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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)

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ClinicalTrials.gov Identifier: NCT03634917
Recruitment Status : Not yet recruiting
First Posted : August 17, 2018
Last Update Posted : August 6, 2020
Sponsor:
Information provided by (Responsible Party):
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.


Condition or disease Intervention/treatment Phase
Alcoholism Drug: Acamprosate Calcium Drug: Calcium Carbonate Drug: Placebo Drug: Placebo lead in Phase 3

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 84 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Basic Science
Official Title: Investigation of the Efficacy of Acamprosate and Calcium in Comparison to Placebo as Validation of a Behavioural Test for Alcohol Dependence (TEMACA)
Estimated Study Start Date : August 5, 2020
Estimated Primary Completion Date : September 30, 2020
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Acamprosate

1 capsule with Acamprosate calcium

  • oral use
  • 3 times / day (morning, noon, evening)
  • 666 mg per capsule
  • 14 - 19 days
Drug: Acamprosate Calcium
1 capsule with 666 mg Acamprosate
Other Name: Campral

Drug: Placebo lead in
1 Capsule with Placebo (lactose monohydrate, micro crystalline cellulose, magnesium stearate)

Active Comparator: 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
Drug: Calcium Carbonate
1 capsule with 1500 mg Calcium Carbonate
Other Name: Calcium

Drug: Placebo lead in
1 Capsule with Placebo (lactose monohydrate, micro crystalline cellulose, magnesium stearate)

Placebo Comparator: Placebo

1 capsule placebo,

  • oral use
  • 3 times / day (morning, noon, evening)
  • 14 - 19 days
Drug: Placebo
1 Capsule with Placebo (lactose monohydrate, micro crystalline cellulose, magnesium stearate)

Drug: Placebo lead in
1 Capsule with Placebo (lactose monohydrate, micro crystalline cellulose, magnesium stearate)




Primary Outcome Measures :
  1. Difference between cumulative CAT trials for alcohol on 1st alcohol self-administration (ASA) day and 2nd ASA day [ Time Frame: 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 :
  1. Difference between "break points" for alcohol on 1st alcohol self-administration (ASA) day and 2nd ASA day [ Time Frame: 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.

  2. Difference between max. achieved blood alcohol concentrations (BAC) on 1st alcohol self-administration (ASA) day and 2nd ASA day [ Time Frame: 18 to 31 day between 1st and 2nd measurement ]
    Max. BAC during alcohol self-administration

  3. Difference between cumulative CAT trials for sodium chloride on 1st alcohol self-administration (ASA) day and 2nd ASA day. [ Time Frame: 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).


  4. 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. [ Time Frame: 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


  5. 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. [ Time Frame: 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.


  6. 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. [ Time Frame: 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.

  7. 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. [ Time Frame: 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


  8. Differences between subjective alcohol effects on 1st ASA day and 2nd ASA day [ Time Frame: 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


  9. Calcium parameters on 1st ASA and 2nd ASA day [ Time Frame: 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

  10. Alcohol craving (OCDS) "Obsessive Compulsive Drinking Scale" (OCDS) [ Time Frame: 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.

  11. Violation of imposed alcohol abstinence [ Time Frame: 15-20 days (abstinence period) ]
    in % of the days with alcohol consumption (measured with timeline follow-back, measured at visit 5)

  12. Readiness to change [ Time Frame: 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.


  13. Drinking habits [ Time Frame: 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,


  14. utilization of addiction care services [ Time Frame: 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

  15. Acid sphingomyelinase (ASM) activities [ Time Frame: 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

  16. Acamprosate blood level [ Time Frame: one-time measurement after 14 - 19 days of medication intake (at visit 5) ]
    measured on 2nd ASA day (visit 5)


Other Outcome Measures:
  1. CIWA-Ar-Score [ Time Frame: 39 - 90 days between screening and visit 6, 32 - 55 days between visit 1 and visit 6 ]

    Clinical Institute Withdrawal Assessment for Alcohol Scale, revised

    It is a 10-item scale for clinical quantitation of the severity of the alcohol withdrawal syndrome.

    Each item is rated on a scale from 0 to 7, except for "Orientation" which is rated on scale 0 to 4.

    The total CIWA-Ar score is the sum of all 10 items.

    measured at Screening, Visits 1-6.


  2. adverse events / serious adverse events [ Time Frame: 32 - 55 days between visit 1 and visit 6 ]

    partially standardized interview about adverse events / serious adverse events

    measured at visits 1-6




Information from the National Library of Medicine

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Ages Eligible for Study:   25 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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
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Responsible Party: Technische Universität Dresden
ClinicalTrials.gov Identifier: NCT03634917    
Other Study ID Numbers: TUD-TEMACA-069
First Posted: August 17, 2018    Key Record Dates
Last Update Posted: August 6, 2020
Last Verified: August 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Technische Universität Dresden:
Acamprosate
Calcium
alcohol self-administration
Additional relevant MeSH terms:
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Alcoholism
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Calcium, Dietary
Acamprosate
Calcium Carbonate
Calcium
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Bone Density Conservation Agents
Antacids
Molecular Mechanisms of Pharmacological Action
Gastrointestinal Agents
Alcohol Deterrents