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

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

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