E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Gastrointestinal esophageal reflux disease (GERD) refractory to proton pump inhibitor therapy |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10017885 |
E.1.2 | Term | Gastrooesophageal reflux disease |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
This is an exploratory trial : 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
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E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects who meet all of the following criteria are eligible for this trial: 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 a. must have a negative urine pregnancy test at screening and before the start of treatment (minimum β-Human Chorionic Gonadotropin [HCG] sensitivity of 25 mIU/ml), and b. must agree to either use an effective form of birth control (i.e., stabilized on oral contraceptives for at least 1 month or using implanted, transdermal or injected contraceptive hormones, an intra-uterine device, or continuous abstinence from heterosexual sexual contact), or a combination of a barrier method and a spermicidal agent (i.e., cervical cap and spermicidal agent, condom and spermicidal agent, or diaphragm and spermicidal agent), until 30 days after the end of treatment, or until the onset of menses (last day of menses to be documented at screening, baseline visit and visit 6). 9. Endoscopy within the last 5 years prior to randomisation, negative for grade C & D oesophagitis. |
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E.4 | Principal exclusion criteria |
Subjects meeting one or more of the following criteria cannot be selected: 1. History of cardiac arrhythmias, uncontrolled bronchospastic disease, 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 (e.g., insulindependent diabetes mellitus, hypopituitarism, hypothyroidism, hypercalcaemia, pseudohypopara-thyroidism), metabolic (e.g., porphyria, hypokalaemia, amyloidal neuropathy) and neurologic diseases (e.g., Parkinson’s disease, multiple sclerosis, meningocele, aganglionosis, hypoganglionosis, hyperganglionosis, autonomic neuropathy, spinal cord injury, Chagas’ disease, major depression). 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 μmol/l). 16. Use of prohibited co-medication less than 7 days before the start of the 2-week runin period (baseline symptom assessment). 17. Any condition that, in the opinion of the Investigator(s), would complicate or compromise the trial (e.g., human immunodeficiency virus [HIV] infection, gastroduodenal ulcer) or the well-being of the subject, or evidence of any clinically relevant pathology that could interfere with 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
This is an exploratory trial.
• the 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;
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The last visit of the last subject |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |