Double-blind, randomised, placebo-controlled, dose-finding phase IIb trial to evaluate the efficacy, safety, and tolerability of a 12-week-treatment with Naronapride in adult participants with at least moderate idiopathic or diabetic gastroparesis

Gastroparesis is a condition that decreases quality of life and increases
morbidity. Currently, there is no drug on the market to relieve or eliminate
the symptoms of gastroparesis. Naronapride is a gastrointestinal prokinetic
agent and a hopeful potential drug that could control the symptoms of the
condition without being expected to cause significant side effects.

This study has been transitioned to CTIS with ID 2023-510195-31-00 check the CTIS register for the current data.

The study aim is to examine different doses of Naronapride film-coated tablets
(for oral intake) versus placebo in patients with idiopathic or diabetic
gastroparesis. In previous clinical trials, Naronapride has been administered
to more than 900 subjects and was generally well tolerated. The current study
would provide data on the efficacy, tolerability and safety of treatment with
different doses of Naronapride over 12 weeks. The study also aims to find out
the optimal dose as well as evaluate further side effects of the drug.

The proposed study is a double-blind, randomized, placebo-controlled, phase IIb
dose-finding clinical trial.

If a subject consents to participate in the study, he/she will be required to
take a dose of Naronapride or placebo over a 12-week study period and complete
a number of study-related questionnaires, as well as undergo examinations.
These questionnaires and examinations are intended to monitor the progression
of gastroparesis symptoms, as well as the safety of the subjects.

Patients participating in the study will be assigned to one of three treatment
groups or the placebo group and will be stratified by type of gastroparesis in
each group (66.7% idiopathic and 33.3% diabetic per group).

Group A: Naronapride 10 mg TID (TID = 3 doses a day)
Group B: Naronapride 20 mg TID
Group C: Naronapride 40 mg TID
Group D: Placebo tablets TID

Drug intake should be done with sufficient liquid (one glass of water) and
occur approximately 30 minutes before each main meal.
Main meals are defined as breakfast, lunch, and dinner. All participants should
maintain their normal eating habits throughout the study. The treatment period
is 12 weeks.

Naronapride is intended for the treatment of idiopathic or diabetic
gastroparesis. Gastroparesis significantly affects the quality of life of
patients through its chronic symptoms of nausea, vomiting, abdominal pain and
bloating, as well as significantly increases mortality. In preclinical and
clinical pharmacodynamic studies evidence of both upper and lower
gastrointestinal effects of Naronapride has been shown, as well as therapeutic
effects in Phase 2 studies in patients with chronic idiopathic constipation.
The data justify investigating the use of Naronapride for 12-week treatment of
idiopathic or diabetic gastroparesis patients (for more information see IB).

A thorough QT trial (a study to monitor heart function) conducted in humans
according to ICH E14 guidelines and related documents has confirmed that
Naronapride, at doses several times greater than the anticipated daily
therapeutic dose, has no effects on heart rate, PR, QRS, QT interval duration
or ECG morphology, indicating that Naronapride has a low potential to delay
ventricular repolarisation (for more information see IB). Nonetheless, regular
ECG monitoring will be conducted during the trial in addition to the
measurement of vital signs to detect potential changes in ventricular
repolarisation. Moreover, results from ECG measurements and related adverse
event documentation will be closely monitored by an independent Data and Safety
Monitoring Board (DSMB) established by the sponsor to monitor the patients*
safety parameters during the trial (for details refer to section 7.5 of the
CIP).

Diagnostic procedures like performance of upper gastrointestinal endoscopy and
abdominal sonography or MRI or computed tomography (CT) and 13C-Spirulina
Gastric Emptying Breath Test (GEBT) are used as validated diagnostic measures
to confirm the diagnosis of gastroparesis and to thoroughly exclude an overlap
of symptoms with other gastrointestinal disorders. Each of these diagnostic
measures will be carried out by experienced physicians only such that
associated risks are minimised.

As CT is an imaging technique based on X-rays and due to the high radiation
exposure during CT, pregnant women must not be examined by computer tomography.
As females of childbearing potential participating in this trial must use a
highly effective method of contraception during the entire trial starting with
the first screening visit (SCR 1, V0) and as a pregnancy urine test is
performed at date of SCR 1 (V0) it is ensured that no pregnant woman will be
exposed to X-rays during the trial.

With the above provisions in place, the risks associated with participating in
the trial are considered low and outweighed by the benefit of a potential
future oral treatment option for idiopathic and diabetic gastroparesis. The
current risk profile is therefore deemed in favour of continued development of
Naronapride.