E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Alcohol dependence and liver impairment related to alcohol consumption |
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E.1.1.1 | Medical condition in easily understood language |
Alcohol dependence with impaired liver function related to alcohol consumption |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001594 |
E.1.2 | Term | Alcohol dependence syndrome |
E.1.2 | System Organ Class | 100000004873 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10021520 |
E.1.2 | Term | Impaired liver function |
E.1.2 | System Organ Class | 100000004871 |
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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 |
Exploratory objectives to be assessed in patients with alcohol dependence and liver impairment treated with 18 mg Selincro® (nalmefene), as-needed, over 12 weeks:
- To explore the reduction of alcohol consumption
- To explore the change in liver stiffness
- To explore the change in Controlled Attenuation Parameter (CAP)
- To explore the change in liver enzymes
- To explore the shift in fibrosis stage
- To explore the associations between reduction of alcohol consumption, liver stiffness, CAP and liver enzymes
To explore the change in patients with alcohol dependence and liver impairment treated with 18 mg Selincro® (nalmefene), as-needed, on:
- Clinical Global Impression
- Quality of life
Safety objective:
To evaluate safety and tolerability of 18 mg Selincro® (nalmefene), as-needed, in patients with alcohol dependence and liver impairment |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The patient has alcohol dependence, diagnosed at screening according to DSM-IV-TR™
The patient has had an average alcohol consumption at, at least, a high drinking risk level (that is >60 g of alcohol/day for men and >40 g of alcohol/day for women) in the 4 weeks preceding the Screening Visit and in the period between the Screening and Inclusion Visits (that is, in the Screening Period).
The patient has liver changes defined by elevated liver stiffness or elevated controlled attenuation parameter (CAP) at the Screening Visit.
- liver stiffness (LS) >6 kPa or CAP >215 dB/m measured by Fibroscan
The patient has a breath alcohol concentration (BrAC) <0.02% at the Screening Visit.
The patient provides a stable address and telephone number
The patient is a man or woman, aged ≥ 18 years
The patient has BMI≤30 kg/m2 |
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E.4 | Principal exclusion criteria |
The patient has any psychiatric disorder or Axis I disorder (DSM-IV-TR™ criteria), established as the primary diagnosis, other than alcohol dependence assessed using the Mini International Neuropsychiatric Interview (MINI) or another diagnostic interview , that in any way will interfere with the ability of the patient to take part in the study.
The patient has reported current use of, or has been tested positive for, drugs of abuse (opiates, methadone, cocaine, amphetamines [including ecstasy], barbiturates).
The patient has severe liver impairment classified with a Child-Pugh Score C, see Panel 4 of the protocol.
The patient has one or more clinical laboratory test values outside the reference range, based on the blood and urine samples taken at the Screening Visit, that are of potential risk to the patient’s safety, or the patient has:
- Severe renal impairment (eGFR <30 mL/min per 1.73 m2), and/or
- Transaminase levels above 5 times the upper limit of the reference range and γGT levels above 10 times the upper limit of the reference range are not allowed unless if considered habitual for the patient by the Investigator, either confirmed by patient records or a repeat measurement during the Screening Period.
The patient has or has had one or more of the following conditions that is/are considered clinically relevant in the context of the study:
− seizure disorder or encephalopathy, and/or
− endocrine disorder : newly diagnosed or unstable diabetes I and II defined by:
o The patient has not previously been diagnosed with diabetes, but meets the following criteria (newly diagnosed diabetes):
- HbA1c >6.5% AND
- Fasting plasma glucose >126 mg/dL (7.0 mmol/L)
If only one parameter is abnormal a retest is mandatory. A new abnormal result is considered as an exclusion.
OR
o The patient has previously been diagnosed with diabetes, but the condition is unstable as determined by the following criteria
- HbA1c >8.0 %
- The patient has had <6 heavy drinking days (HDDs, defined by the European Medicines Agency as a day with an alcohol consumption >60 g for men or >40 g for women) in the 4 weeks preceding the Screening Visit.
- The patient has a recent history of acute alcohol withdrawal syndrome (including hallucinations, seizures, or delirium tremens).
- The patient is, in the opinion of the investigator, at significant risk of suicide
- The patient is currently participating in or has recently completed (within 1 month prior to the Screening Visit) a treatment or support programme for alcohol-use disorders, including Alcohol Anonymous, (participation in a self-support group is allowed), detoxification treatment, and treatment of alcohol withdrawal symptoms
- The patient’s immediate treatment goal is abstinence.
- The patient has physical withdrawal symptoms and requires immediate detoxification |
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E.5 End points |
E.5.1 | Primary end point(s) |
● The therapeutic effect on the reduction of alcohol consumption will be evaluated by
- change from baseline in the number of heavy drinking days (HDDs)
- change from baseline in total alcohol consumption (TAC)
- Response Shift Drinking Risk Level (RSDRL) response: defined as a downward shift from baseline in drinking risk level (DRL); for patients with a very high DRL at baseline, a shift to medium DRL or lower; for patients with a high DRL at baseline, a shift to low DRL or below
- Response Low Drinking Risk Level (RLDRL) response: defined as a downward shift from baseline in DRL to low DRL or below
- response defined as ≥70% reduction in TAC
- response defined as 0 to 4 HDDs (days/month)
● The therapeutic effect on the change in liver stiffness will be evaluated by measurement of liver stiffness and category shift in fibrosis stage.
● The therapeutic effect on the change in controlled attenuation parameter (CAP) will be evaluated by measurement of CAP and category shift in steatosis stage.
● The therapeutic effect on liver function will be evaluated by measurement of transaminases, γ-glutamyl transferase (γGT), change from baseline in bilirubin, albumin, and International Normalized Ratio (INR).
● The clinical global impression will be assessed by two clinician-rated scales: severity of illness (CGI-S) and global improvement (CGI-I).
● The health-related quality of life will be assessed by a patient self-rated questionnaire, Short-Form 36-Item Health Survey (SF-36).
● Safety will be evaluated by adverse events (AEs), clinical safety laboratory tests, vital signs and weight.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
● Reduction of alcohol consumption:
- Change from baseline in the number HDDs at Month 3
- Change from baseline in TAC at Month 3
- RSDRL response at Month 3
- RLDRL response at Month 3
- ≥70% reduction in TAC at Month 3
- 0 to 4 HDDs (days/month) at Month 3
● Measurement of liver stiffness and category shift in fibrosis at Week 12.
● Measurement of controlled attenuation parameter and category shift in steatosis at Week 12.
● Measurement of liver function: transaminases, γ-glutamyl transferase (γGT); change from baseline in bilirubin, albumin, and INR at Week 12.
● Clinical global impression: CGI-S and CGI-I at Week 12.
● Health-related quality of life: SF-36 at Week 12.
● Safety endpoints: changes from baseline.
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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 | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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The end of the study for an individual patient is defined as the last protocol-specified contact with that patient. The overall end of the study is defined as the last protocol-specified contact with the last patient ongoing in the study. |
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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 | 4 |
E.8.9.1 | In the Member State concerned days | |