Perceived Changes in Symptom Burden and Physiological Effects of a Proprietary Phyto-therapeutic Preparation (Amara) in Patients With Functional Dyspepsia: Prospective Study as Investigator Initiated Trial (IIT)
Phase: PHASE4
Conditions: Dyspepsia
Sponsor: Mark Fox

 
 
 
Perceived Changes in Symptom Burden and 
physiological effects of a proprietary phyto-
therapeutic preparation (Amara) in patients with 
functional 
dyspepsia: 
Prospective 
study 
as 
Investigator Initiated Trial (IIT) 
 
Deutsch:  
Subjektive Veränderungen der Symptombelastung und physiologische Wirkungen 
eines 
proprietären Phytotherapeutikums 
(Amara 
Tropfen) bei 
Patienten mit 
funktioneller Dyspepsie (Reizmagensyndrom): „Eine prospektive, Prüfer-initiierte 
Studie (IIT)“ 
 
Short title: Amara-Tropfen beim Reizmagensyndrom 
 
Study Type: 
Intervention Study as an Investigator-Initiated Trial (IIT), Phase IV 
Study Categorisation: 
Risk category according to HRA: A  
Study Registration: 
Clinicaltrials.gov ID: NCT05553587  
Study Identifier: 
Amara-KLA-01-22 
Sponsor, Sponsor-Investigator 
or Principal Investigator: 
Prof Dr med Mark Fox  
Facharzt für Gastroenterologie und Innere Medizin 
Leitender Arzt, Zentrum für Integrative Gastroenterologie 
Leiter, Magen Darm Funktion: Basel, Labor und Klinik für funktionelle 
Magendarm Erkrankungen und Motilitätsstörungen 
Klinik Arlesheim, Pfeffingerhof 1, 4144 Arlesheim 
Tel. +41 (0)76 3580379 
mark.fox@klinik-arlesheim.ch 
Investigational Product: 
Amara drops “a balanced mixture of medicinal plants with tonic and 
aromatic bitter substances, suitable for stimulating digestion” 
Protocol Version and Date: 
Version 1.4 10.11.2023 
 
 
 
CONFIDENTIAL 
The information contained in this document is confidential and the property of the sponsor. The 
information may not - in full or in part - be transmitted, reproduced, published, or disclosed to others 
than the applicable Competent Ethics Committee and Regulatory Authority without prior written 
authorisation from the sponsor except to the extent necessary to obtain informed consent from those 
who will participate in the study. 
 
 

 
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Page 2 of 39 
Version control 
 
Version 
Nr 
Version date 
Modified 
without version 
change 
Protocol Description, comments 
Control 
1.0 
22.03.2022 
 
Original version in English.  
MF 
1.0 
16.04.2022 
 
Updated to include minor edits requested by collaborators MF 
1.1 
16.06.2022 
 
Updated to address minor issues raised by ethics 
commission 
MF 
1.3 
14.09.2023 
 
Inclusion criteria modified to improve recruitment and 
updated to address minor issues requested by 
collaborators 
 
1.4 
10.11.2023 
 
Addition 
of 
further, 
non-invasive 
physiological 
measurements, specifically gastric electrical activity 
acquired by the Gastric Alimetry System (High 
Resolution 
Gastric 
Mapping 
/ 
Electro-
gastrography). Concurrent measurement of heart 
rate will also be obtained  
Inclusion criteria modified / clarified in regard to 
assessment of dyspeptic symptoms by the LDQ and 
psychological state by HADS. 
Timeline of study extended to September 2024 
 
 
 
 

 
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SIGNATURE PAGE 
 
Study number  Amara-KLA-01-22 
 
StudyTitle 
Perceived Changes in Symptom Burden and physiological effects of a 
proprietary phyto-therapeutic preparation (Amara) in patients with 
functional dyspepsia: Prospective study as Investigator Initiated Trial (IIT) 
 
The Sponsor-investigator has approved the protocol version (V1.3 14.09.2023) and confirm 
hereby to conduct the study according to the protocol, current version of the World Health 
Association Declaration of Helsinki, ICH-GCP guidelines or ISO 14155 norm if applicable 
and the local legally applicable requirements. 
 
Sponsor-Investigator: Prof. Dr. med. Mark Fox 
 
 
14.09.2023 
 
 
 
 
Place/Date 
 
Signature 
 
 
 
 
 
 
 
 
 
 
Local Principal Investigator at study site*: 
 
I have read and understood this trial protocol and agree to conduct the trial as set out in 
this study protocol, the current version of the World Health Association Declaration of 
Helsinki, ICH-GCP guidelines or ISO 14155 norm if applicable and the local legally 
applicable requirements. 
 
 
Site: 
 
 
Klinik Arlesheim, Pfeffingerhof 1, 4144 Arlesheim 
Principal Investigator:  Prof. Dr. med. Mark Fox 
 
14.09.2023 
 
 
 
 
Place/Date 
 
Signature 
 
 
 
 
 

 
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TABLE OF CONTENTS 
STUDY SYNOPSIS ................................................................................................................................. 7 
ABBREVIATIONS ................................................................................................................................. 13 
STUDY SCHEDULE .............................................................................................................................. 14 
1. 
STUDY ADMINISTRATIVE STRUCTURE .................................................................................... 15 
1.1 
Sponsor, Sponsor-Investigator .................................................................................................... 15 
1.3 
Principal Investigator(s) ............................................................................................................... 15 
1.3 
Statistician ("Biostatistician") ....................................................................................................... 15 
1.4 
Laboratory ................................................................................................................................... 15 
1.5 
Monitoring institution ................................................................................................................... 15 
1.6 
Data Safety Monitoring Committee ............................................................................................. 15 
1.7 
Any other relevant Committee, Person, Organisation, Institution ............................................... 16 
2. 
ETHICAL AND REGULATORY ASPECTS .................................................................................. 16 
2.1 
Study registration ........................................................................................................................ 16 
2.2 
Categorisation of study................................................................................................................ 16 
2.3 
Competent Ethics Committee (CEC) .......................................................................................... 16 
2.4 
Competent Authorities (CA) ........................................................................................................ 16 
2.5 
Ethical Conduct of the Study ....................................................................................................... 16 
2.6 
Declaration of interest ................................................................................................................. 17 
2.7 
Patient Information and Informed Consent ................................................................................. 17 
2.8 
Participant privacy and confidentiality ......................................................................................... 17 
2.9 
Early termination of the study ...................................................................................................... 17 
2.10 Protocol amendments ................................................................................................................. 17 
3. 
BACKGROUND AND RATIONALE .............................................................................................. 18 
3.1 
Background and Rationale .......................................................................................................... 18 
3.2 
Investigational Product (treatment) and Indication ...................................................................... 19 
3.3 
Preclinical Evidence .................................................................................................................... 19 
3.4 
Clinical Evidence to Date ............................................................................................................ 19 
3.5 
Dose Rationale ............................................................................................................................ 20 
3.6 
Explanation for choice of comparator (or placebo) ..................................................................... 20 
3.7 
Risks / Benefits ............................................................................................................................ 20 
3.8 
Justification of choice of study population ................................................................................... 20 
4. 
STUDY OBJECTIVES ................................................................................................................... 21 
4.1 
Overall Objective ......................................................................................................................... 21 
4.2 
Primary Objective ........................................................................................................................ 21 
4.3 
Secondary Objectives ................................................................................................................. 21 
4.4 
Safety Objectives ........................................................................................................................ 22 
5. 
STUDY OUTCOMES ..................................................................................................................... 22 
5.1 
Primary Outcome ........................................................................................................................ 22 
5.2 
Secondary Outcomes .................................................................................................................. 22 
5.3 
Other Outcomes of Interest ......................................................................................................... 23 
5.4 
Safety Outcomes ......................................................................................................................... 23 
6. 
STUDY DESIGN ............................................................................................................................ 23 
6.1 
General study design and justification of design ......................................................................... 23 
6.2 
Methods of minimising bias ......................................................................................................... 25 
6.2.1 Randomisation .................................................................................................................... 25 

 
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6.2.2 Blinding procedures ............................................................................................................ 25 
6.2.3 Other methods of minimising bias ....................................................................................... 25 
6.3 
Unblinding Procedures ................................................................................................................ 25 
7. 
STUDY POPULATION .................................................................................................................. 25 
7.1 
Eligibility criteria ........................................................................................................................... 25 
7.2 
Recruitment and screening ......................................................................................................... 25 
7.3 
Assignment to study groups ........................................................................................................ 26 
7.4 
Criteria for withdrawal / discontinuation of participants ............................................................... 26 
8. 
STUDY INTERVENTION ............................................................................................................... 26 
8.1 
Identity of Investigational Products (treatment / medical device) ................................................ 26 
8.1.1 Experimental Intervention (treatment / medical device) ...................................................... 26 
8.1.3 Control Intervention (standard/routine/comparator treatment / medical device) ................ 26 
8.1.3 Packaging, Labelling and Supply (re-supply) ..................................................................... 26 
8.1.4 Storage Conditions.............................................................................................................. 27 
8.2 
Administration of experimental and control interventions ........................................................... 27 
8.2.1 Experimental Intervention ................................................................................................... 27 
8.2.2 Control Intervention ............................................................................................................. 27 
8.3 
Dose modifications ...................................................................................................................... 27 
8.4 
Compliance with study intervention ............................................................................................. 27 
8.5 
Data Collection and Follow-up for withdrawn participants .......................................................... 27 
8.6 
Trial specific preventive measures .............................................................................................. 27 
8.7 
Concomitant Interventions (treatments) ...................................................................................... 27 
8.8 
Study Drug Accountability ........................................................................................................... 27 
8.9 
Return or Destruction of Study Drug ........................................................................................... 28 
9. 
STUDY ASSESSMENTS ............................................................................................................... 29 
9.1 
Study flow chart(s) / table of study procedures and assessments .............................................. 29 
9.2 
Assessments of outcomes .......................................................................................................... 30 
9.2.1 Assessment of primary outcome ......................................................................................... 30 
9.2.2 Assessment of secondary outcomes .................................................................................. 30 
9.2.3 Assessment of other outcomes of interest .......................................................................... 30 
9.2.4 Assessment of safety outcomes ......................................................................................... 30 
9.2.5 Assessments in participants who prematurely stop the study ............................................ 30 
9.3 
Procedures at each visit .............................................................................................................. 30 
9.3.1 Screening visit ..................................................................................................................... 30 
9.3.2 Study visits .......................................................................................................................... 31 
10. SAFETY ......................................................................................................................................... 31 
10.1 Drug studies ................................................................................................................................ 31 
10.1.1 Definition and assessment of (serious) adverse events and other safety related events .. 31 
10.1.3 Reporting of serious adverse events (SAE) and other safety related events ..................... 32 
10.1.3 Follow up of Serious Adverse Events ................................................................................. 33 
11. STATISTICAL METHODS ............................................................................................................. 33 
11.1 Hypothesis ................................................................................................................................... 33 
11.3 Determination of Sample Size ..................................................................................................... 33 
11.3 Statistical criteria of termination of trial ....................................................................................... 34 
11.4 Planned Analyses ........................................................................................................................ 34 
11.4.1 Datasets to be analysed, analysis populations ................................................................... 34 

 
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11.4.2 Primary Analysis ................................................................................................................. 34 
11.4.3 Secondary Analyses ........................................................................................................... 34 
11.4.4 Interim analyses .................................................................................................................. 34 
11.4.5 Safety analysis .................................................................................................................... 35 
11.4.6 Deviation(s) from the original statistical plan ...................................................................... 35 
11.5 Handling of missing data and drop-outs...................................................................................... 35 
12. QUALITY ASSURANCE AND CONTROL .................................................................................... 35 
12.1 Data handling and record keeping / archiving ............................................................................. 35 
12.1.1 Case Report Forms ............................................................................................................. 35 
12.1.3 Specification of source documents ..................................................................................... 35 
12.1.3.  
Record keeping / archiving ........................................................................................... 35 
12.2 Data management ....................................................................................................................... 36 
12.2.1 Data Management System ................................................................................................. 36 
12.2.2 Data security, access and back-up ..................................................................................... 36 
12.2.3 Analysis and archiving ........................................................................................................ 36 
12.2.4 Electronic and central data validation ................................................................................. 36 
12.3 Monitoring .................................................................................................................................... 36 
12.4 Audits and Inspections ................................................................................................................ 36 
12.5 Confidentiality, Data Protection ................................................................................................... 36 
12.6 Storage of biological material and related health data ................................................................ 37 
13. PUBLICATION AND DISSEMINATION POLICY.......................................................................... 37 
14. FUNDING AND SUPPORT ............................................................................................................ 37 
14.1 Funding ....................................................................................................................................... 37 
14.2 Other Support .............................................................................................................................. 37 
15. INSURANCE .................................................................................................................................. 37 
16. REFERENCES ............................................................................................................................... 37 
17. APPENDIX ..................................................................................................................................... 39 
 
 
 

 
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STUDY SYNOPSIS   
 
Sponsor-Investigator 
Prof. Dr. med. Mark Fox  
Leitender Arzt, Zentrum für Integrative Gastroenterologie 
Leiter, Magen Darm Funktion: Basel, Labor und Klinik für funktionelle 
Magendarm Erkrankungen und Motilitätsstörungen 
Study Title: 
Perceived Changes in Symptom Burden and physiological effects of a 
proprietary phyto-therapeutic preparation (Amara) in patients with 
functional dyspepsia: Prospective study as Investigator Initiated Trial (IIT) 
Short Title / Study ID: 
Amara bei Dyspepsie, Amara-KLA-01-22 
Protocol Version and 
Date: 
Version 1.4, 10.11.2023 
Trial registration: 
Clinicaltrials.gov ID: NCT05553587  
Study category and 
Rationale 
Risk category A acc. to ordinance HRO Art.7 
The investigational drug is approved with a reduced dossier without 
indication according to Art. 25 para. 1 KPAV (SR 812.212.24). This study 
follows the indication text licensed by Swissmedic: “… Weleda Amara-
Drops can be used for digestive complaints such as heartburn, flatulence 
and bloating after meals, to stimulate the bile flow and for loss of appetite 
and nausea. The effect of Weleda Amara drops is based on a balanced 
mixture of medicinal plants with tonic (invigorating) and aromatic bitter 
substances, which are suitable for stimulating digestion.” Further, no side 
effects have been reported in past studies so far. All these reasons lead 
us to the conclusion that this study is only associated with minimal risks 
and should be classified in risk category A. 
Clinical Phase: 
Confirmatory Trial (Phase IV) 
Background and 
Rationale: 
Functional dyspepsia (FD) with postprandial distress is a common 
functional gastrointestinal (GI) disorder characterized by the occurrence 
of epigastric symptoms such as early satiety (fullness), nausea and 
upper abdominal pain after meals at least twice a week over at least six 
months (Rome IV criteria). By definition, no structural disease is found 
on routine endoscopy or imaging studies. Instead, symptoms are thought 
to be related to abnormal gastrointestinal motility (e.g., impaired gastric 
relaxation, abnormal emptying) and increased sensitivity to gastric 
distension and the digestive process. Additionally, detailed studies of the 
mucosa often reveal low-grade inflammation in the duodenum and 
hyperpermeability (“leaky gut”). 
Epidemiological studies report a 10-30% prevalence of functional 
dyspepsia (FD) worldwide. When dyspeptic symptoms are short in 
duration and relatively mild, many patients wish to self-manage with 
dietary adaptation and /or over the counter (OTC) preparations. Others 
report high rates of intolerance to prescription medications. In these 
patients complementary and alternative medicines (CAM) based on 
natural products, such as plant-based “phytotherapy”, are particularly 
appealing. Several herbal therapies for functional dyspepsia have been 
tested in randomized clinical studies. These include phytochemicals 
such as peppermint oil that inhibits smooth muscle contraction by direct 
blockade of calcium channels and other effects, deglycyrrhizinated 
licorice that increases gastric mucus secretion and may enhance 
mucosal protection and other preparations that combine multiple herbal 
products with the intention of inducing synergistic effects that promote 
normal digestive function. In particular, STW-5 (Iberogast, Bayer) has 

 
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Page 8 of 39 
been shown to have physiological effects on gastric accommodation and 
contractility. A double-blind non-inferiority randomized control trial (RCT) 
comparing Iberogast to cisapride (5-HT4 agonist) showed equal 
effectiveness for both medications. More recently, a meta-analysis of 3 
double blind RCTs provided evidence that Iberogast is more effective 
than placebo to improve dyspeptic symptoms. 
Amara tincture (Weleda, Arlesheim, Switzerland) is a proprietary 
preparation used for many decades in complementary medicine that is 
marketed for the treatment of functional digestive disorders. Patients take 
10-20 drops before meals to relieve loss of appetite, bloating, nausea, and 
other dyspeptic symptoms. These bitter substances are thought to 
promote digestion and relieve symptoms by stimulating the secretion of 
gastric and pancreatic enzymes, upper gastrointestinal motility and gastric 
emptying. These prokinetic effects may be therapeutic in patients with 
functional dyspepsia because there is an association between optimally 
measured delayed gastric emptying (GE) and upper gastrointestinal 
symptoms. To date, the effect of Amara has not been subjected to pre-
clinical or clinical studies. 
The primary aim of this investigator-initiated, prospective, open-label 
therapeutic study is to assess perceived changes in symptom burden 
reported by patients with functional dyspepsia treated with Amara. 
Additionally, the physiological effects of Amara on gastric motor and 
sensory function will be assessed using validated methods. 
Protocol Summary 
A prospective, open label, non-randomized study will assess  
(i) 
Perceived changes in symptom burden reported by patients 
during regular intake of 10-20 Amara Drops before main 
meals using the validated Leuven Dyspepsia Score.  
(ii) 
Physiological effects of 20 drops Amara tincture on gastric 
emptying using the 400ml Nottingham Test Meal with non-
radioactive 13C-acetate breath test and concurrent 
assessment of filling sensation and dyspeptic symptoms by 
Visual Analogue Scores (VAS). 
(iii) 
In a subset of 20 consecutive patients, the 13C-acetate 
breath test will be combined with measurements of gastric 
electrical activity acquired by the Gastric Alimetry System 
(High Resolution Gastric Mapping / Electro-gastrography). At 
the same time heart rate monitoring will be obtained.  
Individuals that fulfill the diagnostic criteria for functional dyspepsia with 
postprandial distress syndrome according to the Rome IV criteria will be 
recruited. At the first study visit (Study Visit #1), Symptom questionnaires 
and other questionnaires to assess general gastroenterological health and 
psychiatric well-being will be completed at the time of recruitment. The 
questionnaires will be sent via e-mail to a patient. The e-mail contains a 
secure link to the questionnaires. The questionnaires will be filled in on a 
patient’s smartphone Additionally, the Lüscher Color Test (LCT) will be 
performed. This non-verbal, non-written test has been developed to 
assess patient’s personality and psychiatric state. This could be of interest 
in patients with disorders of brain-gut interaction that may not admit to the 
role of central factors in their illness. 
Eligible patients will have no clinically relevant medical co-morbidity or 
previous major gastrointestinal surgery (appendectomy, hysterectomy, 
cholecystectomy, hernia repair are not exclusion criteria) and must have 
had a normal upper gastrointestinal pan-endoscopy in the previous 3 
years. If not known, Helicobacter pylori status will be assessed by 13C-
stool antigen test (endoscopy not required). Gastric function will be 
assessed by 13C-breath test measurements with concurrent 
measurements of visceral sensitivity. A 2-4 week run-in period follows 

 
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Page 9 of 39 
the first study visit (no new treatments during this period). The presence 
and severity of dyspeptic symptoms will be reported every day using an 
on-line application downloaded on the patient’s smart phone (an 
electronic reminder will be sent at 21:00 every day). 
The LCT will be repeated during the second study visit (Study Visit #2), 
At this time, gastric function will be assessed by 13C-breath test 
measurements with concurrent high-resolution electro-gastrography 
(Gastric Alimetry System) and heart rate monitoring plus assessment of 
visceral sensitivity after ingestion of a validated 400ml liquid “Nottingham 
Test Meal (NTM)”.  
Amara Drops will be dispensed with 10-20 drops (0.25-0.50ml) taken 
three times a day prior to meals for 4 weeks. Patients are free to vary the 
dose between these limits as considered appropriate. The amount taken 
will be monitored by checking the volume remaining in the bottle at the 
end of the 4-week intervention. During this time, patients will continue 
reporting the presence and severity of dyspeptic symptoms and any side 
effects into the app.  
At the end of the study period (Study Visit #3) the questionnaires 
including LCT and the 13C-breath test measurement with concurrent 
high-resolution electro-gastrography (Gastric Alimetry System) and heart 
rate monitoring plus concurrent assessment of visceral sensitivity will be 
repeated. Additionally, the patients will be asked if their global 
satisfaction was better on Amara treatment, whether they wish to 
continue treatment and /or recommend the treatment to others with 
similar symptoms. Questionnaires and diary entries on side effects are 
also available as paper version.  
Risk / Benefit 
Assessment 
The initial assessment of patients with functional dyspepsia will adhere 
to international guidelines on the investigation of this condition. Amara 
Drops (Weleda) is a proprietary preparation that has been marketed over 
the counter (OTC) for many years. No serious side effects have been 
reported. 13C-breath test gastric emptying studies and other 
measurements of gastric function (e.g. electro-gastrography) are 
indicated in patients with functional dyspepsia that do not respond to 
first-line, dietary management, and empirical treatment. These tests are 
non-invasive and not radioactive and is associated with no adverse 
outcomes. Clinical validation studies report that the intake of the 400ml 
(300kcal) Nottingham Test Meal is tolerated by all healthy controls and 
>95% of patients with functional dyspepsia without inducing vomiting. 
Objectives: 
The aim of the present study is to find out if the regular intake of Amara 
has effects on the perceived symptom burden reported by patients with 
functional dyspepsia. Since dyspeptic symptoms may be associated with 
abnormal gastric motor and sensory function, these aspects will be 
assessed by validated methods.  

 
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Outcomes: 
Primary objective / outcome measure:  
 
change in perceived symptom burden during regular intake of 
Amara assessed by the Leuven Dyspepsia Score between visit 1 
(off treatment) and 3 (on treatment).  
 
Secondary objectives / outcome measures 
 
Assess effect of Amara on other gastrointestinal symptoms using 
validated, patient related outcome measurements (reflux disease 
questionnaire, IBS Symptom Severity Score) 
 
Assess effect of Amara on (i) visceral sensitivity and (ii) gastric 
emptying (13C-breath test) in patients with functional dyspepsia 
with validated 400ml Liquid Nottingham Test Meal. 
 
Assess effect of Amara on pre- and post-prandial gastric 
electrical activity (Gastric Alimetry System) and heart rate in 
patients with functional dyspepsia with validated 400ml Liquid 
Nottingham Test Meal 
 
Study design: 
Prospective, open, monocentric, single arm study (phase IV) as 
Investigator-Initiated Trial (IIT)  
Inclusion / Exclusion 
criteria: 
Inclusion criteria:  
 
Patients referred by their treating physician to the Center for 
integrative Gastroenterology at the Clinic Arlesheim  
 
Age over 18 years and ≦75 years of age 
 
Patients with Diagnosis of Functional Dyspepsia with 
Postprandial Distress (Rome IV criteria) with Leuven Dyspepsia 
Score “at least moderate” severity (≥2/4) on at least two 
subscales (≥4 total) 
 
Signed informed consent  
 
No change in medical treatment (e.g., proton pump inhibitor, 
antidepressants) during the last one month or for the duration of 
the period  
 
Good German or English knowledge (at least level B2 from 
Common European Framework of Reference for Languages)  
Exclusion criteria:  
 
Acute life-threatening conditions  
 
Withdrawal of informed consent  
 
Clinically relevant psychiatric comorbidity (HADS score ≥14) 
 
Advanced liver (Child score > 6) or kidney disease (GFR < 60) 
 
History of major gastrointestinal surgery (appendectomy, 
hysterectomy, cholecystectomy, hernia repair are not exclusion 
criteria) 
 
Allergy to any component of Amara 
 
Pregnancy and lactation  
 
Measurements and 
procedures: 
Participants will fill in a series of questionnaires two times.  

 
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Study Product / 
Intervention:  
In this study the test medication (Amara drops) will be taken by the 
participants before meals. The herbal preparation is manufactured by 
Weleda AG, Arlesheim. Besides the bitter substances Artemisia 
absinthium, Cichorium intybus, Juniperus and Gentiana lutea, Amara 
Drops contain also Centaurium, Peucedanum, Achillea millefolia, Salvia 
officinalis and Taraxacum, all suspended in an alcohol-based tincture.  
The full indication text licensed by Swissmedic is: “According to the 
anthroposophical knowledge of man and nature, Weleda Amara-Drops 
can be used for digestive complaints such as heartburn, flatulence and 
bloating after meals, to stimulate the bile flow and for loss of appetite and 
nausea. The effect of Weleda Amara drops is based on a balanced 
mixture of medicinal plants with tonic (invigorating) and aromatic bitter 
substances, which are suitable for stimulating digestion. Weleda Amara 
drops mildly stimulate the secretion of saliva and gastric juices, promote 
the formation and secretion of bile and thus facilitate the digestion of 
fats. In addition, they are effective against flatulence and cramps.” 
Control Intervention: 
No control group 
Number of 
Participants with 
Rationale: 
Participants: 60 patients with functional dyspepsia with postprandial 
distress (Rome IV criteria). 
There are no previous studies that have assessed the effect of Amara 
Drops in functional dyspepsia. Before randomized double blind controlled 
studies can be considered it is appropriate to assess perceived changes 
in symptom burden and physiological effects of Amara in clinical practice. 
At the same time the feasibility of recruiting this patient group and 
performing gastric emptying and other studies will be assessed. In this 
prospective open label study, placebo effects are likely to be present. 
Previous randomized controlled trials indicate that this can be up to 40%. 
To demonstrate convincing evidence of clinical efficacy a minimum 60% 
response rate above no treatment (run-in phase) must be demonstrated. 
Based on these considerations, for the primary outcome, power 
calculation suggests that at least 58 patients are required to detect 
moderate effects on perceived symptom burden at a convincing level of 
statistical significance (beta 0.9, alpha <0.01).  
Study Duration: 
2 years  
Study Schedule: 
Month Year of First-Participant-In (planned): July 2022 
Month Year of Last-Participant-In (planned): August 2024 
Month Year of Last-Participant-Out (planned): September 2024 
Investigator: 
Prof. Dr. med. Mark Fox  
Leitender Arzt, Zentrum für Integrative Gastroenterologie 
Leiter, Magen Darm Funktion: Basel, Labor und Klinik für funktionelle 
Magendarm Erkrankungen und Motilitätsstörungen  
Tel. +41 (0)763580379 
mark.fox@klinik-arlesheim.ch 
Study Centre: 
Single Centre, Clinic Arlesheim (CLA), Pfeffingerhof 1, 4144 Arlesheim  

 
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Statistical 
Considerations: 
Differences between the scores from the primary and secondary outcome 
measurement variables – at baseline (following run-in) and after either 4-
weeks treatment - will be compared initially by t-test if the data is normally 
distributed and Wilcoxon rank sum test when data are not normally 
distributed. In addition, we will perform univariate and multivariate linear 
regression analysis in which potential covariates will be considered; 
confounding will be evaluated by adding these variables to the linear 
regression model and looking at the change of the regression coefficients. 
These variables will include participants’ gender, age, perceived symptom 
severity and gastric function at baseline. 
In the analysis of the primary outcome two-tailed p ≤0.05 will be 
considered statistically significant. Since the evaluation of the secondary 
endpoints is purely exploratory, other p-values will be calculated but 
reported without claiming significance, 
GCP Statement: 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, the ICH-GCP as well as all national 
legal and regulatory requirements.  
 
 
 
 

 
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ABBREVIATIONS 
 
13C BT 
13C Acetate Breath Test 
AE 
Adverse Event  
BASEC 
Business Administration System for Ethical Committees, 
(https://submissions.swissethics.ch/en/) 
CA 
Competent Authority (e.g. Swissmedic) 
CEC 
Competent Ethics Committee 
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV) 
CRF 
Case Report Form  
CTCAE 
Common terminology criteria for adverse events 
DSUR 
Development safety update report 
eCRF 
Electronic Case Report Form  
EKNZ 
Ethikkommission Nordwest- und Zentralschweiz 
HADS 
Hospital Anxiety and Depression Scale 
GCP 
Good Clinical Practice  
HRA 
Federal Act on Research involving Human Beings (in German: HFG) 
HRV 
Heart Rate Variability 
IB 
Investigator’s Brochure 
IBS-SSS 
Irritable Bowel Syndome Symptom Severity Score 
ICS 
Internal Coherence Scale 
IIT 
Investigator-initiated Trial 
KLA 
Klinik Arlesheim 
LCT 
Lüscher Colour Test 
LDQ 
Leuven Dyspepsia Questionnaire 
NTM 
Nottingham Test Meal 
OTC 
Over The Counter 
PHQ-12 
Patient Health Questionnaire 12-items, depression module 
PI 
Principal Investigator  
RCT 
Randomised Controlled Trial 
RDQ 
Reflux Disease Questionnaire 
SAE 
Serious Adverse Event  
SDV 
Source Data Verification  
SOP 
Standard Operating Procedure 
SPC 
Summary of product characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMF 
Trial Master File  
 
 

 
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STUDY SCHEDULE 
 
 
Study Periods 
Screening 
Physiological 
Measurement 
and Treatment 
Physiological 
Measurement 
and End 
Visit  
1 
2 
3 
Time (days) 
Ca. -14-28d 
1 
28±14d 
Medical History and 
Demographics 
x 
 
 
Leuven Dyspepsia 
Questionnaire (LDQ) 
x 
 
x 
Screening questionnaires 
x 
 
 
Pregnancy test (urine) 
x 
(x) 
 
In-/Exclusion Criteria 
x 
 
 
Patient Information and 
Informed Consent 
x 
 
 
Primary Outcome Measure: 
LDQ total score  
x 
 
x 
Secondary Outcome 
Measure: other GI symptom 
questionnaires 
x 
x 
x 
Lüscher Colour Test 
x 
x 
x 
Physiological Measurement 
(13C BT, HRV) 
 
x 
x 
Intake of the Study 
Medication (Amara Drops) 
 
x 
x 
Compliance with therapy   
 
 
x 
Satisfaction with therapy / 
Whether a prescription of 
Amara is wanted   
 
 
x 
Concomitant Medication, 
Therapy 
x 
x 
x 
Serious Adverse Events 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1. STUDY ADMINISTRATIVE STRUCTURE  
1.1 Sponsor, Sponsor-Investigator  
Prof. Dr med Mark Fox in the position as the Sponsor-Investigator takes on the responsibility as a clinical 
study sponsor and also conducts the clinical trial.  
 
Prof. Dr. med. Mark Fox  
Leitender Arzt, Zentrum für Integrative Gastroenterologie 
Leiter, Magen Darm Funktion: Basel, Labor und Klinik für funktionelle Magendarm Erkrankungen und 
Motilitätsstörungen  
Klinik Arlesheim, CH-4144 Arlesheim 
Tel. +41 (0)763580379 
Mark.fox@klinik-arlesheim.ch 
 
1.2 Principal Investigator(s)  
Prof. Dr. med. Mark Fox  
Leitender Arzt, Zentrum für Integrative Gastroenterologie 
Leiter, Magen Darm Funktion: Basel, Labor und Klinik für funktionelle Magendarm Erkrankungen und 
Motilitätsstörungen  
Klinik Arlesheim, CH-4144 Arlesheim 
Tel. +41 (0)763580379 
Mark.fox@klinik-arlesheim.ch 
 
1.3 Statistician ("Biostatistician")  
Prof. Dr. med. Mark Fox  
Leitender Arzt, Zentrum für Integrative Gastroenterologie 
Leiter, Magen Darm Funktion: Basel, Labor und Klinik für funktionelle Magendarm Erkrankungen und 
Motilitätsstörungen  
Klinik Arlesheim, CH-4144 Arlesheim 
Tel. +41 (0)763580379 
Mark.fox@klinik-arlesheim.ch 
 
1.4 Laboratory 
No laboratory is involved in the trial. 
  
1.5 Monitoring institution 
The test centre has commissioned an independent monitor for the implementation of the monitoring 
visits. The tasked Mrs Susanne Forst holds a Certificate of Advanced Studies (USZ) in Clinical Trial 
Management. Details are set out in the contract between the two parties.  
 
Susanne Forst, Aufwiesenstrasse 20, 8305 Dietlikon, suforst@googlemail.com, +41 (0)76 794 75 30 
 
1.6 Data Safety Monitoring Committee  
Patients in this study are treated for a relatively short time with a drug already on the market and known 
to have a very good safety profile. Since there are also no prior data to suggest that the intervention 
being studied has the potential to harm patients, a DSMC is not needed. 
 

 
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1.7 Any other relevant Committee, Person, Organisation, Institution  
Advisory Board: 
Philipp Busche (chief physician, center for integrative gastroenterology), Clinic Arlesheim 
PD Dr Matthias Kröz (medical and study design expertise), Clinic Arlesheim 
Dr med Martin Schnelle (medical and study design expertise), Weleda AG 
Luitgard Spitznagel (study design, control of data quality and consistency), Weleda AG 
2. ETHICAL AND REGULATORY ASPECTS  
Before the study will be conducted, the protocol, the proposed patient information and consent form as 
well as other study-specific documents will be submitted to the constituted Competent Ethics 
Committee (CEC). The decision of the CEC authority concerning the conduct of the study will be made 
in writing to the Sponsor-Investigator before commencement of this study. The clinical study can only 
begin once approval from the required authority has been received. Any additional requirements 
imposed by the authorities shall be implemented. Any amendment to the protocol must as well be 
approved (if legally required) by these institutions. 
 
2.1 Study registration  
The current study will be registered at Clinicaltrials.gov. “Number” and “Date” will be announced as soon 
as possible. In addition, the current study will be registered on the Swiss National Clinical trial Portal.  
 
2.2 Categorisation of study  
The study medication Amara is authorised in Switzerland without indication. The full indication text 
licensed by Swissmedic is: “According to the anthroposophical knowledge of man and nature, Weleda 
Amara-Drops can be used for digestive complaints such as heartburn, flatulence and bloating after 
meals, to stimulate the bile flow and for loss of appetite and nausea. The effect of Weleda Amara 
drops is based on a balanced mixture of medicinal plants with tonic (invigorating) and aromatic bitter 
substances, which are suitable for stimulating digestion. Weleda Amara drops mildly stimulate the 
secretion of saliva and gastric juices, promote the formation and secretion of bile and thus facilitate the 
digestion of fats. In addition, they are effective against flatulence and cramps.” These indications are 
in accordance with the German Commission C which states the applications of Amara include 
digestive problems, including dyspepsia. This commission’s role is to advise the Federal Institute for 
Medicinal Products and Medical Devices on the approval of anthroposophic medicines by providing 
their anthroposophic medical expertise. Furthermore, in the 15-year period 01.01.3006 - 31.12.2021 
only 26 individual case safety reports (ICSR) with 43 adverse drug reactions (ADRs) were reported 
(see also section 3.4). All these reasons lead us to the conclusion that this study is only associated 
with minimal risks and should be classified in category A. 
 
2.3 Competent Ethics Committee (CEC)  
The investigator Prof Dr med Mark Fox has submitted the application documents to the CEC 
“Ethikkommission Nordwest- und Zentralschweiz (EKNZ)” for examination. Changes of the protocol 
will not be implemented until the EKNZ has reviewed and approved them. This does not apply to 
measures which must be taken immediately to protect the participants or when the changes involve 
only logistical or administrative aspects of the trial. Amendments are reported according to chapter 
2.10. Premature study end or interruption of the study would be reported within 15 days. The regular 
end of the study will be reported to the CEC within 90 days, the final study report will be submitted 
within one year after study end.  
 
2.4 Competent Authorities (CA)  
Competent Authorities (CA) approval is not necessary for the study requested.  
 
2.5 Ethical Conduct of the Study  
The study will be carried out in accordance to the protocol and with principles enunciated in the current 

 
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version of the Declaration of Helsinki [20], the guidelines of Good Clinical Practice (GCP) [21] issued by 
ICH. The CEC and regulatory authorities will receive annual safety and interim reports and be informed 
about study stop/end in agreement with local requirements.  
 
2.6 Declaration of interest  
Weleda AG, the company that provides the preparations of Amara used in this study supported part of 
the costs. Weleda AG has had no influence on the design and implementation of the study nor on 
collection, management or analysis of the data. 
 
2.7 Patient Information and Informed Consent 
The consent form will be submitted when the patient visits the clinic for the physician-patient 
consultation. This consultation takes place regardless of whether the patient participates in the study 
or not. One of the recruiting physicians will then explain to each participant the nature of the study, its 
purpose, the procedures involved, the rights and obligations, the expected duration, the potential risks 
and benefits, possible alternatives to the intervention under investigation, and any discomfort it may 
entail.  
Each participant will be informed that the participation in the study is voluntary and that she/he may 
withdraw from the study at any time and that withdrawal of consent will not affect her/his subsequent 
medical assistance and treatment and that they will also have the right to be informed at any time of 
any further questions relating to the clinical trial. All participants will be informed that her/his medical 
records may be examined by authorised individuals other than their treating physician.  
Enough time will be given to the participants to ask questions and to decide whether to participate or 
not. The participant will read and consider the statement before signing and dating the informed 
consent form. The consent form will also be signed and dated by the physician. The original will be 
retained as part of the study records and a copy of the document will be given to the patient. The 
formal consent of a participant, using the approved consent form, will be obtained before the 
participant is submitted to any study procedure. The study nurse will also attend the interview where 
the physician informs about the study and is available for additional questions.  
Participants will not receive any compensation for participating in this clinical trial. 
 
2.8 Participant privacy and confidentiality  
The following aspects are mentioned in the patient consent form and are therefore known to the 
participants:  
The investigator affirms and upholds the principle of the participant's right to privacy and that they will 
comply with applicable privacy laws. Especially, anonymity of the participants will be guaranteed when 
presenting the data at scientific meetings or publishing them in scientific journals.  
Individual subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Yet, as written in paragraph 13., if journals wish to have the 
raw data submitted, we will do so, though data protection will be maintained so that the data cannot be 
traced back to individuals. Subject confidentiality will be further ensured by utilising subject 
identification codes to correspond to treatment data in the computer files. For data verification 
purposes, authorised representatives of the Sponsor, a competent authority (e.g. Swissmedic), or an 
ethics committee may require direct access to parts of the medical records relevant to the study.  
 
2.9 Early termination of the study  
The Sponsor-Investigator may terminate the study prematurely according to certain circumstances, as 
follows: 
 
ethical concerns, 
 
insufficient participant recruitment, 
 
when the safety of the participants is doubtful or at risk, respectively, 
 
alterations in accepted clinical practice that make the continuation of a clinical trial unwise 
2.10 Protocol amendments 
All study staff are allowed to provide suggestions for a protocol amendment. But the PI is the only one 

 
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who is allowed to amend the protocol. Substantial amendments are only implemented after approval of 
the CEC. 
Under emergency circumstances, deviations from the protocol to protect the rights, safety and well-
being of human subjects may proceed without prior approval of the CEC. Such deviations will be 
documented and reported to the CEC as soon as possible. 
All non-substantial amendments are communicated to the CEC within the Annual Safety Report (ASR).  
3. BACKGROUND AND RATIONALE  
3.1 Background and Rationale  
Functional dyspepsia (FD) with postprandial distress is a common functional gastrointestinal (GI) 
disorder characterized by the occurrence of epigastric symptoms such as early satiety (fullness), 
nausea and upper abdominal pain after meals at least twice a week over at least six months (Rome IV 
criteria).(1) By definition, no structural disease is found on routine laboratory, endoscopy or imaging 
studies. Instead, symptoms are thought to be related to abnormal gastrointestinal motility (e.g. 
impaired gastric relaxation, abnormal emptying) and increased sensitivity to gastric distension and the 
digestive process.(2) Additionally, detailed studies of the mucosa often reveal low-grade inflammation 
in the duodenum and hyperpermeability (“leaky gut”).(3) 
Epidemiological studies report a 10-30% prevalence of functional dyspepsia (FD).(4) When dyspeptic 
symptoms are short in duration and relatively mild, many patients wish to self-manage with dietary 
adaptation and /or over the counter (OTC) preparations.(5) Others report high rates of intolerance to 
prescription medications.(5, 6) In these patients complementary and alternative medicines (CAM) 
based on natural products, such as plant-based “phytotherapy”, are particularly appealing.(7) Several 
herbal therapies for functional dyspepsia have been tested in randomized clinical studies.(8) These 
include phytochemicals such as peppermint oil that inhibits smooth muscle contraction by direct 
blockade of calcium channels and other effects, deglycyrrhizinated licorice that increases gastric 
mucus secretion and may enhance mucosal protection and other preparations that combine multiple 
herbal products with the intention of inducing synergistic effects that promote normal digestive 
function.(9) In particular, STW-5 (Iberogast, Bayer) has been shown to have physiological effects on 
gastric accommodation and contractility. A double-blind non-inferiority randomized control trial (RCT) 
comparing Iberogast to cisapride (5-HT4 agonist) showed equal effectiveness for both 
medications,(10) and a meta-analysis of 3 double blind RCTs provided evidence that Iberogast is 
more effective than placebo in the treatment of dyspeptic symptoms.(11) 
Amara Drops (Weleda, Arlesheim, Switzerland) is a proprietary preparation used for many decades in 
anthroposophic medicine that is marketed for the treatment of functional digestive disorders. Patients 
take 10-20 drops before meals to relieve loss of appetite, bloating, nausea, and other dyspeptic 
symptoms. These bitter substances are thought to promote digestion and relieve symptoms by 
stimulating the secretion of gastric and pancreatic enzymes, upper gastrointestinal motility and gastric 
emptying. These prokinetic effects may be therapeutic in patients with functional dyspepsia because 
there is an association between delayed gastric emptying (GE) and upper gastrointestinal symptoms 
including uncomfortable fullness, nausea and vomiting.(2, 12, 13) To date, the effects of Amara has not 
been subjected to pre-clinical or clinical studies. 
The primary aim of this investigator-initiated, prospective, open-label, therapeutic study is to test if 
Amara has effects on the perceived severity of abdominal symptoms in patients with functional 
dyspepsia. Additionally, the physiological effects of Amara on gastric motor and sensory function will 
be assessed using validated methods 
To test this, a prospective, open label, non-randomized study will assess (i) Perceived effects of regular 
intake of 10-20 Amara Drops prior to main meals on dyspeptic symptoms using the validated Leuven 
Dyspepsia Questionnaire. (ii) Physiological effects of 20 drops Amara tincture on gastric emptying using 
the 400ml Nottingham Test Meal with non-radioactive 13C-acetate breath test and concurrent 
assessment of filling sensation and dyspeptic symptoms by Visual Analogue Scores (VAS). (iii) In a 
subset of 20 consecutive patients, gastric electrical activity before, during and after ingestion of the test 
meal will be measured using the non-invasive Gastric Alimetry System (high-resolution gastric mapping 
/ electro-gastrography) with concurrent heart rate monitoring. Gastric Alimetry is a diagnostic test for 
patients with chronic gastric symptoms, a development of electrogastrography that maps gastric 

 
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neuromuscular activity using a large array of electrodes over the abdomen. The test can help 
differentiate if patients have gastric neuromuscular dysfunction, gastric sensory disorder, gastric outlet 
obstruction or a functional (central) cause of symptoms. Individuals that fulfill the diagnostic criteria for 
functional dyspepsia with postprandial distress syndrome according to the Rome IV criteria will be 
recruited. At the first study visit (Study visit #1), Symptom questionnaires and other questionnaires to 
assess general health and psychiatric well-being will be completed at the time of recruitment. To answer 
the questions, the study participants are sent a one-time link to the questionnaires. Additionally, a 
Lüscher Color Test (LCT) will be performed. This non-verbal, non-written test has been developed to 
assess patient’s personality and psychiatric state. This could be of interest in patients with disorders of 
brain-gut interaction that may not admit to the role of central factors in their illness. 
Eligible patients will have no clinically relevant medical co-morbidity or previous gastrointestinal 
surgery and must have had a normal upper gastrointestinal pan-endoscopy in the previous 3 years. If 
not known, Helicobacter pylori status will be assessed by 13C-stool antigen test (repeat endoscopy not 
required). The first visit is followed by a 2–4-week run-in period. The presence and severity of 
dyspeptic symptoms will be reported using an on-line application downloaded on the patient’s smart 
phone (an electronic reminder will be sent at 21:00 every day). 
The LCT will be repeated during the second study visit (Study visit #2). At this time, gastric function 
will be assessed by 13C-breath test measurements with concurrent assessment of visceral sensitivity.  
Amara Drops will be dispensed with 10-20 drops (0.25-0.50ml) taken three times a day before meals 
for 4 weeks. The patients are free to vary the dose within these parameters as considered appropriate. 
The amount taken will be monitored by checking the volume remaining in the bottle at the end of the 
4-week intervention.  During this time, patients will continue entering their symptoms and any side 
effects into the app. 
At the end of the study period (Study Visit #3) the questionnaires, the LCT and the 13C-breath test 
measurement with concurrent assessment of visceral sensitivity will be repeated. An e-mail with the 
questionnaire link will be send to the patient shortly before the third study visit. Additionally, the 
patients will be asked if their global satisfaction was better on Amara treatment, whether they wish to 
continue treatment and /or recommend the treatment to others with similar symptoms. 
 
3.2 Investigational Product (treatment) and Indication  
Composition of the investigational medicinal product (IMP): The herbal preparation is manufactured by 
Weleda AG, Arlesheim. Besides the bitter substances Artemisia absinthium, Cichorium intybus, 
Juniperus and Gentiana lutea, Amara Drops contain also Centaurium, Peucedanum, Achillea 
millefolia, Salvia officinalis and Taraxacum, all nine plant substances held in an alcohol-based tincture.  
The full indication text licensed by Swissmedic is: “According to the anthroposophical knowledge of 
man and nature, Weleda Amara-Drops can be used for digestive complaints such as heartburn, 
flatulence and bloating after meals, to stimulate the bile flow and for loss of appetite and nausea. The 
effect of Weleda Amara drops is based on a balanced mixture of medicinal plants with tonic 
(invigorating) and aromatic bitter substances, which are suitable for stimulating digestion. Weleda 
Amara drops mildly stimulate the secretion of saliva and gastric juices, promote the formation and 
secretion of bile and thus facilitate the digestion of fats. In addition, they are effective against 
flatulence and cramps.” 
 
3.3 Preclinical Evidence  
Results from preclinical investigations for the individual plant-based preparations in Amara indicate a 
very good safety profile (personal communication Prof. Dr. Carsten Gründemann, Departement 
Pharmazeutische Wissenschaften, Translationale Komplementärmedizin, Universität Basel). This 
supports the clinical experience that Amara is very unlikely to cause ADRs in patients.  
 
3.4 Clinical Evidence to Date  
Prospective studies on the treatment of dyspepsia have been performed with a variety of aromatic bitter 
substances and suggest very good safety/tolerability. Meta-analysis of studies also confirmed that these 
plant-based products can be effective in the management of functional dyspepsia.(8, 11)  

 
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It has also been observed that Anthroposophic physicians which participated in the Evaluation of 
anthroposophic medicine (EvaMed) network in Germany very often prescribed Amara drops for 
dyspeptic symptoms.(14) Based on the observations of the lead investigator, gastroenterology 
colleagues and the EvaMed data, significant improvements in dyspeptic symptoms often reported.  
Based on information provided by the manufacturer, in the 15-year period 01.01.3006 - 31.12.2021 only 
26 individual case safety reports (ICSR) with 43 ADRs were reported. 3 non-serious ICSR occurred in 
Switzerland; 1 serious and 22 non-serious ICSR occurred in Germany. Most ADRs occurred within the 
System Organ Classes (SOC) skin and subcutaneous tissue disorders (11) and gastrointestinal 
disorders (9). One ICSR was assessed as serious due to hospitalisation. The reported ADR was acute 
liver failure and acute renal failure after user of Amara Drops (for about 15-22 days) and Paracetamol 
(duration and dosage unknown). As none of the active ingredients of Amara Drops are known to be 
hepatotoxic, the causal relationship was assessed as unlikely for Amara Drops. But for Paracetamol the 
causal relationship was assessed as possible due to the known hepatotoxic potential. 
 
3.5 Dose Rationale  
Patients will take 3 x 10-20 drops of Amara before meals daily for four weeks (see section 8.1). The 
standard dose of this preparation is 10-15 drops before meals to “stimulate the digestive process”; 
however, patients are encouraged to adapt the dose to their requirements. Patient compliance will be 
assessed using a smart phone application that will record whether medication was taken and the 
severity of symptoms at the end of each day. Patient compliance (i.e. actual intake) will be checked by 
weighing the bottle at the end of the treatment period.  
A 2-4-week run-in period between screening and the start of treatment is applied to ensure that the 
severity of symptoms is representative (patients tend to present during periods with relatively severe 
symptoms, thus run-in periods reduce the influence of spontaneous “regression to the mean” providing 
false positive results). The treatment period of 4-weeks is in accordance with the above-mentioned 
studies for other aromatic bitter substances and represents the minimum recommendation for study 
duration in functional gastrointestinal disorders.(15) 
 
3.6 Explanation for choice of comparator (or placebo)  
No comparator will be used in this study. 
 
3.7 Risks / Benefits  
The initial assessment of patients with functional dyspepsia will adhere to international guidelines on 
the investigation of this condition. It is widely recognized that current pharmacological treatment for 
dyspepsia is sub-optimal and new options are to be welcomed. 
Amara Drops (Weleda) is a proprietary preparation that has been marketed over the counter (OTC) for 
many years. No serious side effects have been reported. Health status can improve thanks to the 
treatment used in this study, fewer dyspeptic symptoms could be possible and by participating in the 
trial, the results can also benefit future patients. However, we cannot guarantee that there will be a 
benefit from participating in this trial.   
There are no expected risks associated with participating in this study. Very rarely, hypersensitivity or 
intolerance reactions may occur, this could include skin rash or gastrointestinal symptoms. Weleda AG 
analysed the safety profile of Amara.  A pharmacovigilance monitoring between 2006 and 2021 showed 
very few reports of adverse drug reactions (see section 3.5). 
Gastric emptying studies are recommended in patients with functional dyspepsia that do not respond 
to first-line, dietary management and empirical treatment.(16) Unlike standard investigation of gastric 
emptying by scintigraphy, the 13C-breath test is not radioactive and is suitable for repeated 
measurements.(17) The 400ml (300kcal) Nottingham Test Meal is based on a proprietary liquid 
nutrient drink (Fresubin, Energy Drink) often provided to patients with gastrointestinal and other 
diseases that require supplementary enteral nutrition. It is not associated with adverse outcomes. 
Clinical validation studies report that intake of the 400ml NTM is tolerated by all healthy controls and 
>95% of patients with functional dyspepsia without inducing vomiting.(18, 19)  
 
3.8 Justification of choice of study population  
Study participants will be recruited from patients referred to Gastroenterologists at Clinic Arlesheim for 

 
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assessment of dyspeptic symptoms. Investigations in this patient group identify an organic cause of 
these persistent symptoms in less than 1 in 4 cases.(16) Instead, functional dyspepsia is considered to 
be a disorder of brain-gut interaction, with symptoms related to both abnormal gastric motor function 
(e.g. delayed gastric emptying) and sensory function (peripheral hypersensitivity but also abnormal 
central processing).(1) Conservative measures (e.g. reduction in dietary fat) and medical treatment (e.g. 
acid suppression, prokinetics) often fail to improve symptoms.(5) Moreover, concerns about long-term 
side effects for certain medications (e.g. domperidone, metoclopramide),(20) and high rates of 
intolerance to prescription medications are reported.(5, 9) For these reasons, there is a clinical need for 
new and effective treatments of functional dyspepsia. Complementary and alternative medicines (CAM) 
based on natural products, such as plant-based “phytotherapy”, are particularly appealing.(7, 9)  
There are no previous studies that have assessed the effect of Amara Drops in functional dyspepsia. 
Before randomized double blind controlled studies can be considered prospective, open-label 
therapeutic study to assess perceived changes in symptom burden will be performed (at the same time 
the feasibility of recruiting this patient group and performing gastric emptying and other studies will be 
assessed). In this prospective open label study, placebo effects are likely to be present. Previous 
randomized controlled trials of therapy in functional gastrointestinal disorders indicate that this can be 
up to 40% in this group.(15) To compensate for this confounding factor and to demonstrate convincing 
changes in perceived symptom burden at least 60% of patients should show improvement on-treatment 
compared to off-treatment (run-in phase). Assuming a moderate effect (Cohen's effect size of 0.4) on 
the primary outcome measure (effect size and standard deviation as in a previous paper by Carbone et 
al. (21)) power calculation suggests that 58 patients are required to detect a significant effect at a 
convincing level of statistical significance (beta 0.9, alpha <0.01).  
Any patients unwilling to participate in the study will not be included the study and will receive 
appropriate investigation and management that may include 13C breath test assessment of gastric 
emptying and Amara drops.   
Furthermore, we guarantee that a physician not participating in the study, safeguards participant interest 
and insures proper medical care (P. Busche, Medical Director Internal Medicine, Specialist in Internal 
Medicine and Gastroenterology at Clinic Arlesheim).  
4. STUDY OBJECTIVES  
4.1 Overall Objective 
The purpose of the present study is to evaluate whether the herbal drug Amara improves the subjective, 
perceived burden of abdominal symptoms in patients with functional dyspepsia. It will also assess if the 
treatment is well tolerated. The present study will also investigate psychological and physiological 
function. This additional information should provide insight into which patients benefit the most from the 
treatment with Amara. The results of this prospective, open-label therapeutic study will also inform the 
study design for any subsequent RCT study in functional dyspepsia. 
 
4.2 Primary Objective 
Document perceived changes in upper gastrointestinal, dyspeptic symptoms reported by patients with 
functional dyspepsia treated with Amara for 4 weeks, as assessed by the Leuven Dyspepsia Score 
between visit 1 (off treatment) and 3 (after treatment)..  
 
4.3 Secondary Objectives 
Assess perceived effect of Amara on other gastrointestinal symptoms using validated, patient related 
outcome measurements (reflux disease questionnaire, IBS Symptom Severity Score).  
Assess effect of Amara on (i) visceral sensitivity and (ii) gastric emptying (13C-breath test) in patients 
with functional dyspepsia with validated 400ml Liquid Nottingham Test Meal. Repeat testing will also 
allow an assessment of reproducibility to be obtained (iii) In a subset of 20 consecutive patients, gastric 
electrical activity will be measured using the non-invasive Gastric Alimetry System (high-resolution 
gastric mapping / electro-gastrography) with concurrent heart rate monitoring.  
 
Participants will be asked also to rate their overall satisfaction with Amara and the number that request 
an additional prescription of Amara for the period after the study will be documented, as an indication of 

 
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perceived effectiveness. 
Additionally, factors that predict the outcome of Amara treatment in functional dyspepsia will be 
assessed. These factors will include (i) age (ii) sex (iii) severity of dyspeptic symptoms (iv) presence of 
other gastrointestinal symptoms (v) presence of psychological comorbidity (vi) presence of heightened 
visceral sensitivity after ingestion of the NTM (vii) abnormal gastric emptying during 13C gastric emptying 
test (viii) compliance with study procedures. 
Additionally, the Lüscher Colour Test will be acquired. This non-verbal, non-written test was developed 
to provide insights into personality and psychological state. This could be of interest in patients with 
disorders of brain-gut interaction that may not admit to the role of central factors in their illness. 
Reproducibility of LCT will be documented by repeating the test at Study visit #1 and #2.  Correlation 
with dyspeptic symptoms, psychological or physiological state will be assessed. 
 
4.4 Safety Objectives 
Perceived safety and tolerability will be assessed. For this purpose, participants will be instructed to 
report possible adverse drug events (ADRs)/ side effects during the treatment period. Participants will 
be encouraged also to report possible late-onset ADRs that occur after treatment. 
5. STUDY OUTCOMES  
5.1 Primary Outcome 
The primary outcome will be the perceived change of dyspeptic symptoms assessed by the Leuven 
Dyspepsia Questionnaire (LDQ) between visit 1 (off treatment) and 3 (after treatment). The 
questionnaire contains 3 domains/questions which related to: a) The inability to finish a meal due to 
early satiety b) The feeling of food lying heavily in the stomach c) Feeling bloated in the stomach. The 
questionnaire is presented to the patients in the form of three questions which define five grades of 
severity (0-4), and which are supported by pictograms expressing the associated severity. Higher total 
scores indicate more severe dyspeptic symptoms. For each subscale 0 normal, 1 mild dyspepsia; 2, 
moderate dyspepsia; 3, severe dyspepsia; 4, very severe dyspepsia. The questionnaire is to be 
evaluated on a daily basis and the mean of the values of the three symptoms is proposed to represent 
the severity of that day. A weekly score can be calculated from the daily scores and is currently proposed 
for the primary use of the scale.(21) 
The LDQ has been developed using standard methods, including focus group interviews and cognitive 
debriefing interviews.(21) The further validation of the score was undertaken with the means of 
interventional studies, evaluating the response of this questionnaire to prokinetic and neuromodulatory 
medications. The LDQ has shown to be a good rating scale to be used as a severity indicator of 
dyspepsia and can be given to the same patient in subsequent sessions to track the change in 
symptoms. A minimally clinically important difference has also been determined. The results of this 
validation work have been published in peer reviewed journals.(22, 23)  
The Leuven Postprandial Distress Scale, which is supported by the European Medicines Agency, is a 
sensitive and reliable patient-reported outcome instrument to assess symptoms in the functional 
dyspepsia/postprandial distress syndrome. Based on this information, the LDQ variable will be the main 
result to verify whether the test medication in this trial is efficacious. In this open-label study in which 
placebo and treatment effects are summed we expect a moderate to large >60% reduction in mean 
symptom burden as measured by the LDQ (results will be shown as mean  SD).  
 
5.2 Secondary Outcomes 
Secondary objectives / outcome measures 
 
Assess perceived effect of Amara on other gastrointestinal symptoms using validated, patient 
related outcome measurements (reflux disease questionnaire, IBS Symptom Severity Score) 
 
Assess effect of Amara on (i) visceral sensitivity and (ii) gastric emptying (13C-breath test) in 
patients with functional dyspepsia with validated 400ml Liquid Nottingham Test Meal. Details 
of the acquisition and analysis of these physiological measurements are in the appendix 
(SOP). (iii) gastric electrical activity before, during and after the test meal as assessed by the 
Gastric Alimetry System (concurrent measurements of heart rate will also be acquired)  

 
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 
Overall satisfaction with Amara treatment will be assessed by a 100mm visual analogue scale 
and whether ongoing prescription is wanted (yes/no).  
 
5.3 Other Outcomes of Interest 
The validity of the Lüscher Colour Test (LCT) in the assessment of patients with functional dyspepsia 
will also be assessed. This will include face validity (debriefing session), construct validity (comparison 
with validated questionnaires assessing psychological patient related outcome measures), 
reproducibility (test re-test validity before and after run-in period), and internal consistency.  Sensitivity 
of LCT to any change in dyspeptic symptoms, psychological or physiological state that occurs during 
the treatment study will also be documented. 
 
5.4 Safety Outcomes 
All perceived events and side effects will be entered by the participant when filling in the questionnaire. 
In addition, they will report any SAE to the study team by use of the mobile application or telephone 
(even after study end/discontinuation until the adverse effect subsides).  
Previous placebo-controlled trials that studied the effects of another aromatic bitter preparation in 
patients with dyspepsia reported side effects similar to placebo.(11) Additionally, safety monitoring has 
identified very few ADRs in the last 15 years (see section 3.4). Participants can indicate possible side 
effects in the questionnaire booklet. Furthermore, participants are instructed to report the start and 
duration, the severity (minor, moderate, severe) of the side effect and what have been done about it.  
6. STUDY DESIGN  
6.1 General study design and justification of design  
The present IIT (Investigator-Initiated Trial) study is a prospective, open, monocentric, single arm, 
intervention study (phase IV) of the category A, as defined in the Ordinance on Clinical Trials in 
Human Research (ClinO) of 20 September 2013 (D. S. Bundesrat, “Verordnung über klinische 
Versuche in der Humanforschung,” vol. 2013, no. September, pp. 3407–3454, 2013), on the basis of 
the Human Research Act (HRA) of 30 September 2011 (Die Bundesversammlung der 
Schweizerischen Eidgenossenschaft, “Bundesgesetz über die Forschung am Menschen 
(Humanforschungsgesetz, HFG),” vol. 1313, no. September, pp. 1–26, 2011). 
A past survey showed that among Anthroposophical physicians the most frequent diagnosis group 
where Amara preparations are prescribed are gastrointestinal disorders such as dyspepsia and 
irritable bowel syndrome (Eva-Med Network 2009, data on file); however, prospective clinical studies 
have not been performed. In the present study we therefore want to investigate the effectiveness of 
Amara drops in patients with functional dyspepsia diagnosed according to Rome IV criteria.(1)  
Study participants will be recruited among the patients referred to the Department of Integrative 
Gastroenterology at the Clinic Arlesheim. Recruitment period will last 18 months. This duration is very 
cautiously estimated with basis on expected at least two referrals for assessment of dyspeptic 
symptoms per week. Best clinical care will be provided regardless of whether the patient is eligible and 
/ or consents to participate in the study. 
At the initial screening assessment at Clinic Arlesheim, patients will be informed about the study by 
one of the research team. If the participants fulfil the inclusion criteria and consent to participate, then 
the team member will administer the questionnaires and help the participant download the mobile 
application to monitor symptoms onto their smart phone (paper version available). Participants who 
signed the informed consent form will fill in a questionnaire with questions about dyspeptic (LDQ) and 
other gastrointestinal symptoms (RDQ, IBS-SSS), anxiety and depression (HADS), somatization 
(PHQ15), the Internal Coherence Scale (ICS) and the Lüscher Colour Test (LCT).  
An appointment will be made 2-4-weeks later for the second study visit at which time the 13C gastric 
emptying study will be performed again. The run-in period is 2-4-weeks. This reduces the influence of 
spontaneous “regression to the mean” (i.e., false positive results).(15)  
Gastric motor and sensory function will be assessed by ingestion of the 400ml, 300kcal Nottingham 
Test Meal (NTM) labelled with 13C acetate. This provides both an assessment of patient symptoms / 
visceral sensitivity to gastric filling with the 400ml liquid nutrient meal and also an assessment of 
gastric emptying. The 400ml NTM can be ingested by >95% of patients with functional dyspepsia.(19, 

 
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24) The 13C isotope is not radioactive, it takes 2-hours to complete and this technique is very 
appropriate for repeated assessment of gastric emptying.(16) In a subset of 20 consecutive patients, 
gastric electrical activity will be measured before, during and after ingestion of the Nottingham Test 
Meal using the non-invasive Gastric Alimetry System (high-resolution gastric mapping / electro-
gastrography). Concurrent heart rate monitoring will provide an assessment of cardiovagal tone / 
autonomic nervous function. 
The treatment period with Amara drops is four weeks per patient; participants will be instructed to take 
10-20 drops of the herbal medicine Amara three times a day before meals over 28 days. This treatment 
period is in accordance with previous studies for aromatic bitter substances and represents the minimum 
recommendation for study duration in functional gastrointestinal disorders.(15) During the treatment 
period patients will record their symptoms using a mobile application (reminder will be sent at 21:00 
every day). In addition, patients can note side effects that they perceive to be caused by Amara. If 
participants do not regularly provide this information, then a team member will call to ask if they have 
any problems. 
At the end of the treatment period the participant will return to Clinic Arlesheim for repeat assessment. 
The LDQ and other patient related outcomes will be assessed again and 13C gastric emptying study will 
be repeated on treatment. 
At the end of the study, all participants will return the supply of Amara. The study team will assess 
compliance by counting the empty bottles and weighing partly used bottles. Patients will be asked 
whether they wish to continue the medication (yes / no). If the response is positive, then ongoing 
treatment will be recommended. Amara is classified by Swissmedic as dispensing category D 
available following discussion with specialist without prescription („Abgabekategorie D: «Abgabe nach 
Fachgespräch»).   
Overall, approximately 30 minutes will be needed to complete the questionnaires on each occasion. 
The total time required per patient during the study is a maximum of 8 hours (reading documents, 
filling in questionnaires, gastric emptying study (twice)). 
During the period the participants are enrolled in this study no additional outpatient examinations are 
planned. If, while someone is participating in the study, acute symptom occur and the need arises for 
early outpatient assessment or inpatient admission to the clinic, the study would be terminated for this 
subject as of this date.  
Limitations:  
 
The study will provide a prospective assessment of perceived treatment effectiveness; 
however, a large non-specific (placebo) effect is likely to be present as in any open-label, 
single-arm study in patients with functional gastrointestinal disease. This limitation is factored 
into the power calculation which requires at least a moderate treatment effect for Amara to be 
considered effective. Note that the secondary analysis that will identify baseline factors (e.g., 
age, sex, symptom severity, gastric emptying rate) that associate with treatment effect will be 
relatively less sensitive to this confounding factor. 
 
In addition to subjective patient related outcome measures, repeat 13C breath testing with the 
Nottingham Test Meal on and off treatment will provide physiological assessment of effects of 
Amara on gastric motor and sensory function. Continuous assessment of patient sensations 
during Drink tests (i.e., gastric filling) may be less impacted by patient recall than 
questionnaires. 13C breath testing provides an indirect assessment gastric emptying based on 
the excretion of 13CO2 in the expired air. Although well validated against scintigraphy, it 
remains uncertain to what extent these results can be affected by individual patient factors 
other than gastric emptying (e.g. metabolism). Note that this limitation will not affect the results 
of this study because we will compare gastric emptying in patients on and off Amara treatment 
(i.e., patients act as their own control). 
 
Amara drops will be distributed for self-administration at home, thus, we rely on participants to 
report their intake accurately. Compliance will be checked as described above. 
 
The four-week duration of drug intake is relatively brief and may underestimate the treatment 
effect.  
 
This study may suffer from the limitation that participants will take other over the counter 
medications or engage in other treatments at home.  
 
This study design does not allow evaluating the efficacy of Amara medication. However, the 
aim of this prospective study is to acquire results on overall effectiveness that will inform the 
design of a randomized controlled study with this aim.  
 

 
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6.2 Methods of minimising bias  
6.2.1 
Randomisation  
Not applicable.  
6.2.2 
Blinding procedures  
Not applicable.  
6.2.3 
Other methods of minimising bias  
 
Validated questionnaires will be used, and a statistical analysis plan is included in the 
protocol.  
 
Participants will record symptoms daily using a mobile application (paper version available). 
The study nurse will call participants if this technology is not used regularly.  
 
Objective assessment of gastric motor and sensory function will complement patient related 
outcome measurements. 
 
Compliance will be checked at the end of the treatment period. 
 
6.3 Unblinding Procedures 
Not applicable.  
7. STUDY POPULATION  
Patients with dyspeptic symptoms referred to gastroenterologists at Clinic Arlesheim for specialist 
investigation and management will be screened for eligibility. 
 
7.1 Eligibility criteria  
Participants fulfilling all of the following inclusion criteria are eligible for the study: 
 
Patients referred by their treating physician to the Center for integrative Gastroenterology at 
the Clinic Arlesheim  
 
Age over 18 years and ≦75 years of age 
 
Patients with diagnostic criteria of Functional Dyspepsia with Postprandial Distress (Rome IV 
criteria) with Leuven Dyspepsia Score “at least moderate” severity (≥2/4) on at least two 
subscales (≥4 total). Normal endoscopy in previous 3 years. 
 
Signed informed consent  
 
No change in medical treatment (e.g., proton pump inhibitor, antidepressants) during the last 
one month or for the duration of the period 
 
No planned introduction or dose increases of (conventional) anxiolytics or antidepressants 
during the last one month or for the duration of the period  
 
Good German knowledge (at least level B2 from Common European Framework of Reference 
for Languages)  
 
The presence of any one of the following exclusion criteria will lead to exclusion of the participant: 
 
Acute life-threatening conditions  
 
Withdrawal of informed consent  
 
Clinically relevant psychiatric comorbidity (HADS score >11 for anxiety or depression) 
 
Advanced liver (Child score > 6) or kidney disease (GFR < 60) 
 
History of major gastrointestinal surgery (appendectomy, hysterectomy, cholecystectomy, 
hernia repair are not exclusion criteria) 
 
Allergy to any component of Amara 
 
Treatment with Amara during the last one month prior to the study  
 
Pregnancy and lactation  
 
7.2 Recruitment and screening  
Patients referred for investigation of dyspeptic symptoms will be called by the department secretary or 

 
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a member of the team to make an appointment for their initial screening consultation at the Clinic 
Arlesheim. As also described in section 6.1, participants will then come to their initial consultation at the 
Clinic Arlesheim. If after this consultation the recruiting physician considers functional dyspepsia to be 
the diagnosis according to Rome IV classification, then the LDQ screening instrument will be used to 
confirm the presence and assess the severity of dyspepsia. A score of “at least moderate” severity (≥2/4) 
on at least two subscales (≥4 total) is the cut-off for study entry. Patients with clinically relevant, severe 
anxiety and depression will also be excluded (HADS ≥14). If no recent results are available, blood tests 
will be obtained to assess liver and kidney function. Total bilirubin, serum albumin, prothrombin time, 
ascites, hepatic encephalopathy and creatinine levels will be tested. At the screening visit, the LDS and 
HADS questionnaires will be completed at the time of recruitment and used as screening instruments. 
This data will be collected using an on-line application (paper versions also available). To rule out 
pregnancy, women of childbearing potential must take a pregnancy test. 
 
If the patient fulfils all inclusion criteria and none of the exclusion criteria, the patient will be asked if 
she/he wants to participate. If she/he does want to participate, she/he will sign the informed consent 
form and will be included in the study. If desired, the study nurse will help the subjects to fill in the 
demographic details and further questionnaires detailed in the method above.  
No payment will be given to study participants. Neither the subjects nor their health insurance companies 
incur additional costs in connection with participation in this study. 
  
7.3 Assignment to study groups  
The present trial is a single arm study.  
 
7.4 Criteria for withdrawal / discontinuation of participants  
In emergency situations, where acute symptoms develop or side effects are suspected to be 
associated with the Amara intake, treatment can be discontinued. The participation can also be 
terminated by the PI, by the Clinic Arlesheim or by the manufacturer of Amara if there is a suspicion of 
damage to health caused by the drug or a product defect, respectively. Also, as mentioned before, if 
there are any signs of patients unwilling to participate in the study it will result in the participant being 
excluded from the study.  
If a participant does no longer fulfil the eligibility criteria at some point of the study, it will lead to the 
discontinuation of this participant from the study.  
Participant recruitment will continue until 60 patients have completed the treatment arm of the study.  
8. STUDY INTERVENTION  
8.1 Identity of Investigational Products (treatment / medical device)  
The dosage of Amara is 3 x 10-20 drops per day prior to meals. 
 
8.1.1 
Experimental Intervention (treatment / medical device) 
The bitter substances Artemisia absinthium, Cichorium intybus, Juniperus and Gentiana lutea, Amara 
Drops contain also Centaurium, Peucedanum, Achillea millefolia, Salvia officinalis and Taraxacum are 
held in an alcohol-based tincture. Amara is an herbal preparation manufactured by Weleda AG 
(Switzerland), according to Good Manufacturing Practice.  
 
8.1.2 
Control Intervention (standard/routine/comparator treatment / medical device)  
No control intervention.  
 
8.1.3 
Packaging, Labelling and Supply (re-supply)  
The Amara drops to be used in this study are a standard commercial product. They will be available in 
the standard labelled, brown glass. One glass bottle contains 50ml (enough for minimum 100 doses à 

 
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20 drops). The manufacturer Weleda AG will supply us with the medication in batches. The pharmacy 
at Clinic Arlesheim will print instructions on the dose and when to take the medication on an additional 
label.   
 
8.1.4 
Storage Conditions  
The recommended storage temperature 15-25° C will be complied with. The Amara bottles to be used 
in the study will be stored in a lockable medicine cabinet at the out-patient clinic in an air-conditioned 
room at constant temperature. 60 glass bottles can be stored at once.  
 
 
8.2 Administration of experimental and control interventions  
 
8.2.1 
Experimental Intervention  
See chapter 8.1.1. 
8.2.2 
Control Intervention 
No control intervention.  
 
8.3 Dose modifications  
Participants can vary the dose of the prescribed drug dose within set limits (10-20 drops with meals). 
This should not be exceeded even in case of worsening symptoms.  
 
8.4 Compliance with study intervention  
Compliance will be assessed by a smart phone app (patients will be asked to confirm intake every day). 
At the end of the study, the bottles will be weighed to determine the actual dose taken during study 
procedures. Before analysing the data, we will determine the target-actual-difference of the Amara drops 
taken for each participant. Less than 50 % of prescribed intake is considered as insufficient compliance. 
In case of insufficient compliance of participants, those data have to be excluded from the per protocol 
analysis.  
 
8.5 Data Collection and Follow-up for withdrawn participants  
In the event of withdrawal, the data collected up to this point will continue to be used. 
 
8.6 Trial specific preventive measures 
Treatment with Amara during the last one month prior to the study is not permitted and leads to the 
exclusion of the study. No specific preventive measures are necessary.  
 
8.7 Concomitant Interventions (treatments)  
Current medications, such as acid suppression or antidepressants, can continue to be taken by the 
participants during the study without dose increase or decrease. This also includes all self-purchased 
preparations that are available without a doctor's prescription and complementary-medical preparations. 
Participants will record the use of additional medication in the CRF. They also have to record if they are 
being treated by other physicians during the study.  
 
8.8 Study Drug Accountability  
Immediately after handing out the study drug a receiving inspection will be carried out using the delivery 
note and the order form. Information on quantities, batch number, damages and shelf life will be 
recorded in writing in the corresponding Standard Operating Procedure (SOP) document.   
In case a participant has signed the informed consent, at the end of the consultation one 50ml bottle of 
Amara will be given to the participant to take home. The distribution of the test substance will be signed 

 
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by the participant and IP on the SOP document. Drugs with the shortest expiry date will be distributed 
first. Regular expiration date checks will be carried out.  
Patient compliance will be assessed using a smart phone application that will record whether medication 
was taken and the severity of symptoms at the end of each day. Patient compliance (i.e. actual intake) 
will be checked by weighing the bottle at the end of the treatment period.  
 
8.9 Return or Destruction of Study Drug  
Participants are asked to send back the glass with the remaining liquid. The study team will check 
compliance (i.e. actual intake) by weighing the bottle at the end of the treatment period and then send 
the investigational product to the pharmacy (Apotheke Klinik Arlesheim) for destruction. The handover 
will be documented in writing in a SOP. 
 

 
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9. STUDY ASSESSMENTS  
9.1 Study flow chart(s) / table of study procedures and assessments 
 
 
 
 
Approval of protocol by EKNZ 
Assessment of eligibility
Excluded
Demographic data collection
& Questionnaires
Run in period (2-4-weeks)
Daily symptom assessment
Questionnaire 
Amara Treatment
(4 weeks)
Daily symptom assessment
Study day #1
Screening
Study Day #2
Baseline assessment
Clinical & Physiological 
without Amara treatment
End Study
Return of Test Substance
Data analysis 
NTM Drink Test
Gastric Emptying off Amara
Excluded
Questionnaire 
NTM Drink Test
Gastric Emptying on Amara
Study Intervention
Study Day #3
Clinical & Physiological 
on Amara treatment
Study completion

 
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9.2 Assessments of outcomes  
The primary study outcome of dyspeptic symptoms will be assessed by the LDQ three times (screening, 
baseline, study completion).  
Secondary study outcomes will be assessed (i) by other validated questionnaires assessing 
gastrointestinal and psychological comorbidity as well as (ii) by physiological measurement of gastric 
motor and sensory function using the NTM Drink Test with 13C measurement of gastric emptying (section 
5). Additionally, the Lüscher Colour Test will be performed to assess the psychological state and 
personality profile potentially changing during treatment (section 5.3).  
 
9.2.1 
Assessment of primary outcome  
See section 5.1.  
 
9.2.2 
Assessment of secondary outcomes 
See section 5.2. 
 
9.2.3 
Assessment of other outcomes of interest 
See section 5.3 
 
9.2.4 
Assessment of safety outcomes 
9.2.4.1 
Adverse events  
AEs will be recorded, although the Swiss law on clinical research does not require the documentation 
of AEs for Category A drug trials. Participants will record possible side effects in the app or booklet and 
are instructed depending on urgency to get in touch with the team of doctors.  
Information to be collected about side effects can be seen in chapter 5.4. 
 
9.2.4.2 
Laboratory parameters 
Urine pregnancy tests will be carried out during the screening visit.  In emergency situations laboratory 
parameters may be assessed if required.  
 
9.2.4.3 
Vital signs 
No vital signs will be assessed in the context of the study except in emergency situations which may 
require it.  
 
9.2.5 
Assessments in participants who prematurely stop the study 
Assessments in participants who are withdrawn from the study prematurely, depend on the type and 
severity of the SAE. Participants who are withdrawn from the study prematurely due to the occurrence 
of exclusion criteria other than SAEs will not require any follow-up. 
See chapter 10. for further information about follow-ups for participants who prematurely stop the study.  
 
9.3 Procedures at each visit 
9.3.1 
Screening visit 
At the orientation consultation/screening visit the investigator will review the case notes, investigation 
results (e.g., laboratory tests, gastroscopy) and interview the patient to ensure that inclusion and 
exclusion criteria are met. In order to comply with the inclusion criteria, pregnancy tests will be performed 
on all women of childbearing age. At the screening visit, the LDS and HADS questionnaires will be 
completed at the time of recruitment and used as screening instruments. This data will be collected 
using an on-line application. After inclusion, further health-related questionnaires will be completed and 

 
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the Lüscher Color Test will be performed.  
A time is booked 2-4 weeks later for the second study visit. A mobile application will be downloaded 
onto the personal smart phone device (Symptom Tracker, Gastric Imaging & Analysis GmbH). Paper 
forms are available if required. During the 2-4 week “run-in” period patients will document their 
symptoms every day using a mobile application. A reminder will be sent to complete this electronic form 
every day at 21:00. 
 
9.3.2 
Study visits 
On the second visit, patients will complete a combined assessment of gastric motor and sensory function 
off treatment with the Nottingham Test Meal, with gastric emptying documented by 13C-Breath Testing. 
On completion of the test, the test substance will be provided to the patient with instructions on how and 
when to take the Amara. An appointment will be made 4-6 weeks after this appointment for the third and 
final visit. Based on this, the start day for the intervention will also be determined. 
During the 4-week intervention, 10-20 drops of Amara will be taken prior to every meal. Patients will 
document their symptoms every day using a mobile application. Adverse events can also be recorded. 
Paper forms are available if required. A reminder will be sent to complete this electronic form every day 
at 21:00. 
Shortly before the third study visit participants receive an e-mail with a questionnaire link. All 
questionnaires will be completed again. If it is noted during the visit that the questionnaires has not been 
filled in, this can be done in the waiting room or during the visit. The patient will complete a combined 
assessment of gastric motor and sensory function on Amara treatment with the Nottingham Test Meal, 
with gastric emptying documented by 13C-Breath Testing. On completion of the test, in addition to the 
PROM, the patient will be asked about their subjective assessment of the intervention, whether ongoing 
treatment is desired and whether they would recommend the treatment to other patients with functional 
dyspepsia. Additionally, compliance with study procedures will be assessed (bottle(s) of Amara will be 
weighed). At the end of the study, patients are reimbursed a lump sum of 50 Swiss francs for expenses 
(gas, parking fee, train ticket etc.). More can be provided if an invoice supported by receipts is sent to 
the principal investigator. 
 
In a subset of 20 consecutive patients, gastric electrical activity will be measured before, during and 
after ingestion of the Nottingham Test Meal on the second and third study visit using the non-invasive 
Gastric Alimetry System (high-resolution gastric mapping / electro-gastrography). Concurrent heart rate 
monitoring will provide an assessment of cardiovagal tone / autonomic nervous function. 
10. SAFETY 
10.1 Drug studies 
The Sponsor’s SOPs provide more detail on safety reporting. 
During the entire duration of the study, all unexpected adverse events (UAW) and serious adverse 
events (SAEs) are collected, investigated, and documented in source documents and case report forms 
(CRF). Study duration encompassed the time from when the participant signs the informed consent until 
the last protocol-specific procedure has been completed.  
 
10.1.1 Definition and assessment of (serious) adverse events and other safety related events 
An Adverse Event (AE) is any untoward medical occurrence in a patient, or a clinical investigation 
participant administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with the study procedure. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. 
ICH E6 1.3 
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that: 
 
results in death, 
 
is life-threatening, 
 
requires in-patient hospitalization or prolongation of existing hospitalisation, 

 
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 
results in persistent or significant disability/incapacity, or 
 
is a congenital anomaly/birth defect. 
In addition, important medical events that may not be immediately life-threatening or result in death, or 
require hospitalisation, but may jeopardise the patient or may require intervention to prevent one of the 
other outcomes listed above should also usually be considered serious. ICH E2A 
SAEs should be followed until resolution or stabilisation. Participants with ongoing SAEs at study 
termination (including safety visit) will be further followed up until recovery or until stabilisation of the 
disease after termination.  
 
Assessment of Causality 
The Sponsor-investigator makes a causality assessment of the event to the study drug, based on the 
criteria listed in the ICH E2A guidelines: 
 
Relationship 
Description 
Definitely 
Temporal relationship 
Improvement after dechallenge* 
Recurrence after rechallenge 
(or other proof of drug cause) 
Probably 
Temporal relationship 
Improvement after dechallenge 
No other cause evident 
Possibly 
Temporal relationship 
Other cause possible 
Unlikely 
Any assessable reaction that does not fulfil the above conditions 
Not related 
Causal relationship can be ruled out 
*Improvement after dechallenge only taken into consideration, if applicable to reaction 
 
Unexpected Adverse Drug Reaction 
An “unexpected” adverse drug reaction is an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g. Investigator’s Brochure for drugs that are not yet 
approved and Product Information for approved drugs, respectively). ICH E2A 
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The Sponsor-Investigator evaluates any SAE that has been reported regarding seriousness, causality 
and expectedness. If the event is related to the investigational product and is both serious and 
unexpected, it is classified as a SUSAR.  
 
Assessment of Severity 
Grades for severity described in the “Common Terminology Criteria for Adverse Events CTCAE Version 
5.0 may be used.  
 
10.1.2 Reporting of serious adverse events (SAE) and other safety related events  
As stated in the contract between the Clinic Arlesheim and Weleda AG, we will comply with our 
pharmacovigilance obligations.  UAWs, SAEs and SUSARs will be reported to Weleda AG (see contact 
below) within a maximum of 24 hours. Any other side effects which are collected through the 
questionnaires will be notified to Weleda AG as soon as possible.  
 

 
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Address: WELEDA AG, Dychweg 14, CH-4144 Arlesheim  
Contact: Yvonne Bäckert, +41 79 793 52 30, pharmacovigilance@weleda.ch 
Reporting of SAEs: 
All SAEs must be reported immediately and within a maximum of 24 hours to the PI of the study. The 
PI will re-evaluate the SAE and make a causality assessment of the event to the study drug.  
SAEs resulting in death are reported to the Ethics Committee via BASEC within 7 days. 
If the possibility arises that a patient can admit the Clinic Arlesheim earlier than expected, it will lead to 
the discontinuation of this participant from the study. This hospital stay will not be considered as an SAE. 
Additionally, if a SAE is a clear result of the underlying disease, this SAE is exempted from expedited 
reporting.  
 
Reporting of SUSARs 
The Sponsor-Investigator needs to report SUSARs to the Ethics Committee via BASEC within 7 days, 
if the event is fatal, or within 15 days (all other events). 
 
Reporting of Safety Signals 
All suspected new risks and relevant new aspects of known adverse reactions that require safety-
related measures, i.e. so called safety signals, must be reported to the Sponsor-Investigator within 24 
hours. The Sponsor-Investigator must report the safety signals within 7 days to the Ethics Committee 
via BASEC.  
 
Reporting and Handling of Pregnancies 
Pregnant participants will be excluded from the clinical study  
 
Periodic reporting of safety 
An annual safety report is submitted once a year to the local Ethics Committee via PI.  
 
10.1.3 Follow up of Serious Adverse Events 
In case of participants terminating the study with reported ongoing SAEs beyond alert, participants will 
have a follow-up check-up as soon as the patient is hospitalized at the Clinic Arlesheim. The procedures 
depend on the type and severity of the SAE.  
 
11. STATISTICAL METHODS  
11.1 Hypothesis 
Null hypothesis: There will be no difference in the primary outcome (LDQ score) between baseline and 
after four weeks of Amara treatment.  
Alternative hypothesis: The LDQ score after four weeks treatment is different from the LDQ-score before 
the treatment. 
In the case of statistical significance, the null hypothesis is rejected and the described difference 
(reduction or increase) is found to be proven according to the alternative hypothesis. 
All secondary outcomes are purely exploratory, where effects are looked at and no Null Hypothesis is 
tested. This study is designed to get an idea of the effect size, since an estimation of the effect size is 
needed in order to calculate the sample size of a subsequent confirmatory study.  
 
11.2 Determination of Sample Size  
In this prospective open label study, placebo effects are likely to be present. Previous randomized 
controlled trials of therapy in functional gastrointestinal disorders indicate that this can be present in up 
to 40% of patients.(15) To compensate for this confounding factor and to demonstrate convincing 

 
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changes in perceived symptom burden at least 60% of patients should show improvement on-treatment 
compared to off-treatment (run-in phase). Assuming a moderate effect (Cohen's effect size of 0.4) on 
the primary outcome measure (effect size and standard deviation as in a previous paper by Carbone et 
al. (21)) power calculation suggests that 58 patients are required to detect a significant effect at a 
convincing level of statistical significance (beta 0.9, alpha <0.05). In the context of this study, the 
inclusion of 60 patients should also be sufficient to inform the design of any, future randomized, placebo-
controlled study.   
 
11.3 Statistical criteria of termination of trial  
Statistical criteria for the termination of the trial are not intended.  
 
11.4 Planned Analyses  
The statistic evaluation will be performed with SPSS (IBM SPSS Statistics, NY: IBM Corp.), version 26 
or higher or Graphpad Prism (MacKiev Software), version 9.3.1 or higher or higher for PC or Mac. The 
demographic data will be analysed with descriptive statistics as average ± standard deviation (SD) for 
continuous variables and with percentage of total (%) for categorical variables.  
Differences between the scores from the primary and secondary endpoint variables – at baseline and 
after 4-weeks treatment - will be compared initially by t-test if the data is normally distributed and 
Wilcoxon rank sum test when data are not normally distributed. In addition, if data is normally distributed 
we will perform univariate and multivariate linear regression analysis in which potential covariates will 
be considered; confounding will be evaluated by adding these variables to the linear regression model 
and looking at the change of the regression coefficients. These variables will include participants age, 
gender, symptom severity, psychological state and gastric function (sensitivity, emptying) at baseline. 
In the analysis of the primary outcome two-tailed p ≤0.05 will be considered statistically significant. Since 
the evaluation of the secondary endpoints is purely exploratory, other p-values will be calculated but 
reported without claiming significance,  
Data will be transferred from the REDCap software to the statistics program Prism for evaluation, where 
data are password protected and only accessible to the persons involved in the study. 
All analyses will be performed at Klinik Arlesheim by the research group of Prof. Dr. Mark Fox, 
Department of Gastroenterology, Klinik Arlesheim.  
 
11.4.1 Datasets to be analysed, analysis populations 
At the end of the study subgroups will be created. We will analyse all outcome variables age, gender, 
dyspepsia symptom severity (LDQ), other gastrointestinal symptoms, psychological state and gastric 
function (sensitivity, emptying) at baseline. 
 
11.4.2 Primary Analysis 
In the intention to treat analysis, all patients who have completed study questionnaires at baseline and 
after four-weeks of treatment will be included. Following covariates will be included in multivariate 
models: age, gender, dyspepsia symptom severity (LDQ), other gastrointestinal symptoms, 
psychological state and gastric function (sensitivity, emptying) at baseline. 
11.4.3 Secondary Analyses 
In the per protocol analysis (after four weeks), only patients who have taken at least half of the study 
medication will be included. Comparisons will be made between scores at study begin and scores after 
four weeks of treatment. Following covariates will be included in multivariate models: age, gender, 
dyspepsia symptom severity (LDQ), other gastrointestinal symptoms, psychological state and gastric 
function (sensitivity, emptying) at baseline. 
11.4.4 Interim analyses 
No interim analyses are planned. 
 

 
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11.4.5 Safety analysis 
The side effects will be analysed with descriptive statistics as percentage of total (%) for categorical 
variables. 
 
11.4.6 Deviation(s) from the original statistical plan  
Any deviations from the original statistical plan will be justified and reported as appropriate.  
 
11.5 Handling of missing data and drop-outs  
Participants who filled out only the screening and/or only the first questionnaire (baseline) will be defined 
as dropouts. These dropouts will be replaced.   
12. QUALITY ASSURANCE AND CONTROL  
The Sponsor-Investigator is responsible for implementing and maintaining quality assurance and quality 
control systems with written SOPs. Every work step will be carried out and recorded accordingly.  
Before the beginning of the study the PI will hold a proper training for all involved study personnel. 
Additionally, the staff will receive written documents concerning the study from the PI.  
 
12.1 Data handling and record keeping / archiving  
 
12.1.1 Case Report Forms  
The electronic Case Report Form (eCRF, or paper equivalent if required) will comprise the participant’s 
number, the standardised questionnaires LDQ, RDQ, IBS-SSS, HADS, PHQ, ICS, as well as socio-
demographic and health-related data (Prüfbogen: Patientendaten, Gesundeheitsfragebogen),  collected 
during screening. Additionally, outcomes of the physiological investigations detailing gastric function will 
be transferred in electronic form from the FAN Fischer 13C Breath Analysis device to the eCRF. The 
Lüscher Colour Test is not validated for use on electronic media. This information will be collected and 
analysed manually. 
Prüfbogen (13-C Atemtest) and Prüfbogen (Checkliste) will be used as paper version. In exceptional 
cases, Prüfbogen (Patientendaten and Gesundheitsfragebogen) can also be completed on paper. 
 
The participants will be identifiable in the eCRF/CRF neither by name nor by initials and nor by date of 
birth. 
Once completed, data will be entered into REDCap. Any data from paper forms will be entered using 
the double data entry method. The data transfer from paper into the eCRF will be done at the Clinic 
Arlesheim. Only persons involved in the study are allowed to make eCRF entries. It will be assured that 
any authorised person making a CRF entry can be identified by name.   
 
12.1.2 Specification of source documents  
The ICF and the SAE standard form are found to be source data. Data collected through questionnaires 
in the CRF should also be considered being source data. Furthermore, any data from the clinical 
information system InesKis will be transferred to REDCap and be considered source data.  
 
12.1.3.  Record keeping / archiving  
All study data (electronic or on paper) will be archived for a minimum of 10 years after the study 
termination or premature termination of the clinical trial. Data on paper will be stored in a lockable cabinet 
in the research department of the Clinic Arlesheim. Digital data will be kept on the internal of the server 
of Clinic Arlesheim, protected by a password and archived for a minimum of 10 years.  
 

 
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12.2 Data management  
 
12.2.1 Data Management System  
An eCRF will be prepared at the Clinic Arlesheim by the Research Group of Prof. Dr. med. Mark Fox 
(Department of Gastroenterology, Clinic Arlesheim) with the REDCap software, a browser-based 
research data base. It is a widely used software in the academic research community. REDCap offers 
daily backups, basic support, and an audit trail feature for even more security.  
 
12.2.2 Data security, access and back-up  
REDCap creates automatic back-ups by the REDCap Team. Additionally, manual back-ups will be made 
by Prof. Dr. med. Mark Fox and stored password-protected on the local server of the Clinic Arlesheim.  
 
12.2.3 Analysis and archiving 
REDCap provides automated export procedures for seamless data downloads to statistical analysis 
software. Data export files will be stored password-protected on the local server of the Clinic Arlesheim. 
Data analysis will be archived at Clinic Arlesheim for a minimum of 10 years. 
 
12.2.4 Electronic and central data validation  
REDCap provides real-time data validation, integrity checks, and other mechanisms for ensuring data 
quality (e.g., double data entry). Data validation ensures that correct data type is being entered and the 
value is within the expected range. Commercial statistical analysis software has built-in data validation 
mechanisms as well. 
 
12.3 Monitoring  
Mrs Forst will be responsible for the verification of the documentation for completeness and topicality 
(TMF), checking the data for completeness and plausibility, source data verification and the preparation 
of the monitoring plan and the monitoring report. All source data and documents are accessible to the 
monitor and all possible questions will be answered during monitoring (see Monitoring Plan). 
 
12.4 Audits and Inspections  
Study documentation and the source data/documents are accessible to auditors/inspectors (also CEC) 
and questions will be answered during inspections. All involved parties will keep the participant data 
strictly confidential. The inspector is independent of any person involved in the study.  
During the audit, the following points are checked, among others: 
- Performance of the study according to the study plan, 
- Validity of the data, 
- Quality of the study according to GCP guidelines. 
After each inspection, the investigator receives a confirmation from the person responsible for the 
inspection. This confirmation is kept at the study centre in the research department. 
 
12.5 Confidentiality, Data Protection  
Direct access to source documents will be permitted for purpose of monitoring, audits and inspections.  
The following people will have access to protocol, dataset, statistical code during and after (publication) 
the study: 
Prof Dr med Mark Fox 
Dr rer nat Daniel Krüerke 
Tiffany Huber 
 

 
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12.6 Storage of biological material and related health data  
No biological material will be collected in the current study. 
 
13. PUBLICATION AND DISSEMINATION POLICY  
Every effort will be made to publish the results of this clinical trial in a peer-reviewed journal. The 
publication or presentation of the results requires prior comment and approval by the PI. All publications 
are subject to the protection of the privacy of all patient data. Data protection is also maintained if 
journals wish to have the raw data submitted so that the data cannot be traced back to individuals. 
14. FUNDING AND SUPPORT  
14.1 Funding  
The study is partly financed by the Clinic Arlesheim partly by Weleda F&E AG. 
Details of the financing are set out in the relevant contracts between the Clinic Arlesheim AG and the 
corresponding funders. 
 
14.2 Other Support  
The IMP is provided free of charge by Weleda AG. This has also placed on record in the contract 
between Weleda F&E AG and the Clinic Arlesheim AG.  
Financial and other support from Weleda F&E AG is linked to the following information obligation: 
Weleda F&E AG undertakes to inform the Clinic Arlesheim AG immediately of any changes in content 
or personnel that occur in connection with the project. 
The Clinic Arlesheim AG undertakes to inform Weleda F&E AG immediately of any personnel changes 
insofar as they affect the implementation of the project and to have these changes approved by Weleda 
F&E. 
15. INSURANCE  
The liability insurance of the Clinic Arlesheim AG will pay for any damages within the scope of the study. 
The insurance certificate can be found in the appendix. 
16. REFERENCES  
1. 
Stanghellini V, Talley NJ, Chan F, Hasler WL, Malagelada J, Suzuki H, et al. Rome IV - 
Gastroduodenal Disorders. Gastroenterology. 2016. 
2. 
Vanheel H, Vanuytsel T, Van Oudenhove L, Farre R, Verbeke K, Tack J. Postprandial symptoms 
originating from the stomach in functional dyspepsia. Neurogastroenterol Motil. 2013;25(11):911-e703. 
3. 
Burns G, Carroll G, Mathe A, Horvat J, Foster P, Walker MM, et al. Evidence for Local and 
Systemic Immune Activation in Functional Dyspepsia and the Irritable Bowel Syndrome: A Systematic 
Review. Am J Gastroenterol. 2019;114(3):429-36. 
4. 
Zagari RM, Law GR, Fuccio L, Cennamo V, Gilthorpe MS, Forman D, et al. Epidemiology of 
functional dyspepsia and subgroups in the Italian general population: an endoscopic study. 
Gastroenterology. 2010;138(4):1302-11. 
5. 
Delaney B, Ford AC, Forman D, Moayyedi P, Qume M. Initial management strategies for 
dyspepsia. Cochrane Database Syst Rev. 2005(4):CD001961. 
6. 
Heikkinen M, Pikkarainen P, Takala J, Rasanen H, Julkunen R. Etiology of dyspepsia: four 
hundred unselected consecutive patients in general practice. Scand J Gastroenterol. 1995;30(6):519-
23. 
7. 
Stake K, Soderlund M, Hultcrantz R, Unge P. A qualitative study of complementary and 
alternative medicine use in uninvestigated dyspepsia. Gastroenterol Nurs. 2009;32(2):107-14. 

 
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8. 
Moayyedi P, Soo S, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions 
for non-ulcer dyspepsia. Cochrane Database Syst Rev. 2006(4):CD001960. 
9. 
Chiarioni G, Pesce M, Fantin A, Sarnelli G. Complementary and alternative treatment in 
functional dyspepsia. United European Gastroenterol J. 2018;6(1):5-12. 
10. 
Rosch W, Vinson B, Sassin I. A randomised clinical trial comparing the efficacy of a herbal 
preparation STW 5 with the prokinetic drug cisapride in patients with dysmotility type of functional 
dyspepsia. Z Gastroenterol. 2002;40(6):401-8. 
11. 
Melzer J, Rosch W, Reichling J, Brignoli R, Saller R. Meta-analysis: phytotherapy of functional 
dyspepsia with the herbal drug preparation STW 5 (Iberogast). Aliment Pharmacol Ther. 2004;20(11-
12):1279-87. 
12. 
Vijayvargiya P, Chedid V, Wang XJ, Atieh J, Maselli D, Burton DD, et al. Associations of gastric 
volumes, ingestive behavior, calorie and volume intake, and fullness in obesity. Am J Physiol 
Gastrointest Liver Physiol. 2020;319(2):G238-G44. 
13. 
Vijayvargiya P, Jameie-Oskooei S, Camilleri M, Chedid V, Erwin PJ, Murad MH. Association 
between delayed gastric emptying and upper gastrointestinal symptoms: a systematic review and meta-
analysis. Gut. 2019;68(5):804-13. 
14. 
Hamre HJ, Glockmann A, Heckenbach K, Matthes H. Use and Safety of Anthroposophic 
Medicinal Products: An Analysis of 44,662 Patients from the EvaMed Pharmacovigilance Network. 
Drugs Real World Outcomes. 2017;4(4):199-213. 
15. 
Corazziari E, Bytzer P, Delvaux M, Holtmann G, Malagelada JR, Morris J, et al. Clinical trial 
guidelines for pharmacological treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 
2003;18(6):569-80. 
16. 
Fox MR, Kahrilas PJ, Roman S, Gyawali CP, Scott SM, Rao SS, et al. Clinical measurement of 
gastrointestinal motility and function: who, when and which test? Nat Rev Gastroenterol Hepatol. 
2018;15(9):568-79. 
17. 
Kim DY, Myung SJ, Camilleri M. Novel testing of human gastric motor and sensory functions: 
rationale, methods, and potential applications in clinical practice. Am J Gastroenterol. 
2000;95(12):3365-73. 
18. 
Parker HL, Tucker E, Blackshaw E, Hoad CL, Marciani L, Perkins A, et al. Clinical assessment 
of gastric emptying and sensory function utilizing gamma scintigraphy: Establishment of reference 
intervals for the liquid and solid components of the Nottingham test meal in healthy subjects. 
Neurogastroenterol Motil. 2017;29(11). 
19. 
Parker HL, Tucker E, Hoad CL, Pal A, Costigan C, Hudders N, et al. Development and validation 
of a large, modular test meal with liquid and solid components for assessment of gastric motor and 
sensory function by non-invasive imaging. Neurogastroenterol Motil. 2016;28(4):554-68. 
20. 
Ehrenpreis ED, Deepak P, Sifuentes H, Devi R, Du H, Leikin JB. The metoclopramide black box 
warning for tardive dyskinesia: effect on clinical practice, adverse event reporting, and prescription drug 
lawsuits. Am J Gastroenterol. 2013;108(6):866-72. 
21. 
Carbone F, Vandenberghe A, Holvoet L, Vanuytsel T, Van Oudenhove L, Jones M, et al. 
Validation of the Leuven Postprandial Distress Scale, a questionnaire for symptom assessment in the 
functional dyspepsia/postprandial distress syndrome. Aliment Pharmacol Ther. 2016;44(9):989-1001. 
22. 
Masuy I, Tack J, Verbeke K, Carbone F. Acotiamide affects antral motility, but has no effect on 
fundic motility, gastric emptying or symptom perception in healthy participants. Neurogastroenterol Motil. 
2019;31(4):e13540. 
23. 
Carbone F, Vanuytsel T, Tack J. The effect of mirtazapine on gastric accommodation, gastric 
sensitivity to distention, and nutrient tolerance in healthy subjects. Neurogastroenterol Motil. 
2017;29(12). 
24. 
Hoad CL, Parker H, Hudders N, Costigan C, Cox EF, Perkins AC, et al. Measurement of gastric 
meal and secretion volumes using magnetic resonance imaging. Phys Med Biol. 2015;60(3):1367-83. 
 
 
 

 
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17. APPENDIX  
- 
Standard Operating Procedure: Assessment of gastric function by 13C-Breath Testing with the 
Nottingham Test Meal 
- 
Questionnaires: Leuven Dyspepsia Questionnaire (LDQ), Reflux Disease Questionnaire 
(RDQ), Irritable Bowel Syndrome Symptom Severity Score (IBS-SSS), Hospital Anxiety and 
Depression Score (HADS), Personal Health Questionnaire (PHQ15), Internal Coherence 
Scale (ICS), Trait autonomous Regulation (Trait aR) 
- 
Protocol Sheet for the Recording of Lüscher Color Test (LCT) Results 
- 
Description of Gastric Alimetry System with Investigator Brochure, FDA approval certificate 
and MHRA registration of conformity 
- 
Case Report Form: Checkliste 
- 
Cover Letter, Patient Information Sheet, Informed Consent 
- 
Monitoring Plan (Draft)  
- 
Contract