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

Phase 3

Completed

• Conditions: Alcoholism
• Interventions: Drug: Acamprosate Calcium; Drug: Calcium Carbonate; Drug: Placebo; Drug: Placebo lead in

• Registration Number: NCT03634917
• Lead Sponsor: Technische Universität Dresden

Brief Summary

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

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

Study Timeline

• Study First Submitted: 2018-07-25
• Study First Submitted QC: 2018-08-14
• Study First Posted: 2018-08-17
• Study Start: 2020-08-05
• Primary Completion: 2023-08-30
• Status Verified: 2024-05
• Study Completion: 2024-05-01
• Last Update Submitted: 2024-05-27
• Last Update Posted: 2024-05-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 82

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Acamprosate	Acamprosate Calcium	1 capsule with Acamprosate calcium * oral use * 3 times / day (morning, noon, evening) * 666 mg per capsule * 14 - 19 days
Acamprosate	Placebo lead in	1 capsule with Acamprosate calcium * oral use * 3 times / day (morning, noon, evening) * 666 mg per capsule * 14 - 19 days
Calcium Carbonate	Calcium Carbonate	1 capsule with Calcium Carbonate * oral use * 3 times / day (morning, noon, evening) * 1500 mg Calcium Carbonate (= 600 mg Calcium 2+) * 14 - 19 days
Calcium Carbonate	Placebo lead in	1 capsule with Calcium Carbonate * oral use * 3 times / day (morning, noon, evening) * 1500 mg Calcium Carbonate (= 600 mg Calcium 2+) * 14 - 19 days
Placebo	Placebo	1 capsule placebo, * oral use * 3 times / day (morning, noon, evening) * 14 - 19 days
Placebo	Placebo lead in	1 capsule placebo, * oral use * 3 times / day (morning, noon, evening) * 14 - 19 days

Primary Outcome Measures

Name	Time	Method
Difference between cumulative CAT trials for alcohol on 1st alcohol self-administration (ASA) day and 2nd ASA day	18 to 31 days between 1st and 2nd measurement	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: 1. Acamprosate and Placebo and; 2. Calcium Carbonate and Placebo

Secondary Outcome Measures

Name	Time	Method
Difference between "break points" for alcohol on 1st alcohol self-administration (ASA) day and 2nd ASA day	18 to 31 day between 1st and 2nd measurement	The "break point" is the number of the last alcohol request before subjects stop to work for more alcohol.
Difference between cumulative CAT trials for sodium chloride on 1st alcohol self-administration (ASA) day and 2nd ASA day.	18 to 31 days between 1st and 2nd measurement	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).
Difference between max. achieved blood alcohol concentrations (BAC) on 1st alcohol self-administration (ASA) day and 2nd ASA day	18 to 31 day between 1st and 2nd measurement	Max. BAC during alcohol self-administration
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.	18 to 31 days between 1st and 2nd measurement	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
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.	18 to 31 days between 1st and 2nd measurement	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.
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.	18 to 31 days between 1st and 2nd measurement	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.
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.	18 to 31 days between 1st and 2nd measurement	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
Differences between subjective alcohol effects on 1st ASA day and 2nd ASA day	18 to 31 days between 1st and 2nd measurement	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
Calcium parameters on 1st ASA and 2nd ASA day	18 to 31 day between 1st and 2nd measurement	magnesium, phosphate, total calcium, albumin, parathormone, 25-hydroxyvitamin D measurement at baseline and difference between 2nd and 1st ASA
Alcohol craving (OCDS) "Obsessive Compulsive Drinking Scale" (OCDS)	18 to 31 days between 1st and 2nd measurement	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.
Violation of imposed alcohol abstinence	15-20 days (abstinence period)	in % of the days with alcohol consumption (measured with timeline follow-back, measured at visit 5)
Readiness to change	39 - 90 days between screening and visit 6, 6-8 weeks between visit 6 and follow-up	"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.
Drinking habits	39 - 90 days between screening and visit 6, 32 - 55 days between visit 1 and visit 6	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,
utilization of addiction care services	39 - 90 days between screening and visit 6, 32 - 55 days between visit 1 and visit 6	does the subject frequent addiction care services at Screening, visit 6 and follow-up
Acid sphingomyelinase (ASM) activities	screening, 18 to 31 day between 1st and 2nd measurement, 2.5 hours from begin to end of ASA	analysis in serum at screening at visits 2 and 5, before and after alcohol self-administration
Acamprosate blood level	one-time measurement after 14 - 19 days of medication intake (at visit 5)	measured on 2nd ASA day (visit 5)

Trial Locations

Locations (1)

Klinik und Poliklinik für Psychiatrie und Psychotherapie; Technische Universität Dresden; 🇩🇪 Dresden, Sachsen, Germany