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Optimizing the Management Of Alcohol Dependence New Therapeutic Options Toronto and Vancouver, September 6, 2007

Optimizing the Management Of Alcohol Dependence New Therapeutic Options Toronto and Vancouver, September 6, 2007 Prof. I. Pelc (M.D., Ph. D.) Université Libre de Bruxelles Lab of Psychological Medicine, Alcohology and Drug addictions. Campral ®. A Novel Agent in the Treatment of

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Optimizing the Management Of Alcohol Dependence New Therapeutic Options Toronto and Vancouver, September 6, 2007

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  1. Optimizing the Management Of Alcohol Dependence New Therapeutic Options Toronto and Vancouver, September 6, 2007 Prof. I. Pelc (M.D., Ph. D.) Université Libre de Bruxelles Lab of Psychological Medicine, Alcohology and Drug addictions

  2. Campral® A Novel Agent in the Treatment of Alcohol Dependence

  3. Campral Global Timelines • Early 1980’s - Acamprosate, a synthetic molecule, was developed for alcohol dependence • 1987 - Authorized for marketing in France • 1995 - Re-launched by Merck Santé • 1996 to 1998 - Launched in European countries • 2004 - Launched in the US • 2007 - Registration and launch in Canada

  4. Campral® Understanding The Neurobiology Of Alcohol Dependence & Campral’s Mechanism Of Action

  5. Acamprosate N-acetyl homo taurine Structural similarity with amino-acids and other gluR ligands for NMDARs and GluRs

  6. Exc Exc Inh Inh Inh Exc Neuro-pharmacological basis of ethanol withdrawal and Campral mechanism of action Acute effects of ethanol Adaptation to chronic alcoholisation Ethanol withdrawal • Potentiationof neuroinhibitory receptors(Taurine, GABA) Downregulation Neuronal hyperexcitability + • Inhibitionof neuroexcitatory receptors(Glutamate, Aspartate) Glutamate release Upregulation Ref: De Witte - Littleton

  7. Exc Inh Campral® Neuro-pharmacological basis of ethanol withdrawal and Campral mechanism of action Acute effects of ethanol Adaptation to chronic alcoholisation Ethanol withdrawalCraving - Cues • Potentiationof neuroinhibitory receptors(Taurine, GABA) Downregulation + Neuronal hyperexcitability - • Inhibitionof neuroexcitatory receptors(Glutamate, Aspartate) - Glutamate release Upregulation Ref: De Witte - Littleton

  8. EFFECTS OF CAMPRAL® ONVOLUNTARY ALCOHOL CONSUMPTION Voluntary consumption (ml) Free-choice paradigm (days)

  9. WITHDRAWAL P < 0.05 Motility / Rat / 12h Ref: De Witte

  10. SUCCESSIVE WITHDRAWAL Log-Rank test p=0.0001 % Lost animals Successive Withdrawal Dahchour A., De Witte P: Acamprosate reduces mortality during repeated experimental withdrawal in rats Alcoologie Addict.,2001,23.3:437-440

  11. Alcohol Withdrawal + Acamprosate (200 mM) Alcohol Withdrawal Dead Control Alive 10 day alcohol exposure (50 or 100 mM) 1 day of withdrawal (staining of dead cells) Acamprosate reduces brain damage during alcohol withdrawal in rats Cell necrosis in cultured rat hippocampal slices revealed with propidium iodide. Ref.: J. Littleton, M. Prendergast

  12. Campral and Animal Models • No effect on non-alcohol-preferring and non-dependent animals • Abolishes the alcohol dependence in dependent animals (Alcohol Consumption and Alcohol Deprivation Effect) • Abolishes the alcohol withdrawal (glutamate release and motility) • Keeps dependent animals alive during multiple successive withdrawals (neuroprotective properties) Ref: De Witte; Spanagel; Koob

  13. Campral® Clinical Studies

  14. Material COMBINED DATA ANALYSIS • 11 Double blind, placebo controlled multicentre studies • 8 European countries • 3 338 alcohol dependent patients Mean Age 42.8 years ± 9.3 Sex: female 19% Mean MAST score 31.8 ± 10.9 Mean CAGE score 3.5 ± 0.76

  15. S, 93 G, 96 P, 97 NL, 97 B, 97 I, 97 S, 98 I, 00 Campral European Double-Blind Trials and Drinking Behavior 60 Rate of Total Abstinence (%): CAP 160 Days to First Drink: TFR 50 120 40 30 80 20 40 10 0 0 B, 92 F, 95 G, 96 P, 97 B, 97 S, 98 I, 00 G, 96 P, 97 B, 97 UK, 00 F, 85 S, 93 A, 96 NL, 97 I, 97 UK, 00 SP, 01 F, 95 A, 96 NL, 97 I, 97 I, 00 B, 96 Cumulative Abstinence Duration (%) CAD Drinks per week 80 25 15 placebo-controlled treatment studies 70 20 60 50 15 40 10 30 20 5 10 0 0 D30 D90 D180 D360

  16. Rates of Continuous Abstinence Survival analysis % %Abstinence rate (no alcohol consumption) Days • Continuous Abstinence Measures: • time to first relapse • absolute abstinence • Comment: this method does not take subsequent abstinent periods • into consideration, and is a conservative measure to assess outcome

  17. Rates of Attendance * * * * Attendance rate (%) Days Differential attrition between treatment groups Comment: drop-out rate in naturalistic trials could be an objective outcome measure of efficacy

  18. Campral’s Sustained Effect On Rate Of Abstinence(Morgan, 2003) Values at all time points p < 0.001

  19. Campral Demonstrates A Significant Effect on Continuous Abstinence at 6 Months

  20. Campral significantly increases the stable recovery duration (SRD) 64 days p= 0.021 48 days Days Last relapse Ref.: ADISA-Study

  21. 32% 14% CAMPRAL +NO Psycho- social Follow-up CAMPRAL + Psychosocial Follow-up Absolute abstinence after 6 months of treatmentin two Belgian studies CAPRISO Study Pelc et al. 1992 Absolute Abstinence ( % patients) Absolute Abstinence ( % patients) 24% 4% Placebo CAMPRAL

  22. CAPRISO STUDY Rate of Complete Abstinence After Detoxification Randomized Placebo-controlled Study * Randomized Psycho-social follow-up Study ** N = 100 N = 104 Acamprosate No FU FU 14% 32% Placebo Acamprosate 4% 24% **Acamprosate in the treatment of alcohol dependence: A 6-month post-detoxification study Professor I. Pelc and colleagues, 1992 * * Capriso Study Professor I. Pelc and colleagues, 2001

  23. Comparison of different types of psychotherapies NEAT Observational, non randomized studies (Pelc et al. 2003) Unadjusted for differences in prognostic factors! ns ns 1289 patients CAD(%): Cumulative Abstinence Duration CAP(%): Complete Abstinence

  24. Campral and Quality of Life (SF-36) Normative Reference Population (UK) Ref.: Pooled NEAT-Study MH Mental health VT Energy and vitality BP Bodily pain GH General health perception HT Health transition over time PF Physical Functioning RP Role limitations due to physical problems RE Role limitations due to emotional problems SF Social functioning

  25. Frequency Of Alcohol Consumption In Patients Who Relapsed Ref.: TEMPESTA-Study 1.5 1.45 * 1.4 n = 330 * * p < 0.05 1.35 * * 1.3 * 1.25 Mean frequency score 1.2 1.15 1.1 1.05 1 0 30 60 90 120 150 180 Treatment period (days) Placebo Frequency-score: 0 = no drinking CAMPRAL ® 1 = up to twice / week 2 = 3-6 times / week 3 = every day of the week Adapted from E. Tempesta et al. Alcohol & Alcoholism Vol. 35, No. 2. Campral and relapse prevention in the treatment of alcohol dependence: a placebo-controlled study.

  26. Number Of Drinks Per Drinking Day In Relapsers Ref.: MICADO-Study Threshold of social drinking (3 drinks per day) • GROUP A:Campral + medical consulting (6 visits of 10 minutes each in weeks 2, 4, 10,16, 22, 28) • GROUP B: Campral + minimal intervention • 6 visits of 10 minutes each in weeks 2, 4, 10,16, 22, 28 • plus 3 sessions of motivational interviewing of 20 minutes each by a physician in weeks 2, 3, 4 • GROUP C:Campral + brief intervention • 6 visits of 10 minutes each in weeks 2, 4, 10,16, 22, 28 • plus 7 sessions of cognitive behavioural therapy of 60 minutes delivered by a • social worker or a psychologist in weeks 2, 3, 4, 5, 6, 7, 8

  27. Campral® (n=839) Placebo (n=784) P Gastro-intestinal Dermatological Muscular Neurological/psychological Genito-urinary/sexual Cardio/pulmonary Tiredness 25.1% 9.1% 8.3% 37.5% 16.4% 7.6% 12.8% 18.4% 9.4% 6.5% 35.2% 11.2% 7.1% 10.8% 0.001 ns ns ns 0.003 ns ns Results Of Pooled Safety Analysis Adverse effects during first month of treatment

  28. Campral & At-Risk Patients • Patients with Hepatic Dysfunction : Pharmacokinetic parameters of Campral are not affected Therefore no adjustment of dosage is required • Patients with Renal Dysfunction : Linear correlation between creatinine clearance values and mean residence time for Campral Contraindication in patients with severe renal dysfunction (creatinine clearance ≤30 mL/min).

  29. Modes Of Drinking: Alcoholism 1. SOCIAL: in a social setting 2. HABIT: from habit, for the taste 3. STRESS: to escape psychological difficulties 4. PHYSICAL DEPENDENCE: to avoid withdrawal symptoms 5. STIMULUS: as a stimulus for activity, for assertiveness Each mode is rated on a 4 level scale Validated for time and inter-Rater reliability: 0 = never 1 = seldom 2 = sometimes 3 = frequently

  30. Comparison Between Performances On The Serial & The Alphabetical Recall Scores On The Alpha-Span Test S c o r e Effect of group: F1,58=43.6, p<.001; Effect of condition: F1,58=90.9, p<.001 Interaction between group and condition: F1,58=54.6, p<.001 * Post-hoc analysis indicated that ALC performed lower only in alphabetic recall (p<.01)

  31. Average Number Of Errors Made By Alcoholics & Controls On The Hayling Test P o i n t s o f p e n a l t y Note. *** p<.001

  32. Alcoholism Strategies of treatment (I) Environment Patient 1. Listening 1. Listening 2. Understanding : Motivational interview Type of consumption(occasional, excessive, dependence) Situations of consumption Co-morbidity, psychosocial difficulties 2. Help and support 3. Caring: Inform Weaning Follow-up

  33. Alcoholism Strategies of treatment (II) Withdrawal at home or hospital Removing pharmacodependence - Valium (Diazepam) or Tiapridal (Tiapride) for substitution - Vitamins B - Hydration (sweetened fruit juices) - Acamprosate (4 to 6 per day from the 3th day) Follow-up Medico-Psycho-Social • Control of abstinence (controlled drinking ?) • Learning of alternative abilities to drinking • Specific Psychotherapies • Acamprosate during 1 year, including during relapses

  34. Alcoholism Strategies of treatment (III) Clinical case Mrs D. born in 1961, higher education, married, 3 children (2 boys, 1 girl), regular work. • Drinking : Initially in occasional social contact, then more regularly and finally excessive drinking. Since 1999 (38 years) : withdrawal symptoms, psychological dependence +, physical dependence ++, loss of control. • 1st request for treatment (en 2000, she’s 39) : medical assessment : N, except γGT 85 (N<36)psychological : major relational disorders with her husband, girl : anorexia nervosa, suicide attempt.social : N Withdrawal (hospital) effective, Acamprosate during 1 year (333 mg 6 times per day). Ambulatory follow-up, individual psychotherapy (assertiveness) and systemic familial therapy. Stabilization during 6 years. • Relapse (in 2006, she’s 45) : in relation to the crisis with her husband. • Withdrawal (at home) : effective, again Acamprosate 1 year. Follow up : dysthymic disorders, antidepressants, decision of marital separation. • Stabilization (2007… 46 years)

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