E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cirrhotic subjects with ascites and hyponatremia |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009213 |
E.1.2 | Term | Cirrhosis of liver |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003445 |
E.1.2 | Term | Ascites |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10021038 |
E.1.2 | Term | Hyponatremia |
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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 |
To assess the safety and tolerability of M0002 after multiple oral dosing compared with placebo. |
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E.2.2 | Secondary objectives of the trial |
To assess the efficacy of M0002 after multiple oral dosing compared with placebo.
To assess the pharmacokinetic behavior and relationship of the plasma drug concentration with the required effect of M0002 after multiple doses.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female. Female subjects should be postmenopausal: prior oophorectomy, amenorrheic for 12 months or more in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression and follicle stimulating hormone and plasma estradiol in the postmenopausal range. 2. 18 – 75 years of age inclusive. 3. Subjects with any form of cirrhosis with ascites and who had at least 1 paracentesis of at least 4 liter in the last 6 months. 4. The diagnosis of cirrhosis must be confirmed by clinical findings such as evidence of portal hypertension (prominent abdominal wall veins, oesophageal varices, hypersplenism) and / or abnormal laboratory tests (LFTs, coagulation disorders (prolonged coagulation time), low platelet count, anaemia, low albumin, low total protein. The presence of ascites must be documented by ultrasound imaging. Duration since diagnosis should be noted. 5. Dose of diuretics of spironolactone and furosemide should be stable for at least one week prior to the screening visit or subject is refractory to diuretics. 6. Subjects must have been on a salt restricted diet (< 5.2 grams sodium/day, 90 mmol) during the screening period prior to the trial drug administration. 7. Subjects (or their legally acceptable representatives) must have read and signed the written informed consent form after the nature of the trial has been fully explained, indicating the subject understands the purpose of and procedures required for the trial and is willing to comply with trial procedures and restrictions. 8. Other treatment for the management of cirrhosis and ascites should be stable for at least 2 weeks prior to trial drug administration. 9. Child-Pugh B and C (< 12) liver cirrhosis. 10.Subjects with hyponatraemia with sodium level between 120 and 132 mmol/L or normonatraemia with sodium level between 133 and 145 mmol/L measured at screening visit and day 1.
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E.4 | Principal exclusion criteria |
1. Women of child bearing potential (WOCBP). 2. Alcohol or drug abuse 4 weeks prior to screening and/or positive test at screening. 3. Malignancy. 4. Known renal impairment (serum creatinine > 2 mg/dL or 24-h creatinine clearance < 40 ml/min). 5. Recent infection (e.g. urinary tract infection, bacteremia, pneumonia, cellulitis) requiring treatment with antibiotics (e.g. ciprofloxacin, norfloxicin) within 14 days prior to trial entry. Long term, prophylactic antibiotic use is not excluded. 6. Surgery requiring general anesthesia within 30 days prior to trial entry. 7. Major pulmonary insufficiency. 8. Head trauma in the past 2 weeks. 9. Adrenal insufficiency, active encephalopathy grade II, uncontrolled hypo- or hyperthyroidism, unstable diabetes. 10. Subjects with spontaneous bacterial peritonitis (confirmed by culture) within 10 days prior to trial drug administration. 11. Gastrointestinal bleed within 10 days prior to trial drug administration. 12. Functional transjugular intrahepatic portasystemic stent shunt (TIPS), peritoneovenous shunt 13. Liver transplantation. 14. Budd-Chiari syndrome 15. Evidence of intravascular hypovolemia or major hemodynamic instability defined as systolic arterial pressure < 80 mm Hg, orthostatic hypotension, and pulse rate > 120 beats per minute. 16. Any evidence of active myocardial ischemia, myocardial infarction in the last 6 months. 17. Subjects with clinically relevant abnormal ECG intervals of morphology of the ECG, QTc > 480 ms. 18. Positive HIV test. 19. Hemoglobin < 9 g/dL. 20. Unstable hepatic disease (acute hepatitis, AST or ALT > 5 x upper limit of normal, bilirubin > 10 mg/dL) 21. Serum potassium > 6.0 mmol/L or < 3 mmol/L, osmolality > 295 mOs/kg. 22. Platelet count < 40 x 10³ / mm³. 23. Significant coagulopathy such as INR > 2. 24. Participation in an investigational drug or device trial within 30 days prior to screening. 25. Use of the following therapeutic agents: salt tablets or hypertonic saline, NSAIDs, corticosteroids, anticoagulants, saline solution, vasopressin analogs, DDAVP, lithium, demeclocycline, oncologic agents, drugs with potent CYP 3A4 inhibitors (such as itraconazole, ketoconazole, erythromycin, ritonavir, indinavir, sequinavir, …) or drugs known to affect platelet function within 14 days prior to trial drug administration. 26. Psychological and/or emotional problems, which would render the informed consent invalid, or limit the ability of the subjects to comply with the trial requirements. 27. 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 clinically relevant pathology that could interfere with the trial results or put the subject’s safety at risk.
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E.5 End points |
E.5.1 | Primary end point(s) |
To assess the safety and tolerability of M0002 after multiple oral dosing compared with placebo |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | No |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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 | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |