journal club presentation on alcohol.pptx

journal club, RCT, Alcohol Gabapentin

1. GABAPENTIN TREATMENT FOR ALCOHOL DEPENDENCE: A RANDOMIZED CLINICAL TRIAL ( JOURNAL CLUB ) Prepared by : Dr Prabidhi Adhikari Moderator: Dr Md Ainuddin Bagban

2. Contents Background Study Objectives Study design Methodology Outcome measures Data analysis Results Discussion Consort checklist Critical analysis References

3. Background (About the journal) JAMA Psychiatry is an international peer-reviewed journal for clinicians, scholars, and research scientists in psychiatry, mental health, behavioral science, and allied fields .  The journal was established in 1919 and was split into 2 separate journals in 1959:  Archives of Neurology and Archives of General Psychiatry . In 2013, their names changed to  JAMA Neurology  and JAMA Psychiatry , respectively. Published monthly by the  American Medical Association .

4. Background (About the journal) The journal's acceptance rate is 15% of the 1200 manuscripts received annually The journal's Impact Factor is 25.91 , ranking among the highest of psychiatry journals. The  editor-in-chief  is Dr. Dost Öngür ( P rofessor of psychiatry at Harvard University ; Chief, Psychotic Disorders Division, McLean Hospital). Motto: T o inform and educate its readers T o stimulate debate and further exploration into the nature, causes, treatment, and public health importance of mental illness.

5. Background (About the article) Principal author: Barbara J. Mason, PhD Other authors: The Scripps research institute : Susan Quello , BA, BS(psychology) Vivian Goodell, MPH Scripps Clinical and Scripps Green Hospital Dr. Farhad Shadan , MD,Phd (IM and sleep medicine) Dr. Mark Kyle, MD(internal medicine) Dr.Adnan Begovic, MD(internal medicine) Publisher: AMA Date of publication: 2014

6. Background (About author ) Barbara J. Mason, Ph.D. is a Professor and Director of the Pearson Center for Alcoholism and Addiction Research, Department of Neuroscience, The Scripps Research Institute, CA. Her work in medication development for the treatment of AUD has been recognized with a MERIT award from the NIH . Distinguished Scientist Award from the American Society of Addiction Medicine She served as principal Investigator for the US multicenter trial of acamprosate for the treatment of alcohol dependence. She has served as a guest expert for the U.S. FDA and as a reviewer of research grants for NIAAA, NIDA and the MRC

7. Background (Disease burden) 2 billion people worldwide consume alcohol 1/3 rd to have diagnosable alcohol use disorder. P athological alcohol use attributes to estimated 3.8% of all deaths and 4.6% of disability-adjusted life-years globally . A lcohol-attributable costs exceed 1% of the gross national product of high-and middle-income countries.

8. Need for study Less than 9% of patients who qualify for medication management of AUD receive a prescription ( Kranzler , 2018) FDA approved medication include acamprosate, naltrexone and disulfiram Drawbacks : Strong side effects Have significant interactions if combined with ethanol Do not reduce the likelihood of binge drinking

9. Why gabapentin ? Modulate (GABA) neurotransmission. Gabapentin normalizes the stress-induced GABA activation in the amygdala that is associated with alcohol dependence. Human laboratory study and clinical studies found gabapentin reduced alcohol-cued craving and sleep disturbance. Earlier studies support the safety and potential efficacy of gabapentin in alcohol dependent patients .

10. Study objective To determine if gabapentin, a widely-prescribed generic calcium channel/GABA modulating medication Increases rates of sustained abstinence and no heavy drinking, and D ecreases alcohol-related insomnia, dysphoria and craving, in a dose-dependent manner.

11. Conflict of Interest disclosures: Dr Mason has served as a consultant for Eli Lilly USA LLC and Johnson & Johnson Pharmaceutical Research & Development LLC Has served as a scientific advisory board member for Lohocla Research Corp. Has had equity interest in Addex Pharmaceuticals and Arkeo Pharmaceuticals Inc Has served as a speaker for Merck KGaA . Has received study drug for a human laboratory study funded by NIAAA and travel support for an investigators’ meeting from Corcept Therapeutics Inc.

12. Funding/Support: This project was funded by NIAAA grant No. R37AA014028 . Gabapentin and matched placebo were provided by Pfizer Pharmaceuticals Inc

13. Study design Duration : 12-weeks and follow ups at w eeks 13 and 24 post-treatment Blinding: Double-blinded Type of study: Placebo-controlled randomized dose-ranging trial Study population: M en and women over 18 years of age with current alcohol dependence Duration : 2004–2010 Place: A single-site outpatient clinical research facility ( The Scripps Research Institute, California )

14. Inclusion Men and women who met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for alcohol dependence Abstinent from alcohol at least 3 days prior to randomization Age 18 and above.

15. Exclusion CIWA-AR score >9   A bstinence > 1 month Dependence on substances other than alcohol or nicotine A urine drug screen positive for benzodiazepines, cocaine, methamphetamine, tetrahydrocannabinol, methadone or opiates Clinically significant medical or psychiatric disorders Treatment with medications that could affect study outcomes T reatment mandated by a legal authority Pregnant or lactating women

16. Ethical considerations: The study protocol was approved by the Scripps Institutional Review Board (Scripps-IRB). Treatment-seeking volunteers with alcohol dependence were recruited primarily via IRB-approved print and internet advertisements. W ritten informed consent was obtained from all participants.

17. Methodology (Sample size) Sample size estimate was derived from results of a prior trial that found an odds ratio (OR) of 2.96 for complete abstinence between drug and placebo. With 80% power and an α level of 0.05 Sample size was (N)=150 Here, P is prevalence of exposure in the general population Z α/2  ( 1.96 for 5% alfa  ) and Z 1-β  ( 0.84 at 80% power ) are normal deviates for type I error (significance level) and Power of study r is n1/n2 = 1 for equal sample size

18. Methodology (Sample collection) Patients were randomized using a computer-generated randomization code provided by laboratory biostatistician. Patients were randomized in a 1:1:1 ratio The randomization code was kept by the study pharmacist who administered the medication Treatment groups did not differ on pre-treatment demographic and clinical variables. Patients were analyzed in the groups to which they were randomized.

19. Methodology (interventions) Participants were provided with weekly medication in a blister card package that was consecutively numbered for each participant and prepared according to the randomization by study pharmacist. Each package contained: 2 identical capsules to be taken 3 times a day. For the gabapentin groups, a placebo capsule was replaced with an identical 300-mg capsule of gabapentin on the : evening of day 1 , the morning of day 2 , the afternoon of day 3 , and fixed dose of 900 mg was achieved on day 4 or 1800 mg was achieved on day 6 .

20. Methodology (Intervention ) Group 1: Gabapentin 900 mg/day Group 2: Gabapentin 1800 mg/day Group 3: Gabapentin 0 mg/day (control) All groups received 20 minutes of weekly manual-guided counseling designed to increase motivation, abstinence, and medication compliance. Participants were maintained on the assigned dose until week 11. At the end of week 11, they were titrated off active medication by substituting 1 placebo capsule for 1 capsule of active medication per day, in the reverse order of the initial dose titration. All participants received only placebo by the end of week 12

21. Methodology(Assessment) The Structured Clinical Interview for DSM IV ( SCID ) Timeline Follow Back Interview (Sobell & Sobell, 1992) with a drinking diary as a memory guide. Validated by weekly breathalyzer determinations, monthly γ-glutamyl transferase ( GGT ) values and collateral informant reports. Alcohol Craving Questionnaire (Singleton et al., 1994) Pittsburgh Sleep Quality Index ( Buysse et al., 1989) Beck Depression Inventory-II (Beck et al., 1996 )

22. Methodology(Assessment) Drinking data were collected by experienced research personnel. Drinking urges were assessed by self-report using the Alcohol Craving Questionnaire–Short Form. Safety evaluations using weekly vital signs, the systematic assessment for treatment emergent events – general inquiry (SAFTEE-GI), urine screening for drugs of abuse; specimens for blood chemistry were analyzed by LabCorp

23. Main outcomes measures Primary: complete abstinence over the 12-week study. Co-primary: rate of no heavy drinking over the 12-week trial Secondary outcomes: standardized measures of alcohol craving, sleep, and mood over the 12-week study period.

24. Defining terminologies Heavy “At Risk” Drinking : Women: ≥ 4 drinks on any single day OR > 7 drinks per week Men: ≥ 5 drinks on any single day OR > 14 drinks per week

25. Outcomes measure tools Used a mixed-effect model of drinking quantity over the 12-weekstudy period, as supportive primary outcomes which included : Number of drinks per week frequency (number of heavy drinking days per week) Change in GGT, as a supportive primary outcome .

26. Checking for Compliance Participants returned their blister cards at each weekly study visit for drug accountability and compliance review. Correct drug assignment was verified retrospectively by determining gabapentin concentration in plasma samples obtained at week 2 and frozen for poststudy analysis by gas chromatography and mass spectrometry.

27. Data analysis Baseline demographic and clinical characteristics were compared by χ 2  and ANOVA as appropriate. All tests were 2-tailed , and an alpha <0.05 was considered statistically significant. Linear dose effects for rates of complete abstinence and no heavy drinking over the 12-week study were assessed using the extended Mantel-Haenszel χ 2  test for linear association.

28. Data analysis Number of patients who provided 12-week data for analysis: Gabapentin 900 mg group: 27 of 54 initially enrolled Gabapentin 1800 mg group: 28 of 47 initially enrolled Control group: 30 of 49 initially enrolled T ime in the study (mean [SD], 9.1 [3.8] weeks) Rate of study completion (85 of 150 participants) did not differ among groups.

29. Results Mean rate of medication compliance, defined as number of pills taken divided by number prescribed during study participation, was 96.2% and did not differ among groups (p=0.79) Groups were similar in their ability to correctly guess the identity of their medication when asked to do so upon study completion ( 59% gabapentin, 45% placebo, p=0.21)

30. Results Rate 1800mg 900mg Control No heavy dinking 44.7% (95% CI,31.4%–58.8%) ( NNT = 5; OR = 2.8) 29.6%(95% CI) (19.1%–42.8%) 22.5%(95% CI) (13.6%–37.2%) Complete abstinence 17%(95% CI, 8.9%–30.1%) ( NNT = 8; OR = 4.8) 11.1%(95% CI) ( 5.2%–22.2%) 4.1%(95% CI) ( 1.1%–13.7%)

31. A . number of drinks consumed per week). 900mg: −2.16 [95% CI, −5.3 to 1.0], (t=5.32, p<0.001 1800mg: −6.66 [95% CI, −9.8 to −3.5, t=−4.13, p<0.001). B. significant linear decreases in the average number of days of heavy drinking per week 900mg: −1.76[95% CI, −2.2 to −1.3], t=−7.22, p<0.001; 1800mg: −2.022 [95% CI, −2.5 to −1.5], t=−8.14, p<0.001)

32. Craving Over the course of treatment, significant dose-dependent reductions were obtained on the Alcohol Craving Questionnaire. (F2 = 3.56;P = .03; gabapentin, 1800 mg, vs placebo: −6.8 [95% CI, −1.5 to −12.1];t = −2.52;P = .01)

33. Mood significant dose-dependent reductions were obtained on The Beck Depression Inventory II. (F2 = 7.37;P = .001; gabapentin,1800 mg, vs placebo: −1.1 [95% CI, −2.0 to −0.3];t = −2.57;P = .01)

34. Sleep Significant dose-dependent reductions were obtained on The Pittsburgh Sleep Quality Index total score. (F2 = 136;P < .001; gabapentin, 1800 mg, vs placebo: −1.5 [95% CI, −2.1 to −0.8]; t = −4.46; P < .001).

35. Adverse effects There were no deaths or serious drug‐related adverse events . Terminations owing to adverse events ( 9 of 150 participants ) Five were rated as drug-related by blinded study physicians: two complaints of headache (900mg ), two complaints of fatigue (one 900mg and one 1800mg ) and one complaint of euphoria and speediness (placebo).

36. CONSORT 2010 check list 1. Title and abstract: 1a. Identification as a randomized trial in the title: Yes 1b. Structured summary of trial design, methods, results, and conclusions : Yes 2. Introduction ( Background and objectives ) 2a. Scientific background and explanation of rationale: Yes 2b. Specific objectives ( Yes )or hypotheses( No ) Methods: 3. Trial design : 3a. Description of trial design (such as parallel, factorial) including allocation ratio ( No ) 3b. Important changes to methods after trial commencement (such as eligibility criteria), with reasons ( No ) 4. Participants 4a. Eligibility criteria for participants : Yes 4b. Settings and locations where the data were collected: Yes 5. Interventions: The interventions for each group with sufficient details to allow replication, including how and when they were actually administered : Yes

37. 6.Outcomes : 6a. Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed: Yes 6b. Any changes to trial outcomes after the trial commenced, with reasons. No 7.Sample size: 7a. How sample size was determined: Yes 7b. When applicable, explanation of any interim analyses and stopping guidelines. Yes  Randomization: 8. Sequence generation: 8a Method used to generate the random allocation sequence. Yes 8b Type of randomization; details of any restriction. Yes 9. Allocation concealment mechanism Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned. Yes 10. Implementation Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions. Yes

38. 11. Blinding : 11a. If done, who was blinded after assignment to interventions and how: Yes 11b. If relevant, description of the similarity of interventions: Yes 12. Statistical methods : 12a. Statistical methods used to compare groups for primary and secondary outcomes: Yes 12b. Methods for additional analyses, such as subgroup analyses and adjusted analyses. Yes Results 13. Participant flow (a diagram is strongly recommended) : 13a. For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analyzed for the primary outcome: Yes 13b. For each group, losses and exclusions after randomization, together with reasons. Yes 14. Recruitment : 14a. Dates defining the periods of recruitment and follow-up. Yes 14b. Why the trial ended or was stopped. Yes

39. 15. Baseline data : 15A. table showing baseline demographic and clinical characteristics for each group: Yes 16. Numbers analyzed: For each group, number of participants (denominator) included in each analysis and whether the analysis was by original assigned groups: Yes 17. Outcomes and estimation : 17a. For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval): Yes 17b. For binary outcomes, presentation of both absolute and relative effect sizes is recommended CONSORT items and examples 18. Ancillary analyses Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory: No 19. Harms All important harms or unintended effects in each group: Yes

40. Discussion 20. Limitations : Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 21. Generalizability : Generalizability (external validity, applicability) of the trial findings 22. Interpretation : Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence Other information: 23. Registration : Registration number and name of trial registry 24. Protocol : Where the full trial protocol can be accessed, if available 25. Funding: Sources of funding and other support, role of funders

41. Critical analysis(strength) Study objective current and relevant to society Appropriate randomized controlled trial design Appropriate dosing of gabapentin compared relative to other studies on substance abuse Study length consistent with other substance abuse trials Washout period 3 days before randomization into trial to standardize groups Multiple measures to analyze alcohol intake in patients (diary, interview, breathalyzer, GGT) Adverse events reported as number of events and severity of events to prove non-significance

42. Critical analysis (limitations) Exclusion of high-risk alcoholics (CIWA- Ar score > 9) Single study site makes it difficult to extrapolate results to entire population Large number of dropouts (56% ) Values from previous studies used for arbitrary effect sizes Possibly unequal baseline values (age, sex, weekly drinks) between groups Short duration of treatment Investigators excluded those possible abusing substances other than alcohol. A majority of alcoholics abuse substances along with alcohol.

43. Conclusion   This study provides results that favor the use of gabapentin to successfully and safely treat AUD, with data that clearly demonstrates that gabapentin reduces HDD along with mood, sleep and craving disturbances, and increases abstinence rates Increased implementation of pharmacological treatment of alcohol dependence in primary care may be a major benefit of gabapentin as a treatment option for alcohol dependence. Further research should be performed to evaluate whether gabapentin is more efficacious used as a monotherapy vs an additive therapy, what long term effects gabapentin has on AUD, and to define the most effective dosage and treatment duration.

44. References JAMA Intern Med. Author manuscript; available in PMC 2015 January 01. Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Medicine. 2010;   www.consort-statement.org

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