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.

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

1. administration of Acamprosate or Calcium Carbonate in comparison to placebo leads to a change in perception of subjective alcohol effects
2. effectiveness of Acamprosate or Calcium can be predicted by calcium parameters (baseline and changes during medication period)
3. administration of Acamprosate or Calcium leads to a reduction in alcohol craving
4. Frequency of alcohol consumption during the imposed abstinence period differs between treatment groups and influences primary outcome
5. study participation modifies motivation to change drinking habits and utilization of addiction care services
6. Acid sphingomyelinase (ASM) activities are applicable as biomarker and predictor of medication effects.
7. safety issues occur due to study medication

Inclusion Criteria:

1. 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
2. willingness to stop alcohol and drug consumption for 15-20 days for the purpose of study participation
3. 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
4. informed consent
5. ability to swallow a placebo capsule
6. not more than 6 consecutive alcohol abstinent days between screening and visit 2

Exclusion Criteria:

1. Current Substance dependence (illegal drugs) ICD-10 or DSM-IV

2. Intention to stop alcohol consumption immediately and permanently

3. Current or previous disease that could cause a clinically relevant hazard (e.g. pancreatitis, cirrhosis)

4. kidney stone disease

5. Current Treatment with psychotropic drugs or current psychiatric disorder in need of treatment

6. 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%)

7. history of epileptic seizure or delirium

8. 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

9. body weight > 120 kg (Screening)

10. 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

11. history of hypersensitivity to alcohol or one of the used medicinal products, of their ingredients or medicinal products with similar chemical structures

12. history of inefficient treatment with Acamprosate

13. participation in another clinical trial within the last 4 weeks before inclusion

14. disorders, which will not allow the subject to assess the character and importance or possible consequences of the clinical trial

15. pregnant or breastfeeding women

16. 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)

17. participant is not expected to comply with the protocol (for example lacking compliance)

18. less than 200 cumulative work trials for alcohol (in constant attention task) on 1st alcohol self-administration day

19. specific contraindications for Acamprosate or Calcium Carbonate (according prescribing information)

    1. hypercalcemia, e.g. due to hyperparathyroidism, overdosage vitamin D, paraneoplastic
    2. renal insufficiency (eGFR < 30ml/min/1.73m²), creatinine >120 µmol/l

20. intake of Vitamin D compounds or cardioactive glycosides