Tailored treatment of functional dyspepsia with nortriptyline: a multi-center double-blind placebo-controlled trial (TENDER)

Dyspeptic symptoms, including upper abdominal pain and symptoms of meal-related
fullness, occur often in the general population in Western countries with an
estimated incidence of up to 40%. Over 70% of patients presenting with
dyspepsia do not have an identifiable cause of their symptoms such as peptic
ulcer disease or Helicobacter gastritis and are therefore referred to as having
functional dyspepsia (FD). As no biomarkers for FD are known, the diagnosis is
made on the basis of symptoms. The current standard for the diagnosis of FD are
the Rome criteria, developed by the Rome Committee. According to the most
recent criteria (Rome IV), issued in May 2016, FD is defined as having
bothersome postprandial fullness, early satiety or epigastric pain/burning, in
the absence of evidence fur structural disease.

The global prevalence of the condition is estimated to be 5-11%, based on Rome
III criteria. However, large regional differences have been reported, with the
prevalence being highest in Western populations, an estimated 10-20%.
Unfortunately, there is currently no definitive therapy that is beneficial for
all FD patients. This is mainly due to the fact that the disorder is quite
heterogeneous and the pathogenesis remains unclear. Several mechanisms have
been suggested to play a role in the pathogenesis including visceral
hypersensitivity, impaired gastric accommodation, delayed gastric emptying and
low-grade duodenal inflammation (increased permeability and mucosal
eosinophilia). According to the Rome criteria, FD is subdivided into epigastric
pain syndrome (EPS) and postprandial distress syndrome (PDS). This subdivision
is based on the assumption that different pathophysiological mechanisms
underlie different dyspeptic symptoms (predominantly sensory abnormalities in
EPS vs. motoric disturbances of gastric physiology in PDS). The rationale for
assigning patients into these two syndrome subtypes in clinical practice is
that the classification may help guide therapy; anti-secretory and analgesic
therapy for EPS and prokinetics for PDS. However, there is significant overlap
between EPS and PDS. In addition, very recently, Vanheel et al. reported on a
comprehensively analysis of 560 patients with FD and provided novel data on
gastric physiological disturbances in PDS and EPS compared with an overlap
group. Interestingly, no differences mbetween the Rome subgroups in the
prevalence of gastric hypersensitivity, impaired gastricaccommodation, and
delayed gastric emptying were found. Furthermore, an association of gastric
hypersensitivity was found with the severity of both PDS symptoms, EPS
symptoms, and the cumulative symptom score, supporting the hypothesis that this
mechanism plays an important role in the pathogenesis of FD symptoms,
regardless of the FD subtype.

Treatment entities for FD include dietary modifications, anti-emetics, gastric
acid inhibitors, prokinetics, psychological interventions and analgesics.
Options cover a wide range and are applied based on predominant symptom and
patient preference. Generally, all patients with dyspepsia are treated with
antisecretory drugs. However, in the absence of gastrointestinal reflux disease
and/or peptic ulcer disease, literature points to a number needed to treat of
14.6 using proton pump inhibitors (PPI) in dyspepsia. Overall, the
effectiveness of PPI treatment in FD appears modest with a therapeutic gain of
approximately 7-10%. Therefore, the implementation of an effective alternative
(and inexpensive) medicinal therapy has the potential to reduce unnecessary PPI
use and has added potential with regards to cost-saving. Accumulating evidence
suggests efficacy for low-dose tricyclic antidepressants (TCAs) in FD. TCAs
were approved in the 1960s and are widely used *off-label* as non-narcotic
analgesics. TCAs are believed to act via noradrenergic and serotonergic
descending inhibitory perceptive pathways and have extensively been used as
neuromodulators in patients with chronic pain.Earlier studies however were of
small size and have not been compelling enough to routinely advocate
antidepressants for FD. Widespread use of TCAs, an otherwise relatively
inexpensive drug group, is further hampered by the fact that these are
traditionally considered antidepressants. There is therefore considerable
reluctance for from both patients and heath care providers to initiate a
therapy with TCAs, especially in the absence of evident psychiatric
comorbidity. In addition, TCAs are often associated with side effects,
including constipation, drowsiness, dry mouth (due to anticholinergic and
antihistaminergic effects), which appear to be dose dependent and occur early
after initiation of therapy preceding the therapeutic effect. This often
results in discontinuation of an otherwise potentially effective therapy. On
the other hand, previous studies have shown that the clinical response is
independent of the total dose of TCAs, supporting the concept of titration of
low dosages in FD (10-50 mg/day) - as opposed to the higher dosages
traditionally used for psychiatric indications (150-300 mg/day). Furthermore,
side effects appear to be dependable on drug metabolism. Fortunately, CYP
genotyping can predict drug metabolism. A pre-treatment assessment of CYP2D6
genotype is used in the present study to exclude abnormal metabolizers, who are
potentially at risk of side-effects and treatment failure. By including only
CYP2D6 extensive metabolizers, we expect to reduce associated side effects,
which often result in discontinuation of TCA therapy. On a group level, this
may increase compliance and ultimately efficacy.

Aim: To investigate the efficacy of nortriptyline in FD patients with a
predicted CYP2D6 extensive metabolizer phenotype. Nortriptyline is a second
generation TCA with significantly fewer anticholinergic side effects compared
to the first generation TCA amitriptyline. In addition, its metabolism only
involves one enzymatic step, which makes clinical response based on
polymorphisms more predictable. Prior to initiation of the drug therapy,
genotyping of the cytochrome P450 enzyme CYP2D6 - the primary enzyme involved
in nortriptyline metabolism - will be performed. CYP2D6 poor, intermediate and
ultrarapid metabolizers are excluded from the current study.

Primary objectives:
1. To assess the efficacy of an escalating dose regimen of nortriptyline as
compared to placebo in FD patients without evidence of significant psychiatric
disease, that have been identified as extensive metabolizers based on their
CYP2D6 genotype.


Secondary objectives:
1. To evaluate the effect of treatment on quality of life, as compared to
placebo.
2. To evaluate the cost-effectiveness of treatment, as compared to placebo.
3. To evaluate the effect of treatment after discontinuation, as compared to
placebo.
4. To evaluate the occurrence of side-effects of nortriptyline as compared to
placebo.

Addendum (open label extension):
Primary objective:
1. To explore the efficacy of low dose (10 mg) nortriptyline in FD patients
without evidence of significant psychiatric disease, that have been identified
as poor or intermediate metabolizers based on their CYP2D6 genotype.

Secondary objectives:
In addition to the objectives described in section 2, we aim to explore the
relationship between CYP2D6 genotype and nortriptyline plasma levels at week 1
of treatment, when dosages are similar in all nortriptyline regimens (i.e.
10mg)

This study is a double-blind placebo-controlled clinical trial in FD patients.
Patients will be randomized into one of three arms:
1. Placebo,
2. Nortriptyline in an escalating dose regimen (see intervention)

The treatment period will be 12 weeks and patients will be followed up for 6
months after discontinuation of the therapy. Patients in each treatment arm
will also receive standard care, including diet and lifestyle coaching.

Following inclusion, patients will be randomly assigned in equal proportions to
one of three groups. Randomization will be performed centrally by the
Department of Pharmacy of the Maastricht University Medical Center (MUMC) by
means of a computer-generated schedule based on the minimization method.
Treatment allocation will be balanced according to inclusion center, gender and
age (18-30; 31-50; 51-65). Site-stratified blocks will be created and balanced
dynamically within each inclusion center using balancing constraint to ensure
overall study balance. The patients, the primary physician of the patient, the
coordinating physician-investigator and study nurse will be blinded to the
treatment assigned.

Addendum:
CYP2D6 genotyping results in four categories:
- Poor metabolizers
- Intermediate metabolizers
- Extensive (normal) metabolizers
- Ultrarapid metabolizers

As described above, only patients that (by genotype) are predicted to being
extensive metabolizers, can be eligible for randomization in this study.
Patients that are excluded on the basis of their genotype however, might still
benefit from nortriptyline. We therefore aim to offer open label nortriptyline
treatment to FD patients recognized as poor or intermediate metabolizer.
Ultrarapid metabolizers will not be eligible for this open label extension.

Nortrilen (nortriptyline)
Week 1-2: 10mg per day
Week 3-4: 25mg per day
Week 5-12: 50gm per day

Placebo treatment will be performed using identical capsules.

Addendum:
poor and intermediate metabolizers will receive 10mg nortriptyline (open
label), without dose escalation.

Subjects may experience minor burden from (digital) visits and study
questionnaires and diaries. There are 3 (digital) visits, including the first
visit in which eligible subjects will be screened before participation. The
screening will take up to 1 hour and will consist of a simple questionnaire, a
general physical exam performed by the physician- investigator and a standard
pregnancy test (in women of fertile age, <55 year only). If deemed suitable by
the investigator, subjects will enter the run-in period. During this period,
patients are asked to report their daily symptom scores to an electronic diary.
If after the run-in period, patients meet the in- and exclusion criteria, they
will enter the treatment period. During the treatment period, subjects are
again asked to complete a (short) diary (8 weeks). Additional questionnaires
are completed in week 4, 8 and 12 and 6 months after treatment.

Only one blood sample is part of the standard procedures in the current study.
The burden of these samples however is kept minimal with the application of a
dried blood spot, which only involves drawing a few drops of blood from the
finger.
On indication (when a patient has significant side effects), a venepuncture
will be performed by either a local study nurse of the coordinating
investigator. This may cause transient mild discomfort. In rare cases, it may
cause a hematoma, which usually is resorbed in several days. During this time,
the arm may feel stiff.

Subjects randomized to placebo may experience small burden due to not receiving
any treatment (although dietary and lifestyle advice continue as usual). Low
dose and personalized regimens used in this study may reduce side effects of
nortriptyline treatment. Nonetheless, side effects can occur. The most frequent
side effects of nortriptyline include dry mouth, headache, nausea,
palpitations, weight gain and blurred vision (due to accommodative
dysfunction). ECG changes can occur, but are most often harmless. An ECG will
be performed prior to the start of treatment in selected patients to ensure
that study medication (nortriptyline) can be started safely. Patients that
require baseline ECG are those with cardiac comorbity (myocardial infarction,
significant arrhythmias or cardiomyopathy), or patients using medication that
can prolong QT time.

Subjects may or may not benefit directly from participating in this study.
There is evidence that TCAs cause relief of FD symptoms. We have reasons to
believe that treatment with nortriptyline on the basis of CYP genotyping will
result in fewer side effects than empirical treatment. Therefore, it is
expected that at least a part of patients randomized nortriptyline treatment
will have some sort of benefit from participating in this study.