A Prospective Randomized Controlled Open Label Trial of Symptom-triggered Benzodiazepine Versus Fixed-dose Gabapentin for Alcohol Withdrawal Syndrome
Phase: PHASE4
Conditions: Alcohol Withdrawal Syndrome
Sponsor: Mayo Clinic

 
 
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Gabapentin for Alcohol Withdrawal Syndrome 
 
 
NCT03012815 
 
 
Version 11/14/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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IRB Minimal Risk Protocol Template  
 
General Study Information 
 
Principal Investigator: Simon Kung, MD and Ruth Bates, MD 
 
 
 
 
 
 
 
 
Study Title: A Prospective Randomized Controlled Open Label Trial of Symptom-triggered Benzodiazepine 
versus Fixed-dose Gabapentin for Alcohol Withdrawal Syndrome 
 
Protocol version number and date:   Version 5,  11/14/2018 
 
Research Question and Aims 
 
Hypothesis: A fixed-dose proactive gabapentin schedule for alcohol withdrawal syndrome will be superior or 
similar, and as safe, compared with a symptom-triggered benzodiazepine approach. 
 
Aims 
1. To demonstrate that fixed dose gabapentin will result in shorter duration of alcohol withdrawal 
compared to symptom-triggered benzodiazepines. (Primary outcome) 
2. To demonstrate that fixed dose gabapentin is comparable to symptom-triggered benzodiazepines for 
secondary outcomes related to patient safety, including adverse outcomes such as seizure and delirium 
tremens. 
3. To demonstrate that fixed dose gabapentin is comparable to symptom-triggered benzodiazepines for 
further secondary outcomes such as severity of withdrawal assessed by CIWA scores, alcohol cravings 
assessed by Penn alcohol craving score (PACS), sleepiness assessed by Epworth Sleepiness Scale 
(EPS), anxiety assessed by Generalized anxiety disorder score (GAD7) and total benzodiazepine use. 
 
Background 
 
Alcohol dependency affects up to 20% of men and 10% of women in their lifetime.(Schuckit MA 2014)  
Alcohol withdrawal syndrome (AWS) can be experienced by approximately 50% of patients with alcohol use 
disorder.  These symptoms such as nausea, sweating, tremor, headache, and anxiety, can start about 8 hours 
after the last alcohol use, and can peak at 72 hours.  About 5% of patients may experience severe withdrawal 
symptoms such as delirium tremens (DTs) or seizures. 
 
The current standard at Mayo for alcohol withdrawal is the use of the CIWA-Ar (Clinical Institute Withdrawal 
Assessment for Alcohol – Revised, henceforth referred to as “CIWA”) instrument to guide initiation and 
subsequent administration of a benzodiazepine, typically oral lorazepam. (Appendix)  This symptom-triggered 
protocol requires repeated assessments of the patient’s subjective signs and symptoms based on a 10 question 

 
 
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rating scale.  If the score is 10 or greater, a benzodiazepine is given with subsequent dosing dependent upon 
sequential CIWA scores. 
 
There are several deficiencies with the symptom-triggered benzodiazepine protocol.  First, the majority of the 
items are subjective, based on patient report of symptoms such as anxiety, tremulousness, and headaches, such 
that patient can overstate their symptoms in order to receive more benzodiazepines.  Second, larger-than-
necessary benzodiazepine dosages can be given per protocol such that additional hospital days are needed to 
allow patients to detoxify from generous benzodiazepine dosing.  Third, it is symptom-triggered and thus 
reactive; in effect, the provider is chasing rather than preventing symptoms.  Fourth, benzodiazepines may 
contribute to recidivism and thereby perpetuate alcohol dependency, and typically chemical dependency 
treatment programs require a patient to have discontinued benzodiazepines before treatment.  
 
Gabapentin is an anticonvulsant medication which has some evidence of benefit for alcohol withdrawal. (Leung 
2015)  There are several benefits of using gabapentin for alcohol withdrawal.  First, it does not have the same 
addictive potential compared with lorazepam.  Second, the fixed schedule dosing provides for immediate use 
rather than waiting for symptom triggers, thus potentially decreasing the duration and severity of alcohol 
withdrawal symptoms.  Third, gabapentin has been shown to decrease alcohol intake and relapse into heavy 
drinking in patients with alcohol dependency. (Furieri FA 2007)  Fourth, gabapentin has a small evidence base 
for improving anxiety, which is a frequent symptom in patients with alcohol use disorder (Berlin RK 2015) and, 
for some patients, is a trigger for relapse. 
 
Clinical use of gabapentin for alcohol withdrawal has been presented by Maldonado at Stanford University 
Hospitals. (Academy of Psychosomatic Medicine Annual Meeting, 2013-2015)  At Mayo Clinic, the Psychiatry 
Consultation-Liaison hospital service has been recommending the use of a modified gabapentin protocol since 
January 2015, which has been clinically accepted on medical, surgical, and psychiatric hospital services.  
Currently, a retrospective review of that experience is in progress.  The purpose of this research is to investigate 
the reactive benzodiazepine versus proactive gabapentin approaches to AWS in a prospective, randomized, 
open-label study. 
 
References 
 
Berlin RK et al. Gabapentin therapy in psychiatric disorders: a systematic review. Prim Care Companion CNS 
Disord 2015;17(5):10.4088. 
 
Furieri FA et al. Gabapentin reduces alcohol consumption and craving: a randomized, double-blink, placebo-
controlled trial. J Clin Psychiatry 2007;68:1691-700. 
 
Leung JG et al. Role of rabapentin in the management of alcohol withdrawal and dependence. Ann 
Pharmacotherapy 2015;49:897-906. 
 
Maldonado JR et al. Prospective validation study of the prediction of alcohol withdrawal severity scale 
(PAWSS) in medically ill inpatients: a new scale for the prediction of complicated alcohol withdrawal 
syndrome. Alcohol Alcohol 2015;50:509-18. 

 
 
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Schuckit MA et al. Recognition and management of withdrawal delirium (delirium tremens). N Engl J Med 
2014;371:2109-13. 
 
Study Design and Methods 
 
Methods 
 
Patients will be randomized to one of two clinical protocols – the benzodiazepine protocol or the 
gabapentin protocol.  Both of these medications are “clinical medications” and not “study medications.” 
 
Randomization 
 
Block randomization will assign the patient to either the benzodiazepine or gabapentin protocol. 
 
Intervention Procedures 
 
The “CIWA scale” a 10 item questionnaire to measure alcohol withdrawal symptoms.(Appendix)  It is 
performed hourly by the patient’s clinical nursing staff.  A score between 0-67 is obtained.  If the score is 10 or 
higher, the patient is felt to have significant alcohol withdrawal symptoms, and an intervention occurs.  When 
the score is less than 10 for 3 consecutive hourly assessments, the frequency of assessments decreases to every 
4 hours.  If there is a score 10 or greater, the assessments return to every hour.  Each time the nursing staff 
obtains the CIWA score, a blood pressure, heart rate, respiratory rate, and temperature are also obtained.  
If the patient is randomized to the symptom-triggered variable benzodiazepine protocol, whenever the CIWA 
score is 10 or higher, lorazepam is administered; dose is dependent on the CIWA score. Refer to the CIWA 
orderset in the Appendix for details.  This approach is currently a clinical standard of care. 
 
If the patient is randomized to the gabapentin protocol, a fixed schedule of gabapentin will be given at the start 
of the protocol: 
• If the patient has normal renal function (estimated CrCl > 60 mL/min), then gabapentin dosing will 
be: 900 mg three times a day (t.i.d.) for 4 days, then 600 mg t.i.d. for 3 days, then 300 mg t.i.d for 2 
days, then discontinue.   
• If the patient has moderate renal impairment (estimated CrCl 30-60 mL/min), then the gabapentin 
dosing will be:  600 mg t.i.d. for 4 days, then 300 mg t.i.d. for 3 days, then 100 mg t.i.d for 2 days, 
then discontinue.   
 
CIWA monitoring is performed for patients receiving gabapentin in the same manner as for those receiving a 
benzodiazepine, but the dose administered is not contingent upon the CIWA score. 
 
If patients are already taking gabapentin at a dose greater than 300 mg t.i.d. at baseline, they will not be eligible 
for this study. If their dose is 300 mg t.i.d. or less, their gabapentin will be replaced with the dosages above.  
This gabapentin protocol for alcohol withdrawal has been used clinically and with increasing frequency at Saint 
Marys Hospital since January 2015, but is not the clinical standard of care.  However, a preliminary order set 

 
 
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has been developed for the clinical use of this protocol. (Appendix)  In this order set, for patients who have a 
history of seizures, the clinician also has the option to add divalproex, another anti-seizure medication. 
 
The current clinical practice is for the patient’s primary treatment team to decide whether to utilize the 
traditional benzodiazepine or the newer gabapentin protocol for patients with alcohol withdrawal. 
 
Patients in both arms of the interventions will receive folate, thiamine, and multivitamin per clinician 
preference. 
 
The patient completes alcohol withdrawal when their CIWA scores are less than 10 for at least 36 hours, or are 
less than 10 and clinician judgement is that the patient is safe to discharge.  Sometimes patients are not 
discharged when their alcohol withdrawal is completed, because of other medical or psychiatric or psychosocial 
issue.   
 
Data collection  
 
Refer to the appendix for the data collection form.  Data collected as part of routine clinical care will be used 
during data analysis.  Data elements include (but are not limited to) demographic information, alcohol use and 
alcohol withdrawal history, PAWSS score assessing risk of alcohol withdrawal, home medications, admission 
lab work and vital signs, and urine drug screen results. Outcome measures include total amount of 
benzodiazepines, use of adjuvant medications, symptom assessments (CIWA scores, rating scales for 
depression symptoms, anxiety symptoms, sleepiness, alcohol cravings). 
 
Suicidal ideation 
 
Patients with alcohol use disorders may express suicidal ideation when intoxicated or afterwards.  If indicated, 
the clinical treatment team may call upon the appropriate psychiatric resources to assess self-harm issues, as per 
usual clinical procedures.  For the Hospital Internal Medicine services, these procedures may include ordering a 
Psychiatry consult or ordering a one-to-one sitter with the patient.  For the Generose services, these procedures 
will consist of notifying the primary psychiatry team.  Because all Generose hospital services are on locked 
units and have standard suicide precautions, any concerns of suicide risk can be managed by the clinical 
inpatient team.   
 
Resources 
 
The co-PI’s are from the Department of Internal Medicine, Division of Hospital Internal Medicine (R.B.) and 
the Department of Psychiatry and Psychology, Hospital Division (S.K.).  The co-investigators are from these 
two departments, as well as from pharmacy.  The Division of Hospital Internal Medicine has access to study 
coordinator and statistical resources.  Ivana Croghan, PhD, will provide overall mentorship. 
 
  (1a)  This is a multisite study involving Mayo Clinic and non Mayo Clinic sites. When checked, describe in 
detail the research procedures or activities that will be conducted by Mayo Clinic study staff. 
 

 
 
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  (1b)  Mayo Clinic study staff will be engaged in research activity at a non Mayo Clinic site.  When checked, 
provide a detailed description of the activity that will be conducted by Mayo Clinic study staff. 
 
 
Subject Information 
 
Target accrual is the proposed total number of subjects to be included in this study at Mayo Clinic. A “Subject” 
may include medical records, images, or specimens generated at Mayo Clinic and/or received from external 
sources.    
 
Target accrual: 400 
 
Subject population (children, adults, groups):  Adults 
 
Patient population 
 
Inpatients at risk of AWS on the Hospital Internal Medicine and Generose Psychiatry inpatient units will be 
eligible.  The Prediction of Alcohol Withdrawal Severity Scale (PAWSS) will be used to screen potential 
patients.(Appendix; Maldonado 2014)  The PAWSS is a 10 item scale of which a total score greater than or 
equal to 4 signifies high risk of AWS.  These patients will be offered the research study.  If the patient scores 
less than 4, no formal AWS protocol would be recommended. 
 
To be as inclusive as possible, we plan to enroll a broad range of patient populations, to better study real world 
conditions.  For example, patients with certain other comorbid substance use disorders and those with suicidal 
ideation will be allowed to enroll.  The use of gabapentin is not expected to worsen these other conditions. 
 
Inclusion criteria 
 
1. PAWSS>4. 
2. Adults age 18 or older. 
3. Sufficient understanding of English. 
4. Hospitalized on Hospital Internal Medicine, Family Medicine or Generose. 
 
Exclusion criteria 
 
1. Severe renal impairment (estimated CrCl < 30). 
2. Intensive Care Unit (ICU) level of care. 
3. Not responsive due to alcohol intoxication or withdrawal. 
4. Already taking gabapentin more than 300 mg three times a day. 
5. Prescribed pregabalin. 
6. Primary seizure disorder. 
7. Acute benzodiazepine withdrawal. 

 
 
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8. Concurrent substance use disorders (such as opioid use disorder, stimulant use disorder) if the disorder is 
assessed to be clinically significant.  Cannabis use disorder will be allowed. 
9. Concurrent anticonvulsant medications for psychiatric indications (e.g. bipolar disorder) will be allowed. 
10. Pregnancy. 
11. Involuntary legal status (e.g., on court commitment). 
12. Patients admitted greater than 16 hours prior to potential enrollment. 
13. Patients receiving great than one therapeutic dose of gabapentin (rather than continuation of home dose) 
prior to enrollment.  
 
Termination criteria 
 
1. Seizure 
2. Delirium tremens 
3. Transfer to ICU 
4. Patient leaves against medical advice 
5. Any other situation in which the clinician feels it is the best interest of the patient to withdraw them 
from the study. 
 
Consent  
 
Our consent process aligns with the ideas presented by the National Institutes of Health (NIH) in their on-line 
document “Research Involving Individuals with Questionable Capacity to Consent” 
(http://grants.nih.gov/grants/policy/questionablecapacity.htm).  Because alcohol intoxication or withdrawal can 
impair a person’s “consent capacity,” we must ensure that person understands the purpose and elements of the 
research study, the potential benefits and risks, and that the research is voluntary.  As this study involves 
medications and protocols which are already in clinical practice (benzodiazepines versus gabapentin), it is 
considered “minimal risk.” 
 
Informed consent will be obtained by study staff.  Patients will also be administered a short questionnaire to 
assess their understanding of the research study and the general procedures, and should answer all 9 questions 
correctly.(Appendix)  Study staff will assess the patient’s consent capacity based on the comprehension 
assessment combined with clinical judgement and, if needed, team discussion. 
 
 
Research Activity 
 
Check all that apply and complete the appropriate sections as instructed.  
  
1. 
  Drug & Device:  Drugs for which an investigational new drug application is not required. Device for 
which (i) an investigational device exemption application is not required; or the medical device is 
cleared/approved for marketing and being used in accordance with its cleared/approved labeling. (Specify in 
the Methods section) 
 

 
 
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2. 
  Blood:  Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture.  
 
3. 
  Biological specimens other than blood:  Prospective collection of human biological specimens by 
noninvasive means that may include: urine, sweat, saliva, buccal scraping, oral/anal/vaginal swab, sputum, 
hair and nail clippings, etc. 
 
4. 
  Tests & Procedures:  Collection of data through noninvasive tests and procedures routinely employed 
in clinical practice that may include: MRI, surface EEG, echo, ultrasound, moderate exercise, muscular 
strength & flexibility testing, biometrics, cognition testing, eye exam, etc.  (Specify in the Methods section) 
 
5. 
  Data (medical record, images, or specimens):  Research involving use of existing and/or prospectively 
collected data. 
 
6. 
  Digital Record:  Collection of electronic data from voice, video, digital, or image recording. (Specify in 
the Methods section) 
 
7. 
  Survey, Interview, Focus Group:  Research on individual or group characteristics or behavior, survey, 
interview, oral history, focus group, program evaluation, etc.  (Specify in the Methods section) 
 
 
 NIH has issued a Certificate of Confidentiality (COC).  When checked, provide the institution and 
investigator named on the COC and explain why one was requested. ________________________ 
 
 
Biospecimens – Categories 2 and 3 
 
(2)  Collection of blood samples. When multiple groups are involved copy and paste the appropriate section 
below for example repeat section b when drawing blood from children and adults with cancer.  
 
a. From healthy, non-pregnant, adult subjects who weigh at least 110 pounds. For a minimal risk 
application, the amount of blood drawn from these subjects may not exceed 550ml in an 8 week period 
and collection may not occur more frequently than 2 times per week. 
Volume per blood draw: _____ml   
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.) ___________ 
 
b. From other adults and children considering age, weight, and health of subject. For a minimal risk 
application, the amount of blood drawn from these subjects may not exceed the lesser of 50 ml or 3 ml 
per kg in an 8 week period, and collection may not occur more frequently than 2 times per week.   
Volume per blood draw: _____ml 
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.) ___________  
 
(3)  Prospective collection of biological specimens other than blood: ______________________________ 

 
 
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Review of medical records, images, specimens – Category 5 
 
 
Check all that apply (data includes medical records, images, specimens).  
 
  (5a)  No data will be collected beyond the IRB submission date.   
 
 
  (5b)  The study involves data that exist at the time of IRB submission and data that will be collected after 
IRB submission. Include this activity in the Methods section.  
Examples 
• The study plans to conduct a retrospective chart review and ask subjects to complete a questionnaire.  
• The study plans to include subjects previously diagnosed with a specific disease and add newly 
diagnosed subjects in the future.  
 
  (5c)  The study will use data that have been collected under another IRB protocol. Include in the Methods 
section and enter the IRB number from which the research material will be obtained. When appropriate, note 
when subjects have provided consent for future use of their data and/or specimens as described in this protocol.  
 
Enter one IRB number per line, add more lines as needed 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 
  (5d)  This study will obtain data generated from other sources. Examples may include receiving data from 
participating sites or an external collaborator, accessing an external database or registry, etc.  Explain the source 
and how the data will be used in the Methods section.  
 
  (6)  Video audio recording: Describe the plan to maintain subject privacy and data confidentiality, 
transcription, store or destroy, etc.  
 
 
 
 
 
 
 

 
 
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HIPAA Identifiers and Protected Health Information (PHI) 
 
Protected health information is medical data that can be linked to the subject directly or through a combination 
of indirect identifiers.  
 
Recording identifiers (including a code) during the conduct of the study allows you to return to the medical 
record or data source to delete duplicate subjects, check a missing or questionable entry, add new data points, 
etc. De-identified data is medical information that has been stripped of all HIPAA identifiers so that it cannot be 
linked back to the subject. De-identified data is rarely used in the conduct of a research study involving a chart 
review.   
 
Review the list of subject identifiers below and, if applicable, check the box next to each HIPAA identifier 
being recorded at the time of data collection or abstraction.  Identifiers apply to any subject enrolled in the 
study including Mayo Clinic staff, patients and their relatives and household members.  
 
Internal refers to the subject’s identifier that will be recorded at Mayo Clinic by the study staff. 
External refers to the subject’s identifier that will be shared outside of Mayo Clinic. 
 
Check all that apply: 
INTERNAL 
EXTERNAL 
Name 
x 
 
Mayo Clinic medical record or patient registration number, lab accession, 
specimen or radiologic image number  
x 
 
Subject ID, subject code or any other person-specific unique identifying 
number, characteristic or code that can link the subject to their medical data   
x 
 
Dates: All elements of dates [month, day, and year] directly related to an 
individual, their birth date, date of death, date of diagnosis, etc.   
Note: Recording a year only is not a unique identifier.  
 
 
Social Security number 
 
 
Medical device identifiers and serial numbers 
 
 
Biometric identifiers, including finger and voice prints, full face photographic 
images and any comparable images 
 
 
Web Universal Resource Locators (URLs), Internet Protocol (IP) address 
numbers, email address 
 
 
Street address, city, county, precinct, zip code, and their equivalent geocodes 
 
 
Phone or fax numbers 
 
 
Account, member, certificate or professional license numbers, health 
beneficiary numbers 
 
 
Vehicle identifiers and serial numbers, including license plate numbers 
 
 
Check ‘None’ when none of the identifiers listed above will be recorded, 
maintained, or shared during the conduct of this study.  (exempt category 4) 
 None 
 None 
 

 
 
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Data Analysis 
 
Power analyses and study endpoints are not required for minimal risk research, pilot or feasibility studies.  
 
  No statistical information. If checked, please explain: 
 
 
Power Statement:  Patients will be randomized 1:1 between the two treatments. The primary objective will be 
testing for noninferiority of the two treatments on the primary endpoint, but it is assumed the gabapentin arm 
will have a superior (shorter) time to outcome. Following Freidlin, Korn, George, and Gray (2007), we assume 
the median time to outcome is 48 hours for larazepam and 40 hours for gabapentin, and a noninferiority margin 
of 8 hours, corresponding to a hazard ratio less than 1.167. Using a one-sided type I error rate of 0.05 and with 
90% power, the total required sample size is 303.  
 
Data Analysis Plan: The primary endpoint will be analyzed using the Log-Rank test between the treatment 
arms, using the intention to treat analysis. The noninferiority margin for the primary outcome is 8 hours, 
corresponding to a hazard ratio less than 1.167.  
 
Interim monitoring for feasibility will be performed when 50% (N = 150) of the patients have been accrued and 
followed for the primary outcome. If the hazard ratio is greater than 1.5, then the study will be stopped and we 
will fail to demonstrate that gabapentin is noninferior to larazepam for the primary outcome. With this stopping 
rule, there is a 50% chance to stop early if the true hazard ratio is 1.5, and only a 1% chance to stop early if the 
hazard ratio is 1.0. 
 
For the analysis of the adverse events, events rates will be estimated within each treatment group and tested 
using a two-sample binomial test for differences in rates. No adjustment for multiple testing will be applied for 
the adverse event rates. 
 
Trends in CIWA scores between treatment groups will be assessed using non-linear mixed effects models with 
random intercepts for each patient. The CIWA scores will be transformed so the empirical distribution of the 
residual terms is approximately normally distributed. We will test for time by treatment arm interaction effects 
within the regression model. Other pre-treatment variables will be assessed for significant interaction with the 
time trend both within and between treatment groups. 
 
Symptom assessment scores will be analyzed using a difference-in-differences model for differential pre-post 
intervention scores between the treatment groups. 
 
 
Endpoints 
 

 
 
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The primary outcome will be the patient’s length of stay, defined as admission time to either: 
1. time of discharge; or,  
2. CIWA score < 10 for 36 hours (as a proxy for when patients are clinically stable for release because 
actual discharge may be delayed for non-medical reasons). 
 
Secondary outcomes include: (assessment scales attached in the Appendix) 
1. Safety: adverse events such as delirium tremens or seizures 
2. Alcohol withdrawal severity: trends as measured by CIWA scores 
3. Validated symptoms assessment scores at baseline (within 24 hours of admission) and 48 hours later: 
a. Sleepiness as assessed by the Epworth Sleepiness Scale 
b. Depressive symptoms as measured by the PHQ-9 (Patient Health Questionnaire-9) 
c. Anxiety symptoms as measured by the GAD-7 (Generalized Anxiety Disorder-7) 
d. Cravings as assessed by the Penn Alcohol Craving Scale 
4. Total amount of benzodiazepines given