The objectives of this exploratory trial are:1. To measure the pharmacodynamic (PD) effect on parameters derived from 24-hpH/impedance (MII) monitoring,2. To explore the effect on symptoms,3. To evaluate the safety and tolerabilityof treatment with…
ID
Source
Brief title
Condition
- Gastrointestinal motility and defaecation conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The three main PD endpoints for the evaluation of PD effects of M0003 will be:
* the average number of liquid-containing reflux events per 24-h period;
* the average proximal extent of all liquid-containing reflux events in the
24-h period;
* average bolus clearance times of all liquid-containing reflux events in the
24-h period;
Secondary outcome
Secundary endpoints are:
- to explore the effect on symptoms by means of the pH-impedance measurements,
de information from the ediary and the 2 questionnaires (PAGI-SYM and PAGI-QoL)
- to evaluate safety and tolerability by means of adverse events, lab tests,
physical examinations, ECGs, blood pressure and heartbeat measurements en
concomitant medication.
Background summary
M0003 is an investigational drug, it has not yet been granted marketing
approval by regulatory agencies such as the European Medicines Agency (EMA).
M0003 is being studied as a potential treatment for gastro-esophageal reflux
disease (GERD) in patients who do not experience adequate relief from their
current medication (proton pump inhibitors, PPIs). M0003 is expected to reduce
the number of reflux events, which in turn could also improve GERD symptoms
(i.e. heartburn and regurgitation). Heartburn can be described as burning pain
rising in the chest or throat; regurgitation can be described as fluid or
liquid from the stomach coming up into the throat.
Although M0003 has not yet been evaluated in GERD patients, 9 Phase I trials
(in healthy volunteers) and 1 Phase II trial (in patients suffering from
delayed emptying of the stomach) have been conducted. So far, 181 subjects have
received M0003, evaluating a wide dose range that covers (and exceeds) the dose
that will be used in the current trial.
The current clinical trial is being performed to gain and extend the knowledge
on the safety, tolerability and therapeutic effect of M0003 in GERD patients.
In total, 90 patients will be included. Half of the participants will receive
M0003 tablets, the other half will be treated with placebo tablets, which look
exactly the same, but do not contain active medicinal product.
Study objective
The objectives of this exploratory trial are:
1. To measure the pharmacodynamic (PD) effect on parameters derived from 24-h
pH/impedance (MII) monitoring,
2. To explore the effect on symptoms,
3. To evaluate the safety and tolerability
of treatment with 0.5 mg M0003 (on top of PPI treatment), t.i.d. for 4 weeks, in
subjects with GERD and with persistent symptoms despite taking a stable dose of
proton pump inhibitors.
Study design
This is a multi-centre, randomized, placebo-controlled, double-blind,
parallel-group trial. Each subject will receive M0003 tablets (0.5 mg t.i.d.)
or matching placebo tablets (t.i.d.) on top of their stable PPI treatment for 4
weeks. Subjects will be randomized in a double-blind manner to either M0003 or
placebo in a 1:1 ratio.
Intervention
Half of the patients wil receive 4 weeks (28 days) of treatment with 0,5 mg
M0003 t.i.d. on top of their PPI treatment and the other half of patients will
receive 4 weeks (28 days) of treatment with placebo t.i.d. on top of their PPI
treatment
Study burden and risks
The proposed trial offers distinct benefits to all participants, regardless of
randomization to
placebo or active dose, and is expected to improve the current understanding of
refractory
GERD through detailed diagnostic evaluation.
The treatment period will have a duration of 4 weeks, preceded by a potential
wash-out period of 7 days in case the subject takes disallowed medication, and
a run-in period of 14 days. The total trial duration will be at least 43 days.
At most, 6 visits will be scheduled during the entire trial.
During the trial following assessments will be performed:
- 4 x a blood sample (in total approx. 28 mL)
- 3 x an ECG
- 3 x a physical examination and weight measurement
- 1 x measurement of height
- 3 x blood pressure and heartrate
- 3 x a urine sample
- 3 x a urine pregnancy test (woman of childbearing potential only)
- 2x a 24h pH-impedancy measurement (possibly preceded by an initial manometry)
The patient needs to keep an ediary during the trial and will be asked to
complete 2 questionaires at 3 occasions during the trial.
Importantly, M0003 has a wide safety margin, and AEs through action at
receptors other than 5-HT4 receptors are highly unlikely. Based on data from
previous trials, the dose chosen for this trial is expected to be well
tolerated. The most common AEs (i.e., GI symptoms, headache, dizziness) usually
occurred on Day 1 of treatment, became less frequent during repeated dosing and
all resolved by the end of the trials. With M0003 alone, AEs were mild to
moderate in intensity, and did not result in discontinuation. M0003-related
SAEs have not been reported.
Furthermore, safety is monitored throughout the entire trial duration and
rescue medication
(Rennie) will be provided in case of excessive GERD symptoms.
Veedijk 58 (1004)
2300 Turnhout
BE
Veedijk 58 (1004)
2300 Turnhout
BE
Listed location countries
Age
Inclusion criteria
1. Written ICF signed voluntarily before the first trial-related activity.
2. Aged between 18 and 70 years, extremes included.
3. Subjects with a history of GERD symptoms (i.e., heartburn and/or regurgitation) during the last 6 months (as assessed by anamnesis/medical history).
4. Subjects on a stable dose of PPIs, compliant for at least 6 weeks prior to screening.
5. Subjects with heartburn and/or regurgitation, with at least one of these symptoms of moderate severity or worse, and at a minimum average frequency of three days a week during the two-week run-in period (determined by completion of a daily diary).
6. A minimum of 25 liquid-containing reflux events over 24 h (pH/MII monitoring).
7. BMI < 35.
8. If the subject is a woman of childbearing potential she must have a negative urine pregnancy test at screening and before the start or treatment and must agree to either use an effective form of birth control or a combination of a barier method and a spermicidal agent until 30 days after the end of treatment, or until onset of menses.
9. Endoscopy within the last 5 years prior to randomisation, negative for grade C & D oesophagitis (according to the Los Angeles classification).
Exclusion criteria
1. History of cardiac arrhythmias, uncontrolled bronchospastic disease and controlled bronchospastic disease with symptoms, cardiovascular disease (e.g., ischemic heart disease or cerebrovascular accident), thyrotoxicosis.
2. Subjects with a family history of sudden death or a congenital QT syndrome.
3. Presence of prolonged QTc (Bazett and Fridericia) on ECG at screening (QTc * 450 msec for males and QTc * 470 msec for females).
4. Subjects with a documented history of long segment (>3 cm) Barrett*s oesophagus.
5. Subjects with documented or suspected large (> 3 cm) hiatus hernia.
6. Subjects with fundoplication, endoscopic anti-reflux procedure or major prior GI surgery.
7. Subjects with clinically significant abnormalities as judged by the investigator at screening physical examination, or in blood haematology and biochemistry tests performed at screening.
8. Subjects with a structural abnormality or structural disease condition of the GI tract.
9. Severe oesophageal motility disorders (e.g., scleroderma, achalasia, nutcracker oesophagus).
10. Subjects who suffer from frequent vomiting (>1/week, as assessed during anamnesis).
11. Current diagnosis of co-existing psychiatric disease (including alcohol or drug abuse); controlled depression and anxiety are allowed, when treated with at most one drug, at a stable dose.
12. Subjects suffering from severe and/or uncontrolled endocrine, metabolic and neurologic diseases. Endocrine and metabolic disorders controlled by appropriate medical therapy will not be excluded, except for insulin-dependent diabetes mellitus.
13. Presence of severe and clinically uncontrolled cardiovascular, liver or lung disease, neurologic, cancer or AIDS.
14. Alarm symptoms suggestive of malignancies or organic disease such as: obstructive dysphagia, odynophagia, GI bleeding, blood in stool or anaemia, weight loss; unless investigated and found to be negative.
15. Impaired renal function, i.e., serum creatinine concentration >2 mg/dl (>180 micromol/l).
16. Use of prohibited co-medication less than 7 days before the start of the 2-week run-in period (baseline symptom assessment).
17. Any condition that, in the opinion of the Investigator(s), would complicate or compromise the trial or the well-being of the subject, or evidence of any clinically relevant pathology that could interfere with the trial results or put subject safety at risk.
18. Participation in an investigational drug trial in 30 days prior to enrolment.
19. Breast-feeding subjects.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-021397-12-NL |
| CCMO | NL33807.018.10 |
| Other | wordt later geregistreerd |