The Chemopreventive Effect of Lithium on Adenoma Development in Patients With Familial Adenomatous Polyposis (FAP); a Pilot Study
Phase: PHASE2
Conditions: Familial Adenomatous Polyposis
Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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RESEARCH PROTOCOL 
 
‘The chemopreventive effect of Lithium on 
adenoma development in patients with familial 
adenomatous polyposis (FAP); a pilot study’ 
 
 
 
 
 
 
 
 
 
 
Correspondence to:  
Prof. dr. E. Dekker  
Department of gastroenterology and hepatology, C2  
Academic Medical Centre  
Meibergdreef 9  
1105 AZ Amsterdam 

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PROTOCOL TITLE ‘The chemopreventive effect of Lithium on adenoma development in 
patients with familial adenomatous polyposis (FAP); a pilot study’ 
 
Protocol ID 
NL80308.018.22 
Short title 
Lithium in FAP  
EudraCT number  
2022-000240-30 
Version 
3 
Date 
02-05-2022 
Coordinating 
investigator/project leader 
 
Prof. dr. E. Dekker  
Department of gastroenterology and hepatology, C2  
Academic Medical Centre  
Meibergdreef 9  
1105 AZ Amsterdam  
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
 
Prof. dr. E. Dekker  
Department of gastroenterology and hepatology, C2  
Academic Medical Centre  
Meibergdreef 9  
1105 AZ Amsterdam 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Prof. dr. L. Vermeulen  
Center for Experimental and Molecular Medicine, G2  
Academic medical center  
Meibergdreef 9  
1105 AZ Amsterdam  
Subsidising party 
KWF Kankerbestrijding 
Postbus 75508 
1070 AM Amsterdam  
Independent expert  
Dr. M. van der Vlugt 
Department of gastroenterology and hepatology, C2  
Academic Medical Centre  

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Meibergdreef 9  
1105 AZ Amsterdam 
Laboratory sites  
Center for Experimental and Molecular Medicine, G2  
Academic medical centre  
Meibergdreef 9  
1105 AZ Amsterdam 
Pharmacy  
TrialApotheek AMC  
 Academic Medical Centre  
Meibergdreef 9  
1105 AZ Amsterdam 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Prof. dr. P. Fockens  
Gastroenterologist 
 
 
Coordinating Investigator/Project 
leader/Principal Investigator 
Prof. dr. E. Dekker  
Gastroenterologist 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................11 
2. 
OBJECTIVES ................................................................................................................13 
3. 
STUDY DESIGN ...........................................................................................................14 
4. 
STUDY POPULATION ..................................................................................................15 
4.1 
Population (base) ...................................................................................................15 
4.2 
Inclusion criteria .....................................................................................................15 
4.3 
Exclusion criteria ....................................................................................................15 
4.4 
Sample size calculation ..........................................................................................16 
5. 
TREATMENT OF SUBJECTS .......................................................................................17 
5.1 
Investigational product/treatment ............................................................................17 
5.2 
Use of co-intervention ............................................................................................17 
5.3 
Escape medication .................................................................................................18 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................19 
6.1 
Name and description of investigational product ....................................................19 
6.2 
Summary of findings from non-clinical studies ........................................................19 
6.3 
Summary of findings from clinical studies ...............................................................20 
6.4 
Summary of known and potential risks and benefits ...............................................20 
6.5 
Description and justification of route of administration and dosage .........................23 
6.6 
Dosages, dosage modifications and method of administration ...............................24 
6.7 
Preparation and labelling of Investigational Medicinal Product ...............................24 
6.8 
Drug accountability .................................................................................................24 
7. 
METHODS ....................................................................................................................26 
7.1 
Study parameters/endpoints ...................................................................................26 
7.1.1 
Main study parameter/endpoint .......................................................................26 
7.1.2 
Secondary study parameters/endpoints ..........................................................26 
7.1.3 
Other study parameters ...................................................................................26 
7.2 
Randomisation, blinding and treatment allocation ..................................................26 
7.3 
Study procedures ...................................................................................................26 
7.4 
Withdrawal of individual subjects ............................................................................28 
7.4.1 
Specific criteria for withdrawal .........................................................................29 
7.5 
Replacement of individual subjects after withdrawal ...............................................29 
7.6 
Follow-up of subjects withdrawn from treatment .....................................................29 
7.7 
Premature termination of the study .........................................................................29 
8. 
SAFETY REPORTING ..................................................................................................30 
8.1 
Temporary halt for reasons of subject safety ..........................................................30 
8.2 
AEs, SAEs and SUSARs ........................................................................................30 
8.2.1 
Adverse events (AEs) ......................................................................................30 
8.2.2 
Serious adverse events (SAEs) .......................................................................30 
8.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................31 
8.3 
Annual safety report ...............................................................................................32 
8.4 
Follow-up of adverse events ...................................................................................32 

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8.5 
Safety Committee ...................................................................................................32 
9. 
STATISTICAL ANALYSIS .............................................................................................34 
9.1 
Primary study parameter(s) ....................................................................................34 
9.2 
Secondary study parameter(s) ...............................................................................34 
9.3 
Other study parameters ..........................................................................................34 
9.4 
Interim analysis ......................................................................................................34 
10. ETHICAL CONSIDERATIONS ......................................................................................35 
10.1 
Regulation statement .............................................................................................35 
10.2 
Recruitment and consent........................................................................................35 
10.3 
Objection by minors or incapacitated subjects ........................................................35 
10.4 
Compensation for injury .........................................................................................35 
10.5 
Incentives. ..............................................................................................................36 
11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .............................37 
11.1 
Handling and storage of data and documents ........................................................37 
11.2 
Monitoring and Quality Assurance ..........................................................................37 
11.3 
Amendments ..........................................................................................................37 
11.4 
Annual progress report ...........................................................................................38 
11.5 
Temporary halt and (prematurely) end of study report ............................................38 
11.6 
Public disclosure and publication policy ..................................................................38 
12. STRUCTURED RISK ANALYSIS ..................................................................................40 
12.1 
Potential issues of concern .....................................................................................40 
12.2 
Synthesis ...............................................................................................................42 
13. REFERENCES ..............................................................................................................44 
14. APPENDIX ....................................................................................................................46 
14.1 
Appendix 1: Drugs that interact with Lithium ...........................................................46 
14.2 
Appendix 2: Side effects questionnaire ...................................................................47 
14.3 
Appendix 3: Patient diary........................................................................................48 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the application form 
that is required for submission to the accredited Ethics Committee; in Dutch: 
Algemeen Beoordelings- en Registratieformulier (ABR-formulier) 
AE 
Adverse Event  
AMC 
Amsterdam UMC, location AMC 
AR 
Adverse Reaction 
APC 
Adenomatous Polypolis Coli  
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
CEMM 
Centre for Experimental and Molecular Medicine 
CRC 
Colorectal Cancer  
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram  
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
FAP 
Familial adenomatous polyposis 
FDA 
The Food and Drug Administration 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
HRQoL  
Health Related Quality of Life  
IB 
Investigator’s Brochure 
IC 
Informed Consent 
ISC 
Intestinal Stem Cell 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
LGI 
Lower Gastrointestinal  
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
NSAID’s 
Non-Steroidal Anti-Inflammatory Drugs 
(S)AE 
(Serious) Adverse Event  

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SPC 
Summary of Product Characteristics; in Dutch: samenvatting van de 
productkenmerken  
Sponsor 
The sponsor is the party that commissions the organisation or performance of 
the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party that 
provides funding for a study but does not commission it is not regarded as the 
sponsor, but referred to as a subsidising party. 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; in 
Dutch: Uitvoeringswet AVG 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
WT 
Wilde Type  
 
 

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SUMMARY 
 
Rationale: Familial adenomatous polyposis (FAP) syndrome is characterized by the 
development of numerous colorectal polyps. If left untreated, these patients have a chance of 
nearly 100% of developing colorectal cancer (CRC) at a young age. Therefore, guidelines 
recommend a prophylactic colectomy during early adulthood. Even after colectomy, most 
patients will develop adenomas in the retained rectum or ileoanal pouch requiring further 
endoscopic surveillance. In a recent study in mouse models, a chemopreventive effect of 
Lithium was observed on the spread of Apc mutated cells within the crypts of normal 
intestinal mucosa, suggesting polyp formation can be prevented. Lithium is used to treat 
patients with bipolar disorders but has never been investigated in patients with FAP aiming to 
reduce polyp burden. We hypothesize that Lithium could reduce the spread of APC mutated 
cells within the crypt of normal intestinal mucosa potentially reducing polyp burden in patients 
with FAP.  
Objective: The aim of this study is to investigate the effect of low-dose Lithium on stem cell 
dynamics, the number and size of polyps and, to assess safety outcomes of this drug in FAP 
patients.   
Study design: A prospective phase II, single arm pilot trial, with a duration of 18 months. 
The drug will be administered between month 6 and 12.  
Study population: Twelve patients with FAP between the age of 18 and 35 not having 
undergone a colectomy (yet), having a genetically confirmed APC mutation and a family 
history with a classical FAP phenotype. 
Intervention: All patients will be treated with Lithium with an oral dose of 300mg a day for six 
months, achieving a therapeutic serum level between 0.2-0.4 mmol/L.  
Main study parameters/endpoints: The main outcome parameter is the effect of Lithium on 
the spread of APC mutant cells within intestinal crypts over time by using an APC specific 
marker NOTUM (a significance reduce of fixed crypts and reduction of fixed clone size of 
50%).  
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: A physical examination and an endoscopy with biopsies will be 
performed at baseline and every six months (four in total). Laboratory testing will be done at 
baseline and every two months during Lithium treatment. Patients will be interviewed by 
phone and Lithium side effect questionnaires will be obtained at baseline and during Lithium 
treatment. Lithium serum levels will be measured at day 12 and 22 after start of the study 
drug (at month 6). When the therapeutic range has been achieved, serum level testing will be 
done every month. Most relevant side-effects that could potential occur include polyuria, 
hyperparathyroidism and hypothyroidism. Most side effects are dose-dependent and will be 

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regularly monitored. Patients with FAP could potentially benefit from a chemopreventive 
therapy such as Lithium to postpone or even avoid invasive types of surgery.  

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1. INTRODUCTION AND RATIONALE 
 
Familial adenomatous polyposis (FAP) is an autosomal dominant disorder with a germline 
mutation in the tumor suppressor gene, Adenomatous Polyposis Coli (APC), with an 
estimated prevalence of 1 out of 5.000 – 7.000 births (1). Although FAP is a hereditary 
disease, a de novo mutation in the APC gene is responsible for approximately 25% of FAP 
cases (2). FAP is characterized by the early onset of hundreds to thousands of polyps in the 
colon and rectum. If left untreated, the risk of developing colorectal cancer (CRC) is nearly 
100% (3). Since the development of adenomatous polyps to CRC takes fifteen to twenty 
years, most untreated patients with FAP will develop CRC between the age of 35 and 45 
(1).To prevent CRC, guidelines suggest prophylactic surgery in these patients dependent on 
polyp burden, personal preference and family history (4). These invasive surgeries are 
mostly performed in the twenties and are known for the risk of postoperative comorbidities (5, 
6). Even after surgery, new polyp formation still occurs in the remaining part of the intestine, 
resulting in further need of endoscopic surveillance and potential interventions (7, 8). 
Therefore, patients with FAP could benefit from therapy preventing polyp formation resulting 
in postponing or even avoiding prophylactic surgery. Up to date, several studies on 
(chemo)preventive therapy for FAP patients were conducted but due to lack of a significant 
effect and adverse events (AE’s), no chemopreventive therapy for patients with FAP is 
routinely used in daily practice (9-11).  
 
A recent study showed a promising chemopreventive effect of Lithiumchloride in Apc-mutant 
mouse models (12). APC is a critical component of the Wnt signaling pathway, an essential 
signaling route involved in the maintenance of intestinal stem cells (ISCs). Loss of APC 
function results in unrestrained activation of the Wnt signaling pathway which can lead to the 
development of premalignant adenomas (13). Given the time it takes to develop CRC and 
the short lifespan of most intestinal cell types, it is generally assumed that cancer is initiated 
in the long-lived ISC compartment (14). Previous work demonstrated that ISCs that have 
acquired an Apc mutation have a competitive benefit over wild type (WT) ISCs (15). In 
addition, recent work has revealed that Apc mutant ISCs act as supercompetitors, that 
actively disadvantage WT ISCs. This supercompetitive advantage is due to the expression of 
of Wnt antagonists (e.g. Notum, Wif1, Dkk2) by Apc mutants to which they themselves are 
insensitive, but result in active replacement of WT ISCs that are heavily dependent on Wnt 
signaling. When all WT ISCs are replaced, the mutant clone is fixed within the crypt and will 
initiate adenoma formation (12). Intervening before fixation of the mutant clones within a 
crypt can act as a therapeutic window. In a recent study, van Neerven et al. discovered a 
benefit of the use of Lithiumchloride in mouse models based on Apc-inactivation (12). This 
study could trace mutant ISCs by labeling these cells for Wnt antagonist Notum, and 
analyzing their spread through the crypts over time. Their competitive benefit was 
determined by quantifying the distribution of Notum clones in crypt bottoms over time. In 
addition, this study revealed that boosting the Wnt pathway in WT ISCs using lithiumchloride 
rendered them resistant to the Wnt antagonists secreted by Apc-mutant cells. As a result, 

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lithiumchloride administration diminished the competitive advantage of Apc mutants, thereby 
reducing crypt fixation and thus preventing adenoma formation (12).  
 
Until now, no clinical data on Lithium use in patients with FAP is available. The aim of this 
study is to investigate the effect of low-dose Lithiumcarbonate on stem cell dynamics and 
number of polyps and to assess safety outcomes of this drug in FAP patients.   

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2. OBJECTIVES 
 
Primary Objective: 
- 
To evaluate the effect of low-dose Lithiumcarbonate on the spread of APC mutant 
cells within intestinal crypts of FAP patients over time. This will be assessed by using 
an APC mutation specific marker (NOTUM) and is defined as a significant reduction 
of fixed crypts and reduction of fixed clone size by 50%.  
 
Secondary Objective(s):  
- 
To evaluate the effect on number of polyps and size, determined as sum of diameter 
of all polyps. 
- 
To evaluate side effects of Lithiumcarbonate in FAP patients using Lithium side 
effects questionnaires; 
- 
To assess the safety of low-dose Lithiumcarbonate use by evaluating adverse events, 
findings during physical examination and laboratory tests.  
 

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3. STUDY DESIGN 
This study is a phase II, single arm pilot trial. Patients will be recruited at the Amsterdam 
UMC, location AMC (AMC). The duration of this study will be 18 months, and patients will 
undergo four colonoscopies in total (at t=0, t=6, t=12, t=18). During each colonoscopy 
biopsies from normal intestinal mucosa will be collected to determine stem cell dynamics. 
Safety outcomes will be monitored by regular physical examination, laboratory testing and 
telephone interviews. A safe therapeutic range will be maintained due to measuring serum 
levels of Lithiumcarbonate, and if necessary doses will be adjusted.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4. STUDY POPULATION 
4.1 Population (base)  
Patients (male and female) diagnosed with FAP, between the age of 18 and 35, not having 
undergone a colectomy (yet), are eligible for this study. We aim to include 12 patients for this 
pilot study, and patient recruitment will take place from the large cohort of FAP patients at the 
AMC. For this study no control group will be included, as the patients represent their own 
control in the non-treatment phase. To evaluate the effect of Lithiumcarbonate on the stem 
cell dynamics, regular biopsies of normal intestinal mucosa will be collected from each 
patient. International guidelines recommend (prophylactic) colectomy to be performed based 
on polyp burden, personal preference and family history, and this is most often performed 
when patients are in their twenties (4). Therefore, in the interest of studying the 
(chemo)preventive effect of Lithiumcarbonate in FAP patients, participants will be included 
up to an age of 35. In preparation of this study, a focus group meeting with 9 patients with 
FAP was organized to discuss the patients’ perspective on this study. Patient representatives 
emphasize the major need of (preventive) therapy for FAP. We believe patients will be 
motivated to participate in a study aiming to delay polyp growth and consequently surgery (7, 
8), and to be able to include twelve patients.  
 
4.2 Inclusion criteria 
Patients must meet all of the following criteria for inclusion in the study: 
- 
Male or female between the age of 18 and 35 years; 
- 
Confirmed APC germline mutation and one of the following: 
o Minimum of 100 colorectal adenomas 
o Minimum of 50 colorectal adenomas and a positive family history of a 
classical FAP phenotype (>100 colorectal adenomas); 
- 
Intact colon; 
- 
Participant is willing and able to give informed consent for participation;  
 
4.3 Exclusion criteria 
Patients that meets any of the following criteria will be excluded from participation in this 
study: 
- 
Participation in any other clinical intervention study; observational trials accepted; 
- 
Lithium use prior to participation of the study; 
- 
Pregnancy, breast-feeding or no use of anticonception; 
- 
No normal intestinal mucosa left for normal tissue biopsy;  
- 
Indication for colectomy within 2 years; 
- 
Known renal impairment, defined as GFR < 60 ml/min; 
- 
Known severe cardiac disorder;  
- 
Known severe brain injury; 

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- 
Hypothyroidism; 
- 
Hyponatremia, defined as Na < 130mmol/L; 
- 
Positive family history of Brugada syndrome   
- 
Co-medication known for interacting with Lithium (please see Table 3). 
- 
Regular NSAID use (defined as more than twice a week for 4 consecutive weeks) 
within 3 months prior to baseline; 
- 
Use of immunosuppressive or anti-inflammatory drugs within 3 months prior to 
baseline;  
- 
Use of any other FAP directed drug therapy within 3 months prior to baseline (use 
of any alternative supplements e.g. turmeric or fish-oil must be noted in 
questionnaire).  
 
4.4 Sample size calculation 
Since this study is not yet been performed in humans with FAP, this study will be a pilot 
study. We believe a number of 12 patients is sufficient for the explorative purpose of this 
study. By performing a paired analysis, the effect of variation between individuals will be 
reduced, and we expect sufficient power to draw significant results. To detect a reduction of 
50% (power stat. 80%, p=0.05) in fitness of APC-mutant cells, we need to analyse sizes of 
APC mutant clones within 11 partially populated crypts. To ensure sufficient material we 
need 840 crypts per patient per time point. A typical biopsy yields 100-250 crypts, therefore 
we will perform 12 biopsies in total (2 biopsies per segment, 6 segments) per patient per time 
point. In that way, sufficient data will be obtained to confirm or refute the study hypothesis.  

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5. TREATMENT OF SUBJECTS 
5.1 Investigational product/treatment  
The investigational product of this study is Lithiumcarbonate. Lithiumcarbonate is a Gsk3β 
inhibitor, which stimulates intrinsic Wnt signalling. The therapeutic range of Lithium 
administered in patients suffering from bipolar disorder is 0.60 – 0.80 mmol/L (16). In the 
recent study of van Neerven et al., a chemopreventive effect of lithiumchloride on clonal 
fixation of Apc-mutant cells in mice was seen using a significantly lower serum level of 0.2 
mmol/L (12). Toxic effects of lithiumcarbonate are mostly seen at serum levels 1.0mmol/L 
or higher (16-20). To limit adverse events and side-effects, we aim to use the lowest 
effective dose and for this reason we maintain a Lithiumcarbonate serum level of 0.20 – 
0.40 mmol/L to analyse the (chemo)preventive effect of Lithiumcarbonate in patients with 
FAP. Serum levels of Lithiumcarbonate will be monitored at day 12 and day 22 after start 
of treatment (blood sample will be collected 12h after oral Lithiumcarbonate dose). When 
a therapeutic range is reached, serum levels will be monitored once a month. If 
necessary, adjustments will be made by the investigator based on serum levels, but also 
laboratory tests and side effects. As described in chapter 4, no control group will be 
included, thus no placebo or comparator will be analysed in this study, and participant 
serve as their own control in the non-treatment phase.  
 
5.2 Use of co-intervention   
Lithiumcarbonate passes the placenta and is associated with congenital malformations 
(21). Therefore, adequate anticonception must be used during participation of this study 
until 6 weeks after Lithiumcarbonate use. Lithiumcarbonate passes during lactation, 
therefore breastfeeding during participation of this study is also not allowed (22). 
Known medications that interact with Lithiumcarbonate are ACE inhibitors, angiotensin II 
receptor antagonists, diuretics, and non-steroidal anti-inflammatory drugs (NSAIDs), as 
shown in table 3. These drugs should be avoided. During the trial, use of new medications 
should always be discussed with the study team and should not be started without their 
knowledge. If medication that interacts with Lithiumcarbonate is prescribed and urgently 
needed, serum levels of Lithiumcarbonate and laboratory tests will be regularly performed.  
Patients will undergo colonoscopies at baseline, at 6 months, at 12 months and at 18 
months follow-up. European guidelines suggest colonoscopy once a year or two yearly 
depending on polyp burden (4). Thus, colonoscopies and planned biopsies within this 
study should be considered as additional interventions.  

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Furthermore, it is known that some natural products, such as turmeric, caffeine and 
eicosapentaenoic acid can play a role in the Wnt pathway (23-25). For that reason, these 
factors will be included in the analysis.   
 
 
5.3 Escape medication  
Since NSAID’s interacts with Lithiumcarbonate, the use of NSAID’s is contra-indicated 
(see Table 3). In case of pain, administration of paracetamol is allowed.  

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6. INVESTIGATIONAL PRODUCT  
6.1 Name and description of investigational product 
The investigational drug is LithiumCarbonate. The Food and Drug Administration (FDA) 
approved Lithium in 1970. Since that moment in time it is used to treat patients suffering from 
mood disorders, such as bipolar disorders and unipolar depressive disorders. The exact 
mechanism of action in the treatment of bipolar diseases is still unknown, but it is suggested 
that Lithiumcarbonate enters competition with magnesium ions resulting in inhibition of 
several enzymes (26, 27). However, previous studies show that Lithiumcarbonate interacts 
with glycogen synthase kinase 3 (GSK-3β), which plays a role in the Wnt signalling pathway 
in stem cells (26-28). When GSK-3β is inhibited using Lithiumcarbonate, it will induce 
transcription due to β-catenin (12, 26). For further information see the SPC text of 
Lithiumcarbonate.  
 
6.2 Summary of findings from non-clinical studies 
This study is based on findings of polyp growth of studies in mouse models, and 
Lithiumcarbonate is not yet investigated for this effect in FAP patients. It is suggested that 
CRC develops when APC is inactivated by biallelic mutation, subsequently these APC 
mutant stem cells outcompete WT stem cells within the crypt and induce in that way polyp 
formation (15). The underlying mechanism remained unclear but van Neerven et al. recently 
described how these mutant stem cells outcompete WT stem cells. Following APC 
inactivation, the Wnt signaling pathway is activated. Subsequently, the mutant stem cells 
secrete Wnt antagonists (e.g. Notum, Wif1, Dkk2) (12). These Wnt antagonist will inhibit the 
Wnt signaling pathway in neighboring WT ISCs. This negative-feedback loop results in 
induction of differentiation, forcing WT ISCs out of the crypt. 
 
Since the mutant stem cells are insensitive to this upregulation of Wnt inhibitors, they 
outcompete the WT stem cells by the ability of replacing them within the crypt. When all WT 
ISCs are replaced by Apc mutant stem cells, the mutant clone is permanently fixed within the 
crypt. When a clone is fixed, replacement by a healthy ISC is no longer possible, resulting in 
polyp formation (12). Therefore, chemoprevention strategies must be applied before fixation 
of a clone takes place. Recently, novel work has demonstrated a reduction in crypt fixation 
after administration of LithiumChloride. Lithiumcarbonate could diminish the competitive 
advantage of Apc mutant ISCs by downstream activation of Wnt signaling in WT ISCs by 
interacting with intracellular GSK-3β.  The inhibition of GSK-3β by Lithiumcarbonate induces 
transcription through β-catenin which leads to downstream activation of Wnt signaling in the 
WT ISCs and by that desensitize WT ISCs to WNT antagonists (12). In this way WT ISCs are 
able to compete with mutant ISCs for a position within the crypt, leading to a reduction of 
fixed mutant crypts.   

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6.3 Summary of findings from clinical studies 
Until now, no study on Lithiumcarbonate in FAP patients is conducted. However, as 
mentioned in 6.1, Lithiumcarbonate is used as treatment for mood disorders since 1970. 
Many studies have been conducted on side-effects, contra-indications and optimal 
therapeutic range (17-20). For further information please see the SPC text of 
Lithiumcarbonate and chapter 6.4-6.6. Although no data is available of Lithiumcarbonate use 
in FAP patients, several studies in patients using Lithiumcarbonate for bipolar disorders 
demonstrated a reduced cancer risk in patients with long-term use of Lithiumcarbonate (29, 
30).  
 
6.4 Summary of known and potential risks and benefits 
 Please see the SPC text of Lithiumcarbonate. Lithiumcarbonate is known for nephrotoxicity 
and several other side-effects. Most of these potential risks are dose-dependent and are 
mainly seen in patients with serum concentrations starting from 0.6-0.8mmol/L (18, 20). 
Table 1 shows the adverse events of Lithiumcarbonate in relation to serum levels at which 
they occur. The most common side-effects (occurring >10%) are weight gain, polyuria, 
polydipsia and tremor of the hands. Less often side-effects (occurring 1-10%) are nausea, 
vomiting and diarrhea, which occur at start of treatment. Later hypothyroidism and 
electrocardiographic changes may appear (17). Additionally, a decrease in renal function is 
associated with Lithiumcarbonate use, however chronic renal failure is correlated with long-
term Lithiumcarbonate use and associated with high serum levels (>1.0mmol/L) (19, 20). 
Therefore Lithiumcarbonate is contra-indicated in patients suffering from severe renal 
impairment and also contra-indicated in known severe cardiac disorders (31). For this study, 
patients will only be included when having a normal renal function (GFR > 60 ml/min). As in 
this study only a low dose of Lithiumcarbonate (aiming a serum level between 0.2-
0.4mmol/L) will be administered for a short period of time (6 months), potential risks and 
side-effects of Lithiumcarbonate will be minimized. During the trial, serum levels of 
Lithiumcarbonate and renal function will be measured, in case of eGFR < 60 ml/min 
Lithiumcarbonate will be stopped (31). However, patients of whom Lithiumcarbonate 
treatment has been discontinued, will not be excluded from the study, colonoscopies with 
biopsies will still be performed (see chapter 7.3).  
 
During this trial, patients will undergo four colonoscopies with biopsies of normal mucosa. 
Colonoscopy is associated with a minimal risk of complications. Bleeding after biopsy has 
been reported to occur in up to 0.36%. Perforation has been reported in 0.03-0.11%, 

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depending on whether or not interventions were performed (32). Potential complications are 
cited in the written patient information. Furthermore, colonoscopies will be performed by 
experienced experts at our center.  
 
In patients with FAP, at a certain moment in time a subtotal colectomy or a proctocolectomy 
with ileoanal pouch anastomosis or an end-ileostomy is performed due to high polyp burden 
and the risk of developing CRC (4). Surgery is invasive and comes with risks of 
complications and reduced functional outcome (5, 6). Nevertheless, polyp formation will 
continue in the remaining proximal and distal intestinal tract, and thus endoscopies are 
indicated for further surveillance (7, 8). The aim of this study is to evaluate the preventive 
effect of Lithiumcarbonate on polyp formation in patients with FAP. Based on the study in 
mice, we expect a significant reduction in polyp burden (12). Such a preventive therapy for 
polyp formation may postpone or prevent colectomy in patients with FAP.  
 
Table 1. Side-effects of Lithiumcarbonate (SPC)  
System/Organ 
Therapeutic 
range 
Serum level 
1.5-2mmol/L 
Serum level > 
2mmol/L 
Independent of 
serum level or 
correlation 
unknown 
Blood and 
lymphatic 
disorders  
Mild 
agranulocytosis 
Leukocytosis  
 
 
Endocrine 
disorders  
Hypothyroidism 
with or without 
goiter* 
 
 
Lowering Protein 
Binding Iodine, 
increased uptake 
of radioactive 
iodine, 
euthyroid goiter, 
hypothyroidism*, 
hyperthyroidism, 
hypercalcemia, 
hypermagnesemia, 
hyperparathyroidism 
diabetes insipidus 
Feeding and 
metabolic 
disorders  
 
Polydipsia 
Thirst  
 
 
Psychological 
disorders 
 
 
Confusion**, 
Apathy 
Delirium 

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Nervous system 
disorders 
Tremors of the 
hands, short-
lived muscles 
shocks in 
arms or legs, 
often at night, 
difficulty 
concentrating 
and 
memory 
problems 
(especially 
particularly in 
elderly 
patients) 
Tremors of the 
hands 
Hyperreflexia, 
drowsiness, 
coma 
changes in the 
EEG, vertigo, 
speech disorders, 
metallic taste, 
benign intracranial 
hypertension*, 
extrapyramidal 
disorders*, 
epileptiform 
insults*. 
encephalopathy, 
cerebellar 
syndrome, 
nystagmus, falls, 
peripheral 
neuropathy*. 
malignant 
neuroleptic 
syndrome** 
serotonin 
syndrome*** 
Ocular disorders  
 
 
 
eye irritation 
(reversible in 
most cases), 
papilledema ****, 
exophthalmia ***** 
Cardiac disorders  Changes in 
ECG**  
 
 
Changes in ECG, 
arrhythmia (in 
particular 
bradycardia), 
sinus node 
dysfunction, 
cardiomyopathy, 
atrioventricular 
block** 
Gastrointestinal 
disorders  
 
nausea, 
vomiting and 
diarrhea, usually 
at the start of 
treatment 
Anorexia, 
xerostomia, 
nausea, 
vomiting, 
diarrhea 
 
Abdominal pain, 
hypersalivation 
Cutaneous and 
subcutaneous 
disorders  
Increase of 
sebum 
production, 
 
 
Leg ulcera, 
exacerbation of 
psoriasis, pruritus, 

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alopecia, the 
occurrence or 
worsening 
of 
acne or psoriasis 
myxedema is 
rarely seen, 
allergic rash 
Frequency not 
known: lichenoid 
drug eruption 
Musculoskelatal 
and connective 
tissue disorders  
 
 
Muscle 
weakness 
Muscle 
fasciculation, 
fasciculations, 
hypertonia 
Rhabdomyolysis 
Renal and urinary 
system disorders  
 
Polyuria,  
Long-term 
administration of 
lithium in high 
doses can have a 
detrimental effect 
on the kidneys 
and lead to 
formation of 
microcysts in the 
kidneys*. 
Polyuria 
 
Microcysts, 
oncocytoma and 
renal carcinoma of 
the Ductus 
Bellinitype 
(in long-term 
administration) 
(frequency not 
known) 
Pregnancy, 
perinatal period 
and 
puerperium 
 
 
 
Neonatal 
abstinence 
syndrome 
(frequency not 
known) 
General 
disorders and 
disorders at 
administration 
site  
 
Weight gain  
 
 
Weight gain, 
peripheral edema, 
urticaria and 
angioedema 
attributed to 
one of the 
excipients. 
* See SPC text of Lithium. 
** When co-administering antipsychotics and lithium. 
*** Serotonin syndrome may be accelerated by concurrent use of serotonergic 
antidepressants. 
**** In some cases without increased intracranial pressure, leading to possible vision loss 
(generally reversible). 
***** Not always associated with disorders of the thyroid gland.  
 
6.5 Description and justification of route of administration and dosage 
We aim to minimize side-effects by administering the lowest Lithiumcarbonate dose that we 
expect to be effective. As described in 5.1 and 6.4, serum levels between 0.2-0.4mmol/L will 
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will be treated with a starting dose of 200mg, after 5 days the dose will be increased to 
300mg once a day. Serum levels will be measured at day 12 and day 22 after start of 
treatment. When a therapeutic range is reached, serum levels will be measured once a 
month. Blood samples for determining serum levels must be collected 12h after oral 
administration of Lithiumcarbonate. If the serum level is not within the therapeutic range, 
dose adjustments will be made. Serum levels will be monitored 12 days after dose 
adjustments, until the therapeutic range is reached or side-effects diminished.  
 
6.6 Dosages, dosage modifications and method of administration 
See chapter 6.5 
 
6.7 Preparation and labelling of Investigational Medicinal Product 
Lithiumcarbonate will be labelled by the AMC Hospital Pharmacy according to GMP 
guidelines (GMP-annex 13). The funding of the drugs will be provided by the study sponsor. 
Since Lithiumcarbonate is a registered drug, the label text originated from the producer will 
be used. An additional label related to the study will be added with the following information: 
name of the study, name of the principal investigator, name of the sponsor (AMC, 
Meibergdreef 9, 1105 AZ Amsterdam, tel 020-5669111), “uitsluitend ten behoeve van klinisch 
onderzoek”, “Buiten bereik van kinderen bewaren”, “Gebruiken volgens voorschrift 
studieprotocol”, patient number, patient name.  
 
 
6.8 Drug accountability 
Storage and disposition of Lithiumcarbonate will be done by the AMC Hospital Pharmacy 
according to patient name and patient number. Medication will be prescribed per 60 tablets. 
The first dispense will take place directly after the second colonoscopy in the AMC (t=6m). 
The tablets will be distributed at the AMC hospital Pharmacy every two months at time of 
consultation in the AMC by the study doctor, since it is not possible for a participant to collect 
a study drug at a local pharmacy. Drug accountability of receipt, dispensed, returned and 
destroyed medication will be kept conform GCP guidelines.  
 
  
 
 
 
 
 
 
 

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7. METHODS 
7.1 Study parameters/endpoints 
7.1.1 Main study parameter/endpoint 
 
Clone sizes will be quantified as proportions of the crypt circumference positive for 
NOTUM (in parts of eight, 1:8 to 8:8). When a whole crypt is positive for NOTUM 
(8:8), this crypt is fixed (crypt fixation) (12).  
7.1.2 Secondary study parameters/endpoints  
 
Difference in number and size of polyps between baseline and end of study 
 
Patient reported side effects of Lithiumcarbonate using a Lithium side effect 
questionnaire (see appendix 2, chapter 14.2)  
 
Safety outcomes by analysing reported adverse events, physical examination and 
laboratory findings. 
7.1.3 Other study parameters  
Other assessments in questionnaire (please see chapter 14.3, appendix 3: patient diary):  
 
Number of cups of coffee per day (decaffeinated coffee not included) 
 
Turmeric use (gram per day) 
 
Number of fish oil capsules per day (amount of eicosapentaenoic acid in terms of mg)  
 
History of smoking, if yes number of pack years 
 
 
7.2 Randomisation, blinding and treatment allocation 
In this study, no randomisation will take place, every participant is given the same treatment.  
All crypt analysis data and adenoma counts will be scored blindly.  
 
7.3 Study procedures 
Baseline and follow-up measurements and monitoring  
 
Medical history at baseline. 
 
Physical examination (including vital signs) at baseline and every six months (at time 
of endoscopy). 
 
Clinical tests including pregnancy test at baseline, month 6 and month 12 (at time of 
endoscopy).  
 
Laboratory testing at baseline and every two months: haemoglobin, thrombocytes, 
leukocytes, GFR, creatinine, urea, sodium, potassium, calcium and TSH (if deviating 
T4).  
 
Testing spot urine sample at baseline and month 12: urine osmolality and creatinine.  

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 
Testing serum levels of Lithiumcarbonate at day 12 and 22 after start of treatment 
(blood sample will be collected 12h after oral administration of Lithiumcarbonate). 
When a therapeutic range is reached, serum levels will be monitored once a month in 
certified laboratory. 
 
Check-ups through telephone interviews to evaluate adverse events and side effects 
using a questionnaire at baseline and during treatment with Lithiumcarbonate (see 
appendix 3, chapter 14.3). During Lithiumcarbonate treatment telephone interviewing 
will be done monthly to evaluate Lithiumcarbonate dose through serum level testing.  
 
Colonoscopy with biopsies at baseline and every six months (a total of four 
endoscopic procedures) performed at the AMC by experienced experts.  
 
24-hour urine volume test in month 13 (test can be done at home).  
 
Assessment of size of fixed clones  
For each patient crypts will be retrieved form normal tissue biopsies through 
colonoscopy (t=0, t=6, t=12, t=18 months). APC mutant stem cell dynamics will be 
determined in these biopsies by tracing the spread of the APC mutant cells using 
specific expression of NOTUM by RNAscope (in situ hybridization). NOTUM-positive 
crypts will be quantified by determining the proportion of the crypt circumference 
positive for NOTUM (in parts of eight, 1:8 to 8:8). This will result in an average clone 
size distribution for each patient per time point, as well as the proportion of fixed 
crypts (8:8). By analyzing the differences in clone size distribution before, during and 
after Lithiumcarbonate treatment we aim to observe a relative reduction in average 
clone size of 50% during the lithiumcarbonate treatment, as well as a reduction in 
crypt fixation of 50%. 
 
Assessment of degree of polyposis  
For the secondary outcome measures, the degree of polyposis will be measured as 
follows: 
 
Baseline and follow-up colonoscopies 
A full colonoscopy will be performed at baseline, and at months 6, 12 and 18 to 
assess polyp burden and to take biopsies. During colonoscopy, Boston Bowel 
Preparation Scale (BBPS) should be at least 6 and cecal intubation achieved. Video 
recording starts at withdrawal of the endoscope form the cecum, which is performed 
fluently in a spiral fashion aiming to visualize the entire colonic mucosa. The biopsy 
forceps will be used to assess the size of polyps if estimated ≥ 3mm. Polyp burden 
will be assessed, based on number of polyps and size (please see table 2), for the 6 
different segments: cecum, ascending colon, transverse colon, descending colon, 
sigmoid and rectum (including retroflexion). When moving from one segment to the 
next segment, the endoscopist will be asked to stop the video and start a new video 
for the next segment. In that way, there will be a separate video for each segment to 

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make sure the two separate reviewers (explained later) will assess the exact same 
segment. For each colonoscopy, the table below will be used to calculate the sum of 
diameter of polyps to determine the total colorectal polyp burden. It is important that 
the endoscopist does not go back and forth with the endoscope during video 
recording and only uses white light endoscopy.  During video recording, no 
polypectomies are performed.  
After video recording, NBI is allowed and polypectomies are performed at the 
discretion of the endoscopist. Polyps ≥5mm should be excised at all colonoscopies.  
Also, two random biopsies of normal mucosa will be taken in each segment, resulting 
in a total of 12 biopsies of normal intestinal mucosa during each endoscopy. In 
addition, 3 random polyps retrieved from a random segment will be excised for 
determination of histology.  
 
After month 18, in total 4 clustered colonoscopy video recordings of each participant 
are available (4x6 of each segment per participant). The 4 videos of the participant 
will be reviewed by two separate independent expert endoscopists in a random order 
and they will assess the polyp burden using the table below. For each segment there 
wil be a  separate video, as explained above. The assessment of the first and second 
reviewer will be compared to identify possible disagreements. If there is a 
disagreement in polyp burden assessment of more than 30%, a third independent 
reviewer will be engaged, after which the average of these three reviewers will be 
used for further analysis.  
  
Table 2: Total polyp burden, based on size and number of polyps. 
Segment 
Number of polyps 
Cecum  
          1-2mm  
        3-5mm 
    6-10mm 
         >10mm 
Ascending colon 
 
     1-2mm  
        3-5mm 
    6-10mm 
         >10mm 
Transverse colon 
 
     1-2mm  
        3-5mm 
    6-10mm 
         >10mm 
Descending colon 
 
     1-2mm  
        3-5mm 
    6-10mm 
         >10mm 
Sigmoid  
 
     1-2mm  
        3-5mm 
    6-10mm 
         >10mm 
Rectum 
 
     1-2mm  
        3-5mm 
    6-10mm 
         >10mm 
Total polyp burden 
 
     1-2mm  
        3-5mm 
    6-10mm 
         >10mm 
 
7.4 Withdrawal of individual subjects 
Subjects can withdraw from the study at any time for any reason if they wish to do so without 
any consequences. The investigator can decide to withdraw a subject from the study for 
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7.4.1 Specific criteria for withdrawal  
If any exclusion criteria will be met during the study, a participant will be withdrawn from 
treatment. 
 
7.5 Replacement of individual subjects after withdrawal 
Subjects who withdraw from the trial after start of Lithiumcarbonate will not be replaced. 
 
7.6 Follow-up of subjects withdrawn from treatment 
In every participant withdrawing from the study for any reason, further surveillance will be 
scheduled according to standard care for FAP patients. 
 
However, when patients withdraw from the study after start of Lithiumcarbonate treatment, 
the time of withdrawn will be handled as timepoint t=12m (please see the flowchart). 
Subsequently, the patient will follow the consecutive procedures as described in this 
protocol.  
 
When withdrawn is conducted due to side-effects of the use of Lithiumcarbonate, follow-up 
will be performed weekly through telephonic interviewing until symptoms disappear.  
 
7.7 Premature termination of the study 
Since Lithiumcarbonate is a long-used medicine and has been well investigated, adverse 
events leading to premature termination of the study is not to be expected. No criteria for 
early termination have been established.  
 
 

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8. SAFETY REPORTING 
8.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety.  The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
8.2 AEs, SAEs and SUSARs 
8.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the investigational product. All 
adverse events reported spontaneously by the subject or observed by the investigator 
or his/her staff will be recorded. 
 
8.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
Subjects will be instructed to contact the investigator to report any symptom and the 
investigator will question each subject regarding symptoms at the time of each 
contact moment (at least monthly). All adverse events, including duration and 
severity, will be captured in the case report forms.  
 

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The investigator will report all SAEs to the sponsor without undue delay after 
obtaining knowledge of the events.  
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 8 
days to complete the initial preliminary report. All other SAEs will be reported within a 
period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
 
8.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational 
product related to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
A. the event must be serious (see chapter 9.2.2); 
B. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 
C. the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in: 
- 
Summary of Product Characteristics (SPC) for an authorised medicinal 
product; 
- 
Investigator’s Brochure for an unauthorised medicinal product. 
 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline to the METC: 
 SUSARs that have arisen in the clinical trial that was assessed by the METC; 
 SUSARs that have arisen in other clinical trials of the same sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be 
submitted once every half year to the METC. This line-listing provides an overview 
of all SUSARs from the study medicine, accompanied by a brief report highlighting 
the main points of concern.  

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The expedited reporting of SUSARs through the web portal Eudravigilance or 
ToetsingOnline is sufficient as notification to the competent authority. 
 
The sponsor will report expedited all SUSARs to the competent authorities in other 
Member States, according to the requirements of the Member States.  
 
The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life-threatening cases the term will 
be maximal 7 days for a preliminary report with another 8 days for completion of the 
report.  
 
8.3 Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, 
and competent authorities of the concerned Member States. 
This safety report consists of: 
 a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 
 a report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 
8.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol  
 
8.5 Safety Committee 
The safety committee will consist of all involved investigators in this study (prof. dr. L. 
Vermeulen, prof. dr. E. Dekker, prof. dr. M. Vervloet, prof dr. A. Dols, dr. T. Bosch, drs. S. 
van Neerven, drs. A. Aelvoet, C. Cohen and drs. J. Linssen). Safety monitoring will be 
conducted through telephonic interviewing, physical examination and lab and serum level 
testing. Serious and non-serious adverse events of any kind will be collected by the PhD 

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candidate and reported to the safety committee immediately. Classifying as serious or non-
serious adverse event, deciding on the toxicity grade, the relatedness to Lithiumcarbonate 
will be done by the safety committee. As well as subsequent measures to be taken. Since 
the effect of Lithiumcarbonate has not been studied in FAP patients, a safety committee is 
needed.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9.  STATISTICAL ANALYSIS 
To describe the study population, baseline characteristics and changes in outcome 
parameters during follow-up, descriptive statistics will be used in this study. SPSS for 
Windows software (Chicago, IL, USA) version 26.0 will be used for these analyses. 
If other statistical analysis will be used, this will be mentioned in the study paper.  
 
9.1 Primary study parameter(s) 
Primary analysis for the primary outcome parameter will be done by analyzing the data using 
two-sided student’s t-test. will be performed. The limit for the statistical significance will be 
established at p < 0.05 with a confidence interval of 95%.  
 
9.2 Secondary study parameter(s)  
Descriptive statistics will be used to describe the changes in outcome measures during 
follow-up. 
 
9.3 Other study parameters 
Not applicable.  
 
9.4 Interim analysis  
Not applicable.  

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10. ETHICAL CONSIDERATIONS 
10.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki 18th 
WMA General Assembly, Helsinki, Finland, June 1964), which was amended by the 64th 
WMA General Assembly, October 2013, Fortaleza, Brazil) and in accordance with the 
Medical Research Involving Human Subjects Act (WMO). The protocol of this study will 
be submitted to the Medical Ethical Committee of the Academic Medical Center, the study 
will not start before formal approval has been granted. Informed consent form by all 
patients is required. The study will also be conducted in accordance with ICH Good 
Clinical Practice (GCP) and all applicable subject privacy requirements. 
 
10.2 Recruitment and consent 
Patients will be recruited from the AMC. Patients will receive information about the study 
written on paper and/or mail and it will be explained in person by the study doctor (a PhD 
candidate) or a colleague doctor. The patients will be informed about the study by 
telephone or at the outpatient clinic. After explanation, informed consent can be given at 
the outpatient clinic by the participant. No time limit will be set on considering 
participation. Withdrawal of informed consent can be done by the participant at any time 
and for any reason. Please see the patient information letter and informed consent (files 
are attached).  
 
10.3 Objection by minors or incapacitated subjects 
Minors and/or incapacitated adults will not be approached for participation of this study.  
 
10.4 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of 
the WMO. The sponsor (also) has an insurance which is in accordance with the legal 
requirements in the Netherlands (Article 7 WMO). The insurance applies to the damage 
that becomes apparent during the study or within 4 years after the end of the study:  
1. € 650.000,-- (i.e. six hundred and fifty thousand Euro) for death or injury for each 
subject who participates in the Research;  
2. € 5.000.000,-- (i.e. five million Euro) for death or injury for all subjects who participate 
in the Research;  

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3. € 7.500.000,-- (i.e. seven million five hundred thousand Euro) for the total damage 
incurred by the organisation for all damage disclosed by scientific research for the 
Sponsor as ‘verrichter’ in the meaning of said Act in each year of insurance coverage.  
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
10.5 Incentives.  
Included participants will receive no reimbursement for entering this study. Travel costs 
will be compensated.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
11.1 Handling and storage of data and documents 
Adenomatous tissue collected endoscopically, as part of routine care, will be stored 
according to regulations of the department of pathology in the AMC. Normal intestinal 
mucosa collected endoscopically, as part of study material to assess NOTUM distribution 
size e.g., will be analysed in the Center for Experimental and Molecular Medicine 
(CEMM). Source documents and CRFs will be stored by the project leader for 15 years 
after closure of the trial. Collected samples will be stored for 5 years. In case of informed 
consent is reached for participation in a biobank, samples will be stored for 15 years. 
Data of the subjects will be coded in order of participation. The code and the data are 
stored in different locations. The code can only be seen by the investigators. Qualified 
authorities can get insight in the code and data, but only when accompanied by the 
investigators. Informed consent forms are kept in separate files, to ensure the data 
security. The handling of personal data will comply with the Dutch Personal Data 
Protection Act (in Dutch: De Wet Algemene Verordening Gegevensbescherming, AVG). 
 
11.2 Monitoring and Quality Assurance  
For this study, monitoring was requested from Clinical Monitoring Center (CMC). After 
approval by the METC, a monitoring intake visit will be scheduled to set up a monitoring 
plan.   
 
11.3 Amendments  
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
 

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11.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
 
11.5 Temporary halt and (prematurely) end of study report 
The sponsor will notify the accredited METC and the competent authority of the end of 
the study within a period of 90 days. The end of the study is defined as the last patient’s 
last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action. 
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and 
the competent authority within 15 days, including the reasons for the premature 
termination. 
 
 Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC and the Competent Authority.  
 
When this drug seems to be effective, there is a strong wish from patients to continue 
taking Lithiumcarbonate. For those participants it will be possible to continue 
Lithiumcarbonate off-label after the study has ended. Non-registered drugs can be 
prescribed by the clinician through a ‘named patient program’ (in Dutch: op 
artsenverklaring). Subsequently each request have to be approved by the Inspection of 
Health care and Youth (in Dutch: Inspectie Gezondheidszorg en Jeugd, IGJ) for each 
individual. Whether this off-label drug will be reimbursed depends on each health 
insurance company.  
 
11.6 Public disclosure and publication policy 
This study will be executed by the following team: prof. dr. E. Dekker (gastroenterologist), 
prof. dr. L. Vermeulen (medical oncologist), T. Bosch (pharmacologist), prof. dr. M. 
Vervloet (nephrologist), dr. A. Dols (psychiatrist), drs. S. van Neerven (molecular 
biologist), drs. J. Linssen (PhD-candidate), drs. A. Aelvoet (PhD-candidate) and C. Cohen 

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(research nurse).   
There will be no conflicts of interest regarding to publication of expected results from this 
study. Scientific results will be published in scientific journals and will be presented on 
congresses (national and international). In case of co-operation between departments, the 
first and subsequent authors will be determined according to the contribution to the (part 
of the) project of the involved departments. Published data will be impossible to relate 
back to the participant.  

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12. STRUCTURED RISK ANALYSIS  
 
12.1 Potential issues of concern 
 
a. Level of knowledge about mechanism of action 
Lithiumcarbonate is been used to treat patients suffering from bipolar disorders. It is 
suggested that Lithium enters competition with magnesium ions which leads to inhibition 
of several enzymes (26, 27). Furthermore, Lithiumcarbonate interacts with glycogen 
synthase kinase 3β (GSK-3β), which plays a role in the Wnt signalling pathway in ISCs 
(26, 27). When GSK-3β is inhibited, for example when Wnt ligands binds to its receptor or 
through Lithiumcarbonate administration, it will activate transcription of Wnt target genes 
through nuclear re-localisation of β-catenin (12, 26). In a recent study, lithiumchloride 
administration resulted in downstream activation of Wnt signalling in WT ISCs, thereby 
desensitizing the WT ISCs to Wnt antagonists secreted by Apc mutants (12). As a result, 
lithiumchloride prevents the fixation of Apc mutant cells in the crypt thereby reducing polyp 
formation in apc-mutant mice (12). This suggest that intervening before clones are fixed 
within the crypt, polyp burden can be reduced and time to progression to dysplasia can be 
prolonged.  
 
b. Previous exposure of human beings with the test product(s) and/or products with a 
similar biological mechanism 
Since 1970 Lithium is approved by the FDA and used to treat patients suffering from 
bipolar disorders. Details about the exposure of human beings with Lithiumcarbonate are 
clearly described in the SPC text. As previous mentioned, Lithiumcarbonate has never 
been investigated in patients with FAP. However, in the study of van Neerven et al. an 
effect of Lithiumchloride was seen on stemmness and clonogenicity in organoids deriving 
from human colon that were incubated with FAP conditioned medium (12). 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo 
human cell material? 
Up to now, Lithiumcarbonate has never been investigated in patients with FAP. As 
previous described, the primary outcome and effect on number of polyps has been 
studied in mouse models.  
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
Please see the SPC text and chapter 12.1a for explanations of working mechanisms. For 
known side-effects, please see Table 1. Drugs that could interact with Lithiumcarbonate 
are described in Table 3 (please see the appendix). 
 
e. Analysis of potential effect 
Side-effects can be found in Table 1. As mentioned in chapter 6.4 the occurrence of side-
effects is dose-dependent (18-20). Most side-effects are mainly seen in serum 
concentrations starting from 0.6-0.8 mmol/L (18, 20) . Toxicity effects of Lithiumcarbonate 

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(such as nephrotoxicity) is associated with serum concentrations starting from 1.0 mmol/L 
(19, 20). In the study on mice, a significant effect of Lithiumchloride on NOTUM clone size 
distributions within the crypt was seen using a serum level of 0.2 mmol/L (12). We believe 
using a serumlevel between 0.2-0.4 mmol/L in the participants of this study, side-effects 
and toxicity will be minimalized and still a promising effect can be expected.   
 
f. Pharmacokinetic considerations 
 
Please see the SPC text for pharmacokinetics of Lithiumcarbonate.  
 
g. Study population 
Research subjects will contain patients diagnosed with FAP, between the age of 18 and 
35 years. The colon of these patients must be intact, patients who underwent a colectomy 
of any kind will be excluded. No exclusion will be made based on sex or race. Female 
participants with a pregnancy wish are not allowed to participate in this study. During 
participation participants must use adequate contraception.  
Due to the high risk (nearly 100%) of developing CRC, patients with FAP are likely to 
undergo colectomy in the twenties to prevent the developing of a tumour (3, 4). These 
types of surgery are known for its high risk of comorbidities (5, 6). Even after surgery 
adenoma formation is seen in these patients, and by that CRC can still develop (7, 8). 
These patients would benefit from a medical treatment preventing polyp formation, and in 
that way postpone or even prevent invasive types of surgery. Until now, no such 
chemopreventive therapy is available. 
 
h. Interaction with other products 
Please see table 3 for drugs that interact with Lithiumcarbonate. The use of any of these 
products is not allowed when enrolled in this study, as mentioned in the exclusion criteria 
(see chapter 4.3). If any of these drugs needs to be started during the study, it must be in 
consideration with the investigator at any time. Dependent on the expected interaction and 
indication of the supplementary drug, additional serum level testing will be conducted or 
the patient will be withdrawn from the study.  
 
i. Predictability of effect 
The primary study outcome will be measured by analyzing NOTUMpos/APC clone size 
distributions within the crypt, defined before the start of six months treatment with 
Lithiumcarbonate and after treatment. We believe by using such a quantifiable outcome 
measurement, results will provide relevant translational data. The combination of the 
secondary study outcome parameters, obtained through endoscopic measurements and 
laboratory findings, with the primary study outcome parameter will provide both clinical 
and translational information. In case this study shows an effect on NOTUM expansion 
and safety outcomes have been achieved, a larger-scale clinical trial of Lithiumcarbonate 
in FAP patients can be conducted whereas Lithiumcarbonate can be administered for a 
longer period of time.  
 

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j. Can effects be managed? 
A hospital pharmacist, a nephrologist and a psychiatrist all with an expertise in 
Lithiumcarbonate use will be actively involved in this study. Through telephonic 
interviewing, physical examination and laboratory testing side effects or adverse events 
can be detected early. If needed, dosage of Lithiumcarbonate will be adjusted. 
Participants will be instructed to contact the investigator when side-effects or adverse 
events occur. In case of an emergency, the patient can contact the gastroenterologist that 
is on call. Contact details will be given.  
 
k. Covid-19 analysis  
Concerning the pandemic due to the covid-19 virus, risks of any further developments 
should be taken into account. In case of increasing covid-19 cases or new restrictions, site 
visits will be minimized and study medication can be sent to the patients home. Also the 
time frame for planning study procedures (e.g. colonoscopy) can be extended since it will 
be more difficult to plan the procedures within a window of 7 days. We are aware that due 
to the pandemic and possible restrictions, the trial can take longer. 
 
12.2 Synthesis 
Lithiumcarbonate is known for its narrow therapeutic dose range and toxicity, as 
mentioned in chapter 6. However, these SE and toxicity is associated with long-term use 
and high serum-levels of Lithiumcarbonate (18-20). In this study a serum level between 
0.2-0.4 mmol/L will be used to treat the participants with a regularly monitoring of serum 
levels. Further safety monitoring will be achieved through telephonic interviewing, physical 
examination and laboratory testing. By doing so, SE and toxicity can be minimalized or 
caught at an early stage. Patients will be excluded based on renal function, cardiac 
disorders, laboratory abnormalities and the use of co-medication that can interact with 
Lithiumcarbonate (for further exclusion criteria, see chapter 4.3).  
 
Colonoscopy is associated with minimal risk of complications. Bleeding after biopsy has 
been reported to occur in up to 0.36%. Perforation has been reported in 0.03-0.11%, 
depending on whether or not a biopsy was performed (32). Potential complications are 
cited in the written patient information. Furthermore, colonoscopies will be performed by 
highly experienced experts.  
 
Included participants in this study are likely to undergo prophylactic surgery within a short 
time, these types of surgery are associated with a high risk of comorbidities (5, 6). If a 
chemopreventive effect is seen in this study, patients with FAP would benefit from therapy 
with Lithiumcarbonate where these types of invasive surgery could be postponed or even 
avoided.  
 
We believe, by implementing the risk management as described above, treatment with 
Lithiumcarbonate in FAP patients is justifiable. Results of this study can be used to set up 

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a larger-scale clinical trial with a longer follow-up period to determine the effect of 
Lithiumcarbonate in FAP patients.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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13. REFERENCES 
1.  
Bussey HJ, Veale AM, Morson BC. Genetics of gastrointestinal polyposis. 
Gastroenterology. 1978;74(6):1325-30. 
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Bisgaard ML, Fenger K, Bülow S, Niebuhr E, Mohr J. Familial adenomatous 
polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat. 1994;3(2):121-5. 
3.  
Bussey HJ. Familial polyposis coli: family studies, histopathology, 
differential diagnosis and results of treatment: Baltimore : Johns Hopkins University Press; 
1975. 
4.  
van Leerdam ME, Roos VH, van Hooft JE, Dekker E, Jover R, Kaminski 
MF, et al. Endoscopic management of polyposis syndromes: European Society of 
Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2019;51(9):877-95. 
5.  
Pasquer A, Benech N, Pioche M, Breton A, Rivory J, Vinet O, et al. 
Prophylactic colectomy and rectal preservation in FAP: systematic endoscopic follow-up and 
adenoma destruction changes natural history of polyposis. Endosc Int Open. 
2021;9(7):E1014-e22. 
6.  
Kartheuser A, Stangherlin P, Brandt D, Remue C, Sempoux C. Restorative 
proctocolectomy and ileal pouch-anal anastomosis for familial adenomatous polyposis 
revisited. Fam Cancer. 2006;5(3):241-60; discussion 61-2. 
7.  
Tajika M, Tanaka T, Ishihara M, Hirayama Y, Oonishi S, Mizuno N, et al. 
Long-term outcomes of metachronous neoplasms in the ileal pouch and rectum after surgical 
treatment in patients with familial adenomatous polyposis. Endosc Int Open. 2019;7(5):E691-
e8. 
8.  
Friederich P, de Jong AE, Mathus-Vliegen LM, Dekker E, Krieken HH, 
Dees J, et al. Risk of developing adenomas and carcinomas in the ileal pouch in patients 
with familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2008;6(11):1237-42. 
9.  
Ricciardiello L, Ahnen DJ, Lynch PM. Chemoprevention of hereditary colon 
cancers: time for new strategies. Nat Rev Gastroenterol Hepatol. 2016;13(6):352-61. 
10. 
Roos VH, Meijer BJ, Kallenberg FGJ, Bastiaansen BAJ, Koens L, 
Bemelman FJ, et al. Sirolimus for the treatment of polyposis of the rectal remnant and ileal 
pouch in four patients with familial adenomatous polyposis: a pilot study. BMJ Open 
Gastroenterol. 2020;7(1). 
11. 
Hull MA, Sprange K, Hepburn T, Tan W, Shafayat A, Rees CJ, et al. 
Eicosapentaenoic acid and aspirin, alone and in combination, for the prevention of colorectal 
adenomas (seAFOod Polyp Prevention trial): a multicentre, randomised, double-blind, 
placebo-controlled, 2 × 2 factorial trial. Lancet. 2018;392(10164):2583-94. 
12. 
van Neerven SM, de Groot NE, Nijman LE, Scicluna BP, van Driel MS, 
Lecca MC, et al. Apc-mutant cells act as supercompetitors in intestinal tumour initiation. 
Nature. 2021;594(7863):436-41. 
13. 
Schneikert J, Behrens J. The canonical Wnt signalling pathway and its APC 
partner in colon cancer development. Gut. 2007;56(3):417-25. 
14. 
Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, et 
al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 
2007;449(7165):1003-7. 
15. 
Vermeulen L, Morrissey E, van der Heijden M, Nicholson AM, Sottoriva A, 
Buczacki S, et al. Defining stem cell dynamics in models of intestinal tumor initiation. 
Science. 2013;342(6161):995-8. 
16. 
Nolen WA, Licht RW, Young AH, Malhi GS, Tohen M, Vieta E, et al. What 
is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A 
systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with 
lithium. Bipolar Disord. 2019;21(5):394-409. 
17. 
Gitlin M. Lithium side effects and toxicity: prevalence and management 
strategies. Int J Bipolar Disord. 2016;4(1):27. 
18. 
Wilting I, Heerdink ER, Mersch PP, den Boer JA, Egberts AC, Nolen WA. 
Association between lithium serum level, mood state, and patient-reported adverse drug 
reactions during long-term lithium treatment: a naturalistic follow-up study. Bipolar Disord. 
2009;11(4):434-40. 
19. 
Azab AN, Shnaider A, Osher Y, Wang D, Bersudsky Y, Belmaker RH. 
Lithium nephrotoxicity. Int J Bipolar Disord. 2015;3(1):28. 

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20. 
Tondo L, Abramowicz M, Alda M, Bauer M, Bocchetta A, Bolzani L, et al. 
Long-term lithium treatment in bipolar disorder: effects on glomerular filtration rate and other 
metabolic parameters. Int J Bipolar Disord. 2017;5(1):27. 
21. 
Munk-Olsen T, Liu X, Viktorin A, Brown HK, Di Florio A, D'Onofrio BM, et al. 
Maternal and infant outcomes associated with lithium use in pregnancy: an international 
collaborative meta-analysis of six cohort studies. Lancet Psychiatry. 2018;5(8):644-52. 
22. 
Uguz F, Sharma V. Mood stabilizers during breastfeeding: a systematic 
review of the recent literature. Bipolar Disord. 2016;18(4):325-33. 
23. 
Zhao Y, Ren J, Hillier J, Lu W, Jones EY. Caffeine inhibits Notum activity 
by binding at the catalytic pocket. Commun Biol. 2020;3(1):555. 
24. 
Panda AK, Chakraborty D, Sarkar I, Khan T, Sa G. New insights into 
therapeutic activity and anticancer properties of curcumin. J Exp Pharmacol. 2017;9:31-45. 
25. 
Song KS, Jing K, Kim JS, Yun EJ, Shin S, Seo KS, et al. Omega-3-
polyunsaturated fatty acids suppress pancreatic cancer cell growth in vitro and in vivo via 
downregulation of Wnt/Beta-catenin signaling. Pancreatology. 2011;11(6):574-84. 
26. 
Gould TD, Manji HK. Glycogen synthase kinase-3: a putative molecular 
target for lithium mimetic drugs. Neuropsychopharmacology. 2005;30(7):1223-37. 
27. 
Ward ME, Musa MN, Bailey L. Clinical pharmacokinetics of lithium. J Clin 
Pharmacol. 1994;34(4):280-5. 
28. 
Klein PS, Melton DA. A molecular mechanism for the effect of lithium on 
development. Proc Natl Acad Sci U S A. 1996;93(16):8455-9. 
29. 
Martinsson L, Westman J, Hällgren J, Ösby U, Backlund L. Lithium 
treatment and cancer incidence in bipolar disorder. Bipolar Disord. 2016;18(1):33-40. 
30. 
Huang RY, Hsieh KP, Huang WW, Yang YH. Use of lithium and cancer risk 
in patients with bipolar disorder: population-based cohort study. Br J Psychiatry. 
2016;209(5):393-9. 
31. 
Multidisciplinaire richtlijn Bipolaire stoornissen (derde revisie). Utrecht De 
Tijdstroom. 2015. 
32. 
Wang L, Mannalithara A, Singh G, Ladabaum U. Low Rates of 
Gastrointestinal and Non-Gastrointestinal Complications for Screening or Surveillance 
Colonoscopies in a Population-Based Study. Gastroenterology. 2018;154(3):540-55.e8. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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14. APPENDIX 
 
14.1 Appendix 1: Drugs that interact with Lithium  
 
Table 3. Drugs that interact with Lithium.  
Interactions that may increase lithium concentrations 
Angiotensin-converting enzyme (ACE) inhibitors 
Angiotensin-II receptor antagonists 
Antibiotics: metronidazole, tetracyclines, cotrimoxazol, trimethoprim 
Diuretics: thiazides, spironolactone, furosemide 
Non-steroidal anti-inflammatory drugs (NSAIDs) 
Selective serotonin re-uptake inhibitors (SSRI’s) 
Other: topiramate, medicines that affect electrolyte balance (e.g. corticosteroids) 
Interactions that may decrease Lithium concentrations 
Carbonic anhydrase inhibitors 
Sodium bicarbonate and sodium chloride containing products 
Xanthines: theophylline, caffeine 
Other: urea 
Interactions that can cause toxicity with normal Lithium concentrations  
Antipsychotics: haloperidol, olanzapine, clozapine 
Calcium channel blockers (verapamil, diltiazem)  
Tricyclic antidepressants 
Others: Carbamazepine, phenytoin, methyldopa, clonazepam 
Interactions that can lead to QT Prolongation (with high concentrations of Lithium) 
NYHA-klasse Ia- en III-anti-aritmica 
Others: arsenic trioxide, chloroquine, chlorpromazine, claritromycine, domperidone, droperidol, 
erytromycin, haloperidol, methadone, pentamidine, pimozide, sotalol 
Other interactions 
Neuromuscular blocking agents 
Lithium may prolong the effects of these agents. 
Triptans, Selective serotonin re-uptake inhibitors 
(SSRI’s) 
Simultaneously use may accelerate serotonin 
syndrome 
 
 
 
 
 
 
 
 

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14.2 Appendix 2: Side effects questionnaire 
 
Bijwerkingen van Lithium  
 
Deze lijst is alleen voor lithiumgebruikers.  
 
Geef aan in welke mate u last heeft van de genoemde bijwerkingen, het gaat uitsluitend om 
uw eigen beleving. 
nee 
licht,  
matig met 
sterk met 
nauwelijks 
enige  
veel hinder 
hinder  
hinder 
 
Hoofdpijn 
 
 
 
 
0 
 
1 
 
2 
 
3 
Duizeligheid  
 
 
 
0 
 
1 
 
2 
 
3 
Vermoeidheid  
 
 
 
0 
 
1 
 
2 
 
3 
Wazig/dubbel zien 
 
 
 
0 
 
1 
 
2 
 
3 
Concentratiestoornissen 
 
 
0 
 
1 
 
2 
 
3 
Geheugenstoornissen  
 
 
0 
 
1 
 
2 
 
3 
Misselijkheid  
 
 
 
0 
 
1 
 
2 
 
3 
Droge mond  
 
 
 
0 
 
1 
 
2 
 
3 
Dorstgevoel  
 
 
 
0 
 
1 
 
2 
 
3 
Toegenomen urineren 
 
 
0 
 
1 
 
2 
 
3 
Verminderde eetlust  
 
 
0 
 
1 
 
2 
 
3 
Toegenomen eetlust  
 
 
0 
 
1 
 
2 
 
3 
Diarree 
 
 
 
 
0 
 
1 
 
2 
 
3 
Obstipatie 
 
 
 
 
0 
 
1 
 
2 
 
3 
Sexuele functiestoornissen 
 
 
0 
 
1 
 
2 
 
3 
Transpireren  
 
 
 
0 
 
1 
 
2 
 
3 
Tremor van handen  
 
 
0 
 
1 
 
2 
 
3 
Spierzwakte  
 
 
 
0 
 
1 
 
2 
 
3 
Coördinatiestoornissen 
 
 
0 
 
1 
 
2 
 
3 
 
 
 
 
 
 

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14.3 Appendix 3: Patient diary 
 
 
 
 
Patiënten dagboek  
 
 
 
 
 
 
 
 
Beste deelnemer, 
 
Sommige zaken (zoals voedingsmiddelen of roken) kunnen mogelijk invloed hebben op de 
ontwikkeling van poliepen. Om hiermee rekening te kunnen houden tijdens dit onderzoek is 
het belangrijk een goed beeld te krijgen van uw wekelijkse inname/gebruik van deze 
producten.  
 
Noteer per week de hoeveelheid die u in die week ingenomen heeft per onderdeel.  
Of u wel of niet rookt hoeft u maar eenmalig in te vullen. Dit dagboek wordt iedere 6 
maanden verzameld. 
 
 
Roken  
 
Vraag 
Antwoord  
(kruis het juiste antwoord aan of vul het getal in) 
1. Rookt u? 
   (indien ja ga verder naar vraag 2) 
               Ja 
  Nee 
2. Hoeveel jaren rookt u? 
                Jaren 
3. Hoeveel sigaretten rookt u per 
dag? 
                Sigaretten  
4. Rookt u….? 
     Sigaretten 
   Shag 
 
 
 
 
 
 
 
 
 
 
 
Datum: …../…../…..                
 
 
              Periode: Visite maand … - Visite maand … 
 
Subjectnummer:……….. 

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Voedingsmiddelen  
 
Week 
Voedingsmiddel 
Hoeveelheid (per week) 
Week 1 
Koffie 
(décafe niet meegerekend) 
           Kopjes    
Visolie (omega3)* 
           Capsules/tabletten 
Kurkuma (geelwortel) 
           Theelepels 
Week 2 
Koffie 
(décafe niet meegerekend) 
           Kopjes    
Visolie (omega3)* 
           Capsules/tabletten 
Kurkuma (geelwortel)  
           Theelepels 
Week 3 
Koffie 
(décafe niet meegerekend) 
           Kopjes  
Visolie (omega3)* 
           Capsules/tabletten  
Kurkuma (geelwortel)  
           Theelepels 
Week 4 
Koffie 
(décafe niet meegerekend) 
           Kopjes 
Visolie (omega3)* 
           Capsules/tabletten  
Kurkuma (geelwortel)  
           Theelepels 
Kurkuma (geelwortel)  
           Theelepels 
 
 
 
 
Datum: …../…../…..                
 
 
              Periode: Visite maand … - Visite maand … 
 
Subjectnummer:……….. 

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Week 5 
Koffie 
(décafe niet meegerekend) 
           Kopjes    
Visolie (omega3)* 
           Capsules/tabletten 
Kurkuma (geelwortel)  
           Theelepels 
Week 6 
Koffie 
(décafe niet meegerekend) 
           Kopjes    
Visolie (omega3)* 
           Capsules/tabletten 
Kurkuma (geelwortel) 
           Theelepels 
Week 7 
Koffie 
(décafe niet meegerekend) 
           Kopjes    
Visolie (omega3)* 
           Capsules/tabletten 
Kurkuma (geelwortel) 
           Theelepels 
Week 8 
Koffie 
(décafe niet meegerekend) 
           Kopjes    
Visolie (omega3)* 
           Capsules/tabletten 
Kurkuma (geelwortel) 
           Theelepels 
Week 9 
Koffie 
(décafe niet meegerekend) 
           Kopjes    
Visolie (omega3)* 
           Capsules/tabletten 
Kurkuma (geelwortel) 
           Theelepels 
 
 
 
Datum: …../…../…..                
 
 
              Periode: Visite maand … - Visite maand … 
 
Subjectnummer:……….. 

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Week 10 
Koffie 
(décafe niet meegerekend) 
           Kopjes    
Visolie (omega3)* 
           Capsules/tabletten 
Kurkuma (geelwortel)  
           Theelepels 
Week 11 
Koffie 
(décafe niet meegerekend) 
           Kopjes    
Visolie (omega3)* 
           Capsules/tabletten 
Kurkuma (geelwortel) 
           Theelepels 
Week 12 
Koffie 
(décafe niet meegerekend) 
           Kopjes    
Visolie (omega3)* 
           Capsules/tabletten 
Kurkuma (geelwortel) 
           Theelepels 
 
* Indien u visoliesupplementen gebruikt, gelieve een foto van het doosje/potje te maken 
zodat u deze kunt tonen naan de onderzoeker.  
 
Datum: …../…../…..                
 
 
              Periode: Visite maand … - Visite maand … 
 
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