*A personalized lifestyle approach for abdominal pain in Irritable Bowel Syndrome and inflammatory bowel disease: a proof of concept study using Experience Sampling Method (ESM) and a digital food diary (Traqq).'

Visceral sensation, including visceral pain is a crucial feedback mechanism,
signaling the body to act on potential harm in internal organs. During
intestinal inflammation, e.g. due to infections or immune mediated conditions,
abdominal pain has potential physiological benefits, following the same
reasoning. However, when abdominal pain persists even after the
gastrointestinal (GI) infection is cleared or the immune mediated inflammation
has attenuated, it hampers patients to resume and participate in daily life
activities. This is seen in Irritable Bowel Syndrome (IBS), which may develop
secondary to a GI infection, or in Inflammatory Bowel Disease (IBD; Crohn*s
disease and Ulcerative Colitis), which are immune mediated inflammatory
intestinal diseases. There is similarity between abdominal pain and other GI
symptoms experienced by patients with IBS and patients with IBD who are in
remission (i.e. in absence of active intestinal inflammation). Therefore, in
IBD these chronic GI symptoms may be referred to as IBS in IBD (from now on
referred to as IBD-IBS) and are currently treated using the same approaches as
IBS. Why some people develop IBS after a GI infection and others don*t, or why
some remissive IBD patients develop chronic abdominal pain even when endoscopic
remission is reached, is unknown, but disturbances along the gut-brain axis are
assumed to play a key role in both disorders. When the affected subjects
understand the origin of the symptoms, know its dynamics and triggers, coping
improves, GI related anxiety is reduced, and the symptoms become less
bothersome in daily life. Therefore, the cornerstone of any treatment of
chronic intermitted abdominal pain in IBS and IBD-IBS is patient education, and
thereafter selecting a personalized treatment approach that matches the
patients* needs and expectations in a process of shared decision making.
However, in both IBS and IBD-IBS, physicians struggle with finding the right
approach to chronic intermitted abdominal pain, leading to doctor-patient
perception gaps. This can partly be explained by the complexity of this symptom
and its origin. The type, intensity, localization, duration, evolution, and
progression of abdominal pain vary greatly between patients. Different factors
may trigger or modulate abdominal pain, such as diet, acute or chronic stress,
and feelings of anxiety, worry or depression. This makes the group of people
with abdominal pain both in IBS and in IBD-IBS heterogeneous, and inevitably
unsuitable for a *one size fits all* approach.
The current study is developed to investigate whether two previously validated
digital applications can be used to aid in this process, to unravel the
dynamics of abdominal pain and potential triggers in individual patients, to
assess the interactions with associated GI symptoms, psychological factors, and
diet. The personalized analysis of abdominal pain, associated factors and its
triggers can then be used to provide insight into the symptom dynamics for the
patient and the treating physician which may aid the selection of the best
treatment approach for the specific patient. To measure differences in
abdominal pain severity at baseline and at the end of the study, the irritable
bowel syndrome symptom severity score (IBS-SSS) is used, since this is the
broadest measurement of pain-related aspects among validated questionnaires.

Irritable Bowel Syndrome (IBS)
IBS is a disorder of gut-brain interaction, characterized by chronic recurrent
abdominal pain, associated with altered bowel habits (i.e. diarrhoea,
constipation or a combination of both), in the absence of an explanatory
organic cause. In the Western countries it affects up to 10% of the general
population, with a female predominance. To aid diagnosis and allow
international comparisons, several international consensus meetings have
culminated in the production of the Rome IV diagnostic criteria for IBS.
Assessment of symptoms is not only relevant with regards to confirming the
diagnosis, but also to the evaluation of the natural disease course over time
and to follow treatment efficacy. This assessment is generally based on symptom
questionnaires; current guidelines on IBS clinical trials from the regulatory
authorities suggest the use of retrospective end-of-day diaries. Currently used
assessment methods to evaluate natural disease course over time and follow-up
of treatment are mainly retrospective, self-reported questionnaires, based on
daily or weekly monitoring. However, those have important limitations. The
documentation of patients* past symptoms can be evidently distorted due to
recall bias, environment and psychological status, and lack of compliance when
done retrospectively, resulting in inaccurate representations of symptom
patterns. Due to the lack of any identifiable biological marker, symptom
monitoring is cardinal in this patient population as it is the only clinical
read-out available for assessing IBS treatment efficacy.

Chronic abdominal symptoms in Inflammatory Bowel Disease (IBD) in remission
The aetiology and evolution of chronic abdominal pain in IBD-IBS are poorly
understood, and treatment is often unsatisfactory. There is a paucity of robust
evidence on the safety and efficacy of potential interventions for the
management of abdominal pain. However, gut-directed psychological therapy and
dietary intervention have proven to be promising approaches.
Although recently the main focus in management of IBD was treatment of
intestinal inflammation, the quality of life of these patients is affected by
several other factors, including chronic abdominal pain, present even when
inflammatory remission is achieved, as well as psychosocial wellbeing. In
general, the medical perspective is slowly changing and it becomes more
important to treat the persistent symptoms after remission is achieved in
general practice.
However, despite the changing perspective in the medical field on the treatment
of chronic abdominal pain or IBS-like symptoms in IBD-IBS, the treatment
options are limited. A personalized approach for the treatment of these
symptoms is needed, but currently lacking in daily clinical practice. A better
understanding of the interaction between abdominal pain and psychological,
lifestyle and environmental factors is needed to pave the way for personalized
approaches.

Experience Sampling Method (ESM)
Experience Sampling Method (ESM), also referred to as Ecological Momentary
Assessment (EMA), a symptom assessment method widely used in the field of
psychology, but minimally implemented in somatic fields, may overcome these
limitations. ESM is an electronic questioning method characterized by repeated,
momentary assessments in the subject*s current state and environment.
Measurements take place at random moments during regular daily life, for
several consecutive days. ESM assessments are completed using a digital device,
which emits an auditory signal every time the subject is supposed to complete
an assessment. Subjects are allowed only a short time after the auditory signal
to respond to the questions and questions always relate to current symptoms. In
a study by Vork et al the scores of the developed ESM-based Patient Reported
Outcome Measure (PROM) were significantly lower than the end-of-day scores. The
difference between the ESM and end-of-week scores was even more pronounced.
Furthermore, patients reported less GI related anxiety with ESM compared with
the Visceral Sensitivity Index. This further supports the notion that it there
is a difference in measuring symptoms of IBS patients during the day compared
to at the end of the day, because of the misperception patients have about
their complaints and trigger factors. The study showed a good validity and
reliability of the developed ESM-based PROM for measuring GI symptoms in an IBS
population. The ESM-based PROM has the advantage of a more detailed view on
individual symptom patterns, with the option to analyse symptom-symptom and
symptom-environment interaction. This can be useful for giving patients more
insight in their symptoms and the relation with environmental factors, like
stress or diet.

Smartphone-based dietary assessment tool (Traqq)
As said before, nutritional factors can be related to abdominal pain in IBS or
IBD-IBS patients. In a study by Lucassen et al a smartphone-based dietary
assessment tool (Traqq) was developed and validated. The application can be
used to record food and drinks during the day. The data is stored on a secure
server. It can be used to collect detailed information about the macro- and
micronutrients the patient has eaten. This tool can be perfectly used to get
more insight in the patients eating pattern to see whether food is a trigger
factor for their symptoms.

Apart from its use to provide insight in IBS disease courses and in clinical
research, ESM can provide patients with feedback about individual triggers of
their symptoms, and thereby function as part of a personalized therapeutic
strategy. This is also true for IBD-IBS. Treatment strategies in IBS and
IBD-IBS are largely based on reassurance, identification and elimination of
triggering factors, and in more severe cases pharmaco- and psychotherapy. The
ESM approach has the potential to increase therapeutic efficacy in IBS and will
assist patients in disease self-management. The Traqq application can provide
more detailed information about the dietary pattern of IBS patients. Traqq in
combination with ESM will give an overview of abdominal pain and associated
symptoms and psychosocial factors are exposed to during the day. The insight
provided using ESM and Traqq may improve patient understanding of their
personal symptom dynamics and triggers, as well as the physician*s insight into
the symptom patters of the specific patients, which may aid treatment choice
and eventually improve the outcome of any treatment provided in daily clinical
care.

This is an unicenter, prospective, proof-of-concept randomized controlled,
non-blinded intervention study that focuses on two patient populations, with
overlapping symptom patterns and treatment approaches, i.e. patients with IBS
and IBD-IBS.

Recruitment procedures are described in paragraph 8.2. Following written
informed consent, the eligibility screening is performed and instructions about
the study procedures will be given. Hereafter, both groups will independently
be randomized into i) an ESM/Traqq arm or ii) a standard care arm. The
intervention group and the control group will complete the IBS-SSS, EQ-5D-5L,
GAD-7, PHQ-9, VSI, and MFI-20 as well as the Rome IV criteria for IBS and
functional dyspepsia at baseline and the intervention group will complete
thereafter the ESM and Traqq applications during the first week. After this
week, the data will be analysed to identify associations between abdominal pain
and psychosocial factors, diet or other GI associated symptoms. The
coordinating investigator will contact the participants of the intervention
group and will ask how they experienced the ESM/Traqq method and whether they
think this helped them to get more insight about the association between
abdominal pain and the trigger factors.
About two weeks later, participants will have their second visitation at the
outpatient clinic with their treating physician. In the intervention group, but
not the control group, the patient and the treating physician will receive the
results of the personal data of the patients based on ESM and Traqq. The
insight participants and their physicians get from this information, will help
them to make changes in lifestyle factors that affect their symptoms or to
choose a pharmacological or non-pharmacological treatment. However, the study
protocol will not indicate which treatment choice should be made by the patient
and their treating physicians. That choice will still be based on shared
decision making, just as in the standard care arm, only with the additional
data provided.
Furthermore, if the patients are referred to a dietician, psychologist, or
both, the digital data obtained in the intervention group can be used to
personalize the therapy. After giving informed consent by the participant for
the data of ESM and Traqq being sent to the dietician or psychologist they are
referred to, the coordinating investigator will send the data digitally to the
dietician or psychologist that is needed for the personalized treatment (see
E1-E2_Informatiebrief en toestemmingsformulier_Versie 1.0 _22.09.2022).
Participants in the control arm will get a consultation with the
gastroenterologist as usual after the same period of time as the intervention
group get their consultation. The participants of the control group will be
given treatment advice only based on this consultation, the PDSkeuzehulp by
shared decision making, according to standard care.
Twelve weeks after the second outpatient visit, independently of the chosen
treatment approach, the participants in both study groups will be asked to
complete IBS-SSS, EQ-5D-5L, GAD-7, PHQ-9, VSI, MFI-20 and Rome IV criteria for
IBS and functional dyspepsia for the second time to evaluate whether there is
an effect on 1) reduction of abdominal pain and 2) quality of life,
psychological aspects or fatigue of the participants due to the insight
provided by ESM and Traqq.
After those twelve weeks, the coordinating investigator will contact the
participants of the intervention group and control group by phone for the last
time. Participants are asked what treatment they have gotten and what lifestyle
modifications they have done to reduce abdominal pain.
To improve compliance for completing the questionnaires by the control group,
the participants in the control group will get the opportunity to use the ESM
and Traqq applications after the study has been completed. This will not be
part of this study but can be beneficial for those individuals who have not got
any additional insight about their symptoms by getting the standard care.

Participating in this study does not bring along important risks, since
subjects only have to complete questionnaires and there are no investigational
products involved. Therefore, this is a low-risk study. However, completing the
PROM several times a day might be quite burdensome and time-consuming for
participants and will intervene with regular daily life. Completing the PROM
questionnaires at baseline and at the end of the study will take approximately
10 minutes. For the intervention group, completing the ESM and Traqq
applications will take approximately one hour per day. Furthermore, since data
are transferred via Internet and partly stored at a participant*s smartphone,
there is a need for securing on an individual*s privacy. This is described into
more detail in section 9.1 *Handling and storage of data and documents*. The
advice for lifestyle modifications, psychological treatments or other
treatments are not different from the treatments used in standard care. The
only difference is that the treatment chosen would fit the individual better,
because by using ESM/Traqq a detailed analysis is made of the individual
triggers. A better, more accurate treatment plan can be made by the general
practitioner, but this only contains the currently available treatments.
Therefore, there will not be any additional risks according these treatments
when participating in this study compared to the standard care.

During the study period, subjects could directly benefit from participation
since they receive a personalized intervention strategy. It is possible that
completing the ESM questionnaires and food diary makes subjects more aware of
their symptom patterns and possible provoking factors in daily life, which
might be beneficial. Moreover, a personalized intervention strategy can treat
specific trigger factors in daily life of a particular individual. These
trigger factors will not be the same for every individual. Therefore, the
beneficial effect of the use of this ESM/Traqq method will be that beside of
standard diagnostics and therapeutic aims, a more personalized manner is used
to relate individual trigger factors to IBS symptoms.

All in all, the risks in this study are not disproportional in association with
the benefits. Participants will be informed about the burdens before
participating. Participants in the control group will be informed at start of
the study about the opportunity to use the ESM and Traqq application afterwards
to see if any improvements can be made regarding their symptoms and trigger
factors. This will not be part of this study.