Investigation of the Efficacy of Acamprosate and Calcium in Comparison to Placebo as Validation of a Behavioural Test for Alcohol Dependence

Study Overview
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Brief Summary
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Validation of a Test System to develop new medications for alcoholism (TEMA) The 'TEMA', a progressive-work alcohol self-administration paradigm, can be validated by reproducing the effect of Acamprosate and prove the effect of Calcium to reduce motivation to work for alcohol after 14 - 19 days of treatment during a period of 15 - 20 days of alcohol abstinence in a randomized, double-blind, placebo-controlled three-arm parallel-group design.

Detailed Description
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Objective of this study is to show that a laboratory alcohol self-administration method can predict the therapeutic potential of new compounds to reduce relapse in alcohol-dependent patients. The 'TEMA' translates several animal behavioral paradigms of alcohol self-administration into corresponding human experiments. 84 at least high risky drinkers (WHO) with at least mild alcohol use disorder perform two alcohol self-administration experiments, one before and one after 14-19 days of randomized double-blinded treatment with Acamprosate, Calcium Carbonate or Placebo. Each alcohol request requires prior work in a constant attention task according to a progressive schedule to earn the next alcohol infusion. Secondary objectives refer to investigations, whether administration of Acamprosate or Calcium Carbonate in comparison to placebo leads to a change in perception of subjective alcohol effects effectiveness of Acamprosate or Calcium can be predicted by calcium parameters (baseline and changes during medication period) administration of Acamprosate or Calcium leads to a reduction in alcohol craving Frequency of alcohol consumption during the imposed abstinence period differs between treatment groups and influences primary outcome study participation modifies motivation to change drinking habits and utilization of addiction care services Acid sphingomyelinase (ASM) activities are applicable as biomarker and predictor of medication effects. safety issues occur due to study medication

Official Title
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Investigation of the Efficacy of Acamprosate and Calcium in Comparison to Placebo as Validation of a Behavioural Test for Alcohol Dependence (TEMACA)

Conditions
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Alcoholism

Intervention / Treatment
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* Drug: Acamprosate Calcium
* Drug: Calcium Carbonate
* Drug: Placebo
* Drug: Placebo lead in


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: male and female volunteers aged 25 to 55 years, who meet or met the diagnostic criteria of an at least mild alcohol use disorder (DSM-5), but do not want to cease alcohol consumption willingness to stop alcohol and drug consumption for 15-20 days for the purpose of study participation at least high risky alcohol drinkers (WHO) in the Timeline Follow-back Interview over the last 45 day with an average amount of alcohol of 60 g/day (men) or 40 g/day (women) with at least 4 drinking days per week informed consent ability to swallow a placebo capsule not more than 6 consecutive alcohol abstinent days between screening and visit 2 Exclusion Criteria: Current Substance dependence (illegal drugs) ICD-10 or DSM-IV Intention to stop alcohol consumption immediately and permanently Current or previous disease that could cause a clinically relevant hazard (e.g. pancreatitis, cirrhosis) kidney stone disease Current Treatment with psychotropic drugs or current psychiatric disorder in need of treatment alcohol withdrawal symptoms (at Screening, visit 1 or visit 2) with CIWA-Ar-Score > 6 points or arterial blood pressure >160 mm Hg or diastolic blood pressure > 100 mm Hg or heart rate >105 bpm (when breath alcohol concentration 0 mg%) history of epileptic seizure or delirium routine laboratory parameters, indicating relevant liver-, pancreas- or kidney injury, an acute infection, anemia or lack of vitamins (ASAT, ALAT, lipase > threefold of the standard at screening, Quick's value < 70%, creatinine > 120 µmol/l, eGFR < 30 mol/min/1.73 m², leucocytes > 13000/µl, haemoglobin < 7.5 mmol/l (men) or 6.5 mmol/l (women), MCV > 105 fl, calcium level at screening > 2.7 mmol/l body weight > 120 kg (Screening) Breath alcohol concentration at screening or visit 1 or visit 2 two times > 0 mg% or drug screening two times positive for opiate, cannabis, cocaine, amphetamine, benzodiazepine history of hypersensitivity to alcohol or one of the used medicinal products, of their ingredients or medicinal products with similar chemical structures history of inefficient treatment with Acamprosate participation in another clinical trial within the last 4 weeks before inclusion disorders, which will not allow the subject to assess the character and importance or possible consequences of the clinical trial pregnant or breastfeeding women women capable of bearing children, except women who fulfil following criteria:- post-menopausal (12 months natural amenorrhoea or 6 month amenorrhoea and Serum FSH >40 ml U/ml) - post operative (6 weeks after ovariectomy on both sides with or without hysterectomy) - regular and correct use of a contraceptive method with an error Quote of < 1 % per year (for example implants, depot injections, oral contraceptive, IUP). It has to be recognized that a combined oral contraception - in contrast to pure progesterone compounds - have a failure rate of < 1 %. Hormone IUDs with a Pearl Index of 1 % are safer than copper IUDs. - sexual abstinence - vasectomy of the Partner) participant is not expected to comply with the protocol (for example lacking compliance) less than 200 cumulative work trials for alcohol (in constant attention task) on 1st alcohol self-administration day specific contraindications for Acamprosate or Calcium Carbonate (according prescribing information) hypercalcemia, e.g. due to hyperparathyroidism, overdosage vitamin D, paraneoplastic renal insufficiency (eGFR < 30ml/min/1.73m²), creatinine >120 µmol/l intake of Vitamin D compounds or cardioactive glycosides

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Acamprosate<br>1 capsule with Acamprosate calcium oral use 3 times / day (morning, noon, evening) 666 mg per capsule 14 - 19 days | Drug: Acamprosate Calcium<br>* 1 capsule with 666 mg Acamprosate<br>* Other names: Campral;Drug: Placebo lead in<br>* 1 Capsule with Placebo (lactose monohydrate, micro crystalline cellulose, magnesium stearate)<br>|
| Active Comparator: Calcium Carbonate<br>1 capsule with Calcium Carbonate oral use 3 times / day (morning, noon, evening) 1500 mg Calcium Carbonate (= 600 mg Calcium 2+) 14 - 19 days | Drug: Calcium Carbonate<br>* 1 capsule with 1500 mg Calcium Carbonate<br>* Other names: Calcium;Drug: Placebo lead in<br>* 1 Capsule with Placebo (lactose monohydrate, micro crystalline cellulose, magnesium stearate)<br>|
| Placebo Comparator: Placebo<br>1 capsule placebo, oral use 3 times / day (morning, noon, evening) 14 - 19 days | Drug: Placebo<br>* 1 Capsule with Placebo (lactose monohydrate, micro crystalline cellulose, magnesium stearate)<br>Drug: Placebo lead in<br>* 1 Capsule with Placebo (lactose monohydrate, micro crystalline cellulose, magnesium stearate)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference between cumulative CAT trials for alcohol on 1st alcohol self-administration (ASA) day and 2nd ASA day | Each alcohol request requires prior work according to a progressive schedule (i.e., runs of the constant attention task) to earn the next alcohol infusion. Primary outcome measure is the difference in the cumulative number of work sets for alcohol in the constant attention task (CAT) between first alcohol self-administration day (baseline, without medication, visit 2) and the second alcohol self-administration day (after 14-19 days medication, visit 5). Comparison between: Acamprosate and Placebo and Calcium Carbonate and Placebo | 18 to 31 days between 1st and 2nd measurement | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference between break points for alcohol on 1st alcohol self-administration (ASA) day and 2nd ASA day | The break point is the number of the last alcohol request before subjects stop to work for more alcohol. | 18 to 31 day between 1st and 2nd measurement | 
| Difference between max. achieved blood alcohol concentrations (BAC) on 1st alcohol self-administration (ASA) day and 2nd ASA day | Max. BAC during alcohol self-administration | 18 to 31 day between 1st and 2nd measurement | 
| Difference between cumulative CAT trials for sodium chloride on 1st alcohol self-administration (ASA) day and 2nd ASA day. | Sodium chloride is an alternative reinforcer on alcohol self-administration. Each Sodium chloride request requires prior work according to a progressive schedule (i.e., runs of the constant attention task) to earn the next sodium chloride infusion. Outcome measure is the difference in the cumulative number of work sets for sodium chloride (as an alternative reinforce) in the constant attention task (CAT) between first alcohol self-administration day (baseline, without medication, visit 2) and the second alcohol self-administration day (after 14-19 days medication, visit 5). | 18 to 31 days between 1st and 2nd measurement | 
| Differences in 1st and 2nd half of self-administration periods between cumulative CAT trials for alcohol on 1st alcohol self-administration (ASA) day and 2nd ASA day of 1st and 2nd half of self-administration periods. | Each alcohol request requires prior work according to a progressive schedule (i.e., runs of the constant attention task) to earn the next alcohol infusion. Outcome measure is the difference in the cumulative number of work sets for alcohol in the constant attention task (CAT) between first alcohol self-administration day (baseline, without medication, visit 2) and the second alcohol self-administration day (after 14-19 days medication, visit 5), considering the 1st and 2nd half of the self-administration period separately | 18 to 31 days between 1st and 2nd measurement | 
| Differences in 1st and 2nd half of self-administration periods between break points for alcohol on 1st alcohol self-administration (ASA) day and 2nd ASA day. | The break point is the number of the last alcohol request before subjects stop to work for more alcohol. Outcome measure is the the difference in break points for alcohol between first alcohol self-administration day (baseline, without medication, visit 2) and the second alcohol self-administration day (after 14-19 days medication, visit 5), considering the 1st and 2nd half of the self-administration period separately. | 18 to 31 days between 1st and 2nd measurement | 
| Differences in 1st and 2nd half of self-administration periods between max. achieved blood alcohol concentrations (BAC) for alcohol on 1st alcohol self-administration (ASA) day and 2nd ASA day. | Outcome measure is the the difference in max. achieved blood alcohol concentrations between first alcohol self-administration day (baseline, without medication, visit 2) and the second alcohol self-administration day (after 14-19 days medication, visit 5), considering the 1st and 2nd half of the self-administration period separately. | 18 to 31 days between 1st and 2nd measurement | 
| Differences in 1st and 2nd half of self-administration periods between cumulative CAT trials for sodium chloride on 1st alcohol self-administration (ASA) day and 2nd ASA day. | Sodium chloride is an alternative reinforcer on alcohol self-administration. Each Sodium chloride request requires prior work according to a progressive schedule (i.e., runs of the constant attention task) to earn the next sodium chloride infusion. Outcome measure is the difference in the cumulative number of work sets for sodium chloride in the constant attention task (CAT) between first alcohol self-administration day (baseline, without medication, visit 2) and the second alcohol self-administration day (after 14-19 days medication, visit 5), considering the 1st and 2nd half of the self-administration period separately | 18 to 31 days between 1st and 2nd measurement | 
| Differences between subjective alcohol effects on 1st ASA day and 2nd ASA day | alcohol-induced changes in stimulation, sedation, negative alcohol effects, craving, well-being, subjective feeling of drunkenness, subjective number of drinks and thirst measured with visual analogue scales (Quizzer) before, 2 x during and after the alcohol infusion period. scale ranges: minimum = 0 to maximum = 100 Higher values on a scale represent an increase of aforementioned subjective alcohol effects. Comparison between 1st ASA and 2nd ASA day | 18 to 31 days between 1st and 2nd measurement | 
| Calcium parameters on 1st ASA and 2nd ASA day | magnesium, phosphate, total calcium, albumin, parathormone, 25-hydroxyvitamin D measurement at baseline and difference between 2nd and 1st ASA | 18 to 31 day between 1st and 2nd measurement | 
| Alcohol craving (OCDS) Obsessive Compulsive Drinking Scale (OCDS) | Craving measured with Obsessive Compulsive Drinking Scale (OCDS) before 1st and 2nd ASA The OCDS is a 14-item self-rating instrument. It provides a total and two subscale (1: obsessive, 2. compulsive) scores, that measure aspects of alcohol craving. | 18 to 31 days between 1st and 2nd measurement | 
| Violation of imposed alcohol abstinence | in % of the days with alcohol consumption (measured with timeline follow-back, measured at visit 5) | 15-20 days (abstinence period) | 
| Readiness to change | Readiness to change questionnaire 12-item instrument for measuring the stage of change at screening, visit 6 and follow-up. The test has three four-item subscales to allocate patients to a stage of change: pre-contemplation (P), contemplation (C) or action (A), based on the stages of change model (by Prochaska and DiClementel) Answers are given on a scale ranging from 'strongly disagree' (-2) through 0 to to 'strongly agree' (+2) . The range for each subscale is -8 to +8. Each subject is allocated to the stage on which it reached the highest score. | 39 - 90 days between screening and visit 6, 6-8 weeks between visit 6 and follow-up | 
| Drinking habits | Drinking habits measured with Timeline Follow-back Interview over 45 days before study start (measured at screening) and over the entire study duration (measured at visits 1, 3, 5, 6 and follow-up) a) % drinking days, b) average amount of alcohol per drinking day, c) % of binge days (alcohol consumption over 60 g /d (men) or 48 g / d (women)), d) average amount of alcohol per binge day, | 39 - 90 days between screening and visit 6, 32 - 55 days between visit 1 and visit 6 | 
| utilization of addiction care services | does the subject frequent addiction care services at Screening, visit 6 and follow-up | 39 - 90 days between screening and visit 6, 32 - 55 days between visit 1 and visit 6 | 
| Acid sphingomyelinase (ASM) activities | analysis in serum at screening at visits 2 and 5, before and after alcohol self-administration | screening, 18 to 31 day between 1st and 2nd measurement, 2.5 hours from begin to end of ASA | 
| Acamprosate blood level | measured on 2nd ASA day (visit 5) | one-time measurement after 14 - 19 days of medication intake (at visit 5) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acamprosate, Calcium, alcohol self-administration