from 
Deutsche Gesellschaft für Schlafforschung und Schlafmedizin, DGSM) 
o 
Insomnia Severity Index (ISI): changes in ISI at Visit 1 compared to Baseline 1 
o 
Pittsburgh Sleep Quality Index (PSQI): changes in PSQI at Follow-Up Visit compared to 
Baseline 1 
o 
Sleep diary parameters: changes in subjective SE, SOL, WASO, TST, and NWAK 
compared to baseline. 
 
Daytime Performance by  
• 
Resting state EEG:  
o 
Changes in time course of EEG vigilance fluctuations during wakefulness assessed by 
Vigilance Algorithm Leipzig (VIGALL) version 2.1 (validated with the Multiple Sleep 
Latency Test (MSLT) by (Olbrich, Pawlowski et al. 2015) at Visit 1 compared to Baseline 
1 
o 
Changes in EEG asymmetry index at Visit 1 compared to Baseline 1 
o 
Regional changes in spectral characteristics of EEG using relative power indices in delta-
theta-alpha-beta frequency ranges at Visit 1 compared to Baseline 1 
• 
Resting state heart rate (HR), heart rate variability (HRV) and electrodermal activity (EDA) at Visit 
1 compared to Baseline 1 
• 
Questionnaires: Epworth Sleepiness Scale (ESS), Würzburg Fatigue Inventory (WEIMuS) and 
Beck's Depression Inventory-II (BDI-II) at Visit 1 compared to Baseline 1, and Quality of Life 
(QoL) by QoL questionnaire Short Form-36 (SF-36v2) and Beck's Anxiety Inventory (BAI) at 
Follow-Up Visit compared to Baseline 1 
• 
Neuropsychological tests assessing general cognitive functioning, alertness, vigilance, and 
sustained attention: three subtests from electronic Tests of Attentional Performance (TAP) test 
battery at Visit 1 compared to Baseline 1 
 
Stress Processing 
Given the reported Hypothalamic-pituitary-adrenal (HPA) axis dysregulation in the form of an altered 
cortisol secretion pattern in insomnia patients, a secondary outcome is to demonstrate changes in 
decreased resting state stress parameters in saliva as well as stress reactivity to physiological challenge 
using the Cold Pressor Test (CPT) in terms of changes in serum levels of cortisol in short-term insomnia 
patients treated with Neurexan®. 
 
 
• 
Resting state stress response by  
o 
Changes in stress biomarkers in saliva compared to baseline 
▪ 
Cortisol 
▪ 
Alpha-amylase 
▪ 
Dehydroepiandrosterone sulfate (DHEA-S) 
▪ 
Time course of stress biomarkers release synchronized to the awakening time 
(5 time points after awakening: 0 minutes, 15 minutes, 30 minutes, 45 minutes, 
60 minutes for the assessment of Cortisol Awakening Response (CAR))  
▪ 
Diurnal profile of stress biomarkers by collecting saliva samples at 3-hourly 
intervals over 12 hours (4 time points) synchronized to the awakening time. 
 
 

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Clinical Trial Code: C2104 
 
Clinical Trial Protocol, 27 February 2025 final version 4.0 
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Sponsor: 
Name of Medical Product: 
Active Ingredient(s): 
Biologische Heilmittel Heel 
GmbH 
Neurexan® tablets 
Homeopathic preparation, containing 
herbal and mineral ingredients as 
described in the Clinical Trial Protocol 
EudraCT number: 2022-003565-38 
Indication: Short-Term Insomnia 
• 
Stress response induced by CPT 
o 
Changes in subjective pain rating and pain tolerance at Visit 1 compared to Baseline 1. 
 
Blood sampling: 
o 
Changes in the cortisol time course: Visit 1 before CPT, 20 minutes, and 50 minutes after 
CPT compared to Baseline 1 
o 
Changes in dehydroepiandrosterone sulfate (DHEA-S) time course: Visit 1 before CPT, 
20 minutes, and 50 minutes after CPT compared to Baseline 1 
o 
Changes in the time course of adrenalin, noradrenalin and the inflammatory response 
(IL-6 and TNF-α): Visit 1 before CPT, 20 minutes, and 50 minutes after CPT compared to 
Baseline 1. 
 
Autonomic stress response:  
o 
Changes in heart rate and associated HRV measures, electrodermal activity (EDA): Visit 
1 compared to Baseline 1. 
 
EEG stress response: 
o 
Changes in time course of EEG vigilance fluctuations during wakefulness assessed by 
VIGALL version 2.1 (validated with the Multiple Sleep Latency Test (MSLT) by (Olbrich, 
Pawlowski et al. 2015) at Visit 1 compared to Baseline 1 
o 
Changes in EEG asymmetry index at Visit 1 compared to Baseline 1 
o 
Regional changes in spectral characteristics of EEG using relative power in delta-theta-
alpha-beta frequency ranges at Visit 1 compared to Baseline 1. 
 
• 
Stress questionnaires 
Changes in subjective stress levels compared to Baseline 1 as assessed by 
• 
Subclinical Stress Symptom Questionnaire-25 (SSQ-25) at Follow-Up Visit 
• 
Primary Appraisal Secondary Appraisal (PASA) at Visit 1 
• 
Perceived Stress Scale-10 (PSS-10) at Follow-Up Visit 
• 
Continuous (over the whole trial period) daily stress assessment using AMS-ePRO® 
functionality and EMAs. 
 
Further secondary objectives are to assess correlations between: 
• 
Changes in sleep parameters, stress parameters, and daytime performance 
• 
Changes in sleep parameters, stress parameters, and inflammatory parameters. 
 
Methodology, Trial Design 
Randomized, double-blind, placebo-controlled exploratory monocentric clinical trial 
 
Number of Patients (Planned): 
Estimation of sample size is based on the demonstration of improved sleep efficiency (SE) in short-term 
insomnia patients treated with Neurexan® as assessed by polysomnography. The standard deviation (SD) 
of SE is estimated at 10%. With α= 5%, two-sided and an expected mean difference of 6.7% between 
patients treated with Neurexan® and Placebo, a power of 80% is achieved with 72 patients. Expecting a 
dropout rate of 10%, the total number of patients needed is 80.  
Patients will be randomly assigned to treatment group Neurexan® or Placebo with a 1:1 allocation and 
stratification by sex. 

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Clinical Trial Code: C2104 
 
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Sponsor: 
Name of Medical Product: 
Active Ingredient(s): 
Biologische Heilmittel Heel 
GmbH 
Neurexan® tablets 
Homeopathic preparation, containing 
herbal and mineral ingredients as 
described in the Clinical Trial Protocol 
EudraCT number: 2022-003565-38 
Indication: Short-Term Insomnia 
Diagnosis and Inclusion Criteria: 
The patients have to meet all of the following inclusion criteria at Screening Visit: 
1. Insomnia definition according to DSM-5 criteria; episode duration less than 3 months 
2. Short-term insomnia with moderate symptoms according to ISI of at least 8 and below 22 
being present for at least one week, but no longer than 3 months prior to Screening Visit  
3. Reports habitual bedtime, defined as the time the participant attempts to sleep, between 
21:00 and 01:00  
4. Reports regular time spent in bed, either sleeping or trying to sleep, between 6 and 9 hours 
5. ≥18 years of age, not older than 65 years 
6. Legally competent male or female patient 
7. Signed Informed Consent 
8. Females of childbearing potential must agree to maintain highly effective or acceptable birth 
control throughout the trial (CTFG 2020). 
Highly effective (failure rate of less than 1% per year) 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: oral, intravaginal, transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, 
injectable, implantable 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system  
• 
Bilateral tubal occlusion 
• 
Vasectomized partner (provided partner is sole sexual partner and if vasectomized 
partner has received medical assessment of the surgical success) 
• 
Sexual abstinence (only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with investigational treatment) 
Acceptable birth control methods which may not be considered as highly effective (failure rate 
of more than 1% per year) 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
• 
Male or female condom with or without spermicide 
• 
Cap, diaphragm or sponge with spermicide 
• 
Combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier methods) 
9. Body Mass Index (BMI) between 18.5 and 29.9 kg/m2 at Screening Visit 
10. Use of digital device e.g., smartphone, tablet or laptop  
11. German speaking and reading. 
 
Exclusion Criteria: 
Potential trial patients will be excluded if at least one of the following exclusion criteria is present: 
1. Patients with insomnia symptoms present longer than 90 days prior to Screening Visit 
2. Based on the diagnostic interview, reported history (within 2 years) of other sleep disorders 
(e.g., chronic insomnia, circadian rhythm sleep disorders, restless legs syndrome (RLS), 
obstructive sleep apnea (OSA)), i.e., STOPBang questionnaire (SBQ) score ≥5, International 
Restless Legs Scale score ≥16) 

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Sponsor: 
Name of Medical Product: 
Active Ingredient(s): 
Biologische Heilmittel Heel 
GmbH 
Neurexan® tablets 
Homeopathic preparation, containing 
herbal and mineral ingredients as 
described in the Clinical Trial Protocol 
EudraCT number: 2022-003565-38 
Indication: Short-Term Insomnia 
3. Based on the first polysomnographic screening night at Baseline 1, insomnia due to sleep 
apnea or periodic limb movement disorder (PLMD): OSA (Apnea Hypopnea Index of >5 
events/ hour), PLMD (Periodic Limb Movement Index (PLMI) >15 events/ hour) 
4. Rotating shift work with overnight shifts 
5. History of psychiatric disorders within the last 6 months prior to Screening Visit according to 
the Structured Clinical Interview for DSM-5® Disorders – Clinician Version (SCID-5-CV) 
6. History of sensitivity to any component of Neurexan® 
7. Unwilling or unable to comply with all the requirements of the clinical trial protocol 
8. Cognitive impairment (cut-off of 24 points in the Montreal Cognitive Assessment [MoCA]; 
Thomann, Berres et al. 2020) at Screening Visit 
9. Any history of or current abuse of alcohol and/or amphetamines, benzodiazepines, cocaine, 
marijuana, methaqualone, methadone, opioids, propoxyphene, barbiturates, phencyclidine; 
or expected to take during trial participation (urine drug screening at Screening Visit and 
adaptation nights) 
10. Current use of medication affecting sleep, i.e., antidepressants, antipsychotics, diuretics, 
blood pressure drugs, anti-dementia drugs (e.g., piracetam), herbal and homeopathic 
medicine, hormone preparations (e.g., thyroxine) with the exception of hormonal 
contraceptives 
11. Use of Neurexan® within the last two weeks from Screening Visit 
12. Non-pharmacological insomnia therapies (e.g., cognitive behavioral therapy within the last 
6 months of Screening Visit, sleep restriction therapy, complementary and alternative 
therapies as meditation, Traditional Chinese Medicine, aromatherapy) 
13. Excessive consumption of xanthine-containing beverages (more than 7 cups daily of coffee 
or tea or other beverages containing xanthines) 
14. Use of nicotine during the last 6 months prior to Screening Visit 
15. Participation in any interventional clinical study within the past 30 days prior to Screening 
Visit 
16. Any relationship of dependence with the Sponsor or with the Investigator 
17. Active infection/ disease (C-reactive protein [CRP] >5 mg/l) 
18. Hypertension defined as systolic blood pressure ≥140 mmHg (Burnier, 2018) 
19. History of neurological, rheumatic, chronic pain, immune, cardiovascular, pulmonary, liver/ 
kidney, or metabolic disorder within the last 6 months prior to Screening Visit 
20. Nocturia 
21. Pregnancy (as proven by positive urine pregnancy test at Screening Visit) or breastfeeding 
22. Patients with moderate to severe skin allergies and/or eczema 
23. Raynaud's disease 
24. Donation of blood or platelets 3 months prior to or in-between in-hospital visits. 
 
Patient screening will include blood tests for complete blood count (CBC) and differentials, as well as 
thyroid hormone and blood glucose; urinary toxicology screens will also be conducted (exclusion criterion 
number 9). The medical history and physical examination will be conducted by a trial physician. 
 
Test Product, Dose, Duration of Treatment and Mode of Administration: 
Neurexan®: Passiflora incarnata dilution (Dil.) D2 (0.6 mg/ tablet), Avena sativa Dil. D2 (0.6 mg/ tablet), 
Coffea arabica Dil. D12 (0.6 mg/ tablet), Zincum isovalerianicum Dil. D4 (0.6 mg/ tablet), lactose 
monohydrate, magnesium stearate. 
2 tablets sublingually 3 times daily for 14 days. 

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Clinical Trial Code: C2104 
 
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Sponsor: 
Name of Medical Product: 
Active Ingredient(s): 
Biologische Heilmittel Heel 
GmbH 
Neurexan® tablets 
Homeopathic preparation, containing 
herbal and mineral ingredients as 
described in the Clinical Trial Protocol 
EudraCT number: 2022-003565-38 
Indication: Short-Term Insomnia 
Placebo Therapy, Dose, and Mode of Administration: 
Placebo: Lactose monohydrate, magnesium stearate. 
2 tablets sublingually 3 times daily for 14 days. 
Rescue Medication, Dose and Mode of Administration: 
None 
Supportive Therapy: 
None 
Criteria for Evaluation: 
Analysis Populations:  
The screening population is defined as all patients who signed informed consent. 
The safety population is defined as all patients who were randomized and received at least one dose of 
investigational medication. All safety analyses will be based on the treatment actually taken by the patient 
(‘as treated’).  
The Intention-To-Treat (ITT) population is defined as patients who were randomized and received at least 
one dose of investigational medication and had at least one post-dose assessment. 
The Per-Protocol Population (PPP) is defined as all patients who received investigational treatment and 
fulfil the following criteria: 
• 
The absence of any important major protocol deviations 
• 
No technical difficulties during PSG 
• 
Patients who were correctly stratified and received the correct treatment 
• 
Sufficient treatment compliance of 80%-120%. 
 
Primary Efficacy Variable 
• 
The primary efficacy variable for changes in sleep pattern will be sleep efficiency (SE) measured 
by polysomnography  
 
Secondary Efficacy Variables 
Polysomnography 
• 
Sleep Onset Latency (SOL) 
• 
Wake After Sleep Onset (WASO) 
• 
Total Sleep Time (TST) 
• 
Number of Awakenings (NWAK) 
• 
Latencies to sleeping states 1, 2, 3 (S1, S2, S3), Rapid Eye Movement (REM) sleep 
• 
Arousal Index (ArI). 
Biochemical parameters 
• 
Resting state cortisol and other stress-related parameters in saliva 
• 
Serum cortisol levels and other stress-related parameters in response to the stress induction by 
Cold Pressor Test (CPT). 
• 
Stress test induced inflammation parameters in blood serum. 
Actigraphy 
• 
Continuous in-home assessment of sleep  
• 
Daytime activity. 
Patient Questionnaires 
• 
Subclinical Stress Symptom Questionnaire-25 (SSQ-25) 
• 
Primary Appraisal Secondary Appraisal (PASA) 
• 
Perceived Stress Scale-10 (PSS-10) 

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Clinical Trial Code: C2104 
 
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Sponsor: 
Name of Medical Product: 
Active Ingredient(s): 
Biologische Heilmittel Heel 
GmbH 
Neurexan® tablets 
Homeopathic preparation, containing 
herbal and mineral ingredients as 
described in the Clinical Trial Protocol 
EudraCT number: 2022-003565-38 
Indication: Short-Term Insomnia 
• 
Epworth Sleepiness Scale (ESS) 
• 
Würzburg Fatigue Inventory (WEIMuS) 
• 
Short Form-36 (SF-36v2)  
• 
Insomnia Severity Index (ISI) 
• 
Pittsburgh Sleep Quality Index (PSQI) 
• 
Beck's Depression Inventory-II (BDI-II)  
• 
Beck's Anxiety Inventory (BAI). 
Sleep diary data (adapted from DGSM): subjective SE, SOL, WASO, TST, NWAK 
Continuous digitally recorded stress assessments (AMS-ePRO®) 
Neurexan® response 
Exploratory Efficacy Variables 
• 
EEG based vigilance fluctuations during resting state  
• 
EEG based vigilance fluctuations during CPT 
• 
EEG based asymmetry index during resting state 
• 
EEG based asymmetry index during CPT 
• 
Regional changes in spectral characteristics of EEG during resting state  
• 
Regional changes in spectral characteristics of EEG during CPT 
• 
Cognitive performance in three attentional tasks 
• 
PSG sleep parameters derived from the two adaptation nights at Baseline 1 and Visit 1 
 
Safety Variables 
• 
Adverse Events (AEs) 
• 
Treatment-Emergent Adverse Events (TEAEs) 
• 
Other observations related to safety (physical examinations, vital signs, laboratory 
assessments). 
Subgroup Analyses 
• 
Age 
• 
Sex (female/ male)  
• 
Neurexan® responder vs. non-responder 
• 
Duration of short-term insomnia (≤ 1 month, > 1 month) 
• 
Cortisol response influenced by hormonal contraceptives 

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Clinical Trial Code: C2104 
 
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Sponsor: 
Name of Medical Product: 
Active Ingredient(s): 
Biologische Heilmittel Heel 
GmbH 
Neurexan® tablets 
Homeopathic preparation, containing 
herbal and mineral ingredients as 
described in the Clinical Trial Protocol 
EudraCT number: 2022-003565-38 
Indication: Short-Term Insomnia 
Statistical Methods:  
The primary endpoint of this trial is sleep efficiency measured by polysomnography in patients treated with 
Neurexan®. Analysis of Covariance (ANCOVA) will be used to test the hypothesis H0: µNeurexan - µPlacebo = 
0 vs. H1: µNeurexan - µPlacebo ≠ 0. The model will include treatment and the stratification factor sex and will 
account for sleep efficiency at Baseline 2 as covariate. The test will be performed using a Type I error level 
of 5%, two-sided.  
Analyses of secondary objectives on efficacy will include ANCOVA and Fisher’s exact test, as appropriate. 
These analyses will be exploratory in nature without adjustment for multiplicity.  
Correlations may be analyzed using Spearman's rank correlation coefficient or another appropriate 
method.  
Efficacy analyses will be performed based on the ITT population. The PPP will be used additionally to 
explore the robustness of the findings. Further on, robustness analyses will include the Wilcoxon rank-
sum test. Difference from baseline will be used, as appropriate.   
Clinical safety will be addressed by assessing AEs, TEAEs, physical examinations, vital signs and as 
needed laboratory assessments in a descriptive manner. Safety analyses will be performed with the safety 
population. 
 
Contract Research Organization:   
AMS Advanced Medical Services GmbH 
 
 
 
 
 
Am Exerzierplatz 2 
 
 
 
 
 
68167 Mannheim/ Germany 
 
 
 
 
 
Phone:  +49 621 95700100 
 
 
 
 
 
Fax:      +49 621 95700140 
Statistics: 
 
 
 
AMS Advanced Medical Services GmbH 
 
 
 
 
 
Am Exerzierplatz 2 
 
 
 
 
 
68167 Mannheim/ Germany 
 
 
 

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°Demographics include sex, height and weight. 
*Starting IMP treatment after having performed all Baseline 2 assessments and after randomization at midday Day 0 for 
14 consecutive days (+ maximum 2 days allowance) until Visit 2 (Day 13). 
°°Sleep diary will be completed daily; starting at Screening Visit until End of Trial 
#Stress biomarkers in saliva: cortisol, alpha-amylase, dehydroepiandrosterone sulfate (DHEA-S) at 5 time points: after 
awakening from PSG nights at Baseline 1/ Day -1, Baseline 2/ Day 0, Visit 1/ Day 13 and Visit 2/ Day 14 collection of 
around 0.5 to 1 ml saliva at 0 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes (5 time points) for the 
assessment of Cortisol Awakening Response (CAR) and additionally at Baseline 1/ Day -1 and Visit 1/ Day 13 diurnal 
profile of stress biomarkers by collecting saliva samples at 3-hourly intervals over 12 hours (4 time points) synchronized 
to the awakening time.  
1Including subjective pain rating and pain tolerance, blood sampling before CPT, 20 minutes and 50 minutes after CPT 
to assess biomarkers cortisol and DHEA-S, adrenalin, noradrenalin and inflammatory response (IL-6 and TNF-α), 
autonomic and cortical stress response (heart rate, HRV, electrodermal activity (EDA) and EEG). 
2In case of premature discontinuation reason to be given. 
 
 

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3. Introduction  
3.1 
Background and Rationale 
Healthy sleep is essential for a good daytime performance and a healthy life. However, the annual 
incidence of new onset or acute insomnia is almost one-third of the population (Ellis, Perlis et al. 
2012, Perlis, Vargas et al. 2020). Short-term or acute insomnia is the most frequent type of 
insomnia and is defined as the subjective perception of difficulty with sleep initiation, duration, 
consolidation, or quality that occurs despite adequate opportunity for sleep, for at least 3 days per 
week and is present for less than 3 months. These sleep disturbances cause clinically significant 
distress or impairment in daytime functioning. 
The diagnosis of insomnia is made based on the diagnostic criteria as defined in the recent version 
of the Diagnostic Statistical Manual of Mental Disorders, version 5 (DSM-5). Furthermore, based 
on the DSM-5 criteria it is essential to rule out other causes of insomnia, such as medical or mental 
disorders or the use of medication or stimulating substances. Patient-reported questionnaires such 
as the Insomnia Severity Index (ISI) and the Pittsburgh Sleep Quality Index (PSQI) are tools to aid 
in the diagnosis of insomnia. The gold standard to assess sleep disorders is polysomnography 
(PSG). In addition, actigraphy with wearable devices can deliver further useful information to 
monitor habitual sleep–wake patterns in the in-home setting.  
The concept of hyperarousal as an important etiological factor in insomnia is used to explain the 
relationship between sleep disturbances and stress dysregulation. 
Several studies using physiological markers of stress and arousal such as hypothalamic-pituitary-
adrenal (HPA) axis provided support for the assumed relationship between stress and sleep. Thus, 
the summary of present literature indicates a dynamic and bidirectional relationship between stress 
and sleep. Acute insomnia is often triggered by stressful life events (such as major life events or 
daily hassles), and physiologically and cognitive-emotionally induced hyperarousal can interfere 
with sleep and lead to a chronicity of insomnia in a subset of the population. 
Hyperarousal is described as a state of increased somatic, cortical, and cognitive activation at 
daytime and/or at night leading to increases in cortisol levels, body temperature, metabolic rate 
and heart rate (Kay and Buysse 2017, Vargas, Nguyen et al. 2020). 
There is some evidence for the notion that patients with insomnia exhibit exaggerated maladaptive 
neurobiological and cognitive–emotional reactivity to stress. For example, patients with insomnia 
tend to respond differently to stressful events compared to normal sleepers (Morin, Rodrigue et al. 
2003), which may lead to a hyperarousal state and interfere with sleep . 
Stress leads to the activation of the hypothalamic-pituitary-adrenal axis (HPA axis) and the 
autonomic nervous system which are known to cause arousal and sleeplessness (McEwen, Bowles 
et al. 2015). 
Furthermore, there is evidence for the direct relationship between stress and inflammatory 
response in the periphery and in the brain. Glucocorticoids as released during a stress response 
have an impact on the expression of several pro-inflammatory cytokines (e.g., interleukin-6 (IL-6)). 
Strong stressors could over-activate the immune system, leading to the imbalance of inflammation 
and anti-inflammation. Previous studies have reported associations between disrupted sleep and 
inflammatory responses. Although the physiological mechanisms underlying these relationships 
remain unclear, it is conceivable to assume this association is mediated by alteration in the stress 
processing and response. 

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Neurexan®, a medicinal product consisting of 3 herbal extracts (Avena sativa, Coffea arabica, 
Passiflora incarnata) and one mineral salt (Zincum isovalerianicum) in low ponderable 
concentrations, showed effects on stress response and sleep efficacy in various studies. 
The efficacy of Neurexan® on psychological and neuroendocrine responses under acute stress was 
investigated in a placebo-controlled double-blind trial in healthy volunteers. A significantly 
decreased neuroendocrine response to an acute stressor (Trier Social Stress Test, TSST) after 
Neurexan® intake was observed. Neurexan® led to reduced salivary cortisol and plasma adrenaline 
levels after stress exposure, but did not affect the subjective stress ratings, heart rate and blood 
pressure (Doering, Wegner et al. 2016). In another placebo-controlled cross-over trial with mildly 
or moderately stressed healthy volunteers it could be shown that Neurexan® modulates the stress 
response. With functional magnetic resonance imaging (fMRI) a significantly reduced neuronal 
activation in the left amygdala was demonstrated after a single dose of Neurexan® compared to 
Placebo (Herrmann, Vicheva et al. 2020). In a study using electroencephalogram (EEG) to 
investigate Neurexan® efficiency on stress-induced changes, it was demonstrated that elevated 
frontotemporal beta2 power was ameliorated by intake of Neurexan®, indicating that Neurexan® 
effectively helps to cope with induced stress situations (Dimpfel 2019). Neurexan®’s effectiveness 
for patients with symptoms of nervousness and restlessness was assessed in an observational 
study with 777 participants. Compared to patients treated with valerian extracts patients treated 
with Neurexan® showed significantly decreased summary scores for nervousness/restlessness 
(Hübner, Von Haselen et al. 2009). Furthermore, in a very recent study, it was demonstrated that 
Neurexan® reduces plasma cortisol levels in high performance sled dogs after an exercise inducing 
stress response compared to placebo (Keller, Conradi et al. 2021).  
A non-interventional study investigated the effect of Neurexan® in patients with insomnia compared 
to valerian extracts over a treatment period of 14 days. Sleep duration and latency were evaluated 
based on sleep diaries. The total duration of sleep increased and sleep latency decreased in both 
groups. Significantly more patients reported a lack of daytime fatigue with Neurexan® treatment 
than with valerian treatment (49% vs. 32%; p < 0.05) (Waldschütz and Klein 2008). 
All above-mentioned previous studies with Neurexan® indicate a measurable effect on the stress 
response. Furthermore, there is some evidence corroborating an effect of Neurexan® on sleep 
parameters. 
However, there is still a lack of evidence regarding the effect of Neurexan® on objective and 
subjective sleep parameters and daytime performance in insomnia patients based on randomized 
controlled trial (RCT) data as well as its relationship with assumed changes in the stress and 
inflammatory response.  
The aim of this double-blind randomized controlled phase II trial is to investigate the effects of 
Neurexan® on sleep efficiency (SE) measured by polysomnography as well as other sleep related 
parameters in a specific sample of patients with short-term insomnia according to DSM-5, its impact 
on daytime performance, stress and inflammatory response as well as relationships between 
postulated changes in stress and inflammatory response and sleep patterns. 
 
 

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3.2 
Investigational Drug 
Neurexan® is a medicinal product sold over the counter in Germany that is marketed as tablets for 
oral use.  
Neurexan® is a preparation of 4 diluted biological components. Active ingredients of Neurexan® are 
Passiflora incarnata (P. incarnata, purple passionflower) D2 0.6 mg, Avena sativa (A. sativa, 
common oats) D2 0.6 mg, Coffea arabica (C. arabica, coffee) D12 0.6 mg and Zincum 
isovalerianicum (isovalerate of zinc) D4 0.6 mg. 
P. incarnata intake has been positively associated with several health benefits such as in treatment 
of insomnia, nervous tension and anxiety in healthy individuals and patients (Janda, Wojtkowska 
et al. 2020). Preparations from A. sativa are used as a nervous system restorative for acute and 
chronic anxiety and tension, stress and excitation as reported by the German Commission E, an 
independent scientific advisory board of the German Federal Institute for Drugs and Medical 
Devices. C. arabica is used for hedonistic and psychostimulant purpose (Harland 2000, Dórea and 
da Costa 2005). 
Neurexan® has been investigated in post-marketing surveillance studies in patients with various 
stress associated complaints such as sleep disturbances, jitteriness, listlessness or nocturnal 
anxiety (Waldschütz and Klein 2008, Hübner, Von Haselen et al. 2009). 
In a prospective non-randomized comparison with valerian compounds patients receiving 
Neurexan® reported a stronger decrease in nervousness than the group receiving valerian (Hübner, 
Von Haselen et al. 2009). Due to the observational design these results cannot provide conclusive 
evidence for the efficacy of Neurexan®. 
In Table 1, the quantitative composition of the finished product per standard and maximum daily 
dose is presented. The 2 last columns show the amount of mother tincture per standard daily dose 
and maximum daily dose in adults. All doses can be regarded as safe in all age groups according 
to the Advisory Board on Homeopathy of the German Drug Regulatory Authority (Monograph 
Commission D). The potency of all components corresponds to the recommendations of 
Commission D. The recommended dose for adults and children from 12 years of age is one tablet 
to be dissolved in the mouth 3 times daily. In acute disorders, one tablet can be taken up to 12 times 
per day. 
Table 1: Qualitative and quantitative composition of Neurexan® 
Active 
substance 
(Scientific name 
of raw material) 
Used plant part/  
Starting material/ 
Production method for 
the active substance/ Key 
specification parameter 
Used potency 
(calculated 
potency 
corresponding 
to final 
dilution) 
Mass of 
used 
potency 
per 
1 tablet 
(mg) 
Amount per 
daily standard 
dose 
(3 tablets) 
Amount per 
maximum daily 
dose 
(12 tablets) 
Avena sativa 
mother tincture 
(Avena sativa L.) 
Fresh, aerial parts 
harvested during flowering 
season 
Method 1.1.1, Ph. Eur. 
equivalent to Method 1a, 
GHP 
dry residue ≥ 2% 
2 (4.7) 
0.6 
1.8 mg Dil D2 
= 180 µg Dil D1 
= 36 µg mother 
tincture (contains 
18 µg expressed 
juice) 
7.2 mg Dil D2 
= 720 µg Dil D1 
= 144 µg mother 
tincture (contains  
72 µg expressed 
juice) 
Coffea arabica 
mother tincture 
(Coffea arabica 
L.) 
Ripe, dried, unroasted 
seeds deprived from the 
exocarp 
Method 1.1.8, Ph. Eur. 
12 (14.7) 
0.6 
1.8 mg Dil D12 
= 1.8 x 10-11 mg 
Dil D1 
= mother tincture 
7.2 mg Dil D12 
= 7.2 x 10-11 mg Dil 
D1 
= mother tincture 

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Active 
substance 
(Scientific name 
of raw material) 
Used plant part/  
Starting material/ 
Production method for 
the active substance/ Key 
specification parameter 
Used potency 
(calculated 
potency 
corresponding 
to final 
dilution) 
Mass of 
used 
potency 
per 
1 tablet 
(mg) 
Amount per 
daily standard 
dose 
(3 tablets) 
Amount per 
maximum daily 
dose 
(12 tablets) 
equivalent to Method 4a, 
GHP;  
Ø ≥ 0.1% caffeine 
with at least 1.8 x 
10-14 mg alkaloids 
with at least 7.2 x 
10-14 mg alkaloids 
Passiflora 
incarnata mother 
tincture 
(Passiflora 
incarnata L.) 
Fresh aerial parts of 
Passiflora incarnata L. 
Method 1.1.5, Ph. Eur. 
equivalent to Method 3a, 
GHP 
dry residue ≥ 1.6% 
2 (4.7) 
0.6 
1.8 mg Dil D2 
= 180 µg Dil D1 
= 54 µg mother 
tincture 
7.2 mg Dil D2 
= 720 µg Dil D1 
= 216 µg mother 
tincture 
Zincum 
isovalerianicum 
Dil D2 (Zincum 
isovalerianicum) 
Zinc oxide + 
isovaleric acid 
Zn(C5H9O2)2 x 
2 H2O 
Zincum isovalerianicum 
(in German: Zinksalz der 
Isovaleriansäure) 
Method 3.1.1, Ph. Eur. 
equivalent to Method 5a, 
GHP  
Dil D2 = 0.93 – 1.08% 
substance 
4 (6.7) 
0.6 
1.8 mg Dil D4 
= 18 µg Dil D2 
with ca. 0.18 µg 
substance 
7.2 mg Dil D4 
= 72 µg Dil D2 
with ca. 0.72 µg 
substance 
Calculation of dried plant material was done according to the Homeopathic Medicinal Products Working Group document 
“Points to consider on non-clinical safety of homeopathic medicinal products of botanical, mineral and chemical origin” 
Pharmacology 
The therapeutic dilemma in acute insomnia is its multicausality which implies a multi-target 
approach. Monocausal treatment approaches act only on a certain spectrum of the disease profile, 
which often results in only inadequate, partial improvement in the symptoms (e.g., short-acting 
benzodiazepines or non-benzodiazepine hypnotics). Neurexan® is a multi-component medication 
containing components with different actions to treat a multicausal disease. Multi-target is to be 
understood as involving action on different effectors, which produces a variety of effects. The 
precise molecular mode of action of multi-target / multi-component drugs is difficult to analyze, for 
Neurexan® it is still unknown. Nevertheless, many preclinical and clinical studies have 
demonstrated effects on stress associated complaints such as sleep disturbances, exercise-
induced stress, amygdala activation, jitteriness, listlessness or nocturnal anxiety (Davies, Bignell 
et al. 2002, Waldschütz and Klein 2008, Hübner, Von Haselen et al. 2009, Doering, Wegner et al. 
2016, Herrmann, Vicheva et al. 2020, Keller, Conradi et al. 2021). 
Pharmacokinetics 
As we do not have pharmacokinetics (PK) data due to the nature of our products (unclear which 
compound / which ingredient affects what – and there are numerous per product) and there are no 
linear dose-dependent effects, there is no information available on the pharmacokinetic profile as 
related to pharmacology. Therefore, the documentation and discussion of bibliographic or other 
data on the pharmacokinetic profile is not considered. 
Toxicology 
Experimental toxicological studies with the medicinal product Neurexan® are not available. No 
systematic toxicological studies with the active substances of Neurexan® have been conducted so 
far. 

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The assessment of the non-clinical safety of Neurexan® is based mostly on results of experimental 
in vitro and in vivo studies, which have been published within recent decades, either on the starting 
materials or diluted plant ingredients. The study designs as well as the measured parameters in 
general are adequate for the assessment of the preclinical safety of Neurexan®.  
The assessment of pharmacological and toxicological properties of Neurexan® is based on the 
review of relevant experimental data and evidence as published in the scientific literature on the 
starting materials of the active substances. Specifically, the aspects of genotoxicity, 
carcinogenicity, reproductive and developmental toxicity are considered explicitly.  
Integrated Overview and Conclusions 
Neurexan® is a medicinal product in accordance with the European Commission directive 
2001/83/EC as amended. It contains several single remedies as active substances (see Table 1). 
The toxicological profile of the active substances and ingredients of the considered product is well 
or sufficiently described and allows final conclusions on the safety of Neurexan®. No significant 
risks concerning acute and chronic toxicity, genotoxicity and mutagenicity, developmental and 
reproductive toxicity, immunotoxicity and local tolerability have become apparent. It is unlikely or 
highly impossible, that the active constituents pose any drug-associated risks at the given 
concentration in the finished product and the given posology. 
The reviewed data as well as the calculated daily quantity of the single active substances revealed 
that toxic or adverse effects are not expected following an oral administration in adults as well as 
in children and adolescents below 18 years of age or the elderly. 
Moreover, the long-term clinical experiences as well as the post-marketing experience in many 
countries with the active ingredients in this combination generally support Neurexan® to be a 
combination without any toxic risks. 
3.3 
Risk-Benefit Evaluation 
Expected Benefit / Efficacy 
The intake of Neurexan® has been associated with improved sleep and lower nervousness / 
restlessness. Waldschütz and Klein investigated sleep quality in 409 individuals suffering from 
insomnia by comparing Neurexan® treatment to valerian treatment (Waldschütz and Klein 2008). 
Both treatments resulted in improved sleep quality. Moreover, individuals receiving Neurexan® 
reported lower daytime fatigue than those with a valerian therapy. In addition, Neurexan® may lower 
symptoms of nervousness / restlessness such as excitability / jitteriness, hyperactivity, sleep 
disturbances, nocturnal anxiety, difficulties with concentration / forgetfulness, fatigue, listlessness, 
moroseness, gastrointestinal disturbances and headache / pressure (Hübner, Von Haselen et al. 
2009). Furthermore, preliminary results indicate that the intake of Neurexan® changes electrical 
brain activity as compared to placebo under stress. In a double-blind, randomized, placebo-
controlled trial with cross-over design, different arithmetic tasks were used to induce stress 
experimentally (Dimpfel 2019). The trial was conducted on 30 healthy participants aged 30-60 who 
received 4 Neurexan® or 4 Placebo tablets. β2 power was used as a surrogate marker for stress-
induced anxiety. The stress test resulted in elevated β2 power in both experimental groups. 
However, a smaller increase in β2 power was observed in participants receiving Neurexan® as 
compared to the Placebo group. This was interpreted in terms of better coping abilities under 
stressful challenges. Doering and colleagues reported diminished salivary cortisol and plasma 
adrenaline levels in verum relative to placebo group. Although no reduced subjective stress rating 

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was found as an effect of Neurexan® intake, significant neuroendocrine changes were present 
(Doering, Wegner et al. 2016). 
Possible Risks / Safety 
In a large-scale observational study with 553 participants receiving Neurexan® two adverse events 
with a possible relationship to study treatment were reported, nystagmus and increased 
restlessness (Hübner, Von Haselen et al. 2009). Furthermore, a mild caffeine intolerance 
associated with Neurexan® intake has been reported (reported by 1/156 study participants) 
(Waldschütz and Klein 2008). Adverse reactions from post-marketing spontaneous reporting 
concern hypersensitivity reactions, such as transient skin reactions. 
There are no safety concerns for the use of Neurexan® in children and adolescents below 18 years 
of age. There are also no safety concerns regarding the use in elderly or any other especially 
sensitive patient groups. This is due to the low quantity of each substance (stock) administered, 
which are significantly below any toxic dosages. 
Specific product-related data on the use during pregnancy and lactation is not available. 
Considering the available - scarce - data on the developmental and reproductive toxicity and 
considering the characteristics of each active substance used in the product, there are no concerns 
or apparent risks in this patient group.  
Moreover, the long-term clinical experience as well as the post-marketing experience in many 
countries with the active ingredients in this combination generally supports Neurexan® to be a 
combination without any safety concerns. 
4. Trial Objectives and Endpoints 
This double-blind randomized controlled trial aims to investigate the effects of Neurexan® on sleep 
efficiency measured by polysomnography as well as on other sleep related parameters in patients 
with short-term insomnia according to DSM-5. In addition, Neurexan®’s impact on daytime 
performance, stress and the inflammatory response as well as the relationship between postulated 
changes in the stress and inflammatory response and sleep patterns are to be investigated.  
The objective of this clinical trial is to demonstrate the effects of daily treatment with Neurexan® on 
improvements of objective and subjective measures of sleep quality, daytime performance and 
stress responsiveness in patients with short-term insomnia patients according to DSM-5 (Diagnostic 
and Statistical Manual of Mental Disorders, 5th edition). 
 
Primary Objective and Endpoint 
The primary objective is to demonstrate an improvement of sleep efficiency (SE) measured by 
polysomnography on daily treatment with Neurexan® in short-term insomnia. 
The primary endpoint of this trial is to assess Neurexan® related changes in SE at Visit 2 compared 
to Baseline 2 as revealed by polysomnography (PSG). 
 
Secondary Objectives and Endpoints 
The secondary objectives are to assess further PSG-based objective as well as subjective sleep 
parameters, daytime performance and stress processing in patients with short-term insomnia 
treated daily with Neurexan® compared to Placebo.  
 

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Secondary endpoints are described in the following. 
Sleep Pattern by 
• 
Further objective sleep parameters revealed by polysomnography (PSG) 
To be assessed as change at Visit 2 compared to Baseline 2 
o Sleep Onset Latency (SOL): changes in SOL compared to Baseline 2 
o Wake After Sleep Onset (WASO): changes in WASO compared to Baseline 2 
o Total Sleep Time (TST): changes in TST compared to Baseline 2 
o Number of awakenings (NWAK): changes in NWAK compared to Baseline 2 
o Number of arousals during (Arousal Index; ArI) changes in Arousal Index compared to 
Baseline 2 
o Latencies to sleeping stages S1, S2, S3, and Rapid Eye Movement (REM): changes in 
these latencies compared to Baseline 2.  
• 
Objective in-home assessment of sleep pattern revealed by actigraphy (24/7) 
o A portable device, i.e., an actigraphy watch will be used to continuously monitor 
movement information over the whole clinical trial duration for actimetric sleep–wake 
detection to investigate habitual sleep–wake patterns and daily activity. 
• 
Subjective sleep pattern assessed using sleep questionnaires and sleep diary (adapted from 
Deutsche Gesellschaft für Schlafforschung und Schlafmedizin, DGSM), to be recorded on 
AMS-ePRO® 
o Insomnia Severity Index (ISI): changes in ISI at Visit 1 compared to Baseline 1. 
o Pittsburgh Sleep Quality Index (PSQI): changes in PSQI at Follow-Up Visit compared to 
Baseline 1.  
o Sleep diary parameters: changes in subjective SE, SOL, WASO, TST, and NWAK 
compared to baseline. 
Daytime Performance by  
• 
Resting state EEG:  
o Changes in time course of EEG vigilance fluctuations during wakefulness assessed by 
Vigilance Algorithm Leipzig (VIGALL) version 2.1 (validated with the Multiple Sleep 
Latency Test (MSLT) by (Olbrich, Pawlowski et al. 2015) at Visit 1 compared to Baseline 1 
o 
Changes in EEG asymmetry index at Visit 1 compared to Baseline 1 
o 
Regional changes in spectral characteristics of EEG using relative power in delta-theta-
alpha-beta frequency ranges at Visit 1 compared to Baseline 1  
• 
Resting state heart rate (HR) and heart rate variability (HRV) and electrodermal activity (EDA) 
at Visit 1 compared to Baseline 1 
• 
Questionnaires: Epworth Sleepiness Scale (ESS), Würzburg Fatigue Inventory (WEIMuS) and 
Beck's Depression Inventory-II (BDI-II) at Visit 1 compared to Baseline 1, and Quality of Life 
(QoL) by QoL questionnaire Short Form-36 version 2.0 (SF-36v2)  and Beck's Anxiety Inventory 
(BAI) at Follow-Up Visit compared to Baseline 1 
• 
Neuropsychological tests assessing general cognitive functioning, alertness, vigilance, and 
sustained attention: three subtests from electronic Tests of Attentional Performance (TAP) test 
battery at Visit 1 compared to Baseline 1. 
 
 

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Stress Processing  
Given the reported HPA axis dysregulation in the form of an altered cortisol secretion pattern in 
insomnia patients, a secondary outcome is to demonstrate changes in decreased resting state 
stress parameters in saliva as well as stress reactivity to physiological challenge using the Cold 
Pressor Test (CPT) in terms of changes in serum levels of cortisol in short-term insomnia patients 
treated with Neurexan®.  
• 
Resting state stress response by  
o Changes in stress biomarkers in saliva compared to baseline 
▪ 
Cortisol  
▪ 
Alpha-amylase  
▪ 
Dehydroepiandrosterone sulfate (DHEA-S) 
▪ 
Time course of stress biomarkers release synchronized to the awakening time (5 
time points after awakening: 0 minutes, 15 minutes, 30 minutes, 45 minutes, 
60 minutes for the assessment of Cortisol Awakening Response (CAR)) 
▪ 
Diurnal profile of stress biomarkers by collecting saliva samples at 3-hourly 
intervals over 12 hours (4 time points) synchronized to the awakening time. 
• 
Stress response induced by CPT 
o Changes in subjective pain rating and pain tolerance at Visit 1 compared to Baseline 1 
Blood sampling 
o Changes in the cortisol time course: Visit 1 before CPT, 20 minutes, and 50 minutes after 
CPT compared to Baseline 1 
o Changes in dehydroepiandrosterone sulfate (DHEA-S) time course: Visit 1 before CPT, 20 
minutes, and 50 minutes after CPT; Visit 1 compared to Baseline 1 
o Changes in the time course of adrenalin, noradrenalin and the inflammatory response (IL-6 
and TNF-α): Visit 1 before CPT, 20 minutes, and 50 minutes after CPT compared to 
Baseline 1. 
Autonomic stress response:  
o Changes in heart rate and associated HRV measures, electrodermal activity (EDA); Visit 1 
compared to Baseline 1. 
EEG stress response: 
o Changes in time course of EEG vigilance fluctuations during wakefulness assessed by 
VIGALL version 2.1 (validated with the Multiple Sleep Latency Test (MSLT) by (Olbrich, 
Pawlowski et al. 2015) at Visit 1 compared to Baseline 1 
o Changes in EEG asymmetry index at Visit 1 compared to Baseline 1 
o Regional changes in spectral characteristics of EEG using relative power indices in delta-
theta-alpha-beta frequency ranges at Visit 1 compared to Baseline 1. 
• 
Stress questionnaires 
Changes in subjective stress levels compared to Baseline 1 as assessed by 
• 
Subclinical Stress Symptom Questionnaire-25 (SSQ-25) at Follow-Up Visit 
• 
Primary Appraisal Secondary Appraisal (PASA) at Visit 1 
• 
Perceived Stress Scale-10 (PSS-10) at Follow-Up Visit 

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• 
Continuous (over the whole trial period) daily stress assessment using AMS-
ePRO® functionality and Ecological Momentary Assessments (EMAs). 
Further secondary objectives are to assess correlations between: 
• 
Changes in sleep parameters, stress parameters, and daytime performance 
• 
Changes in sleep parameters, stress parameters, and inflammatory parameters  
5. Trial Design 
 
Trial Type and Design Features  
This monocentric exploratory clinical trial is designed as a prospective, double-blind, placebo-
controlled, randomized trial to evaluate the effects of Neurexan® regarding sleep, daytime 
performance, stress and inflammatory response in a patient cohort with short-term insomnia.  
It is planned to randomize a total of 80 patients with short-term insomnia. Eligible patients are to 
be allocated in a 1:1 randomization to either Neurexan® or Placebo treatment. 
 
Investigational Treatment 
The trial treatment consists of 2 tablets taken sublingually 3 times daily for a period of 14 days. The 
trial treatment is either Neurexan® or Placebo, which is randomly assigned. The trial treatment 
should be taken at approximately midday, evening and bedtime and not to be taken with meals. 
 
Trial Duration 
The First Patient First Visit (FPFV) was in June 2023. A total of 80 patients will be randomized 
within approximately 32 months. The Last Patient Last Visit (LPLV) is planned to be in January 
2026. 
The total trial duration for each patient is 37 to maximum 60 days (Table 3). Patients start with a 
Screening Visit 8 to 28 days prior to first investigational treatment (on Day 0), followed by two 
baseline visits for a PSG adaptation (‘screening’) night at Baseline 1/ Day -2 to -1 and the primary 
outcome relevant PSG night at Day -1 to Day 0, respectively. Patients are randomized to their 
investigational treatment after completion of visit Baseline 2 / Day 0. Patients will take their 
investigational treatment for 14 consecutive days (starting at Day 0 to Day 13). Patients will visit 
the investigational site at Day 12 +2 for a PSG adaptation night and at Day 13 +2 for the primary 
outcome relevant PSG night. On Day 28 +3 a Follow-up Visit will take place to collect paper-based 
patient-reported outcome data of BAI, PSQI, PSS-10, SF-36v2 and SSQ-25 questionnaires and 
the End of Trial (EoT) documentation is to be completed. 
 
Discussion of Trial Design 
This double-blind placebo-controlled randomized trial is well suited to address the lack of RCT data 
on Neurexan® efficiency on objective sleep parameters using PSG, on daytime performance and 
on its relationship with assumed changes to stress and inflammatory response. 

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Trial Administrative Structure 
5.5.1 Sponsor 
The Sponsor of trial C2104 is Biologische Heilmittel Heel GmbH (Dr.-Reckeweg-Straße 2-4, 
76532 Baden-Baden, Germany). 
5.5.2 Contract Research Organization (CRO) 
The Sponsor delegates the conduct of the trial (‘full service’) to the CRO AMS Advanced Medical 
Services GmbH (Mannheim, Germany).  
5.5.3 Central Laboratories 
The local routine laboratory of the investigational site (Institut für Klinische Chemie und 
Laboratoriumsdiagnostik IKCL, University Hospital Jena) will analyze safety laboratory blood 
samples (see section 9.2.4) as well as blood biomarker samples (see section 9.1.8) and will provide 
frozen interim storage of saliva samples in their biobank. Saliva biomarker samples (9.1.2) will be 
analyzed at Dresden LabService GmbH.  
5.5.4 Participating Site 
This is a monocentric trial conducted at the Department of Psychiatry and Psychotherapy of the 
Jena University Hospital (Philosophenweg 3, 07743 Jena, Germany). 
5.5.5 Trial Coordinating Investigator 
The Coordinating and Principal Investigator of trial C2104 is Prof Dr Martin Walter, chair of the 
Department of Psychiatry and Psychotherapy of the Jena University Hospital.  
5.5.6 Prerequisites for the Start of the Trial 
The trial may start as soon as all applicable approvals of both the competent Ethics Committee and 
the Competent Authority (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) have been 
obtained. The investigational site may start trial activities no sooner than all applicable approvals 
are obtained and when investigational medicinal products (IMPs) are available at the site.  
6. Patient Screening, Randomization, Discontinuation and Withdrawal 
Randomization of 80 patients suffering from short-term insomnia is planned for the trial. If a patient 
fulfils all of the inclusion criteria and none of the exclusion criteria, his/her eligibility will be assessed 
during the Screening Visit and he/she will be randomly assigned to Neurexan® or Placebo treatment 
with 1:1 allocation and stratification by sex.  
 
Inclusion Criteria 
Eligible patients have to meet all of the following inclusion criteria at Screening Visit (Day -28 to -8): 
1. Insomnia definition according to DSM-5 criteria; episode duration less than 3 months 
2. Short-term insomnia with moderate symptoms according to ISI of at least 8 and below 22 
being present for at least one week, but no longer than 3 months prior to Screening Visit  
3. Reports habitual bedtime, defined as the time the participant attempts to sleep, between 
21:00 and 01:00 

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4. Reports regular time spent in bed, either sleeping or trying to sleep, between 6 and 
9 hours 
5. ≥18 years of age, not older than 65 years 
6. Legally competent male or female patient 
7. Signed Informed Consent 
8. Females of childbearing potential must agree to maintain highly effective or acceptable 
birth control throughout the trial (CTFG 2020).  
Highly effective (failure rate of less than 1% per year) 
• 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: oral, intravaginal, transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral, injectable, implantable 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system  
• 
Bilateral tubal occlusion 
• 
Vasectomized partner (provided partner is sole sexual partner and if vasectomized 
partner has received medical assessment of the surgical success) 
• 
Sexual abstinence (only if defined as refraining from heterosexual intercourse during 
the entire period of risk associated with investigational treatment) 
Acceptable birth control methods which may not be considered as highly effective (failure 
rate of more than 1% per year) 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action 
• 
Male or female condom with or without spermicide 
• 
Cap, diaphragm or sponge with spermicide 
• 
Combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier methods)  
9. Body Mass Index (BMI) between 18.5 and 29.9 kg/m2 at Screening Visit 
10. Use of digital device e.g., smartphone, tablet or laptop  
11. German speaking and reading. 
 
 

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Exclusion Criteria 
Potential trial patients will be excluded if at least one of the following exclusion criteria is present: 
1. Patients with insomnia symptoms present longer than 90 days prior to Screening Visit 
2. Based on the diagnostic interview, reported history (within 2 years) of other sleep 
disorders (e.g., chronic insomnia, circadian rhythm sleep disorders, restless legs 
syndrome (RLS), obstructive sleep apnea (OSA)), i.e., STOPBang (SBQ) questionnaire 
score ≥5, International Restless Legs Scale score ≥16) 
3. Based on the first polysomnographic screening night at Baseline 1, insomnia due to sleep 
apnea or periodic limb movement disorder (PLMD): OSA (Apnea Hypopnea Index of >5 
events/ hour), PLMD (Periodic Limb Movement Index (PLMI) >15 events/ hour) 
4. Rotating shift work with overnight shifts 
5. History of psychiatric disorders within the last 6 months prior to Screening Visit according 
to the Structured Clinical Interview for DSM-5® Disorders – Clinician Version (SCID-5-CV) 
6. History of sensitivity to any component of Neurexan® 
7. Unwilling or unable to comply with all the requirements of the clinical trial protocol 
8. Cognitive impairment (cut-off of 24 points in the Montreal Cognitive Assessment [MoCA]; 
Thomann, Berres et al. 2020) at Screening Visit 
9. Any history of or current abuse of alcohol and/or amphetamines, benzodiazepines, 
cocaine, marijuana, methaqualone, methadone, opioids, propoxyphene, barbiturates, 
phencyclidine; or expected to take during trial participation (urine drug screening at 
Screening Visit and adaptation nights) 
10. Current use of medication affecting sleep, i.e., antidepressants, antipsychotics, diuretics, 
blood pressure drugs, anti-dementia drugs (e.g., piracetam), herbal and homeopathic 
medicine, hormone preparations (e.g., thyroxine) with the exception of hormonal 
contraceptives 
11. Use of Neurexan® within the last two weeks from Screening Visit 
12. Non-pharmacological insomnia therapies (e.g., cognitive behavioral therapy within the last 
6 months of Screening Visit, sleep restriction therapy, complementary and alternative 
therapies as meditation, Traditional Chinese Medicine, aromatherapy) 
13. Excessive consumption of xanthine-containing beverages (more than 7 cups daily of 
coffee or tea or other beverages containing xanthines) 
14. Use of nicotine during the last 6 months prior to Screening Visit  
15. Participation in any interventional clinical study within the past 30 days prior to Screening 
Visit 
16. Any relationship of dependence with the Sponsor or with the Investigator 
17. Active infection/ disease (C-Reactive Protein [CRP] >5 mg/l) 
18. Hypertension defined as systolic blood pressure ≥140 mmHg (Burnier, 2018) 
19. History of neurological, rheumatic, chronic pain, immune, cardiovascular, pulmonary, liver/ 
kidney, or metabolic disorder within the last 6 months prior to Screening Visit 

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20. Nocturia 
21. Pregnancy (as proven by positive urine pregnancy test at Screening Visit) or breastfeeding 
22. Patients with moderate to severe skin allergies and/or eczema 
23. Raynaud's disease 
24. Donation of blood or platelets 3 months prior to or in-between in-hospital visits. 
 
Patient screening will include blood tests for complete blood count (CBC) and differentials, as well 
as thyroid hormone and blood glucose; urinary toxicology screens will also be conducted (exclusion 
criterion number 9). The eligibility of patients based on safety laboratory parameters (except CRP) 
are at the discretion of the investigator. 
The medical history and physical examination will be conducted by a trial physician. 
 
Patient Premature Withdrawal from Trial/ Withdrawal Criteria 
Possible reasons for a premature discontinuation of randomized patient participation in this trial 
are: 
• 
AE(s) that endanger the patients’ safety, making it ethically unacceptable to continue 
• 
Deterioration of the patient’s clinical condition(s) that requires appropriate therapy/ 
treatment during the trial period 
• 
Insufficient treatment compliance as specified in the protocol (see section 11.3.2) 
• 
Intake of prohibited concomitant medication (see section 7.6.1) that might influence the 
trial procedures or the results  
• 
Patient’s unwillingness or inability to adhere to trial requirements (lack of patient’s 
compliance) 
• 
Patients requiring quarantine due to acute infections such as SARS-CoV2 
• 
Positive test for SARS-CoV2 (not part of trial procedures) 
• 
Positive test for drugs, alcohol (breath alcohol test and urine drug screening) 
• 
Daytime napping at PSG days 
• 
Pregnancy 
• 
Withdrawal of Informed Consent 
• 
Lost to follow-up 
• 
Death. 
If possible, a remotely prematurely withdrawn patient should be invited for a last onsite visit to 
return remaining IMP and the Actiwatch. The procedures of the Follow-Up Visit should be followed. 
Prematurely withdrawn patients (‘Drop Outs’) will not be replaced. 
 
Premature Termination of the Trial by the Sponsor 
The Sponsor reserves the right to prematurely terminate the trial at any time, after discussion with 
the Coordinating/ Principal Investigator. The Sponsor may terminate the trial if  
• 
Drug-related AEs occur that constitute a serious risk to the health of the participating 
patients, 
• 
The risk-benefit assessment becomes negative. 

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telephone with the Sponsor to ensure whether unblinding is necessary and that appropriate steps 
for patient management are taken. The unblinding has to be documented by the Investigator. 
Details of the unblinding procedure will be explained in the Safety Reporting Plan for this trial. 
 
Manufacturing, Packaging and Labelling 
All IMP in this trial will be prepared, packed and labelled under the responsibility of a qualified 
person of the Sponsor in accordance with Good Manufacturing Practice (GMP) and all applicable 
local laws and regulations. 
Neurexan® and Placebo will be packed in white cylindrical containers with 100 tablets, labelled 
including tamper-proof seal and released by the Sponsor.  
Labelling implements the use of the computer-generated randomization plan in a treatment ratio of 
1:1 and stratification by sex. IMP containers for males and for females are provided, distinguishable 
by randomization numbers and IMP label color. 
All IMP must be kept in a secure place (locked room and/or locked cupboard with restricted access). 
Based on available stability date no special storage conditions are required for the medication.  
 
Storage and Dispensing of Trial Medication(s) 
The Investigator is responsible for ensuring IMP accountability, including reconciliation of drugs 
and maintenance of drug records. 
• 
Upon receipt of IMP, the Investigator (or pharmacist) will check for accurate delivery and 
acknowledge receipt by signing and dating the documentation provided by the Sponsor. A 
copy of each document will be filed in the Trial Master File and another copy be retained 
for the Investigator Site File. 
• 
The dispensing of the IMP will be carefully recorded at the site on the appropriate drug 
accountability forms provided by the Sponsor and an accurate accounting will be available 
for verification by the monitor at each monitoring visit. 
• 
IMP accountability records will include: 
- 
Confirmation of IMP delivery to the trial site 
- 
The inventory of IMP at the site provided by the Sponsor 
- 
The use of each dose by each patient 
- 
The return of unused IMP 
- 
Dates, quantities, batch numbers, expiry dates and the patient IDs assigned. 
• 
The Investigator should maintain records that adequately document: 
- 
The patients were provided the amount of IMP specified in the protocol/ amendment(s) 
- 
All IMP provided by the Sponsor were fully reconciled. 
 
Patients should be instructed to bring with them to Visit 1 their IMP container with remaining tablets 
in order to allow the assessment of compliance with trial treatment (“pill count”).  
IMP that has been dispensed to a patient must not be re dispensed to a different patient. Unused 
IMP must not be discarded or used for any purpose other than the present trial. The monitor will 
collect the IMP accountability forms and check all IMP returns (both unopened and opened 
containers) prior to making arrangements for their return to the Sponsor authorized according to 
Sponsor instructions. 

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Concomitant Medications/ Treatment 
7.6.1 
Prohibited Medications/ Substances/ Treatments During the Trial 
• 
Abuse of alcohol and/or use of amphetamines, benzodiazepines, cocaine, marijuana, 
methaqualone, methadone, opioids, propoxyphene, barbiturates, phencyclidine 
• 
Use of nicotine 
• 
Medication affecting sleep, i.e., antidepressants, antipsychotics, diuretics, blood pressure 
drugs, anti-dementia drugs (e.g., piracetam), herbal medicine, hormone and homeopathic 
preparations (e.g., thyroxine) with the exception of contraceptives 
• 
Use of Neurexan® different than IMP 
• 
Non-pharmacological insomnia therapies (i.e., cognitive behavioral therapy, sleep 
restriction therapy, complementary and alternative therapies as meditation, Traditional 
Chinese Medicine, aromatherapy) 
• 
Excessive consumption of xanthine-containing beverages (more than 7 cups daily of 
coffee or tea or other beverages containing xanthines). 
8. Trial Procedures 
 
Visit Schedule  
During the trial 6 regular trial visits are scheduled.  
A Screening Visit (Day -28 to -8) will be performed to decide about the patient’s eligibility for trial 
participation. Once the patient gave his/her informed consent he/she will complete the Insomnia 
Severity Index (ISI) questionnaire on AMS-ePRO®. A urine and breath alcohol test will be conducted 
on drugs and alcohol. 
The following procedures will be performed: 
• 
Obtain written informed consent from the patient (section 12.4) 
• 
Completion of ISI on AMS-ePRO® (section 9.1.14) 
• 
Diagnosis of short-term insomnia based on DSM-5 
• 
Check if patient agrees to continuously (day and night) wear the actimetric device on the wrist 
(section 9.1.5) 
• 
Check applicable eligibility criteria (inclusion and exclusion criteria, section 6.1 and 6.2) 
• 
Documentation of demographics 
• 
Documentation of medical history and concomitant diseases  
• 
Documentation of concomitant medication  
• 
Physical examination (section 9.2.3) 
• 
Assessment of vital signs (heart rate, systolic/ diastolic blood pressure) (section 9.2.2) 
• 
Collection of 8.4 ml blood for safety laboratory analyses (complete blood count (CBC) with 
differential, thyroid hormones, blood glucose, C-reactive protein (CRP), erythrocyte 
sedimentation rate (ESR), liver enzymes (aspartate aminotransferase [ASAT], alanine 
transaminase [ALAT], gamma-glutamyl transferase [gamma GT], alkaline phosphatase), 
(section 9.2.4) 
• 
Urine pregnancy test in women with childbearing potential (section 9.1.12) 
• 
Urine collection for test on drugs (section 9.1.11) 
• 
Breath alcohol test (section 9.1.11) 

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• 
Adverse Event recording from Screening Visit onwards (starting with written informed 
consent) until End of Trial (section 9.2.1). 
• 
Instruction in the use of the actigraphy watch, i.e., Actiwatch Spectrum Plus, and its handing 
over. 
From Screening Visit onwards daily until the End of Trial (Follow-up Visit/ Day 28+3) patients must 
wear an actigraphy watch recording their sleeping and activity cycles, complete a sleep diary and 
answer digital questionnaires regarding stress level (AMS-ePRO®). 
 
At Baseline 1 (Day -2 to Day -1) patients will have their first night at the trial site for PSG adaptation 
and screening for exclusion criterion 3. Patients complete their electronic sleep diary (adapted from 
DGSM, on AMS-ePRO®) to be kept until the End of Trial (Follow-up Visit/ Day 28+3) and 
questionnaires on sleep, mood, stress and quality of life. In the evening before the Baseline 1 night 
urine and breath alcohol tests will be conducted on drugs and alcohol, respectively. After awakening 
(Day -1) resting state stress parameters in saliva are to be collected (at 5 time points) and every 
3 hours (at 4 time points). In the course of the morning, patients will perform neuropsychological 
tests from the TAP battery. An rsEEG and measurement of resting heart rate and HRV will be 
performed at approximately 15 minutes prior CPT. Around 12:00 at Day -1 a CPT will be conducted, 
before and afterwards blood samples will be collected. Patients will complete a subjective pain and 
stress rating during CPT test.  
The following procedures will be performed: 
• 
Urine collection for test on drugs in the evening at Day -2 (section 9.1.11) 
• 
Breath alcohol test in the evening at Day -2 (section 9.1.11) 
• 
Completion of the following questionnaires:  
o a) on paper: BAI, BDI-II, WEIMuS, PSQI, PSS-10, SF-36v2, SSQ-25  
o b) on AMS-ePRO®: ESS, ISI, PASA (section 9.1.14) 
• 
PSG for screening of exclusion criterion 3 and for adaptation to the unfamiliar sleep lab 
environment in the night between Day -2 and Day -1 (section 9.1.1) 
• 
Check exclusion criterion 3 at Day -1 
• 
Collection of 0.5 to 1 ml saliva to measure cortisol, DHEA-S and alpha-amylase at awakening 
(0 minutes), and after 15 minutes, 30 minutes, 45 minutes, 60 minutes, 3 hours, 6 hours, 
9 hours and 12 hours after awakening at Day -1 (section 9.1.2) 
• 
Neuropsychological tests (TAP) at Day -1 (section 9.1.10) 
• 
Resting state EEG, resting state HR and HRV to measure daytime performance at Day -1 
(section 9.1.3) 
• 
CPT around 12:00 including subjective pain rating and pain tolerance, heart rate and 
associated HRV measures, electrodermal activity, and EEG at Day -1 (section 9.1.7) 
• 
Collection of approximately 12.5 ml blood for measuring cortisol, DHEA-S, adrenaline, 
noradrenaline, inflammation markers (IL-6 and TNF-α) prior to CPT, 20 minutes and 
50 minutes after CPT at Day -1 (section 0) 
• 
Adverse events at Day -2 (section 10) 
• 
Changes in concomitant medication at Day -2  
• 
Complete sleep diary and stress assessment (in AMS-ePRO®). 
 

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At Baseline 2 (Day -1 to Day 0) patients will stay at the site for a second night for PSG. After 
awakening (Day 0) resting state stress parameters in saliva are to be collected (at 5 time points). 
Patients will be randomly assigned to treatment group Neurexan® or Placebo with a 1:1 allocation 
and stratification by sex.  
The following procedures will be performed:  
• 
Urine collection for test on drugs in the evening at Day -1 (section 9.1.11) 
• 
Breath alcohol test in the evening at Day -1 (section 9.1.11) 
• 
Baseline 2 PSG night to measure primary, i.e., SE and secondary endpoints, i.e., SOL, 
WASO, TST, NWAK, and ArI during sleep in the night between Day -1 and Day 0 (section 
9.1.1)  
• 
Collection of 0.5 to 1 ml saliva to measure cortisol, DHEA-S and alpha-amylase at awakening 
(0 minutes), and at 15 minutes, 30 minutes, 45 minutes, 60 minutes after awakening at Day 0 
(section 9.1.2) 
• 
Adverse events at Day -1 and Day 0 (section 9.2.1) 
• 
Changes in concomitant medication at Day -1 and Day 0 
• 
Randomization to treatment group at Day 0 (section 11.2) 
• 
Distribution of IMP and instruction regarding use of IMP at Day 0 
• 
Starting IMP treatment after having performed all Baseline 2 assessments at midday Day 0 
(section 7.1) 
• 
Complete sleep diary and stress assessment (in AMS-ePRO®). 
 
Patients will continue to take their trial treatment for 14 consecutive days (Day 0 - Day 13).  
 
At Visit 1 (Day 12 to Day 13; +2 days) patients return to the trial site for another PSG adaptation 
night. A urine and breath alcohol test will be conducted on drugs and alcohol, respectively. After 
awakening (Day 13) resting state stress parameters in saliva are to be collected (at 5 time points) 
and every 3-hours (at 4 time points). In the course of the morning, patients will perform 
neuropsychological tests from the TAP battery. An rsEEG and measurement of resting heart rate 
and HRV and EDA will be performed at approximately 15 minutes prior CPT. Around 12:00 at 
Day 13 a CPT will be performed, blood samples will be collected (before CPT and 20 minutes and 
50 minutes after CPT) and patients will complete a subjective pain and stress rating. During CPT 
an EEG will be performed and heart rate and HRV will be measured. Additionally, patients will 
complete questionnaires on sleep, stress and quality of life on paper (BDI-II, WEIMuS) and on 
AMS-ePRO® (ESS, ISI, PASA).  
 
The following procedures will be performed:  
• 
Urine collection for test on drugs in the evening at Day 12 (section 9.1.11) 
• 
Breath alcohol test in the evening at Day 12 (section 9.1.11) 
• 
PSG night, again for adaptation to the unfamiliar sleep lab environment between Day 12 and 
Day 13 (section 9.1.1) 
• 
Collection of 0.5 to 1 ml saliva to measure cortisol, DHEA-S and alpha-amylase at awakening 
(0 minutes), and at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 3 hours, 6 hours, 
9 hours and 12 hours after awakening at Day 13 (section 9.1.2) 
• 
Neuropsychological tests (TAP) at Day 13 (section 9.1.10) 

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• 
Resting state EEG, resting state HR and HRV to measure daytime performance at Day 13 
(section 9.1.3) 
• 
CPT around 12:00 including subjective pain and stress rating, heart rate and associated HRV 
measures, electrodermal activity, and EEG at Day 13 (section 9.1.7) 
• 
Collection of approximately 12.5 ml blood for measuring cortisol, DHEA-S, adrenaline, 
noradrenaline, inflammation markers (IL-6 and TNF-α) prior to CPT, 20 minutes and 
50 minutes after CPT at Day 13 (section 9.1.8) 
• 
Completion of the following questionnaires: ESS, ISI, PASA (AMS-ePRO®); BDI-II and 
WEIMuS (both paper-based; section 9.1.14)  
• 
Adverse events at Day 12 (section 9.2.1) 
• 
Changes in concomitant medication at Day 12  
• 
Complete sleep diary and stress assessment (in AMS-ePRO®). 
 
At Visit 2 (Day 13 to Day 14; + 2 days but on the next day after Visit 1) patients will stay at the site 
for a second night for PSG. After awakening (Day 14) resting state stress parameters in saliva are 
to be collected (at 5 time points).  
The following procedures will be performed:  
• 
Urine collection for test on drugs in the evening at Day 13 (section 9.1.11) 
• 
Breath alcohol test in the evening at Day 13 (section 9.1.11) 
• 
Last IMP intake in the night of Day 13 prior to sleep 
• 
PSG recording to measure SOL, WASO, TST, NWAK, and arousal indices during sleep in 
the night between Day 13 and Day 14 (section 9.1.1) 
• 
Collection of 0.5 to 1 ml saliva to measure cortisol, DHEA-S and alpha-amylase at awakening 
(0 minutes), and at 15 minutes, 30 minutes, 45 minutes, 60 minutes after awakening at 
Day 14 (section 9.1.2) 
• 
Adverse events at Day 13 and Day 14 (section 9.2.1) 
• 
Changes in concomitant medication at Day 13 and Day 14  
• 
Complete sleep diary and stress assessment (in AMS-ePRO®) 
• 
Return of IMP. 
 
At Follow-up Visit (Day 28; + 3 days) patients will have one last Visit at the trial site to complete 
questionnaires on sleep, stress and quality of life (BAI, PSQI, PSS-10, SF-36v2, SSQ-25, based on 
paper). Patients will complete their electronic sleep diary (AMS-ePRO®) and return their portable 
actimetric device. 
• 
Completion of the following paper-based questionnaires (BAI, PSQI, PSS-10, SF-36v2, SSQ-
25) 
• 
Completion of the last daily sleep diary and stress assessment (AMS-ePRO®) 
• 
Return of portable actimetric device 
• 
Adverse events between Visit 2 and until Follow-up Visit (section 9.2.1) 
• 
Changes in concomitant medication between Visit 2 and Follow-up Visit. 
 
Following all above-mentioned procedures including the Follow-up Visit (Day 28 + 3 days) to collect 
patient-reported outcomes on questionnaire, the End of Trial (EoT) documentation will be completed. 

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The EoT documentation is also to be completed in the electronic Case Report Form (eCRF) in the 
event of premature termination/ discontinuation, with reasons to be given (section 6.3). 

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°Demographics include sex, height and weight. 
*Starting IMP treatment after having performed all Baseline 2 assessments and after randomization at midday Day 0 for 
14 consecutive days (+ maximum 2 days allowance) until Visit 2 (Day 13). 
°°Sleep diary will be completed daily; starting at Screening Visit until End of Trial 
#Stress biomarkers in saliva: cortisol, alpha-amylase, dehydroepiandrosterone sulfate (DHEA-S) at 5 time points: after 
awakening from PSG nights at Baseline 1/ Day -1, Baseline 2/ Day 0, Visit 1/ Day 13 and Visit 2/ Day 14 collection of 
around 0.5 to 1 ml saliva at 0 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes (5 time points) for the 
assessment of Cortisol Awakening Response (CAR) and additionally at Baseline 1/ Day -1 and Visit 1/ Day 13 diurnal 
profile of stress biomarkers by collecting saliva samples at 3-hourly intervals over 12 hours (4 time points) synchronized 
to the awakening time.  
1Including subjective pain rating and pain tolerance, blood sampling before CPT, 20 minutes and 50 minutes after CPT 
to assess biomarkers cortisol and DHEA-S, adrenalin, noradrenalin and inflammatory response (IL-6 and TNF-α), 
autonomic and cortical stress response (heart rate, HRV, electrodermal activity (EDA) and EEG). 
2In case of premature discontinuation reason to be given. 
 
 
 

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*Only at Baseline 1 and Visit 1. 
Saliva samples are collected in 2 ml SaliCap sampling tubes (TECAN/ IBL International, Hamburg, 
Germany, ref. no. RE69985) using short drinking straws. One sample of 0.5 to 1 ml saliva is sufficient 
to analyze cortisol, alpha-amylase and DHEA-S. 
After instruction by the site personnel, samples are collected independently by each trial participant. 
Salivary samples are stored frozen at -80°C (+/- 10°C fluctuation) for interim storage (approximately 
3 months) at the biobank of the local laboratory of the investigational site (Institut für Klinische 
Chemie und Laboratoriumsdiagnostik, IKCL, Jena University Hospital) before shipping to the saliva 
biomarker laboratory.  
Stress parameter levels in saliva will be analyzed at Dresden LabService GmbH, Dresden, Germany, 
using commercial immunoassays from IBL International, Hamburg, Germany (i.e., Cortisol Saliva 
Luminescence ImmunoAssay (CLIA); and DHEA-S Saliva Enzyme-Linked Immunosorbent Assay 
(ELISA) following manufacturer’s instructions. Saliva alpha-amylase will be analyzed following the 
method of Rohleder and colleagues (Rohleder, Nater et al. 2004). 
9.1.3 
Electroencephalography (EEG)  
Electroencephalography (EEG) is a widely used technique to investigate human brain functioning. 
In addition to EEG recordings during PSG nights, patients will undergo continuous EEG 
measurements at Baseline 1 (Day -1) and Visit 1 (Day 13). These include a resting-state EEG before 
the CPT, an EEG recording during the CPT, and a resting-state EEG after the CPT.  
Changes in time course of EEG vigilance fluctuations during wakefulness will be assessed by 
VIGALL version 2.1 (validated with the Multiple Sleep Latency Test (MSLT) by Olbrich et al. 2015) 
at Visit 1 compared to Baseline 1. EEG asymmetry index results from the subtraction of the alpha’s 
power natural logarithm of the right hemisphere from that of the left hemisphere and represents a 
robust stress feature (Giannakakis, Grigoriadis et al. 2015). Changes in the EEG asymmetry index 
at Visit 1 will be compared to Baseline 1. 
Regional changes in spectral characteristics of EEG using relative power indices in delta-theta-
alpha-beta frequency ranges are assessed. 
9.1.4 
Heart Rate (HR), Heart Rate Variability (HRV) and Electrodermal 
Activity (EDA) 
The two peripheral branches of the autonomic nervous system (ANS), the parasympathetic and the 
sympathetic system, modulate the intrinsic activity of the cardiac pacemaker cells in the sinoatrial 
node. While the parasympathetic or vagal activity reducing energy expenditure is anabolic and health 
promoting, the sympathetic branch is needed for an adequate stress response. Thus, the heart rate 
and its variability mirror the resulting homeostasis of an organism influenced by physical as well as 
by psychological variables, such as stress in a certain environment. 
The control of cardiovascular function is critical to adaptive behavior and can be measured by heart 
rate variability (HRV) reflecting dynamic interactions between excitatory and inhibitory autonomic 
control mechanism. The following HRV parameters will be selected:  
• 
RMSSD (Root Mean Square of Successive Differences) as an index of parasympathetic 
activity in the time domain 
• 
Baevsky’s stress index (SI) as an index of sympathetic activity 

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• 
LF/HF (low frequency/ high frequency power) ratio as a frequency-based feature for 
sympathovagal balance. 
Electrodermal activity (EDA) is a measure of changes in conductance at the skin surface due to 
sweat production, which is sympathetically controlled. It is therefore considered a sensitive measure 
of stress by reflecting activity within the sympathetic branch of the ANS.  
HR, HRV and EDA will be assessed in resting state during rsEEG and under stress response during 
CPT as well as during sleep in the PSG (only HR and HRV indices). 
9.1.5 
Actigraphy 
After patients have given their informed consent, they will receive and wear continuously (day and 
night except during PSG) an actigraphy watch (Actiwatch Spectrum Plus, Philips GmbH), which will 
continuously monitor movement information over the whole trial duration (Screening Visit/ Day -28 
to -8 until Follow-up Visit/ Day 28) to assess SE, SOL, WASO, TST and NWAK as well as to track 
daily activity to investigate habitual sleep–wake patterns. At Screening Visit patients will be asked 
whether they will accept to continuously (day and night) wear the actigraphy watch around their wrist. 
Actiwatch is a water-resistant medical device that continuously records motion and light.  
9.1.6 
ePRO Designed Stress Questionnaires (EMAs) 
Patients perceived stress levels (using Ecological Momentary Assessments, EMAs) will be reported 
by the patients inside the AMS-ePRO® which can be accessed via the patients’ own smartphone, 
tablet or laptop (Bring Your Own Device = BYOD). Patients will report their stress levels daily over 
the whole clinical trial duration (Screening Visit until Follow-up Visit/ Day 28). 
The site staff will assist patients with the installation of the app and give instructions for use.  
9.1.7 
Cold Pressor Test (CPT) 
The CPT is used to induce a stressor and to assess the patients’ stress response. CPT involves 
placing a hand or forearm in cold water (∼0°C), a stimulus that induces stress response as pain is 
slowly increasing from mild to moderate intensity and is terminated by the patient by voluntary 
withdrawal of the limb.  
CPT will be performed twice with each patient during this trial, following PSG adaptation nights at 
Baseline 1 (Day -1) and at Visit 1 (Day 13). 
During CPT an EEG is performed to assess changes in EEG vigilance fluctuations, in the EEG 
asymmetry index and spectral characteristics of EEG due to stress induction. The patients’ heart 
rate, HRV and EDA are measured during CPT to assess changes in the autonomic stress response.  
Before conduction of the CPT (baseline), 20 minutes and 50 minutes after CPT blood (12.5 ml/ blood 
sample) will be taken to assess cortisol and DHEA-S, adrenalin and noradrenalin and inflammatory 
response (IL-6 and TNF-α).  
Patients will complete a subjective pain rating questionnaire to measure the individual pain level 
during CPT on a numeric rating scale (0 to 10). Pain tolerance will be measured by the amount of 
time the patient spent with the hand or forearm in ice water. 
 
 

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9.1.8 
Blood Samples for Stress Response 
At Baseline 1 (Day -1) and Visit 1 (Day 13) patients will have repeated blood sampling. 
Blood samples will be collected totally 6 times (3 times at each CPT) to assess stress response 
based on the assessment of biomarkers cortisol, DHEA-S, adrenaline and noradrenaline levels as 
well as to assess the inflammatory response based on IL-6 and TNF-α. 
Each blood sample consists of 12.5 ml blood that will be split up in 3 monovettes (all from Sarstedt, 
Nümbrecht, Germany) as following:  
• 
4.9 ml blood will be collected in an S-Monovette® Serum Gel (ref no 04.1935.001) for the analysis 
of cortisol, DHEA-S and TNF-α,  
• 
4.9 ml blood will be collected in an S-Monovette® K3 EDTA (ref no 04.1931.001) for the analysis 
of adrenalin and noradrenalin, and  
• 
2.7 ml blood will be collected in an S-Monovette® Lithium-heparin gel (ref no. 04.1928.001) for 
the analysis of IL-6. 
Blood biomarker samples will be analyzed at the local laboratory of the investigational site (Institut 
für Klinische Chemie und Laboratoriumsdiagnostik IKCL, University Hospital Jena). 
9.1.9 
Sleep Diary 
After patients have given their informed consent, they will receive access to an electronic sleep diary 
(adapted from DGSM - Deutsche Gesellschaft für Schlafforschung und Schlafmedizin, on AMS-
ePRO®), which they are asked to complete every day starting at Screening Visit (Day -28 to -8) in 
the evening until End of Trial (Follow-up Visit/ Day 28). Beside subjective sleep parameters patients 
will also report their daily intake of IMP, adverse events and concomitant medication, if any.  
9.1.10 Neuropsychological Tests (TAP) 
With neuropsychological tests the Investigator assesses the patients’ alertness, vigilance and 
sustained attention. These tests will be performed at Baseline 1 and at Visit 1 and last approximately 
60 minutes. The electronic Tests of Attentional Performance® (TAP; Zimmermann and Fimm 2002) 
version 2.3.1 will be used to investigate changes in the alertness, vigilance and sustained attention 
(three subtests of the TAP). 
9.1.11 Urine Test and Alcohol Breath Test 
Urine drug screening test and an alcohol breath test will be performed at Screening Visit 
(Day -28 to -8) and prior to the PSG nights (Baseline 1, Baseline 2, Visit 1 and Visit 2). 
9.1.12 Pregnancy Test 
Urine pregnancy test will be performed at Screening Visit/ Day -28 to -8 in women with childbearing 
potential.  
9.1.13 Blood Pressure 
Blood pressure will be measured at Screening Visit to assess the patients’ eligibility. The blood 
pressure will be measured at rest (patient should be at rest for at least 20 minutes). Measurement 
will be repeated 3 times with a break of 1 minute in between each measurement. The last measured 
systolic value will be taken to assess eligibility (see exclusion criterion no. 18). 
Blood pressure measurements for the assessment of vital signs will be performed correspondingly. 

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9.1.14 Patient Questionnaires 
Patient-Reported Outcomes (PROs) will be used in this trial to assess insomnia, the patients’ 
perceived stress level and the patients’ quality of life. Patients will complete the following 
questionnaires twice, at Baseline 1 (either in the evening prior to Baseline 1 PSG night or next 
morning following Baseline 1 PSG night) and either at Visit 1 (either in the evening prior to Visit 1 
PSG night or next morning following Visit 1 PSG night), or at Follow-up Visit. 
 
Pittsburgh Sleep Quality Index (PSQI) 
The Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality 
and disturbances. Nineteen individual items generate 7 component scores: subjective sleep quality, 
sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping 
medication, and daytime dysfunction. The PSQI is well suited for measuring change in insomnia and 
will be completed on paper at Baseline 1 and at Follow-up Visit. 
 
Insomnia Severity Index (ISI) 
The ISI is a questionnaire widely used to assess nature, severity and impact of insomnia. It has 
7 questions, which are summarized to a total score. The ISI will be completed electronically at 
Screening Visit, Baseline 1 and at Visit 1 (AMS-ePRO®). 
 
Epworth Sleepiness Scale (ESS) 
The ESS is a validated measure of the patient's general level of daytime sleepiness. The patient 
rates the chances to fall asleep in 8 different situations commonly encountered in daily life. The total 
ESS score is based on a scale of 0 to 24. The higher the score, the higher the patient’s level of 
daytime sleepiness. The ESS will be completed electronically at Baseline 1 and at Visit 1 (AMS-
ePRO®). 
 
Würzburg Fatigue Inventory (WEIMuS) 
The WEIMuS is a 17-item scale designed to assess fatigue as a symptom of a variety of different 
chronic conditions and disorders. The scale addresses fatigue’s effects on daily functioning, querying 
its relationship to motivation, physical activity, work, family, and social life, and asking respondents 
to rate the ease with which they are fatigued and the degree to which the symptom poses a problem 
for them. The WEIMuS will be completed on paper at Baseline 1 and at Visit 1. 
 
Short Form-36 Health Survey Version 2 (SF-36v2) 
The SF-36v2 questionnaire (Short Form Health 36, version 2.0) questionnaire is a globally 
established, validated and frequently used questionnaire regarding the quality of life. It consists of 
36 questions on general health. The SF-36v2 will be completed on paper at Baseline 1 and at Follow-
up Visit. 
 
Subclinical Stress Symptom Questionnaire-25 (SSQ-25) 
The Subclinical Stress Symptom Questionnaire (SSQ-25) is a comprehensive, reliable, and valid 
instrument that allows a valid assessment and differentiation of subclinical stress symptoms. This 
questionnaire consists of 25 questions regarding symptoms following stressful events and will be 
completed on paper at Baseline 1 and at Follow-up Visit. 
 
Primary Appraisal Secondary Appraisal (PASA) 
Primary Appraisal Secondary Appraisal (PASA) assesses 4 anticipatory cognitive appraisal 
processes, threat, challenge, self-concept of own abilities and control expectancy. Each of these 
primary PASA scales comprises 4 items that are rated on a 6-point Likert scale ranging from strongly 

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disagree to strongly agree. The PASA will be completed electronically at Baseline 1 and at Visit 1 
(AMS-ePRO®). 
 
Perceived Stress Scale-10 (PSS-10) 
The PSS (Cohen, Kamarck et al. 1983) is a widely used psychological instrument for measuring 
stress perception. It measures how unpredictable, uncontrollable, and overloaded individuals judge 
their lives within the last month. The English version of the PSS-10 comprises 10 items that are 
answered on a five-point rating scale ranging from 0 = ‘never’ to 4 = ‘very often’ and will be 
completed on paper at Baseline 1 and at Follow-up Visit. A German translation of the English PSS-
10 version is used. 
 
Beck's Depression Inventory-II (BDI-II) 
The BDI-II is a 21-item, self-report rating inventory that measures characteristic attitudes and 
symptoms of depression. The BDI-II is a new revised edition of BDI and includes items intending to 
index symptoms of severe depression, which would require hospitalization. It will be completed on 
paper at Baseline 1 and at Visit 1. 
 
Beck's Anxiety Inventory (BAI) 
The BAI is a 21-item multiple-choice self-report inventory that measures the severity of anxiety in 
adults and adolescents. Because the items in the BAI describe the emotional, physiological, and 
cognitive symptoms of anxiety but not depression, it can discriminate anxiety from depression. The 
BAI will be completed on paper at Baseline 1 and at Follow-up Visit. 
 
Safety Parameters 
9.2.1 
Adverse Events 
Definition, collection and reporting of adverse events are described in section 10. 
9.2.2 
Vital Signs 
Vital signs (heart rate, systolic/ diastolic blood pressure) will be collected at Screening Visit. 
9.2.3 
Physical Examination 
At Screening Visit (Day -28 to -8) a physical examination will be performed. Physical status of 
cardiovascular, respiratory, musculoskeletal and gastrointestinal systems, head and eyes and other 
abnormalities, if applicable, will be recorded in the eCRF. 
9.2.4 
Safety Laboratory  
Safety laboratory blood samples will be collected once at Screening Visit (and up to 2 working days 
later) using S-Monovette® Lithium-Heparin Gel (2.7 ml for CRP, liver enzymes and thyroid 
hormones), S-Monovette® GlucoEXACT (3.1 ml for blood glucose), S-Monovette® K3 EDTA (2.6 ml 
for complete blood count [CBC] with differential and Erythrocyte Sedimentation Rate [ESR]), totally 
8.4 ml. Samples will be consecutively analyzed at the local routine laboratory of the investigational 
site, the Institut für Klinische Chemie und Laboratoriumsdiagnostik (IKCL), Jena University Hospital. 
The following parameters will be analyzed: 
• 
Complete Blood Count (CBC with differential) 
• 
Thyroid hormones 
• 
Blood glucose 
• 
C-Reactive Protein (CRP) 

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• 
Erythrocyte Sedimentation Rate (ESR) 
• 
Liver enzymes (ASAT, ALAT, gamma GT, alkaline phosphatase). 
 
 
 
Appropriateness of Measurements 
All clinical procedures that will be used in this trial are standard and generally accepted. 
 
 

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10. Safety Reporting 
 Definitions 
10.1.1 Adverse Event (AE) 
According to ICH E2A an Adverse Event (AE) is defined as: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an IMP, whether or not 
considered related to the IMP. 
10.1.2 Treatment-Emergent Adverse Events (TEAE)  
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the 
initiation of the treatment or any AE already present that worsens in either intensity or frequency 
following exposure to the treatment. 
All AEs collected from visit Baseline 2 (Day -1 to 0) until 1 day (24 hours) following last IMP intake 
are considered as TEAEs in this clinical trial. 
10.1.3 Adverse Drug Reaction (ADR) 
An Adverse Drug Reaction (ADR) is any untoward and unintended response to an IMP that is 
considered to have a reasonable possibility of a causal relationship with the treatment, i.e., the 
relationship cannot be ruled out. 
10.1.4 Serious Adverse Event/ Serious Adverse Drug Reaction (SAE/ SADR) 
A Serious Adverse Event (SAE) or Serious Adverse Reaction (SADR) is any untoward medical 
occurrence or effect that at any dose: 
• 
Results in death 
• 
Is life-threatening (note: the term “life-threatening” refers to an event in which the patient 
was at risk of death at the time of the event; it does not refer to an event which 
hypothetically may cause death if it is more severe) 
• 
Requires inpatient hospitalization (overnight stay) or prolongation of existing 
hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is of special interest at the Investigator’s discretion 
• 
Or other medically important condition. 
Other medically important conditions are defined as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the patient or 
may require intervention to prevent one or more of the outcomes listed in the definition above.  
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsion that does not result in hospitalization, or 
development of drug dependency or drug abuse. 

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However, medical judgement has to be exercised in deciding whether an event is serious in any 
other situations considered medically relevant. 
The evaluation of the AE as being serious or not-serious is made independently of any attribution 
of causality. Events requiring treatment on an emergency outpatient basis (not resulting in 
admission to hospital) and not fulfilling any of the definitions of seriousness given above are NOT 
considered to be SAEs. 
10.1.5  Medical Events not to be Considered AEs or SAEs 
The following events should not be recorded as an AE/ SAE if recorded at the screening period 
and/or the basic examination of a clinical trial: 
• 
A pre-planned procedure, e.g., surgery and invasive procedures, unless the condition for 
which the procedure was planned has worsened since Baseline 1. 
• 
Complications to pre-planned procedures should be recorded as AEs. 
• 
A pre-existing condition found as a result of screening procedures. 
• 
Pregnancy is not considered to be an AE. 
Note: Any worsening in severity or frequency of a concomitant illness or any new illness diagnosed 
in the trial period has to be regarded as AEs/ SAEs. 
10.1.6 Unexpected Adverse Reaction (UAR) 
An Unexpected Adverse Reaction (UAR) is an ADR, the nature or severity of which is not consistent 
with the information available on the IMP reference safety information. 
10.1.7 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a serious ADR, the nature or 
severity of which is not consistent with the applicable reference safety information. 
 Criteria for Clinically Relevant Abnormal Findings 
The assessment whether abnormal laboratory findings are of clinical relevance will be done by the 
Investigator and documented in the electronic Case Report Form (eCRF). 
 Recording of AEs 
All AEs that occur during the entire course of the trial after the patient has signed the informed 
consent are to be collected and reported in the eCRF, regardless of whether they are reported by 
the patient, elicited by Investigator questioning, detected through physical examination, or by other 
means.  
For the case that AEs are still ongoing at the end of the trial, Investigators should make a 
reasonable effort to obtain a final status of the AE and, where possible, an end date even if the end 
date is later than the final trial-specific visit for the patient concerned. Information dated after the 
end of the trial for the patient concerned will not be part of the data collection in the eCRF.  
 Evaluation of AEs 
As far as possible, each AE is described by: 
• 
Duration (start and end dates) 
• 
Start/ end of (investigational) medication 

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• 
Intensity (mild, moderate, severe)  
• 
Investigator assessed causality (relationship to the IMP) 
• 
Action(s) taken (change of investigational medication, treatment of AE etc.) including start 
and end of respective action 
• 
Concomitant diseases and respective medication in general 
• 
Outcome. 
10.4.1 AE Intensity 
AE intensity determined by the Investigator on the basis of his/her direct observations or the 
patient’s reporting: 
• 
Mild: causes no limitation of usual activities; the patient may experience slight discomfort 
• 
Moderate: causes some limitation of usual activities; the patient may experience annoying 
discomfort 
• 
Severe: causes inability to carry out usual activities; the patient may experience 
intolerable discomfort or pain. 
10.4.2 AE Causality 
Any AE has to be judged for causality (relationship to investigational medication and relationship 
to trial procedures). The Investigator will assess causal relationship between the IMP and all AEs 
whether there is a reasonable possibility that the drug caused the event. 
The assessment will be based on the question ‘Do you consider that there is a reasonable 
possibility that the AE may have been caused by the IMP?’. The evaluated answer will be `yes` or 
`no`. 
In case a reasonable possibility cannot be excluded, reasonable possibility of causal relationship 
should be considered until further evidence will be available to exclude it. 
For AEs the causal relationship to other medications and trial procedures will also be assessed. In 
case of reasonable possibility that the AE may have been caused by trial procedures or other 
medication the evaluated answer will be `yes`.  
Data collection will be set up in a way that allows to distinguish between IMP relatedness and 
procedure relatedness. 
Emerging information from procedure-related AEs, if any, will be taken into account for continuous 
risk-management and re-assessment if the intended procedures remain adequate. Procedures will 
be revised where there is evidence that risk or burden for the trial participants is not acceptable.  
10.4.3 Handling of AEs  
If an AE occurs, appropriate diagnostic and therapeutic measures are to be taken and the IMP has 
to be discontinued if appropriate. Follow-up evaluations of the patient are to be performed until the 
patient recovers or until the Investigator considers the situation to be no longer clinically significant 
or until the degree of a permanent disability can be assessed. 
Investigators monitor and register all AEs on the AE form of the eCRF at each visit.  
For any AE a specific diagnosis rather than signs or symptoms have to be given in the eCRF. In 
absence of a specific diagnosis, an individual AE form has to be filled in for each sign or symptom 
to allow proper coding according to Medical Dictionary for Regulatory Activities (MedDRA). 

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MedDRA coding will be based on the latest version available at trial start throughout the trial to 
achieve consistency. 
Persistent AEs will be entered once in the eCRF until they are resolved or if a new event has to be 
documented due to deterioration. These AEs will be carefully monitored; further details of 
monitoring of persistent AEs will be provided in the Monitoring Plan. If an AE is still not resolved at 
the end of the trial for the individual patient, this will be documented as ongoing at trial completion. 
For recurrent AEs, i.e., AEs of the same nature, but with a different date of onset, an individual AE 
form has to be completed for each of them. 
AEs occurring after the termination of the trial individually and/or of the trial in total are to be 
reported to Biologische Heilmittel Heel GmbH even after the clinical trial has been completed if, in 
the judgement of the Investigator, there is an association between the event and the previous use 
of the product under investigation. 
 Reporting of Serious Adverse Events (SAEs) 
10.5.1 Responsibility of Investigator 
If the AE is classified as serious, the Investigator has to complete and also sign the SAE module in 
the eCRF. It is the responsibility of the Investigator to send the SAE report out of the eCRF within 
24 hours after becoming aware of it and print the report out of the eCRF and file it in the Investigator 
Site File. At the earliest possible date, the SAE report form has to be followed by a detailed report 
and any documentation that might have become available, e.g., hospital records, autopsy reports, 
and/or other pertinent documents. 
All the above documents will be sent by fax or scan via email to the Drug Safety Department of the 
designated CRO within 24 hours (see contact details below) and the original of the form will be 
retained in the patient file (keeping a photocopy in the Investigator Site File). Personal data of the 
patient have to be deleted or redacted, the patient number and trial code have to be used for patient 
identification. 
For reporting SAEs in the event of technical failure of eCRF, a paper form of the SAE report has to 
be completed and faxed or emailed as scan within 24 hours using the following contact:  
AMS Advanced Medical Services GmbH Safety Department 
Fax no.: +49 621700 95 950 
Email: safety-C2104@ams-europe.com 
 
At the earliest possible date, the SAE report form has to be completed in the eCRF and procedures 
described in the first paragraph of this section should be followed. A detailed follow-up report and 
any documentation that may be available, e.g., hospital case records, autopsy reports, and/or other 
pertinent documents will be sent via fax or scan via email.  
 
The primary person responsible for Safety at the Pharmacovigilance Department of Biologische 
Heilmittel Heel GmbH is: 
 
Biologische Heilmittel Heel GmbH 
Dr.-Reckeweg-Straße 2-4 
76532 Baden-Baden, Germany 
Phone: 
 
Fax: +49 7221 501-3099 
Email: drugsafety@heel.com 

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The Qualified Person for Pharmacovigilance (QPPV) at Biologische Heilmittel Heel GmbH is: 
 
 
Biologische Heilmittel Heel GmbH 
Dr.-Reckeweg-Straße 2-4 
76532 Baden-Baden, Germany 
Phone: 
 
Fax: +49 7221 501-3099 
 
Availability in emergency patient safety situation (24 hours/day and 7 days/week) 
Mobile: +49 160 88 29 373 
10.5.2 Responsibility of Sponsor 
The Sponsor will assess if an SAE is in line with the IMP’s existing reference safety information 
(thus ‘expected’) or if the SAE is not in line with the existing reference safety information (thus 
‘unexpected’).  
All Suspected Unexpected Serious Adverse Reactions (SUSARs) will be reported to the Competent 
Authority(ies) concerned and to the Ethics Committee(s) concerned as soon as possible but within 
a maximum of 15 days (fatal or life-threatening SUSARs within a maximum of 7 days) of first 
knowledge by the Sponsor. 
Relevant follow-up information of fatal or life-threatening SUSARs will be communicated 
subsequently within an additional 8 days. 
Any circumstances which require a review of the risk-benefit assessment of the IMP will be reported 
to the Competent Authority(ies) and to the Ethics Committee(s) as soon as possible but within a 
maximum of 15 days.  
Throughout the clinical trial, the Sponsor shall provide the Competent Authority(ies) and the Ethics 
Committee(s) with yearly safety assessment reports, Development Safety Update Reports 
(DSURs), which list Suspected Serious Adverse Reactions (expected and unexpected).  
The Sponsor shall within 15 days notify the Competent Authority(ies) concerned and the Ethics 
Committee(s) concerned when the clinical trial has been suspended or interrupted by the Sponsor, 
giving the reasons for the suspension or interruption. 
 Follow-up of AEs 
Regardless of the duration of the trial, every patient suffering from an AE must be monitored by the 
Investigator and/or the Sponsor independently from trial termination at least for SAEs until its 
complete resolution or until its cause has been established. 
 Pregnancy 
Females who are pregnant or breastfeeding are not allowed to participate in this clinical trial. Urine 
pregnancy test will be performed for women of childbearing potential at Screening Visit before first 
IMP administration to exclude pregnancy. Women are considered of childbearing potential, i.e., 
fertile, following menarche and until becoming postmenopausal unless permanently sterile. 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. 

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A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
Women of childbearing potential must agree to maintain highly effective or acceptable birth control 
throughout the trial (CTFG 2020).  
Highly effective (failure rate of less than 1% per year) 
• 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: oral, intravaginal, transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral, injectable, implantable 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system  
• 
Bilateral tubal occlusion 
• 
Vasectomized partner (provided partner is sole sexual partner and if vasectomized 
partner has received medical assessment of the surgical success) 
• 
Sexual abstinence (only if defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatments) 
Acceptable birth control methods which may not be considered as highly effective (failure rate of 
more than 1% per year) 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action 
• 
Male or female condom with or without spermicide 
• 
Cap, diaphragm or sponge with spermicide 
• 
Combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier methods) 
All pregnancies observed during the course of the trial and their outcomes should be reported to 
the CRO and/or the Sponsor. If a patient becomes pregnant the investigational product should be 
discontinued immediately and the patient should be withdrawn from the trial. The Investigator or 
other site personnel will have to inform the CRO and/or the Sponsor within 24 hours of when he or 
she becomes aware of the pregnancy. 
A Pregnancy Report Form should be used for reporting and sending via fax or scan via email to: 
AMS Advanced Medical Services GmbH Safety Department 
Fax no.: +49-(0)621700 95 950 
Email: safety-C2104@ams-europe.com 
Contact details of Drug Safety at Heel see in section 10.5.1 above. 
The designated CRO and/or Sponsor representative liaise with the Investigator to ensure that all 
relevant information is provided within 24 hours in case of SAEs and within 30 days for pregnancies 
without any complications. 
Pregnancy itself is not considered as AE, but any complications e.g., congenital abnormalities, birth 
defects, and spontaneous miscarriages should be handled and reported as SAEs. 

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11. Statistical Methods and Data Analysis 
 Sample Size Estimation 
Estimation of sample size is based on the demonstration of improved sleep efficiency (SE) in short-
term insomnia patients treated with Neurexan® as assessed by polysomnography. The standard 
deviation (SD) of SE is estimated at 10%. With α= 5%, two-sided and an expected mean difference 
of 6.7% between patients treated with Neurexan® and Placebo, a power of 80% is achieved with 
72 patients. Expecting a dropout rate of 10%, the total number of patients needed is 80.  
 Randomization 
Patients eligible for treatment will be randomized to one of two treatment arms according to a 
computer-generated randomization plan in a ratio of 1:1 and stratification by sex. Placebo tablets 
will be identical in appearance, packaging and labelling to Neurexan®. The randomization schedule 
will be ‘blocked’ to avoid temporal bias.  
Patients’ allocation to treatment will take place after completion of all baseline assessments prior to 
beginning of trial treatment.  
The randomization list will be generated according to the appropriate Standard Operating 
Procedures (SOPs). Sealed copies will be stored by the Trial Statistician and the Sponsor/ Drug 
Safety and will not be opened prior to termination of the double-blinded trial, i.e., after data base 
lock. 
 
 Statistical Planning 
A detailed methodology for summary and statistical analysis of the data collected in this trial will be 
documented in a Statistical Analysis Plan (SAP). This has to be finalized at the latest prior to 
database lock. This document may modify the plans outlined in the protocol; however, any major 
modification of the primary endpoint definition and/or its analysis would also be reflected in a protocol 
amendment to be submitted to the Competent Authorities and Independent Ethics Committee for 
endorsement. 
All programming of tables, figures, listings and statistical analyses will be performed using the 
statistical software package SAS® version 9.4 or higher.  
The statistical planning and evaluation of the trial will be carried out by a qualified biostatistician in 
accordance with the ICH guidelines and adequate biostatistical SOPs. 
 
Definition of Baseline 
The last available information at or prior to Baseline 2/ Day 0 collected before randomization and 
subsequent first IMP intake will be defined as baseline value. For PSG derived parameters the 
baseline is defined as the night from Day -1 to Day 0 (Baseline 2). 
 
 

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Subgroup Analyses 
The following subgroups will be defined: 
• 
Age 
• 
Sex (female/ male) 
• 
Neurexan® responder vs. non-responder  
• 
Duration of short-term insomnia (≤ 1 month, > 1 month) 
• 
Cortisol response influenced by hormonal contraceptives 
Other subgroups may be specified in the SAP or during the Blind Data Review Meeting (BDRM).  
 
Descriptive Analyses 
All variables will be described by treatment group using descriptive statistics. 
For continuous variables the number of observations (n), arithmetic mean, standard deviation (SD), 
minimum, median, 25%-, 75%-quantile, maximum, 95% confidence interval (CI) (2-sided), and the 
number of missing data will be presented.  
For categorical variables n, frequency and percentage, 95% CI (where applicable), and number of 
missing data will be presented. 
11.3.1 Hypothesis 
The null and alternative hypotheses for the comparison of Neurexan® versus Placebo can be 
formulated as follows: 
 
 
 
 
The statistical null hypothesis of no difference between the 2 treatment groups (Neurexan® versus 
Placebo) in terms of the change of sleep efficiency measured by polysomnography from Baseline 2 
to Visit 2 will be tested in a confirmatory sense based on the Intention-To-Treat (ITT) population. The 
test of the null hypothesis will be carried out two-sided. The null hypothesis will be rejected and the 
superiority of a treatment (Neurexan® or Placebo) will be claimed if the p-value will be equal or less 
than 0.05. 
 
Sensitivity Analyses 
Efficacy analyses will be performed with the ITT population and additionally with the Per-Protocol 
Population (PPP) to explore the robustness of the findings. The decision to perform a Per-Protocol 
(PP) analysis will be based on the number of patients excluded from the PPP. If this number is 
sufficiently low (less than 10% of the ITT population), no PP analysis will be performed. This decision 
will be taken prior to database lock.  
Another sensitivity analysis will compare observed cases and data imputed with the last observation 
carried forward (LOCF) method (Section 11.4.3). 
Further on, robustness analyses will include the Wilcoxon rank-sum test. Difference from baseline 
will be used, as appropriate.  
H0: µN = µP 
HA: µN ≠ µP 
H0: Null-hypothesis; HA: Alternative Hypothesis; N: Neurexan®; P: Placebo 
Treatment; µ: mean/ rate of population 

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11.3.2 Analysis Populations 
Analyses will be based on the safety population, ITT population, and the Per-Protocol Population 
(PPP).  
The screening population is defined as all patients who signed informed consent. 
The safety population is defined as all patients who were randomized and received at least one 
dose of investigational medication. All safety analyses will be based on the treatment actually taken 
by the patient (‘as treated’).  
The ITT population is defined as patients who were randomized and received at least one dose of 
investigational medication and had at least one post-dose assessment. 
The Per-Protocol Population (PPP) is defined as all patients who received investigational treatment 
and fulfil the following criteria: 
• 
The absence of any important major protocol deviations 
• 
No technical difficulties during PSG 
• 
Patients who were correctly stratified and received the correct treatment 
• 
Sufficient treatment compliance of 80%-120%. 
Treatment compliance will be defined via the amount of IMP that has been taken between first intake 
at Baseline 2/ second day and last intake at Visit 2/ first day in relation to the amount that should 
have been taken by a patient. 
Protocol deviations will be collected during the entire trial and will be classified as minor or major at 
the BDRM. Protocol deviations that may affect the efficacy outcome of patients will be classified as 
major. The decision about major protocol deviations and assignments to populations will be taken in 
a blinded fashion and will be documented in the BDRM meeting minutes prior to unblinding of the 
trial. 
 Efficacy Analysis 
11.4.1 Primary Efficacy 
The primary efficacy variable for changes in sleep pattern will be sleep efficiency (SE) measured by 
polysomnography at Baseline 2 and Visit 2, calculated as the ratio of total sleep time (TST) to time 
in bed (TIB), as difference at Visit 2 to Baseline 2. Analysis of Covariance (ANCOVA) will be used to 
test the hypothesis of section 11.3.1. The model will include treatment and the stratification factor 
sex and will account for sleep efficiency at baseline as covariate. The test will be performed using a 
Type I error level of 5%, two-sided.  
11.4.2 Secondary Efficacy 
For all secondary variables, exploratory statistics comparing the 2 treatment groups will be 
performed. Difference from baseline will be used, as appropriate. Group comparisons of continuous 
numeric parameters will be tested using an ANCOVA including treatment, the stratification factor 
sex, and the baseline value of continuous numeric parameters as covariate; comparisons of 
dichotomous variables are specified by using the Fisher’s Exact Test.  

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Secondary analyses on efficacy will be exploratory in nature without adjustment for multiplicity. All 
secondary analyses will be performed with two-sided hypotheses on superiority using a Type I error 
level of 5%. 
Secondary efficacy variables are the following: 
Polysomnography at Baseline 2 and Visit 2 
• 
SOL 
• 
WASO 
• 
TST 
• 
NWAK 
• 
Latencies to S1, S2, S3, REM  
• 
Arousal Index (ArI). 
Biochemical parameters 
• 
Resting state cortisol and other stress-related parameters in saliva 
• 
Serum cortisol levels and other stress-related parameters in response to the stress 
induction by CPT 
• 
Stress test induced inflammation parameters in blood serum. 
Actigraphy 
• 
Continuous in-home assessment of sleep 
• 
Daytime activity. 
Patient Questionnaires 
• 
Subclinical Stress Symptom Questionnaire-25 (SSQ-25) 
• 
Primary Appraisal Secondary Appraisal (PASA) 
• 
Perceived Stress Scale-10 (PSS-10) 
• 
Epworth Sleepiness Scale (ESS) 
• 
Würzburg Fatigue Inventory (WEIMuS) 
• 
Short Form-36 (SF-36v2)  
• 
Insomnia Severity Index (ISI) 
• 
Pittsburgh Sleep Quality Index (PSQI) 
• 
Beck's Depression Inventory-II (BDI-II)  
• 
Beck's Anxiety Inventory (BAI). 
Sleep diary (adapted from DGSM) data: subjective SE, SOL, WASO, TST, NWAK 
Continuous digital stress assessments  
Neurexan® response 
Exploratory Efficacy Variables 
• 
EEG based vigilance fluctuations during resting state  
• 
EEG based vigilance fluctuations during CPT 
• 
EEG based asymmetry index during resting state 
• 
EEG based vigilance fluctuations during CPT 
• 
Regional changes in spectral characteristics of EEG during resting state  
• 
Regional changes in spectral characteristics of EEG during CPT 
• 
Cognitive performance in three attentional tasks 

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• 
PSG sleep parameters derived from the two adaptation nights at Baseline 1 and Visit 1. 
 
Correlations between  
• 
Changes in sleep parameters, stress parameters, and daytime performance 
• 
Changes in sleep parameters, stress parameters, and inflammatory parameters 
may be analyzed using Spearman's rank correlation coefficient or other appropriate method.  
 
More details for analyzing the secondary efficacy parameters will be given in the SAP. 
11.4.3 Handling of Missing Data 
In general, for the patient data listings, no imputation of missing or incomplete dates will be applied. 
Data will be presented as collected. 
The last observation carried forward (LOCF) method will impute missing data values using the last 
observation observed prior to the missing value, i.e., the last observation prior to the missing value 
is carried forward to the future missing time point(s). Only on-treatment, post-Baseline 2 observations 
will be used in the LOCF procedure, i.e., baseline values will not be used to impute values. 
A more detailed description of the handling of missing data will be provided in the SAP. 
 Safety Analysis 
Clinical safety will be addressed by assessing AEs, TEAEs, physical examinations, vital signs and 
as needed laboratory assessments in a descriptive manner. AEs and TEAEs will be presented by 
MedDRA Preferred Term and System Organ Class in different categories. Safety analyses will be 
performed with the safety population. All events will be listed. 
Safety variables are: 
• 
AEs 
• 
TEAEs 
• 
Other observations related to safety (physical examinations, vital signs, laboratory 
assessments). 
 
 

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12. Ethical and Regulatory Requirements 
 Independent Ethics Committee (IEC) 
The trial may start as soon as the availability of the consent of the respective Independent Ethics 
Committee (IEC) is available.  
The clinical trial protocol (including all substantial amendments) together with the written informed 
consent form and informed consent updates, patient recruitment procedures (e.g., advertisements), 
any other written information to be provided to patients, and any other documents needed by the 
IEC will be submitted for approval to the IEC which is in charge according to local regulatory 
requirements. Written approval of the trial needs to be obtained from the IEC prior to the start of 
the trial. 
 
Competent Authorities 
In accordance with national legal requirements, all documents required to assess and approve the 
trial will be submitted prior to the start of the trial to the German Competent Authority ‘Bundesinstitut 
für Arzneimittel und Medizinprodukte’ (BfArM) for approval.  
Additionally, all notifications to the local authority of the federal state Thuringia (German: 
Bundesland Thüringen) will be made as laid down in the relevant national regulations. The 
Investigator will receive copies of the substantial submissions and notifications for information. 
An End of Trial notification will be forwarded to the Competent Authorities and the Ethics Committee 
within 90 days after the trial has been completed (defined as Last Patient Last Visit) or in the event 
of premature termination of the trial within 15 days. 
The Competent Authorities and the IEC will be informed of all subsequent protocol amendments 
and of all SUSARs occurring during the trial and all other events that have an impact on the safety 
of the patients or the conduct of the trial. 
Irrespective of the outcome of the clinical trial, the trial results are to be reported within one year 
from the end of the clinical trial to regulatory authorities and published in international databases.  
A summary of the results understandable to laypersons will be made available in the EU database 
irrespective of the outcome of the trial. 
 
Ethical Conduct of the Trial 
The trial will be conducted in accordance with the EU Regulation 536/2014, the ICH guideline for 
Good Clinical Practice (GCP) last adopted December 2016 and the ethical principles laid down in 
the current version of the Declaration of Helsinki. The trial was originally submitted under the EU 
Clinical Trials Directive (EC) No. 2001/20/EC and transitioned in 2024 to the EU Clinical Trials 
Regulation (EU CTR No. 536/2014). Current national regulations and guidelines will also be 
followed. 
 
Patient Information and Consent 
The patients will be informed about the nature and importance of the trial; they will receive a 
detailed description of the foreseeable risks and discomforts and of the procedures to be followed. 
The patients will be informed that they are free to withdraw from the trial at any time without any 
disadvantages. Prior to the start of the trial the patients will agree to the participation in the trial by 
dating and signing the informed consent form. 

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The patients will also agree that data and documents gained through their participation in the trial 
can be checked by clinical monitors or other personnel by the Sponsor as well as by the responsible 
authorities. 
The patient information/ informed consent form must be approved (along with the protocol) by the 
Ethics Committee. Consent must be in a language fully comprehensible to the prospective trial 
participant. Voluntary written informed consent will be obtained from each participant at Screening 
Visit prior to any trial-related procedures. The consent will be signed and dated by the patient and 
by the Investigator who conducted the informed consent interview. All patients will be fully informed 
about the meaning, aim and conduct of the trial. This will take place under conditions where the 
patient has adequate time to consider the risks and benefits associated with his/her participation in 
the trial. The patients will have the possibility to ask all of their questions. 
It is the responsibility of the Investigator to assure that a written informed consent is obtained from 
each trial participant in accordance with International Conference on Harmonisation guidelines on 
Good Clinical Practice (ICH GCP) and local regulations. The signed informed consent will be 
retained onsite with the trial records. Each trial participant will receive a copy of the signed informed 
consent. 
The Investigator should maintain a log of all patients who signed the informed consent form and 
indicate if the patient received investigational drug or, if not, the reason why. The patient’s medical 
records should also document that and when the informed consent form was signed and dated 
prior to any trial-related procedures being performed. 
The eCRF contains a section on which the Investigator will confirm having given proper explanation 
and obtaining the patient’s consent to take part in the trial. 
 
Amendments to the Protocol 
The procedures described in this protocol must be adhered to during the trial. Subsequent 
amendments must be produced in writing and justified. They are subject to the same approval 
process as the protocol itself. Amendments will be distributed with appropriate instructions to all 
persons/ institutions who have received the protocol. For each amendment it is necessary to check 
whether additional explanation to the patient is needed, and whether this qualifies to set up a 
revised patient information/ informed consent form to be submitted to the relevant Ethics 
Committee for its opinion. 
 
Patient Insurance 
In accordance with the relevant national regulations, the Sponsor has taken out a patient liability 
insurance for all patients who have given their consent to participate in the clinical trial. This cover 
is designed for the event that a fatality, physical injury, or damage to health occur during the clinical 
trial’s execution. 
The Sponsor has taken out this patient liability insurance valid for Germany: 
HDI Global SE, HDI-Platz 1, D-30659 Hannover, policy no. 70-509683-03087/390 
 
The policies regarding compensation for injury for patients are described in the compensation 
information leaflet and are available upon request. A copy of the compensation information leaflet 
will be given to the patient upon request in accordance with the country specific requirements. 

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Confidentiality 
Adequate records have to be maintained for the trial, including patient medical records, eCRFs, 
laboratory reports, worksheets, nursing notes, signed informed consent forms, investigational 
product forms, SAE paper forms (to be used in case an eCRF is not available), and information 
regarding patient premature discontinuation (drop out) and reasons for discontinuation. The 
confidentiality of each record with unique patient identification is to be guaranteed by the 
Investigator. 
This clinical trial protocol and other trial documents contain trade secrets and commercial 
information that is privileged and confidential. Such information is not to be disclosed unless 
required by laws or regulations. The Investigator agrees to use this information only in conducting 
this trial and is not allowed to use it for any other purposes without written consent from the 
Sponsor. Results obtained from this trial are the property of the Sponsor. 
 
Serious Breaches 
A serious breach is any deviation of the approved protocol version or the Clinical Trials Regulation 
that is likely to affect the safety, rights of trial participants and/or data reliability and robustness to 
a significant degree in a clinical trial. 
Serious breaches require immediate attention of the Investigator. Any suspected serious breaches 
must be reported to the Sponsor within 24 hours after becoming aware of it using the following 
contact details: 
Emails: C2104@heel.com, drugsafety@heel.com 
Phone: +49 160 88 29 373 
 
13. Data from Patients and Sites: Handling and Record Keeping 
Detailed procedures will be separately provided in the Data Management, Monitoring, and Quality 
Plans. 
 Data Handling 
All data obtained during this clinical trial will be captured electronically in a project-specific 
programmed Electronic Data Capture (EDC) application, also referred to as electronic Case Report 
Form (eCRF). All patient data have to be reported in the eCRF in a pseudonymized form. Patients 
are identified by a unique 7-digit patient identification number starting with 4901- and being 
generated in the eCRF. 
The Investigator will be responsible for the completeness, accuracy, and legibility of the information 
in the eCRF and other trial documents. For documents other than eCRF, only black ballpoint pen 
is to be used and any change of data is to be done by striking out the incorrect data with a single 
line and dating and initialing the changes made. 
The clinical monitors have to verify the eCRF entries according to the source documents. The 
frequency, extent and responsibilities of the monitoring methods are defined in the Monitoring Plan.  
The Investigator must ensure that eCRFs are completed in a timely manner to ensure quality of 
data and to have oversight on patient safety. The Investigator has to electronically sign it off. 

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A copy of the eCRF including audit trail is to be archived by the Investigator together with the trial 
documents, source data, and laboratory records (if applicable) for the time required by relevant 
guidelines and national regulations. Any evaluations documented on paper will be entered into the 
eCRF. The original entries on paper documents, including those completed by the patient, will be 
considered source data. 
 Monitoring 
To ensure compliance an onsite visit will be held prior to initiation of patient recruitment (Site 
Initiation Visit). The protocol, eCRFs, trial treatment supplies, handling of trial medication, and other 
trial procedures will be explained in detail. 
A clinical monitor assigned by the designated CRO will conduct regular onsite visits for the purpose 
of clinical monitoring to ensure that the rights and wellbeing of patients are protected; that trial data 
are accurate, complete, and verifiable with source data; and that the trial is conducted in 
compliance with the protocol, GCP, and the applicable regulatory requirements. 
The Investigator must agree to allow the appointed monitor and other authorized representatives 
of the designated CRO and/or the Sponsor to inspect all eCRFs and corresponding source 
documents (e.g., original medical records, patient records and other relevant records); to allow 
access to the investigational product and other clinical supplies, dispensing, and storage areas; 
and to agree to assist with their activities, if requested. The Investigator should provide adequate 
time and facilities for monitoring visits. 
The monitor will query any missing or spurious data with the Investigator, which should be resolved 
in a timely manner. A monitoring log will be maintained to record each visit of the monitor, the 
reason for the visit, the monitor’s signature, and the Investigator’s or designee’s confirmation 
signature. 
During the Site Initiation Visit the monitor explains to the Investigator all the documents and 
procedures related to this trial. A detailed description of monitoring is defined in the Standard 
Operating Procedures (SOPs) of the designated CRO and in the Monitoring Plan. 
Regular onsite monitoring visits are carried out at appropriate intervals in order to clarify questions 
and to review all eCRFs in terms of completeness and plausibility and to perform Source Data 
Verification (SDV). Remote monitoring might be performed if appropriate. Details as frequency, 
extent and responsibilities of the monitoring methods are defined in the Monitoring Plan. 
The Investigator has to maintain these data up to date and well documented in the medical files 
(‘source’). 
Personnel changes at the Investigator’s site and changes in responsibilities must be notified 
immediately. 
The following is also constantly monitored: the trial’s logistic workflow, compliance with regulations 
and the trial medication(s) handling. 
The monitor is the Investigator’s permanent contact person. Unusual incidents will be documented 
immediately and forwarded to the Sponsor Project Manager. 
The remaining trial medication will be returned to the Sponsor whenever requested by the Sponsor, 
but at the latest on or shortly after the clinical trial’s completion. 

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 Data Management 
The designated CRO will perform the activities associated with the Data Management of this trial, 
including the production of an eCRF, setting up a relevant clinical database, along with appropriate 
validation of data and resolution of queries. All data will be entered into the eCRF. Automated and 
manual checks will be made against the data to ensure completeness and consistency. Resolution 
of queries will be implemented in the clinical database. 
13.3.1 Source Data 
For every patient, the original patient’s file (“source”) should clearly document at least: 
• 
Last and first name 
• 
Date of birth 
• 
Sex 
• 
Date of the consent form signature 
• 
Date of entry in the trial (Screening Visit) 
• 
Trial protocol number (C2104) 
• 
Diagnosis of short-term insomnia 
• 
Concomitant diseases and medication taken at entry in the trial (Screening Visit) 
• 
Concomitant medication during the trial 
• 
Date of each trial visit 
• 
Date and time of all trial-related measurements 
• 
Date and time of IMP distribution (Baseline 2/ Day 0) 
• 
Paper-based patient-reported outcomes (PROs, completed questionnaires) 
• 
AEs and changes in the concomitant therapy throughout the trial 
• 
End of Trial Treatment and End of Trial status 
• 
Date of the trial termination (Follow-up Visit/ Day 28, in case of premature withdrawal/ Drop Out 
the reason must be indicated). 
The Investigator will permit trial-related monitoring, audits, and regulatory inspections, providing 
direct access to all source data/ documents. All persons involved are bound to maintain strict 
confidentiality concerning the identification of the patients. 
13.3.2 Electronic Case Report Form (eCRF) 
All data obtained during this clinical trial will be captured electronically in a project-specific 
programmed EDC application, also referred to as electronic Case Report Form (eCRF). The eCRF 
is specifically designed for the collection of the clinical data detailed in this trial protocol. The EDC 
application used for this trial is the Clinical Data Management System Clincase® (supplied by 
Quadratek Data Solutions Ltd (Clincase®), which is fully validated and compliant with United States 
Food and Drug Administration (FDA) 21 Code of Federal Regulations (CFR) part 11). The project-
specific eCRF will be subjected to system validation according to Good Automated Manufacturing 
Practice (GAMP) 5 prior to go live. Only authorized staff will have access to the EDC system via a 
secure website (Secure Sockets Layer [SSL] encryption), using unique user name and password. 
Data will be entered into eCRFs in accordance with instructions from the Sponsor and/or designee. 
Data captured on standardized paper questionnaires, obtained in interviews (e.g., anamnestic data, 
concomitant diseases, concomitant medications, adverse events, etc) or laboratory results from 
safety laboratory assessments will be entered into eCRFs by the Investigator or authorized site 

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staff. Each Investigator is responsible for ensuring that accurate data are entered into the EDC 
system in a timely manner and are assigned to the correct patient. The Investigator confirms this 
by electronically signing the documentation, equivalent to a traditional handwritten signature. Each 
initial data entry, each data modification (incl. reason for change), as well as all actions in the eCRF 
are tracked in an audit trail, including username, date and time. 
13.3.3 Direct Entries 
The eCRF itself will be the source for the following data (Direct Entry) as defined by the Monitoring 
Plan, e.g.: 
• 
Pregnancy test results 
• 
Breath alcohol and urine drug test results 
• 
Physical examination results 
• 
Vital signs. 
13.3.4 Coding 
AEs will be standardized for terminology and classification, using MedDRA (the latest available 
version at trial start will be used for the entire duration of the trial). 
Concomitant medical conditions and medical history terms will be standardized for terminology and 
classification, using the most current MedDRA Dictionary Version at First Patient First Visit 
(Version 26.0). 
Concomitant drugs will be standardized for terminology and classification using World Health 
Organization (WHO)-Drug Dictionary (version B3 Global of March 2023). Both coding dictionaries 
will be updated to the recent version prior to final analysis.  
13.3.5 Confidentiality of Personal Data 
The Investigators, the designated CRO, and the Sponsor will preserve the confidentiality of all 
patients taking part in the trial, in accordance with ICH GCP and local regulations. During this trial, 
all clinical data will be collected and stored only pseudonymously.  
The confidentiality of all patient identities will be maintained except during onsite Source Data 
Verification (SDV), when clinical monitors, auditors, and other authorized agents of the Sponsor or 
its designee, as well as any other applicable regulatory authorities, will be granted direct access to 
the trial patients' original medical records.  
No material bearing a patient’s name will be kept on file by the designated CRO or Sponsor. The 
data retained from this trial will be protected in accordance with all applicable legal requirements. 
 Record Keeping 
The Investigator agrees to retain copies of the eCRF, the Investigator Site File and other relevant 
trial-related documents (e.g., the protocol and any protocol amendments, the IMP reference safety 
information, IEC approval, signed patient informed consent forms, and source documents for each 
patient in the trial) in a secure place as long as needed to comply with national and international 
regulations. 
The Investigator has to archive all essential records and documents for 25 years as specified by 
EU regulation 536/2014. According to ICH GCP, these documents have to be retained until at least 

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2 years after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the trial medication (ICH GCP 
section 4.9.5). 
The Investigator will be informed by the Sponsor when the documents need not to be retained any 
longer. The Investigator will inform the Sponsor of the storage location of the essential documents 
and must contact the Sponsor for approval before disposing of any. The Investigator should take 
measures to prevent accidental or premature destruction of these documents. 
In case the Investigator retires, relocates, or for any other reason withdraws from the responsibility 
for maintaining records for the period of time required, custody of the records has to be transferred 
to any other person who accepts responsibility for the records, e.g., another Investigator, or the 
Sponsor. Notice of such transfer has to be given in writing to the Sponsor. 
13.4.1 Investigator Site File (ISF) 
The Investigator will be provided with an Investigator Site File (ISF). In the ISF the Investigator will 
store those documents necessary for the clinical trial. As part of the monitoring procedures, the ISF 
will be checked for up to date information and completeness in accordance with the national and 
international regulations. 
The Investigator records in the Patient Identification Log the following details for all persons giving 
their consent to participate in the trial: name (first and surname), date of birth and the assigned 
unique 7-digit trial patient number. The Screening Visit date must also be documented. This Patient 
Identification Log allows patients identification and remains onsite with the Investigator. 
All trial documentation, including the Patient Identification Log, will be properly archived in 
accordance with the Sponsor’s instructions. 
 
14. General Regulations, Agreements and Organizational Procedures 
 Responsibilities of the Investigator (Among Others) 
The Investigator agrees to carry out the trial in accordance with the guidelines and procedures 
outlined in this clinical trial protocol. The Investigator especially consents to strictly adhere to the 
ethical principles (see section 12 of this protocol). 
The Investigator knows that he/she must, according to professional regulations for physicians, 
obtain the approval of the Ethics Committee.  
Any deviation from the trial protocol must, before its implementation, be agreed by the Sponsor in 
writing, and by the Ethics Committee initially consulted.  
Changes to the protocol require a written ‘amendment to the protocol’ and written approval by the 
Coordinating/ Principal Investigator. Changes are allowed only if they are ethically justifiable. The 
amendment must be passed on to all participating Investigators with the obligation to adhere to its 
provisions. If warranted, the patient information has to be changed accordingly.  
It is within the responsibility of the Investigator that an eCRF is completed consecutively and signed 
after the patient has finished the trial for each patient participating in the trial. All data that the 
Investigator provides to the Sponsor or its delegate(s) will be verified and signed by the Investigator 

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or his adequately qualified Deputy. Verification and signature will take place on an ongoing basis 
for each relevant data section (e.g., newly completed visit in a given patient).  
All entries on paper must be made in black ballpoint pen; corrections are made by placing a single 
horizontal line through the incorrect entry, so that it can still be seen, and placing the revised entry 
beside it. The revised entry must be filled in, initialed and dated by a member of the Investigator's 
research team authorized to make paper entries. Correction fluid must not be used. 
Upon Sponsor’s request or latest at the conclusion of the trial, the Investigator will return all partly 
used, unused and empty drug containers to the Sponsor. 
By signing this protocol, the Investigator confirms that he/she has read the entire trial protocol, 
agrees to its procedures, and will comply strictly with the formulated guidelines. 
 Audits and Inspections 
In the interests of quality assurance, independent experts appointed by the Sponsor may carry out 
audits during the clinical trial’s implementation phase and after its completion. In conjunction with 
the audit it may also be examined whether the planning, implementation and analysis of the clinical 
trial meets the relevant statutory regulations and the requirements of GCP. This includes a review 
of data maintenance and organization at the investigational site, inspection of equipment and 
laboratories and of the source documents. The Investigator will permit direct access to all trial 
documents, drug accountability records, medical records, and source data. 
Regulatory Authorities may perform an inspection of the trial, even up to several years after its 
completion. If an inspection is announced, the Sponsor must be informed immediately. 
 Final Report and Publication/ Registry 
An integrated Clinical Trial Report in accordance with the ICH Harmonized Tripartite Guideline (E3) 
(Structure and content of clinical study reports) will be developed. 
14.3.1 Confidentiality 
Any information provided by the Sponsor related to this trial and all data and records generated in 
the course of the trial conduct, in particular the objectives and contents of this clinical trial as well 
as its results are to be treated as confidential and may not be made accessible to third parties. All 
aforementioned information, data or records shall not be used for any other purpose than 
conducting the trial without prior written approval of the Sponsor. If confidential information will be 
disclosed to employees participating in the trial, the disclosing person shall ensure that the 
respective employees are bound by this confidentiality obligation. 
14.3.2 Data Ownership 
All data and records provided by the Sponsor or generated during the trial (other than patient’s 
medical records) and all data and inventions discovered in the course of conducting the trial, 
whether patentable or not, are the sole and exclusive property of the Sponsor to the extent legally 
possible. 
14.3.3 Publications  
Any publication of the results, either in part or in total, will require the prior written agreement of the 
Coordinating/ Principal Investigator and the Sponsor. With this written agreement the Coordinating/ 

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Principal Investigator and Sponsor will engage to form a Publication Steering Committee to the 
extent it is necessary, composed of all relevant stakeholders, the Coordinating/ Principal 
Investigator, Sponsor and other parties as needed and publish the primary clinical trial manuscript 
within 18 months from trial completion. All parties to follow Good Publication Practice and 
(CONsolidated Standards of Reporting Trials) CONSORT guidelines in planning, writing and 
approving publications. The Publication Steering Committee will determine the publication strategy 
and plan, and will also invite relevant stakeholders including Sponsor to author publications 
according International Committee of Medical Journal Editors (ICMJE) authorship criteria. 
Publication authors will draft and approve the congress abstracts, manuscripts and/or other 
publications. Professional medical writers may be involved to support authors. 
 

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15. References 
 
Burnier, M. (2018). "Hypertension Guidelines." European Heart Journal 39(11): 908-910. 
CTFG Clinical Trials Facilitation and Coordination Group (2020). “Recommendations related to 
contraception and pregnancy testing in clinical trials”. CTFG 21/19/2020 version 1.1. 
Cohen, S., T. Kamarck and R. Mermelstein (1983). "A global measure of perceived stress." J Health 
Soc Behav 24(4): 385-396. 
Davies, H., G. R. Bignell, C. Cox, P. Stephens, S. Edkins, S. Clegg, J. Teague, H. Woffendin, M. J. 
Garnett, W. Bottomley, N. Davis, E. Dicks, R. Ewing, Y. Floyd, K. Gray, S. Hall, R. Hawes, 
J. Hughes, V. Kosmidou, A. Menzies, C. Mould, A. Parker, C. Stevens, S. Watt, S. Hooper, 
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16. 
Appendices 
None