Clinical trial NCT03970109
Conditions: Alcohol Use Disorder
Keywords: pharmacotherapy human laboratory study novel medication
Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Start date: 2019-10-08; Completion date: 2020-05-22
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary: The primary objective of this study was to evaluate the effects of 2 different doses of ANS-6637, 200 mg (given as 2 x 100 mg tablets) and 600 mg (given as 2 x 300 mg tablets) once a day, and matched placebo, on alcohol cue-elicited alcohol craving during a human laboratory paradigm after 1 week of daily dosing among subjects with moderate to severe alcohol use disorder (AUD) as confirmed by the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5™).

Secondary: Secondary objectives included evaluation of ANS-6637 200 mg, ANS-6637 600 mg, and matched placebo on reduction of alcohol consumption, alcohol craving, cigarette smoking (among smokers) and nicotine use (among nicotine users), mood, sleep, alcohol use negative consequences, study retention, and safety and tolerability throughout the last 4 weeks of the treatment phase of the study.

Detailed description:
Methodology: This study was a 3-arm, double-blind, randomized, placebo-controlled, parallel group, 3-site study designed to assess the effects of ANS-6637 as compared with placebo on responses to in vivo alcohol cue exposure in the human laboratory setting. After signing informed consent, subjects were screened for eligibility and had other baseline assessments. Screening was permitted over a 14-day period and most baseline assessments were performed on the day of randomization. If eligible for the study, 81 subjects were to be randomized using a stratified permuted block randomization procedure in an approximate 1:1:1 ratio (targeting 27 subjects per group and 27 subjects per each of 3 clinical sites) to receive either ANS-6637 200 mg once daily, ANS-6637 600 mg once daily, or matched placebo for 5 weeks. Clinical site was used as the stratification variable. Subjects were seen in the clinic at screening, at randomization and 5 other times during the study. A final followup telephone interview was conducted 2 weeks after the end of study in-clinic visit. After the first week of investigational product (IP) administration at Study Week 2, subjects underwent a cue reactivity session including 4 individual visual analog scale (VAS) items assessing alcohol craving and one item assessing beverage liking.

Number of Subjects (planned and analyzed): 81 planned; 43 analyzed. The study was put on clinical hold and then stopped early due to clinically significant AEs.

Investigational Product, Dosage, and Mode of Administration:

The target doses were 200 mg (2 x 100 mg tablets) and 600 mg (2 x 300 mg tablets) of ANS-6637 by oral administration once daily for 5 weeks. Subjects in the placebo group took an equivalent number of identically matched placebo tablets (2 per day) by oral administration once daily for 5 weeks.

Duration of Treatment: Each subject participated in the study for up to 10 weeks, including up to 2 weeks of screening, 5 weeks of treatment, one end-of-study visit during the week following the last treatment dose, and a final telephone contact 2 weeks after completing treatment for a safety follow-up.

Statistical Methods (Data Analysis): The original analytical plan was revised slightly due to early stopping of the study as only approximately half of the subjects were randomized to the study at that time.

Analysis Populations:

Modified intention-to-treat (mITT) Analysis Set: The mITT set was defined as subjects randomized to participate in the study that took at least one dose of IP and had a non-missing VAS craving primary endpoint.

Safety Analysis Set: The safety analysis set includes all subjects who took at least one dose of IP.

As the study closed prematurely, only the mITT and Safety Analysis sets were evaluated.

Analysis of the Primary Efficacy Endpoint: Each mITT subject had an initial alcohol cue for "strength" of alcohol craving score from the VAS that was the primary endpoint. Analysis of covariance (ANCOVA) with the "strength" of alcohol craving value as the dependent variable and the pretreatment "strength' of alcohol craving score from the first alcohol cue were an independent fixed effect. Clinical site was included as an independent factor. There were 3 comparisons (ANS-6637 600 mg vs placebo; ANS-6637 200 mg vs. placebo; and ANS-6637 600 mg vs. ANS-6637 200 mg). The Tukey's method was used to adjust for multiple comparisons. No imputation for missing endpoint data was performed.

Analysis of the Secondary Endpoints: There were 3 additional questions asked during the cue session for each beverage cue. Each of these questions was analyzed in the same manner as the primary endpoint. Continuous secondary endpoints during the last 4 weeks of treatment period were analyzed using a mixed-effects model with site, assessment time, and baseline drinking as fixed factors. Models also included time by treatment group interaction term. Analysis of the dichotomous secondary endpoints during the last 4 weeks of treatment period were conducted via logistic regression. No imputation for missing endpoint data was performed for secondary endpoints.

Arms: arm 1: 200 mg ANS-6637 (given as 2 x 100 mg tablet) once a day arm 2: 600 mg ANS-6637 (given as 2 x 300 mg tablet) once a day arm 3: 2 placebo tablets once a day
Interventions: intervention 1: ANS-6637 intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: 200 mg (given as 2 x 100 mg tablet) and 600 mg (given as 2 x 300 mg tablet) once a day intervention 2: Placebo oral tablet

Protocol documents:
ICF_002.pdf: 
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INFORMED CONSENT DOCUMENT 
AGREEMENT TO BE IN A RESEARCH STUDY 
 
NAME OF SPONSOR COMPANY: 
National Institute on Alcohol Abuse and 
Alcoholism (NIAAA) 
 
PROTOCOL NUMBER AND TITLE OF STUDY: 
HLAB-002; “Human Laboratory Study 
of ANS-6637 for Alcohol Use Disorder” 
 
NAME OF PERSON IN CHARGE  
OF THE RESEARCH STUDY  
(STUDY DOCTOR/INVESTIGATOR): 
 
 
$$Name of Investigator$$ 
 
TELEPHONE NUMBER(S), DAYTIME: 
 
 
$$Day Number$$ 
AFTER HOURS: 
 
 
 
 
 
$$After Hours$$ 
 
KEY INFORMATION 
 
1. This is a research study and your participation is voluntary.  
2. This research study is to look at the effects of two different doses of ANS-6637 (the study drug) 
compared with placebo (like a sugar pill) on how much you crave alcohol and should take up to 10 
weeks of your time.  
3. You will be asked to visit the clinic weekly for 6 weeks and have a telephone call one week after the 
last study visit. You will be given a breathalyzer test to ensure you are able to provide consent and 
participate in the study assessments. You will be asked to give blood for testing how your liver, 
kidney and body are functioning and for checking to see if you have a genetic marker. You will be 
asked about your cravings for alcohol and about your drinking. This study uses a smartphone to check 
to make sure you took your study medication. The study drug is “investigational”. This means that it 
has not been approved by the United States Food and Drug Administration (FDA). 
4. If you drink alcohol, you may feel flushing or heat sensation, heart fluttering, nausea, breathlessness, 
rash, and headache while taking this study drug. The complete list of risks / discomforts is listed later 
in this informed consent.  
5. The main benefit to you (or others) for taking part in this study is your drinking habits may change. 
6. There are several alternative treatments that may be effective for treating alcohol problems, including 
other medications and/or counseling. These other treatments are not offered to you as part of this 
research study, but if you decide not to participate, or are not eligible, study personnel will give you 
contact information for existing treatment programs in your area. 
 
INTRODUCTION 
 
You are deciding if you would like to volunteer for a medical research study. You must read this form 
before you agree to take part in this study. If you agree, you must sign this form to show you would like to 
participate. This form will give you more information about this study. Please ask as many questions as you 
need to before you decide if you want to be in the study. Do not sign this form if you have any questions 
that have not been answered. 
 
The investigator is being paid by the sponsor (NIAAA) to conduct this research study. Amygdala 
Neuroscience is the pharmaceutical company that manufactures ANS 6637 and placebo for this study.  
 
 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
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You must be honest with the investigator about your health history or you may harm yourself by 
participating in this study. 
 
PURPOSE OF THE STUDY 
 
The purpose of this study is to determine if the study drug decreases craving for alcohol and reductions in 
alcohol drinking while taking the study drug. The purpose is also to test the safety of this drug in persons 
who drink alcohol. The study drug being tested in this clinical trial is ANS-6637. It is a class of drug 
called an aldehyde dehydrogenase 2 (ALDH – 2) inhibitor that may lower the dopamine surge in the brain 
and stop alcohol craving. It is considered “investigational” as the FDA has not approved this drug.  
 
In this document, you may see the terms “medication”, “treatment”, and “treatment period”; these are 
terms used in research studies as mentioned above and does not mean that you will be receiving medical 
treatment for any condition. These terms apply to the study drug and parts of the study where you will 
receive the study drug or placebo. 
 
If you qualify for the study, you will receive tablets to take orally with a glass of water containing: 
Placebo OR 200 mg ANS-6637 OR 600 mg ANS-6637 once a day for 5 weeks. Placebo tablets contain 
no active ingredient. 
 
This is a double-blind study, which means that neither you nor the investigator will know which drug you 
are taking. The study staff can get this information if needed for an emergency. 
 
The drug you receive will be assigned by chance, like the flip of a coin. An approximately equal number 
of people will be assigned to receive placebo, 200 mg ANS-6637, or 600 mg ANS-6637.  
 
HOW LONG THE STUDY WILL LAST AND HOW MANY PEOPLE WILL BE IN THE STUDY 
 
The study will last about 10 weeks and involve up to 7 visits to the clinic. About 81 men and women, 
ages 21 and over with moderate to severe alcohol use disorder, are expected to be in this study. 
 
TO BE IN THIS STUDY 
 
You cannot be in this study if you are taking any drugs of abuse (illegal). A urine test will be performed 
to check for the use of these drugs. If you are female able to become pregnant you will be given a 
pregnancy test that must be negative. Both men and women must use an acceptable method of birth 
control during the study or will not be allowed to participate. 
 
Subject Responsibilities: 
 
While participating in this research study, you must agree to: 
 
Not give the study drug to other people and keep it out of the reach of children 
 
Be willing and able to follow the study directions and procedures 
 
Tell the study staff about any side effects or problems 
 
Ask questions as you think of them 
 
Tell the investigator or the study staff if you change your mind about staying in the study. 


Protocol number HLAB-002 
$$Name of Investigator$$ 
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 
Provide a valid form of identification (ID). Acceptable forms of ID are as follows: Driver’s 
License, Passport, Military ID, State or National ID, Cedula Government Issued ID, or Medicare 
or Medicaid card. 
 
Undergo a physical exam to assess your overall health and wellness and have an 
electrocardiogram (ECG) to measure the electrical activity of your heart. 
 
Have vital signs taken (blood pressure and heart rate).  
 
Provide a blood sample to assess how your liver, kidneys, thyroid gland, and immune system are 
working. 
 
Provide a urine sample to test for drug use and alcohol consumption. 
 
Give your medical history and have your weight measured. 
 
Provide your age, gender, occupation, and income. 
 
Provide the names of any prescription and “over-the-counter” drugs you may be taking now or in 
the recent past. 
 
Answer questions about your mental health, and any withdrawal symptoms from alcohol. 
 
Provide your daily alcohol use  
 
If you are a female, provide a urine sample to test for pregnancy and agree to use an acceptable 
method of birth control. 
 
If you are male, agree to use acceptable birth control with your female partner (if applicable). 
 
Agree to use a smart phone (either your own or one provided to you) that has an application to 
remind you to take your study drug and record when you have taken your study drug. 
 
WHAT WILL HAPPEN DURING THE STUDY 
 
Study Procedures: 
 
Visit #1: Screening: (up to 14 days) 
 
The screening phase will be completed within 14 days and will involve one clinic visit. Additional visits 
may be requested if laboratory tests need to be repeated.  
 
If you decide to volunteer for this study, your first visit will take approximately 2 1/2 to 3 hours to 
complete. This involves a number of tests to make sure that you meet all of the requirements for 
participation and that you can safely take the study drug. You will not be given study drug during this 
first screening visit. 
 
At the beginning of Screening Visit #1, your blood alcohol level will be measured using a breathalyzer. If 
your blood alcohol is greater than 0.000, you may not be able to complete your visit as scheduled. If your 
blood alcohol level is very slightly higher than 0.000, study staff may give you the option of waiting until 
it reaches 0.000 to continue with your first visit. If you blood alcohol level is 0.080 or higher and you 
drove to your visit, study staff will ask you to remain in the clinic until you are capable of leaving without 
risking your (or others) safety. 
 
During this visit you will be asked to: 
 
Provide a valid form of identification (ID). Acceptable forms of ID are as follows: Driver’s 
License, Passport, Military ID, State or National ID, Cedula Government Issued ID, or Medicare 
or Medicaid card. 
 
Provide your age, gender, occupation, and income. 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
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 
Provide a urine sample to test for drug use.  
 
Undergo a physical exam to assess your overall health and wellness and have an 
electrocardiogram (ECG) to measure the electrical activity of your heart. 
 
Give your medical history and have your weight measured. 
 
Have vital signs taken (blood pressure, heart rate, and temperature).  
 
Answer questions about your mental health. 
 
Provide a blood sample to assess how your liver, kidneys, thyroid gland and immune system are 
working. 
 
If you are a female, provide a urine sample to test for pregnancy and answer questions about your 
birth control method(s). 
 
If you are a male, you will be asked about birth control method(s). 
 
Provide your daily alcohol use for the past 28 days. 
 
Provide the names of any prescription and “over-the-counter” drugs you may be taking now or in 
the recent past. 
 
Answer questions about any withdrawal symptoms from alcohol. 
 
Participate in an exercise (called a cue session) where you will be shown beverages (including 
your favorite alcoholic beverage) and complete computerized questions about your craving for 
the beverages. 
 
You will also be asked to provide addresses and telephone numbers for yourself and other people, such as 
family members or friends who will know how to contact you if you fail to show up for clinic visits, or if 
study personnel have problems getting in touch with you. In doing so, you give study personnel 
permission to contact these people to find out how to contact you. Please be aware that telling others you 
are in this study could jeopardize your privacy. 
 
At the end of this visit, you will be told if you are still eligible to participate in the study and have a 
second visit scheduled to complete the final screening tests and start study participation.  
 
Visit #2: Completion of Screening and Start of Study Treatments (Week 1) 
 
If you are still eligible for the study, a second screening and study start visit will be scheduled. At the 
beginning of this visit your blood alcohol level will be measured using a breathalyzer. If your blood 
alcohol is greater than 0.02, the same rules apply that were described above.  
 
At this visit you will be asked to: 
 
Provide a urine sample to test for drug use. 
 
Update your medical history. 
 
Undergo a physical exam if new problems have occurred. 
 
Have vital signs and weight taken. 
 
Answer questions about thoughts or attempts of harming yourself, and alcohol withdrawal 
symptoms. 
 
Provide a urine sample for a pregnancy test if you are female. 
 
Review of acceptable birth control methods (men and women).  
 
Provide the names of any prescription and “over-the-counter” drugs or herbal remedies you may 
be taking. 
 
Provide your daily alcohol use since your last visit and your drinking goal at the end of the study. 


Protocol number HLAB-002 
$$Name of Investigator$$ 
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If you are still eligible, you will be asked to: 
 
Provide blood samples for DNA marker testing for ALDH2 (a specific genetic marker that does 
not affect your ability to participate in the study). If you have a certain type of this gene, you are 
likely to have a flushing reaction to alcohol. This is a heat sensation with redness of the face, 
neck, or chest. 
 
Fill out questionnaires or answer questions about your mood, desire to quit drinking, sleep, 
drinking urges, smoking cigarettes, and use of other nicotine products. 
 
At this visit if you are eligible, you will start an alcohol education program called Take Control which is 
designed to help people cut back or stop drinking and will be given a bottle containing tablets of the study 
drug. 
 
During this Study, you will monitor yourself taking your study drug on a smartphone application. This 
application is provided by a company named AiCure that will collect and store your data during the 
conduct of the study. You will be able to download the application with help by the study site staff. If you 
do not have a smartphone or do not want to use your own device, you have an option to use a device 
provided by the study site. If you download the application, you will be reimbursed $10.00 per month to 
account for the cost of data transmission. You will be required to use the application to monitor each time 
you take the study drug while you are enrolled in the study. 
 
The application will be used only for the purpose of making sure you are taking your dose. If you are 
provided with a device, you will not be able to make general phone calls, respond to text messages, or use 
the device to access the Internet. This application uses artificial intelligence to confirm that the same 
person uses the device, and that the study drug is correct and taken properly. The application’s interactive 
software will send a message to a secure server, confirming that you took the study drug. The application 
will record the date and time that you took the drug so that the study site can confirm it was taken for that 
day.  
 
To protect your identity at all times, all of your video recordings and data are encrypted by the application 
and will be automatically forwarded to a secure server. The cloud-based server is compliant with the 
Health Insurance Portability and Accountability Act (HIPAA), which protects the privacy and security of 
healthcare information. The data are securely stored and only accessible to healthcare providers and other 
authorized personnel through two-way authentication. The study site staff can tell you more about this 
application and how it will be used. 
 
Before starting use of the smartphone application, the study site staff will assist you in setting up the 
application so that the application can confirm your identity and register your preferred settings. Through 
prompts, the application will assist you to practice monitoring yourself taking the study drug. During the 
practice training session, you will be asked to take something called a “dummy” tablet (Smarties candy). 
The practice “dummy” tablet will be used only for the training session. You will not take the “dummy” 
tablet home with you. The “dummy” tablet does not contain any active drug, and will be digested just like 
food.  
 
You will practice several times to learn how to use the application and how to take the study drug. The 
study staff will help you set the application so that it will remind you to take the study drug in the 
morning. It is important that you remember to use the application on the smartphone device every time 
you take your drug. If you are not using the device or not taking your drug correctly, you may be 
discontinued from the Study. 
 


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Treatment (Weeks #1 to #5) 
 
During the first week (Week #1), you will be contacted two times by study staff by phone to see how you 
are feeling. Also at the second phone contact, you will be reminded about things to do before your next 
visit. You will be reminded on this phone call to take the study drug as usual in the morning and to not 
drink caffeine after arriving for this visit until study tests are completed and that you must refrain from 
smoking about 1-1.5 hours before the testing and during the testing. 
 
During the Weeks 2 to 5 visits, the following information will be collected and tests will be performed: 
 
Your blood alcohol level will be measured using a breathalyzer. If your blood alcohol is greater 
than 0.020, you may not be able to complete your visit as scheduled. If your blood alcohol level is 
very slightly higher than 0.020, study staff may give you the option of waiting until it reaches 
0.000 to continue with your visit. If you blood alcohol level is 0.080 or higher and you drove to 
your visit, study staff will ask you to remain in the clinic until you are capable of leaving without 
risking your (or others) safety. 
 
A urine sample to test for drug use. 
 
A blood sample to measure drug levels in your blood (Week 2 and 4 only) 
 
A blood sample to check your liver, kidney and thyroid gland functions (at Weeks 2 and 4 blood 
will also be collected to check your immune system) 
 
Update your contact information. 
 
Questions about thoughts or attempts of harming yourself, and alcohol withdrawal symptoms. 
 
Vital signs and weight measured. 
 
Questions about any medications you are taking (or have taken since the last visit). 
 
Your study drug bottle collected and a new bottle(s) provided. 
 
Asked about your cravings for alcohol and alcohol withdrawal symptoms. 
 
View an alcohol education program called Take Control. 
 
Fill out questionnaires or answer questions about your mood, desire to quit drinking, sleep, 
drinking urges, smoking cigarettes, and use of other nicotine products. 
 
Your daily alcohol use since your last visit. 
 
Week #2 only - Participate in a second cue session (like the one done at the screening visit) where 
you will be shown beverages (including your favorite alcoholic beverage) and complete 
computerized questions about your craving for the beverages. 
 
End of Study Visit – Week #6 
 
At Week 6, the last clinic visit, the following information will be collected and tests will be performed: 
 
Your blood alcohol level will be measured using a breathalyzer. If your blood alcohol is greater 
than 0.020, you may not be able to complete your visit as scheduled. If your blood alcohol level is 
very slightly higher than 0.020, study staff may give you the option of waiting until it reaches 
0.000 to continue with your visit. If you blood alcohol level is 0.080 or higher and you drove to 
your visit, study staff will ask you to remain in the clinic until you are capable of leaving without 
risking your (or others) safety. 
 
A urine sample to test for drug use. 
 
A blood sample to check your liver, kidney, thyroid gland, and immune system functions  
 
Questions about thoughts or attempts of harming yourself, and alcohol withdrawal symptoms. 
 
Vital signs and weight measured. 


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 
Questions about any medications you are taking (or have taken since the last visit). 
 
An ECG will be performed. 
 
Questions about your cravings for alcohol and alcohol withdrawal symptoms. 
 
Fill out questionnaires or answer questions about your mood, desire to quit drinking, sleep, 
drinking urges, smoking cigarettes, and use of other nicotine products. 
 
Your daily alcohol use since your last visit. 
 
Questions about your experience with the study drug.  
 
You will also be provided with information about your options for continued treatment of your alcohol 
use disorder. 
 
You will be required to bring your used and unused bottles with you every time you attend a clinic visit.  
 
For your own safety and to ensure our study results are valid, we ask that you provide truthful and honest 
information when answering any of the study related questions. Not telling study staff about parts of your 
previous medical history, medications you are taking, or symptoms you are having, could put your health 
at risk and ruin the study findings. Please provide staff with complete and honest answers throughout the 
study. 
 
If you experience a side effect, you may have unscheduled visit(s) to make sure you are well at the 
discretion of the investigator. 
 
Follow-up Contact: (2 weeks after last in-clinic visit) 
 
Two weeks after you complete the study, a study staff member will contact you by telephone to ask you 
questions about your alcohol use and any side effects you may have had since you stopped taking the 
study drug. If study staff is not able to reach you by telephone, they may contact friends or family 
members you provided at screening to get your new contact information. Please be aware that if you tell 
others that you are in this study, this could be a risk your confidentiality. In order to maintain your 
confidentiality when attempting to contact you or a contact person by telephone, the research staff will 
not say that you are a participant in this research study. Once we have contacted you and/or the contacts 
you gave us, your participation in the study will end. 
 
Blood Samples: 
 
Blood samples will be taken by single needle-sticks or by a tube that is left in your arm during the blood 
collection. You cannot choose how the blood is taken. 
 
There will be about 7 blood draws during the course of the study. The total amount of blood drawn will 
be about 86 mL or 1/3 cup. For comparison, the standard blood donation is about 480 mL (two cups).  
 
POSSIBLE SIDE EFFECTS AND RISKS  
 
If you do not understand what any of these side effects mean, please ask the investigator or study staff to 
explain these terms to you.  
 
 


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Because this drug is investigational, all of its side effects or reactions may not be known. There may be 
rare and unknown side effects. Some of these may be life threatening. 
 
You must tell the investigator or study staff about all side effects that you have. If you are not honest about 
your side effects, you may harm yourself by staying in this study. 
 
There have been 5 studies in humans to look at the safety of ANS-6637. The first study included 111 
healthy subjects, both smokers and non-smokers. This trial studied the safety, tolerability and effect of 
food on ANS-6637. A total of 23 of 84 subjects experienced side effects when given ANS-6637. Side 
effects reported include runny nose, dizziness, itchiness, rash, abdominal pain, dry mouth, fatigue and 
nausea. One subject was withdrawn from the study after developing an itchy rash and one was withdrawn 
due to heart rhythm changes. 
 
In the second study, 12 healthy adults were given a drink of alcohol (in an amount equal to about 6 
ounces of beer). Side effects from just drinking alcohol without ANS-6637 were mild reports of feeling 
hot (2 subjects) and mild headache (3 subjects). Itching, redness, and a papule (small bump)  on the chest 
were reported by one subject for each of these events. Four days later, one female subject received one 
200 mg dose of ANS-6637 with the same amount of alcohol. Side effects that were mild in this subject 
included feeling cold (abdomen), feeling hot (back and arm), chest pain (not in the heart), throat pain, 
tingling in the hands, decrease appetite, and lack of energy. Moderate effects were face and neck flushing, 
feeling hot, feeling heart beating strongly and rapidly, anxiety, dizziness, nausea, and headache. The most 
severe effect was dizziness when standing up and fainting. All of these effects resolved. 
 
In the third study, healthy adults were given 25 mg or 50 mg of ANS-6637 with different amounts of 
alcohol at the same time. Two of 15 people who took 25 mg of ANS-6637 with a drink of alcohol 
equivalent to about one or two 6 ounce beers had a mild heat sensation. One person who took 50 mg of 
ANS-6637 with alcohol at the same time had an increased heart rate (increase of 28 beats per minute) 
within an hour that was accompanied by flushing (skin redness). The other person who took 50 mg of 
ANS-6637 with alcohol also had increased heart rate (from 50 beats per minute before to 113 beats per 
minute about 1 hour after dosing) with a decrease in blood pressure and flushing. 
 
The fourth study examined the safety and tolerability of 6 dose levels (25 mg to 600 mg) of ANS-6637 
with up to 5 drinks of vodka containing 40% every 30 minutes in healthy, male alcohol drinkers as 
compared to healthy males who received a placebo (sugar pill). Of the 48 people who received ANS-6637 
in combination with alcohol more were likely to report experiencing a heat sensation, heart fluttering, 
breathlessness and headache than the 12 people who received the placebo pill. These effects were mostly 
mild. They were also more likely to experience flushing (skin/face becomes red and hot). Fewer people 
taking ANS-6637 reported feeling drunk than those who took placebo.  
 
One study subject experienced evidence of liver damage and other side effects that were considered 
serious and possibly related to the study drug.  Some study subjects have had laboratory value changes 
indicating a temporary mild change in their thyroid hormone levels.  These changes were not associated 
with symptoms of overactive or underactive thyroid function.  These laboratory changes returned to 
normal after the study medication was stopped. 
 
In a fifth study of 12 healthy subjects, slight reversible increases in serum creatinine, some within normal 
limits, and presumed mildly reduced kidney function have been noted in several participants receiving 
multiple 600 mg daily doses. Creatinine levels returned to normal limits 7 days after the last dose in a 
participant who had creatinine levels above the normal range.   
 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
Page 9 of 21 
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MAY 26, 2020 
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Animal studies have shown there may be a risk to a developing baby during pregnancy. 
 
There may be risks associated with the use of the study drug and other medications that are not known at 
this time. Before starting any new drug while you are in the study, you must get your study doctor’s 
permission. 
 
ADDITIONAL RISKS OR DISCOMFORTS 
 
Common discomforts of participating in a research study: 
 
Some of the questions about your personal habits, lifestyle, and drug and alcohol use may 
embarrass you. If any question makes you feel uncomfortable you may discuss its importance and 
the need to answer it with the specially trained interviewer. You may refuse to answer a question 
if it is upsetting to you.  
 
You may become bored with answering questionnaires.  
 
Physical discomforts of participating in this study: 
 
The drawing of blood may cause pain, redness, bruising bleeding, lightheadedness, nerve 
damage, blood clots, which may cause inflammation, swelling and pain, and on rare occasions, 
infection. You may briefly feel the prick of the needle when it is inserted into your vein. You may 
feel dizzy or faint when your blood is drawn. Precautions will be taken to minimize these risks. If 
you feel faint tell the study staff right away. 
 
ECGs may cause discomfort and/or irritation of the skin (redness and itching) from the adhesive 
electrodes. Hair on your chest may need to be removed in order to obtain the best electrical 
contact between the adhesive electrodes and your skin.  Irritation from hair removal (shaving) 
also could occur. 
 
Risks to Providing a DNA Sample: 
 
The results of genetic testing provide a similar amount of information as many non-genetic tests 
that are part of ordinary medical practice. The results do not present a social risk that is 
meaningfully different than other test results from this study. Your test results are confidential. 
However, if your test results go into the wrong hands, the confidentiality of your health 
information may be lost. The sponsor, NIAAA, will make every effort to make sure no one gets 
your test results except people or companies you read about in this form. In addition, the Genetic 
Information Nondiscrimination Act of 2008 prohibits the use of genetic information in health 
insurance and employment decisions. 
 
Be aware that this Federal law does not protect you against genetic discrimination by companies 
that sell life insurance, disability insurance, or long term-care insurance, nor does it prohibit 
discrimination on the basis of a genetic disease or disorder that you already know about.   
 
RISKS FROM ALCOHOL WITHDRAWAL 
 
Some people may experience symptoms of alcohol withdrawal if they stop drinking suddenly. At your 
screening visit, you will be given information to help you recognize the symptoms of withdrawal. You 
will be monitored carefully throughout the study in case you begin to have symptoms of alcohol 
withdrawal. If you experience any of these symptoms, you will be instructed to call the clinical site using 
the 24-hour phone number provided to you. When you contact the clinical site, a staff member will ask 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
Page 10 of 21 
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MAY 26, 2020 
NOT TO BE USED FOR SUBJECT ENROLLMENT 
 
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you questions to determine if you are having serious withdrawal symptoms. If you have serious 
withdrawal, staff may advise that you go to the nearest emergency room. During your in-person clinic 
visits and telephone interviews throughout the study, you will be assessed for withdrawal symptoms you 
might be experiencing. You will be asked about changes in your health and drinking status. If you 
experience significant withdrawal symptoms, you should go to your local emergency room for evaluation. 
 
BIRTH CONTROL, DANGERS OF PREGNANCY AND BREASTFEEDING 
 
Animal studies have shown there may be a risk to a developing baby in pregnancy. For that reason it is 
very important that you not become pregnant or father a child while you are in this study. 
 
If you are a female, you must not get pregnant while in this study or for 1 week after stopping the study 
drug. The only certain way to not get pregnant is to not have sex. If you are a female and choose to have 
sex, you must use a type of birth control listed below, unless you are surgically sterile, your partner is 
surgically sterile or you are postmenopausal for one year:  
 
oral contraceptives; 
 
contraceptive sponge; 
 
patch; 
 
double barrier (diaphragm/spermicidal or condom/spermicidal); 
 
intrauterine contraceptive system; 
 
etonogestrel implant; 
 
medroxyprogesterone acetate contraceptive injection; 
 
complete abstinence from sexual intercourse, and/or  
 
hormonal vaginal contraceptive ring. 
 
If you are a man, you must use birth control if you choose to have sex with women while in this study. 
You must also not donate sperm during the study and for at least 1 week after stopping the Study drug. 
 
Methods of birth control for males include:  
 
surgical sterilization (vasectomy with documentation of azoospermia); 
 
your participant’s female partner uses oral contraceptives (combination estrogen/progesterone 
pills), injectable progesterone or sub dermal implants (commenced at least 14 days before study 
drug dosing)  
 
your female partner uses a medically prescribed topically applied transdermal contraceptive patch 
(commenced at least 14 days before study drug dosing); 
 
your female partner has undergone documented tubal ligation (female sterilization) or is 
postmenopausal (one year); 
 
your female partner has undergone documented placement of an intrauterine device or 
intrauterine system; and/or 
 
true abstinence: when this is in line with your preferred and usual lifestyle. 
 
Even if you use birth control during the study, there is a chance you or your partner could become 
pregnant. If you or your partner are pregnant or become pregnant during the study, the study drug or 
procedure may involve unforeseeable risks to the unborn baby. A pregnancy test is not always right, 
especially in the early stages of pregnancy. 
 
 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
Page 11 of 21 
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MAY 26, 2020 
NOT TO BE USED FOR SUBJECT ENROLLMENT 
 
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You cannot be in the study if you are breastfeeding. It is not known whether the study drug can be given 
to breast fed babies. Therefore, if you are breastfeeding a child you cannot participate in the study.  
 
POSSIBLE BENEFITS OF THE STUDY  
 
There is no known benefit of ANS-6637 in the treatment of alcohol use disorder and there are other 
known drug treatments for this disease. ANS-6637 is thought to decrease your consumption of alcohol; 
however, we cannot guarantee that you will receive this benefit. Viewing the Take Control alcohol 
education modules may help you become aware of how much you drink and the risks associated with 
drinking in excess. Participation in this study may or may not help you cut back or quit drinking. 
However, by participating in this study you will receive information and advice about reducing your 
drinking, as well as close medical attention and monitoring of your overall well-being. Your participation 
in this study will also contribute to knowledge about ways to help others reduce or stop drinking alcohol. 
 
There is no promise that your condition will get better. It might stay the same or it might get worse, 
especially if you get the placebo. 
 
ALTERNATIVES TO PARTICIPATING IN THE STUDY  
 
There are several alternative treatments that may be effective for treating alcohol problems, including 
other medications and/or counseling. These other treatments are not offered to you as part of this research 
study, but if you decide not to participate, or are not eligible, study personnel will give you contact 
information for existing treatment programs in your area. 
 
SHARING OF YOUR PROTECTED HEALTH INFORMATION (CONFIDENTIALITY) 
 
Your records of being in this study will be kept private except when ordered by law. The following 
people will have access to your study records: 
 
 
The investigator 
 
Sponsor company or research institution [including monitor(s) and auditor(s)] 
 
NIAAA research collaborators from Amygdala Inc. (the company that provides the 
investigational product(s)) 
 
Fast-Track Drugs & Biologics, LLC (a company hired by NIAAA to monitor your study 
information and health and welfare during the study) 
 
AiCure (the company that provides the smart phone application) 
 
The study site’s financial analyst for clinical research (if applicable) 
 
The United States Food and Drug Administration (FDA) 
 
The Office of Human Research Protections in the U.S. Department of Health and Human 
Services 
 
Other state or federal regulatory agencies 
 
IntegReview IRB 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include 
a summary of the results. You can search this Web site at any time. 
 
 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
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The Institutional Review Board (IRB), IntegReview, and accrediting agencies may inspect and copy your 
records, which may have your name on them. Therefore, total confidentiality cannot be guaranteed. If the 
study results are presented at meetings or printed in publications, your name will not be used. 
 
ADDITIONAL REQUIRED PRIVACY LANGUAGE 
 
By submitting my personal telephone number(s), I grant the Study site and AiCure permission to contact 
me at this number by SMS (text) messaging or by phone if: 
 
 
study medication is not taken or not taken correctly; or 
 
the Study smartphone or app requires updates or alterations. 
 
Additionally, I grant the Study site and AiCure permission to contact me on the smartphone-like device if 
my personal telephone number(s) cannot be reached. 
 
CERTIFICATE OF CONFIDENTIALITY 
 
This study is covered by a Certificate of Confidentiality (CoC) from the National Institutes of Health. All 
studies funded by the National Institutes of Health that involve identifiable information or biological 
samples are covered by a CoC.  
 
The CoC is issued to protect the investigators on this study from being forced to tell people that are not 
connected with this study about your participation in this study, even under a subpoena. This protection, 
however, is not absolute. The protection offered by the CoC does not stop us from voluntarily reporting 
information about suspected or known sexual, physical, or other abuse of a child or older person, or a 
subject's threats of violence to self or others. 
 
If any member of the research team is given such information, he or she will make a report to the 
appropriate authorities. Individuals who participate as research subjects in the specified research project 
are protected permanently during any time the Certificate is in effect - even if the subject gave the 
researcher data before the Certificate is issued. Also, because this research is sponsored by NIAAA, staff 
from NIAAA and other DHHS agencies may review records that identify you but only for the purposes of 
audit for quality and accuracy or program evaluation.  
 
Even when a CoC is in place, you must still continue to actively protect your own privacy. If you 
voluntarily give your written consent to anyone to receive information about your participation in the 
research or freely volunteer information to anyone other than the study staff that you are a research 
participant in this study, then we may not use the CoC to withhold this information. 
 
IN CASE OF STUDY RELATED INJURY 
 
No medical care, evaluations or financial compensation for research-related injuries or illness will be 
provided. The costs of such additional treatment will be paid by you or by your health insurance carrier. 
You also have the right to pursue legal remedy if you believe that your injuries justify such action. 
Compensation for injury/illness may be payable under the Federal Tort Claims Act. The availability of 
this compensation may vary depending upon the circumstances involved and there are certain limitations. 
 
 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
Page 13 of 21 
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MAY 26, 2020 
NOT TO BE USED FOR SUBJECT ENROLLMENT 
 
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Please be aware that some insurance plans may not pay for research-related injuries. You should contact 
your insurance company for more information. 
 
EMERGENCY CARE 
 
If you are experiencing a life-threatening medical emergency call 911 or go to your nearest emergency 
room. 
 
If you experience any medical problems or psychological symptoms at any time during your participation, 
please contact your study doctor. 
 
You will be given and encouraged to carry a wallet card that identifies the research study by number, 
states that you are taking either study drug or placebo, and indicates that you are participating in a double-
blind clinical trial; This card does not identify the purpose of this study. This card provides the name and 
phone number of the main study doctor who can provide information to other doctors in the event of an 
emergency. The card also instructs the emergency room, or other doctor treating you to provide 
information to the study doctor about your care.  
 
LEGAL RIGHTS 
 
You will not lose any of your legal rights by signing this consent form. 
 
CONTACT INFORMATION 
 
If you have questions, concerns, or complaints about this study or to report a study related injury, contact: 
 
$$Name of Investigator$$ 
$$Day Number$$ daytime telephone number  
$$After Hours$$ after hours number  
 
If you are unable to reach anyone at the number(s) listed above and you require immediate (life 
threatening) medical attention, please go to the nearest emergency room. 
 
If you do not want to talk to the investigator or study staff, if you have concerns or complaints about the 
research, or to ask questions about your rights as a study subject you may contact IntegReview. 
IntegReview is a group of people that has reviewed this research study. The main goal of this review is to 
protect the rights and well-being of the human subjects participating in research studies. IntegReview’s 
policy indicates that all concerns/complaints are to be submitted in writing for review at a convened IRB 
meeting to: 
 
Mailing Address:            OR            Email Address: 
Chairperson 
IntegReview IRB 
3815 S. Capital of Texas Highway 
Suite 320 
Austin, Texas 78704 
integreview@integreview.com 
 
 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
Page 14 of 21 
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INTEGREVIEW IRB 
MAY 26, 2020 
NOT TO BE USED FOR SUBJECT ENROLLMENT 
 
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If you are unable to provide your concerns/complaints in writing or if this is an emergency situation 
regarding subject safety, contact our office at: 
 
512-326-3001 or 
toll free at 1-877-562-1589 
between 8 a.m. and 5 p.m. Central Time 
 
IntegReview has approved the information in this consent form and has given approval for the 
investigator to do the study. This does not mean IntegReview has approved your being in the study. You 
must consider the information in this consent form for yourself and decide if you want to be in this study. 
 
COSTS 
 
Although there will be no cost to you for any treatment or testing that is done as part of this research 
study, you may be responsible for care related to injury or complications that could arise from 
participation in the study.  
 
PAYMENT FOR BEING IN THE STUDY 
 
You may receive up to $595.00 for being in the study. You will be paid per completed visit as follows: 
  
Visit 
Compensation 
Visit 1 Screening 
$30.00 
Visit 2 Week 1 - Study Start 
$50.00 
Visit 3 Week 2 - Cue Session 
$100.00 
Visit 4 Week 3 
$75.00 
Visit 5 Week 4 
$75.00 
Visit 6 Week 5 
$75.00 
Visit 7 Week 6 
$90.00 
Telephone checkup Week 8 
$100.00 
 
If you must have additional unscheduled study visits during or after study for safety follow-up, you will 
be paid in gift cards for these visits. For each additional visit you attend, you will receive a gift card 
valued at $50.00. If you choose to leave or are withdrawn from the study for any reason before finishing 
all visits you will be paid only for each completed visit. You will receive payment within 2 weeks after 
your last study visit. 
 
You may be required to report the payment received for this study to the Internal Revenue Service as 
taxable income. 
 
VOLUNTEERING TO BE IN THE STUDY 
 
It is your choice if you want to be in the study. No one can force you to be in the study. You may not 
want to be in this study or you may leave the study at any time without penalty or loss of benefits to 
which you are otherwise entitled. You can still get healthcare in the future.  
 
 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
Page 15 of 21 
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MAY 26, 2020 
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Employees of the investigator or sponsor are not allowed to participate in this study. Students at any site 
University are also not allowed to participate.   
 
OR  
 
Students of this institution are allowed to participate in this study. If you are a student: 
 
 
The decision to participate or not will not affect your grade, recommendations, employment or the like. 
 
For mandatory participation or for extra credit, you will be given other options for fulfilling the research 
requirement, such as writing short papers or book reports, special projects, and brief quizzes on 
additional reading. 
 
Failure to participate will not have a negative effect on your relationship with the investigator or the 
faculty. 
 
The investigator, the sponsor company, IntegReview, or the FDA, if applicable, may take you out of the 
study without your permission, at any time, for the following reasons: 
 
 
If you do not follow the investigator’s instructions  
 
If we find out you should not be in the study 
 
If the study is stopped 
 
If it becomes harmful to your health 
 
You become pregnant 
 
You have a physical illness that prevents you from taking the study drug 
 
You start to drink more alcohol 
 
Confinement in a controlled environment (like a hospital or jail) 
 
Psychiatric Crisis 
 
If you leave the study or if you are taken out of the study, you may be asked to return for a final visit to 
have some end of study evaluations or tests. If information generated from this study is published or 
presented, your identity will not be revealed. If you leave the study, no more information about you will 
be collected for this study. However, all of the information you gave us before you left the study will still 
be used.  
 
NEW FINDINGS 
 
If there is new information or any significant new findings that could relate to your willingness to 
continue participation we will tell you. You can then decide if you still want to be in the study.  
 
REQUIRED FOR CALIFORNIA SITES ONLY 
SUBJECT’S BILL OF RIGHTS 
 
You will be given a separate copy of the California Experimental Research Subject’s Bill of Rights.  If 
you have not received a copy of this document, please notify study staff. 
 
 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
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RESEARCH RESULTS 
 
Researchers are required to publish the results of this study. These results will be based on outcomes for 
the entire group of participants and will not identify you as a participant. No individual information about 
you or your participation in this research will be made public without your express written permission. 
You will not be told the results of this research; however, after the end of the study, you may request and 
be provided with the name of the study drug that you received, ANS-6637 or placebo. 
 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
Page 17 of 21 
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INTEGREVIEW IRB 
MAY 26, 2020 
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AGREEMENT TO BE IN THE STUDY 
 
This consent form contains important information to help you decide if you want to be in the study. If you 
have any questions that are not answered in this consent form, ask one of the study staff.  
 
Please answer YES or NO to the following questions: 
 
A. 
Is this document in a language you understand?  
 
 
 
 
 
 
 
B. 
Do you understand the information in this consent form?  
 
 
 
 
 
 
C. 
Have you been given enough time to ask questions and talk about the study? 
 
 
 
 
D. 
Have all of your questions been answered to your satisfaction? 
 
 
 
 
 
 
E. 
Do you think you received enough information about the study?  
 
 
 
 
 
F. 
Do you volunteer to be in this study of your own free will and without being  
pressured by the investigator or study staff? 
 
 
 
 
 
 
 
 
G. 
Do you know that you can leave the study at any time without giving 
a reason and without affecting your health care?  
 
 
 
 
 
 
 
H. 
Do you know that your health records from this study may be reviewed 
by the study sponsor and by government authorities? 
 
 
 
 
 
 
 
I. 
Do you know that you cannot be in another study while you are in this study? 
 
 
 
 
IF YOU ANSWERED “NO” TO ANY OF THE ABOVE QUESTIONS, 
OR YOU ARE UNABLE TO ANSWER ANY OF THE ABOVE QUESTIONS, 
YOU SHOULD NOT SIGN THIS CONSENT FORM. 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Adult Study Subject 
 
 
 
 
 
 
 
 
 
 
Signature of Adult Study Subject 
 
 
 
 
 
Date/Time 
 
  
  
 
 
 
 
 
 
 
 
 
 
Printed Name of Person Explaining Consent Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Explaining Consent Form 
 
 
 
 
Date/Time 
 
 
 
You will receive a signed and dated copy of this consent form to keep. 
 
 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
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Attachment #1 
CONSENT FORM QUESTIONS 
 
ANS-6637 for Alcohol Use Disorder 
 
Check the appropriate response: 
TRUE 
FALSE 
1) If a study participant becomes pregnant while participating in this study, 
she will be taken off the study drug. 
 
 
2) ANS-6637 has already been approved by the Food and Drug 
Administration (FDA) as a treatment for alcohol use disorder. 
 
 
3) You will take two pills per day of ANS-6637 or placebo. 
 
 
4) You are expected to give truthful answers about your drinking. 
 
 
5) You will be told whether you are receiving ANS-6637 or placebo. 
 
 
6) You will have to give blood and urine samples during the course of the 
study. 
 
 
7) The study staff may end your participation in this study if they feel that it is 
in your best interest. 
 
 
8) You will be compensated for your time and travel. 
 
 
9) You must bring your drug bottles to every visit. 
 
 
10) You will never be contacted by telephone during the study. 
 
 
11) You must inform the study staff of starting any new medications that you 
take during the study. 
 
 
12) The research data I provide in this study may be made available to the 
general research community, but will be de-identified so that any 
personally identifiable data will removed. 
 
 
 
The correct answers to the questions above have been discussed with me. 
 
 
 
 
Participant Signature 
 
 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
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CHANGE TO 14 PT FONT FOR CA SITES: 
PROTECTED HEALTH INFORMATION COLLECTED DURING THIS STUDY 
 
Health information about you will be collected if you choose to be part of this research study. Health 
information is protected by law as explained in the study site’s Privacy Notice. If you have not received this 
notice, please request a copy from the investigator. At the study site, your information will only be used or 
shared as explained and authorized in this consent form or when required by law. The government Privacy 
Act (Systems of Record Notice #09-25-0200) applies to the information to be collected from you. The 
authority to collect study information is under 42 USC 285n as it applies to NIAAA. 
 
The investigator and staff involved with the study will keep your protected health information collected 
for the study strictly confidential. Protected health information covered by the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA), including your name, initials, and other identifying 
information will not be released or published without your permission unless required by law. The 
following protected health information will be collected and used for research:  
 
Name 
 
Address 
 
Valid form of ID  
 
Telephone number 
 
Information from a brief psychiatric examination 
 
Emergency contact information 
 
Initial telephone screening information 
 
Current and past medications and therapies 
 
Information from a physical examination that includes body weight, blood pressure, and heart 
rate  
 
Electrocardiogram results 
 
Blood alcohol test results 
 
Urine drug screen results 
 
Pregnancy test results if you are female 
 
Clinical laboratory test results 
 
Genetics test results 
 
Healthcare, drinking, mood, sleep, and questionnaires/forms 
 
To participate in this research, you must allow the study team to use your protected health information. If you 
do not want us to use your protected health information, you may not participate in this study.  
 
Research data are assessments and information collected by the clinical site from you during this research 
study.  
 
Documents that contain your name, such as the consent form signed by you, will be securely stored 
separately from your research data. All research data will be coded in a way that does not identify you by 
name or initials and will be kept in a secure place that allows only selected study personnel to have access to 
this information. However, there may be some rare cases beyond our control where your data could be 
accidentally disclosed, and we cannot protect your privacy. 
 
 
 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
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APPROVED BY 
INTEGREVIEW IRB 
MAY 26, 2020 
NOT TO BE USED FOR SUBJECT ENROLLMENT 
 
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As required by law (HIPAA), special steps will be taken to keep confidential any information that can be 
used to personally identify you (for example: your name, initials, birthdate, address, telephone number, 
and social security number). This personally identifying information will not be released or published 
without your permission unless required by law.  
 
If you withdraw your permission:  
 
We will no longer use or share medical information about you for this research study, except when 
the law allows us to do so.  
 
We are unable to take back any information we have already shared with your permission.  
 
We may continue using and sharing the information obtained before your withdrawal if it is 
necessary for the soundness of the overall research.  
 
We will keep a record of your research data as long as the law requires. 
 
If you would like to revoke your HIPAA Authorization, please provide written notice to the study doctor.  If 
you revoke your HIPAA Authorization, you can no longer participate in this study.  
 
WHO MAY USE AND SHARE YOUR PROTECTED HEALTH INFORMATION 
 
You have the right to know who will be able to access your protected health information and why they 
may access it. Staff designated by the agencies named below may review records that identify you for the 
purpose of monitoring and quality control. However, it is the policy of these agencies and the study 
researchers that every effort will be made not to release information that identifies you.  
 
Representatives of the following people/groups within the study site may use your protected health 
information. 
 
The principal investigator 
 
The Institutional Review Board (if applicable) 
 
The study site’s Human Subjects Protection Office 
 
The study site’s Financial Analyst for Clinical Research, if applicable 
 
The above people/groups may share your protected health information with the following people/groups 
outside the study site for their use in connection with this research study. These groups include: 
 
The Office of Human Research Protections in the U. S. Department of Health and Human Services 
 
Food and Drug Administration (FDA) 
 
IntegReview IRB  
 
NIAAA (the Funding Sponsor) 
 
NIAAA research collaborators from Amygdala Inc. (the company that provides the 
investigational products) 
 
Fast-Track Drugs & Biologics, LLC (a company hired by NIAAA to monitor your study 
information and health and welfare during the study) 
 
AiCure (the company that provides the smart phone application) 
 
In all disclosures outside of the study site, you will not be identified by name, social security number, 
address, telephone number, or any other direct personal identifier. In records and information disclosed 
outside of the study site, you will be assigned a unique code number. 
 


Protocol number HLAB-002 
$$Name of Investigator$$ 
Informed Consent 
 
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APPROVED BY 
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The Principal Investigator or study staff will inform you if there are any additions to the list above during 
your active participation in the trial. Any additions will be subject to the study site’s procedures 
developed to protect your privacy. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by US 
law. This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time. 
 
 
_____________________________________________________       ________________ 
Signature of Subject 
Date 
 

Prot_000.pdf: 
ANS-6637 – Human Laboratory Paradigm  
 
 
 
 
 
 
 
 
 
 
 
NIAAA, NIH 
Protocol Number: HLAB-002 
 
Version 6: Date: 27Mar2020 
3 
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Confidential 
1. 
Protocol Synopsis 
Name of Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA) 
Name of Investigational Product: ANS-6637  
Name of Active Ingredient: ANS-6637  
Protocol Number: HLAB-002 
Study Title: Human Laboratory Study of ANS-6637 for Alcohol Use Disorder 
NIAAA Principal Investigator (PI): Raye Litten, Ph.D. 
Clinical Centers/PIs: Robert Miranda, Ph.D., Brown University; Stephanie O’Malley, Ph.D., Yale University; 
Joseph P. Schacht, Ph.D., Medical University of South Carolina 
Study Period: Approximately 1 year 
Phase of Development: 2 
Objectives: 
Primary: The primary objective of this study is to evaluate the effects of two different doses of ANS-6637, 
200 mg (given as 2 x 100 mg tablet) and 600 mg (given as 2 x 300 mg tablet) once a day, and matched placebo, 
on alcohol cue-elicited alcohol craving during a human laboratory paradigm after 1 week of daily dosing among 
subjects with moderate to severe alcohol use disorder (AUD) as confirmed by the Diagnostic and Statistical 
Manual of Mental Disorders – Fifth Edition (DSM-5™). 
Secondary: Secondary objectives include evaluation of ANS-6637 200 mg, ANS-6637 600 mg, and matched 
placebo on reduction of alcohol consumption, alcohol craving, cigarette smoking (among smokers) and nicotine 
use (among nicotine users), mood, sleep, alcohol use negative consequences, study retention, and safety and 
tolerability throughout the last 4 weeks of the treatment phase of the study. 
Methodology: This study is a 3-arm, double-blind, randomized, placebo-controlled, parallel group, 3-site study 
designed to assess the effects of ANS-6637 as compared with placebo on responses to in vivo alcohol cue 
exposure in the human laboratory setting. After signing informed consent, subjects will be screened for eligibility 
and have other baseline assessments. Screening is permitted over a 14-day period and most baseline assessments 
will be performed on the day of randomization. Assessments include alcohol breathalyzer test (before signing 
consent), medical history, physical examination, vital signs, electrocardiogram (ECG), drinking history by the 
timeline follow-back (TLFB) method, Clinical Institute Withdrawal Assessment for Alcohol-revised 
(CIWA-AR), prior medication use, MINI neuropsychiatric interview, urine drug test, smoking quantity frequency 
and nicotine use interview, clinical laboratory tests including chemistry, hematology, thyroid function tests, and 
medical urinalysis, craving responses during cue reactivity session, Columbia Suicide Severity Rating Scale 
(CSSR-S), drinking goal, Penn Alcohol Craving Scale (PACS), Pittsburg Sleep Quality Index (PSQI), PROMIS 
Alcohol Negative Consequences short form, Profile of Moods State (POMS), blood sample for aldehyde 
dehydrogenase 2 (ALDH2) deficiency genetic test and confirmation that subjects are treatment seeking and 
desire a reduction or cessation of drinking. Women of child-bearing potential will have a pregnancy test.  
If eligible for the study, 81 subjects will be randomized using a stratified permuted block randomization 
procedure in an approximate 1:1:1 ratio (targeting 27 subjects per group and 27 subjects per each of 3 clinical 
sites) to receive either ANS-6637 200 mg once daily, ANS-6637 600 mg once daily, or matched placebo for 5 
weeks. Clinical site will be used as the stratification variable. 
Subjects will be seen in the clinic at screening, at randomization and 5 other times during the study. A final 
follow-up telephone interview will occur 2 weeks after the end of study in-clinic visit. After the first week of 
investigational product administration at Study Week 2, subjects will undergo a cue reactivity session including 
4 individual visual analog scale (VAS) items assessing alcohol craving and 1 item assessing beverage liking. 
Other assessments during the treatment period include TLFB, clinical laboratory tests, blood for serum levels of 
study drug for determining medication compliance, vital signs, ECG, concomitant medications, CIWA-AR, 
C-SSRS, pregnancy test, male and female birth control methods, adverse events (AEs), PACS, smoking 
quantity/frequency, PSQI, and POMS. The end of study visit will include all of the weekly assessments and a 


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Protocol Number: HLAB-002 
 
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final ECG, Exit Interview, PROMIS questionnaire, and a treatment referral. 
Number of Subjects (Planned): 81 
Main Inclusion/Exclusion Criteria: Subjects will be male and female at least 21 years of age with 4 or more 
DSM-5™ symptoms of AUD (moderate to severe AUD). They must also be seeking treatment for AUD and if 
male, report drinking an average of at least 35 drinks per week or if female report drinking an average of at 
least 28 drinks per week prior to consent, and have at least 1 heavy drinking day (4 or more drinks per day for 
women/5 or more drinks per day for men) during the 7-day period prior to randomization.  
Investigational Product, Dosage and Mode of Administration: 
The target doses are 200 mg (2 x 100 mg tablets) and 600 mg (2 x 300 mg tablets) of ANS-6637 by oral 
administration once daily for 5 weeks.  
Reference Therapy, Dosage and Mode of Administration: Subjects in the placebo group will take an 
equivalent number of identically matched placebo tablets (2 per day) by oral administration once daily for 5 
weeks. 
Duration of Study: Each subject will participate in the study for up to 10 weeks, including up to 2 weeks of 
screening, 5 weeks of treatment, one end-of-study visit during the week following the last treatment dose, 
and a final telephone contact 2 weeks after completing treatment for a safety follow-up. 
Criteria for Evaluation: 
Primary: The primary efficacy endpoint is the “strength” of alcohol craving Visual Analog Scale (VAS) score 
(item 1 below) upon presentation of the first alcohol cue at Week 2 – after one week of investigational product 
treatment. 
Confirmatory secondary endpoints include the VAS scores for the other 3 VAS scales (items 2 through 4 below) 
for the first alcohol cue and the average score of the 4 VAS craving items; and the difference score (alcohol cue 
VAS score minus water cue VAS score) for all 4 of the individual VAS craving items and their average score. 
The beverage liking VAS item is also a confirmatory secondary endpoint. The 4 VAS craving items in order of 
appearance are: 
1. 
How strong is your craving to drink alcohol? - note this is the primary efficacy endpoint  
2.      Having a drink would make things just perfect.  
3. 
If I could drink alcohol now, I would drink it. 
4. 
It would be hard to turn down a drink right now. 
The beverage liking item is: How much did you like the beverage just shown to you? 
Secondary: Secondary efficacy endpoints will be analyzed over the last 4 weeks of the treatment period. 
1. 
Percentage of subjects with no heavy drinking days. A “heavy drinking day” is 4 or more drinks 
per drinking day for women and 5 or more drinks per drinking day for men. 
2. 
Percentage of subjects abstinent from alcohol. 
3. 
Percentage of subjects with at least a World Health Organization (WHO) 2-level decrease in 
alcohol consumption. 
4. 
Percentage of subjects with at least a WHO 1-level decrease in alcohol consumption. 
5. 
Percentage of days abstinent per week. 
6. 
Percentage of heavy drinking days per week. 
7. 
Percentage of very heavy drinking days per week. A “very heavy drinking day” is 8 or more drinks 
per drinking day for women and 10 or more drinks per drinking day for men. 
8. 
Weekly mean number of drinks per week. 
9. 
Weekly mean drinks per drinking day. 
10. Cigarettes smoked per week among smokers. 
11. Percentage of subjects with no nicotine use among those reporting nicotine use at baseline. 
12. Alcohol craving score (PACS). 
13. Sleep quality (PSQI) score. 
14. Profile of Mood States (POMS) score (and subscale scores). 


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15. PROMIS Alcohol Negative Consequences score. 
Safety Endpoints: Safety endpoints will be analyzed over the entire treatment and follow-up period. 
1. 
Vital signs 
2. 
Body weight 
3. 
Clinical laboratory parameters 
4. 
BAC by breathalyzer 
5. 
Urine drug tests 
6. 
AEs (included elicited AEs and AEs in subjects taking a CYP 3A4 sensitive substrate)   
7. 
ECG results 
8. 
CIWA-AR scores 
9. 
Frequency of subjects with suicidal ideation at any time during the treatment period (C-SSRS) 
10. Concomitant medication use 
11. Alcohol Craving Questionnaire – Short Form – Revised (ACQ-SF-SR) score (pre- and post-cue 
response sessions) 
Compliance: Self report of compliance with study drug self-administration is confirmed by digital photography 
(AiCure software) with investigational products and GS-548351plasma levels. GS-548351 is the active moiety of 
the prodrug ANS-6637. 
Statistical Methods (Data Analysis): 
Analysis Populations: 
Modified intention-to-treat (mITT) Analysis Set: The mITT set is defined as subjects randomized to 
participate in the study that took at least one dose of investigational product and had a non-missing VAS 
craving primary endpoint. 
Evaluable Analysis Set: The evaluable analysis set for the secondary endpoints is defined as those subjects 
randomized to the study who took at least 2 tablets per day for at least 80% of days in Weeks 1-5. 
Safety Analysis Set: The safety analysis set includes all subjects who took at least one dose of 
investigational product.  
Analysis of the Primary Efficacy Endpoint: Each subject will have an initial alcohol cue for “strength” of 
alcohol craving score from the VAS that is the primary endpoint. Analysis of covariance (ANCOVA) with the 
“strength” of alcohol craving value as the dependent variable and the pretreatment “strength’ of alcohol craving 
score from the first alcohol cue as an independent fixed effect. Clinical site will also be included as an 
independent factor. There are 3 comparisons (ANS-6637 600 mg vs placebo; ANS-6637 200 mg vs. placebo; 
and ANS-6637 600 mg vs. ANS-6637 200 mg) and Tukey’s method will be used to adjust for multiple 
comparisons. .No imputation for missing endpoint data will be performed.  
Analysis of the Secondary Endpoints: There are 3 additional questions asked during the cue session for each 
beverage cue. Each of these questions will be analyzed in the same manner as the primary endpoint. Tukey’s 
method will be used within question and not across questions. An overall mean of the 4 questions will also be 
analyzed in the same manner. The difference between the first alcohol cue and water cue for each VAS item will 
be computed at both the pre and post treatment time points. The difference values for each VAS item and the 
average difference will be analyzed similarly to the primary endpoint. Continuous secondary endpoints (percent 
heavy drinking days, percent very heavy drinking days, percent days abstinent, drinks per week, drinks per 
drinking day, number of cigarettes smoked per week, PACS, POMS, and PROMIS, and PSQI score) during the 
last 4 weeks of treatment period will be analyzed using a mixed-effects model  with site, assessment time, and 
baseline drinking as fixed factors. Models will also include time by treatment group interaction term. Additional 
covariates may be included that are significantly correlated with outcome and/or if there are differences across 
the treatment groups. 
Analysis of the dichotomous secondary endpoints (percentage subjects with no heavy drinking days, percentage 
subjects abstinent from alcohol, percentage of subjects achieving at least a one and two-level shift in WHO 
alcohol consumption, and percentage of subjects with no nicotine use among subjects with any use during the 
week before randomization) during the last 4 weeks of treatment period will be conducted via logistic 
regression. Covariates may be included provided there are a sufficient number of events.  
No imputation for missing endpoint data will be performed for secondary endpoints.  


ANS-6637 – Human Laboratory Paradigm  
 
 
 
 
 
 
 
 
 
 
 
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Safety Analyses: AEs will be coded using the most recent version of the Medical Dictionary of Regulatory 
Activities (MedDRA) preferred terms and will be grouped by system, organ, and class (SOC) designation. The 
severity, frequency, and relationship of AEs to investigational product will be presented by preferred term by 
SOC grouping. Listings of each individual AE including start date, stop date, severity, relationship, outcome, 
and duration will be provided. Each AE (based on preferred terminology) will be counted once only for a given 
study subject. If the same AE occurred on multiple occasions, the highest severity and relationship to 
investigational product will be assumed. Thus, study participants are not counted multiple times in a given 
numerator in the calculation of frequencies for a specific AE. The elicited AEs of flushing or heart rate 
increases (palpitations) will be presented as counts and frequencies over all subjects and separately over the 
subjects who reported any of these as counts and frequencies of reported events by treatment group and severity 
score for ALDH2 deficient and ALDH2 non-deficient subjects. Laboratory data, vital signs, ECG results, 
alcohol breathalyzer results, urine drug test results, and CIWA scores will be reported as summary statistics. 
The numbers and proportion of subjects who reported CIWA scores ≥ 10 at any time after the start of dosing 
will be presented. Changes in clinical laboratory tests and vital signs will also be presented as summary 
statistics of change from baseline. The number and percentage of subjects with a higher ACQ-SF-R score post 
cue session will be provided by treatment group. 
Compliance and Participation Outcomes: Medication compliance is defined as the amount of investigational 
products taken as a proportion of the total amount prescribed. Compliance will also be evaluated by 
determining the proportion of subjects who were prescribed ANS-6637, reported taking ANS-6637 (by AiCure 
assessment), and had a plasma sample with detectable GS-548351, the active moiety of ANS-6637. The 
participation rate is the percentage of subjects with complete drinking data. Compliance and participation rates 
will be reported on a weekly basis and across the entire trial duration. Compliance by GS-548351 plasma levels 
will be reported as number and percentage of subjects with a level above the limit of detection at each time 
point among subjects who were prescribed ANS-6637 and pill ingestion was confirmed by self-report or 
AiCure assessment. Descriptive statistics will also be provided. 
Baseline Descriptive Statistics: Summaries of the characteristics of the subjects in each of the study groups at 
baseline will be prepared for the mITT, evaluable, and safety analysis sets. Baseline characteristics will be 
compared between the ANS-6637 groups and placebo group using appropriate statistical methods. 
 
 


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Table of Contents 
1. 
Protocol Synopsis .................................................................................................................. 3 
2. 
List of Abbreviations and Definition of Terms ................................................................... 11 
3. 
Introduction ......................................................................................................................... 14 
3.1. 
Human Laboratory Studies ..................................................................................... 14 
3.2. 
Rationale for Studying ANS-6637 ......................................................................... 15 
3.3. 
Pharmacology of ANS-6637 .................................................................................. 16 
3.4. 
Safety of ANS-6637 ............................................................................................... 17 
3.4.1. Interactions of ANS-6637 with Alcohol .................................................... 17 
3.4.2. Heart Rate Changes in Study GS-US-272-1180 ....................................... 20 
3.4.3. Clinical Laboratory Adverse Events with ANS-6637 ............................... 20 
3.4.4. Changes in Body Weight and Appetite ..................................................... 20 
3.5. 
Comparative Results of ANS-6637 with Another ALDH2 Inhibitor (Disulfiram) 20 
3.6. 
Drug-Drug Interaction Study (SEARCHPK) ......................................................... 21 
3.7. 
Discussion of the Study Design .............................................................................. 22 
4. 
Study Objectives .................................................................................................................. 23 
4.1. 
Primary Objective ................................................................................................... 23 
4.2. 
Secondary Objectives ............................................................................................. 23 
5. 
Investigational Plan ............................................................................................................. 24 
6. 
Study Interventions .............................................................................................................. 28 
6.1. 
Investigational Products: ANS-6637 and Placebo .................................................. 28 
6.2. 
Investigational Product Storage .............................................................................. 28 
6.3. 
Investigational Product Administration .................................................................. 28 
6.4. 
Investigational Product Dispensing ........................................................................ 28 
6.5. 
Investigational Product Accountability .................................................................. 29 
6.6. 
Medication Adherence and Reminder System ....................................................... 30 
6.6.1. System Description.................................................................................... 30 
6.6.2. Subject Risk ............................................................................................... 31 
6.6.3. Subject Confidentiality .............................................................................. 31 
6.7. 
Take Control Behavioral Platform ......................................................................... 31 
6.8. 
Concomitant Medications ....................................................................................... 32 
7. 
Study Procedures ................................................................................................................. 34 
7.1. 
Recruitment of Subjects ......................................................................................... 34 
7.2. 
Informed Consent ................................................................................................... 34 
7.3. 
Selection and Withdrawal of Subjects .................................................................... 34 
7.3.1. Inclusion Criteria ....................................................................................... 34 
7.3.2. Exclusion Criteria ...................................................................................... 36 
7.4. 
Eligibility Screening Assessments ......................................................................... 39 
7.5. 
Baseline and Final Eligibility Assessments ............................................................ 40 
7.6. 
Measures Taken to Minimize/Avoid Bias .............................................................. 41 
7.6.1. Randomization (Day 1) ............................................................................. 41 
7.6.2. Blinding ..................................................................................................... 42 
7.7. 
Interventions on Week 1, Day 1 ............................................................................. 42 
7.8. 
Week 1 Telephone Contact .................................................................................... 42 
7.9. 
Treatment Period .................................................................................................... 43 
7.10. 
Telephone Assessments .......................................................................................... 43 


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Protocol Number: HLAB-002 
 
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7.11. 
Final Clinic Visit .................................................................................................... 44 
7.12. 
Telephone Follow-up ............................................................................................. 44 
7.13. 
Duration of Subject Participation ........................................................................... 44 
7.14. 
Dose-adjustment Criteria ........................................................................................ 44 
7.14.1. Safety Criteria for Dose Adjustment or Stopping Doses ........................... 44 
7.14.2. Investigational Product Dose Reduction ................................................... 44 
7.14.3. Investigational Product Discontinuation ................................................... 45 
7.15. 
Subject Withdrawal or Discontinuation Procedures ............................................... 45 
7.16. 
Situations Requiring Discontinuation from the Study as Well as from 
Investigational Product ........................................................................................... 45 
7.17. 
Study Termination Criteria ..................................................................................... 46 
8. 
Study Endpoints................................................................................................................... 47 
8.1. 
Efficacy Endpoints ................................................................................................. 47 
8.1.1. Primary Efficacy Endpoint ........................................................................ 47 
8.1.2. Secondary Efficacy Endpoints .................................................................. 47 
8.2. 
Safety Endpoints ..................................................................................................... 48 
8.3. 
Compliance ............................................................................................................. 48 
9. 
Safety Monitoring Plan ........................................................................................................ 49 
10. 
Assessment Methods ........................................................................................................... 50 
10.1. 
Alcohol Breathalyzer .............................................................................................. 50 
10.2. 
Adverse Events and Serious Adverse Events ......................................................... 50 
10.2.1. Adverse Event Definition .......................................................................... 50 
10.2.2. Serious Adverse Events and Serious Unexpected Adverse Events 
Definition .................................................................................................. 50 
10.2.3. Methods/Timing for Assessing, Recording, and Analyzing Safety 
Endpoints ................................................................................................... 51 
10.2.4. Elicited Adverse Events ............................................................................ 51 
10.2.5. Classification of Adverse Event Severity and Relationship to 
Investigational Product .............................................................................. 52 
10.2.6. Outcomes and Actions Taken .................................................................... 53 
10.2.7. Reporting Serious Adverse Events ............................................................ 54 
10.2.7.1. 
24 hour Reporting Requirements (Initial Report) .................. 54 
10.2.7.2. 
Reporting to the IRB .............................................................. 55 
10.3. 
ALDH2 Genetic Test .............................................................................................. 55 
10.4. 
Alcohol Craving Scale – Short Form – Revised (ACQ-SF-R) ............................... 55 
10.5. 
Birth Control Record .............................................................................................. 55 
10.6. 
Brief Drinking Questionnaire ................................................................................. 55 
10.7. 
Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-AR) ........ 56 
10.8. 
Clinical Laboratory Tests ....................................................................................... 56 
10.8.1. Chemistry Tests ......................................................................................... 56 
10.8.2. Hematology Tests ...................................................................................... 56 
10.8.3. Thyroid Panel ............................................................................................ 57 
10.8.4. Medical Urinalysis .................................................................................... 57 
10.8.5. Pregnancy Test .......................................................................................... 57 
10.9. 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................................... 57 
10.10. Cigarette Smoking Quantity-Frequency and Nicotine Use Questionnaire ............. 57 
10.11. Cue Reactivity Sessions ......................................................................................... 58 
10.11.1. Screening Session ...................................................................................... 58 


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10.11.2. During Treatment Session ......................................................................... 58 
10.12. Demographics ......................................................................................................... 60 
10.13. Drinking Goal ......................................................................................................... 60 
10.14. ECG ........................................................................................................................ 61 
10.15. Eligibility Checklist ................................................................................................ 61 
10.16. Exit Interview ......................................................................................................... 61 
10.17. GS-548351 Plasma Levels ..................................................................................... 61 
10.18. Locator Form .......................................................................................................... 62 
10.19. Medical History ...................................................................................................... 62 
10.20. MINI ....................................................................................................................... 62 
10.21. Penn Alcohol Craving Scale ................................................................................... 62 
10.22. Pittsburg Sleep Quality Index ................................................................................. 62 
10.23. PROMIS Alcohol Negative Consequences ............................................................ 63 
10.24. Prior and Concomitant Medications ....................................................................... 63 
10.25. Profile of Mood State ............................................................................................. 63 
10.26. Physical Examination and Weight .......................................................................... 63 
10.27. Subject Disposition ................................................................................................. 64 
10.28. TLFB Interview ...................................................................................................... 64 
10.29. Urine Drug Test ...................................................................................................... 65 
10.30. Vital Signs .............................................................................................................. 65 
10.31. World Health Organization Drinking Risk Categorical Scale ................................ 66 
11. 
Statistical Methods and Determination of Sample Size ...................................................... 67 
11.1. 
Statistical Hypotheses ............................................................................................. 67 
11.2. 
Analysis Populations .............................................................................................. 68 
11.3. 
General Approach ................................................................................................... 68 
11.4. 
Analysis Addressing the Primary Efficacy Endpoint ............................................. 68 
11.5. 
Secondary Efficacy Endpoints Analysis................................................................. 69 
11.6. 
Safety Outcomes ..................................................................................................... 69 
11.7. 
Baseline Descriptive Statistics ............................................................................... 70 
11.8. 
Compliance and Participation Outcomes ................................................................ 70 
11.9. 
Exploratory Endpoints ............................................................................................ 70 
11.10. Sample Size Justification ........................................................................................ 70 
12. 
Quality Control and Quality Assurance ............................................................................... 71 
12.1. 
Study Monitoring ................................................................................................... 71 
12.2. 
Audits and Inspections ........................................................................................... 71 
13. 
Ethics ................................................................................................................................... 72 
13.1. 
Central Institutional Review Board ........................................................................ 72 
13.2. 
Review/Approval of Study Protocol ...................................................................... 72 
13.2.1. Protocol Modifications .............................................................................. 72 
13.2.2. Protocol Deviation Reporting Procedures ................................................. 72 
13.3. 
Ethical Conduct of the Study .................................................................................. 72 
13.3.1. Confidentiality ........................................................................................... 73 
13.3.1.1. 
Confidentiality of Data .......................................................... 73 
13.3.1.2. 
Confidentiality of Subject Records ........................................ 73 
13.3.2. Compensation for Participation ................................................................. 73 
13.3.3. Written Informed Consent ......................................................................... 73 
13.3.4. Delegation of Responsibilities and Adequate Resources .......................... 74 
13.3.5. Financial Disclosure .................................................................................. 74 


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14. 
Data Handling and Record Keeping .................................................................................... 75 
14.1. 
Subject Identification and Confidentiality .............................................................. 75 
14.2. 
Inspection of Records ............................................................................................. 75 
14.3. 
Retention of Records .............................................................................................. 76 
14.4. 
Trial Registration .................................................................................................... 76 
15. 
Publication Policy ................................................................................................................ 77 
16. 
Protocol Signature Page ...................................................................................................... 78 
17. 
References ........................................................................................................................... 79 
 
List of Tables 
Table 1: 
List of Abbreviations and Definition of Terms ................................................................... 11 
Table 2: 
Pharmacokinetics of GS-548351 after Single and Multiple Doses in Healthy Subjects 
(Study GS-US-272-0101) .................................................................................................... 17 
Table 3: 
Schedule of Assessments ..................................................................................................... 25 
Table 4: 
Investigational Product Dispensing Plan ............................................................................. 29 
Table 5: 
Schedule of Events for Cue Reactivity Session During Treatment ..................................... 59 
Table 6: 
Standard Drink Unit Definitions.......................................................................................... 65 
 
List of Figures 
Figure 1: 
Mean (SE) Heart Rate Values over Time after Ethanol Administration by ANS-6637 
Treatment ............................................................................................................................. 19 
 


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2. 
List of Abbreviations and Definition of Terms 
Table 1: 
List of Abbreviations and Definition of Terms 
Abbreviation 
Definition 
4-HNE 
4-hydroxy-2E-nonel 
ACQ-SF-R 
Alcohol Craving Questionnaire – Short Form – Revised 
AE 
adverse event 
ALDH2 
aldehyde dehydrogenase 2 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUD 
Alcohol Use Disorder 
BAC 
blood alcohol concentration 
CAP 
College of American Pathologists 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Act 
CIWA-AR 
Clinical Institute Withdrawal Assessment for Alcohol-revised 
CrCl 
creatinine clearance 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
common terminology criteria for adverse events 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DA 
dopamine 
dL 
deciliter 
DOPAL 
dopamine aldehyde 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDTA 
ethylenediaminetetraacetic acid 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EtG 
ethylglucuronide 
EtOH 
ethanol 
FDA 
Food and Drug Administration 
g 
gram 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HIPAA 
Health Insurance Portability Accountability Act 


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Abbreviation 
Definition 
hr 
hour 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
L 
liter 
LS 
least squares 
MAOI 
monoamine oxidase inhibitors 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
μg 
microgram 
 MDMA 
       3,4-methylenedioxy-methamphetamine 
min 
minutes 
MINI 
MINI Neuropsychiatric Interview 
mITT 
modified intention-to-treat 
mL 
milliliter 
mm 
millimeter 
NIAAA 
National Institutes on Alcohol Abuse and Alcoholism 
OTC 
over-the-counter 
oz 
ounce 
PACS 
Penn Alcohol Craving Scale 
PI 
principal investigator 
PK 
pharmacokinetic 
POMS 
Profile of Moods State 
PSQI 
Pittsburg Sleep Quality Index 
PT 
preferred term 
pTH 
tyrosine hydroxylase 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SE 
standard error 
SER 
severe ethanol reaction 
SD 
standard deviation 
SDU 
standard drinking unit 
SOC 
System, organ, class 
SNRI 
serotonin-norepinephrine reuptake inhibitors 
SSRI 
selective serotonin reuptake inhibitors 
t½ 
half-life 
TEAE 
treatment emergent adverse events 
T3 
triiodothyronine 
T4 
thyroxine 
THC 
tetrahydrocannabinol 
THP 
tetrahydropapaveroline 
TLFB 
timeline followback 
Tmax 
time to maximum plasma concentration 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 


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Abbreviation 
Definition 
US 
United States 
VAS 
visual analog scale 
VTA 
ventral tegmental area 
WHO 
World Health Organization 


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3. 
Introduction 
Alcohol use disorder (AUD) (alcohol dependence and abuse) affects 76 million adults 
world-wide, including 18 million Americans, and is responsible for a myriad of medical, 
psychological, social, economic and personal problems (Litten-2012). Tragically, more than 
2.5 million individuals including 80,000 Americans die each year from alcohol-related events. 
The total economic cost to society is a staggering $224 billion each year in the United States 
(US) (NIAAA-2014). 
3.1. 
Human Laboratory Studies 
Human laboratory studies of acute responses to alcohol, alcohol cues, or other pharmacological 
and/or experimental manipulations have progressed in important ways, and have the potential to 
greatly advance our understanding neurobehavioral mechanisms of alcohol effects on behavior 
(Plebani-2014). These studies may help identify important individual difference factors affecting 
alcohol response, such as personal traits, drinking characteristics, and genotype, and aid in our 
understanding of the variability in cue and craving states, and provide additional information 
relevant to the design of clinical studies to assess the effectiveness of pharmacological agents. 
The study to be conducted in this protocol utilizes an alcohol cue reactivity model to attempt to 
recreate in the laboratory risk conditions for relapse similar to those experienced by alcoholics in 
their natural environment (Niaura-1988; Litt-1999). 
Human laboratory studies have been conducted that examine the effect of positive and negative 
affective stimuli and beverage cues on craving in non-treatment-seeking subjects with alcohol 
dependence. In a study reported by Mason (2008), the moderating effects of a priming exposure 
to both positive and negative affective stimuli on beverage cue-induced craving were examined. 
Subjects were exposed to a standardized set of pleasant, neutral, or unpleasant visual stimuli 
followed by alcohol or water cues and psychophysiological cue reactivity measures were 
obtained during beverage presentation and subjective reactivity measures were taken following 
beverage presentation. Psychophysiological measures included heart rate, skin conductance, and 
facial electromyogram which were monitored throughout each experimental trial as confirmatory 
measures of the primary subjective measures of craving and emotion. Alcohol craving in 
response to each affect-beverage condition was assessed using 4 individual Visual Analog Scales 
(VAS). In addition, the Self-Assessment Manikin (Bradley-1994) was utilized as a non-verbal 
pictorial assessment technique to measure emotional reactivity (valence, arousal, and dominance) 
associated with a person's affective reaction to stimuli. 
Results of mixed-effect analyses of subjective outcome measures in the Mason (2008) study 
showed statistically significant main effects of alcoholic beverage cue on three of four individual 
craving questions, and on the mean of the four items. The effect size for alcoholic beverage cue 
on subjective craving measures ranged from 0.58 (strength of craving), to 0.22 (difficult to turn 
down); the composite effect size was 0.45. Positive affect independent of beverage cue 
significantly increased craving strength and showed a trend for a significant increase in the 
composite craving scale. Effect sizes for positive affect ranged from 0.55 (difficult to turn down) 
to nearly zero (make things perfect). For negative affect, the largest effect size was 0.18 (strength 
of craving), and none of the effects of negative affective stimuli on measure of craving were 


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statistically significant. No interaction effects were detected between alcoholic beverage cue and 
affective stimuli on any outcome measure of craving. An important finding of this study is that 
positive affective stimuli commonly associated with drinking situations can induce craving in the 
absence of alcohol cues. 
Another human laboratory proof-of-concept study was conducted by Mason (2009) to evaluate 
the effectiveness of gabapentin to attenuate some of the symptoms of protracted abstinence from 
alcohol. The laboratory study design was intended to model and predict the critical first week on 
medication during a clinical trial, when participants’ sleep and mood disturbances, or other side 
effects, could dramatically affect medication compliance and increase the risk for subject 
discontinuation. The experimental design mirrored the human lab study model where positive 
affective stimuli induced induce craving (Mason-2008). This study design employed a 4-hour 
cue reactivity protocol which included a baseline evaluation, followed by the cue reactivity 
procedures, and subsequent debriefing. As in the previous human lab study, 3 affective stimuli 
(positive, neutral, negative) and 2 beverage cues (alcohol and water) were deployed within-
subjects, in a block-factorial design of 6 repeated measures. All six mood-beverage cue 
combinations were presented to each subject (with order varying systematically across subjects) 
during the course of a single afternoon. Alcohol craving was assessed using four separate VAS 
measurements and psychophysiological measures of heart rate, skin conductance, and 
electromyogram were recorded. 
This study results showed that subjects randomized to receive gabapentin had significantly 
attenuated craving responses to three of the four subjective craving measures (how strong is your 
urge to drink, I would drink now if I could, it would be difficult to turn down a drink now) 
Mason (2009). In contrast, gabapentin reduced arousal induced by all three types of cues 
(beverage, positive affect, and negative affect) as measured by SAM emotional reactions. Given 
that subjects randomized to receive gabapentin had reduced alcohol craving, and analysis of the 
secondary study endpoints demonstrated significantly improved measures of sleep quality, the 
hypothesis was supported that gabapentin may be effective for treating the protracted abstinence 
phase in alcohol dependence. 
3.2. 
Rationale for Studying ANS-6637 
Alcohol has been shown to stimulate an increase in dopamine (DA) levels predominately in the 
nucleus accumbens, which is believed to play a central role in the reward or reinforcement 
process in the brain (Di Chiara-1988, Boileau-2003, Tizabi-2002). Aldehyde 
dehydrogenase 2 (ALDH2) inhibition has been shown to attenuate the alcohol-induced surge in 
DA, without affecting basal levels of DA, prevent operant self-administration of alcohol, and 
eliminate cue-induced reinstatement of alcohol seeking even when alcohol is not available 
(Arolfo-2006). To further demonstrate a central effect of ALDH2 inhibition on alcohol seeking 
behavior, ALDH2 antisense injected into the ventral tegmental area (VTA) of inbred alcohol 
preferring (iP) rats was shown to decrease alcohol drinking in a time course that correlates with 
the expression of antisense. These observations suggest that ANS-6637 inhibiting ALDH2 in the 
VTA appears to attenuate alcohol seeking behavior and support the hypothesis that 
administration of selective, reversible inhibitor of ALDH2 may be of therapeutic potential in 
reducing the rewarding effects of ethanol.  


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3.3. 
Pharmacology of ANS-6637 
ANS-6637 is the orally bioavailable prodrug of the selective, potent, reversible inhibitor of 
ALDH2, GS-548351 is being developed by Amygdala Neurosciences. Nonclinical studies have 
demonstrated that selective reversible ALDH2 inhibitors, such as GS-455534 (a.k.a. 
CVT-10216), can reduce consumption of alcohol (Arolfo-2009, Feltenstein-2008), cocaine, 
nicotine, heroin, and methamphetamine, and abnormal cravings for carbohydrate and fatty acids 
in animal models. ALDH2 inhibition during drug or cue stimulated activation of DA synthesis, 
which leads to drug seeking behavior, is thought to restore DA homeostasis and attenuate 
craving (Arolfo-2009, Yao-2010). Importantly, inhibition of ALDH2 only interferes with 
addictive drug-stimulated increases in DA signaling and does not change basal levels of DA in 
vitro (Yao-2010) and in an animal model of binge eating (Bocarsly-2014). It is believed that 
ALDH2 inhibition interferes with the metabolic clearance of dopamine aldehyde (DOPAL) 
allowing for DOPAL to condense with DA to form tetrahydropapaveroline (THP). THP is a 
selective inhibitor of activated phosphorylated tyrosine hydroxylase (p-TH), which is the 
rate-limiting step in DA synthesis. In a rat model of alcohol self-administration exposure to an 
ALDH2 inhibitor did not affect baseline levels of dopamine since THP does not inhibit activities 
of other enzymes involved in DA metabolism, but rather a targeted suppression of dopaminergic 
surges (Feltenstein-2008; Diamond-2015). The initial Phase 1 trial demonstrated that single and 
multiple doses ANS-6637 (100 mg, 300 mg, 600 mg, and 900 mg) was well-tolerated with only 
mild AEs. The Phase 1b study, completed in 2017 (NCT03203499), showed that ANS-6637 
(25 mg, 50 mg, 100 mg, 200 mg, 400 mg, and 600 mg) was safe and well-tolerated even during 
excessive alcohol drinking, demonstrating that ALDH2 inhibition with oral ANS-6637 is suitable 
even for patients with comorbid alcohol use. 
Plasma pharmacokinetic (PK) parameters of the active metabolite GS-548351 for single and 
multiple oral doses of ANS-6637 (300 and 600 mg) are shown in Table 2. When ANS-6637 was 
administered as single ascending doses in the fasted state, GS-548351 exhibited approximately 
dose-proportional PK over the dose range of 100 to 600 mg and less than dose proportional PK 
over the dose range of 600 to 900 mg. The median GS-548351 tmax ranged from 2.00 to 3.01 
hours after dosing and demonstrated low intersubject variability in PK parameters[(<30% 
coefficient of variation (CV)]. The median terminal half-life (t½) of GS-548351 ranged from 
16.49 to 19.48 hours. The PK parameters following a single dose of ANS-6637 at 100 mg in 
smokers (data available in the Investigators Brochure) and nonsmokers were comparable.  
Mean steady-state PK parameters of GS-548351 following once per day dosing of ANS-6637 
(300 and 600 mg/day) under fasted conditions for 10 days are presented in Table 2. Median 
plasma t½ values ranged from 16.41 to 19.24 hours, which were comparable with median values 
observed after single doses. Upon multiple dosing of ANS-6637, GS-548351 exhibited slightly 
less than dose-proportional PK (Cmax and AUC(0-tau)). GS-548351 plasma concentrations 
accumulated upon multiple dosing in accordance with its half-life and dosing interval at a dose 
of ANS-6637 of 300 mg once daily. However, at the 600 mg once daily dose levels, there was 
less accumulation of GS-548351 from Days 1 to 10 of dosing compared with the lower dose 
level.  
Plasma concentrations of GS-548351 following administration of ANS-6637 as a single, 300-mg 
oral dose under fed (high-fat meal; test treatment) or fasted (reference treatment) conditions in 


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healthy nonsmokers was determined. There was a slight decrease in Cmax (23%) when ANS-6637 
was administered in the fed state (high-fat meal) as compared with the fasted state, but 
GS-548351 exposure (AUC0-inf) was comparable (7% decrease) in the fed state as compared with 
the fasted state. The slight decrease in Cmax in the fed state is unlikely to be clinically relevant. 
Table 2: 
Pharmacokinetics of GS-548351 after Single and Multiple Doses in Healthy 
Subjects (Study GS-US-272-0101) 
 
Single Dose  
ANS-6637 
Multiple Dose ANS-6637 after 10 
days of once daily dosing 
GS-548351 Mean (CV)a 
PK Parameter 
300 mg  
(N = 6) 
600 mg  
(N = 6) 
300 mg QDb  
(N = 5) 
600 mg QD  
(N = 5) 
Cmax (ng/mL)  
5756.7  
(28.6) 
13,433.3  
(13.9) 
7534.0  
(20.4) 
13,080.0  
(12.4) 
Tmax (h) 
2.00  
(2.00, 3.05) 
2.00  
(2.00, 3.00) 
1.50 (1.50, 3.00) 
2.00  
(2.00, 4.00) 
t1/2 (h) 
17.43  
(16.04, 19.07) 
18.12  
(17.32, 18.57) 
17.65 (16.70, 
18.25) 
16.87  
(16.77, 17.46) 
AUC0-last (h•ng/mL)  
90,688.0 
(24.8) 
184,251.0  
(21.1) 
 
 
AUC0-inf (h•ng/mL)c  
106,699.8 
(27.6) 
211,984.2  
(24.2) 
 
 
AUC(0-tau) (h•ng/mL) 
 
 
85,038.0 (16.2) 
141,653.2 (17.9) 
a CV= coefficient of variation 
b Once daily. 
c AUC=area under the concentration curve. 
3.4. 
Safety of ANS-6637 
ALDH2 is the second enzyme of the major oxidative pathway of alcohol metabolism that 
converts acetaldehyde to acetic acid. Since it is known that ALDH2 deficiency may lead to 
increases in plasma acetaldehyde (see for example Bae-2012) levels, it was important to 
demonstrate the safety of ANS-6637 when given in combination with ethanol. 
3.4.1. 
Interactions of ANS-6637 with Alcohol  
A Phase 1b a single-center, randomized, double-blind, placebo-controlled, single-ascending-dose 
cohort study to evaluate the safety and tolerability of the co-administration of up to 6 dose levels 
of ANS-6637 and ethanol in 48 healthy male alcohol drinkers (Study ANS-A-C1-001). Dose 
levels included doses of 25 mg, 50 mg, 100 mg, 200 mg, 400 mg and 600 mg. Study drug 
administration occurred approximately 1 hour following ingestion of a standardized (moderate 
fat) meal. Approximately 2 hours after receiving the study drug, subjects began a session of 
repeat ethanol administration, during which they received up to 5 doses of ethanol (14 g each) 
every 30 minutes, or until a stopping criterion applied. 
In general, all treatments were well tolerated in this study. There were no deaths or serious 
adverse events (SAEs) and no subject was discontinued due to an AE. Two (5.6%) subjects did 
not consume all 5 ethanol administrations due to treatment emergent adverse events (TEAE). 


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The majority of TEAEs were mild in severity (152 [92.7%] events); 1 (0.6%) severe TEAE was 
experienced by a subject administered ANS-6637 100 mg. The majority of TEAEs were judged 
to be related to study drug (i.e., ANS-6637 or ethanol) in both ANS-6637–treated (118 [88.7%] 
events) and placebo-treated (19 [61.3%] events) groups. The most commonly reported TEAEs 
(≥20%) were flushing, headache, feeling hot, and feeling drunk. The incidence of flushing and 
feeling hot was higher following administration of ANS-6637, while that of feeling drunk was 
higher following placebo; the incidence of headache was reported at a similar incidence with 
ANS-6637 and placebo. In general, there was no clear dose response for the most common 
TEAEs; however, flushing, headache and feeling drunk appeared to increase with increasing 
dose of ANS-6637, though feeling drunk was reported for only a small number of subjects. 
All mean laboratory values were within normal ranges at baseline and follow-up, with the 
exception of an abnormal non-clinically significant increase in mean creatine kinase at follow-up 
in the ANS-6637 100 mg dose group, primarily driven by 1 subject who had an abnormal, but 
not clinically significant creatine kinase value of 1350 U/L (repeat 3 days later: 583 U/L). There 
were no TEAEs related to laboratory values. 
Mean vital signs values were within normal ranges at the time points tested. Administration of 
ANS-6637 doses >25 mg resulted in increases in mean heart rate on Day 1 beginning 15 minutes 
after first ethanol administration; greater increases in heart rate were observed for higher 
ANS-6637 doses (i.e., 200 mg, 400 mg and 600 mg). Statistically significant increases in heart 
rate for ANS-6637–treated subjects compared with placebo-treated subjects began at 45 minutes 
after first ethanol administration until the last measured time point (135 minutes after first 
ethanol administration). The range of statistically significant differences from placebo was 
+15.3 to +35.9 beats per minute for ANS-6637 200 mg through 600 mg, and +14.7 to +19.4 
beats per minute for ANS-6637 50 mg and 100 mg. Heart rates remained below the stopping 
criteria of 160 bpm (specifically agreed to by FDA) during the entire 5-drink alcohol challenge 
and generally plateaued after the third alcohol challenge. One subject (at 200 mg) registered a 
heart rate of 129 bpm. Increases in heart rate were commonly not associated with staff prompted, 
subject reported ‘palpitations’. There were no significant changes in diastolic or systolic blood 
pressure. The time course for heart rate increases is shown in Figure 1. 


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Figure 1: 
Mean (SE) Heart Rate Values over Time after Ethanol Administration by 
ANS-6637 Treatment 
 
Five TEAEs of tachycardia were reported: 1 subject who received ANS-6637 50 mg had 
tachyarrhythmia, 3 subjects who received ANS-6637 200 mg had sinus tachycardia, and 
1 subject who received ANS-6637 200 mg had tachycardia. All TEAEs began after consuming 
ethanol. The TEAEs were judged to be mild in severity and at least possibly related to study drug 
(i.e., ANS-6637 or ethanol). One subject in the ANS-6637 200 mg group also experienced a 
TEAE of tachypnea after consuming ethanol that was judged to be mild and possibly related to 
study drug (i.e., ANS-6637 or ethanol). Mean electrocardiogram (ECG) interval measures were 
similar between baseline and follow-up and there were no TEAEs related to ECG values. 
A number of clinically significant findings related to general appearance on physical 
examinations were reported, the majority of which were related to flushing observed on Day 1. 
On the ethanol response subjective assessment, ANS-6637-treated subjects were more likely to 
report feeling heat sensation and feeling palpitations compared with placebo-treated subjects. 
Only a small number of subjects reported feeling breathless or headache, but these were also 
more commonly reported among ANS-6637-treated subjects. There were no differences between 
placebo- and ANS-6637-treated subjects on the nausea or vomiting subscales. There was no 
notable GS-548351 exposure-ethanol response relationship. Flushing was not observed in any 
subjects who received ANS-6637 25 mg. Flushing was observed for all other ANS-6637 doses 
and placebo, with the most reports of severe flushing observed between 45 minutes and 
135 minutes after the first ethanol administration, corresponding to between 2 and 5 drinks 
consumed. Flushing was observed in far fewer subjects following placebo than with ANS-6637. 


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3.4.2. 
Heart Rate Changes in Study GS-US-272-1180 
Study GS-US-272-1180 preceded the Phase 1b study and was a Phase 1, fixed-sequence, 
double-blind, placebo-controlled study, which evaluated the potential for a pharmacodynamic 
interaction upon co-administration of ANS-6637 and ethanol in healthy adult subjects. The only 
subject who received both ANS-6637 200 mg and ethanol 0.25 g/kg developed a 
protocol-defined severe ethanol reaction (SER) within 10 minutes of the start of ethanol 
consumption. This reaction was characterized by a maximum increase in heart rate of 65 bpm 
above baseline, with a heart rate of 80 and 145 bpm pre- and post-dose, respectively. AEs that 
occurred after ANS-6637 and ethanol co-administration included the following: mild feeling 
cold (reported as in the abdomen), feeling hot (reported as in the back and left arm and also in 
general), non-cardiac chest pain, oropharyngeal pain, paresthesia (reported as of the hands), 
decreased appetite, and asthenia; moderate AEs of flushing (reported as of the face and neck), 
palpitations, anxiety, tachycardia, dizziness, nausea, dyspnea, and headache (reported as 
temporal); and severe AEs of postural dizziness and presyncope. The AEs that occurred after 
ANS-6637 and ethanol coadministration began as early as 9 minutes after ingestion of ethanol 
(flushing [face]) and up to approximately 2 hours after ethanol ingestion (feeling hot [back]), 
with the exception of decreased appetite and headache. The decreased appetite was reported 
approximately 10 hours after the start of ethanol consumption on Day 4 and headache was 
reported 1 day later. The AEs associated with the SER resolved without sequelae. Intravenous 
fluids were administered approximately 2 hours after ingestion of ethanol to treat the pre-
syncopal episode. 
3.4.3. 
Clinical Laboratory Adverse Events with ANS-6637 
In Study GS-US-272-0101, one subject, a nonsmoker who received ANS-6637, had SAEs 
[hyperbilirubinemia and abnormal alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), and alkaline phosphatase (ALP)], which were assessed by the investigator as mild in 
severity and related to study drug. These laboratory findings were observed on Day 21, 11 days 
after completing study drug, and resolved by Day 68. Therefore, levels of ALT, AST, ALP, and 
total bilirubin will be monitored in study subjects in this study. Transient abnormal laboratory 
test results for thyroid stimulating hormone (TSH) and free T4 were observed in some subjects, 
the clinical importance of which is currently unknown. A thyroid panel is included in this study 
to monitor for changes in thyroid hormone levels. No other patterns of laboratory abnormalities 
indicating a relationship to study drug or dose were observed across cohorts.  
3.4.4. 
Changes in Body Weight and Appetite 
In repeat dose non-clinical studies in male and female rats, daily oral administration of 
ANS-6637 to at a dose of 1,000 mg/kg/day for 4 weeks or at doses of 1,000/600 mg/kg/day for 
13 weeks produced decreases in body weight gain and food consumption. Therefore, body 
weights will be monitored weekly in this study and subjects will be queried about appetite 
changes. 
3.5. 
Comparative Results of ANS-6637 with Another ALDH2 Inhibitor (Disulfiram) 
The results of Study ANS-A-C1-001 are in contrast to results reported with disulfiram, a 
non-selective, irreversible, ALDH2 inhibitor and the slight reduction in diastolic blood pressure 


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observed in heterozygous carriers of the ALDH2*2 polymorphism after alcohol consumption 
(Roache-2011, Bae-2012). The combination of disulfiram with alcohol resulted in increased 
heart rate (to over 120 bpm), reductions in diastolic blood pressure (to below 50 mm Hg) and a 
significant QT interval prolongation (Roache-2011). The reported adverse reactions to disulfiram 
with alcohol have been attributed to acetaldehyde accumulation due to ALDH2 inhibition; 
however, the precise mechanism for these effects has not been determined. Disulfiram and its 
major metabolite diethylthiocarbonate (Johansson-1991, Koppaka-2012) are nonspecific 
irreversible inhibitors of ALDH1 (Koppaka-2012) and ALDH1B1 (Stagos-2010) and are widely 
toxic (Mathieu-2015). Indeed, disulfiram is a more potent inhibitor of ALDH1 than ALDH2, 
resulting in the accumulation of known toxic substrates, e.g. 4-hydroxy-2E-nonel (4-HNE), 
which may synergize with acetaldehyde to produce severe adverse reactions. 4-HNE is largely 
metabolized by ALDH1B1, not ALDH2 (Stagos-2010). Therefore, we do not anticipate increases 
in 4-HNE in the presence of ANS-6637 due to its selectivity for inhibition of ALDH2.  
The physiological effects of ethanol ingestion in healthy male carriers of the mutant ALDH2 
genotype (Bae-2012), which results in ALDH2 deficiency, were similar to that observed with 
oral ANS-6637 in combination with alcohol (that is an increase in heart rate and mild to 
moderate flushing) (Study ANS-A-C1-001). However, oral ANS-6637 in combination with 
alcohol showed no change in blood pressure in contrast to a slightly greater reduction of diastolic 
blood pressure in mutant ALDH2 genotype carriers at the highest dose of alcohol tested (mean 
decrease of 14 mmHg from baseline), which was greater than the change observed in wildtype 
ALDH2 genotype carriers (mean decrease of 9 mmHg) (Bae-2012). 
3.6. 
Drug-Drug Interaction Study (SEARCHPK) 
The effect of oral ANS-6637 on CYP3A4 metabolic activity was evaluated in healthy volunteers 
by studying the pharmacokinetics of midazolam, a CYP3A4 sensitive substrate (SEARCH PK). 
This open label, fixed sequence intra-subject drug-drug interaction study was designed to 
evaluate the effect of oral ANS-6637 at steady state (600 mg once daily for 5 days) on single 
dose pharmacokinetics of midazolam and its metabolite 1′-hydroxymidazolam, in healthy male 
and female volunteers (N=12). A clinically relevant effect was pre-specified to be if the 90% 
confidence interval (CI) for the geometric mean ratio area under the curve time 0-infinity (AUC0-
inf) was outside of the boundary of 70-143%. Preliminary pharmacokinetic results indicate that 
the AUC0-inf of midazolam and 1′-hydroxymidazolam in combination with oral ANS-6637 
compared to midazolam alone are within the 70-143% pre-specified boundary, indicating there 
was no clinically meaningful effect of steady state oral ANS-6637 on overall exposure to 
midazolam.  
In SEARCH PK, there were no deaths or SAEs, no subject was discontinued due to a treatment 
related adverse event and no subject received a concomitant medication to treat an AE. All 
subjects reported at least one AE, the majority of which were mild in severity and considered to 
be related to a study drug (ANS-6637 or MDZ). The most common AE was fatigue that occurred 
following midazolam administration, which is expected based on the known pharmacology of 
midazolam.  
In one subject on the last day of oral ANS-6637 dosing, the same day midazolam was 
administered, ALT was elevated (94 IU/L). The following day after the last dose of oral ANS-


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6637 and midazolam ALT value increased to 193 IU/L. At a physician follow-up visit 4 and 15 
days later, the ALT value had decreased to 79 IU/L and 41 IU/L, respectively. The AE was 
judged to be severe and probably related to ANS-6637 and possibly related to midazolam. 
All other mean clinical laboratory values were within normal ranges over time, with the 
exception of serum creatinine on the fifth and final day of oral ANS-6637 administration and 24-
hrs after last dose of ANS-6637 resulting in decreases in calculated estimated glomerular 
filtration rate (eGFR). In five of 12 subjects, eGFR was calculated to be <90 mL/min/1.73m2 
(moderate severity). In these 5 subjects, the average increase in serum creatinine from baseline 
was 0.1 mg/dL and average decrease in eGFR was 6 mL/min/1.73m2. Urinalysis was without 
evidence of hematuria, leukocyturia, casts, or other signs of renal tubular damage. 
In four of the five subjects with moderate decrease in eGFR serum creatinine was not increased 
above the normal range (0.67-1.17 mg/dL).  In one subject, with a pre-dose serum creatinine of 
1.08 mg/dL (eGFR = 92 mL/min/1.73m2), the serum creatinine was 1.35 mg/dL (eGFR = 69 
mL/min/1.73m2) on the fifth and final day of oral ANS-6637 administration and was 1.34 mg/dL 
(eGFR = 70 mL/min/1.73m2) 24-hrs after last dose of ANS-6637. At last study visit (7 days after 
the last dose of ANS-6637) the serum creatinine (1.08 mg/dL, eGFR = 91 mL/min/1.73m2) was 
the same as baseline level. The subject had dry mucous membranes on physical examination, and 
urinalysis was unremarkable. 
3.7. 
Discussion of the Study Design 
The current study design uses paired evaluation of 2 beverage cues (water and alcohol). The 
difference between the cues on a single question of “strength” of craving from a VAS is the 
primary response. The average response within treatment group is compared using t-tests. This 
design has been utilized in other studies evaluating diminution of alcohol craving by candidate 
drugs being developed for AUD. 
To verify a safe return to a baseline state following the cue exposure trials, the Alcohol Craving 
Questionnaire short form revised (ACQ-SF-R) (Singleton-1994) will be administered both prior 
to and following the cue reactivity procedure to ensure that the trials had not resulted in a 
prolonged subjective urge to drink. 
The 4-week treatment period starting with the first visit of Week 2  and ending with the final 
assessments at the beginning of Week 6 is designed to obtain a preliminary assessment of the 
effects of ANS-6637 on drinking patterns, and other secondary endpoints including sleep, 
cigarette smoking and other nicotine use, craving, withdrawal, mood indicative of an effect on 
efficacy (reduction in drinking, reduction in craving, reduction in nicotine products use, 
improvement in sleep, and improvement in mood problems) and safety. 
Other safety assessments, clinical laboratory measurements, vital signs, ECG, elicited adverse 
events, body weight and appetite changes are consistent with prior non-clinical and clinical study 
findings. 


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4. 
Study Objectives 
4.1. 
Primary Objective 
The primary objective of this study is to evaluate the effects of two different doses of ANS-6637, 
200 mg (given as 2 x 100 mg tablet) and 600 mg (given as 2 x 300 mg tablet) once a day, and 
matched placebo, on alcohol cue-elicited alcohol craving during a human laboratory paradigm 
after 1 week of daily dosing among subjects with moderate to severe alcohol use disorder (AUD) 
as confirmed by the Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
(DSM-5™). 
4.2. 
Secondary Objectives 
Secondary objectives include evaluation of ANS-6637 200 mg once-daily, ANS-6637 600 mg 
once daily, and matched placebo on reduction of alcohol consumption, alcohol craving weekly 
(PACS), cigarette smoking (among smokers), nicotine use (among nicotine users), mood, sleep, 
study retention, alcohol negative consequences, and safety and tolerability throughout the last 4 
weeks of the treatment period. 
 


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5. 
Investigational Plan 
This is a 3-arm, double-blind, randomized, placebo-controlled, parallel group, 3-site study 
designed to assess the effects of ANS-6637 as compared with placebo on responses to in vivo 
alcohol cue exposure in the human laboratory setting. After signing informed consent, subjects 
will be screened for eligibility and have other baseline assessments. Screening is permitted over 
a 14-day period and most baseline assessments will be performed on the day of randomization. 
Assessments include alcohol breathalyzer test (before signing consent), medical history, physical 
examination, vital signs, ECG, drinking history by the timeline follow-back (TLFB) method, 
Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-AR), prior medication 
use, MINI neuropsychiatric interview, urine drug test, smoking quantity frequency interview, 
clinical laboratory tests including chemistry, hematology, thyroid function tests, and medical 
urinalysis, response to cue reactivity, Columbia Suicide Severity Rating Scale (CSSR-S), 
drinking goal, PACS, Pittsburg Sleep Quality Index (PSQI), PROMIS Alcohol Negative 
Consequences short form, Profile of Moods State (POMS), blood sample for ALDH2 deficiency 
genetics test, and confirmation that subjects are treatment seeking and desire a reduction or 
cessation of drinking. Women of child-bearing potential will have a pregnancy test. If eligible for 
the study, 81 subjects will be randomized using a stratified permuted block randomization 
procedure in an approximate 1:1:1 ratio (targeting 27 subjects per group and 27 subjects per each 
of 3 clinical sites) to receive either ANS-6637 200 mg once daily, ANS-6637 600 mg once daily, 
or matched placebo for 5 weeks. Clinical site will be used as a stratification variable. 
After the first week of investigational product administration (at the Week 2 visit), subjects will 
undergo a cue reactivity session including 4 individual VAS items assessing alcohol craving and 
1 item assessing beverage liking. If the session cannot be conducted at that visit, it can be 
rescheduled for another session no more than 7 days thereafter. An ACQ-SF-R questionnaire will 
be administered before and after presentation of beverages during the cue reactivity session on 
the screening visit and study Week 2 visit to ensure that subjects have returned to levels at or 
below those prior to the session.  If the participant’s craving levels do not return to pre-session 
levels, then they will meet with a licensed psychologist or other mental health professional to 
address residual urges to drink. Other assessments at baseline (prior to the first dose of 
investigational product) and/or during the treatment period include clinical laboratory tests, 
blood for medication compliance, vital signs, ECG, concomitant medications, CIWA-AR, 
pregnancy test and birth control methods (males and females), drinking goal, AEs, PACS, 
smoking quantity/frequency, PSQI, and POMS. 
Study assessments and procedures will be performed at the visits and time points outlined in the 
Schedule of Assessments (Table 3).


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Table 3: 
Schedule of Assessments 
Study Phase 
Screening 
Treatment 
End of Studya 
Follow-up 
Call 
Clinic Visit # 
1 
2 
3 
4 
5 
6 
7 
 
Study Week (Days)b 
-2 to -1 
(-14 to -1) 
1 
(1 to 7) 
2 
(8 to 14) 
3 
(15 to 21) 
4 
(22 to 28) 
5 
(29 to 35) 
6 
(36 to 42) 
8 
(50 to 56) 
Informed Consent 
X 
 
 
 
 
 
 
 
Alcohol Breathalyzer 
X 
X 
X 
X 
X 
X 
X 
 
Urine Drug Testc 
X 
X 
X 
X 
X 
X 
X 
 
Locator Form 
X 
Update 
Update 
Update 
Update 
Update 
Update 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
Update 
 
 
 
 
 
 
Physical Exam  
X 
Update 
 
 
 
 
 
 
Body Weight 
X 
X 
X 
X 
X 
X 
X 
 
MINI V 7.0 
X 
 
 
 
 
 
 
 
C-SSRS 
 
X 
X 
X 
X 
X 
X 
 
Clinical Chemistryd 
X 
 
X 
X 
X 
X 
X 
 
Hematologye 
X 
 
 
X 
 
 
X 
 
Thyroid Function Testsf 
X 
 
X 
X 
X 
X 
X 
 
Medical Urinalysis 
X 
 
 
X 
 
 
X 
 
Pregnancy Test  
X 
X 
X 
X 
X 
X 
X 
 
Birth control methods (all subjects) 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signsg 
X 
X 
X 
X 
X 
X 
X 
 
Eligibility Checklist 
X 
X 
 
 
 
 
 
 
Drinking Goal 
 
X 
 
 
 
 
 
 
ECG 
X 
 
 
X 
 
 
X 
 
Prior and Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Phase 
Screening 
Treatment 
End of Studya 
Follow-up 
Call 
Clinic Visit # 
1 
2 
3 
4 
5 
6 
7 
 
Study Week (Days)b 
-2 to -1 
(-14 to -1) 
1 
(1 to 7) 
2 
(8 to 14) 
3 
(15 to 21) 
4 
(22 to 28) 
5 
(29 to 35) 
6 
(36 to 42) 
8 
(50 to 56) 
CIWA-AR 
X 
X 
X 
X 
X 
X 
X 
X 
Screening Cue Reactivity Session: 
VAS Scales, typical alcoholic 
beverage 
X 
 
 
 
 
 
 
 
Pharmacogenetic sampling (ALDH2)  
 
X 
 
 
 
 
 
 
Randomization 
 
X (Day 1) 
 
 
 
 
 
 
Blood for Drug Concentration 
 
 
X 
 
X 
 
 
 
Drug compliance/ accountability/  
Review AiCure 
 
Dispense 
Day 1 
X 
X 
X 
X 
X 
 
AEs (open ended question) and 
elicited AE questions 
 
X 
X 
X 
X 
X 
X 
X 
Brief Telephone Interviewh 
 
2 times 
during the 
week 
As needed if the subject misses a clinic visit 
 
Take Control 
 
X 
X 
Xi 
X 
X 
X 
 
Treatment Cue Reactivity Session: 
VAS Scales, typical alcoholic 
beverage 
 
 
X 
 
 
 
 
 
 
TLFB 
X 
X 
X 
X 
X 
X 
X 
 
Brief Drinking Questionnaire 
AS NEEDED 
 
 
 
 
 
 
 
Exit Interview 
 
 
 
 
 
 
X 
 
ACQ-SF-R 
2X pre/post 
cue session 
 
2X 
pre/post 
cue 
session 
 
 
 
 
 
PACS 
 
X 
X 
X 
X 
X 
X 
 


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Study Phase 
Screening 
Treatment 
End of Studya 
Follow-up 
Call 
Clinic Visit # 
1 
2 
3 
4 
5 
6 
7 
 
Study Week (Days)b 
-2 to -1 
(-14 to -1) 
1 
(1 to 7) 
2 
(8 to 14) 
3 
(15 to 21) 
4 
(22 to 28) 
5 
(29 to 35) 
6 
(36 to 42) 
8 
(50 to 56) 
Smoking quantity/frequency and 
nicotine use 
 
X 
X 
X 
X 
X 
X 
 
PSQI 
 
X 
 
 
 
 
X 
 
POMS 
 
X 
 
 
X 
 
X 
 
PROMIS Alcohol Negative 
Consequences 
 
X 
 
 
 
 
X 
 
Treatment Referral 
 
 
 
 
 
 
X 
 
Follow-Up Telephone Interview 
 
 
 
 
 
 
 
X 
Final Subject Disposition 
 
 
 
 
 
 
 
X 
a EOS - end of study. These assessments are to be done at Week 6 or if the subject discontinues early and agrees to a final clinic visit. 
b Within each study week, there should be a least two days elapsed since the visit in the prior week. 
c Test for opiates (i.e., morphine test), cocaine, amphetamines, methamphetamine, THC, buprenorphine, methadone, benzodiazepines, oxycodone, barbiturates, 
3,4-methylenedioxy-methamphetamine (MDMA – also known as ecstasy), and EtG. 
d AST, ALT, alkaline phosphatase, total bilirubin, creatinine, gamma glutamyl transferase (GGT), and albumin. CrCl will also be calculated each time creatine is 
measured. 
e Hematology tests include complete blood cell count with differential. 
f The thyroid panel includes: thyroid-stimulating hormone (TSH), thyroxine (T4) and free thyroxine (free T4), and triiodothyronine (T3). 
g Sitting blood pressure and heart rate. 
h AEs, concomitant medications, CIWA-AR, and drug compliance reminder. Telephone calls during the first week, should be separated by at least one day 
between calls, and will include assessments for AEs, concomitant medications, CIWA-AR, and a drug compliance reminder. The second call should be several 
days before the cue session to remind the subject of the planned visit. 
i Two Take Control modules will be viewed at this visit. 
 
 


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6. 
Study Interventions 
6.1. 
Investigational Products: ANS-6637 and Placebo 
ANS-6637 tablets in 100 mg and 300 mg strength will be supplied by Amygdala Neurosciences, 
Inc., along with identical matching placebo tablets. The 100 mg and 300 mg ANS-6637 are 
identical in appearance. Tablets will be supplied in bottles containing 30 tablets. Drug kits 
containing 3 bottles of tablets labeled with a randomization kit number will be supplied to 
clinical sites, by Catalent Inc., for dispensing to study subjects. 
6.2. 
Investigational Product Storage 
ANS-6637 tablets and matching placebo tablets should be stored at a controlled room 
temperature of 25°C (77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F). Kits 
should be stored in a secure area at the clinical site. 
6.3. 
Investigational Product Administration 
ANS-6637 and placebo tablets will be self-administered by subjects once daily preferably in the 
morning. On the day of the cue reactive session at Week 2, the daily dose must be taken prior to 
arrival at the clinic; however, this cue session should be scheduled as late in the day as possible. 
The daily dose will be 2 x 100 mg tablets (200 mg total daily dose), or 2 x 300 mg tablets 
(600 mg total daily dose), or 2 placebo tablets. The first dose will be taken in the study clinic on 
the day of randomization regardless of the time of day. Subjects will be provided with water to 
take with first dose.  
6.4. 
Investigational Product Dispensing 
Each study drug kit will contain 3 bottles of investigational product with 30 tablets per bottle. 
This is sufficient for 15 days of dosing. Subjects are scheduled to come to the clinic each week 
and will be asked to bring the bottle(s) that were previously dispensed for accountability. 
Dispensing and accountability (tablet counts) will be performed as shown in Table 4. 


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Table 4: 
Investigational Product Dispensing Plan 
Study Week 
Dispensing – Return Plan 
Week 1 
Dispense Bottle 1 and administer the first dose to the subject in the clinic – Demonstrate the use of 
the AiCure application on the smart phone. 
Week 2 
Subject returns with Bottle 1, perform a tablet count and return Bottle 1 to the subject. Dispense 
Bottle 2. Subject leaves with Bottle 1 and 2. Check AiCure to complete drug compliance. 
Week 3 
Subject returns with Bottles 1 and 2. Perform a tablet count on both Bottles. Keep Bottle 1 in the 
clinic (should have 2 tablets if subject returns 14 days after the first visit). Return Bottle 2 to the 
subject and dispense Bottle 3. Check AiCure to complete drug compliance. 
Week 4 
Subject returns with Bottles 2 and 3. Perform a tablet count on both Bottles. Keep Bottle 2 and 
return Bottle 3 to the subject. Check AiCure to complete drug compliance. 
Week 5 
Subject returns Bottle 3. Perform a tablet count and return Bottle 3 to the subject. Check AiCure to 
complete drug compliance. 
Week 6 
Subject returns Bottle 3. Perform a tablet count for final accountability. Store bottles with leftover 
tablets until the end of the study. Check AiCure to complete drug compliance. 
6.5. 
Investigational Product Accountability 
The site principal investigator (PI) or designated study personnel will maintain a log of the 
receipt of all investigational products and record of dispensing of all investigational products to 
the subject. Investigational product for each subject will be inventoried and accounted for 
throughout the trial. The site PI or his/her staff will count the tablets returned at each visit for 
each bottle that was dispensed and returned. Subject compliance will also be monitored using a 
Medication Adherence and Reminder System provided by AiCure application. A detailed 
description of this electronic platform is described in section 6.7. Comparison of the Medication 
Adherence and Reminder System records with the tablet counts will be used for drug compliance 
and drug accountability. If discrepancies are noted, subjects will also be asked to account for any 
missing tablets or other discrepancies.  
Missed Doses: If a subject misses more than one dose of investigational product, he/she will be 
instructed to re-start taking the investigational product at the dosage level that s/he was taking 
before stopping (in case the dose was reduced). If one dose of investigational product is missed, 
he/she should take it at the usual time they take their next dose of investigational product. The 
subject should not double up doses. 
Dose Reduction and Discontinuation. In the judgement of the investigator, if the subject 
experiences intolerable AEs that appear to be related to the investigational products, or the 
subject experiences significant loss of appetite or body weight (e.g. >5% of baseline body 
weight) not associated with a self-directed or prescribed weight loss regimen, or reports at least 
moderately severe palpitations requiring an intervention (CTCAE Grade 2) at any in clinic visit, 
the dose may be reduced to 1 tablet once daily. If the AE resolves at the lower dose, no attempt 
to increase the dose to the original target should be made. If the investigational product is still 
intolerable at the lower dose it should be discontinued, but the subject should continue in the 
study and return for all follow-up safety visits. 


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6.6. 
Medication Adherence and Reminder System 
6.6.1. 
System Description 
This Study will employ a medication adherence monitoring platform (“Platform”) for all subjects 
in the study.  The Platform uses artificial intelligence on smartphones to confirm medication 
ingestion. In addition, built-in reminders and a communication system allow real-time 
intervention in case of drug interruptions.  
Use of this Platform will in no way supersede or replace the physician and/or prescribed 
medication protocol of the subjects. Because the Platform does not change the medication 
protocol of the patients, but rather encourages adherence to the predefined protocol, use of this 
Platform presents minimal risk to the subjects. Use of the Platform will be required for all 
subjects in the study. 
The monitoring Platform requires that all subjects take each dose of the medication while using a 
smartphone. The Platform will be provided to subjects preloaded on a smartphone, or subjects 
will download the Platform onto their own mobile device during the first visit.  
When at home, study subjects will receive a medication reminder at a time within a predefined 
window. This notification reminds subjects to take their medication dose while using the 
Platform.  Subjects will follow a series of prescribed steps in front of the front-facing webcam to 
visually confirm their ingestion of the medication. The application on the smartphone will make 
an automated determination of whether the subject has properly taken their medication at the 
prescribed time. There is no need for a healthcare provider to review the administration, nor 
would a healthcare provider need to be available at the time the patient takes their medication. 
The amount of guidance that the device provides to the subject is automatically reduced as the 
subject becomes more proficient at using the application. 
After the device confirms proper medication ingestion, video recordings will be encrypted and 
transmitted to a secure centralized location for further analysis, including testing for duplicate 
enrollment.  The captured data and video is reviewable through a roles and rules restricted 
system ensuring privacy of the information. The system is compliant with the Health Insurance 
Portability and Accountability Act (HIPAA), which protects the privacy and security of 
healthcare information. 
Phone numbers of the subjects may also be collected and stored in an encrypted manner. Storing 
the phone numbers will allow for direct communication with subjects, including automated 
messaging from the Platform device and contact by healthcare providers or other monitoring 
personnel.  At no time is the phone number visible to healthcare providers or monitoring 
personnel.  Individuals outside the clinical sites will not be provided with subject names, nor will 
they be given access to subject’s medical records. 
The Platform may provide significant benefits to Study subjects as well as to the other 
stakeholders in the trial.  Subjects will benefit from rapid and tailored intervention in case of 
non-adherence (drug interruptions) without having to visit the clinic for unscheduled visits.  
Healthcare providers will have access to real-time and continuous adherence data without having 
to rely on self-reported data or frequent study visits by subjects. Subjects who regularly fail to 
take their medication will be contacted by healthcare providers or other Study monitoring 
personnel for retraining. 


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6.6.2. 
Subject Risk 
The Platform provides no more than minimal risk to subjects. This protocol only introduces a 
smartphone-based monitoring application that prompts the user to take their medication, verifies 
ingestion, and stores encrypted data securely for analysis. Use of the Platform does not affect 
titration, dosage, route of administration or treatment duration.  
All Study data, including any identifiable subject information, will be obtained and encrypted by 
the application.  Subjects will be assigned a unique code number according to the protocol and 
their identity will not be stored with the study data obtained. After the subject has taken the 
medication and confirmation of proper ingestion has been completed, the encrypted data will be 
automatically forwarded to a secure server. The server is compliant with the HIPAA, which 
protects the privacy and security of healthcare information. The data will be securely stored and 
only accessible to healthcare providers and other authorized personnel through two-way 
authentication.  
The data may also be retained in a secure manner beyond the term of the trial and utilized to 
improve the operation of the Platform, categorize adherence activity by disease state or other 
useful categories, and/or for regulatory filings by the Platform Provider to support future 
applications for the Platform Provider’s product. Individuals who are not associated with the care 
and treatment of patients will not have access to patient identity or any medical records.  
6.6.3. 
Subject Confidentiality 
The Platform Provider will protect subjects’ personal information to the full extent required by 
law.  However, information from this Study, including de-identified video recording(s) of subject 
performance of various actions, may be submitted to the Study site, and potentially to the U.S. 
Food and Drug Administration (FDA). Both information obtained by the application, and 
information in the subject Informed Consent, may be examined by the study site or the study 
site’s representatives, and may also be reviewed by the FDA and other regulatory agencies, or 
IRBs. All of these parties are bound to safeguard the rights, safety and well-being of all clinical 
trial subjects, and to maintain all information in confidence. 
The results of this research project may be presented at meetings or in publications; however, 
specific subject will not be identified by name in these presentations and/or publications. 
Information from this Study may also be retained by the Platform Provider for the purpose of 
improving the Platform, to allow for future analysis of various facial and other parameters, the 
reporting of high level statistical analysis of the Platform, to improve the internal workings of the 
system running on the smartphone device, or for regulatory filings by the Platform Provider to 
support future applications for the Provider’s product. 
6.7. 
Take Control Behavioral Platform 
The behavioral platform “Take Control” (Devine-2016) will consist of a series of 7  
computerized modules viewed by subjects at 6 visits. Subjects will view a single module of 
“Take Control” at each clinic visit starting at the randomization visit on Week 1, Day 1 with the 
exception of the Week 3 visit, where two modules will be viewed. If a visit is missed, missed 
modules will be reviewed at the next visit. The paper versions of the modules are not to be given 
to the subject to take home and must remain at the clinic. The intervention is derived from a self-


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help approach developed by NIAAA that provides evidence-based, field tested information for 
individuals with alcohol problems, and suggestions for making changes in their drinking. The 
NIAAA material is publically available in a NIAAA booklet entitled “Rethinking Drinking” and 
on a NIAAA website http://rethinkingdrinking.niaaa.nih.gov. Delivering these materials in a 
computerized method in this trial has the advantage of standardizing the amount of educational 
material received by the subject. Subject viewing of the Take Control Modules will be recorded 
on an eCRF. 
6.8. 
Concomitant Medications 
Concomitant medications must be approved by the investigator. Subjects will be instructed to 
check with study staff before taking any new medications or stopping current medications. 
Subjects will be informed that starting any new medication without consulting study staff could 
pose health risks and/or result in their discontinuation for the study drug.  
Oral ANS-6637 is believed to suppress the surge in dopamine associated with substance use 
disorders and therefore, patients with attention-deficit/hyperactivity disorder treated with 
dopamine stimulants, or patients with restless legs syndrome, or Parkinson’s disease treated with 
dopamine agonists will be excluded. In addition, there have been reports indicating an 
association of ALDH2*2 polymorphisms and pesticide (irreversible inhibitors of ALDH2) 
exposure and the incidence of Parkinson’s and reduced cognitive function in patients with 
Parkinson’s (Fitzmaurice-2014, Ritz-2016, Yu-216, Zhao-2015). Therefore, subjects with a 
family history of Parkinson’s will also be excluded. 
For study inclusion, subjects cannot have taken any anti-convulsants, hypnotics, barbiturates, 
antipsychotics, psychomotor stimulants (such as methylphenidate), or benzodiazepines within 
5 half-lives prior to the date of randomization. In addition, if a subject is taking a medication for 
depression or anxiety, he or she must have been taking a stable dose in the 2-months prior to 
randomization and plan to continue during the study. This includes drugs such as the following: 
• selective serotonin reuptake inhibitors (SSRIs) 
• dual uptake inhibitors 
• serotonin-norepinephrine reuptake inhibitors (SNRIs) 
• tricyclic antidepressants 
• monoamine oxidase inhibitors (MAOIs) 
Pharmaceutical treatments approved for treatment of alcoholism or treatments known to be used 
off-label or experimentally for treatment of alcoholism are prohibited during the study. The 
following drugs approved for the treatment of alcoholism are prohibited at screening and during 
the study: 
• Oral naltrexone 
• Depot naltrexone (Vivitrol) 
• Disulfiram (Antabuse) 
• Acamprosate (Campral) 


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• Nalmefene (Selincro) 
• Varenicline (Chantix) 
• Topiramate  
• Baclofen 
• Prazosin 
• Ondansetron 
• Zonisamide 
Investigators should also be aware of potential drug-drug interactions of ANS-6637. The 
dissolution rate and solubility of ANS-6637 from a solid formulation are driven primarily by the 
pH-dependent gastrointestinal tract environment. Since ANS-6637 is ionizable, there is a 
potential for drug-drug interactions with proton pump inhibitors and histamine-2 antagonists; 
however, these classes of medications are not specifically prohibited during the study. Substrate-
dependent inhibition of CYP3A by GS-548351 has been observed in vitro, suggesting the 
potential for ANS-6637 administration to increase the exposure of CYP3A-sensitive substrates. 
Medications that are CYP3A-sensitive substrates with a narrow therapeutic index are prohibited 
during the study, but otherwise are not excluded.  Examples include: alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and 
tacrolimus. AEs will be monitored closely in any subjects taking a concomitant medication that 
is a CYP3A-sensitive substrate. 
Management of investigational products and concomitant medications during the study is at the 
discretion of the PI or designated medical doctor. The PI or designee may consult with the 
medical monitor if there are any questions regarding concurrent or prior medications. 
The Study Manual of Procedures provides a list of prohibited medications and medications that 
are permitted with restrictions or that require close safety monitoring. Refer to the Manual or 
Procedures for guidance when making decisions about subject safety management and use of 
concomitant medications. 
 


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7. 
Study Procedures 
7.1. 
Recruitment of Subjects 
Subject recruitment methods at each site will be based on their local population; however, 
standard tactics will be used (including but not limited to: flyers, social media, newspaper 
advertisements, radio advertisements, and television advertisements). The central institutional 
review board (IRB) and NIAAA will approve all advertising materials used for subject 
recruitment. Advertising materials may also require local institutional review depending on the 
clinical site’s policies. Interested candidates responding to recruitment materials by telephone 
will be asked to complete a standardized telephone interview that includes questions about their 
drinking behavior, health status, interest in participation, and availability for the entire trial. 
Study staff will ask these questions without revealing the entry criteria for the study. Candidates 
who report drinking and other information consistent with the entry criteria and appear to be 
available and interested in the study will meet with the investigator or designated investigational 
staff ideally within 14 days after the initial inquiry to start the informed consent and assessment 
process. 
7.2. 
Informed Consent 
At the first screening visit, candidates will meet with either the PI or his/her designee and receive 
an explanation of the study purpose and requirements. If still interested after receiving an 
explanation of the study, the candidate will be given an opportunity to review, inquire about, and 
sign the study informed consent form approved by the central IRB. Subjects must have blood 
alcohol content (BAC) of 0.000 measured by breathalyzer when signing the informed consent 
document (tested shortly before or just after providing consent). Repeat measurements of BAC 
are permitted at the discretion of the investigator. Subjects will be given a copy of the signed 
informed consent form. 
7.3. 
Selection and Withdrawal of Subjects 
7.3.1. 
Inclusion Criteria 
To be eligible, the subject must: 
1. Be at least 21 years of age. 
2. Meet the DSM-5 criteria for alcohol use disorder of at least moderate severity. 
3. If male, report drinking a weekly average of at least 35 drinks per week or if female 
report drinking a weekly average of at least 28 drinks per week for the 28-day period 
prior to consent. 
4. Have at least 1 heavy drinking day (4 or more drinks for women/5 or more drinks for 
men) during the 7-day period prior to randomization. 
5. Be seeking treatment for AUD and desire a reduction or cessation of drinking. 
6. Be able to verbalize an understanding of the consent form, able to provide written 
informed consent, verbalize willingness to complete study procedures, able to understand 


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written and oral instructions in English and able to complete the questionnaires required 
by the protocol. 
7. Agree (if the subject is female and of child bearing potential) to use at least one of the 
following methods of birth control to at least 7 days post the last dose of study drug, 
unless she is surgically sterile, partner is surgically sterile or she is postmenopausal (one 
year): 
a. oral contraceptives, 
b. contraceptive sponge, 
c. patch, 
d. double barrier (diaphragm/spermicidal or condom/spermicidal), 
e. intrauterine contraceptive system, 
f. etonogestrel implant, 
g. medroxyprogesterone acetate contraceptive injection, 
h. complete abstinence from sexual intercourse, and/or 
hormonal vaginal contraceptive ring. 
8. Agree (if male) to use acceptable methods of contraception if the male participant’s 
partner could become pregnant from the time of the first administration of the study drug 
until 7 days following the final administration of the study drug. One of the following 
acceptable methods of contraception must be utilized: 
a. Surgical sterilization (vasectomy); 
b. The participant’s female partner uses oral contraceptives (combination 
estrogen/progesterone pills), injectable progesterone or sub dermal implants 
(commenced at least 14 days prior to study drug administration to the male 
participant)  
c. The participant’s female partner uses a medically prescribed topically applied 
transdermal contraceptive patch (commenced at least 14 days prior to study drug 
administration to the male participant); 
d. The participant’s female partner has undergone tubal ligation (female sterilization) or 
is postmenopausal (one year); 
e. The participant’s female partner has undergone placement of an intrauterine device or 
intrauterine system; 
f. True abstinence: when this is in line with the preferred and usual lifestyle of the 
participant.  
9. Agree (if male) to refrain from sperm donation from the randomization visit to at least 7 
days after the last dose of study drug.  
10. Be able to take oral medication and be willing to adhere to the medication regimen. 
11. Complete all assessments required at screening and baseline. 
12. Have a place to live in the 2 weeks prior to randomization and not be at risk that s/he will 
lose his/her housing in the next 2 months. 
13. Not anticipate any significant problems with transportation arrangements or available 
time to travel to the study site over the next 2 months. 


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14. Not have any unresolved legal problems that could jeopardize continuation or completion 
of the study. 
15. Provide contact information of someone, such as a family member, spouse, or significant 
other, who may be able to contact the subject in case of a missed clinic appointment. 
16. Have a BAC by breathalyzer equal to 0.000 when s/he signed the informed consent 
document. 
17. If taking a medication for depression or anxiety, must have been taking a stable dose in 
the 2-months prior to randomization and plan to continue during the study. This includes 
drugs such as the following: 
a. Selective serotonin reuptake inhibitors (SSRIs) 
b. Dual uptake inhibitors 
c. Serotonin-norepinephrine reuptake inhibitors (SNRIs) 
d. Tricyclic antidepressants 
e. Monoamine oxidase inhibitors (MAOIs) 
18. Be someone who in the opinion of the investigator would be expected to complete the 
study protocol. 
19. Agree to the schedule of visits, verbally acknowledge that s/he will be able to attend each 
scheduled visit, participate in phone visits and that s/he does not have any already 
scheduled events or a job that may substantially interfere with study participation. 
20. Be willing to use a smartphone’s video capability to record daily oral ingestion of tablets 
for the entire 5-week treatment period (subject’s own smartphone or one provided by 
AiCure). 
21. Have sitting (3 to 5 minutes) vital signs at the screening visit within the following limits: 
a. Systolic blood pressure 90 to 160 mmHg  
b. Diastolic blood pressure of 50 to 95 mmHg  
c. Heart rate of 40 to 90 beats per minute  
Note: Vital signs may be repeated once if outside the limits above and if within the limits on 
a second evaluation, the subject may be included. 
7.3.2. 
Exclusion Criteria 
Subjects must not have any of the following: 
1. Current (past 12 months) substance use disorder of at least moderate severity (4 or more 
criteria) for any psychoactive substance other than alcohol and nicotine, including 
sedatives and hypnotics, as defined by DSM-5 criteria. 
2. Urine drug test positive performed during screening or baseline for any of the following 
substances: 
a. benzodiazepines, 
b. cocaine, 
c. opioids, 
d. amphetamines, 


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e. methamphetamine, 
f. buprenorphine, 
g. methadone, 
h. barbiturates, 
i. oxycodone, 
j. and/or 3,4-methylenedioxy-methamphetamine (MDMA). 
Note: Testing for THC will be included in the urine drug test; however, subjects who test 
positive for THC are still eligible to participate in the study unless they have moderate or 
greater severity for cannabis use disorder as indicated by DSM-5 criteria. The results for 
THC will be recorded for information only. If positive for opioids or oxycodone but recent 
opiate use for acute pain is reported by the subject, then the subject can be included at the 
discretion of the investigator. 
3. VAS craving rating (“How strong is your craving to drink alcohol”) during first 
presentation of alcohol cue <5 during the screening cue reactivity session. 
4. Have been hospitalized for alcohol intoxication delirium, alcohol withdrawal delirium, 
alcohol-induced persisting dementia or amnestic disorder, or have had an alcohol 
withdrawal seizure, alcohol-induced psychotic disorder with a primary diagnosis of AUD 
or a history of any seizure disorder. 
5. Have participated in any behavioral and/or pharmacological intervention research study 
for the treatment of alcoholism where the last intervention was within 3 years prior to 
signing the informed consent. 
6. Be mandated by the court to obtain treatment for alcohol-dependence, or has probation or 
parole requirements that might interfere with study participation. 
7. Be anyone who in the opinion of the investigator could not be safely withdrawn from 
alcohol without medical detoxification. 
8. Have undergone medical detoxification (e.g., reports using a benzodiazepine) during the 
screening phase (prior to randomization). 
9. Have been treated with a pharmacotherapy for alcohol use disorder within 6 months prior 
to randomization. 
10. Have any of the following, based on DSM-5 criteria as assessed using the MINI: 
a. Current or lifetime diagnosis of psychotic disorders, 
b. Current bipolar disorder, 
c. Current major depressive episode, 
d. Current (past 3 months) eating disorder (anorexia or bulimia), or 
e. Within past year diagnosis of panic disorder with or without agoraphobia. 
Note: Subjects diagnosed with psychiatric disorders not specifically excluded above may be 
included at the discretion of the PI as long as the concurrent treatment for the comorbid 
psychiatric condition does not compromise the study integrity by virtue of its type, duration, 
or intensity. 
11. Have any of the following: 


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a. attempted suicide past year, 
b. current (past year) suicide behavior disorder in accordance with DSM-5 criteria as 
assessed using the MINI (see note below about assessment of subjects diagnosed at 
low risk), 
c. current (since screening MINI) suicidality risk as indicated during the conduct of the 
C-SSRS with concurrence after a study physician’s evaluation if the response to 
C-SSRS questions 1 or 2 is “yes”). 
Note: The MINI suicidality module rates scores of 1 to 8 as a diagnosis of low risk of suicidality. 
As the MINI questions that could result in a low risk score are considered inadequate to fully 
determine the potential suicidal risk of an individual (e.g., “Feel hopeless” and “Think that you 
would be better off dead or wish you were dead?” responses of “yes” dictates a score of 1 for 
each question), any subject who scores in the low risk category should be evaluated further by a 
study physician who should document whether the subject is appropriate for study inclusion 
based on his/her clinical judgment of the potential suicide risk of the subject. Likewise, if the 
subject responds “yes” to either the first two questions on the screening C-SSRS performed on 
the day of randomization as a final eligibility check, the subject should also evaluated by a study 
physician for current suicidality risk, who should document the subject’s suitability for study 
inclusion. 
12. Have moderate or serious dementia as assessed by clinical exam. 
13. Be pregnant or breast-feeding or have plans to become pregnant at any time during the 
study or within 7 days after the last dose of investigational product. 
14. Have clinically significant abnormal laboratory values, including elevation of liver 
enzymes (AST or ALT > 2.5 x upper limit of normal or total bilirubin > 1.5 x the upper 
limit of normal). 
15. Have abnormal calculated creatinine clearance defined as < 80 mL/min for subjects ≤ 55 
years of age and < 65 mL/min for subjects > 55 years of age. 
16. Have a serious or unstable medical illness or any potentially life-threatening or 
progressive medical condition other than addiction that may compromise subject safety 
or study conduct. 
17. Be currently undergoing psychotherapy by a licensed therapist or psychiatrist for alcohol 
problems. 
NOTE: Current psychotherapy should be considered on a case-by-case basis. 
Psychotherapy for a disorder that may be related to the subject’s use of alcohol should be 
exclusionary. However, shorter term focused behavioral therapy for defined problems for 
non-alcohol related problems may be acceptable. 
18. Have data suggesting cirrhosis of the liver (albumin < 3.2 g/dL, or ascites by physical 
exam). 
19. Have been previously treated with ANS-6637 for any reason. 
20. Have had gastric bypass surgery. 
21. Have had a severe reaction to disulfiram while drinking alcohol requiring medical 
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22. Have a history of atherosclerotic cardiovascular disease including angina pectoris, 
myocardial infarction, stroke, transient ischemic attack, peripheral vascular disease or 
revascularization procedures or clinically significant ECG indicative of cardiovascular 
disease. Note: medically controlled hypertension is not exclusionary. 
23. History of syncope, palpitations, or unexplained dizziness at screening.  
24. Had a prior history of any severe adverse reactions to ethanol [e.g., flushing (noticeable 
redness of the neck or throat) and/or increased heart rate (subject reports sensation of 
increased heart rate or palpitations) after drinking alcohol]. 
25. Report heavy drinking of alcohol within 2 days on TLFB prior to screening and have a 
negative result on EtG urine test.  
26. Have Parkinson's Disease or a family history of Parkinson's Disease. 
27. Have restless legs syndrome and receiving dopamine agonist treatment. 
28. Have attention-deficit disorder and receiving dopamine stimulant treatment. 
29. Are taking a prohibited medication. 
7.4. 
Eligibility Screening Assessments 
After providing written informed consent, subjects complete the Screening Visit for initial 
evaluation of eligibility. A screening cue session will be conducted to familiarize subjects with 
the human lab setting and identify non-cue-reactive subjects for study exclusion (VAS alcohol 
craving rating upon first presentation of alcohol cue < score of 5 on the item, “How strong is 
your craving to drink alcohol?”). 
During the first screening visit (additional visits are permitted if needed), subjects will undergo 
the following assessments (assessments may be performed in any order, except that consent and 
BAC must be completed first). However, it is recommended to perform physical examinations 
including vital signs prior to blood draws. 
• Alcohol breathalyzer (must have a BAC of 0.000 to continue with assessments) 
• Informed Consent 
• Demographics and locator form 
• Urine drug test  
• Medical history 
• Physical examination and weight 
• Vital signs 
• MINI Version 7.0.2 
• Clinical chemistry, hematology, thyroid function tests, and medical urinalysis 
• Pregnancy test for females of child bearing potential and birth control methods for 
males and females 
• ECG 


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• Screening Cue Session (VAS craving scales and ACQ-SF-R) 
• TLFB for the previous 28 days 
• Prior medication use 
• CIWA-AR 
• Eligibility checklist initial screening questions 
If any of these assessments reveal that the subject is not eligible for the study, screening can be 
immediately terminated. 
Potential subjects must agree to adhere to the following prohibitions and restrictions during the 
course of the study to be eligible for participation and will be reminded of these restrictions 
during the telephone call prior to the cue reactive session at Week 2: 
• Refrain from consuming caffeine after arriving for the lab session until study 
assessments are completed. 
• Refrain from smoking during the cue-reactivity sessions (if the subject is a smoker, 
then smoking is permitted and encouraged approximately one hour before arriving at 
the cue reactivity session. 
Subjects will be instructed that if they are taking a medication for depression or anxiety that they 
should continue to do so throughout the study. They will also be instructed not to take ANS-6637 
outside of the study during their time in the study and that they should report any new 
medications they are taking at each visit or telephone contract. 
Clinical laboratory tests may be repeated at the discretion of the investigator if the first 
assessment yields values outside normal laboratory limits. The eligibility checklist will be 
reviewed, and if the subject is still eligible after the assessments are completed at the first 
screening visit (or additional screening visits), the subject will be scheduled for the final 
eligibility baseline visit. It is recommended that hypertensive subjects be referred to their 
primary care physician for additional assessments and possible treatment, and then be further 
evaluated for study inclusion. 
7.5. 
Baseline and Final Eligibility Assessments 
If the subject is eligible after performing all the initial screening assessments, s/he will be 
scheduled to start the study and will come to the clinic for a final eligibility check and 
randomization visit. The following assessments will be performed at this visit: 
• Alcohol breathalyzer (must have a BAC of 0.02 or less to continue with assessments) 
• Urine drug test 
• Update medical history 
• Update physical exam (if needed) 
• Update locator form (if needed)  
• Vital signs 


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• CIWA-AR 
• C-SSRS 
• Pregnancy test for females of child bearing potential 
• Birth control methods (both males and females) 
• Prior medications update 
• TLFB 
*Note that the MINI will be used to rule out subjects who attempted suicide in the past year 
and current (past year) suicidal ideation at initial screening, with the C-SSRS providing an 
update on current suicidal ideation since screening. 
An eligibility checklist will be completed and reviewed by a study investigator and, if the subject 
is still eligible, he/she will complete the following assessments: 
• PACS 
• Drinking Goal 
• Smoking Quantity Frequency and Nicotine Use Questionnaire 
• PSQI 
• POMS 
• PROMIS Alcohol Consequences 
• Blood sample for ALDH2 genetic test 
• Body weight 
7.6. 
Measures Taken to Minimize/Avoid Bias 
7.6.1. 
Randomization (Day 1) 
If eligible for the study, subjects will be randomized in an approximate 1:1:1 ratio to receive one 
of the doses of ANS-6637 or placebo using a stratified permuted block randomization procedure 
with clinical site as the stratification variable. 
Randomizations will be performed via an interactive web-based randomization system (IWRS) 
provided by the data coordinating center. 
If the subject is randomized and is never dispensed study drug, then the subject will be 
considered a randomization failure and an additional subject will be randomized with the next 
randomization sequence at the time he/she is randomized at that site. The IWRS will handle this 
randomization assignment. Likewise, if the subject was randomized and then is determined to 
not be eligible for the study, and never took study drug, then another subject will be randomized 
such that the total numbers of subjects who were eligible, randomized, and dispensed study drug 
meet the enrollment goals. In the case of a subject who was eligible, randomized, and dispensed 
study drug but did not return for follow-up visits, this subject will not be replaced. Any subject 
who took study drug but was later determined to be ineligible will likewise not be replaced. The 


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reason(s) that a subject was considered a randomization failure or screen failure will be 
documented in source documents and eCRFs. 
7.6.2. 
Blinding 
ANS-6637 (both strengths) and placebo tablets will be identically matched in appearance. The 
site investigator or designated approved study physician will make the decision to un-blind the 
identity of the investigational product in the event that the study blind needs to be broken to 
make medical decisions regarding subject treatment. If it is determined that unblinding is 
necessary to assess AEs or SAEs for expedited reporting, NIAAA may decide to request 
unblinding of a subject. The site investigator will automatically notify NIAAA that a subject was 
unblinded who will notify the Medical Monitor. 
7.7. 
Interventions on Week 1, Day 1 
Subjects will view a single module of Take Control during this clinic visit prior to dispensing 
study drug. 
After the subject is randomized, he/she will receive the first bottle of study drug. Site staff will 
explain the dosing plan to the subject and how to use the AiCure application on their 
smartphone. The subject will be observed taking the first dose of study drug and the use the 
AiCure application for medication compliance. 
Every study subject will be provided with a wallet card and instructed to carry this card that 
identifies the potential investigational products that s/he could be taking during the study. The 
card will provide the name and 24-hour phone number of the investigator (physician) at the site 
who can be contacted in the event of an emergency. The card will also instruct the non-study 
physician rendering emergency care to contact the study physician and inform him/her about the 
care. 
If possible, clinic visits should be scheduled on the same day of the week that the subject took 
the first dose of study drug; however, visits may be scheduled any day during the study week, 
but at least two days should have elapsed since the prior week’s visit. Visits can be conducted 
outside of the scheduled study week, but only based upon subject request (e.g., for reasons 
related to patient non-compliance with the study schedule). Each subject will receive a visit 
schedule to take home for future reference. 
7.8. 
Week 1 Telephone Contact 
During Week 1, subjects will be called two times for a safety assessment and will be given a 
reminder to continue taking their investigational product as prescribed. Telephone calls during 
the first week should be separated by at least one day between calls. The second call should be 
scheduled several days before the Cue Session at Week 2, to remind the subject of the pending 
visit and to complete all of the rest of the safety telephone assessments. The subject will also be 
instructed at this visit to take their investigational product tablets as usual in the morning. If the 
subject is a smoker, remind them that they will not be permitted to smoke or use other nicotine 
products after arrival at the clinic, until after the cue session is completed. However, smokers 
will be encouraged to smoke approximately 1 hour prior to coming to the clinic to help control 
urges to smoke during the cue session. 


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7.9. 
Treatment Period 
During Study Weeks 1 through 5, an alcohol breathalyzer will be administered at each visit, prior 
to any study assessments, to determine if the subject meets the BAC requirement of a BAC ≤ 
0.020 before proceeding with assessments. If the subject has a BAC > 0.02 and cannot wait for 
levels to return to ≤ 0.02, then the following safety assessments should be performed: vital signs, 
ECG if at Week 3 or 6, clinical laboratory tests (including pregnancy test if female), and urine 
drug test. Otherwise, the assessments listed in Table 3 will then be performed during these visits. 
If a subject arrives for a clinic visit who is too intoxicated to participate in study procedures, the 
site staff should follow their site specific standard operating procedure for managing these 
subjects. 
The cue reactivity session will be performed at Week 2 (see section 10.11.2 for details). 
The final in-clinic assessment will occur during Week 6. This visit should occur after the subject 
takes the last dose of study drug. 
Additional in-clinic visits are permitted under the protocol, if needed, due to the following 
circumstances: (1) the subject has concerns either about the medication or their drinking and 
wishes to be seen at a time other than their next scheduled in-clinic visit, or, (2) the subject has 
missed a visit and wishes to resume regular participation before their next scheduled visit, (3) the 
subject has reported some change in health, functioning, or circumstances which necessitate a 
visit to conduct safety assessments and evaluate the risk of continued participation in the trial, or 
(4) clinical laboratory measurements need to be repeated. 
Subjects desiring additional counseling or professional therapy for non-crisis psychiatric matters 
(e.g., marital problems, work issues) should be encouraged to postpone such activity until their 
study participation is concluded at the discretion of study physician. 
7.10. 
Telephone Assessments 
The brief telephone interview (approximately 10 minutes) will occur in accordance with the 
schedule in Table 3 or if a subject misses a clinic visit but agrees to check-in by telephone to 
assess AEs, concomitant medication use and the emergence of withdrawal symptoms, to 
encourage the subject to continue taking investigational products, to verify that the subject is 
taking the prescribed dose, and to remind the subject of the next scheduled visit and dose 
increases. If necessary, a TLFB interview can also be conducted. A summary of the telephone 
script follows: 
1. AEs: An open-ended question will be asked as follows: “How have you been feeling 
since your last clinic visit or phone contact?” If the subject reports a new AE, the 
resolution of an AE, or a change in the severity of an AE, ask additional questions to 
determine the severity and dates of occurrence or resolution. 
2. Elicited AEs: Ask if the subject experienced about flushing reactions, noticeable heart 
rate increases or palpitations, and appetite changes. 
3. CIWA-AR: Subjects will be assessed for the emergence of withdrawal symptoms using 
the CIWA-AR. The subject may be asked about changes in drinking status after 
responses to the CIWA-AR interview indicate significant withdrawal. 


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4. Concomitant Medications: Ask the following question: “Have you taken any new 
medications since you were last seen in the clinic or since our last call? If the subject 
responds affirmatively, record the name of the medication, the daily dose, route of 
administration, and reason used. If the medication is contraindicated for the study, then 
notify the PI or designee. 
5. Drug Compliance: If the subject has not been using the AiCure smart phone application, 
provide retraining if necessary, verify that the subject is taking the prescribed dose,  
remind them to take investigational product, and remind them to return the drug bottles 
with remaining tablets at the next visit. 
Additional reminders: Remind the subject of their next scheduled clinic visit, and adjust the date 
within the visit week if they have a conflict. 
7.11. 
Final Clinic Visit 
The final clinic visit occurs during Week 6; at which time the subject will have completed taking 
investigational product by the end of Week 5. The subject will complete study assessments in 
accordance with Table 3 and will be provided with a referral to a treatment program for their 
AUD. If a subject withdraws from the study early for any reason, the subject should be asked to 
return to the clinic for the conduct of the final clinic visit assessments. 
7.12. 
Telephone Follow-up 
Subjects will be contacted by telephone for a follow-up interview 2 weeks after the final in-clinic 
visit. During the telephone follow-up interview, the subject will be asked about any ongoing AEs 
that they may have been experiencing at the last clinic visit and any newly emerged medical 
conditions/AEs since that visit. To prompt reporting of new AEs, the subject will also be asked 
about any ongoing or new medication use. 
7.13. 
Duration of Subject Participation 
The total time period that each individual subject will participate is up to 10 weeks including up 
to 2 weeks for screening, 5 weeks of study interventions, 1 week for an end-of-study visit, and a 
final safety follow-up telephone contact from 2 weeks after completion of study drug dosing. 
7.14. 
Dose-adjustment Criteria 
7.14.1. 
Safety Criteria for Dose Adjustment or Stopping Doses 
The PI or sub-investigator will follow the protocol to identify and intervene with subjects 
experiencing clinical deterioration during study participation. Criteria to determine when a 
subject requires a higher level of care and discontinuation from the trial intervention are detailed 
below. 
7.14.2. 
Investigational Product Dose Reduction 
The daily dosage of investigational product may be reduced by the study physician for any AE 
determined, by the study physician, to compromise the subject’s ability to maintain activities of 
daily living or if the subject reports undue discomfort. The dose may be reduced to 1 tablet once 
daily.  


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7.14.3. 
Investigational Product Discontinuation 
Subjects who are discontinued from investigational product after the Week 2 assessments should 
continue in the study and complete all assessments. If the subject discontinues before this time 
point, then they will not be eligible for the Week 2 Cue Reactivity assessment and will be 
discontinued from further study participation. 
1. Pregnancy. Females who become pregnant during the course of the study interventions 
will be immediately discontinued from the investigational product. The investigator must 
report a pregnancy within 1 working day of the site being aware to the NIAAA Study 
Manager and the Medical Monitor. Pregnant females will be followed to determine the 
outcome of the pregnancy, fetus, and/or newborn child. 
2. Physical Illness. Subjects will need to be removed from investigational products if they 
have a serious illness or a disabling condition that precludes them from taking the 
investigational product. 
3. Elevated Liver Enzymes. Subjects whose ALT or AST is greater than 5X ULN should 
have these tests repeated as soon as possible and if still elevated should discontinue 
investigational products. If the repeat values are less than the criteria above, the subject 
should be monitored using clinical judgment. If ALT or AST levels are in the range of 
3-4.9x ULN and total bilirubin is in the range of 1.5x-1.9x ULN, then the subject may be 
at risk for clinically significant hepatic dysfunction. The first action will be to have the 
laboratory test repeated as soon as possible to confirm the result. If the value was 
confirmed, then the subject will be withdrawn from receiving the study drug but will 
continue to be followed for the duration of the study as long as the subject agrees to 
continue in the study. Subjects discontinued from investigational products for elevated 
liver enzymes should be referred to their own physician for follow-up. 
4. Adverse Events. If the subject experiences any AEs that are considered study drug 
related and for which the investigator has determined that continuation of the study drug 
could be detrimental to the health of the subject, then drug will immediately 
discontinued. 
7.15. 
Subject Withdrawal or Discontinuation Procedures 
Each subject has the right to withdraw consent and withdraw from the study at any time. In 
addition, the investigator may find it necessary to discontinue a subject for any reason, including 
the occurrence of an AE or noncompliance with the protocol. 
In the event that a subject withdraws or is discontinued from the study, the reason(s) for the 
discontinuation from the study will be recorded and a pregnancy test (females only), vital signs, 
clinical laboratory, C-SSRS, TLFB and an assessment of AEs will be performed as soon as 
possible after discontinuation from the study. Other assessments scheduled for the end of study 
visit will be collected if possible (Table 3). 
7.16. 
Situations Requiring Discontinuation from the Study as Well as from 
Investigational Product 
It is possible that there will be some subjects who cannot be safely managed in the clinical study 
even though investigational products have been discontinued. Examples are given below. 


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1. Increased Drinking. Subjects whose alcohol problem worsens, and, in the opinion of the 
site medical staff, require a more intense level of care than provided in the study may 
have investigational product suspended, and referred to more appropriate care. 
2. Psychiatric Crises. Examples of psychiatric crises include but are not limited to the 
following: 
a. Acute psychosis (hallucinations, impaired reality testing, paranoid ideation, etc.) 
requiring medication and/or hospitalization or intensive outpatient intervention; 
b. Suicidal or homicidal ideation that results in a credible threat of violence directed at 
oneself or others; or, 
c. Hospitalization for psychiatric symptoms. 
Subjects requiring more intensive treatment resulting from acute psychosis or suicidal/homicidal 
behavior will be referred to local treatment centers, emergency departments, or hospitalization as 
appropriate, but will not be provided with medication or psychotherapy by study staff. 
3. Absence from the Protocol due to Confinement in a Controlled Environment. If a 
subject is confined to a controlled environment (such a hospital or jail where access to 
alcohol is presumably restricted) for less than 2 weeks, they can resume full participation 
in the trial if in the judgment of the investigator, the subject is still a good candidate for 
the study and continues to meet eligibility requirements. Before resuming investigational 
products the subject should be assessed by the study physician for appropriateness to 
resume the trial (e.g. any new medications or symptoms, pregnancy test, etc.). The 
decision to restart study drug at the full dose will be made in the judgment of the 
investigator based on the subject’s time off study drug and past experience with side 
effects with the study drug. 
If a subject is in a controlled environment (such a hospital or jail where access to alcohol is 
presumably restricted) for 2 weeks or more, the subject will be discontinued from the study. 
7.17. 
Study Termination Criteria 
NIAAA may terminate this study prematurely, either in its entirety or at any sites, for reasonable 
cause provided that written notice is submitted in advance of the intended termination. The 
investigator may also terminate the study at his/her site for reasonable cause, after providing 
written notice to NIAAA in advance of the intended termination. Advance notice is not required 
by either party if the study is stopped due to safety concerns. If NIAAA terminates the study for 
safety reasons, NIAAA will immediately notify the investigators by telephone and subsequently 
provide written instructions for study termination. 
 


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8. 
Study Endpoints 
8.1. 
Efficacy Endpoints 
8.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the “strength” of alcohol craving VAS score (item 1 below) 
upon presentation of the first alcohol cue at Week 2 – after one week of investigational product 
treatment. 
Confirmatory secondary endpoints include the VAS scores for the other 3 VAS scales (items 2 
through 4 below) for the first alcohol cue and the average score of the 4 VAS craving items; and 
the difference score (alcohol craving VAS scores minus the water craving VAS score) for all 4 of 
the individual VAS craving items and their average score. The beverage liking VAS item is also 
a confirmatory secondary endpoint The 4 VAS craving items in the order of presentation are: 
1. How strong is your craving to drink alcohol? - note this is the primary efficacy endpoint. 
2. Having a drink would make things just perfect. 
3. If I could drink alcohol now, I would drink it. 
4. It would be hard to turn down a drink right now. 
The beverage liking item is: How much did you like the beverage just given to you? 
8.1.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be analyzed over the last 4 weeks of the treatment period of 
treatment. 
1. Percentage of subjects with no heavy drinking days. A “heavy drinking day” is 4 or more 
drinks per drinking day for women and 5 or more drinks per drinking day for men. 
2. Percentage of subjects abstinent from alcohol 
3. Percentage of subjects with at least a WHO 2-level decrease in alcohol consumption 
4. Percentage of subjects with at least a WHO 1-level decrease in alcohol consumption 
5. Percentage of days abstinent per week 
6. Percentage of heavy drinking days per week 
7. Percentage of very heavy drinking days per week. A “very heavy drinking day” is 8 or 
more drinks per drinking day for women and 10 or more drinks per drinking day for men. 
8. Weekly mean number of drinks per week 
9. Weekly mean drinks per drinking day 
10. Cigarettes smoked per week among smokers 
11. Percentage of subjects with no nicotine use among nicotine users 
12. Alcohol craving score (PACS) 


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13. Sleep quality (PSQI) score 
14. Profile of Mood States (POMS) score 
15. PROMIS Alcohol Negative Consequences Score 
8.2. 
Safety Endpoints 
Safety endpoints will be analyzed over the entire treatment and follow-up period. 
1. Vital signs 
2. Body weight 
3. Clinical laboratory parameters 
4. BAC by breathalyzer 
5. Urine drug tests 
6. AEs and elicited AEs (flushing or heat sensation, heart rate increases or heart 
palpitations, and appetite change and AEs in subjects taking CYP3A-sensitive substrates) 
7. ECG results 
8. CIWA-AR scores 
9. Frequency of subjects with suicidal ideation at any time during the treatment period 
(C-SSRS) 
10. Concomitant medication use 
11. ACQ-SF-SR score (pre- and post-cue response sessions) 
8.3. 
Compliance 
Compliance will be assessed using the AiCure smart phone application and by tablet counts of 
returned bottles at regular clinic visits. In addition, blood will be collected to determine plasma 
levels of GS-548351. Compliance will be calculated as the percentage of investigational products 
taken as prescribed and by the total amount of medication consumed. Participation in study visits 
will be evaluated as the percentage of subjects with complete drinking data. Compliance 
determined by GS-548351 plasma levels will be reported as number and percentage of subjects 
with a level above the limit of detection at each time point. 
 
 


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9. 
Safety Monitoring Plan 
Safety monitoring will be conducted throughout the study; therefore safety concerns will be 
identified by continuous review of the data by the PI, clinic staff, clinical monitor, medical 
monitor, and NIAAA. 
The IRB, Medical Monitor, PI, Clinical Monitors and NIAAA (or its affiliates) will review any 
safety concerns throughout the trial. In addition, a data and safety monitoring board (DSMB) will 
participate in this study. The roles of these individuals/committee are described below. 
Medical Monitor: A Medical Monitor has been appointed by NIAAA for the study. The 
Medical Monitor will be available for making recommendations to the investigator and NIAAA 
on the severity of any SAEs, and the relatedness to the study interventions. The Medical Monitor 
will also be responsible for tracking and assessing trends in the AEs reported. 
Clinical Monitors: All investigators will allow representatives of NIAAA to periodically 
monitor, at mutually convenient times during and after the study, all study data. These 
monitoring visits provide NIAAA with the opportunity to evaluate the progress of the study and 
to obtain information about potential problems. The monitors will assure that submitted data are 
accurate and in agreement with any paper source documentation used; verify that investigational 
products are properly stored and accounted for, verify that subjects’ consent for study 
participation has been properly obtained and documented, confirm that research subjects entered 
into the study meet inclusion and exclusion criteria, and assure that all essential documentation 
required by Good Clinical Practices (GCP) guidelines are appropriately filed. 
Monitors will conduct a site initiation visit prior to the start of the study. At this visit, they will 
assure that proper study-related documentation exists, assist in training investigators and other 
site personnel in study procedures and GCP guidelines, confirm receipt of study supplies, and 
assure that acceptable facilities are available to conduct the study. 
Routine monitoring visits by NIAAA’s representatives will be scheduled at appropriate intervals 
but more frequently at the beginning of the study. At these visits, the monitors will verify that 
study procedures are being conducted according to the protocol guidelines, monitor eCRFs 
against source documents, review AEs and SAEs, and perform drug accountability. At the end of 
the study, they will confirm that the site has the appropriate essential documents on file, advise 
on storage of study records, and inspect the return and destruction records for unused 
investigational products. 
DSMB: An independent DSMB of external advisors will meet prior to the start of the study, and 
periodically during enrollment and follow-up and at trial end to review safety data. The Board 
will be blinded to subjects’ actual randomized group assignments but may request at any time 
that the blind be broken by the data center, if concerns arise from the blinded data. Ad hoc 
meetings will be convened if SAEs occur that are considered at least possibly related to the 
investigational product. 
 


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10. 
Assessment Methods 
All study assessments will be performed at the visits and time points outlined in the Schedule of 
Assessments (Table 3). The following sections outline the details and procedures associated with 
the assessments. All assessments will be recorded on a source document with the exception of 
staff or subject completed questionnaires. 
10.1. 
Alcohol Breathalyzer 
An alcohol breathalyzer will be administered at consent, at screening, and at every in-clinic visit 
as a safety measure. Acceptable BAC level at consent is equal to 0.000 and ≤ 0.020 for all other 
in-clinic visits prior to performing other assessments. However, if the BAC is > 0.02, then safety 
assessments will be performed as described in section 7.9.  
10.2. 
Adverse Events and Serious Adverse Events 
The investigator and study site staff are responsible for the detection, documentation, 
classification, reporting, and follow up of events meeting the definition of an AE or SAE. 
10.2.1. 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and may not necessarily have a causal relationship with 
the administered treatment. An AE can therefore be any unfavorable and unintended sign 
(including a clinically significant laboratory abnormality), symptom, or disease temporally 
associated with the use of an investigational product, whether or not related to the investigational 
product. Pre-existing conditions, diseases, or disorders are not considered AEs unless there is a 
change in severity or frequency. 
10.2.2. 
Serious Adverse Events and Serious Unexpected Adverse Events Definition 
An SAE is any untoward medical occurrence that meets one of the following: 
• Results in death 
• Is life-threatening (at the time of the event) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
A serious and unexpected AE is an SAE that is not identified in nature, intensity, or frequency in 
the risk information included in the Product Label for the drug. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the study subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in the definition. 


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10.2.3. 
Methods/Timing for Assessing, Recording, and Analyzing Safety Endpoints 
AEs will be assessed at study visits starting after the first administration of investigational 
product until the final follow-up visit. However, SAEs will be collected from the time of 
informed consent onward. General symptoms will be collected via an open ended question: How 
have you been feeling since your last visit or the last time we spoke? Elicited AEs will be 
assessed as described in section 10.2.4. 
AEs will be documented in the source records, and recorded on the eCRF using accepted medical 
terms and/or the diagnoses that accurately characterize the event. When a diagnosis is known, the 
AE term recorded on the CRF will be the diagnosis rather than a constellation of symptoms. The 
investigator will assess all AEs for seriousness, relationship to investigational product, and 
severity. When an event has not resolved by study closure, it will be documented on the AE CRF 
as “ongoing”. 
If a woman has a positive pregnancy test after enrollment, the NIAAA Medical Monitor will be 
contacted and the pregnancy will be recorded as an AE. The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been terminated or completed. 
The outcome of the pregnancy will be reported to the NIAAA Medical Monitor without delay 
within 24 hours of knowledge of the event if the outcome is a SAE (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed by study physicians until satisfactory resolution (the event either 
resolved or stabilized and is not expected to resolve in the near term). AEs must be reported up 
to 2 weeks following completion of, or termination from investigational product administration. 
At the follow-up telephone contact, AEs will be recorded and followed to resolution only if they 
are serious, or if the study physician assesses them to be clinically significant. 
Besides routine monitoring of AEs during the conduct of the study, data presented to the DSMB 
will include an analysis of AEs in subjects taking a CYP3A-sensitive substrate as well as at the 
conclusion of the study. 
10.2.4. 
Elicited Adverse Events 
In addition to asked the open ended question regarding AEs, 3 specific questions about AEs will 
be asked at clinic visits and telephone calls: 
1. Have you noticed any changes in your appetite? 
2. Have you noticed a heat sensation (flushing or feeling hot) while you were drinking 
alcohol? 
3. Have you noticed any increases in your heart rate or heart palpitations while you were 
drinking alcohol? 
If the subject responds affirmatively to any of the above questions, then a designed clinician will 
interview the subject to determine the severity and relationship of the AE to the study drug, and 
if any actions should be taken (i.e., dose reduction or discontinuation of the study drug). 


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10.2.5. 
Classification of Adverse Event Severity and Relationship to Investigational 
Product 
For each recorded AE or SAE, a physician-investigator must make an assessment of severity. For 
those AEs included in the National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE version 5.0), these severity criteria will apply. For those not listed in the 
CTCAE, the following criteria will be used: 
Mild: 
An event that is usually transient, requiring no special treatment, and does 
not generally interfere with the subject’s daily activities. 
Moderate: 
An event that interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the 
subject. The event is usually ameliorated with additional specific 
therapeutic intervention. 
Severe: 
An event that interrupts usual activities of daily living or significantly 
affects clinical status. The event poses a significant risk of harm to the 
subject and hospitalization may be required, and typically requires 
intensive therapeutic intervention. 
Life-
threatening 
An event that puts the subject into imminent risk of death without 
intervention. 
 
Abnormal clinical laboratory findings for which a severity grade is available in the National 
Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 5.0) will be 
reported as an AE unless the value was outside normal laboratory limits at baseline and did not 
increase by a severity grade level at the follow-up assessment. For laboratory tests not listed in 
the CTCAE that are outside of normal laboratory limits, the investigator must make a 
determination if test results are clinically significant. An abnormal lab value will be deemed 
clinically significant if either of the following conditions is met: 
• The abnormality suggests a disease and/or organ toxicity that is new or has worsened 
from baseline. 
• The abnormality is of a degree that requires additional active management, e.g., 
change of dose, discontinuation of the drug, close observation, more frequent 
follow-up assessments, or further diagnostic investigation.  
Likewise if blood pressure (BP) was elevated at baseline (systolic BP 120 - 150 mmHg or 
diastolic BP 80 - 90 mmHg) and increased to a level indicative of an increase in the severity 
grade, hypertension will be reported as an AE and the severity grade will be in accordance with 
the criteria in the CTCAE version 5.0.  
The investigator must make an assessment of relationship to the investigational product based on 
the following criteria: 
Unrelated: 
The subject did not receive the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the 
investigational product is not reasonable, or there is another obvious cause of 
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Unlikely: 
There is evidence of exposure to the investigational product but there is 
another more likely cause of the AE/SAE. 
Possible: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the 
investigational product is reasonable, but the AE/SAE could have been due 
to another equally likely cause. 
Probable: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the 
investigational product is reasonable, and the AE/SAE is more likely 
explained by the investigational product than by any other cause. 
Definite 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the 
investigational product is reasonable, the AE/SAE is more likely explained 
by the investigational product than by any other cause, and the AE/SAE 
shows a pattern consistent with previous knowledge of the investigational 
product or investigational product class. 
10.2.6. 
Outcomes and Actions Taken 
All unresolved AEs will be followed for a minimum of 14 days (unless the AE is an ongoing 
pregnancy which must be followed to conclusion) after the subject’s final study visit, unless the 
investigator’s judgment dictates otherwise, the event has resolved or stabilized prior to the 
14-day period, or the subject is lost to follow-up. 
Investigators are not obligated to actively seek AEs or SAEs in former study subjects that occur 
following the follow-up period. 
For each recorded AE or SAE, the investigator must make an assessment of outcome at the time 
of last observation, as follows: 
Fatal: 
The subject died. 
Resolved without Sequelae: 
The AE or SAE has ended. 
Resolved with Sequelae: 
The AE or SAE has ended but changes are noted 
from baseline. 
Unresolved – Ongoing: 
The AE has not ended and is ongoing at the end of the 
reporting period (i.e., 14 days after the final Follow-up 
visit) or the investigator deems that further follow up is 
not medically required 
Unknown – Lost to Follow-up: 
Lost to follow-up at least 2 repeated unsuccessful 
attempts to contact the subject. 
 
Actions taken with respect to investigational agents (discontinuation or not) will also be 
recorded. In addition, if the AE was treated (medications or other physical measures), this will 
also be recorded. 


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10.2.7. 
Reporting Serious Adverse Events 
10.2.7.1. 24 hour Reporting Requirements (Initial Report) 
Any SAE, including death due to any cause, which occurs to any subject from the time of 
admission through discharge whether or not related to the investigational product, must be 
reported within 24 hours of knowledge of the event to the NIAAA Medical Monitor or alternate. 
Ms. Megan Ryan will coordinate communications to the Medical Monitors. Contact her as 
follows: 
Megan Ryan: Tel: (301) 443-4225; Email: mryan1@mail.nih.gov  
The following information must be provided with the initial report of an SAE or unexpected AE. 
A reporting form will be provided. 
• Name of person reporting the SAE/unexpected AE 
• Subject's I.D. number 
• Name of the PI and institution 
• Date the subject signed informed consent 
• Date first dose of investigational product was ingested 
• Description of the SAE/unexpected AE 
• Date and time of Onset 
• Date/time of administration of last dose of investigational product prior to the 
SAE/unexpected AE 
• Severity of the SAE/unexpected AE 
• Investigator's assessment of the relationship of the SAE/unexpected AE to 
investigational product (related, possibly related, probably related, unlikely related, 
not related) 
• Any action taken with the investigational product, alteration to protocol defined 
schedule, diagnostics, and treatments secondary to the SAE/unexpected AE. 
3-Day Supporting Documentation Requirements 
Written documentation for all SAEs/unexpected AEs must be received by the NIAAA Medical 
Monitor/Alternate within 3 days of reporting the event. Required documents that must be 
submitted include the following: 
• SAE Form 
• Concomitant Medication eCRF pages 
• AE eCRF pages 
• Copies of source documents pertinent to the event (lab reports, ECG tracings, medical 
chart notes, etc.) 


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• Any other relevant information necessary to facilitate the investigator’s judgment 
regarding the SAE’s relatedness to the severity OR by request of the Medical 
Monitor/Alternate 
These documents must be submitted by either email attachments or via overnight courier. 
10.2.7.2. Reporting to the IRB 
Unanticipated problems involving risk to subjects or others, SAEs related to participation in the 
study and all subject deaths should be promptly reported by phone, email, or fax to the central 
IRB. 
Investigators are required to forward safety information provided by the sponsor’s representative 
to the IRB. 
10.3. 
ALDH2 Genetic Test  
An approximately 2.5 mL sample of whole blood sample will be collected to assess ALDH2 
status after the subject is determined to be eligible for the study at the randomization visit. If for 
some reason, the sample was not collected at baseline, it can be collected at any subsequent visit 
as this is a genetic test. Samples will be sent to QPS LLC Delaware Technology Park, 3 
Innovation Way, Suite 240, Newark, DE 19711 for analysis at the end of the study. QPS will 
provide sample kits for blood collection. Additional details on sample collection, storage, and 
shipment for analysis will be provided in the Study Manual of Procedures. 
10.4. 
Alcohol Craving Scale – Short Form – Revised (ACQ-SF-R) 
The ACQ-SF-R contains 12-items adapted from the 47-item ACQ-NOW developed by Singleton 
(1994) to assess craving for alcohol among alcohol users in the current context (right now). 
There are 4 subscale scores for compulsivity, expectancy, purposefulness and emotionality and a 
total score. Each item has a 1 to 7 raw score (from strongly disagree to strongly agree). The sum 
of the raw scores for each factor is divided by 3 to yield a factor based score. Items 3, 8, and 11 
are reverse keyed. A general craving index is derived by summing all items and dividing by 12. 
This form takes ~5 minutes to complete. This questionnaire will be completed by the subject and 
will be both the source and an eCRF. 
10.5. 
Birth Control Record 
Birth control methods for both males and females will be recorded on a source document and an 
eCRF. 
10.6. 
Brief Drinking Questionnaire 
If a subject has completed the human lab assessment and is withdrawn from the study early and 
is no longer participating in clinic visits or providing TLFB drinking data but is willing to be 
contacted by phone at the week most proximal to dropout, then they will be asked a series of 6 
questions that assess quantity and frequency of drinking, heavy drinking, and maximal drinking 
since the last day that non-missing TLFB data was provided. Phone calls will continue until the 
end of the treatment period, as deemed acceptable by the patient, to obtain data on the secondary 
drinking endpoints. The rules regarding standard drinking units (SDU) applies (see Table 6 for a 


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definition of SDU). These data will be recorded on a source document and an eCRF. This does 
not apply to subjects who are willing to supply daily drinking data by the TLFB method. 
10.7. 
Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-AR) 
The CIWA-AR modified telephone version is an adaptation for telephone administration of the 
CIWA-AR a brief 10-item measure used to provide a quantitative index of the severity of the 
alcohol withdrawal syndrome (Sullivan-1989). The CIWA-AR has been used both in clinical and 
research applications and has demonstrated both reliability and validity (Sellers-1992, 
Stuppaeck-1994). This questionnaire will be administered by a clinical staff member and subject 
responses will be recorded and will be both the source and an eCRF. 
10.8. 
Clinical Laboratory Tests 
10.8.1. 
Chemistry Tests 
Clinical laboratory tests will be performed at the clinical site’s local clinical laboratory. 
Laboratories performing these assessments should be directly regulated by the College of 
American Pathologists (CAP) or Clinical Laboratory Improvement Act (CLIA) guidelines. The 
laboratory will need to provide a copy of current certification. All clinical laboratory data will be 
reviewed by the investigator for clinical significance. The total blood volume is approximately 
76 mL. Additional laboratory samples may be taken at the discretion of the investigator if the 
results of any tests fall outside reference ranges or clinical symptoms necessitate testing to ensure 
safety. Clinical chemistry tests include: creatinine, total bilirubin, ALT, AST, alkaline 
phosphatase, GGT, and albumin. 
Serum creatinine levels will be used to calculate creatinine clearance (CrCl) according to the 
Cockroft-Gault (1976) formula as follows: 
 
Males 
CrCl (mL/min) = 
(140 – age in years) x body weight in kg 
72 x serum creatinine mg/dL 
Females 
CrCl (mL/min) = 
0.85 x (140 – age in years) x body weight in kg 
72 x serum creatinine mg/dL 
For any laboratory test value outside the reference range that the investigator considers clinically 
significant: 
• The investigator will repeat the test to verify the out-of-range value 
• The investigator will follow the out-of-range value to a satisfactory clinical resolution 
• A laboratory test value that requires a subject to be discontinued from the study or 
requires a subject to receive treatment will be recorded as an AE 
10.8.2. 
Hematology Tests 
Hematology tests include: complete blood cell count with differential. 


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10.8.3. 
Thyroid Panel 
The thyroid panel includes: thyroid-stimulating hormone (TSH), thyroxine (T4) and free 
thyroxine (free T4), and triiodothyronine (T3). 
10.8.4. 
Medical Urinalysis 
A dipstick urinalysis will be performed that tests for specific gravity, ketones, pH, protein, blood, 
glucose, nitrites, bilirubin, and leukocyte esterase. If the dipstick is positive for blood, leukocyte 
esterase, or protein, then a microscopic analysis will be performed at the discretion of the 
investigator. 
10.8.5. 
Pregnancy Test  
An FDA approved rapid result urine pregnancy test will be used (i.e., dipstick test). If applicable, 
subjects will be asked to sign a release of information form for study personnel to access medical 
records to obtain information regarding the outcome of a pregnancy that occurred during the 
study. 
10.9. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a 4-page form asking questions about suicidal ideation, intensity of ideation, and 
suicidal behavior developed by Posner and collaborators at the New York State Psychiatric 
Institute (Oquendo-2003). This scale is intended for use by trained administrators. The questions 
contained in the C-SSRS are suggested probes. Ultimately, the determination of the presence of 
suicidality depends on clinical judgment. Training is required before administering the C-SSRS 
through a 30-minute interactive slide presentation followed by a question-answer session through 
the Columbia Lighthouse Project web site (http://cssrs.columbia.edu). Those completing the 
training are certified to administer the C-SSRS, and will receive a training certificate. As the 
MINI will be used to establish subject initial eligibility with respect to suicidality, the “Since 
Last Visit” version of the C-SSRS will be used at each clinic visit starting with Visit 1 at Week 
1. At Visit 1, Week 1, this scale will be used to assess current suicidal ideation since the MINI 
interview. This questionnaire will be administered by a clinical staff member and subject 
responses will be recorded on an eCRF. 
10.10. 
Cigarette Smoking Quantity-Frequency and Nicotine Use Questionnaire 
A smoking quantity frequency and nicotine use interview will include 3 questions to assess 
nicotine use via cigarette smoking or via other products during the study: 1) Over the past week, 
on how many days did you smoke cigarettes?; 2) On the days you smoked during the past week, 
how many cigarettes did you smoke on average?; and 3) Over the past week, on how many days 
did you use other nicotine products (ex. chew, cigars, cigarellos, e-cigarettes, vape, gum, patch, 
etc...)? This questionnaire will be completed by the subject electronically and will be both the 
source and eCRF. 


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10.11. 
Cue Reactivity Sessions 
10.11.1. 
Screening Session 
Subjects will be familiarized with laboratory procedures during a practice cue reactivity session 
during screening. The methodology is presented in Mason (2009). 
Subjects will be escorted to a comfortable chair in a lighting-controlled, sound-attenuated room 
for the screening alcohol cue reactivity session. Subjects will be given a 4 ounce (oz) glass of 
water to drink before starting the session. Following a 90 second rest period, a standardized glass 
of water will be placed on a small table after which subject will be instructed to pick it up and 
smell it, but not drink it, for duration of 3 minutes. Immediately after, the subject will complete a 
series of four VAS craving questions. The water will be removed and after a 90 second rest 
period, the subject’s typical alcoholic beverage will be placed on a small table after which the 
subject will be instructed to pick it up and smell it, but not drink it, for duration of 3 minutes. 
Immediately after, the subject will complete the same 4 VAS craving questions and a beverage 
liking VAS item. The alcohol beverage will be removed and without any waiting period, the 
same alcoholic beverage will be placed on a small table after which subject will be instructed to 
pick it up and smell it, but not drink it, for duration of 3 minutes. Immediately after, the subject 
will complete the same 4 VAS craving questions and a beverage liking VAS item (see Section 
10.11.2 for the beverage liking item).   
Alcohol craving in response to a water and typical alcohol beverage cue is assessed using 4 
individual VAS items adapted from the ACQ (Singleton-1994).  
The VAS craving scale items include in the following order: 
1. How strong is your craving to drink alcohol? 
2. Having a drink would make things just perfect. 
3. If I could drink alcohol now, I would drink it. 
4. It would be hard to turn down a drink right now. 
Anchors (scores) for items 1, 3, and 4 are: Strongly Disagree (0) to Strongly Agree (20). 
Anchors (scores) for question 2 are: None (0) to Extremely Strong (20). 
Subjects must have a VAS alcohol craving rating on the VAS item, “How strong is your craving 
to drink alcohol?” upon the first presentation of the alcohol cue >5 during this Mini Cue session 
at screening to be eligible for the study. 
10.11.2. 
During Treatment Session 
This assessment, conducted at Week 2, should be scheduled for as late in the afternoon as 
possible. Check subject compliance with investigational product using the AiCure smartphone 
application. If for some reason, the application is not working, check with the subject by 
self-report if they have taken at least 1 of the 2 prescribed tablets per day for the 3 days prior to 
the session and the on the morning of the session. Subjects must fulfill the following criteria 
before conducting the session: 


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1. Must have taken at least half the target dose per day during the 3 days prior to the 
session. 
2. Must have taken at least half of the morning dose of investigational product on the day of 
the session. 
3. Must have BAC ≤ 0.02 prior to starting the session. 
4. Must have CIWA score < 8. 
If any of the above conditions are not met, then the session cannot be conducted at that visit but 
can be rescheduled for another session no more than 7 days thereafter.  
If the criteria above are met, then the session will be conducted as presented in Table 5. A 
detailed description of the study procedures is provided in the Study Manual of Procedures 
(MOP). All subjects will be required to drink 4oz of water and will be offered a restroom break 
prior to the session start. 
Table 5: 
Schedule of Events for Cue Reactivity Session During Treatment 
Visit Start 
Subject arrives; all assessments for Study Week 2 are conducted (except Take 
Control) including: alcohol breathalyzer, urine drug test, C-SSRS, vital signs, 
concomitant medications, AEs, CIWA-AR, ACQ-SF-R, PK blood draw, drug 
accountability, TLFB, PACS, smoking quantity/frequency and nicotine use. 
Preparation for 
Session 
Prepare the subject for the session including a 90 second rest period prior to 
presenting the water cue to the subject  
Session Start 
Step 1: In vivo beverage cue: water is placed in front of subject for 3 minutes. 
Step 2: Ratings: subjects completes VAS craving and beverage liking VAS in 
presence of beverage cue. 
Step 3: Beverage removed from testing area after completion of ratings. 
Step 4: After a 90 second wait, repeat steps 1- 3 using presentation of the 
subject’s typical alcohol beverage. 
Step 5: Without waiting, repeat steps 1-3 again using another preparation and 
presentation of the subject’s typical alcohol beverage 
Post Session 
ACQ-SF-R is assessed to verify that craving has returned to pre-test levels or 
below.  
Take Control module will be viewed. 
Study Drug Bottle 1 is returned to the subject and Study Drug Bottle 2 is 
dispensed. 
The next appointment is scheduled.  
After confirmation of eligibility to participate in the session and completion of clinical 
assessments, subjects will be escorted to a comfortable chair in a lighting-controlled, 
sound-attenuated room for the cue reactivity session.  
During the cue session, subjects will be presented with a standardized glass of water (first 
session) then their typical alcoholic beverage (e.g., vodka, lager beer) (second session), followed 
by another preparation and presentation of the typical alcoholic beverage (third session). The 
water or alcohol beverage is presented in the subject’s preferred mode of consumption (e.g., 
small tumbler for vodka, Pilsner glass for beer), and subject is instructed to hold and smell the 


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beverage for 3 minutes. Specific alcohol brand preferences are accommodated whenever 
possible, including choices of mixers (e.g., vodka will be poured into a glass along with orange 
juice if the typical drink were a screwdriver). 
Following each beverage exposure period, subjects will complete all VAS scales (subjective 
craving and emotional response) by making selections from the computer screen (or paper form 
in the event that a computer or tablet is not available). The beverage will then be removed, then 
the procedure will be repeated for the remaining beverage(s). 
The assessments to be conducted during the Cue Reactivity Sessions include: 
1. Same 4 VAS scales that were conducted during the screening session (section 10.11.1). 
2. Beverage liking question 
The beverage liking question is a 20-point VAS item as follows: 
 “How much did you like the beverage just given to you?” (with an anchor of 0 on the left 
indicating “Strongly Dislike” and a 20 on the right indicating “Strongly Like”).  
All of the subjective measures will be recorded by the subject directly on an eCRF. In addition, 
the name (brand and type) of the typical beverage and the alcohol by volume (% alcohol) content 
will also be recorded on an eCRF by a member of the study staff. If a computer is not available, 
paper forms will be provided as a source document that will be transcribed into the eCRF. 
10.12. 
Demographics 
Demographics data include the subject’s age, gender, race/ethnicity, marital status, education, 
employment pattern, occupation, and income level. These data will be collected by site staff on a 
source document and onto an eCRF. 
10.13. 
Drinking Goal 
A subject’s drinking goal will be assessed to determine the desire and motivation to completely 
abstain from drinking alcohol or reduce drinking without abstinence. 
The Drinking Goal Questionnaire includes 4-items that will be administered by a member of the 
study staff. The questions include: 
1. What goal have you chosen for yourself about drinking by the end of the study? 
a. To stop drinking 
b. Reduce drinking but not stop 
2. Subjects who respond to question 1 with “Reduce drinking but not stop” will be asked to 
estimate, having achieved their drinking goal, the number of drinks they might consume 
on each day of a typical week. 
All subjects will be asked questions capturing: 
3. The level of motivation to reach this goal. Responses are a 1 to 10 scale with 1=not 
motivated and 10 = extremely motivated. 
4. The level of confidence to reach this goal. Responses are a 1 to 10 scale with 1=not 
confident and 10 = extremely confident. 


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10.14. 
ECG 
A 12-lead resting ECG will be obtained. Any abnormalities will be noted and an assessment of 
clinical significance will be done by a study physician. These data will be collected by site staff 
on a source document and onto an eCRF. 
10.15. 
Eligibility Checklist 
The Eligibility Checklist which includes all inclusion and exclusion criteria will be reviewed in 
stages as follows: 1) after screening measures are completed and before scheduling the Study 
Day 1 visit and 2) prior to randomization on Study Day 1. If the subject is not eligible for the 
study, the reasons for ineligibility will be recorded on an eCRF. These subjects will be 
considered screen failures. 
10.16. 
Exit Interview 
At the Week 6 visit, the subject will complete a questionnaire regarding their study experience. 
Questions will include: 
1. Did you think you were receiving the study drug or the placebo?  
2. What is your desire to please people? 
3. If you had the opportunity in the future to take the study drug again, would you continue 
to take it for more than 5 weeks?  
4. Did you limit your drinking because of flushing (a heat reaction or facial redness)?   
5. Did you limit your drinking because of nausea or other effects?  
6. Did your friends or family notice flushing?  
7. If your friends or family noticed flushing, did this change your drinking?   
8. Did you ever miss a dose of medication to avoid these effects? 
9. Did you use any other services during the study to help you reduce drinking? 
This eCRF will be used as the source document. 
10.17. 
GS-548351 Plasma Levels 
GS-548351 (the active moiety of the prodrug ANS-6637) will be measured plasma using a 
validated liquid chromatography – mass spectrometry assay. Venous blood will be collected 
twice during the study (see Table 3) to assess subject compliance with investigational products. 
Details of blood collection, sample preparation, storage and shipment to a central laboratory for 
testing will be described in the Study MOP. Briefly, samples for determining plasma levels of 
will be collected at Weeks 2 and 4. If the blood collection is missed at Weeks 2 or 4, then the 
sample will be collected at the next blood draw. Blood will be collected in 6 mL Vacutainer™ 
tubes containing K2-EDTA anticoagulant. Plasma will be collected after centrifugation (at room 
temperature or refrigerated) and two aliquots of each subject’s plasma will be stored at  < -20°C 
for up to one year, then at ≤ - 70°C, thereafter. One aliquot of each replicate plasma sample will 


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be shipped on dry ice to the testing lab at the end of the study for analysis. PPD Laboratories, 
3230 Deming Way, Middleton, WI 53562 will be the testing laboratory. Collection tubes, labels, 
and associated shippers will be provided by PPD. 
10.18. 
Locator Form 
After signing informed consent, subjects will be asked to provide names, addresses, and phone 
numbers of several friends and/or family members who can be contacted if the subject cannot be 
located (Locator Form). This locator form will be used to assist in contacting subjects between 
visits and at follow-up. This form asks subjects his/her name, address, and phone number and to 
provide names, addresses, and phone numbers of several friends and family members who can be 
contacted if the subject cannot be located. This information is essential and will be collected 
during screening, and will be updated throughout the study as necessary. This information will 
remain exclusively at the site. 
10.19. 
Medical History 
A medical history will be taken for all potential study subjects to assure medical fitness during 
screening. The medical history will be updated on the day planned for randomization by asking 
the subject if anything has changed since the initial screening interview. Besides general medical 
history items, potential study subjects will be asked about family history of Parkinson’s Disease 
and personal history of Parkinson’s disease, history of severe reactions to alcohol consumption 
(flushing and heart rate increases/palpitations). 
10.20. 
MINI 
The MINI (paper version 7.0.3) is a short structured diagnostic interview, developed jointly by 
psychiatrists and clinicians in the United States and Europe, for DSM-5 and ICD-10 psychiatric 
disorders (Sheehan-1998). With an administration time of approximately 15 minutes, it was 
designed to meet the need for a short but accurate structured psychiatric interview for multicenter 
clinical trials and epidemiology studies and to be used as a first step in outcome tracking in 
non- research clinical settings. Diagnoses recorded on the MINI will be recorded on the 
interview form and entered onto an eCRF. The individual items of the Alcohol Use Disorder 
Module will be also collected on an eCRF in addition to all other diagnoses. 
10.21. 
Penn Alcohol Craving Scale 
The PACS is a five-item self-administered instrument for assessing craving (Flannery-1999). 
Frequency, intensity, and duration of thoughts about drinking are assessed along with ability to 
resist drinking. The final item asks the responder to provide an average rating of his/her craving 
over the course of the past week. The questions on the PACS use descriptors coupled with 
numerical ratings ranging from 0 to 6. This questionnaire will be completed by the subject and 
will be both the source and an eCRF. 
10.22. 
Pittsburg Sleep Quality Index 
The PSQI is a 19-item questionnaire with 6 subscales (subjective sleep quality, sleep latency, 
sleep duration, habitual sleep disturbances, use of sleep medication and day time dysfunction) 
(Buysse-1989). Each subscale is rated from 0 to 3 with the higher scores reflecting more severe 


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sleep complaints. The addition of all the scores permits an analysis of the subject’s overall sleep 
experience in the past 30 days. The lower the overall score, the better the person sleeps. 
The tool has an adequate internal reliability, validity and consistency for clinical and community 
samples of the various populations. This questionnaire will be completed by the subject and will 
be both the source and an eCRF. 
10.23. 
PROMIS Alcohol Negative Consequences 
For negative consequences for alcohol use, the short form of the PROMIS Alcohol Negative 
Consequences questionnaire will be used to assess outcomes of alcohol use over the past 30 days 
(Pilkonis-2013).  
The 7 PROMIS items include:  
• Drinking created problems between me and others 
• I disappointed others when I drank 
• I was unreliable after I drank 
• Others complained about my drinking 
• I used poor judgment when I drank 
• I said or did embarrassing things when I drank 
• I had trouble getting things done after I drank 
Each item is rated on a 5 point scale including: Never (1), Rarely (2), Sometimes (3), Often (4),  
and Almost Always (5) for the past 30 days.   
10.24. 
Prior and Concomitant Medications 
All medications taken by the subject 2-months prior to the start of screening, during the 
screening period, and through the final follow-up contact will be recorded. All medications 
reported by the subject will be recorded on a source document and an eCRF. 
10.25. 
Profile of Mood State 
The POMS measures dimensions of affect or mood (McNair-2005). It consists of 65 adjectives 
to which the subject responds according to a 5-point scale ranging from “not at all” to 
“extremely.” Six subscale scores will be computed for items grouped as follows: Tension- 
Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and 
Confusion=Bewilderment. A total mood disturbance score will also be computed which consists 
of the sum of the 5 of the six subscale scores (the Vigor-Activity score is not included). This 
questionnaire will be completed by the subject and will be both the source and an eCRF. 
10.26. 
Physical Examination and Weight 
A physical examination of the oral cavity, head, eyes, ears, nose, and throat, cardiovascular 
system, lungs, abdomen, extremities, skin, neuropsychiatric mental status and sensory/motor 
status, musculoskeletal system and general appearance will be performed during screening. The 
physical exam will be updated on the day planned for randomization by querying the subject 


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about any physical changes since the screening examination. Weight (kg) will also be collected. 
These data will be recorded on a source document and an eCRF. 
10.27. 
Subject Disposition 
A subject disposition eCRF will be completed for all subjects who are randomized to the study 
and who are dispensed investigational product. This CRF will be used to record the following 
data as applicable: 1) completion status of the subject at the end of their participation and if they 
were discontinued early, and reason for early discontinuation. 
Completion status is as follows: 
1. Subject completed full study (Week 6). 
2. Subject completed the full intervention phase of the study (Week 5). 
3. Subject was withdrawn prior to the Week 6 visit (reasons for early withdrawal are to be 
specified). 
4. If the subject discontinued study medications, the date of discontinuation. 
Even if the subject had investigational product suspended for any reason but attended clinic 
visits, the above definitions still apply. 
In addition, if the subject was confined and/or incarcerated at any time during the study, the dates 
of confinement and/or incarceration will be collected. 
10.28. 
TLFB Interview 
Drinking behavior will be assessed using the TLFB methodology (Sobell-1992). The TLFB is a 
semi-structured interview that provides estimates of the daily quantity of alcohol consumption 
during specified time periods. It uses a calendar prompt and a number of other memory aids 
(e.g., holidays, payday, and other personally relevant dates) to facilitate accurate recall of 
drinking or other drug use during the target period. The procedure has been widely used in 
clinical and research contexts. It has demonstrated adequate levels of reliability and validity 
when administered as an in-person interview, over the telephone, and when administered via 
computer (Carey-1997, Sobell-1988, Sobell-1996). After consent is signed, the TLFB interview 
will be performed for the 28-day period prior to signing consent. Thereafter, the interview will 
be for the previous days between the last assessment and the day prior to the day of the 
assessment. It is estimated that a 28-day TLFB assessment will take 20 minutes to complete. In 
the event of missed visits, collection of missed drinking data at the following visit is required. 
If a subject requests to withdraw from the study but agrees to continued telephone contact to 
assess drinking, the TLFB will be performed over the phone for the duration of the study at a 
frequency acceptable to the study subject and site staff. 
An Excel spreadsheet customized for use in this study will be used for double data entry by 
clinical site staff to collect the TLFB drinking data. This spreadsheet contains a calculator to 
determine standard drink units (SDUs). This spreadsheet will be reviewed, compared with source 
documents and collected by study monitors for upload into the main study database. 
Drinking days are defined as the number of days in which the subject reported any alcohol 
consumption (i.e., > 0 standard drinking units [SDUs]). A standard drink contains approximately 


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0.6 fluid ounces (oz) of pure alcohol. The data given by the subjects on amount and type of 
alcoholic beverage(s) consumed will be converted to SDUs. Standard drink unit definitions are 
provided in Table 6. 
Table 6: 
Standard Drink Unit Definitions 
For Beer (~ 5% alcohol), the approximate number of SDUs in: 
• 12 oz = 1.0 
• 16 oz = 1.3 
• 24 oz = 2.0 
• 40 oz = 3.3 
For malt liquor (~ 7% alcohol), the approximate number of SDUs in: 
• 12 oz = 1.4 
• 16 oz = 1.9 
• 22 oz = 2.6 
• 40 oz = 4.7 
For table wine (~ 12% alcohol), the approximate number of SDUs in: 
• 750 mL bottle = 25oz = 5.0 
• 5 oz glass = 1.0 
• 10 oz glass = 2.0 
For 80 proof spirits (~ 40% alcohol), or hard liquor, the approximate number of 
SDUs in: 
• 1.5 oz (mixed drink) = 1.0 
• 16 oz (pint) = 8.5 
• 25 oz (a fifth) = 17.0 
• 1.75 L (59 oz) = 39.0 
 
10.29. 
Urine Drug Test 
An FDA cleared, CLIA waived urine drug test card will be used to assess candidates for recent 
use of opiates (i.e., morphine test), cocaine, amphetamines, methamphetamine, THC, 
buprenorphine, methadone, benzodiazepines, oxycodone, barbiturates, 3,4-methylenedioxy-
methamphetamine (MDMA – also known as ecstasy), and EtG. If positive for opioids but recent 
opiate use for acute pain is reported by the subject, then the subject can be re-screened. If 
positive for these drugs at other times during the study, the subject will not be removed from the 
study but should be asked about medication use and possibly re-evaluate their medical history for 
substance abuse. EtG is a biomarker of recent alcohol consumption that provides an objective 
measure of abstinence (Jatlow-2014). These data will be recorded on a source document and 
eCRF. 
10.30. 
Vital Signs 
Vital signs to be assessed include sitting blood pressure and pulse rate. Vital signs will be taken 
after resting seated in a chair for at least 3-5 min with both feet on the floor, legs not crossed 
with the arm used for the blood pressure measurement at approximately chest height with 
support. These data will be recorded on a source document and an eCRF. 


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10.31. 
World Health Organization Drinking Risk Categorical Scale 
The WHO has developed a drinking risk categorical scale that can be used in a responder 
analysis approach to assess clinically relevant decreases in alcohol consumption (Aubin-2015). 
Two dichotomous endpoints will be analyzed: WHO 1-level and WHO 2-level decrease in 
alcohol consumption. The WHO 1- and 2-level decrease endpoints are the percentage of subjects 
experiencing at least a 1- and 2-level decrease in WHO levels of alcohol consumption, 
respectively, from the level at baseline (the period including the 28 days before screening) to the 
level during the treatment phase (e.g., Study Weeks 9-12).  
The WHO levels of average alcohol consumption per day are as follows: 
             
 
 
Males              Females 
Low Risk        
1 to 40g            1 to 20g 
Medium Risk    
41 to 60g          21 to 40g 
High Risk       
61 to 100g        41 to 60g 
Very High Risk  101+g               61+g 
where 14g = 1 SDU (WHO-2000). In computing the WHO alcohol consumption level, average 
drinks per day will be used, computed as the sum of all drinks in the 28 day period divided by 
the number of days with non-missing drinking data in that period. Abstinent subjects will be 
included in a separate “Abstinent” category.  
 


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11. 
Statistical Methods and Determination of Sample Size 
A formal statistical analysis plan (SAP) will be finalized prior to locking the database and 
commencing with the analysis. The main study database can be locked prior to receipt of the 
plasma concentration data and the ALDH2 genetics testing data from the central laboratories. 
11.1. 
Statistical Hypotheses 
Primary Efficacy Endpoint: Subjects treated with ANS-6637 600 mg/day will report 
significantly lower VAS alcohol craving ratings in response to in vivo alcohol cues during human 
lab testing than ANS-6637 200 mg/day and placebo-treated subjects. Subjects treated with 
ANS-6637 200 mg/day will have significantly lower VAS alcohol craving ratings in response to 
in vivo alcohol cues than placebo-treated subjects.  
The hypotheses for the confirmatory secondary endpoints for the cue reactivity sessions are the 
same as for the primary endpoint.  
Secondary Efficacy Endpoints: In the same dose-response manner, it is hypothesized that, 
during the last 4 weeks of the treatment period, the ANS-6637 groups, as compared to the 
placebo group, will: 
1. Increase the percentage of subjects with no heavy drinking days. A “heavy drinking day” 
is 4 or more drinks per drinking day for women and 5 or more drinks per drinking day for 
men. 
2. Increase the percentage of subjects abstinent from alcohol 
3. Increase the percentage of subjects with at least a WHO 2-level decrease in alcohol 
consumption 
4. Increase the percentage of subjects with at least a WHO 1-level decrease in alcohol 
consumption 
5. Increase the percentage of days abstinent per week 
6. Decrease the percentage of heavy drinking days per week 
7. Decrease the percentage of very heavy drinking days per week 
8. Decrease the weekly mean number of drinks per week 
9. Decrease the weekly mean drinks per drinking day 
10. Decrease the weekly mean cigarettes smoked per week among smokers 
11. Increase the percentage of subjects abstinent from nicotine use among subjects who used 
any nicotine products in the week before randomization 
12. Decrease the mean alcohol craving score (PACS) 
13. Decrease the mean PSQI score 
14. Decrease total mood disturbance (POMS) 


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11.2. 
Analysis Populations 
The study analysis populations will consist of the following: 
Modified Intention-to-Treat (mITT) Analysis Set: The mITT set is defined as subjects 
randomized to participate in the study that took at least one dose of investigational product and 
had a non-missing VAS craving primary endpoint. 
Evaluable Analysis Set: The evaluable analysis set for the secondary endpoints is defined as 
those subjects randomized to the study who took 2 tablets per day for at least 80% of days in 
Weeks 1-5.  
Safety Analysis Set: The safety analysis set includes all subjects who took at least one dose of 
investigational product. 
The mITT analysis set will be used for all efficacy endpoints listed in Section 11.1. Safety 
analyses will be conducted on the safety analysis set. The Evaluable analysis set will only be 
used for the primary and confirmatory efficacy endpoints and for select secondary efficacy 
endpoints. Selected secondary efficacy endpoints include for the evaluable subset analysis: 
• Weekly percentage of heavy drinking days 
• Mean number of drinks per week 
• PACS scores 
11.3. 
General Approach 
For descriptive purposes, dichotomous and categorical variables will be presented as number of 
observations and percentages; continuous variables will be given as means, standard deviations 
(SD), median, minimum (min) and maximum (max). Statistical tests will be two-tailed at a 0.05 
Type I error rate. P-values for the primary and confirmatory endpoints will use multiplicity 
adjustment to maintain a family-wise 0.05 significance level.  P-values for secondary endpoints 
of < 0.05 will be considered statistically significant with no adjustment. Endpoint data will also 
be screened for outliers and skewness. 
Continuous endpoint data that are not normally distributed will be transformed. Cohen’s d will be 
used to calculate the effect size for means and Cohen’s h will be used to calculate the effect size 
for proportions. Odds ratios will be provided for all dichotomous outcomes. 
11.4. 
Analysis Addressing the Primary Efficacy Endpoint 
Each subject will have an initial alcohol cue for “strength” of alcohol craving score from the 
VAS that is the primary endpoint. Analysis of covariance (ANCOVA) will be used to compare 
groups with the “strength” of alcohol craving value as the dependent variable and the 
pretreatment “strength’ of alcohol craving score from the first alcohol cue as an independent 
fixed effect. Clinical site will also be included as an independent factor. There are 3 comparisons 
(ANS-6637 600 mg vs placebo; ANS-6637 200 mg vs. placebo; ANS-6637 600 mg vs. ANS-
6637 200 mg) and Tukey’s method will be used to maintain a family-wise 0.05 significance 
level. 
 


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No imputation for missing endpoint data will be performed. 
11.5. 
Secondary Efficacy Endpoints Analysis 
There are 3 additional questions asked during the cue sessions for each beverage cue. Each of 
these questions will be analyzed in the same manner as the primary endpoint. Tukey’s method 
will be used within question and not across questions. An average of the 4 questions will also be 
analyzed in the same manner. The difference between the first alcohol cue and water cue for 
each VAS item will be computed at both the pre and post treatment time points. The difference 
values for each VAS item and the average difference will be analyzed similarly to the primary 
endpoint. Continuous secondary endpoints (percent heavy drinking days, percent very heavy 
drinking days, percent days abstinent, drinks per week, drinks per drinking day, number of 
cigarettes smoked per week, PACS, POMS, and PSQI score) during the last 4 weeks of treatment 
period will be analyzed using a mixed-effects model with site, assessment time, and baseline 
drinking as fixed factors. Models will also include time by treatment group interaction term. 
Additional covariates may be included that are significantly correlated with outcome and/or if 
there are differences across the treatment groups. 
Analysis of the dichotomous secondary endpoints (percentage subjects with no heavy drinking 
days, percentage subjects abstinent from alcohol, percentage of subjects achieving at least a one 
and two-level shift in WHO alcohol consumption, and no nicotine use among subjects with any 
use in the week prior to randomization) during the last 4-weeks of the treatment period will be 
conducted via logistic regression. Covariates may be included provided there are a sufficient 
number of events. 
No imputation for missing secondary endpoint data will be performed. 
11.6. 
Safety Outcomes 
AEs will be coded using the most recent version of the Medical Dictionary of Regulatory 
Activities (MedDRA) preferred terms and will be grouped by system, organ, and class (SOC) 
designation. The severity, frequency, and relationship of AEs to investigational product will be 
presented by preferred term by SOC grouping. Listings of each individual AE including start 
date, stop date, severity, relationship, outcome, and duration will be provided. Each AE (based 
on preferred terminology) will be counted once only for a given study participant. If the same 
AE occurred on multiple occasions, the highest severity will be assumed. Thus, study 
participants are not counted multiple times in a given numerator in the calculation of frequencies 
for a specific AE. The elicited AEs of flushing, heat sensation, heart rate increases or palpitations 
will be presented as counts and frequencies over all subjects and separately over the subjects 
who reported any of these as counts and frequencies of reported events by treatment groups and 
severity score for ALDH2 deficient and ALDH2 non-deficient subjects. A separate listing of 
AEs and summary table will be presented for subjects who took a drug that was a CYP3A-
sensitive substrate at any time during the study. Laboratory data, vital signs, ECG results, alcohol 
breathalyzer results, urine drug test results, and CIWA scores will be reported as summary 
statistics. The numbers and proportion of subjects who reported CIWA scores ≥ 10 at any time 
after the start of dosing will be presented. Changes in clinical laboratory tests and vital signs will 
also be presented as summary statistics of change from baseline. The number and percentage of 
subjects with a higher ACQ-SF-R score post cue session will be provided by treatment group. 


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11.7. 
Baseline Descriptive Statistics 
Summaries of the characteristics of the subjects in each of the study groups at baseline will be 
prepared for the mITT, evaluable, and safety analysis sets. Baseline characteristics will be 
compared between the ANS-6637 groups and placebo groups using appropriate statistical 
methods. 
11.8. 
Compliance and Participation Outcomes 
Medication compliance is defined as the amount of investigational products taken as a proportion 
of the total amount prescribed. Compliance will also be evaluated by determining the proportion 
of subjects who were prescribed ANS-6637, reported taking ANS-6637 (by AiCure assessment), 
and had a plasma sample with detectable GS-548351, the active moiety of ANS-6637. The 
participation rate is the percentage of subjects with complete drinking data. Compliance and 
participation rates will be reported on a weekly basis and across the entire trial duration. 
Compliance by GS-548351 plasma levels will be reported as number and percentage of subjects 
with a level above the limit of detection at each time point. Descriptive statistics will also be 
provided. 
11.9. 
Exploratory Endpoints 
The VAS responses to the second alcohol cue will be explored to determine if there are 
differences and if these differences might have any influence on the endpoints to guide for the 
design of future studies. 
11.10. 
Sample Size Justification 
Analysis of covariance with clinical site and baseline cue as the covariates will be used to model 
the primary outcome – the VAS craving score for the first alcohol cue. Statistical power was 
estimated using [PASS 13] with the following parameters. The treatment effect parameter—a 
maximal 3-point medication-placebo difference on the strength of VAS craving in response to 
the alcohol cue—was obtained from Roberts (2017), which used a similar cue reactivity 
paradigm. The mean values on this outcome at Week 2 are assumed to be 11 for 600 mg 
ANS-667, 12.5 for 200 mg ANS-667, and 14 for placebo and a standard deviation between 
subjects of 4. Clinical site and the baseline VAS craving for the alcohol cue were assumed to 
have correlations of 0.13 and 0.39, respectively, with the primary outcome. These correlations, 
coupled with assumed standard deviations for site and baseline VAS craving for the alcohol cue 
of 0.82 and 4, respectively, yield explained variation of 26%. These assumptions, with a sample 
size of 27 subjects per arm (81 total subjects), provides 82% statistical power with a 0.05 two-
sided significance level. Using the Tukey test to adjust for the pairwise treatment arm 
comparisons reduces the power to 81% with a family-wise Type 1 error of 0.05 in 1000 
simulations given the above assumptions. 


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12. 
Quality Control and Quality Assurance 
This study will be conducted under International Conference on Harmonization (ICH) Good 
Clinical Practice (GCP) guidelines and all applicable regulatory requirements. 
Actions to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers; the review of protocol procedures with the 
investigator and study personnel prior to study start; the design of suitable source documents 
with appropriate instructions for use; the internal audit of source data according to GCP and 
internal procedures to ensure their accuracy, completeness, and verifiability; as well as the 
periodic site monitoring by the Sponsor’s representatives (clinical monitors). Clinical monitors 
will review source documents and CRFs for accuracy and completeness during on-site 
monitoring visits; any discrepancies will be resolved with the investigator, as appropriate. 
Significant and/or repeated noncompliance will be investigated and remedial action instituted 
when appropriate. Failure to comply with remedial actions may result in study site termination 
and regulatory authority notification. 
12.1. 
Study Monitoring 
Study monitoring will be the responsibility of designated clinical monitors of NIAAA. Monitors 
will assure compliance with the clinical protocol and ICH GCPs, human subject’s protection, 
drug accountability, maintenance of the site regulatory file, and conformance of CRF data with 
source documents. Monitoring visits by clinical monitors will be scheduled to take place at the 
initiation of the study, during the study at appropriate intervals, and after the last subject has 
completed the study. A report of monitoring observations will be provided to the PI (for 
corrective actions) and the Sponsor. 
12.2. 
Audits and Inspections 
Authorized representatives of the Sponsor and the IRB may visit the site to perform audits or 
inspections, including source data verification. The purpose of the audit or inspection is to 
systematically and independently examine all study related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, GCP guidelines, and any applicable regulatory 
requirements. 
The PI should contact NIAAA if contacted by a regulatory agency about an inspection. 


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13. 
Ethics 
13.1. 
Central Institutional Review Board 
The study will be conducted under a protocol reviewed by a central IRB; the study is to be 
conducted by scientifically and medically qualified persons; the benefits of the study are in 
proportion to the risks; the rights and welfare of the subjects will be respected; the physicians 
conducting the study will ensure that the hazards do not outweigh the potential benefits; the 
results to be reported will be accurate; subjects will give their informed consent and will be 
competent to do so and not under duress; and all study staff will comply with the ethical 
principles in 21 Code of Federal Regulations (CFR) Parts 50 and 56 and the Belmont Principles. 
13.2. 
Review/Approval of Study Protocol 
The study may not begin until the IND has been submitted to the FDA and the 30-day waiting 
period has expired without notification by FDA to the Sponsor of any clinical hold issues. 
NIAAA will be the study Sponsor. The site must obtain written approval from the IRB to 
conduct the study before study initiation. NIAAA will issue a formal authorization letter for the 
study to be initiated at the site. Progress reports will be submitted to the IRB by the Investigator 
at the frequency requested by the IRB. 
13.2.1. 
Protocol Modifications 
All necessary protocol changes will be submitted in writing as protocol amendments to the IRB 
by Fast-Track for approval prior to implementation. NIAAA will submit all protocol 
amendments to the FDA. 
13.2.2. 
Protocol Deviation Reporting Procedures 
All subject-specific deviations from the protocol are to be documented. The PI or designee will 
be responsible for identifying and reporting all deviations, which are occurrences involving a 
procedure that did not follow the study protocol. Any protocol deviation that adversely affects 
the safety or rights of a subject or scientific integrity of the study is considered a major deviation 
and will be reported immediately to the NIAAA Project Manager and the central IRB. 
13.3. 
Ethical Conduct of the Study 
This study will be conducted in accordance with all applicable Federal human research 
protections requirements and the Belmont Principles of respect for persons, beneficence, and 
justice.  
The procedures set out in this study are designed to ensure that the sponsor’s representative and 
all study personnel abide by the principles of the ICH GCP Guideline and the Code of Federal 
Regulations (CFR). The PI confirms this by signing this study protocol and Form FDA 1572. 
 


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13.3.1. 
Confidentiality 
13.3.1.1. Confidentiality of Data 
Particular attention is drawn to the regulations promulgated by the FDA under the Freedom of 
Information Act providing, in part, that proprietary information furnished to clinical investigators 
and IRB will be kept confidential by the FDA only if maintained in confidence by the clinical 
investigator and IRB. 
By signing this protocol the investigator affirms to NIAAA that information furnished to the 
investigator by NIAAA will be maintained in confidence and such information will be divulged 
to the IRB or similar or expert committee; affiliated institution; and employees only under an 
appropriate understanding of confidentiality with such board or committee, affiliated institution 
and employees. 
13.3.1.2. Confidentiality of Subject Records 
To maintain subject confidentiality, all laboratory specimens, CRFs, reports and other records 
will be identified by a subject number only. Research and clinical records will be stored in a 
locked cabinet. Only research staff, NIAAA program officials, and NIAAA clinical monitors 
will have access to the records. Subject information will not be released without written 
permission, except as necessary for monitoring by representatives of NIAAA. Upon approval of 
the study by an IRB, an application will be filed with NIAAA for a Certificate of Confidentiality. 
By signing the protocol, the investigator agrees that within local regulatory restrictions and 
ethical considerations, NIAAA or any regulatory agency may consult and/or copy study 
documents in order to verify CRF data. 
13.3.2. 
Compensation for Participation 
Subjects will be compensated for travel expenses and for time contributed to this research study 
in the form of cash or vouchers. Compensation will be provided in increasing amounts with each 
subject visit and is detailed in the informed consent form. Payments will be in the amounts 
equivalent to $30 for the screening visit, $50 for the randomization visit, $100 for the Week 2 
cue reactivity session, $75 for Visits 4, 5, and 6, $90 for the final clinic visit (Visit 7), and $100 
for the final telephone follow-up, for a total of $595. 
13.3.3. 
Written Informed Consent 
The informed consent process and document will be reviewed and approved by the IRB and 
sponsor’s representative prior to initiation of the study. The consent document contains a full 
explanation of the possible risks, advantages, and alternate treatment options, and availability of 
treatment in the case of injury, in accordance with 21 CFR Part 50. The consent document 
indicates that by signature, the subject, permits access to relevant medical records by NIAAA or 
designated clinical monitors. 
A written informed consent document, in compliance with 21 CFR Part 50, 32 CFR Part 219, 
and the Belmont Principles, and HIPAA Authorization will be signed by the subject before any 
study-related procedures are initiated for each subject. 


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All potential subjects for the study will be given a current copy of the Informed Consent Form to 
read. All aspects of the study and informed consent will be explained in lay language to the 
subject by either the investigator, or a medically trained designee. Any subject who is unable to 
demonstrate understanding of the information contained in the informed consent will be 
excluded from study participation. 
All study subjects will be given a copy of the signed informed consent. 
13.3.4. 
Delegation of Responsibilities and Adequate Resources 
The PI should have adequate time to conduct the study properly and should have an adequate 
number of qualified staff to assist with the conduct of the study. 
The term “investigator” used throughout this protocol refers to the PI and/or qualified 
subinvestigators. The PI may delegate responsibilities to other study site personnel. The PI shall 
delegate tasks only to individuals qualified by education, training, and experience to perform the 
delegated tasks. The PI shall have direct oversight of all delegated activities and shall document 
delegation of responsibilities. The PI is responsible for ensuring all delegated staff has been 
properly trained on the protocol and their assigned study responsibilities. A delegation log 
identifying all delegated duties and the individual to whom they have been delegated will be 
maintained at the study site.  
13.3.5. 
Financial Disclosure 
Clinical investigators are required to provide financial disclosure information for the submission 
of certification or disclosure statements required under 21 CFR § 54. As defined in 21 CFR § 
54.2, a clinical investigator is a listed or identified investigator or subinvestigator who is directly 
involved in the treatment or evaluation of research subjects. The term also includes the spouse 
and each dependent child of the investigator. In addition, investigators must promptly update 
financial disclosure information if any relevant changes occur during the course of the 
investigation and for 1 year following completion of the study. 
 


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14. 
Data Handling and Record Keeping 
Source documents include but are not limited to original documents, data and records such as 
hospital/medical records (including electronic health records), clinic charts, laboratory results, 
data recorded in automated instruments, and pharmacy records, etc. This study will use an 
electronic data management system (EDMS) (IBM Clinical Development) and eCRFs provided 
by Fast-Track. Data will be transcribed from source documentation into web-based eCRFs. Only 
questionnaire data will be entered directly into eCRF (i.e., without prior written or electronic 
record of data). Paper copies of the eCRFs will be provided in the event that the site cannot 
access the EDMS at the time the questionnaire is being completed. The transcribed data will be 
consistent with the source documents or the discrepancies will be explained.  
Clinical monitors will review all source records and compare them to the data entered into the 
eCRF. All entries, corrections, and alterations will be made by the investigator or other 
authorized study personnel. Any errors identified during monitoring will have a query posted by 
monitor for site staff to address. The EDMS system maintains a full audit trail of data entry, data 
corrections, and data queries. 
Data from this study will be submitted to the National Institute on Alcohol Abuse and 
Alcoholism Database (NIAAADA) at the National Institutes of Health (NIH). NIAAADA is a 
data repository that allows researchers studying alcohol use disorder to collect and share de-
identified information with each other. 
14.1. 
Subject Identification and Confidentiality 
Subjects will be identified on eCRFs by a unique subject number. No personal identifier will be 
used in any publication or communication used to support this research study. The subject 
number will be used if it becomes necessary to identify data specific to a single subject. The 
Sponsor’s representative and designated clinical monitors of Fast-Track, the IRB, and the FDA 
are eligible to review medical and research records related to this study as a part of their 
responsibility to protect human subjects in clinical research. Personal identifiers will be removed 
from photocopied or electronic medical and research records. 
14.2. 
Inspection of Records 
The sponsor’s representative or designee will be allowed to visit the investigation facilities for 
the purpose of monitoring any aspect of the study. The investigator agrees to allow the monitor 
to inspect the drug storage area, investigational product stocks, drug accountability records, 
subject charts, study source documents, and other records relative to study conduct. 
Subjects’ health information is used to report results of research to the sponsor’s representative 
and Federal regulators and may be reviewed during study audits for compliance with study plans, 
regulations, and research policies. The consent document indicates that by signature, the subject 
permits access to relevant medical records by the sponsor’s representative and by representatives 
of the FDA. 
Upon a subject’s termination from the trial, completed eCRFs will be ready and available for on-
site review by the sponsor’s representative at scheduled monitoring visits. 


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14.3. 
Retention of Records 
The investigator is responsible for creating and/or maintaining all study documentation required 
by Title 21 Code of Federal Regulations (21CFR) Parts 50, 54, 56, and 312, ICH E6 section 8, as 
well as any other documentation defined in the protocol. The investigator must provide key 
documents to the Sponsor prior to start of the study. A complete list of required regulatory 
documents will be provided in the study Manual of Procedures. 
Federal and local regulations require that the investigator retain a copy of all regulatory 
documents and records that support the data for this study for whichever of the following is the 
longest period of time: 
• A period of 2 years following the final date of approval by the FDA or other regulatory 
agency of the study drug for the purposes that were the subject of the investigation; or 
• A period of 5 years following the date on which the results of the investigation were 
submitted to the FDA or other regulatory agency in support of, or as part of, an 
application for a research or marketing permit for the study drug for the purposes that 
were the subject of the investigation. 
The Sponsor will notify investigators once one of the above 2 timeframes has been satisfied. 
If the investigation does not result in the submission of the data in support of, or as part of, an 
application for a research or marketing permit, records must be retained for a period of 2 years 
following notification by the Sponsor that the entire clinical investigation (not merely the 
investigator’s portion) is completed, terminated, or discontinued or 2 years following withdrawal 
of the Investigational New Drug application/Clinical Trial Authorization or request for 
marketing approval (New Drug Application/Marketing Authorization Application).  
If the investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a person who will accept the 
responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian. Study records should not be destroyed without consultation with the Sponsor. 
14.4. 
Trial Registration 
NIAAA has registered the trial on the National Library of Medicine’s Clinical Trials Registry on 
the world wide web at http://www.clinicaltrials.gov. 
 


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15. 
Publication Policy 
Review of manuscripts resulting from this study or from data generated during this study must 
occur according to the NIAAA Publications Policy prior to submission for publication. 
Authorship shall be consistent with NIAAA policies. 


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17. 
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Lange LG, Diamond I. Suppression of heavy drinking and alcohol seeking by a selective 
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SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
PROTOCOL NO: HLAB-002 
 
Human Laboratory Study of ANS-6637 for Alcohol Use Disorder 
Protocol Version No.: 5.0 Version Date: 04Feb2020 
 
 
Study Sponsor:  National Institute on Alcohol Abuse and Alcoholism 
 
 
 
Version Number 1.0 
Date: 16 March 2020 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
3    
 
 Table of Contents 
1. 
ABBREVIATIONS ............................................................................................................. 12 
2. 
INTRODUCTION ............................................................................................................... 14 
3. 
PROTOCOL SUMMARY .................................................................................................. 15 
3.1. 
Study Objectives ..................................................................................................... 15 
3.1.1. 
Primary ...................................................................................................... 15 
3.1.2. 
Secondary .................................................................................................. 15 
3.2. 
Study Design .......................................................................................................... 15 
3.3. 
Study Endpoints ..................................................................................................... 20 
3.3.1. 
Primary Efficacy Endpoint ........................................................................ 20 
3.3.2. 
Secondary Efficacy Endpoints .................................................................. 20 
3.3.3. 
Safety Endpoints........................................................................................ 21 
3.3.4. 
Compliance ................................................................................................ 21 
4. 
DEFINITION OF ANALYSIS SETS ................................................................................. 22 
5. 
ASSSESSMENT AND JUSTIFICATION OF STUDY ENDPOINTS .............................. 23 
5.1. 
Alcohol Craving Visual Analog Scales .................................................................. 23 
5.2. 
Alcohol Consumption Endpoints ........................................................................... 23 
5.2.1. 
Daily Quantity of Alcohol Consumption .................................................. 23 
5.2.2. 
Drinking Days ........................................................................................... 23 
5.2.3. 
Very Heavy and Heavy Drinking Day ...................................................... 24 
5.2.4. 
Days at Risk .............................................................................................. 24 
5.2.5. 
Percentage of Subjects with No Heavy Drinking Days and Percentage of 
Subjects Abstinent from Alcohol .............................................................. 24 
5.2.6. 
Weekly Percentage of Heavy Drinking Days and Weekly Percentage of 
Days Abstinent .......................................................................................... 25 
5.2.7. 
Weekly Mean Number of Drinks and Weekly Mean Number of Drinks per 
Drinking Day ............................................................................................. 25 
5.2.8. 
World Health Organization Drinking Risk Categorical Scale ................... 25 
5.3. 
Alcohol-Related Craving, Consequences, and Withdrawal ................................... 26 
5.4. 
Mood ...................................................................................................................... 27 
5.5. 
Sleep Quality .......................................................................................................... 27 
5.6. 
Cigarette Smoking Quantity-Frequency and Nicotine Use Questionnaire ............. 27 
6. 
HYPOTHESES TO BE TESTED ....................................................................................... 28 
6.1. 
Primary Efficacy Endpoint ..................................................................................... 28 
6.2. 
Secondary Efficacy Endpoints ............................................................................... 28 
7. 
SAMPLE SIZE CONSIDERATIONS ................................................................................ 29 
8. 
DATA QUALITY ASSURANCE ...................................................................................... 30 
9. 
STATISTICAL CONSIDERATIONS ................................................................................ 31 
9.1. 
General Considerations .......................................................................................... 31 
9.2. 
Participant Accountability and Protocol Deviations .............................................. 31 
9.3. 
Demographics and Other Baseline Characteristics ................................................ 31 
9.4. 
Efficacy Analysis ................................................................................................... 32 
9.4.1. 
Primary Analysis of the Primary Efficacy Endpoint ................................. 32 
9.4.2. 
Confirmatory Secondary Endpoints .......................................................... 32 
9.4.3. 
Analysis of the Secondary Efficacy Endpoints ......................................... 32 
9.4.3.1. 
Secondary Drinking Endpoints .............................................. 33 


 
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9.4.3.2. 
Alcohol Consequences and Craving Scales ........................... 33 
9.4.3.3. 
Smoking and Any Nicotine Use ............................................ 34 
9.4.3.4. 
Sleep and Mood Scales .......................................................... 34 
9.4.4. 
Covariate Adjustment for the Analysis of Secondary Efficacy Endpoints 34 
9.5. 
Handling of Missing Data ...................................................................................... 35 
9.6. 
Safety Analysis ....................................................................................................... 35 
9.6.1. 
Adverse Events .......................................................................................... 35 
9.6.2. 
Clinical Laboratory and Point of Care Tests ............................................. 35 
9.6.3. 
Vital Signs, ECG, and Body Weight ......................................................... 36 
9.6.4. 
CIWA-AR Scores ...................................................................................... 36 
9.6.5. 
ACQ-SF-R Scores ..................................................................................... 36 
9.7. 
Drug Exposure and Retention Analyses ................................................................. 36 
9.8. 
Blood Alcohol Content ........................................................................................... 36 
9.9. 
Exploratory Analyses ............................................................................................. 36 
9.9.1. 
Value of the Second Alcohol Cue ............................................................. 36 
9.9.2 
Supplemental Exploratory Analyses ......................................................... 37 
10. 
VALIDATION OF PROGRAMMING CODE ................................................................... 38 
11. 
REFERENCES .................................................................................................................... 39 
12. 
TABLE, LISTING, AND FIGURE SHELLS ..................................................................... 41 
12.1. 
Tables ..................................................................................................................... 41 
12.1.1. Subject Disposition, Participation, Compliance ........................................ 41 
12.1.2. Demographic and Baseline Characteristics ............................................... 54 
12.1.3. Primary Efficacy Endpoint ........................................................................ 89 
12.1.4. Confirmatory Secondary Efficacy Endpoints ............................................ 94 
12.1.5. Secondary Efficacy Endpoints ................................................................ 109 
12.1.6. Safety Analyses ....................................................................................... 129 
12.1.7. Exploratory Analyses .............................................................................. 155 
12.2. 
Listings ................................................................................................................. 157 
12.3. 
Figures .................................................................................................................. 196 
 
List of Tables 
Table 1: 
Subject Disposition - All Randomized Subjects .................................................................. 42 
Table 2: 
Exposure to Investigational Products Using AICure Data – mITT Subjects ...................... 44 
Table 3: 
Total Exposure to Investigational Products Using AICure Data – Evaluable Subjects ...... 44 
Table 4: 
Compliance to Investigational Products Using AICure Data – mITT Subjects .................. 45 
Table 5: 
Compliance to Investigational Products Using AICure Data – Evaluable Subjects ............ 45 
Table 6: 
AiCure  Interventions mITT Subjects ................................................................................. 45 
Table 7: 
 AiCure  Interventions  – Evaluable Subjects ...................................................................... 45 
Table 8: 
Summary of GS-54851 Blood Levels – ANS6637 Groups (mITT Subjects) ..................... 46 
Table 9: 
Summary of GS-54851 Blood Levels – ANS6637 Groups (Evaluable Subjects) ............... 46 
Table 10: 
AiCure Report of ANS-6637 Versus GS-5851 Blood Levels – mITT Subjects ................. 47 
Table 11:  
AiCure Report of ANS-6637 Versus GS-5851 Blood Levels – Evaluable Subjects ........... 48 


 
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Table 12: 
 Exit Interview – mITT Subjects ......................................................................................... 48 
Table 13: 
 Exit Interview – Evaluable Subjects ................................................................................... 51 
Table 14: 
 Dropouts by Treatment Group and Week – mITT Subjects ............................................... 52 
Table 15: 
Number and Percent of Subjects Using Summary Drinking Questions after Discontinuing 
TLFB – mITT Subjects ....................................................................................................... 53 
Table 16: 
Demographic Characteristics - mITT Subjects ................................................................... 55 
Table 17: 
Dichotomized Demographic Characteristics – mITT Subjects ........................................... 59 
Table 18: 
Demographic Characteristics – Evaluable Subjects ............................................................ 60 
Table 19; 
Dichotomized Demographic Characteristics – Evaluable Subjects ..................................... 60 
Table 20: 
Screening Cue Reactivity – mITT Subjects ........................................................................ 61 
Table 21: 
Screening Cue Reactivity – Evaluable Subjects .................................................................. 70 
Table 22: 
Psychiatric Baseline Characteristics – mITT Subjects ........................................................ 71 
Table 23: 
Baseline POMS – mITT Subjects ........................................................................................ 72 
Table 24: 
Baseline POMS – Evaluable Subjects ................................................................................. 75 
Table 25: 
Baseline PSQI – mITT Subjects .......................................................................................... 76 
Table 26: 
 Baseline PSQI – Evaluable Subjects .................................................................................. 76 
Table 27: 
Baseline Drinking-related Behavior and Characteristics – mITT Subjects ......................... 77 
Table 28: 
 Baseline Drinking-related Behavior and Characteristics – Evaluable Subjects ................. 79 
Table 29: 
Baseline Drinking by TLFB – mITT Subjects .................................................................... 80 
Table 30: 
Baseline Drinking by TLFB – Evaluable Subjects .............................................................. 83 
Table 31: 
Baseline Alcohol-Related Craving, Consequences, Withdrawal and ALDH2 – mITT 
Subjects ............................................................................................................................... 84 
Table 32: 
Baseline Alcohol-Related Craving, Consequences, Withdrawal and ALDH2 – Evaluable 
Subjects ............................................................................................................................... 86 
Table 33: 
Baseline Other Substance Use – mITT Subjects ................................................................. 87 
Table 34: 
Baseline Other Substance Use – Evaluable Subjects .......................................................... 88 
Table 35: 
Week 2 Strength of Craving Scores – mITT Subjects ......................................................... 90 
Table 36: 
Week 2 Strength of Craving1 Scores – Evaluable Subjects ................................................. 91 
Table 37: 
ANCOVA Strength of Craving1 – mITT Subjects .............................................................. 92 
Table 38: 
ANCOVA Strength of Craving – Evaluable Subjects ......................................................... 93 
Table 39:  
ANCOVA Strength of Craving (Difference Alcohol-Water) – mITT Subjects .................. 95 
Table 40: 
ANCOVA Strength of Craving (Difference Alcohol-Water)  – Evaluable Subjects .......... 96 
Table 41: 
Drinking Makes Things Perfect Scores – mITT Subjects ................................................... 96 


 
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Table 42: 
Drinking Makes Things Perfect Scores – Evaluable Subjects............................................. 98 
Table 43: 
ANCOVA Drinking Makes Things Perfect1  – mITT Subjects .......................................... 99 
Table 44: 
ANCOVA Drinking Makes Things Perfect  – Evaluable Subjects ................................... 100 
Table 45: 
ANCOVA Drinking Makes Things Perfect1 (Difference Alcohol-Water) – mITT Subjects101 
Table 46: 
ANCOVA Drinking Makes Things Perfect (Difference Alcohol-Water) – Evaluable 
Subjects ............................................................................................................................. 102 
Table 47: 
Drink Now Scores– mITT Subjects .................................................................................. 103 
Table 48: 
Drink Now Scores – Evaluable Subjects ........................................................................... 104 
Table 49: 
ANCOVA Drink Now1  – mITT Subjects ......................................................................... 105 
Table 50: 
ANCOVA Drink Now1  – Evaluable Subjects .................................................................. 106 
Table 51: 
ANCOVA Drink Now1 (Difference Alcohol-Water) – mITT Subjects ............................ 106 
Table 52: 
ANCOVA Drink Now1 (Difference Alcohol-Water) – Evaluable Subjects ...................... 106 
Table 53: 
Turn Down Drink Scores – mITT Subjects ....................................................................... 106 
Table 54: 
Turn Down Drink Scores – Evaluable Subjects ................................................................ 106 
Table 55: 
ANCOVA Turn Down Drink1 – mITT Subjects ............................................................... 107 
Table 56: 
ANCOVA Turn Down Drink1  – Evaluable Subjects ....................................................... 107 
Table 57: 
ANCOVA Turn Down Drink1 (Difference Alcohol-Water) – mITT Subjects.................. 107 
Table 58: 
ANCOVA Turn Down Drink1 (Difference Alcohol-Water) – Evaluable Subjects ........... 107 
Table 59: 
Average of Cue Scores – mITT Subjects .......................................................................... 107 
Table 60: 
Average of Cue Scores – Evaluable Subjects .................................................................... 107 
Table 61:  
ANCOVA Average of Cue Scores1 – mITT Subjects ....................................................... 107 
Table 62: 
ANCOVA Average of Cue Scores1 – Evaluable Subjects ................................................ 107 
Table 63: 
ANCOVA Average of Cue Scores1 (Difference Alcohol-Water) – mITT Subjects ......... 107 
Table 64: 
ANCOVA Average of Cue Scores1 (Difference Alcohol-Water) – Evaluable Subjects ... 107 
Table 65: 
Beverage Liking Scores – mITT Subjects ......................................................................... 108 
Table 66: 
Beverage Liking Scores – Evaluable Subjects .................................................................. 108 
Table 67: 
Percentage of Subjects No Heavy Drinking Days Weeks 2-5 – mITT Subjects ............... 110 
Table 68: 
Percentage of Subjects with No Heavy Drinking Days Weeks 2-5 – Full Model Logistic 
Regression (mITT) ............................................................................................................ 110 
Table 69: 
Percentage of Subjects Abstinent from Alcohol Weeks 2-5 – mITT Subjects .................. 111 
Table 70: 
Percentage of Subjects Abstinent from Alcohol Weeks 2-5 – Full Model Logistic 
Regression (mITT) ............................................................................................................ 112 
Table 71:  
WHO 1-Level Decrease in Alcohol Consumption (mITT) – Weeks 2-5 .......................... 112 


 
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Table 72: 
WHO 1-Level Decrease in Alcohol Consumption (mITT) – Full Model, Logistic 
Regression, Weeks 2-5 ...................................................................................................... 113 
Table 73: 
WHO 2-Level Decrease in Alcohol Consumption (mITT) – Weeks 2-5 .......................... 114 
Table 74: 
WHO 2-Level Decrease in Alcohol Consumption (mITT) – Full Model, Logistic 
Regression, Weeks 2-5 ...................................................................................................... 114 
Table 75: 
Percentage of Days Abstinent per Week (mITT) – Weeks 2-5 ......................................... 114 
Table 76: 
Percentage of Days Abstinent per Week (mITT) -- Full Model, Mixed Effects, Weeks 2-5115 
Table 77: 
Percentage of Heavy Drinking Days per Week (mITT) – Weeks 2-5 ............................... 118 
Table 78: 
Percentage of Heavy Drinking Days per Week (mITT) – Full Model, Mixed Effects, 
Weeks 2-5 .......................................................................................................................... 118 
Table 79: 
Percentage of Very Heavy Drinking Days per Week (mITT) – Weeks 2-5 ...................... 118 
Table 80: 
Percentage of Very Heavy Drinking Days per Week (mITT) – Full Model, Mixed Effects, 
Weeks 2-5 .......................................................................................................................... 118 
Table 81: 
Drinks per Week (mITT) – Weeks 2-5 .............................................................................. 118 
Table 82: 
Drinks per Week (mITT) – Full Model, Mixed Effects, Weeks 2-5 ................................. 118 
Table 83: 
Drinks per Drinking Day (mITT) – Weeks 2-5 ................................................................. 118 
Table 84: 
Drinks per Drinking Day (mITT) – Full Model, Mixed Effects, Weeks 2-5 .................... 118 
Table 85: 
Mean Cigarettes Smoked Among Smokers (mITT) – Weeks 2-5 ..................................... 118 
Table 86: 
Mean Cigarettes Smoked Among Smokers (mITT) – Full Model, Mixed Effects, Weeks 2-
5 ......................................................................................................................................... 118 
Table 87: 
PACS (mITT) – Weeks 2-5 ............................................................................................... 118 
Table 88: 
PACS (mITT) – Full Model, Mixed Effects, Weeks 2-5 .................................................. 118 
Table 89: 
Percentage of Subjects Abstinent from Nicotine Use1 Weeks 2-5 – Among Subjects that 
Used Nicotine Products at Baseline .................................................................................. 119 
Table 90: 
Percentage of Subjects Abstinent from Nicotine Use1 Weeks 2-5 – Full Model Logistic 
Regression (Among Nicotine Users at Baseline) .............................................................. 119 
Table 91: 
Percentage of Subjects Abstinent from Smoking Weeks 2-5 – Among Baseline Smokers121 
Table 92: 
Percentage of Subjects Abstinent from Smoking Weeks 2-5 – Full Model Logistic 
Regression (Among Baseline Smokers) ............................................................................ 121 
Table 93: 
PSQI Scores – mITT Subjects ........................................................................................... 121 
Table 94: 
ANCOVA PSQI Score – mITT Subjects .......................................................................... 121 
Table 95: 
POMS Total Mood Disturbance Score – mITT ................................................................. 123 
Table 96: 
POMS Total Mood Disturbance Score (mITT) – Full Model, Mixed Effects, Weeks 4 + 6123 
Table 97: 
POMS Tension-Anxiety Score – mITT Subjects .............................................................. 126 
Table 98: 
POMS Tension-Anxiety Score (mITT) – Full Model, Mixed Effects, Weeks 4 + 6 ......... 126 


 
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Table 99: 
POMS Anger-Hostility Score – mITT Subjects ................................................................ 126 
Table 100: 
POMS Anger-Hostility Score (mITT) – Full Model, Mixed Effects, Weeks 4 + 6 .......... 126 
Table 101: 
POMS Vigor-Activity Score – mITT Subjects .................................................................. 126 
Table 102: 
POMS Vigor-Activity Score (mITT) – Full Model, Mixed Effects, Weeks 4 + 6 ............ 126 
Table 103: 
POMS Fatigue-Inertia Score – mITT Subjects .................................................................. 126 
Table 104: 
POMS Fatigue-Inertia Score (mITT) – Full Model, Mixed Effects, Weeks 4 + 6 ............ 126 
Table 105 
POMS Confusion-Bewilderment Score – mITT Subjects ................................................. 126 
Table 106: 
POMS Confusion-Bewilderment Score (mITT) – Full Model, Mixed Effects, Weeks 4 + 6126 
Table 107: 
POMS Depression-Dejection Score – mITT Subjects....................................................... 126 
Table 108: 
POMS Depression-Dejection Score (mITT) – Full Model, Mixed Effects, Weeks 4 + 6 . 126 
Table 109: 
PROMIS Negative Consequences of Alcohol Scores – mITT Subjects ........................... 126 
Table 110: 
ANCOVA PROMIS Negative Consequences of Alcohol – mITT Subjects ..................... 127 
Table 111: 
Overall Summary of Adverse Events – Safety Subjects ................................................... 130 
Table 112: 
Overall Summary of Adverse Events p-values – Safety Subjects ..................................... 131 
Table 113: 
 Number and Percentage of Subjects with Adverse Events - Safety Subjects ................... 132 
Table 114: 
Number and Percentage of Subjects with Adverse Events p-values - Safety Subjects ..... 132 
Table 115: 
Number and Percentage of Subjects with Adverse Events by ALDH2 Status – Safety 
Subjects ............................................................................................................................. 133 
Table 116: 
Number and Percentage of Subjects with Adverse Events by Treatment Arm - ALDH2 
Deficient Subjects .............................................................................................................. 133 
Table 117: 
Number and Percentage of Subjects with Adverse Events by Treatment Arm p-values - 
ALDH2 Deficient Subjects ................................................................................................ 134 
Table 118: 
Number and Percentage of Subjects with Adverse Events by Treatment Arm - ALDH2 
Non-Deficient Subjects ..................................................................................................... 134 
Table 119: 
Number and Percentage of Subjects with Adverse Events by Treatment Arm p-values - 
ALDH2 Non-Deficient Subjects ....................................................................................... 134 
Table 120: 
Number and Percentage of Subjects Taking Drugs with Potential for Interaction ............ 134 
Table 121:  
Elicited Adverse Event Questions – Safety Subjects ........................................................ 135 
Table 122: 
Elicited Adverse Event Questions p-values – Safety Subjects .......................................... 135 
Table 123: 
Number of Elicited Adverse Events – Safety Subjects ..................................................... 136 
Table 124: 
Summary of Subjects with Adverse Events by Severity and Relationship – Placebo ....... 137 
Table 125: 
Summary of Subjects with Adverse Events by Severity and Relationship – ANS-6637 200 
mg ...................................................................................................................................... 138 


 
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Table 126: 
Summary of Subjects with Adverse Events by Severity and Relationship – ANS-6637 600 
mg ...................................................................................................................................... 138 
Table 127: 
Number and Percentage of Subjects with Adverse Events by Maximum Severity - Safety 
Subjects ............................................................................................................................. 139 
Table 128: 
Number and Percentage of Subjects Adverse Events by Relatedness - Safety Subjects ... 140 
Table 129: 
Number and Percentage of Subjects with Treatment-Related Adverse Events by Maximum 
Severity- Safety Subjects ................................................................................................... 141 
Table 130: 
Number and Percentage of Subjects with Adverse Events Occurring in >= 10% of Subjects 
in Any One Group - Safety Subjects ................................................................................. 142 
Table 131: 
Number and Percentage of Subjects with Adverse Events Occurring in >= 10% of Subjects 
in Any One Group p-values - Safety Subjects ................................................................... 143 
Table 132: 
Number and Percentage of Subjects with Adverse Events Leading to Discontinuation of 
Study - Safety Subjects ...................................................................................................... 144 
Table 133: 
Number and Percentage of Subjects with Adverse Events Leading to Discontinuation of 
Study Medication – Safety Subjects .................................................................................. 145 
Table 134: 
 CIWA-AR Score > 10 at Least Once During Treatment – Safety Subjects ..................... 146 
Table 135: 
Summary of Vital Signs and Body Weights – Safety Subjects ......................................... 147 
Table 136: 
 Summary of ECG Results - Safety Subjects .................................................................... 148 
Table 137: 
Summary of Blood Chemistries and Thyroid Function – Safety Subjects ........................ 149 
Table 138: 
Summary of Urinalysis Continuous Data – Safety Subjects ............................................. 149 
Table 139: 
Summary of Urine Glucose and Nitrites – Safety Subjects ............................................... 150 
Table 140: 
Summary of Urine Protein, Ketones, Billirubin, Leukocyte Esterace, and Blood – Safety 
Subjects ............................................................................................................................. 151 
Table 141: 
Summary of Positive Urine Drug Tests, Preganancy Test or BAC > 0.02 Any Time During 
the Study– Safety Subjects ................................................................................................ 152 
Table 142: 
Frequency of Subjects with Suicidal Ideation Any Time During the Study – Safety 
Subjects ............................................................................................................................. 153 
Table 143: 
Return to Baseline ACQ-SF-R Scores – Safety Subjects .................................................. 154 
Table 144: 
Difference Between First and Second Alcohol Cues – mITT Subjects ............................. 156 
 
 
 
List of Listings 
Listing 1: Subject Disposition - All Subjects ............................................................................................ 158 
Listing 2. Enrollment and Randomization – All Consented Subjects ....................................................... 159 


 
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Listing 3: Reason not Eligible – Screen Failures ...................................................................................... 159 
Listing 4: Protocol Deviations – Safety Subjects ...................................................................................... 160 
Listing 5: Subjects Excluded from the Efficacy Analysis or Evaluable Set ............................................. 161 
Listing 6: Demographics Data – Safety Subjects ...................................................................................... 162 
Listing 7: Baseline Drinking Characteristics – mITT Subjects ................................................................ 164 
Listing 8: Baseline Smoking Characteristics – mITT Subjects ................................................................ 166 
Listing 9: MINI DSM5 Disorders – Safety Subjects ................................................................................ 166 
Listing 10: MINI DSM-5 AUD – Safety Subjects .................................................................................... 167 
Listing 11: Medical History – Safety Subjects ......................................................................................... 167 
Listing 12: Drinking Goal – mITT Subjects ............................................................................................. 168 
Listing 13: Physical Exam – Safety Subjects ............................................................................................ 168 
Listing 14: Daily and Weekly Standard Drink Units (TLFB) During Treatment – mITT Subjects ......... 169 
Listing 15: Brief Drinking Questionnaire – mITT Subjects ..................................................................... 169 
Listing 16: Cue Reactivity – mITT Subjects ............................................................................................ 170 
Listing 17: Cue Session Beverage – mITT Subjects ................................................................................. 171 
Listing 18: Drinking Consequences and Craving Scores – mITT Subjects .............................................. 172 
Listing 19: Pittsburg Sleep Quality Index Scores – mITT Subjects ......................................................... 172 
Listing 20: Smoking and Other Nicotine Use Data– mITT Subjects ........................................................ 173 
Listing 21: MINI AUD– Safety Subjects .................................................................................................. 174 
Listing 22. Exit Interview – mITT Subjects ............................................................................................. 175 
Listing 23: Drug Exposure from AiCure– mITT Subjects ........................................................................ 177 
Listing 24: Drug Accountability – Safety Subjects................................................................................... 177 
Listing 25: Take Control – mITT Subjects ............................................................................................... 178 
Listing 26: Adverse Events – Safety Subjects .......................................................................................... 179 
Listing 27: Adverse Events – Subjects Taking CYP3A Substrate ............................................................ 180 
Listing 28: Serious Adverse Events – Safety Subjects ............................................................................. 181 
Listing 29: Elicited Adverse Events – Safety Subjects ............................................................................. 183 
Listing 30: POMS Scores – mITT Subjects .............................................................................................. 183 
Listing 31. Columbia-Suicide Severity Scale – Safety Subjects ............................................................... 184 
Listing 32: Blood Chemistries and Thyroid Results – Safety Subjects .................................................... 186 
Listing 33: Hematology – Safety Subjects ................................................................................................ 187 
Listing 35: Urinalysis – Safety Subjects ................................................................................................... 188 


 
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Listing 35: Urinalysis Microscopy1 – Safety Subjects .............................................................................. 189 
Listing 36: Pregnancy Test/Birth Control Data – Safety Subjects ............................................................ 190 
Listing 37: Blood Alcohol Concentration – Safety Subjects .................................................................... 191 
Listing 38. Urine Drug Screen – Safety Subjects ..................................................................................... 191 
Listing 39: Vital Signs and Body Weights– Safety Subjects .................................................................... 192 
Listing 40. ECG – Safety Subjects............................................................................................................ 193 
Listing 41. Prior and Concomitant Medications – Safety Subjects........................................................... 194 
Listing 42: Blood for Drug Concentrations – Safety Subjects .................................................................. 194 
Listing 43: Comments – Safety Subjects .................................................................................................. 195 
 
 
List of Figures 
Figure 1: 
Percentage of Subjects No Heavy Drinking Days Weeks 2-5 ........................................... 197 
Figure 2: 
Percentage of Subjects Abstinent Weeks 2-5 .................................................................... 197 
Figure 3: 
Weekly Percentage of Subjects No Heavy Drinking Days (mITT)................................... 197 
Figure 4: 
Weekly Percentage of Subjects Abstinent (mITT) ............................................................ 197 
Figure 5: 
Weekly Percentage WHO 1-Level Decrease in Alcohol Consumption (mITT) ............... 197 
Figure 6: 
Weekly Percentage WHO 2-Level Decrease in Alcohol Consumption No Imputation 
(mITT) ............................................................................................................................... 197 
Figure 7: 
Percentage Days Abstinent per Week Least Squares Means – (mITT) ............................. 197 
Figure 8: 
Percent Heavy Drinking Days per Week Lease Squares Means –(mITT) ........................ 197 
Figure 9: 
Mean Drinks per Week Lease Squares Means – (mITT) .................................................. 197 
Figure 10: 
Mean Drinks per Drinking Day by Week Least Squares Means –  (mITT) ...................... 197 
Figure 11: 
Weekly Number of Cigarettes Smoked in Smokers Over Entire Treatment Period – Least 
Squares Means (mITT) ...................................................................................................... 197 
Figure 12: 
Clinical Chemistry, Urinalysis, and Hematology Values Over Time ............................... 197 
 


 
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1. 
ABBREVIATIONS 
Abbreviation 
Definition 
ACQ-SF-R 
Alcohol Craving Scale – Short Form  
AE 
Adverse event 
AICc 
Akaike Information Criterion corrected for finite samples 
ALDH2 
Aldehyde dehydrogenase 2 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUD 
Alcohol Use Disorder 
BAC 
Blood alcohol concentration 
CI 
Confidence interval 
CIWA-AR 
Clinical Institute Withdrawal Assessment for Alcohol-revised 
CrCl 
Creatinine clearance 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common terminology criteria for adverse events 
dL 
Deciliter 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDMS 
Electronic Data Management System 
EOS 
End of study 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
g 
Gram 
GGT 
Gamma-glutamyl transferase 
hr 
Hour 
ICH 
International Conference on Harmonization 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
μg 
Microgram 
min 
Minutes 
MINI 
MINI Neuropsychiatric Interview 
mITT 
Modified intention-to-treat 
mL 
Milliliter 
mm 
Millimeter 
NHDD 
No heavy drinking days 
NIAAA 
National Institutes on Alcohol Abuse and Alcoholism 
oz 
Ounce 


 
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Abbreviation 
Definition 
PACS 
Penn Alcohol Craving Scale 
POMS 
Profile of Mood State 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PSNHDD 
Percentage of subjects with no heavy drinking days 
PSQI 
Pittsburg Sleep Quality Index 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDU 
Standard drinking unit 
SOC 
System Organ Class 
THC 
Tetrahydrocannabinol 
TLFB 
Timeline followback  
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
WHO 
World Health Organization 


 
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2. 
INTRODUCTION 
This statistical analysis plan (SAP) for Protocol No. HLAB-002, “Human Laboratory Study of 
ANS-6637 for Alcohol Use Disorder” describes and expands upon the analytical plan presented 
in the protocol.  
This document contains all planned analyses, reasons and justifications for these analyses for all 
study data. This plan also includes sample tables, figures, and listings that will be populated. The 
SAP will follow the International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) Guidelines as indicated in Topic E3 
(Structure and Content of Clinical Study Reports), Topic E8 (General Considerations for Clinical 
Trials) and Topic E9 (Statistical Principles for Clinical Trials). The structure and content of the 
SAP provides sufficient detail to meet the requirements identified by the FDA and ICH. 
The following sources were used in preparation of this SAP: 
• Protocol # HLAB-002, Protocol Version No.: 5.0; Version Date: 04 Feb 2020 
• ICH Guidance Topics E9, E3 and E8 


 
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3. 
PROTOCOL SUMMARY 
3.1. 
Study Objectives 
3.1.1. 
Primary 
The primary objective of this study is to evaluate the effects of two different doses of ANS-6637, 
200 mg (given as 2 x 100 mg tablet) and 600 mg (given as 2 x 300 mg tablet) once a day, and 
matched placebo, on alcohol cue-elicited alcohol craving during a human laboratory paradigm 
after 1 week of daily dosing among subjects with moderate to severe alcohol use disorder (AUD) 
as confirmed by the Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
(DSM-5™). 
3.1.2. 
Secondary 
Secondary objectives include evaluation of ANS-6637 200 mg once-daily, ANS-6637 600 mg 
once daily, and matched placebo on reduction of alcohol consumption, alcohol craving weekly 
(PACS), cigarette smoking (among smokers), nicotine use (among nicotine users), mood, sleep, 
study retention, alcohol negative consequences, and safety and tolerability throughout the last 4 
weeks of the treatment period. 
3.2. 
Study Design 
This study is a 3-arm, double-blind, randomized, placebo-controlled, parallel group, 3-site study 
designed to assess the effects of ANS-6637 as compared with placebo on responses to in vivo 
alcohol cue exposure in the human laboratory setting. After signing informed consent, subjects 
will be screened for eligibility and have other baseline assessments. Screening is permitted over 
a 14-day period and most baseline assessments will be performed on the day of randomization. 
Assessments include alcohol breathalyzer test (before signing consent), medical history, physical 
examination, vital signs, electrocardiogram (ECG), drinking history by the timeline follow-back 
(TLFB) method, Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-AR), 
prior medication use, MINI neuropsychiatric interview, urine drug test, smoking quantity 
frequency and nicotine use interview, clinical laboratory tests including chemistry, hematology, 
thyroid function tests, and medical urinalysis, craving responses during cue reactivity session, 
Columbia Suicide Severity Rating Scale (C-SSRS), drinking goal, Penn Alcohol Craving Scale 
(PACS), Pittsburg Sleep Quality Index (PSQI), PROMIS Alcohol Negative Consequences short 
form, Profile of Moods State (POMS), blood sample for aldehyde dehydrogenase 2 (ALDH2) 
deficiency genetic test and confirmation that subjects are treatment seeking and desire a 
reduction or cessation of drinking. Women of child-bearing potential will have a pregnancy test. 
If eligible for the study, 81 subjects will be randomized using a stratified permuted block 
randomization procedure in an approximate 1:1:1 ratio (targeting 27 subjects per group and 
27 subjects per each of 3 clinical sites) to receive either ANS-6637 200 mg once daily, ANS-
6637 600 mg once daily, or matched placebo for 5 weeks. Subjects will be seen in the clinic at 
screening, at randomization and 5 other times during the study. A final follow-up telephone 
interview will occur 2 weeks after the end of study in-clinic visit. 


 
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Study assessments and procedures will be performed at the visits and time points outlined in the 
Schedule of Assessments (Table 1).


 
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Table 1: 
Schedule of Assessments  
Study Phase 
Screening 
Treatment 
End of Studya 
Follow-up 
Call 
Clinic Visit # 
1 
2 
3 
4 
5 
6 
7 
 
Study Week (Days)b 
-2 to -1 
(-14 to -1) 
1 
(1 to 7) 
2 
(8 to 14) 
3 
(15 to 21) 
4 
(22 to 28) 
5 
(29 to 35) 
6 
(36 to 42) 
8 
(50 to 56) 
Informed Consent 
X 
 
 
 
 
 
 
 
Alcohol Breathalyzer 
X 
X 
X 
X 
X 
X 
X 
 
Urine Drug Testc 
X 
X 
X 
X 
X 
X 
X 
 
Locator Form 
X 
Update 
Update 
Update 
Update 
Update 
Update 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
Update 
 
 
 
 
 
 
Physical Exam  
X 
Update 
 
 
 
 
 
 
Body Weight 
X 
X 
X 
X 
X 
X 
X 
 
MINI V 7.0 
X 
 
 
 
 
 
 
 
C-SSRS 
 
X 
X 
X 
X 
X 
X 
 
Clinical Chemistryd 
X 
 
X 
X 
X 
X 
X 
 
Hematologye 
X 
 
 
X 
 
 
X 
 
Thyroid Function Testsf 
X 
 
X 
X 
X 
X 
X 
 
Medical Urinalysis 
X 
 
 
X 
 
 
X 
 
Pregnancy Test  
X 
X 
X 
X 
X 
X 
X 
 
Birth control methods (all subjects) 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signsg 
X 
X 
X 
X 
X 
X 
X 
 
Eligibility Checklist 
X 
X 
 
 
 
 
 
 
Drinking Goal 
 
X 
 
 
 
 
 
 
ECG 
X 
 
 
X 
 
 
X 
 
Prior and Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 


 
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Study Phase 
Screening 
Treatment 
End of Studya 
Follow-up 
Call 
Clinic Visit # 
1 
2 
3 
4 
5 
6 
7 
 
Study Week (Days)b 
-2 to -1 
(-14 to -1) 
1 
(1 to 7) 
2 
(8 to 14) 
3 
(15 to 21) 
4 
(22 to 28) 
5 
(29 to 35) 
6 
(36 to 42) 
8 
(50 to 56) 
CIWA-AR 
X 
X 
X 
X 
X 
X 
X 
X 
Screening Cue Reactivity Session: 
VAS Scales, typical alcoholic 
beverage 
X 
 
 
 
 
 
 
 
Pharmacogenetic sampling (ALDH2)  
 
X 
 
 
 
 
 
 
Randomization 
 
X (Day 1) 
 
 
 
 
 
 
Blood for Drug Concentration 
 
 
X 
 
X 
 
 
 
Drug compliance/ accountability/  
Review AiCure 
 
Dispense 
Day 1 
X 
X 
X 
X 
X 
 
AEs (open ended question) and 
elicited AE questions 
 
X 
X 
X 
X 
X 
X 
X 
Brief Telephone Interviewh 
 
2 times 
during the 
week 
As needed if the subject misses a clinic visit 
 
Take Control 
 
X 
X 
Xi 
X 
X 
X 
 
Treatment Cue Reactivity Session: 
VAS Scales, typical alcoholic 
beverage 
 
 
X 
 
 
 
 
 
 
TLFB 
X 
X 
X 
X 
X 
X 
X 
 
Brief Drinking Questionnaire 
AS NEEDED 
 
 
 
 
 
 
 
Exit Interview 
 
 
 
 
 
 
X 
 
ACQ-SF-R 
2X pre/post 
cue session 
 
2X 
pre/post 
cue 
session 
 
 
 
 
 
PACS 
 
X 
X 
X 
X 
X 
X 
 


 
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Study Phase 
Screening 
Treatment 
End of Studya 
Follow-up 
Call 
Clinic Visit # 
1 
2 
3 
4 
5 
6 
7 
 
Study Week (Days)b 
-2 to -1 
(-14 to -1) 
1 
(1 to 7) 
2 
(8 to 14) 
3 
(15 to 21) 
4 
(22 to 28) 
5 
(29 to 35) 
6 
(36 to 42) 
8 
(50 to 56) 
Smoking quantity/frequency and 
nicotine use 
 
X 
X 
X 
X 
X 
X 
 
PSQI 
 
X 
 
 
 
 
X 
 
POMS 
 
X 
 
 
X 
 
X 
 
PROMIS Alcohol Negative 
Consequences 
 
X 
 
 
 
 
X 
 
Treatment Referral 
 
 
 
 
 
 
X 
 
Follow-Up Telephone Interview 
 
 
 
 
 
 
 
X 
Final Subject Disposition 
 
 
 
 
 
 
 
X 
a EOS - end of study. These assessments are to be done at Week 6 or if the subject discontinues early and agrees to a final clinic visit. 
b Within each study week, there should be a least two days elapsed since the visit in the prior week. 
c Test for opiates (i.e., morphine test), cocaine, amphetamines, methamphetamine, THC, buprenorphine, methadone, benzodiazepines, oxycodone, barbiturates, 
3,4-methylenedioxy-methamphetamine (MDMA – also known as ecstasy), and EtG. 
d AST, ALT, alkaline phosphatase, total bilirubin, creatinine, gamma glutamyl transferase (GGT), and albumin. CrCl will also be calculated each time creatine is 
measured. 
e Hematology tests include complete blood cell count with differential. 
f The thyroid panel includes: thyroid-stimulating hormone (TSH), thyroxine (T4) and free thyroxine (free T4), and triiodothyronine (T3). 
g Sitting blood pressure and heart rate. 
h AEs, concomitant medications, CIWA-AR, and drug compliance reminder. Telephone calls during the first week, should be separated by at least one day 
between calls, and will include assessments for AEs, concomitant medications, CIWA-AR, and a drug compliance reminder. The second call should be several 
days before the cue session to remind the subject of the planned visit. 
i Two Take Control modules will be viewed at this visit. 
 
 


 
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3.3. 
Study Endpoints 
3.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the “strength” of alcohol craving VAS score (item 1 below) 
upon presentation of the first alcohol cue at Week 2 – after one week of investigational product 
treatment. 
Confirmatory secondary endpoints include the VAS score for the other 3 VAS scales (items 2 
through 4 below) for the first alcohol cue and the average score of the 4 VAS craving items; and 
the difference score (alcohol craving VAS scores minus the water craving VAS score). 
Tbeverage liking VAS item is also a confirmatory secondary endpoint. The 4 VAS craving items 
in the order of presentation are: 
1. How strong is your craving to drink alcohol? - note this is the primary efficacy endpoint. 
2. Having a drink would make things just perfect. 
3. If I could drink alcohol now, I would drink it. 
4. It would be hard to turn down a drink right now. 
The beverage liking item is: How much did you like the beverage just given to you? 
3.3.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be analyzed over the last 4 weeks of the treatment period of 
treatment. 
1. Percentage of subjects with no heavy drinking days. A “heavy drinking day” is 4 or more 
drinks per drinking day for women and 5 or more drinks per drinking day for men. 
2. Percentage of subjects abstinent from alcohol 
3. Percentage of subjects with at least a WHO 2-level decrease in alcohol consumption 
4. Percentage of subjects with at least a WHO 1-level decrease in alcohol consumption 
5. Percentage of days abstinent per week 
6. Percentage of heavy drinking days per week 
7. Percentage of very heavy drinking days per week. A “very heavy drinking day” is 8 or 
more drinks per drinking day for women and 10 or more drinks per drinking day for men. 
8. Weekly mean number of drinks per week 
9. Weekly mean drinks per drinking day 
10. Cigarettes smoked per week among smokers 
11. Percentage of subjects with no nicotine use among those reporting nicotine use at 
baseline 
12. Alcohol craving score (PACS) 
13. Sleep quality (PSQI) score 


 
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14. Profile of Mood States (POMS) score 
15. PROMIS Alcohol Negative Consequences Score 
3.3.3. 
Safety Endpoints 
1. Vital signs 
2. Body weight 
3. Clinical laboratory parameters 
4. BAC by breathalyzer 
5. Urine drug tests 
6. AEs and elicited AEs (flushing or heat sensation, heart rate increases or heart 
palpitations, and appetite change and AEs in subjects taking CYP3A-sensitive substrates) 
7. ECG results 
8. CIWA-AR scores 
9. Frequency of subjects with suicidal ideation at any time during the treatment period 
(C-SSRS) 
10. Concomitant medication use 
11. ACQ-SF-SR score (pre- and post-cue response sessions) 
3.3.4. 
Compliance 
Compliance will be assessed using the AiCure smart phone application and by tablet counts of 
returned bottles at regular clinic visits. In addition, blood will be collected to determine plasma 
levels of GS-548351. Compliance will be calculated as the percentage of investigational products 
taken as prescribed and by the total amount of medication consumed. Participation in study visits 
will be evaluated as the percentage of subjects with complete drinking data. Compliance 
determined by GS-548351 plasma levels will be reported as number and percentage of subjects 
with a level above the limit of detection at each time point. 
 


 
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4. 
DEFINITION OF ANALYSIS SETS 
The study analysis populations will consist of the following: 
Modified Intention-to-Treat (mITT) Analysis Set: The mITT set is defined as subjects 
randomized to participate in the study that took at least one dose of investigational product and 
had a non-missing VAS craving primary endpoint. 
Evaluable Analysis Set: The evaluable analysis set for the secondary endpoints is defined as 
those subjects randomized to the study who took at least 2 tablets per day for at least 80% of 
days in Weeks 1-5.  
Safety Analysis Set: The safety analysis set includes all subjects who took at least one dose of 
investigational product. 
The analysis of the primary and confirmatory efficacy endpoints will be conducted on both the 
mITT and evaluable analysis sets. Secondary endpoint analyses will be performed on the mITT 
set only. Safety analyses will be conducted on the safety analysis set. 


 
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5. 
ASSSESSMENT AND JUSTIFICATION OF STUDY ENDPOINTS 
5.1. 
Alcohol Craving Visual Analog Scales 
Alcohol craving in response to a water and typical alcohol beverage cue is assessed using 4 
individual VAS items adapted from the ACQ (Singleton-1994).  
The VAS craving scale items include in the following order: 
1. How strong is your craving to drink alcohol? 
2. Having a drink would make things just perfect. 
3. If I could drink alcohol now, I would drink it. 
4. It would be hard to turn down a drink right now. 
Anchors (scores) for items 1, 3, and 4 are: Strongly Disagree (0) to Strongly Agree (20). 
Anchors (scores) for question 2 are: None (0) to Extremely Strong (20). 
Since the typical alcohol beverage is presented twice, the first presentation and associated VAS 
is to be used in the analysis. 
There will be no imputation for missing values. 
5.2. 
Alcohol Consumption Endpoints 
5.2.1. 
Daily Quantity of Alcohol Consumption 
Drinking will be assessed using the TLFB methodology and Form 90 structured assessment 
pattern chart. The TLFB is a semi-structured interview that provides estimates of the daily 
quantity of alcohol consumption during specified time periods. It uses a calendar prompt and a 
number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to 
facilitate accurate recall of drinking or other drug use during the target period. The procedure has 
been widely used in clinical and research contexts. It has demonstrated adequate levels of 
reliability and validity when administered as an in-person interview, over the telephone, and 
when administered via computer (Carey-1997, Sobell et al-1988, Sobell et al-1996). 
If a subject is withdrawn from the study early and is no longer participating in clinic visits or 
providing TLFB drinking data but is willing to be contacted by phone at the week most proximal 
to dropout, then they will be asked about any drinking and heavy drinking during the time since 
last contact. Phone calls will continue until the end of the treatment period, as deemed acceptable 
by the patient. The two questions cover whether the subject had any heavy drinking days or 
drinking days during the period covered and will be used to capture drinking data in the absence 
of individual daily TLFB drinking data. 
5.2.2. 
Drinking Days 
A drinking day is one calendar day in which the subject reported any alcohol consumption (i.e., 
> 0 standard drinking units [SDUs]). A standard drink contains approximately 0.6 fluid ounces 
(oz) of pure alcohol. The data given by the subjects on amount and type of alcoholic beverage(s) 
consumed will be converted to SDUs. Standard drink unit definitions are provided in Table 2. 


 
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Table 2: 
Standard Drink Unit Definitions 
For Beer (~ 5% alcohol), the approximate number of SDUs in: 
• 12 oz = 1.0 
• 16 oz = 1.3 
• 24 oz = 2.0 
• 40 oz = 3.3 
For malt liquor (~ 7% alcohol), the approximate number of SDUs in: 
• 12 oz = 1.4 
• 16 oz = 1.9 
• 22 oz = 2.6 
• 40 oz = 4.7 
For table wine (~ 12% alcohol), the approximate number of SDUs in: 
• 750 mL bottle = 25oz = 5.0 
• 5 oz glass = 1.0 
• 10 oz glass = 2.0 
For 80 proof spirits (~ 40% alcohol), or hard liquor, the approximate number of 
SDUs in: 
• 1.5 oz (mixed drink) = 1.0 
• 16 oz (pint) = 8.5 
• 25 oz (a fifth) = 17.0 
• 1.75 L (59 oz) = 39.0 
5.2.3. 
Very Heavy and Heavy Drinking Day 
A very heavy drinking day is defined as 8 or more drinks per day for a woman, and 10 or more 
for men. A heavy drinking day is defined as a day with 5 or more drinks (SDUs) for males and 4 
or more drinks (SDUs) for females.  
5.2.4. 
Days at Risk 
If a subject is being treated at an inpatient facility, is incarcerated, or otherwise under 
confinement, the days spent in under these conditions is considered a reduction in the days at risk 
for drinking and is deducted from the denominator in calculations of rates of drinking days. 
5.2.5. 
Percentage of Subjects with No Heavy Drinking Days and Percentage of 
Subjects Abstinent from Alcohol 
The percentage of subjects with no heavy drinking days is the number of subjects that have no 
heavy drinking days during the period of interest divided by the number of subjects with at least 
one day of non-missing drinking data during the period of interest, multiplied by 100.  
The percentage of subjects abstinent from alcohol is calculated similarly, except the numerator is 
the number of subjects that have no drinking days during the period of interest. 


 
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5.2.6. 
Weekly Percentage of Heavy Drinking Days and Weekly Percentage of Days 
Abstinent 
Weekly percentage of heavy drinking days is the number of heavy drinking days in a 7-day 
period divided by 7 then multiplied by 100. The TLFB permits capturing data in a subsequent 
visit if a visit is missed; however, if fewer than 7 days are observed then the denominator is the 
number of days observed in the 7-day period. At least 3 days in a week must be observed; 
otherwise, the week is considered missing. 
Weekly percentage of days abstinent is similarly calculated by using the number of days 
abstinent instead of the number of heavy drinking days. 
5.2.7. 
Weekly Mean Number of Drinks and Weekly Mean Number of Drinks per 
Drinking Day 
Weekly mean number of drinks is the sum of SDUs calculated to the tenths over 7 calendar days 
divided by the number of days with non-missing data. The quotient is multiplied by 7. At least 3 
days in a week must be observed; otherwise, the week is considered missing.  
Weekly mean number of drinks per drinking days utilizes the same numerator, and the 
denominator is the number of days with greater than 0 SDUs. Weeks where all days within the 
week are abstinent are assigned a value of 0 for weekly drinks per drinking day.  
5.2.8. 
World Health Organization Drinking Risk Categorical Scale 
The WHO has developed a drinking risk categorical scale that can be used in a responder 
analysis approach to assess clinically relevant decreases in alcohol consumption (Aubin et al-
2015). Two dichotomous endpoints will be analyzed: WHO 1-level and WHO 2-level decrease 
in alcohol consumption. The WHO 1-level and 2-level decrease endpoints are the percentage of 
subjects experiencing at least a 1-level or 2-level decrease in WHO levels of alcohol 
consumption, respectively, from the level at baseline (the period including the 28 days before 
screening) to the level during the last 4 weeks of the maintenance phase (Study Weeks 2-5). The 
WHO levels of average alcohol consumption per day are as follows: 
              
 
Males              Females 
Low Risk       
1 to 40g            1 to 20g 
Medium Risk    41 to 60g          21 to 40g 
High Risk      
61 to 100g       41 to 60g 
Very High Risk  101+g               61+g 
where 14g = 1 SDU (WHO-2000). In computing the alcohol consumption level, average drinks 
per day will be used, computed as the sum of all drinking in the 28 day period divided by the 
number of days with non-missing drinking data in that period. Abstinent subjects will be 
included in a separate “Abstinent” category. A subject must have at least 1 week of data during 
the last 4 weeks of the maintenance phase to be considered non-missing. 


 
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5.3. 
Alcohol-Related Craving, Consequences, and Withdrawal 
Alcohol-related craving is measured using the ACQ-SF-R scale and PACS; alcohol-related 
consequences are measured using the PROMIS Alcohol Negative Consequences scale; and 
alcohol-related withdrawal is measured using the CIWA-AR scale. The PACS and PROMIS 
Alcohol Negative Consequences are used as efficacy endpoints, while the ACQ-SF-R and 
CIWA-AR scales are safety endpoints. 
The ACQ-SF-R contains 12-items adapted from the 47-item ACQ-NOW developed by Singleton 
et al (1994) to assess craving for alcohol among alcohol users in the current context (right now). 
Items 3, 8, and 11 are reverse keyed. A general craving index is derived by summing all items 
and dividing by 12. If an item is missing, then the number of items is reduced by the number 
missing, and the sum is only the sum of the answered items. At least 10 items must be endorsed 
for the general craving index of ACQ-SF-R to be considered non-missing (i.e., scored).  
The PACS is a five-item self-administered instrument for assessing craving (Flannery-1999). 
Frequency, intensity, and duration of thoughts about drinking are assessed along with ability to 
resist drinking. The final item asks the responder to provide an average rating of his/her craving 
over the course of the past week. The questions on the PACS use descriptors coupled with 
numerical ratings ranging from 0 to 6. The items are summed for a total score. 
PROMIS Alcohol Negative Consequences scale is for negative consequences from alcohol use. 
The short form of the PROMIS Alcohol Negative Consequences questionnaire will be used to 
assess outcomes of alcohol use over the past 30 days (Pilkonis-2013).  
The 7 PROMIS items include:  
• Drinking created problems between me and others 
• I disappointed others when I drank 
• I was unreliable after I drank 
• Others complained about my drinking 
• I used poor judgment when I drank 
• I said or did embarrassing things when I drank 
• I had trouble getting things done after I drank 
Each item is rated on a 5 point scale including: Never (1), Rarely (2), Sometimes (3), Often (4),  
and Almost Always (5) for the past 30 days. A subject’s total score is converted to a T-score 
using scoring table provided by NIH PROMIS. 
The CIWA-AR modified telephone version is an adaptation for telephone administration of the 
CIWA-AR a brief 10-item measure used to provide a quantitative index of the severity of the 
alcohol withdrawal syndrome (Sullivan et al-1989). The CIWA-AR has been used both in 
clinical and research applications and has demonstrated both reliability and validity (Sellers et 
al-1992, Stuppaeck et al-1994). The total score is the sum of the individual item scores. Since 
this is an interview scale, no missing items are anticipated. A score ≥ 10 is considered an 
indication that the subject is undergoing alcohol withdrawal. 


 
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5.4. 
Mood 
Mood will be measured with the POMS. 
The POMS measures dimensions of affect or mood (McNair and Heuchert-2005). It consists of 
65 adjectives to which the subject responds according to a 5-point scale ranging from “not at all 
(0)” to “extremely (5).” Six subscale scores will be computed for items grouped as follows: 
Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and 
Confusion-Bewilderment. A Total Mood Disturbance score will also be computed which consists 
of the sum of Tension-Anxiety, Depression-Dejection, Anger-Hostility, Fatigue-Inertia, and 
Confusion-Bewilderment scores then subtracting the Vigor-Activity subscale score. A missing 
value within a subscale will be replaced by the average score of the answered items within the 
subscale; if 2 or more items within a subscale are missing then the entire subscale is missing 
(Macefield et al-2010). 
5.5. 
Sleep Quality 
Sleep quality will be measured using the PSQI. The PSQI is a 19-item questionnaire (Buysse et 
al-1989). The addition of all the scores permits an analysis of the subject’s overall sleep 
experience in the past 30 days. The lower the overall score, the better the person sleeps. A score 
≥ 5 is indictive of a sleep disturbance. If any of the items is missing, then the entire form is 
missing for that evaluation (PSQI website). 
5.6. 
Cigarette Smoking Quantity-Frequency and Nicotine Use Questionnaire 
A smoking quantity frequency and nicotine use interview will include 3 questions to assess 
nicotine use via cigarette smoking or via other products during the study: 1) Over the past week, 
on how many days did you smoke cigarettes?; 2) On the days you smoked during the past week, 
how many cigarettes did you smoke on average?; and 3) Over the past week, on how many days 
did you use other nicotine products (ex. chew, cigars, cigarellos, e-cigarettes, vape, gum, patch, 
etc...)? At baseline subjects that answer “0” to question #1 are considered non-smokers for the 
study. Cigarettes per week is the answer to question #1 multiplied by the answer to question #2. 
At baseline, subjects who report smoking (question #1) or the use of other nicotine product 
(question #3) will be considered nicotine users. The responses to questions #1 and #3 will be 
used to calculate the percentage of subjects abstinent from nicotine use among nicotine users. No 
imputation for missing values will be used. 


 
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6. 
HYPOTHESES TO BE TESTED 
6.1. 
Primary Efficacy Endpoint 
Subjects treated with ANS-6637 600 mg/day will report significantly lower VAS craving ratings 
in response to in vivo alcohol cues during human lab testing than ANS-6637 200 mg/day and 
placebo-treated subjects. Subjects treated with ANS-6637 200 mg/day will have significantly 
lower VAS craving ratings in response to in vivo alcohol cues than placebo-treated subjects. 
The hypotheses for the confirmatory secondary endpoints for the cue reactivity sessions are the 
same as for the primary endpoint.  
6.2. 
Secondary Efficacy Endpoints 
In the same dose-response manner, it is hypothesized that, during the last 4 weeks of the 
treatment period, the ANS-6637 groups, as compared to the placebo group, will: 
1. Increase the percentage of subjects with no heavy drinking days. A “heavy drinking day” 
is 4 or more drinks per drinking day for women and 5 or more drinks per drinking day for 
men. 
2. Increase the percentage of subjects abstinent from alcohol 
3. Increase the percentage of subjects with at least a WHO 2-level decrease in alcohol 
consumption 
4. Increase the percentage of subjects with at least a WHO 1-level decrease in alcohol 
consumption 
5. Increase the percentage of days abstinent per week 
6. Decrease the percentage of heavy drinking days per week 
7. Decrease the percentage of very heavy drinking days per week 
8. Decrease the weekly mean number of drinks per week 
9. Decrease the weekly mean drinks per drinking day 
10. Decrease the weekly mean cigarettes smoked per week among smokers 
11. Increase the percentage of subjects abstinent from nicotine use among subjects who used 
any nicotine products in the week before randomization 
12. Decrease the mean alcohol craving score (PACS) 
13. Decrease the mean PSQI score 
14. Decrease total mood disturbance (POMS) 
15. Decrease in alcohol negative consequences (PROMIS) 
 
 


 
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7. 
SAMPLE SIZE CONSIDERATIONS 
Analysis of covariance with clinical site and baseline cue as the covariates will be used to model 
the primary outcome – the VAS craving score for the first alcohol cue. Statistical power was 
estimated using [PASS 13] with the following parameters. The treatment effect parameter—a 
maximal 3-point medication-placebo difference on the strength of VAS craving in response to 
the alcohol cue—was obtained from Roberts (2017), which used a similar cue reactivity 
paradigm. The mean values on this outcome at Week 2 are assumed to be 11 for 600 mg 
ANS-667, 12.5 for 200 mg ANS-667, and 14 for placebo and a standard deviation between 
subjects of 4. Clinical site and the baseline VAS craving for the alcohol cue were assumed to 
have correlations of 0.13 and 0.39, respectively, with the primary outcome. These correlations, 
coupled with assumed standard deviations for site and baseline VAS craving for the alcohol cue 
of 0.82 and 4, respectively, yield explained variation of 26%. These assumptions, with a sample 
size of 27 subjects per arm (81 total subjects), provides 82% statistical power with a 0.05 two-
sided significance level. Using the Tukey test to adjust for the pairwise treatment arm 
comparisons reduces the power to 81% with a family-wise Type 1 error of 0.05 in 1000 
simulations given the above assumptions. 


 
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8. 
DATA QUALITY ASSURANCE 
Data quality assurance will start with training of clinical investigative staff on data collection and 
assessment procedures including a Manual of Operations that describes what data to collect and 
procedures for completion of eCRFs. Completed eCRFs will be reviewed by Fast-Track Drugs 
and Biologics clinical monitors on a regular basis throughout the trial by comparison against the 
source documents. 
Study data will come from the eCRFs, TLFB spreadsheets, coded AEs, AiCure Drug 
Compliance system outputs, genetics testing lab spreadsheets and PK drug levels from the PK 
lab spreadsheetseCRFs for this study were created using an electronic data management system 
(EDMS) based on IBM clinical development system. eCRFs were created using an established 
data dictionary for each variable including the field name, field type, field attributes, and coding 
for variables. Range checks, alpha-numeric requirements, and null/not null parameters were 
programmed as applicable. The back end database application is Oracle. Data entered into the 
EDMS system will be reviewed by Fast-Track clinical monitors and data managers. If 
incomplete or inaccurate data are found, the data will be queried in the system for site staff to 
address. The site will resolve data inconsistencies and errors using the EDMS with full audit trail 
of corrections being maintained within the system. Corrections and changes to the data will be 
reviewed by Fast-Track clinical monitors and data managers. TLFB spreadsheets have a double 
data entry check system and additionally, Fast-Track staff will verify the data entries with the 
drinking calandar to verify the correct percentages of alcohol by volume. QA review of 
laboratory data outputs is the responsibility of the individual testing laboratories; however, Fast-
Track staff will verify that there is a result reported for each specimen that was recorded in the 
database as being collected. Coded AEs will be cross checked by a second trained MedDRA 
coder. 
Additional edit checks will be written to detect anomalies in the database. These checks will 
address inconsistencies (within visits, across visits), invalid/unusual values, missing values, and 
protocol violations. Edit checking will be validated on test data or actual clinical trial data. In 
addition to programmed edit checks, quality control examination of data will also be performed 
on reviews of data listings. 
 
 


 
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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
General Considerations 
For descriptive purposes, dichotomous and categorical variables will be presented as number of 
observations and percentages; continuous variables will be given as means, standard deviations 
(SD), median, miniumum (min) and maximum(max). Statistical tests will be two-tailed at a 0.05 
Type I error rate. P-values for the primary and secondary endpoints of < 0.05 will be considered 
statistically significant. Endpoint data will also be screened for outliers and skewness. 
Appropriate non-parametric tests will be used to compare treatment groups on continuous 
baseline characteristics that are not normally distributed. Continuous endpoint data that are not 
normally distributed will be transformed using either a square root, logarithmic, or inverse 
transformation, the selection of which is determined by skewness and kurtosis statistics with 
values closest to zero. Cohen’s d will be used to calculate the effect size for means and Cohen’s 
h or odds ratios will be used to calculate the effect size for proportions. Descriptive statistics – 
mean, SD, median, min and max – of all endpoint data will be provided for each assement point 
or summarized at each week for drinking endpoints. All data will be presented in listings. 
9.2. 
Participant Accountability and Protocol Deviations 
A summary will be prepared to show dropouts/retention over time in each group, along with the 
reason for early discontinuation. The number of missing observations will be presented between 
groups. Protocol deviations will be presented as summaries by type of deviation. 
9.3. 
Demographics and Other Baseline Characteristics 
Summaries of the characteristics of the subjects in each of the study groups at baseline will be 
prepared for the mITT, and evaluable analysis sets. Demographic characteristics (e.g., age, 
gender, race, ethnicity, marital status, employment, and education) and other baseline 
characteristics including ALDH2 genetics testing results, screening cue session VAS scale scores 
and ACQ-SF-R pre and post session score, mood scales (e.g., POMS total and subscale scores), 
PSQI, and drinking goal, MINI AUD scores and other DSM-5 diagnoses will be summarized by 
treatment group for the mITT and evaluable subjects. ANOVA or chi-square tests will be used 
on baseline characteristics to test the hypothesis of effective randomization. Imbalance in any of 
these factors is an indication of ineffective randomization which may bias the results observed on 
any of the endpoints. 
Baseline drinking parameters in the 28-days prior to the start of screening, age started drinking 
regularly, medical treatments for drinking in the past year, and other services used for alcohol 
problems in the past 4 weeks prior to consent will be summarized by treatment group for the 
mITT subjects. ANOVA will be used for baseline drinking paramenters to test the hypothesis of 
effective randomization. The number and percentage of subjects with mild, moderate and severe 
symptoms of AUD and summary statistics for total number of symptoms will also be presented. 
The quantity of cigarettes smoked per week in the week prior to randomization will be presented 
for those subjects who reported any smoking. The numbers and percentages of subjects who 
report other nicotine product use at baseline, any nicotine use, and who test positive for THC will 
also be presented. Because smoking, any nicotine use, and positive THC are subsets and are not 


 
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32    
 
controlled by randomization, balance across treatment groups will be assessed using ANOVA 
and chi-square tests. 
Baseline drinking-associated consequences (CIWA-AR and PROMIS Alcohol Negative 
Consequences scores) and drinking-associated-craving (PACS) total score and subscales will be 
summarized in the tables. ANOVA will be used to test for balance across the treatment groups 
and evaluate the hypothesis of ineffective randomization. 
Continuous variables will be summarized using means, standard deviations, medians, minimum, 
and maximum values. Categorical variables will be summarized using counts and percentages. 
9.4. 
Efficacy Analysis 
9.4.1. 
Primary Analysis of the Primary Efficacy Endpoint 
Each subject will have an initial alcohol cue for “strength” of craving score from the VAS that is 
the primary endpoint. Analysis of covariance (ANCOVA) with the ”strength” of alcohol craving 
value as the dependent variable and the pretreatment “strength’ of alcohol craving score from the 
first alcohol cue as an independent fixed effect. Clinical site will also be included as an 
independent factor. There are 3 comparisons (ANS-6637 600 mg vs placebo; ANS-6637 200 mg 
vs. placebo; ANS-6637 600 mg vs. ANS-6637 200 mg) and Tukey’s method will be used to 
maintain a family-wise 0.05 significance level. 
No imputation for missing endpoint data will be performed. 
9.4.2. 
Confirmatory Secondary Endpoints 
There are 3 additional VAS craving questions and a beverage liking question asked during the 
human lab session. Each of these questions will be analyzed in the same manner as listed in 
Section 9.4.1. Tukey’s method will be used within question and not across questions. An overall 
mean of the 4 VAS craving items will also be analyzed similarly for just the alcohol beverage 
cue. The difference between the first alcohol cue and water cue for each VAS item will be 
computed at both the pre and post treatment time points. The difference values for each VAS 
item and the average difference will be analyzed similarly to the primary endpoint.   
9.4.3. 
Analysis of the Secondary Efficacy Endpoints 
Secondary efficacy endpoints will also be analyzed based on data collected during the last 4 
weeks of the maintenance period (Weeks 2 through 5), including TLFB and other questionnaire 
data assessed at Week 6 that reflect data collected during this period. 
In general, every continuous secondary efficacy endpoint is analyzed using a repeated measures 
mixed effects model where subjects are random effects; factors and covariates are fixed effects. 
The analyses will be performed using SAS PROC MIXED procedure. The information criterion 
is requested from every mixed effects model. Subjects are treated as a class variable and not 
continuous. The week (Weeks 2 through 5), treatment group, and clinical site are also treated as 
class variables. 
The primary analysis model for all continuous endpoints is: 


 
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• Appropriately transformed endpoint = treatment + week + treatment*week + clinical site 
+ baseline equivalent of endpoint + other covariates (identified in Section 9.4.4) 
This model will also be created for the untransformed endpoint. The solution statement from 
SAS PROC MIXED is requested to provide the solution for the fixed effects parameters. A 
REPEATED statement specifies that values are repeated each week and subjects are nested 
within treatment group. The covariance structure is specified.  
The selection of the covariance structure is performed using a simple repeated mixed effects 
model that includes treatment group as the only fixed effect and subject nested within treatment 
group as the only random effect. The covariance structure for each continuous secondary 
endpoint is selected from autoregressive, compound symmetry, Toeplitz, and unstructured. The 
Akaike Information Criterion (AICc) corrected for a finite sample is obtained from each of the 
four models for the four possible covariance structures to determine model fit. The smallest 
(minimum) AICc associated with one of the covariance structurs is selected and the difference 
for each of the other three covariance structures are calculated. A graph is produced of the model 
fit statistics and relative difference for the four possible covariance structures. The graphs across 
the continuous endpoints are compared to determine which covariance structure will be selected 
for all continuous endpoints or if one or more models need different covariance structures. 
Results based on the primary analysis model and the model of the untransformed endpoint will 
be presented in tabular form. The overall least squares means and least square means for each 
time point along with the 95% confidence intervals (CI) will be presented for the untransformed 
endpoint only, while two-tailed p-values and Cohen’s d will be presented for both the 
untransformed and transformed data. Inference and Cohen’s d will be based upon the results 
using appropriately transformed data. Graphs of all secondary endpoints will be produced.  
9.4.3.1. 
Secondary Drinking Endpoints 
Percentage of days abstinent per week, percentage of subjects abstinent, percentage of heavy 
drinking days per week, percentage of very heavy drinking days, weekly mean number of drinks 
per week, and weekly mean number of drinks per drinking day will be analyzed using the mixed 
effects model specified in Section 9.4.3. Covariates for these models will be identified as in 
Section 9.4.4.  
Percentage of subjects with a WHO 1-level decrease, and WHO 2-level decrease in alcohol 
consumption risk category will be analyzed during the last 4 weeks of the maintenance period 
(Weeks 2 through 5) using a logistic regression model. Covariates for the logistic regression will 
be identified as in Section 9.4.4. 2x2 contingency tables will report the WHO 1-level decrease, 
and WHO 2-level decrease along with Cohen’s h, odds ratios and 95% CIs. The Wald statistic 
will be used to test for treatment differences. 
No adjustment for multiple comparisons and no imputation will be used for these endpoints. 
9.4.3.2. 
Alcohol Consequences and Craving Scales 
The PACS is assessed weekly and will be analyzed similarly to the drinking endpoint (Section 
9.4.3.1). PROMIS alcohol negative consequences scale is assessed at baseline and Study Week 6 


 
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which will be used for the secondary endpoint. Analysis of covariance will be used to analyze 
the PROMIS scale similarly to the primary endpoint (Section 9.4.1). 
No imputation or multiplicity adjustment will be used for this endpoint.  
9.4.3.3. 
Smoking and Any Nicotine Use  
The mean number of cigarettes smoked in the past week is measured at weekly. The sample is 
the mITT subjects who smoked at baseline. The data will be analyzed as described in Section 
9.4.3. Covariates for this endpoint will be identified in Section 9.4.4. Amount of other nicotine 
products is not captured, only number of days of use of other nicotine products. The analysis of 
days of use in subjects using other nicotine products at baseline will use the same method as 
cigarettes smoked. In addition, 2 tables will examine the number of subjects that are abstinent 
from cigarettes and any nicotine product use. There will be one logistic regression, if there are 
sufficient number of subjects abstaining from nicotine use, with abstaining as the dependent 
variable and covariates as described in Section 9.4.4. No imputation will be used for these 
endpoints. 
9.4.3.4. 
Sleep and Mood Scales 
The PSQI total score POMS 6 subscales and total disturbance score are continuous variables. 
The secondary endpoints for the POMS is  assessed at Study Weeks 4 and 6. The PSQI total 
score is assessed at Week 6. The data will be analyzed as described in Section 9.4.3. Covariates 
for these models will be identified as in Section 9.4.4.  
No imputation or multiplicity adjustment will be used for these endpoints. 
9.4.4. 
Covariate Adjustment for the Analysis of Secondary Efficacy Endpoints 
Covariates for continuous secondary efficacy endpoints include the baseline equivalent of the 
endpoint, clinical site, treatment, time and the treatment by time interaction. Additional 
covariates for the secondary efficacy endpoints may include baseline characteristics with a 
theoretical and/or empirical basis for a relationship with a particular secondary endpoint. Such 
characteristics may include, but are not limited to, drinking goal (stop drinking versus reduce 
drinking but not stop), age, and baseline alcohol craving scale total score. Prior to the unblinding 
of the data, matrices of correlations between these baseline characteristics and each of the 
secondary efficacy endpoints, pooled across blinded treatment assignment, will be produced 
(using Pearson for continuous variables, Spearman for categorical outcomes). Selection of 
baseline variables to include as covariates in the models will be based on consideration of the 
following criteria: at least modest correlation with outcome (i.e., r>0.20) and clinical expertise. 
Each endpoint may have a unique set of covariates. Care is taken to only select a limited number 
of covariates such that the models are not over fitted. 
Covariates for the dichotomous secondary endpoints, percentage of subjects abstinent, WHO 1-
level risk category decrease, and WHO 2-level risk category decrease in alcohol consumption, 
will use phi correlation with dichotomous variables, chi-square statistic for categorical variables, 
and biserial correlation. Fewer covariates for the logistic regression may be used depending upon 
the number of events. If the number of events permits the inclusion of a baseline drinking 
covariate, the percentage of days abstinent will be used as the covariate for the percent subjects 
abstinent endpoint and the percent heavy drinking days will be used as the covariate for the 


 
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percent subjects with no heavy drinking days endpoint; however, no baseline drinking covariate 
will be employed for the endpoint, percent subjects with a WHO decrease in alcohol 
consumption, as this endpoint already adjusts for baseline drinking in its calculation. 
9.5. 
Handling of Missing Data 
The primary endpoint of craving cannot be imputed; likewise, for the other craving questions 
given during the human lab session. Secondary endpoints analyzed with mixed effects or logistic 
regression models are capable of handling missing data, so no imputation will be utilized. 
PROMIS scores are analyzed using ANCOVA which cannot handle missing data; therefore, only 
subjects with an assessment during the treatment period will be used and no imputation. 
9.6. 
Safety Analysis 
9.6.1. 
Adverse Events 
There are both voluntary and elicited AEs. Voluntary AEs will be coded using the most recent 
version of the Medical Dictionary for Regulatory Activities (MedDRA) and will be grouped by 
system, organ, and class (SOC) and preferred term (PT) designation. The severity, frequency, 
and relationship of AEs to investigational product will be presented by SOC and PT groupings. 
Subjects asked questions about appetite, heat sensation, and increased heart rate will be reported 
separately. All subjects that answer “yes” to any of the elicited questions will have a separate 
listing presenting their adverse events. AEs will be presented by ALDH2 deficient and ALDH2 
non-deficient patients and by subjects who did or did not take any drugs with potential for drug-
drug interactions including proton pump inhibitors, histamine-2 antagonists,. OATP1B1 and 
OATP1B3 transporters, OAT1 and OAT3 transporters, MATE1, MATE-2K, and OCT2 
transporters, P-gp transporter tnhibitors, and BCRP transporters. Listings of each individual AE 
including start date, stop date, severity, relationship, outcome, and duration will be provided. 
Each AE (based on PT) will be counted once only for a given study subject. If the same AE 
occurred on multiple occasions, the highest severity will be assumed. Thus, study subjects are 
not counted multiple times in a given numerator in the calculation of frequencies for a specific 
AE. C-SSRS reports of suicidality or suicidal ideation will be reported as AEs and analyzed as 
AEs if the investigator determines after an interview with the subject, that the responses are 
consistent with suicidal ideation or attempt.  
9.6.2. 
Clinical Laboratory and Point of Care Tests 
For clinical laboratory data, descriptive statistics will be generated for all tests performed at 
screening and at each clinic visit. If a laboratory analysis is repeated, the last measurement 
performed prior to the clinic visit will be used in the summary statistics for that clinic visit. If an 
unscheduled clinical laboratory visit occurs prior to a scheduled visit that is missed due to 
dropout, then the unscheduled visit will be used in the summary statistics for the missed 
scheduled clinical visit. If an unscheduled clinical laboratory visit occurs between two scheduled 
clinical visits, then the data from the unscheduled visit only be presented in the listings and not in 
summary statistics. In addition, at each post-randomization clinic visit descriptive statistics for 
change from baseline will be generated. Laboratory values will be plotted as mean ± standard 
error over time. All laboratory measurements will be presented in the listings. 


 
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Number and percentage of positive urine drug tests and pregnancy tests for screening visits and 
all treatment and follow-up visits will be tabulated. Results of all urine drug tests and pregnancy 
tests will be presented in the listings. The percentage of subjects with a positive urine drug test at 
any time post start of treatment will also be presented by test type and treatment group. 
9.6.3. 
Vital Signs, ECG, and Body Weight 
Vital signs will be presented as summary statistics and change from baseline. The percentage of 
ECG results considered abnormal and clinically significant will be provided. Body weight will 
be presented as summary statistics and change from screening. Vital signs, ECG results, and 
weight measurements for all visits will be presented in the listings. 
9.6.4. 
CIWA-AR Scores 
The number and percentage of subjects who reported CIWA-AR scores ≥ 10 at any time after the 
start of dosing will be presented. 
9.6.5. 
ACQ-SF-R Scores 
Summary statistics for ACQ-SF-R raw scores prior to after each cue session will be presented. 
The number and percentage of subjects with a higher ACQ-SF-R score post each cue session will 
be provided by treatment group. 
9.7. 
Drug Exposure and Retention Analyses 
Drug exposure will be presented for each treatment group as the mean number of tablets taken by 
week and overall through AiCure during the entire treatment phase. The analysis will include the 
total number of tablets taken and the percent compliance. AiCure data will also be used for the 
number subjects receiving reminder intervention (phone calls, texts, or in person visits). In 
addition, medication bottles are returned and the number of tablets remaining in those bottles are 
documented. It is assumed that the missing tablets would have been consumed. Compliance will 
also be evaluated by determining the proportion of subjects who were prescribed ANS-6637, 
reported taking ANS-6637 (by AiCure assessment), and had a plasma sample with detectable 
GS-548351, the active moiety of ANS-6637. Compliance by GS-548351 plasma levels will be 
reported as number and percentage of subjects with a level above the limit of detection at each 
time point. Descriptive statistics of plasma levels will also be provided. 
9.8. 
Blood Alcohol Content 
The number and percent of subjects at any clinic visit that have a BAC > 0 will be tabulated. All 
BAC measurements will be presented in the listings. 
9.9. 
Exploratory Analyses 
9.9.1. 
Value of the Second Alcohol Cue 
Each subject will be presented with a water cue followed by an alcohol cue then followed by a 
second alcohol cue. Each VAS question will be asked after each cue. To determine whether there 
is any difference with the 2nd alcohol cue at baseline the combined data across treatment groups 
will be used. Paired t-tests will be used for each question to test the hypothesis that no difference 


 
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in response between the first and second alcohol cue. This analysis will be peformed at Week 2 
lab session.  
If there is a difference between the first and second alcohol cue then the primary endpoint 
analysis as indicated in Sections 9.4.1 and 9.4.2 will be repeated with the 2nd alcohol cue VAS in 
addition to the 1st alcohol cue. Only those VAS questions that showed a difference between the 
first and second alcohol cue will be examined.  
9.9.2 
Supplemental Exploratory Analyses 
Two additional exploratory analyses are defined as: 1. Explore moderators of the treatment effect 
on primary and secondary outcomes; 2. Examine the relationship between cue-reactivity craving 
in the lab and naturalistic secondary outcomes. These two exploratory endpoints will not be 
analyzed at the same time as the primary and secondary endpoints. 


 
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10. 
VALIDATION OF PROGRAMMING CODE 
All SAS codes used to generate tables and listings will be validated and reviewed before being 
finalized. The validation process will be used to determine that the numbers are produced by a 
statistically valid method and that the execution of the computations is correct. Qualified 
personnel who have not previously been involved in the production of the original programming 
codes will perform the validation procedures. Methods of validation include independent 
programming and comparison to data listings. Tables will be reviewed for accuracy, consistency 
with this plan, consistency within tables, and consistency with corresponding output. Once 
validation is complete, a quality control reviewer will perform a final review of the documents 
for accuracy and consistency. Upon completion of validation and quality review procedures, all 
documentation will be collected and filed in the study documentation files at Fast-Track. 


 
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11. 
REFERENCES 
Aubin HJ, Reimer J, Nutt DJ, Bladstrom A, Torup L, Francois C, Chick J. Clinical relevance of 
as-needed treatment with nalmefene in alcohol dependent patients. Eur Addict Res. 
2015;21:160–68. 
Buysse, D. J., Reynolds, C. F., 3rd, Monk, T. H., et al. The Pittsburgh Sleep Quality Index: a 
new instrument for psychiatric practice and research. Psychiatry Res. 1989;28:193-213. 
Carey KB. Reliability and validity of the time-line follow-back interview among psychiatric 
outpatients: a preliminary report. Psych Addic Behav. 1997;11, 26-33. 
Flannery BA, Volpicelli JR, Pettinati HM. Psychometric properties of the Penn Alcohol Craving 
Scale. Alcohol Clin Exp Res 1999;23:1289-95. 
Macefield RC, Metcalfe C, Lane JA, Donovan JL, Avery KNL, Blazeby JM, Down L, Neal DE, 
Hamdy FC, Vedhara K. Impact of prostate cance testing: evaluation of the emotional 
consequences of a negative biopsy result. Br J Cancer 2010;102:1335-1340. 
Mason BJ, Light JM, Williams LD, Drobes DJ. Proof-of-concept human laboratory study for 
protracted abstinence in alcohol dependence: Effects of gabapentin. Addict Biol. 2009;14:73-83. 
Mason BJ, Quello S, Goodell V, Shadan F. Gabapentin treatment for alcohol dependence. 
JAMA. 2014;174:70-77. 
McNair DM, Heuchert JWP. Profile of Mood States (POMS) Multi-Health Systems, Tonawanda, 
NY. 2005. 
Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number 
of events per variable in logistic regression analysis. 1996;49:1373-1379. 
Pilkonis PA, Yu L, Colditz J, Dodds N, Johnston KL, Maihoefer C, Stover AM, Daley DC, 
McCarty D. Item banks for alcohol use from the Patient-Reported Outcomes Measurement 
Information System (PROMIS): use, consequences, and expectancies. Drug Alcohol Depend. 
2013;130:167-77. 
Roberts W, Harrison ELR, McKee S. Effects of varenicline on alcohol cue reactivity in heavy 
drinkers. Psychopharmacology (Berl). 2017;234:2737-2745. 
Sellers EM, Sullivan JT, Somer G, Sykora K. Characterization of DSM-III-R criteria for 
uncomplicated alcohol withdrawal: proposal for a diagnostic inventory and revised withdrawal 
scale. In Naranjo, C. A. and Sellers, E. M. (Eds.) Novel pharmacological interventions for 
alcoholism. New York (pp. 369-71). 1992. 
Singleton EG, Tiffany, ST, Henningfield JE. Development and validation of a new questionnaire 
to assess craving for alcohol. In: Harris LS (ed) Problems of Drug Dependence, 1994; 
Proceedings of the 56th Annual Scientific Meeting, The College on Problems of Drug 
Dependence, Inc. National Institute of Drug Abuse Research Monograph Series. Vol. 153. 
Rockville, MD 1995. p. 289. 


 
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Sobell LC, Sobell MB, Leo GI, Cancilla A. Reliability of a timeline method: assessing normal 
drinkers' reports of recent drinking and a comparative evaluation across several populations. Br J 
Addict. 1988;83:393-402. 
Sobell LC, Brown J, Leo GI, Sobell MB. The reliability of the Alcohol Timeline Followback 
when administered by telephone and by computer. Drug Alcohol Depend 1996;42:49-54. 
Stuppaeck CH, Barnas C, Falk M, Guenther V, Hummer M, Oberbauer H, Pycha R, Whitworth 
AB, Fleischhacker WW. Assessment of the alcohol withdrawal syndrome--validity and 
reliability of the translated and modified Clinical Institute Withdrawal Assessment for Alcohol 
scale (CIWA-A). Addiction. 1994;89:1287-92. 
Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol 
withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-AR). 
Br J Addict. 1989;84:1353-7. 
World Health Organization (WHO): International Guide for Monitoring Alcohol Consumption 
and Related Harm. Geneva, WHO, 2000. Available at: 
http://whqlibdoc.who.int/hq/2000/who_msd_msb_00.4.pdf. 
 
 


 
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12. 
TABLE, LISTING, AND FIGURE SHELLS 
12.1. 
Tables 
12.1.1. 
Subject Disposition, Participation, Compliance 
 
 
 


 
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Table 1: Subject Disposition - All Randomized Subjects 
 
 
           Treatment Group 
 
 
 Placebo 
ANS-6637-
200mg 
ANS-6637-
600mg 
Total 
 
 
n (%) 
n (%) 
n (%) 
n (%) 
p-value1 
 
 
 
 
 
 
Number of Subjects Consented 
 
 
 
xx 
 
Number of Subjects Screen Failed 
 
 
 
xx 
 
Number of Subjects Randomized 
xx 
xx 
xx 
xx 
0.xxx 
Number of Subjects Randomized not Receiving Study Drug 
x (xx.x) 
x (xx.x) 
x (xx.x) 
x (xx.x) 
0.xxx 
Number of mITT Subjects 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xxx (xx.x) 
0.xxx 
Number of Completed2 Subjects 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xxx (xx.x) 
0.xxx 
Number of Evaluable Subjects 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xxx (xx.x) 
0.xxx 
Number of Subjects Discontinuing Medication, Remaining in Study 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
0.xxx 
Number of Subjects Discontinuing Medication, Drop out of Study 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
0.xxx 
Reason for Early 
 
 
 
 
 
   Lost to follow up 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
   Died 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
   Adverse Event  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
   Logistical or practical reasons 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
   Lack of perceived efficacy 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
   Absent from the protocol due to confinement in a controlled 
environment 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
   Determined after randomization to be ineligible 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 


 
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Notes: 1 p-value from chi-square test (c), and Fisher’s exact test (f). Fisher’s exact test is used when any expected number in a cell for a specific row is 
less than 5. 
2Completed is defined as completing the full intervention phase (Weeks 2-5) of the study making the subject available for all endpoint analyses 
Programmer Notes: The discontinuation reasons are as given on the CRF. Include only the reasons actually used for the subjects in the study. If 
a subject discontinued, but the specific reason is missing, include ‘Missing’ as a row in the table. Use the order of discontinuation reasons as 
presented on the CRF page. 
 
 
   Subject withdrew consent 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
   Clinical deterioration 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
   Prefer another treatment 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
   Protocol noncompliance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
   Other reason 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 


 
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Table 2: 
Exposure to Investigational Products Using AICure Data – mITT Subjects 
 
Placebo 
                        ANS-6637  200mg 
 
ANS-6637 600mg 
 
 
N 
Mean 
(SD3) 
Med 
(Min-Max) 
N 
Mean (SD) 
Med 
(Min-Max) 
N 
Mean (SD) 
Med 
(Min-Max) 
p-value1 
Week 1 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
0.xxx 
Week 2 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
0.xxx 
Week 3 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
0.xxx 
Week 4 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
0.xxx 
Week 5 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
0.xxx 
  Total Dose2 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
0.xxx 
1 p-value from F-test from ANOVA 
2 Dose is the total number of capsules taken 
3 SD is standard deviation 
 
Table 3: 
Total Exposure to Investigational Products Using AICure Data – Evaluable Subjects 
Same as Table 2 only using evaluable subjects 
 
 
 


 
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Table 4: 
Compliance to Investigational Products Using AICure Data – mITT Subjects 
Same analysis as Table 2 using compliance rather than dose. Compliance is the number of capsules taken/number of capsules 
prescribed. 
 
Table 5: 
Compliance to Investigational Products Using AICure Data – Evaluable Subjects 
Same analysis as Table 4 using evaluable subjects 
 
Table 6: 
AiCure  Interventions mITT Subjects 
 
Placebo 
ANS 6637 200 mg 
ANS 6637 600 mg 
 
N 
# Receiving ≥ 1 
N 
# Receiving ≥ 1 
N 
# Receiving ≥ 1 
Interventions1 
xx 
xx 
xx 
xx 
xx 
xx 
1 Interventions includes texts, emails, and phone calls  
 
Table 7: 
 AiCure  Interventions  – Evaluable Subjects 
Same as Table 6 only using evaluable subjects 
 
 
 
 
 
 


 
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Table 8: Summary of GS-54851 Blood Levels – ANS6637 Groups (mITT Subjects) 
 
ANS-6637 200mg 
ANS-6637  600mg 
 
N 
% > LLD1 
Mean (SD2) 
(Min-Max) 
N 
% > LLD 
Mean (SD) 
(Min-Max) 
    Week 2 
xx 
xx.x 
xx.x (xx.x) 
(xx.x-xx.x) 
xx 
xx.x 
xx.x (xx.x) 
(xx.x-xx.x) 
    Week 4 
xx 
xx.x 
xx.x (xx.x) 
(xx.x-xx.x) 
xx 
xx.x 
xx.x (xx.x) 
(xx.x-xx.x) 
1 LLD is lowest level of detection 
2 SD is standard deviation 
 
Table 9: 
Summary of GS-54851 Blood Levels – ANS6637 Groups (Evaluable Subjects) 
Same as Table 8 only using evaluable subjects. 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
47    
 
Table 10: 
AiCure Report of ANS-6637 Versus GS-5851 Blood Levels – mITT Subjects 
 
Pill Count Indicates Drug 
Taken 
  
Timing 
Blood level 
Indicates Drug 
Takena 
Yes, n (%) 
No, n (%) 
p-valueb 
kappac 
Week 2 
Yes 
 
 
 
 
 
No 
 
 
 
 
Week 4 
Yes 
 
 
 
 
 
No 
 
 
 
 
Overall 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
a 
Blood level of  ≥80 ng/mL indicates drug taken 
b 
Chi-square test for independence 
c 
Kappa test for agreement 
note this will be repeated for ANS-6637 600 mg 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
48    
 
 
 
Table 11:  
AiCure Report of ANS-6637 Versus GS-5851 Blood Levels – Evaluable Subjects 
Repeat of Table 10 using evaluable subjects 
 
 
 
 
Table 12: 
 Exit Interview – mITT Subjects 
 
 Placebo 
ANS-6637 
200 mg 
ANS-6637 
600 mg 
         Total 
 
Question 
(N=xx) 
(N=xx) 
(N=xx) 
       (N=xxx) 
p-value1 
Did you think you were receiving 
the study drug or the placebo?  
 
 
 
 
0.xxx 
  Placebo 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Study Drug 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Don’t know; No idea 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Refuse to answer 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
What is your desire to please 
people? 
 
 
 
 
0.xxx 
  More than average 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
49    
 
 
 Placebo 
ANS-6637 
200 mg 
ANS-6637 
600 mg 
         Total 
 
Question 
(N=xx) 
(N=xx) 
(N=xx) 
       (N=xxx) 
p-value1 
  Average 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Less than average  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Refuse to answer 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Take the study drug again, for 
more than 5 weeks?   
  Yes  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 Refuse to answer 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Did you limit your drinking 
because of flushing (a heat 
reaction or facial redness)? 
 
 
 
0.xxx 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  No  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Refuse to answer  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Did you limit your drinking because of nausea or other effects? 
 
 
               0.xxx 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  No  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Refuse to answer  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
50    
 
 
 Placebo 
ANS-6637 
200 mg 
ANS-6637 
600 mg 
         Total 
 
Question 
(N=xx) 
(N=xx) 
(N=xx) 
       (N=xxx) 
p-value1 
Did your friends or family 
notice flushing? 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Refuse to answer 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
If your friends or family 
noticed flushing, did  this 
change your drinking? 
 
 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Refuse to answer 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Did you ever miss a dose of 
medication to avoid these 
effects? 
 
 
 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Refuse to answer 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
51    
 
 
 Placebo 
ANS-6637 
200 mg 
ANS-6637 
600 mg 
         Total 
 
Question 
(N=xx) 
(N=xx) 
(N=xx) 
       (N=xxx) 
p-value1 
Did you use any other services 
during the study to help you 
reduce drinking? 
  Yes  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 Refuse to answer 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
1 p-value from chi-squared test (c) unless one of the cells expected is less than 5 then Fisher’s exact test is used (f). Refuse to answer is not included in 
statistical test. 
 
 
Table 13: 
 Exit Interview – Evaluable Subjects 
Same as Table 12 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
52    
 
Table 14: 
 Dropouts by Treatment Group and Week – mITT Subjects 
 
 Placebo 
ANS-6637 200 
mg 
ANS-6637 600 mg 
Total 
Study 
Week2 
n 
Cumulative 
n (%) 
n 
Cumulative 
n (%) 
n 
Cumulative 
n (%) 
n 
Cumulative 
 n (%) 
p-value1 
Week 1 
xx 
xx (xx.x) 
xx 
xx  (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
0.xxx 
Week 2 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
0.xxx 
Week 3 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
0.xxx 
Week 4 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
0.xxx 
Week 5 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
0.xxx 
Week 6 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
xx (xx.x) 
0.xxx 
1 Fisher’s exact test is used since the frequencies are expected to be low 
2Subjects are considered dropouts when they stop providing TLFB and other data. Subjects that discontinue study drug but provide data are not 
considered dropouts. 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
53    
 
Table 15: 
Number and Percent of Subjects Using Summary Drinking Questions after Discontinuing TLFB – mITT 
Subjects 
 
Placebo 
ANS-6637 200 
mg 
ANS-6637 
200 mg 
Total 
 
Study Week 
n (%)  
n (%) 
n (%) 
n (%) 
p-value1 
Week 3 
xx (xx.x) 
xx 
xx 
 xx.x% 
0.xxx 
Week 4 
xx 
xx 
xx 
 xx.x% 
0.xxx 
Week 5 
xx 
xx 
xx 
 xx.x% 
0.xxx 
Week 6 
xx 
xx 
xx 
 xx.x% 
0.xxx 
Overall 
xx 
xx 
xx 
 xx.x% 
0.xxx 
1Fisher’s exact test is used because frequencies are expected to be low 
Note only rows with values above 0 will be presented 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
54    
 
 
12.1.2. 
Demographic and Baseline Characteristics 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
55    
 
Table 16: Demographic Characteristics - mITT Subjects 
 
 
ANS-6637 
ANS-6637 
 
 
Characteristic 
 Placebo 
200 mg 
600 mg 
Total 
p-value1 
Age (years) 
 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
xx 
 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
  SD2 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Gender 
 
 
 
 
0.xxx 
  N 
 
 
 
 
 
  Male 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Female 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Race 
 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
xx 
 
  White 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  African-American or Black  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Asian 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Native Hawaiian or Other Pacific Islander 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
56    
 
 
 
ANS-6637 
ANS-6637 
 
 
Characteristic 
 Placebo 
200 mg 
600 mg 
Total 
p-value1 
  American Indian or Alaskan Native 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Other 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Ethnicity 
 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
xx 
 
  Hispanic or Latino 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Not Hispanic or Latino 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Education (years) 
 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
xx 
 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
  SD 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
  Median 
xx 
xx 
xx 
xx 
 
Min-Max 
(xx-xx) 
(xx 
xx) 
(xx 
 
Marital Status 
 
 
 
 
0.xxx 
  Legally Married 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Living with Partner / Cohabitating 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Widowed 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Separated 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
57    
 
 
 
ANS-6637 
ANS-6637 
 
 
Characteristic 
 Placebo 
200 mg 
600 mg 
Total 
p-value1 
  Divorced 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Never Married 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Employment 
 
 
 
 
0.xxx 
  Full-time > 35 hrs /week 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Part-time regular 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Part-time irregular 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Student 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Military Service 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Unemployed 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Retired/Disabled 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Homemaker 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  In controlled environment 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Annual Income 
 
 
 
 
0.xxx 
  $0-$15,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  $15,001-$30,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  $30,001-$45,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  $45,001-$60,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
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ANS-6637 
ANS-6637 
 
 
Characteristic 
 Placebo 
200 mg 
600 mg 
Total 
p-value1 
  $60,001-$75,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  $75,001-$90,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  $90,001-$105,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  $105,001-$120,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Greater than $120,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  None given 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Occupation 
 
 
 
 
0.xxx 
  Executive of large business or major 
professional 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Manager of medium business or minor 
professional 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Administrator of large business, owner of small 
business, or semi-professional 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Clerical or sales worker, technician 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Skilled worker 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Semi-skilled worker 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Unskilled worker 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Unemployed 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
59    
 
 
 
ANS-6637 
ANS-6637 
 
 
Characteristic 
 Placebo 
200 mg 
600 mg 
Total 
p-value1 
  Never worked 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Not given 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Other 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
1c = chi-squared test, f=Fisher’s exact test, w=Wilcoxon signed rank test 
2 SD is standard deviation 
 
Table 17: 
Dichotomized Demographic Characteristics – mITT Subjects 
 
 
ANS-6637 
ANS-6637 
 
 
Characteristic 
 Placebo 
200 mg 
600 mg 
Total 
p-value1 
Race/Ethnicity 
 
 
 
 
0.xxx 
  White 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  African-American or Black  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Hispanic 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Other 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Education  
 
 
 
 
0.xxx 
  Less than High School 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  High School or Greater 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
60    
 
 
 
ANS-6637 
ANS-6637 
 
 
Characteristic 
 Placebo 
200 mg 
600 mg 
Total 
p-value1 
Marital Status 
 
 
 
 
0.xxx 
  Legally Married 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Not Married 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Employment 
 
 
 
 
0.xxx 
  Unemployed 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Employed 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
1c = chi-squared test, f=Fisher’s exact test, w=Wilcoxon signed rank test 
 
Table 18: 
Demographic Characteristics – Evaluable Subjects 
Same as Table 16 
 
Table 19; 
Dichotomized Demographic Characteristics – Evaluable Subjects 
Same as Table 17 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
61    
 
Table 20: 
Screening Cue Reactivity – mITT Subjects 
 
 
 
Placebo 
 
N=xx 
 
ANS-6637 200 
mg 
N=xx 
ANS-6637 600 
mg 
N=xx 
Total 
 
N=xx 
p-value1 
Cue 
Question 
Statistic 
 
 
 
 
 
Water 
Craving 
Strength 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD2) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Drinking makes 
things perfect 
 
 
 
 
 
0.xxx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Drink now 
 
 
 
 
 
0.xxx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
62    
 
 
 
 
Placebo 
 
N=xx 
 
ANS-6637 200 
mg 
N=xx 
ANS-6637 600 
mg 
N=xx 
Total 
 
N=xx 
p-value1 
 
Turn down drink  
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Average 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Alcohol 1 
Craving 
Strength 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Drinking makes 
things perfect 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
63    
 
 
 
 
Placebo 
 
N=xx 
 
ANS-6637 200 
mg 
N=xx 
ANS-6637 600 
mg 
N=xx 
Total 
 
N=xx 
p-value1 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Drink now 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Turn down drink  
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Average 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
64    
 
 
 
 
Placebo 
 
N=xx 
 
ANS-6637 200 
mg 
N=xx 
ANS-6637 600 
mg 
N=xx 
Total 
 
N=xx 
p-value1 
Alcohol 2 
Craving 
Strength 
 
 
 
 
 
0.xxxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Driking makes 
things perfect 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Drink now 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Turn down drink  
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
65    
 
 
 
 
Placebo 
 
N=xx 
 
ANS-6637 200 
mg 
N=xx 
ANS-6637 600 
mg 
N=xx 
Total 
 
N=xx 
p-value1 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Average 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Alcohol1 - 
Water 
Craving 
Strength 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Drinking makes 
things perfect 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
66    
 
 
 
 
Placebo 
 
N=xx 
 
ANS-6637 200 
mg 
N=xx 
ANS-6637 600 
mg 
N=xx 
Total 
 
N=xx 
p-value1 
 
Drink now 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Turn down drink  
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Average 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Alcohol2 - 
Water 
Craving 
Strength 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
67    
 
 
 
 
Placebo 
 
N=xx 
 
ANS-6637 200 
mg 
N=xx 
ANS-6637 600 
mg 
N=xx 
Total 
 
N=xx 
p-value1 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Drinking makes 
things perfect 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Drink now 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Turn down 
drink 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
68    
 
 
 
 
Placebo 
 
N=xx 
 
ANS-6637 200 
mg 
N=xx 
ANS-6637 600 
mg 
N=xx 
Total 
 
N=xx 
p-value1 
 
Average 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Alcohol1 – 
Alcohol2 
Craving 
Strength 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Drinking makes 
things perfect 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Drink now 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
69    
 
 
 
 
Placebo 
 
N=xx 
 
ANS-6637 200 
mg 
N=xx 
ANS-6637 600 
mg 
N=xx 
Total 
 
N=xx 
p-value1 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Turn down 
drink 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Average 
 
 
 
 
 
0.xxx 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
  Median 
xx 
xx 
xx 
xx 
 
 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
1 ANOVA and F-test is used to examine balance across treatment groups 
2 SD is standard deviation 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
70    
 
Table 21: 
Screening Cue Reactivity – Evaluable Subjects 
Same as Table 20 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
71    
 
Table 22: 
Psychiatric Baseline Characteristics – mITT Subjects 
 
 Placebo 
ANS-6637 300 mg 
ANS-6637 600 mg 
Total 
Characteristic 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
DSM-5 Disorders 
 
 
 
 
  Depression 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Suicidality 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Manic 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Hypomanic 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Bipolar 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Panic 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Agoraphobia 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Social Phobia 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Obsessive Compulsive 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Posttraumatic Stress 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 Substance Abuse 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Psychotic 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Mood 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Anorexia 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Bulemia 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
72    
 
 
 Placebo 
ANS-6637 300 mg 
ANS-6637 600 mg 
Total 
Characteristic 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
  Binge-eating 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Generalized Anxiety 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Medical Organic 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Antisocial Personality 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Table 23: 
Baseline POMS – mITT Subjects 
Characteristic 
Placebo 
ANS-6637 200 
mg 
ANS-6637 600 mg 
Total 
p-value1 
Tension-Anxiety 
 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
xx 
 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
  SD2 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
 
(xx-xx) 
 
Depression-Dejection 
 
 
 
 
0.xxx 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
73    
 
Characteristic 
Placebo 
ANS-6637 200 
mg 
ANS-6637 600 mg 
Total 
p-value1 
  N 
xx 
xx 
xx 
xx 
 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
  SD 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
 
(xx-xx) 
 
Anger-Hostility 
 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
xx 
 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
  SD 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
 
(xx-xx) 
 
Fatigue-Inertia 
 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
xx 
 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
  SD 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
74    
 
Characteristic 
Placebo 
ANS-6637 200 
mg 
ANS-6637 600 mg 
Total 
p-value1 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
 
(xx-xx) 
 
Confusion-Bewilderment 
 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
xx 
 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
  SD 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
 
(xx-xx) 
 
Vigor-Activity 
 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
xx 
 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
  SD 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
 
(xx-xx) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
75    
 
Characteristic 
Placebo 
ANS-6637 200 
mg 
ANS-6637 600 mg 
Total 
p-value1 
Total Mood Disturbance 
 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
xx 
 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
  SD 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
 
(xx-xx) 
 
1ANOVA F-test 
2SD is standard deviation 
 
Table 24: 
Baseline POMS – Evaluable Subjects 
Same as Table 23 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
76    
 
Table 25: 
Baseline PSQI – mITT Subjects 
Characteristic 
Placebo 
ANS-6637 200 mg 
ANS-6637 600 mg 
Total 
p-value1 
Overall Sleep Experience 
 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
xx 
 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
  SD2 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
 
(xx-xx) 
 
1ANOVA F-test 
2 SD is standard deviation 
 
 
Table 26: 
 Baseline PSQI – Evaluable Subjects 
Same as Table 25 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
77    
 
Table 27: 
Baseline Drinking-related Behavior and Characteristics – mITT Subjects 
 
Placebo 
ANS-6637 200 mg 
ANS-6637 600 mg 
Total 
 
Characteristic 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
p-value1 
Drinking Goal (n, %) 
 
 
 
 
 
   Stop Drinking 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
   Reduce but not stop 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
# Drinks/Week Goal in Subjects that Want to Reduce Drinking 
 
 
 
 
   N 
xx 
xx 
xx 
xx 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD2 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
   Median 
xx 
xx 
xx 
xx 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Motivation to achieve goal 
 
 
 
 
   N 
xx 
xx 
xx 
xx 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
   Median 
xx 
xx 
xx 
xx 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Confidence in achieving goal 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
78    
 
 
Placebo 
ANS-6637 200 mg 
ANS-6637 600 mg 
Total 
 
Characteristic 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
p-value1 
   N 
xx 
xx 
xx 
xx 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
   Median 
xx 
xx 
xx 
xx 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
AUD Symptom Severity (n, %) 
 
 
 
 
0.xxx 
    Moderate (4 or 5 symptoms) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
    Severe (6 or more symptoms) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
AUD Number of Symptoms (n, %) 
 
 
 
 
 
  4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  5   
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  6 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  7 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  8 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  9 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 10 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 11 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
79    
 
 
Placebo 
ANS-6637 200 mg 
ANS-6637 600 mg 
Total 
 
Characteristic 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
p-value1 
AUD Number of Symptoms (continuous) 
 
 
 
 
0.xxx 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
  SD 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
  Median 
xx 
xx 
xx 
xx 
 
Note: Percentages are based on the number of non-missing values in each variable.  
1 ANOVA F-test  
2SD is standard deviation 
 
Table 28: 
 Baseline Drinking-related Behavior and Characteristics – Evaluable Subjects 
Same as Table 27 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
80    
 
Table 29: 
Baseline Drinking by TLFB – mITT Subjects 
 
Placebo 
ANS-6637 
200mg 
ANS-6637 600 
mg 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
  Drinks/Week (Pre-screening Days -1 to -28) 
 
 
 
 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD2 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
  Drinks/Week (7 Days Prior to Randomization) 
 
 
 
 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
  Drinks/Week (Percent Change Pre-screening 
Days -1 to -28 to 7 Days Prior to Randomization) 
 
 
 
 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
81    
 
 
Placebo 
ANS-6637 
200mg 
ANS-6637 600 
mg 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
  Drinks/Drinking Day (Pre-screening Days -1 to -
28) 
 
 
 
 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
  Drinks/Drinking Day (7Days Prior to 
Randomization) 
 
 
 
 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
  Drinks/Drinking Day (Percent Change Pre-
screening Days -1 to -28 to 7 Days Prior to 
Randomization) 
 
 
 
 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
82    
 
 
Placebo 
ANS-6637 
200mg 
ANS-6637 600 
mg 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Percentage of Heavy Drinking Days  
  (Pre-screening Days -1 to -28) 
 
 
 
 
0.xxx 
   Mean 
xx.x% 
xx.x% 
xx.x% 
xx.x% 
 
   SD 
xx.x% 
xx.x% 
xx.x% 
xx.x% 
 
   Median 
xx.x% 
xx.x% 
xx.x% 
xx.x% 
 
   Min-Max 
(xx%-xx%) 
(xx%-xx%) 
(xx%-xx%) 
(xx%-xx%) 
 
 Percentage of Very Heavy Drinking Days  
  (Pre-screening Days -1 to -28) 
 
 
 
 
0.xxx 
   Mean 
xx.x% 
xx.x% 
xx.x% 
xx.x% 
 
   SD 
xx.x% 
xx.x% 
xx.x% 
xx.x% 
 
   Median 
xx.x% 
xx.x% 
xx.x% 
xx.x% 
 
   Min-Max 
(xx%-xx%) 
(xx%-xx%) 
(xx%-xx%) 
(xx%-xx%) 
 
 Percentage Days Abstinent  
  (Pre-screening Days -1 to -28) 
 
 
 
 
0.xxx 
   Mean 
xx.x% 
xx.x% 
xx.x% 
xx.x% 
 
   SD 
xx.x% 
xx.x% 
xx.x% 
xx.x% 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
83    
 
 
Placebo 
ANS-6637 
200mg 
ANS-6637 600 
mg 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
   Median 
xx.x% 
xx.x% 
xx.x% 
xx.x% 
 
   Min-Max 
(xx%-xx%) 
(xx%-xx%) 
(xx%-xx%) 
(xx%-xx%) 
 
WHO Risk Level 
 
 
 
 
0.xxx 
  High Risk 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 Very High Risk 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Note: Percentages are based on the number of non-missing values in each variable.  
1Chi-square test for categorical variables and ANOVA F-test for continuous variables 
2 SD is standard deviation 
 
Table 30: 
Baseline Drinking by TLFB – Evaluable Subjects 
Same as Table 29 
 


 
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Table 31: 
Baseline Alcohol-Related Craving, Consequences, Withdrawal and ALDH2 – mITT Subjects 
 
Placebo 
ANS-6637 
200mg 
ANS-6637 600 
mg 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Pre-cue ACQ-SF-R2 
 
 
 
 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD3 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
   Scale Min-Max 
 
 
 
(xx.x – xx.x) 
 
Post-cue ACQ-SF-R 
 
 
 
 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Pre-Post ACQ-SF-R 
 
 
 
 
 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 


 
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   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 PROMIS4 Alcohol Negative 
Consequences (T-scores) 
 
 
 
 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 PACS5 
 
 
 
 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
   Scale Min-Max 
 
 
 
(xx.x – xx.x) 
 
 CIWA-AR6 
 
 
 
 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
   Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
 


 
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Placebo 
ANS-6637 
200mg 
ANS-6637 600 
mg 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
   Scale Min-Max 
 
 
 
(xx.x – xx.x) 
 
Withdrawal Symptoms (CIWA ≥ 10) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
ALDH2 
 
 
 
 
0.xxx 
  Positive 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Negative 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Not Done 
xx 
xx 
xx 
xx 
 
1ANOVA F-test for continuous variables and chi-square test for categorical 
2ACQ-SF-R is Alcohol Craving Questionnaire – Short Form – Revised 
3 SD is standard deviation 
4 PROMIS is Patient-reported Outcomes Information System 
5 PACS is Penn Alcohol Craving Scale 
6 CIWA-AR is Clinical Institute Withdrawal Assessment for Alcohol-revised 
 
 
Table 32: 
Baseline Alcohol-Related Craving, Consequences, Withdrawal and ALDH2 – Evaluable Subjects 
Same as Table 31 
 
 


 
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 Table 33: 
Baseline Other Substance Use – mITT Subjects 
 
Placebo 
ANS-6637 
200 mg 
ANS-6637 600 mg 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Smoker (n, %) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
0.xxx 
Days Smoked in the Past Week 
 
 
 
 
 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD2 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
   (Min-Max) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Average Cigarettes Smoked Per Week (among 
Smokers) 
 
 
 
 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
   SD 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Any Other Nicotine Product Use (doesn’t include 
cigarettes) (n, %) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
0.xxx 
Days Used Other Nicotine Products Per Week 
 
 
 
 
0.xxx 
   Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 


 
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Placebo 
ANS-6637 
200 mg 
ANS-6637 600 mg 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
   SD 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Any Nicotine Use (cigarettes + other) (n, %) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
0.xxx 
THC 
 
 
 
 
0.xxx 
  Negative 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Positive 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Note: Percentages are based on the number of non-missing values in each variable.  
1ANOVA F-test for continuous variables and chi-square test for categorical 
2 SD is standard Deviation 
Table 34: 
Baseline Other Substance Use – Evaluable Subjects 
Same as Table 33 
 


 
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12.1.3. 
Primary Efficacy Endpoint


 
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Table 35: 
Week 2 Strength of Craving Scores – mITT Subjects 
 
 
Placebo 
N=xx 
ANS-6637 200 mg 
N=xx 
ANS-6637 
600 mg 
N=xx 
Total 
N=xx 
Cue 
Statistic 
 
 
 
 
Water 
 
 
 
 
 
 
  Mean (SD1) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
Alcohol 1 
 
 
 
 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
Alcohol 2 
 
 
 
 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
Alcohol 1 - Water 
 
 
 
 
 


 
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Placebo 
N=xx 
ANS-6637 200 mg 
N=xx 
ANS-6637 
600 mg 
N=xx 
Total 
N=xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
Alcohol 2 - Water 
 
 
 
 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
Alcohol 2 – 
Alcohol 1 
 
 
 
 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
1 SD is standard deviation 
 
Table 36: 
Week 2 Strength of Craving1 Scores – Evaluable Subjects 
Same as Table 35 


 
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Table 37: 
ANCOVA Strength of Craving1 – mITT Subjects  
Type III Wald Tests 
Parameter 
Num DF2 
Den DF3 
F Value 
 
p-value 
ARM 
2 
xx 
xxx.xx 
0.xxx 
Site 
2 
xx 
xxx.xx 
0.xxx 
Baseline Cue4 
1 
xx 
xxx.xx 
0.xxx 
1Strength of craving from 1st alcohol cue; 32Numerator degrees of freedom; 3 Demonimator degrees of freedom 
4 Baseline Cue is the baseline equivalent of the outcome obtained after the presentation of the first alcohol cue at baseline 
 
Least Squares Means  
Arm 
Mean 
SE1 
p-value2 
Lower CI3 
Upper CI 
placebo 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
200 mg 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
1 SE is standard error; 2 Wald test; 3 Lower and upper limit of 95% confidence interval 
 
 


 
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Least Squares Means for Differences 
 
 
 
 
 
 
Tukey 
Arm1 
Arm 2 
Difference 
SE1 
Cohen’s d 
p-value2 
Lower CI3 
Upper CI 
200 mg 
placebo 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
placebo 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
200 mg 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
1 SE is standard error; 2 Tukey’s test; 3 Lower and upper limit of 95% confidence interval 
 
Table 38: 
ANCOVA Strength of Craving – Evaluable Subjects 
Follow the same analysis as Table 37 
 
 
 
 


 
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12.1.4. 
Confirmatory Secondary Efficacy Endpoints


 
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Table 39:  
ANCOVA Strength of Craving (Difference Alcohol-Water) – mITT Subjects 
Type III Wald Test 
Parameter 
Num DF1 
Den DF2 
F Value 
p-value 
ARM 
2 
xx 
xxx.xx 
0.xxx 
Site 
2 
xx 
xxx.xx 
0.xxx 
Baseline Cue4 
1 
xx 
xxx.xx 
0.xxx 
1Strength of craving from 1st alcohol cue; 2Numerator degrees of freedom; 3 Demonimator degrees of freedom 
4 Baseline Cue is the baseline equivalent of the outcome obtained after the presentation of the first alcohol cue at baseline 
 
Least Squares Means Difference 
 
 
 
 
 
 
Tukey 
Arm1 
Arm 2 
Difference 
SE1 
Cohen’s d 
p-value2 
Lower CI1 
Upper CI 
200 mg 
placebo 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
placebo 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
200 mg 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
1 SE is standard error; 2 Tukey’s test; 3 Lower and upper limit of 95% confidence interval 
 
Least Squares Means  
Arm 
Mean 
SE1 
p-value2 
Lower CI3 
Upper CI 


 
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Arm 
Mean 
SE1 
p-value2 
Lower CI3 
Upper CI 
placebo 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
200 mg 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
1 SE is standard error; 2 Wald test; 3 Lower and upper limit of 95% confidence interval 
 
Table 40: 
ANCOVA Strength of Craving (Difference Alcohol-Water)  – Evaluable Subjects 
Same as Table 39 
 
Table 41: 
Drinking Makes Things Perfect Scores – mITT Subjects 
 
 
Placebo 
N=xx 
ANS-6637 200 
mg 
N=xx 
ANS-6637 
600 mg 
N=xx 
Total 
N=xx 
Cue 
Statistic 
 
 
 
 
Water 
 
 
 
 
 
 
  Mean (SD1) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
Alcohol 1 
 
 
 
 
 


 
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Placebo 
N=xx 
ANS-6637 200 
mg 
N=xx 
ANS-6637 
600 mg 
N=xx 
Total 
N=xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
Alcohol 2 
 
 
 
 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
Alcohol 1 - Water  
 
 
 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
Alcohol 2 - Water  
 
 
 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 


 
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Placebo 
N=xx 
ANS-6637 200 
mg 
N=xx 
ANS-6637 
600 mg 
N=xx 
Total 
N=xx 
Alcohol 2 – 
Alcohol 1 
 
 
 
 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
1 SD is standard deviation 
 
Table 42: 
Drinking Makes Things Perfect Scores – Evaluable Subjects 
Same as Table 41 
 
 


 
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Table 43: 
ANCOVA Drinking Makes Things Perfect1  – mITT Subjects 
Type III Wald Test 
Parameter 
Num DF2 
Den DF3 
F Value 
p-value 
ARM 
2 
xx 
xxx.xx 
0.xxx 
Site 
2 
xx 
xxx.xx 
0.xxx 
Baseline Cue4 
1 
xx 
xxx.xx 
0.xxx 
1 Drinking makes things perfect from 1st alcohol cue; 2Numerator degrees of freedom; 3 Demonimator degrees of freedom 
4 Baseline Cue is the baseline equivalent of the outcome obtained after the presentation of the first alcohol cue at baseline  
Least Squares Means  
Arm 
Mean 
SE1 
p-value2 
Lower CI3 
Upper CI 
placebo 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
200 mg 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
1 SE is standard error; 2 Wald test; 3 Lower and upper limit of 95% confidence interval 
 
 
 


 
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Least Squares Means for Differences 
 
 
 
 
 
 
 
Tukey 
Arm1 
Arm 2 
Difference 
SE1 
Cohen’s d 
p-value2 
Lower CI3 
Upper CI 
200 mg 
placebo 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
placebo 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
200 mg 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
1 SE is standard error; 2 Tukey’s test; 3 Lower and upper limit of 95% confidence interval 
 
 
 
 
Table 44: 
ANCOVA Drinking Makes Things Perfect  – Evaluable Subjects 
Same analysis as Table 43 
 
 
 
 
 
 


 
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Table 45: 
ANCOVA Drinking Makes Things Perfect1 (Difference Alcohol-Water) – mITT Subjects 
Type III Wald Test 
Parameter 
Num DF2 
Den DF3 
F Value 
p-value 
ARM 
2 
xx 
xxx.xx 
0.xxx 
Site 
2 
xx 
xxx.xx 
0.xxx 
Baseline Cue4 
1 
xx 
xxx.xx 
0.xxx 
1 Drinking makes things perfect from 1st alcohol cue; 2Numerator degrees of freedom; 3 Demonimator degrees of freedom 
4 Baseline Cue is the baseline equivalent of the outcome obtained after the presentation of the first alcohol cue at baseline  
Least Squares Means Differences 
 
 
 
 
 
 
Tukey 
Arm1 
Arm 2 
Difference 
SE1 
Cohen’s d 
p-value2 
Lower CI1 
Upper CI 
200 mg 
placebo 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
placebo 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
200 mg 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
1 SE is standard error; 2 Tukey’s test; 3 Lower and upper limit of 95% confidence interval 
 
 
 
 
 


 
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Least Squares Means  
Arm 
Mean 
SE1 
p-value2 
Lower CI3 
Upper CI 
placebo 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
200 mg 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
1 SE is standard error; 2 Wald test; 3 Lower and upper limit of 95% confidence interval 
 
 
Table 46: 
ANCOVA Drinking Makes Things Perfect (Difference Alcohol-Water) – Evaluable Subjects 
Same analysis as Table 45 
 
 
 
 
 
 
 
 


 
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Table 47: 
Drink Now Scores– mITT Subjects 
 
 
Placebo 
N=xx 
ANS-6637 200 
mg 
N=xx 
ANS-6637 
600 mg 
N=xx 
Total 
N=xx 
Cue 
Statistic 
 
 
 
 
Water 
 
 
 
 
 
 
  Mean (SD1) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
Alcohol 1 
 
 
 
 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
Alcohol 2 
 
 
 
 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
Alcohol 1 - Water  
 
 
 
 


 
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Placebo 
N=xx 
ANS-6637 200 
mg 
N=xx 
ANS-6637 
600 mg 
N=xx 
Total 
N=xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
Alcohol 2 - Water  
 
 
 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
Alcohol 2 – 
Alcohol 1 
 
 
 
 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
1 SD is standard deviation 
 
Table 48: 
Drink Now Scores – Evaluable Subjects 
Same as Table 47 
 


 
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Table 49: 
ANCOVA Drink Now1  – mITT Subjects 
Type III Wald Test 
Parameter 
Num DF2 
Den DF3 
F Value 
p-value 
ARM 
2 
xx 
xxx.xx 
0.xxx 
Site 
2 
xx 
xxx.xx 
0.xxx 
Baseline Cue4 
1 
xx 
xxx.xx 
0.xxx 
1 Drinking now from 1st alcohol cue; 2Numerator degrees of freedom; 3 Demonimator degrees of freedom 
4 Baseline Cue is the baseline equivalent of the outcome obtained after the presentation of the first alcohol cue at baseline  
Least Squares Means  
Arm 
Mean 
SE1 
p-value2 
Lower CI3 
Upper CI 
placebo 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
200 mg 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
0.xxx 
1 SE is standard error; 2 Wald test; 3 Lower and upper limit of 95% confidence interval 
 
 


 
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Least Squares Means for Differences 
 
 
 
 
 
 
 
Tukey 
Arm1 
Arm 2 
Difference 
SE1 
Cohen’s d 
p-value2 
Lower CI3 
Upper CI 
200 mg 
placebo 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
placebo 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
600 mg 
200 mg 
xx.xx 
0.xxx 
x.xx 
0.xxx 
0.xxx 
0.xxx 
1 SE is standard error; 2 Tukey’s test; 3 Lower and upper limit of 95% confidence interval 
 
 
 
Table 50: 
ANCOVA Drink Now1  – Evaluable Subjects 
Same analysis as Table 49 
Table 51: 
ANCOVA Drink Now1 (Difference Alcohol-Water) – mITT Subjects 
Same analysis as Table 45 with difference as the dependent variable 
Table 52: 
ANCOVA Drink Now1 (Difference Alcohol-Water) – Evaluable Subjects 
Same analysis as Table 51 
Table 53: 
Turn Down Drink Scores – mITT Subjects 
Same analysis as Table 47 
Table 54: 
Turn Down Drink Scores – Evaluable Subjects 
Same analysis as Table 53 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
107    
 
Table 55: 
ANCOVA Turn Down Drink1 – mITT Subjects 
Same analysis as Table 49 
Table 56: 
ANCOVA Turn Down Drink1  – Evaluable Subjects 
Same analysis as Table 55 
Table 57: 
ANCOVA Turn Down Drink1 (Difference Alcohol-Water) – mITT Subjects 
Same analysis as Table 45  
Table 58: 
ANCOVA Turn Down Drink1 (Difference Alcohol-Water) – Evaluable Subjects 
Same analysis as Table 57 
Table 59: 
Average of Cue Scores – mITT Subjects 
Same analysis as Table 47 
Table 60: 
Average of Cue Scores – Evaluable Subjects 
Same as Table 59 
Table 61:  
ANCOVA Average of Cue Scores1 – mITT Subjects 
Same analysis as Table 49 
  
Table 62: 
ANCOVA Average of Cue Scores1 – Evaluable Subjects 
 Same analysis as Table 61 
Table 63: 
ANCOVA Average of Cue Scores1 (Difference Alcohol-Water) – mITT Subjects 
Same analysis as Table 45  
Table 64: 
ANCOVA Average of Cue Scores1 (Difference Alcohol-Water) – Evaluable Subjects 
Same analysis as Table 63 
 


 
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Table 65: 
Beverage Liking Scores – mITT Subjects 
Same analysis as Table 47 
Table 66: 
Beverage Liking Scores – Evaluable Subjects 
Same analysis as Table 65 
 
 
 


 
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109    
 
 
12.1.5. 
Secondary Efficacy Endpoints 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
110    
 
Table 67: 
Percentage of Subjects No Heavy Drinking Days Weeks 2-5 – mITT Subjects 
 
Placebo 
ANS-6637 
200 mg 
ANS-6637 
600 mg 
Total 
 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
No Heavy Drinking Days 
 
 
 
 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Table 68: 
Percentage of Subjects with No Heavy Drinking Days Weeks 2-5 – Full Model Logistic Regression (mITT) 
 
 
 
 
 
 
 
 
 
95% CI3 
Parameter 
  
DF1 Estimate 
Standard  
Error 
Wald  
Chi-Square 
Pr > Chi- 
Square 
Cohen’s h OR2 
Upper CI 
Lower CI 
Intercept 
  
1 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
 
Treatment 
Overall 
X 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
 
Treatment4 
200 mg 
X 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
0.xxx 
xx.xxx xx.xxx 
xx.xxx 
Treatment 
600 mg 
X 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
0.xxx 
xx.xxx xx.xxx 
xx.xxx 
Site 
Overall 
X 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
 


 
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111    
 
 
 
 
 
 
 
 
 
 
95% CI3 
Parameter 
  
DF1 Estimate 
Standard  
Error 
Wald  
Chi-Square 
Pr > Chi- 
Square 
Cohen’s h OR2 
Upper CI 
Lower CI 
Site5 
1 
X 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
xx.xxx xx.xxx 
xx.xxx 
Site 
2 
X 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
xx.xxx xx.xxx 
xx.xxx 
Cov 
 
X 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
xx.xxx xx.xxx 
xx.xxx 
1  DF is degrees of freedom; 2 OR is odds ratio; 3 CI is confidence interval;  4 Comparison to placebo for each active treatment; 
5 Site 3 is reference for the OR 
Programming note: COV is baseline equivalent of dependent variable and any other covariate(s) which have not been specified at the time of writing of SAP 
Contrast 
 
 
 
 
 
 
 
 
 
95% CI3 
Parameter 
 
DF1 Estimate 
Standard  
Error 
Wald  
Chi-Square 
Pr > Chi- 
Square 
Cohen’s h OR2 
Upper CI 
Lower CI 
600 mg 
200 mg 
1 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
0.xxx 
xx.xxx xx.xxx 
xx.xxx 
1  DF is degrees of freedom; 2 OR is odds ratio; 3 CI is confidence interval. 
 
 
 
Table 69: 
Percentage of Subjects Abstinent from Alcohol Weeks 2-5 – mITT Subjects 
Presented in same manner as Table 67 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
112    
 
 
Table 70: 
Percentage of Subjects Abstinent from Alcohol Weeks 2-5 – Full Model Logistic Regression (mITT) 
Prented in same manner as Table 68 programming note: baseline PDA is a covariate for PSA outcome 
 
 
 
 
 
 
 
 
Table 71:  
WHO 1-Level Decrease in Alcohol Consumption (mITT) – Weeks 2-5 
 
 
Placebo 
ANS-6637 
200mg 
ANS-6637 
600 mg 
Total 
 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
WHO 1-Level 
Decrease 
 
 
 
 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
113    
 
Table 72: 
WHO 1-Level Decrease in Alcohol Consumption (mITT) – Full Model, Logistic Regression, Weeks 2-5 
 
 
 
 
 
 
 
 
 
95% CI3 
Parameter 
  
DF1 
Estimate 
Standard 
Error 
Wald Chi-
Square 
Pr > Chi-
Square 
Cohen’s 
h 
OR2 
Upper CI 
Lower CI 
Intercept 
  
1 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
 
Treatment 
Overall 
2 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
 
Treatment4 
200mg 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
Treatment 
600mg 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
Site 
Overall 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
 
Site5 
1 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
xx.xxx 
xx.xxx 
xx.xxx 
Site 
2 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
xx.xxx 
xx.xxx 
xx.xxx 
Cov 
 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
xx.xxx 
xx.xxx 
xx.xxx 
1  DF is degrees of freedom; 2 OR is odds ratio; 3 CI is confidence interval;  4 Comparison to placebo for each active treatment; 
5 Site 3 is reference for the OR 
Programming note: COV is baseline equivalent of dependent variable and any other covariate(s) which have not been specified at the time of writing of SAP 
 
Contrast 
 
 
 
 
 
 
 
 
 
95% CI3 
Parameter 
 
DF1 Estimate 
Standard  
Error 
Wald  
Chi-Square 
Pr > Chi- 
Square 
Cohen’s h OR2 
Upper CI 
Lower CI 
600 mg 
200 mg 
1 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
0.xxx 
xx.xxx xx.xxx 
xx.xxx 
1  DF is degrees of freedom; 2 OR is odds ratio; 3 CI is confidence interval. 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
114    
 
 
Table 73: 
WHO 2-Level Decrease in Alcohol Consumption (mITT) – Weeks 2-5 
Same as Table 71 
Table 74: 
WHO 2-Level Decrease in Alcohol Consumption (mITT) – Full Model, Logistic Regression, Weeks 2-5 
Same as Table 72  
 
Table 75: 
Percentage of Days Abstinent per Week (mITT) – Weeks 2-5 
 
Placebo 
 
ANS-6637 
200mg 
ANS-6637  
600 mg 
Study 
Week 
N 
Mean (SD1) 
Median 
(Min-Max) 
N 
Mean (SD) 
Median 
(Min-Max) 
N 
Mean (SD) 
Median 
(Min-Max) 
2 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
3 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
4 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
5 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
1 SD is standard deviation 
 
 
 


 
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115    
 
Table 76: 
Percentage of Days Abstinent per Week (mITT) -- Full Model, Mixed Effects, Weeks 2-5  
Type III Wald Tests 
Parameter 
Num DF1 
Den DF2 
F Value 
 
p-value 
ARM 
2 
xxx 
xxx.xx 
0.xxx 
Week 
3 
xxx 
xxx.xx 
0.xxx 
Site 
2 
xxx 
xxx.xx 
0.xxx 
Cov 
x 
xxx 
xxx.xx 
0.xxx 
ARM*Week 
5 
xxx 
xxx.xx 
0.xxx 
1 Numerator degrees of freedom; 2 Denominator degrees of freedom 
 
 
 
Programming note: Cov is the baseline equivalent of the dependent variable and any additional covariates included in 
the model. 
Least Squares Means 
 
 
 
 
95% CI2 
 
 
Untransformed 
Arm 
Week 
Estimate 
SE1 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
ANS-6637 
(200mg) 
2 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
2 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
2 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
ANS-6637 
(200mg) 
3 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
3 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
3 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 


 
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95% CI2 
 
 
Untransformed 
Arm 
Week 
Estimate 
SE1 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
ANS-6637 
(200mg) 
4 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
4 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
4 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
ANS-6637 
(200mg) 
5 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
5 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
5 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
ANS-6637 
(200mg) 
Overall  
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
Overall  
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
Overall 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
1 SE is standard error; 2 CI is confidence interval 
Programming note:If a transformation of the dependent variable is used add 2 columns: p-value and Cohen’s d for the transformed model. 
 
Contrasts 
 
 
 
 
95% CI3 
 
 
Untransformed 
Arm1 
Week 
Estimate 
SE2 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
ANS-6637 
(600mg) 
2 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
3 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 


 
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117    
 
 
 
 
 
95% CI3 
 
 
Untransformed 
Arm1 
Week 
Estimate 
SE2 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
ANS-6637 
(600mg) 
4 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
5 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
Overall 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
1 ANS-6637 200 mg is the reference group; 2 SE is standard error; 3 CI is confidence interval 
Programming note:If a transformation of the dependent variable is used add 2 columns: p-value and Cohen’s d for the transformed model. 
 
Table 75 is the template for Tables 77, 79, 81, 83, 85, and 87. Table 76 is the template for Tables 78, 80, 82, 84, 86, and 88. 


 
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Table 77: 
Percentage of Heavy Drinking Days per Week (mITT) – Weeks 2-5 
Table 78: 
Percentage of Heavy Drinking Days per Week (mITT) – Full Model, Mixed Effects, Weeks 2-5 
Table 79: 
Percentage of Very Heavy Drinking Days per Week (mITT) – Weeks 2-5 
 
Table 80: 
Percentage of Very Heavy Drinking Days per Week (mITT) – Full Model, Mixed Effects, Weeks 2-5 
Table 81: 
Drinks per Week (mITT) – Weeks 2-5 
 
Table 82: 
Drinks per Week (mITT) – Full Model, Mixed Effects, Weeks 2-5 
Table 83: 
Drinks per Drinking Day (mITT) – Weeks 2-5 
 
Table 84: 
Drinks per Drinking Day (mITT) – Full Model, Mixed Effects, Weeks 2-5 
Table 85: 
Mean Cigarettes Smoked Among Smokers (mITT) – Weeks 2-5 
 
Table 86: 
Mean Cigarettes Smoked Among Smokers (mITT) – Full Model, Mixed Effects, Weeks 2-5 
Table 87: 
PACS (mITT) – Weeks 2-5 
 
Table 88: 
PACS (mITT) – Full Model, Mixed Effects, Weeks 2-5 
 
 
 
 
 
 


 
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Table 89: 
Percentage of Subjects Abstinent from Nicotine Use1 Weeks 2-5 – Among Subjects that Used Nicotine Products 
at Baseline 
 
Placebo 
ANS-6637  
200 mg 
ANS-6637 600 
mg 
Total 
 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
No Nicotine Use 
 
 
 
 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
1 Nicotine use includes cigarettes or other nicotine products 
 
Table 90: 
Percentage of Subjects Abstinent from Nicotine Use1 Weeks 2-5 – Full Model Logistic Regression (Among 
Nicotine Users at Baseline) 
 
 
 
 
 
 
 
 
 
95% CI4 
Parameter 
  
DF
2 
Estimate Standard  
Error 
Wald  
Chi-Square 
Pr > Chi- 
Square 
Cohen’s h OR3 
Upper CI 
Lower CI 
Intercept 
  
1 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
 
Treatment 
Overall 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
 
Treatment5 
200 mg 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
0.xxx 
xx.xxx xx.xxx 
xx.xxx 
Treatment 
600 mg 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
0.xxx 
xx.xxx xx.xxx 
xx.xxx 


 
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120    
 
 
 
 
 
 
 
 
 
 
95% CI4 
Parameter 
  
DF
2 
Estimate Standard  
Error 
Wald  
Chi-Square 
Pr > Chi- 
Square 
Cohen’s h OR3 
Upper CI 
Lower CI 
Site 
Overall 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
 
Site6 
1 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
xx.xxx xx.xxx 
xx.xxx 
Site 
2 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
xx.xxx xx.xxx 
xx.xxx 
Cov 
 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
xx.xxx xx.xxx 
xx.xxx 
1  Nicotine use includes either cigarettes or other nicotine products; 2 DF is degrees of freedom; 3 OR is odds ratio; 4 CI is confidence 
interval;  5 Comparison to placebo for each active treatment;6 Site 3 is reference for the OR 
Programming note: COV is baseline equivalent of dependent variable and any other covariate(s) which have not been specified at the time of writing of SAP 
 
Contrast 
 
 
 
 
 
 
 
 
 
95% CI3 
Parameter 
 
DF1 Estimate 
Standard  
Error 
Wald  
Chi-Square 
Pr > Chi- 
Square 
Cohen’s h OR2 
Upper CI 
Lower CI 
600 mg 
200 mg 
1 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
0.xxx 
xx.xxx xx.xxx 
xx.xxx 
1  DF is degrees of freedom; 2 OR is odds ratio; 3 CI is confidence interval. 
 
 


 
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Table 91: 
Percentage of Subjects Abstinent from Smoking Weeks 2-5 – Among Baseline Smokers 
Same analysis as Table 89 
 
Table 92: 
Percentage of Subjects Abstinent from Smoking Weeks 2-5 – Full Model Logistic Regression (Among Baseline 
Smokers) 
Same analysis as Table 90 
 
Table 93: 
PSQI Scores – mITT Subjects 
 
Placebo 
 
ANS-6637 
200mg 
ANS-6637 
600 mg 
Study 
Week 
N 
Mean (SD1) 
Median 
(Min-Max) 
N 
Mean (SD) 
Median 
(Min-Max) 
N 
Mean (SD) 
Median 
(Min-Max) 
6 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
1 SD is standard deviation 
 
Table 94: 
ANCOVA PSQI Score – mITT Subjects  
Type III Wald Tests 
Parameter 
Num DF1 
Den DF2 
F Value 
p-value 
ARM 
2 
xx 
xxx.xx 
0.xxx 
Site 
2 
xx 
xxx.xx 
0.xxx 
Baseline PSQI 
1 
xx 
xxx.xx 
0.xxx 


 
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122    
 
1 Numerator degrees of freedom; 2 Denominator degrees of freedom 
 
Least Squares Means 
 
 
 
 
95% CI2 
 
 
Untransformed 
Arm 
Week 
Estimate SE1 
Lower 
CI 
Upper CI Difference 
SE 
p-value Cohen’s 
d 
ANS-6637 
(200mg) 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 0.xxx 
xx.xxx 
Placebo 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
1 SE is standard error; 2 CI is confidence interval 
Programming note:If a transformation of the dependent variable is used add 2 columns: p-value and Cohen’s d for the transformed model. 
 
Contrasts 
 
 
 
 
95% CI3 
 
 
Untransformed 
Arm1 
Week 
Estimate 
SE2 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
ANS-6637 
(600mg) 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
1 ANS-6637 200 mg is the reference group; 2 SE is standard error; 3 CI is confidence interval 
Programming note:If a transformation of the dependent variable is used add 2 columns: p-value and Cohen’s d for the transformed model. 
 


 
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123    
 
 
Table 95: 
POMS Total Mood Disturbance Score – mITT 
 
Placebo 
 
ANS-6637 
200mg 
ANS-6637  
600 mg 
Study 
Week 
N 
Mean (SD1) 
Median 
(Min-Max) 
N 
Mean (SD) 
Median 
(Min-Max) 
N 
Mean (SD) 
Median 
(Min-Max) 
4 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
6 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
1 SD is standard deviation 
 
Table 96: 
POMS Total Mood Disturbance Score (mITT) – Full Model, Mixed Effects, Weeks 4 + 6 
Type III Wald Tests 
Parameter 
Num DF1 Den DF2 F Value 
 
p-value 
ARM 
2 
xxx 
xxx.xx 
0.xxx 
Week 
1 
xxx 
xxx.xx 
0.xxx 
Site 
2 
xxx 
xxx.xx 
0.xxx 
Cov 
x 
xxx 
xxx.xx 
0.xxx 
ARM*Week x 
xxx 
xxx.xx 
0.xxx 


 
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124    
 
1 Numerator degrees of freedom; 2 Denominator degrees of freedom 
 
 
 
Programming note: Cov is the baseline equivalent of the dependent variable and any additional covariates included in the model. 
 
Least Squares Means 
 
 
 
 
95% CI2 
 
 
Untransformed 
Arm 
Week 
Estimate 
SE1 
Lower CI 
Upper CI 
Difference SE 
p-value 
Cohen’s d 
ANS-6637 
(200mg) 
4 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
4 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
4 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
ANS-6637 
(200mg) 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
ANS-6637 
(200mg) 
Overall  
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
Overall  
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
Overall 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
1 SE is standard error; 2 CI is confidence interval 
Programming note:If a transformation of the dependent variable is used add 2 columns: p-value and Cohen’s d for the transformed model. 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
125    
 
 
 
Contrasts 
 
 
 
 
95% CI3 
 
 
Untransformed 
Arm1 
Week 
Estimate 
SE2 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
ANS-6637 
(600mg) 
4 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
Overall 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
1 ANS-6637 200 mg is the reference group; 2 SE is standard error; 3 CI is confidence interval 
Programming note:If a transformation of the dependent variable is used add 2 columns: p-value and Cohen’s d for the transformed model. 
 
 
 
 
 
 
 
Table 95 is the template for Tables 97, 99, 101, 103, 105, and 107. Table 96 is the template for Tables 98, 100, 102, 104, 106, and 108 
 


 
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126    
 
Table 97: 
POMS Tension-Anxiety Score – mITT Subjects 
Table 98: 
POMS Tension-Anxiety Score (mITT) – Full Model, Mixed Effects, Weeks 4 + 6 
Table 99: 
POMS Anger-Hostility Score – mITT Subjects 
Table 100: 
POMS Anger-Hostility Score (mITT) – Full Model, Mixed Effects, Weeks 4 + 6 
Table 101: 
POMS Vigor-Activity Score – mITT Subjects 
Table 102: 
POMS Vigor-Activity Score (mITT) – Full Model, Mixed Effects, Weeks 4 + 6 
Table 103: 
POMS Fatigue-Inertia Score – mITT Subjects 
Table 104: 
POMS Fatigue-Inertia Score (mITT) – Full Model, Mixed Effects, Weeks 4 + 6 
Table 105 
POMS Confusion-Bewilderment Score – mITT Subjects 
Table 106: 
POMS Confusion-Bewilderment Score (mITT) – Full Model, Mixed Effects, Weeks 4 + 6 
Table 107: 
POMS Depression-Dejection Score – mITT Subjects 
Table 108: 
POMS Depression-Dejection Score (mITT) – Full Model, Mixed Effects, Weeks 4 + 6 
 
 
Table 109: 
PROMIS Negative Consequences of Alcohol Scores – mITT Subjects 
 
Placebo 
 
ANS-6637 
200mg 
ANS-6637 
600 mg 
Study 
Week 
N 
Mean (SD1) 
Median 
(Min-Max) 
N 
Mean (SD) 
Median 
(Min-Max) 
N 
Mean (SD) 
Median 
(Min-Max) 
6 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
xx 
xxx (xx) 
xxx 
(xx-xx) 
1 SD is standard deviation 
 


 
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Table 110: 
ANCOVA PROMIS Negative Consequences of Alcohol – mITT Subjects 
Type III Wald Test 
Parameter 
Num DF1 
Den DF2 
F Value 
p-value 
ARM 
2 
xx 
xxx.xx 
0.xxx 
Site 
2 
xx 
xxx.xx 
0.xxx 
Baseline PROMIS 
1 
xx 
xxx.xx 
0.xxx 
1 Numerator degrees of freedom; 2 Demonimator degrees of freedom 
 
Least Squares Means 
 
 
 
 
95% CI2 
 
 
Untransformed 
Arm 
Week 
Estimate SE1 
Lower 
CI 
Upper CI Difference 
SE 
p-value Cohen’s 
d 
ANS-6637 
(200mg) 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 0.xxx 
xx.xxx 
ANS-6637 
(600mg) 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 0.xxx 
xx.xxx 
Placebo 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
1 SE is standard error; 2 CI is confidence interval 
Programming note:If a transformation of the dependent variable is used add 2 columns: p-value and Cohen’s d for the transformed model. 
 


 
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Contrasts 
 
 
 
 
95% CI3 
 
 
Untransformed 
Arm1 
Week 
Estimate 
SE2 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
ANS-6637 
(600mg) 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
1 ANS-6637 200 mg is the reference group; 2 SE is standard error; 3 CI is confidence interval 
Programming note:If a transformation of the dependent variable is used add 2 columns: p-value and Cohen’s d for the transformed model. 
 
 
 
 


 
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12.1.6. 
Safety Analyses


 
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Table 111: 
Overall Summary of Adverse Events – Safety Subjects 
 
Placebo 
ANS-6637-
200mg 
ANS-6637 600 
mg 
Total 
 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
 
 
 
 
 
Number of AEs 
xx 
xx 
xx 
xx 
Number of SAEs 
xx 
xx 
xx 
xx 
Number (%) of subjects with at least one AE 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Number (%) of subjects with at least one SAE 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Number (%) of subjects with at least one AE related1 to study 
product 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Number of AEs by severity 
 
 
 
 
     Mild 
xx 
xx 
xx 
xx 
     Moderate 
xx 
xx 
xx 
xx 
    Severe 
xx 
xx 
xx 
xx 
Number of AEs by relationship to study product 
 
 
 
 
     At least possibly related 
xx 
xx 
xx 
xx 
     Unrelated 
xx 
xx 
xx 
xx 
Number of AEs by SAE status 
 
 
 
 


 
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Placebo 
ANS-6637-
200mg 
ANS-6637 600 
mg 
Total 
 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xxx) 
     No 
xx 
xx 
xx 
xx 
      Yes 
xx 
xx 
xx 
xx 
 
1 Related is possible, probable, or definite 
 
Table 112: 
Overall Summary of Adverse Events p-values – Safety Subjects 
 
ANS-6637 200 
mg vs Placebo 
ANS-6637 600 
mg vs Placebo 
ANS-6637 200 mg vs 
ANS-6637 600 mg 
 
 
 
 
Number of subjects with at least one AE 
0.xxx 
0.xxx 
0.xxx 
Number of subjects with at least one SAE 
0.xxx 
0.xxx 
0.xxx 
Number of subjects with at least one AE related to study product 
0.xxx 
0.xxx 
0.xxx 
 p-value from chi-square test (c), unless a row has expected fewer than 5 in a cell then Fisher’s exact test (f) 
 
 
 
 


 
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Table 113: 
 Number and Percentage of Subjects with Adverse Events - Safety Subjects 
 
MedDRA System Organ Class/ 
Placebo 
ANS-6637-200mg 
ANS-6637 600 mg 
   Preferred Term 
(N=xx) 
(N=xx) 
(N=xx) 
- Any Adverse Events -  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
SOC 
 
 
 
   - Overall -  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
      Preferred term 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
      Preferred term 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Notes: Percentages are based on the total number of subjects, as given in the column heading. 
Multiple occurrences of a specific adverse event for a subject are counted once in the frequency for the adverse event. Likewise, multiple 
occurrences of adverse events within a specific preferred term for a subject are counted once in the frequency for the preferred term. 
Programmer’s Notes: Order System Organ Class alphabetically and preferred term alphabetically within System Organ Class. 
 
Table 114: 
Number and Percentage of Subjects with Adverse Events p-values - Safety Subjects 
MedDRA System Organ Class 
ANS-6637 200 mg 
vs Placebo 
ANS-6637 600 mg 
vs Placebo 
ANS-6637 200 mg 
vs ANS-6637 600 
mg 
Gastrointestinal disorders 
0.xxx 
0.xxx 
0.xxx 
Infections and infestations 
0.xxx 
0.xxx 
0.xxx 
 p-value from chi-square test (c), unless a row has expected fewer than 5 in a cell then Fisher’s exact test (f) 
 
Programming note: Include all SOCs that are in Table 111 


 
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Table 115: 
Number and Percentage of Subjects with Adverse Events by ALDH2 Status – Safety Subjects 
 
MedDRA System Organ Class/ 
ALDH2 Deficient 
ALDH2 Non-deficient 
 
   Preferred Term 
(N=xx) 
(N=xx) 
p-value 
- Any Adverse Events -  
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
SOC 
 
 
 
   - Overall -  
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
      Preferred term 1 
xx (xx.x%) 
xx (xx.x%) 
 
      Preferred term 2 
xx (xx.x%) 
xx (xx.x%) 
 
Notes: Percentages are based on the total number of subjects, as given in the column heading. 
 p-value from chi-square test (c), unless a row has expected fewer than 5 in a cell then Fisher’s exact test (f) 
Multiple occurrences of a specific adverse event for a subject are counted once in the frequency for the adverse event. Likewise, 
multiple occurrences of adverse events within a specific preferred term for a subject are counted once in the frequency for the 
preferred term. 
Programmer’s Notes: Order System Organ Class alphabetically and preferred term alphabetically within System Organ Class. 
 
 
 
Table 116: 
Number and Percentage of Subjects with Adverse Events by Treatment Arm - ALDH2 Deficient Subjects 
Same analysis as Table 113 


 
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Table 117: 
Number and Percentage of Subjects with Adverse Events by Treatment Arm p-values - ALDH2 Deficient 
Subjects 
Same analysis as Table 114 
 
Table 118: 
Number and Percentage of Subjects with Adverse Events by Treatment Arm - ALDH2 Non-Deficient Subjects 
Same analysis as Table 113 
 
Table 119: 
Number and Percentage of Subjects with Adverse Events by Treatment Arm p-values - ALDH2 Non-Deficient 
Subjects 
Same analysis as Table 114 
 
 
 
Table 120: 
Number and Percentage of Subjects Taking Drugs with Potential for Interaction 
 
Placebo 
ANS 6637-200 mg 
ANS-6637 600 mg 
 
(N=xx) 
(N=xx) 
(N=xx) 
p-value 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
p-value from chi-square test 
Programmer note: add a footnote of the drugs that are included 
 
 


 
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Table 121:  
Elicited Adverse Event Questions – Safety Subjects 
 
Placebo 
(N=xx) 1 
ANS-6637-200mg 
(N=xx) 
ANS-6637 600 mg 
(N=xx) 
Total 
(N=xx) 
Changes in Appetite 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Heat Sensation (flushing or 
feeling hot) while drinking 
alcohol 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Heart Rate or Palpatations 
while drinking alcohol 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
1Number and percentage of subjects reporting this elicited AE. 
 
 
Table 122: 
Elicited Adverse Event Questions p-values – Safety Subjects 
 
ANS-6637-200mg vs 
Placebo 
ANS-6637-600mg vs 
Placebo 
ANS-6637 200 mg vs ANS-
6637 600 mg 
Changes in Appetite 
0.xxx 
0.xxx 
0.xxx 
Heat Sensation (flushing or 
feeling hot) while drinking 
alcohol 
0.xxx 
0.xxx 
0.xxx 
Heart Rate or Palpatations 
while drinking alcohol 
0.xxx 
0.xxx 
0.xxx 
p-value from chi-square test 


 
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136    
 
 
 
Table 123: 
Number of Elicited Adverse Events – Safety Subjects 
 
Placebo 
ANS-6637-200mg 
ANS-6637 600 mg 
Changes in Appetite 
xx  
xx  
xx  
Heat Sensation (flushing or 
feeling hot) while drinking 
alcohol 
xx  
xx  
xx  
Heart Rate or Palpatations 
while drinking alcohol 
xx  
xx  
xx  
Number of response, not number of subjects 


 
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Table 124: 
Summary of Subjects with Adverse Events by Severity and Relationship – Placebo 
Number of Subjects (%) (N=x)  
 
 
Mild 
Moderate 
Severe 
Life-threatening 
All Grades 
SOC 
MedDRA 
PT 
R 
NR 
R 
NR 
R 
NR 
R 
NR 
R 
NR 
R + NR 
 
 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
Notes: Events are counted once per subject at the highest severity grade and closest relationship to the investigational product. R= related to investigational 
product (possibly, probably, definitely). NR = not related to investigational product (unrelated, unlikely). 


 
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Table 125: 
Summary of Subjects with Adverse Events by Severity and Relationship – ANS-6637 200 mg 
Number of Subjects (%) (N=x)  
 
 
Mild 
Moderate 
Severe 
Life-threatening 
All Grades 
SOC 
MedDRA 
PT 
R 
NR 
R 
NR 
R 
NR 
R 
NR 
R 
NR 
R + NR 
 
 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
Notes: Events are counted once per subject at the highest severity grade and closest relationship to the investigational product. R= related to investigational 
product (possibly, probably, definitely). NR = not related to investigational product (unrelated, unlikely). 
 
 
 
Table 126: 
Summary of Subjects with Adverse Events by Severity and Relationship – ANS-6637 600 mg 
Number of Subjects (%) (N=x)  
 
 
Mild 
Moderate 
Severe 
Life-threatening 
All Grades 
SOC 
MedDRA 
PT 
R 
NR 
R 
NR 
R 
NR 
R 
NR 
R 
NR 
R + NR 
 
 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
Notes: Events are counted once per subject at the highest severity grade and closest relationship to the investigational product. R= related to investigational 
product (possibly, probably, definitely). NR = not related to investigational product (unrelated, unlikely). 
 
 


 
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Table 127: 
Number and Percentage of Subjects with Adverse Events by Maximum Severity - Safety Subjects 
 
MedDRA SOC/ 
Placebo 
  Preferred Term 
(N=xx) 
 
Mild 
Moderate 
Severe 
Life-
threatening 
 
 
 
 
 
- Any Adverse Events -  
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
SOC 
 
 
 
 
   - Overall -  
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
      Preferred term 1 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
      Preferred term 2 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
Notes: Percentages are based on the total number of subjects, as given in the column heading. 
Multiple occurrences of a specific adverse event for a subject are counted once in the frequency for the adverse event. Likewise, multiple occurrences of 
adverse events within a specific preferred term for a subject are counted once in the frequency for the preferred term. 
Repeat for ANS 6637-600 mg and ANS-6637 200 mg 
Programmer’s Notes: Order System Organ Class alphabetically and preferred term alphabetically within System Organ Class. 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
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Table 128: 
Number and Percentage of Subjects Adverse Events by Relatedness - Safety Subjects 
 
MedDRA SOC/ 
Placebo 
ANS 6637 - 200 mg 
ANS-6637 600 mg 
  Preferred Term 
(n=xx) 
(n=xx) 
(n=xx) 
 
Related1 
Not-Related2 
Related 
Not-Related 
Related 
Not-Related 
 
 
 
 
 
 
 
SOC 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
   - Overall -  
 
 
 
 
 
 
      Preferred term 1 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
      Preferred term 2 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
1Related are possibly, probably or definitely related to investigational product 
2 Not Related to investigational product (not related or unlikely) 


 
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 Table 129: 
Number and Percentage of Subjects with Treatment-Related Adverse Events by Maximum Severity- Safety 
Subjects 
 
MedDRA SOC/ 
Placebo 
  Preferred Term 
(N=xx) 
 
Mild 
Moderate 
Severe 
Life-
threatening 
SOC 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
   - Overall -  
 
 
 
 
      Preferred term 1 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
      Preferred term 2 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
 
Notes: Percentages are based on the total number of subjects, as given in the column heading. 
Multiple occurrences of a specific adverse event for a subject are counted once in the frequency for the adverse event. Likewise, multiple 
occurrences of adverse events within a specific preferred term for a subject are counted once in the frequency for the preferred term. 
Repeat for ANS 6637-600 mg and ANS-6637 200 mg 
Programmer’s Notes: Order System Organ Class alphabetically and preferred term alphabetically within System Organ Class. 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
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Table 130: 
Number and Percentage of Subjects with Adverse Events Occurring in >= 10% of Subjects in Any One Group - 
Safety Subjects 
 
MedDRA SOC/ 
Placebo 
ANS 6637-200 mg 
ANS-6637 600 mg 
  Preferred Term 
(N=xx) 
(N=xx) 
(N=xx) 
SOC 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
   - Overall -  
 
 
 
      Preferred term 1 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
      Preferred term 2 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
Notes: Percentages are based on the total number of subjects, as given in the column heading. 
Multiple occurrences of a specific adverse event for a subject are counted once in the frequency for the adverse event. Likewise, multiple 
occurrences of adverse events within a specific preferred term for a subject are counted once in the frequency for the preferred term. At least 5% 
occurring in either arm to be included in the table. 
Programmer’s Notes: Order System Organ Class alphabetically and preferred term alphabetically within System Organ Class. 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
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Table 131: 
Number and Percentage of Subjects with Adverse Events Occurring in >= 10% of Subjects in Any One Group 
p-values - Safety Subjects 
 
MedDRA SOC/ 
 
 
 
  Preferred Term 
ANS-6637-200mg 
vs Placebo 
ANS-6637-600mg 
vs Placebo 
ANS-6637 200 mg 
vs ANS-6637 600 
mg 
SOC 
0.xxx 
0.xxx 
0.xxx 
   - Overall -  
 
 
 
      Preferred term 1 
0.xxx 
0.xxx 
0.xxx 
      Preferred term 2 
0.xxx 
0.xxx 
0.xxx 
p-values from Fisher’s exact test 
 
 
 


 
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Table 132: 
Number and Percentage of Subjects with Adverse Events Leading to Discontinuation of Study - Safety Subjects 
MedDRA SOC/ 
Placebo 
ANS 6637-200 mg 
ANS-6637 600 mg 
  Preferred Term 
(N=xx) 
(N=xx) 
(N=xx) 
SOC 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
   - Overall -  
 
 
 
      Preferred term 1 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
      Preferred term 2 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
 
 
 
 
Notes: Percentages are based on the total number of subjects, as given in the column heading. 
Multiple occurrences of a specific adverse event for a subject are counted once in the frequency for the adverse event. Likewise, multiple 
occurrences of adverse events within a specific preferred term for a subject are counted once in the frequency for the preferred term. 
Programmer’s Notes: Order System Organ Class alphabetically and preferred term alphabetically within System Organ Class. 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
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Table 133: 
Number and Percentage of Subjects with Adverse Events Leading to Discontinuation of Study Medication – 
Safety Subjects 
MedDRA SOC/ 
Placebo 
ANS 6637-200 mg 
ANS-6637 600 mg 
  Preferred Term 
(N=xx) 
(N=xx) 
(N=xx) 
SOC 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
   - Overall -  
 
 
 
      Preferred term 1 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
      Preferred term 2 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
Notes: Percentages are based on the total number of subjects, as given in the column heading. 
Multiple occurrences of a specific adverse event for a subject are counted once in the frequency for the adverse event. Likewise, multiple 
occurrences of adverse events within a specific preferred term for a subject are counted once in the frequency for the preferred term. 
Programmer’s Notes: Order System Organ Class alphabetically and preferred term alphabetically within System Organ Class. 
 
 
 
 
 
 
 
 


 
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Table 134: 
 CIWA-AR Score > 10 at Least Once During Treatment – Safety Subjects 
 
 
Placebo 
ANS 6637-
200 mg 
ANS-6637 
600 mg 
 
 
 
95% CI2 
 
(N=xx) 
(N=xx) 
(N=xx) 
p-value1 
Cohen’s h 
Odds Ratio 
OR3 Lower CI 
OR Upper CI 
CIWA-AR Score >= 10 
 
 
 
 
 
 
 
 
  Never 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
  At Least Once 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
 
 
 
 
200 mg vs Placebo 
 
 
 
 
0.xx 
xx.xxx 
xx.xxx 
xx.xxx 
600 mg vs Placebo 
 
 
 
 
0.xx 
xx.xxx 
xx.xxx 
xx.xxx 
200 mg vs 600 mg 
 
 
 
 
0.xx 
xx.xxx 
xx.xxx 
xx.xxx 
1 Chi-squared test; 2 CI is confidence interval; 3 OR is odds ratio 
 
 
 
 
 
 
 
 


 
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Table 135: 
Summary of Vital Signs and Body Weights – Safety Subjects 
Parameter 
N 
Mean 
SD 
Med 
Max 
Min 
Vital Sign (units) 
 
 
 
 
 
 
 Screening 
 
 
 
 
 
 
   Placebo 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   200 mg 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   600 mg 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Week 2 
 
 
 
 
 
 
   Placebo 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   200 mg 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   600 mg 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Change from baseline 
 
 
 
 
 
 
   Placebo 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   200 mg 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   600 mg 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Weeks 3,4,5,6 
 
 
 
 
 
 
Programmers note: vital signs include pulse rate, systolic blood pressure, and diastolic blood pressure. Body weight (kg) will also be presented. 


 
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Table 136: 
 Summary of ECG Results - Safety Subjects 
 
Placebo 
ANS 6637-200 mg 
ANS-6637 600 mg 
Result 
(N=xx) 
(N=xx) 
(N=xx) 
Screening 
 
 
 
  Normal 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
  Abnormal, Not Clinically Significant 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
  Abnormal, Clinically Significant 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
Week 3 
 
 
 
  Normal 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
  Abnormal, Not Clinically Significant 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
  Abnormal, Clinically Significant 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
Week 6 
 
 
 
  Normal 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
  Abnormal, Not Clinically Significant 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
  Abnormal, Clinically Significant 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
 


 
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Table 137: 
Summary of Blood Chemistries and Thyroid Function – Safety Subjects 
 
Placebo 
                        ANS-6637  200mg 
 
ANS-6637 600 mg 
 
N 
Mean (SD) 
Med 
(Min-Max) 
N 
Mean (SD) 
Med 
(Min-Max) 
N 
Mean (SD) 
Med 
(Min-Max) 
  Chemistry (units) 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Value 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
Week 2 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
Change from baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
    Week 3, 4, 5, 6 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
Programmers note: table will include creatinine, ALT, AST, total bilirubin, alkaline phosphate, albumin, CrCl, GGT and thyroid function tests. 
Table 138: 
Summary of Urinalysis Continuous Data – Safety Subjects 
 
Placebo 
                        ANS-6637  200mg 
 
ANS-6637 600 mg 
 
N 
Mean (SD) 
Med 
(Min-Max) 
N 
Mean (SD) 
Med 
(Min-Max) 
N 
Mean (SD) 
Med 
(Min-Max) 
  Urinalysis (units) 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Value 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
Week 4 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
Change from baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
    Week 7 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x-xx.x) 
Programmers note: table will PH, specific gravity, and glucose result, . 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
150    
 
Table 139: 
Summary of Urine Glucose and Nitrites – Safety Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
ANS-6637-200mg 
ANS-6637 600 mg 
 
Positive 
Negative 
Positive 
Negative 
Positive 
Negative 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Glucose 
 
 
 
 
 
 
   Baseline 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Week 4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Week 7 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Nitrites 
 
 
 
 
 
 
   Baseline 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Week 4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Week 7 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
151    
 
Table 140: 
Summary of Urine Protein, Ketones, Billirubin, Leukocyte Esterace, and Blood – Safety Subjects 
 
Programmer Note: Billirubin and Leukocyte Esterace follow the same as Protein 
 
 
 
Placebo 
ANS-6637 200 mg 
ANS-6637 600 mg 
 
Baseline 
Week 4 
Week 7 
Baseline 
Week 4 
Week 7 
Baseline 
Week 4 
Week 7 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Blood 
 
 
 
 
 
 
 
 
 
   Negative 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Trace 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   1+ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   2+ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   3+ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   4+ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Ketones 
 
 
 
 
 
 
 
 
 
   Negative 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Trace 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   1+ (small) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   2+ (medium) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   3+ (large) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Protein 
 
 
 
 
 
 
 
 
 
   Negative 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Trace 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   1+ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   2+ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   3+ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   4+ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
152    
 
 
 
Table 141: 
Summary of Positive Urine Drug Tests, Preganancy Test or BAC > 0.02 Any Time During the Study– Safety 
Subjects 
 
Number (% Positive) 
Test 
Placebo 
ANS 6637-200 mg 
ANS-6637 600 mg 
 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
THC 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Cocaine 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Opioids 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Methamphetamine 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Amphetamine 
xx (xx%) 
xx (xx%) 
xx (xx%) 
MDMA 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Benzodiazapines 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Buprenorphine 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Methadone 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Oxycodone 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Ethylglucuronide (EtG) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Pregnancy 
xx (xx%) 
xx (xx%) 
xx (xx%) 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
153    
 
 
Number (% Positive) 
Test 
Placebo 
ANS 6637-200 mg 
ANS-6637 600 mg 
 
(N=xx) 
(N=xx) 
(N=xx) 
BAC > 0.02 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
Table 142: 
Frequency of Subjects with Suicidal Ideation Any Time During the Study – Safety Subjects 
Number of Subjects Reporting Suicidal Ideation by C-SSRS (%) 
 
 
Placebo 
ANS 6637-200 mg 
ANS-6637 600 
mg 
ANS-6637-
200mg vs 
Placebo 
ANS-6637-
600mg vs 
Placebo 
ANS-6637 200 
mg vs ANS-
6637 600 mg 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
0.xxx 
0.xxx 
0.xxx 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
154    
 
Table 143: 
Return to Baseline ACQ-SF-R Scores – Safety Subjects 
 
Number (% Positive) 
Test 
Placebo 
ANS 6637-200 mg 
ANS-6637 600 mg 
 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
Screening 
 
 
 
Increased Craving, n (%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Week 2 
 
 
 
Increased Craving, n (%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
155    
 
12.1.7. 
Exploratory Analyses


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
156    
 
Table 144: 
Difference Between First and Second Alcohol Cues – mITT Subjects 
Cue Question 
1st Alcohol Cue 
2nd Alcohol Cue 
Difference 
p-value1 
Baseline 
Mean (SD2 ) 
Mean (SD) 
Mean (SD) 
 
  Perfect 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
0.xxx 
  Craving 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
0.xxx 
  Drink now 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
0.xxx 
  Turn down 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
0.xxx 
  Average of 4 questions 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
0.xxx 
Week 2 
 
 
 
 
  Perfect 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
0.xxx 
  Craving 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
0.xxx 
  Drink now 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
0.xxx 
  Turn down 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
0.xxx 
  Average of 4 questions 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
0.xxx 
1t-test; 2 SD is standard deviation 
 
 
  


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
157    
 
 
12.2. 
Listings


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
158    
 
 
Listing 1: Subject Disposition - All Subjects 
Subject 
ID  
Date of 
Consent  
Treatment 
Group 
mITT  
Eval- 
uable  
Safety 
Study 
Completion 
(Day) Date of 
Study 
Completion 
or Early 
Discontinuati
on 
Reason for 
Early 
Discontinuation 
Subject 
confined 
or incar-
cerated 
Start Date/ End 
Date of 
incarceration 
xxx 
ddmmmyyyy 
ANS 6637-
200 mg 
Yes 
Yes 
Yes 
Yes 
(xx) 
ddmmmyyyy 
xxxxxx 
Yes 
ddmmmyyyy / 
ddmmmyyyy 
 
 
ANS 6637-
600 mg 
No 
No 
No 
No 
 
 
No 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 
 
Note: Day is relative to Study Day 0. 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
159    
 
Listing 2. Enrollment and Randomization – All Consented Subjects 
Subject ID  
Treatment Group 
Date of Consent 
Did the subject meet 
all eligibility criteria? 
Randomized? 
Date of Randomization 
Kit Number 
xxx 
ANS 6637-200 mg 
ddmmmyyyy 
Yes 
Yes 
ddmmmyyyy 
xxx 
 
ANS 6637-600 mg 
 
No 
No 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 3: Reason not Eligible – Screen Failures 
Subject ID 
Criterion Type 
Criterion 
xxx 
Inclusion Criteria 
 
 
Exclusion Criteria 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
160    
 
Listing 4: Protocol Deviations – Safety Subjects 
Subject ID  
Treatment Group 
Deviation Date 
Protocol Deviation 
Details 
xxx 
ANS 6637-200 mg 
ddmmmyyyy 
Subject Failed to Meet the 
Inclusion/Exclusion Criteria 
 
 
ANS 6637-600 mg 
 
Source Documentation was Not Available 
 
 
Placebo 
 
Pregnancy Test Not Performed 
 
 
 
 
Required study data was not obtained or 
obtained late due to site error 
 
 
 
 
Informed Consent Deviation 
 
 
 
 
AE/SAE Reporting Deviation 
 
 
 
 
Other Deviation: 
xxxxxxxxxxxxxxx 
 
 
 
 
 
Note: Only subjects with protocol deviation are listed. 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
161    
 
Listing 5: Subjects Excluded from the Efficacy Analysis or Evaluable Set 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Reason for Exclusion from mITT  
 
Reason for Exclusion from Evaluable 
Set 
xxx 
ANS 6637-200 mg 
xxxxxx 
 
 
ANS 6637-600 mg 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
Note: Only subjects excluded from the efficacy analysis or evaluable set are listed. 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
162    
 
Listing 6: Demographics Data – Safety Subjects 
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Gender 
Age 
(yrs) 
Ethnicity 
 
Race 
Marital Status 
 
 
 
 
 
 
 
xxx 
ANS 6637-200 mg 
Male 
xx 
Hispanic or Latino 
American Indian or Alaska 
Native 
  Married 
 
ANS 6637-600 mg 
Female 
 
Not Hispanic or Latino 
Asian 
  Divorced 
 
Placebo 
 
 
Unknown 
Native Hawaiian or Other 
Pacific Islander 
  Living with Partner 
 
 
 
 
 
Black or African American 
  Widowed 
 
 
 
 
 
White 
  Separated 
 
 
 
 
 
Other 
  Never Married 
 
 
 
 
 
Unknown 
  Unknown 
 
 
 
 
 
 
  Missing 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
163    
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Years of Formal 
Education 
(GED=12years) 
Usual Employment 
Pattern in the last 30 
days 
Subject’s Annual 
Household Income 
Subject’s Usual Occupation 
ALDH2 Status 
xxx 
ANS 6637-
200 mg 
xxx 
Full-time, 35+ hrs/week 
$0-$15,000 
  Executive of large business or 
major professional 
Deficient 
 
ANS 6637-
600 mg 
 
Part-time, regular hours 
$15,001-$30,000 
  Manager of medium business or 
minor professional 
Non-deficient 
 
Placebo 
 
Part-time, irregular 
hours/daywork 
$30,001-$45,000 
  Administrator of large business, 
owner of small business, or semi-
professional 
 
 
 
 
Student 
$45,001-$60,000 
  Clerical or sales worker, 
technician 
 
 
 
 
Military service 
$60,001-$75,000 
  Skilled worker 
 
 
 
 
Unemployed 
$75,001-$90,000 
  Semi-skilled worker 
 
 
 
 
Retired/Disabled 
$90,001-$105,000 
  Unskilled worker 
 
 
 
 
Homemaker 
$105,001-$120,000 
  Unemployed 
 
 
 
 
In controlled 
environment 
>$120,000 
  Never worked 
 
 
 
 
Unknown 
Not Given 
  Not given 
 
 
 
 
 
 
  Other 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
164    
 
 
 
 
Listing 7: Baseline Drinking Characteristics – mITT Subjects 
 
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Drinks/Day 
(Days -1 to -
28) 
Drinks/Day  
(Days -1 to -14 
Pre- 
randomization) 
Drinks/ 
Drinking Day  
(Days -1 to -28) 
Drinks/Drinking 
Day (Days -1 to -
14 Pre-
randomization) 
Weekly % 
Heavy Drinking 
Days  
(Days -1 to -28) 
Weekly % 
Heavy Drinking 
Days 
 (Days -1 to -14  
Pre-
randomization) 
xxx 
ANS 6637-
200 mg 
xxx.x 
xxx.x 
xxxx 
xxx.x 
xxx.x 
xxx.x 
 
ANS 6637-
600 mg 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
165    
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Weekly %Very 
Heavy Drinking 
Days  
(Days -1 to -28) 
Weekly % Very 
Heavy Drinking 
Days  
(Days -1 to -14 
Pre-
randomization) 
Weekly % Days 
Abstinent 
 (Days -1 to -28) 
Weekly % Days 
Abstinent (Days 
-1 to -14 Pre-
randomization) 
 
 
 
 
 
 
xxx 
ANS 6637-
200 mg 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
 
ANS 6637-
600 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Exclude the three abstinent days during pre-randomization period. 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
166    
 
Listing 8: Baseline Smoking Characteristics – mITT Subjects 
 
 
 
 
 
Subject 
ID  
Treatment Group 
Over the past week, how 
many days did you 
smoke cigarettes? 
How many 
cigarettes on 
average per day? 
Over the past week, 
how many days did you 
use nicotine products? 
xxx 
ANS 6637-200 mg 
None 
xxx 
None 
 
ANS 6637-600 mg 
1, 2, 3, 4, 5 
 
1, 2, 3, 4, 5 
 
Placebo 
6, 7 
 
6, 7 
 
 
Refused to answer 
 
Refused to answer 
 
Listing 9: MINI DSM5 Disorders – Safety Subjects 
 
 
 
 
 
Subject 
ID  
Treatment Group 
Visit Date 
Diagnosis 
Timeframe 
xxx 
ANS 6637-200 mg 
ddmmmyyyy 
xxxxxx 
Current (2 weeks ) 
 
ANS 6637-600 mg 
 
 
Past  
 
Placebo 
 
 
Recurrent  
 
 
 
 
 
 
Note: Only subjects with a diagnosis of a disorder will be listed. 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
167    
 
Listing 10: MINI DSM-5 AUD – Safety Subjects 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Visit Date 
# of Symptoms 
xxx 
ANS 6637-200 
mg 
ddmmmyyyy 
xx 
 
ANS 6637-600 
mg 
 
 
 
Placebo 
 
 
 
Listing 11: Medical History – Safety Subjects 
Subject 
ID  
Treatment 
Group 
 
Medical History 
Term 
 
Start Date  
Ongoing 
xxx 
ANS 6637-200 mg 
xxxxxxxxxxx 
ddmmmyyyy 
No 
 
ANS 6637-600 mg 
 
 
Yes 
 
Placebo 
 
 
 
Programming note: Only identify items that were scored “yes” 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
168    
 
Listing 12: Drinking Goal – mITT Subjects 
Subject 
ID  
Treatment 
Group 
Visit Date 
Time 
What goal have you chosen 
for yourself about drinking 
by the end of the study? 
What might a typical 
week look like at the end 
of the study having 
achieved your goal? 
(number of drinks per 
day) 
Motivation 
to reach goal 
Confidence to 
reach goal 
xxx 
ANS 6637-
200 mg 
ddmmmyyyy 
hh:mm 
To stop drinking 
xx 
xx 
xx 
 
ANS 6637-
600 mg 
 
 
Reduce drinking but not stop 
 
 
 
 
Placebo 
 
 
 
 
 
 
  
Listing 13: Physical Exam – Safety Subjects 
Subject 
ID 
Treatment 
Group 
 
Exam Date  
 
Finding 
Any abnormal 
finding during the 
physical exam?  
Describe clinically 
significant findings  
xxx 
ANS 6637-200 mg 
ddmmmyyyy 
xxxxxxxxxxx 
Yes  
xxxxxxxx 
 
ANS 6637-600 mg 
 
 
No  
 
 
Placebo 
 
 
 
 
Programming Note: Only report the items that are abnormal 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
169    
 
Listing 14: Daily and Weekly Standard Drink Units (TLFB) During Treatment – mITT Subjects 
Subject 
ID 
Treatment 
Group 
Week 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Mean 
drinks/day 
Mean drinks/ 
drinking day 
Heavy 
drinking 
days 
% days 
abstinent 
xxx 
ANS 6637-
200 mg 
1 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
ANS 6637-
600 mg 
2 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
3, etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 15: Brief Drinking Questionnaire – mITT Subjects 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Date of 
Assessment 
Date that the last day 
of non-missing 
drinking data was 
collected by TLFB  
This is a period of XX 
days since the last day of 
drinking data that was 
collected by TLFB 
Did the subject 
drink during 
this period? 
How many days 
during this 
period did the 
subject drink? 
xxx 
ANS 6637-
200 mg 
ddmmmyyyy 
ddmmmyyyy 
xx 
Yes 
xx 
 
ANS 6637-
600 mg 
 
 
 
No 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
170    
 
Subject 
ID  
Treatment 
Group 
Date of 
Assessment 
How many 
alcoholic 
drinks on a 
typical day? 
How many heavy 
drinking days? 
Maximum 
number of drinks 
on any one day? 
How many days did 
you drink this 
maximum number? 
xxx 
ANS 6637-
200 mg 
ddmmmyyyy 
xx 
xx 
xx 
xx 
 
ANS 6637-
600 mg 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
Listing 16: Cue Reactivity – mITT Subjects 
Subject 
ID  
Treatment 
Group 
Visit 
Date of 
Assessment 
Assessment 
Time 
Cue 
How strong is 
your craving to 
drink alcohol? 
Having a drink 
would make things 
just perfect 
If I could drink 
alcohol now, I 
would drink it 
xxx 
ANS 6637-
200 mg 
Screening 
ddmmmyyyy 
hh:mm 
Water 
xx 
xx 
xx 
 
ANS 6637-
600 mg 
Week 2 
 
 
Alcohol 1 
 
 
 
 
Placebo 
 
 
 
Alcohol 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
171    
 
Subject 
ID  
Treatment 
Group 
Visit 
Cue 
It would be hard 
to turn down a 
drink right now 
How much did 
you like the 
beverage just 
given to you? 
Sum of first 4 
questions 
xxx 
ANS 6637-
200 mg 
Screening 
Water 
xx 
xx 
xx 
 
ANS 6637-
600 mg 
Week 2 
Alcohol 1 
 
 
 
 
Placebo 
 
Alcohol 2 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 17: Cue Session Beverage – mITT Subjects 
Subject 
ID  
Treatment Group 
If subject smoked 
prior to cue session, 
time smoked 
Typical 
Beverage Brand 
Typical 
Beverage Type 
Typical Alcohol 
Beverage % ABV 
(Used for Cue Session) 
xxx 
ANS 6637-200 mg 
hh:mm 
xxxxxx 
xxxxxxx 
xx 
 
ANS 6637-600 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
172    
 
Listing 18: Drinking Consequences and Craving Scores – mITT Subjects 
 
 
 
 
 
 
 
 
Subject 
ID 
Treatment 
Group 
Week 
CIWA-AR 
ACQ-SF-R Pre 
ACQ-SF-R Post 
PACS 
PROMIS Negative 
Consequences 
 
 
 
 
 
 
 
 
xxx 
ANS 6637-
200 mg 
 
xxx 
xxx 
xxx 
xxx 
xxx 
 
ANS 6637-
600 mg 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
Listing 19: Pittsburg Sleep Quality Index Scores – mITT Subjects 
Subject ID 
Treatment Group 
Week 
Total score 
xxx 
ANS 6637-200 mg 
Screening 
xx 
 
ANS 6637-600 mg 
Week 6 
 
 
Placebo 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
173    
 
Listing 20: Smoking and Other Nicotine Use Data– mITT Subjects 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Week 
Visit Date 
Over the past 
week, how 
many days did 
you smoke 
cigarettes? 
On the days you 
smoked, how 
many cigarettes 
did you smoke 
on average? 
How many days 
use nicotine 
products during 
the past week? 
 
 
 
 
 
 
 
xxx 
ANS 6637-200 mg 
 
ddmmmyyyy 
x 
xx 
x 
 
ANS 6637-600 mg 
 
 
 
 
 
 
Placebo 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
174    
 
Listing 21: MINI AUD– Safety Subjects  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Item 
# of Symptoms 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
xxx 
ANS 6637-
200 mg 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
 
 
ANS 6637-
600 mg 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
 
 
Placebo 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
 
 
Item # 
List of Items 
1 
a. During the times when you drank alcohol, did you end up drinking more than you planned when you started? 
2 
b. Did you repeatedly want to reduce or control your alcohol use? Did you try to cut down or control your alcohol use, but 
failed? IF YES TO EITHER, MARK YES. 
3 
c. On the days that you drank, did you spend substantial time obtaining alcohol, drinking, or recovering from the effects of 
alcohol? 
4 
d. Did you crave or have a strong desire or urge to use alcohol? 
5 
e. Did you spend less time meeting your responsibilities at work, at school, or at home, because of your repeated 
drinking? 
6 
f. If your drinking caused problems with your family or other people, did you still keep on drinking? 
7 
g. Were you intoxicated more than once in any situation where you or others were physically at risk, for example, driving 
a car, riding a motorbike, using machinery, boating, etc.? 
8 
h. Did you continue to use alcohol, even though it was clear that the alcohol had caused or worsened psychological or 
physical problems? 
9 
i. Did you reduce or give up important work, social or recreational activities because of your drinking? 
10 
j. Did you need to drink a lot more in order to get the same effect that you got when you first started drinking or did you 
get much less effect with continued use of the same amount? 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
175    
 
11 
K1. When you cut down on heavy or prolonged drinking did you have any of the following: [increased sweating or heart 
rate; hand tremor or “the shakes”; trouble sleeping; nausea or vomiting; hearing or seeing things other people could not 
see or hear or having sensations in your skin for no apparent reason; agitation; anxiety; seizures]  (If yes to 2 or more of 
these, check yes for this question), OR 
 
K2. Did you drink alcohol to reduce or avoid withdrawal symptoms or to avoid being hung over? If K1 or K2 = yes, then 
score as yes. 
 
Listing 22. Exit Interview – mITT Subjects 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Visit Date 
Did you think you 
were receiving 
the study drug or 
the placebo? 
What is your desire to 
please people? 
If you had the 
opportunity in the 
future to take the 
study drug again, 
would you continue to 
take it for more than 5 
weeks? 
Did you limit your 
drinking because of 
flushing (a heat reaction 
or facial redness)? 
 
 
 
 
 
 
 
xxx 
ANS 6637-
200 mg 
ddmmmyyyy 
Placebo 
More than average 
Yes  
Yes  
 
ANS 6637-
600 mg 
 
Study Drug 
Average 
No  
No  
 
Placebo 
 
Don’t know 
Less than average 
Refuse to answer  
Refuse to answer  
 
 
 
Refuse to answer 
Refuse to answer 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
176    
 
 
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Visit Date 
Did you limit 
your drinking 
because of 
nausea or other 
effects? 
Did your 
friends or 
family 
notice 
flushing? 
If your friends or 
family noticed 
flushing, did this 
change your 
drinking? 
Did you ever 
miss a dose of 
medication to 
avoid these 
effects? 
Did you use any 
other services 
during the study 
to help you 
reduce drinking? 
xxx 
ANS 6637-
200 mg 
ddmmmyyyy 
Yes  
Yes  
Yes  
Yes  
Yes  
 
ANS 6637-
600 mg 
 
No  
No  
No  
No  
No  
 
Placebo 
 
Refuse to answer  
Refuse to 
answer  
Refuse to answer  
Refuse to answer  
Refuse to answer  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
177    
 
Listing 23: Drug Exposure from AiCure– mITT Subjects 
 
 
 
Tablets Taken 
 
 
Subject 
ID 
Treatment 
Group 
Study 
Week 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Total 
Taken 
Total 
Expected 
xxx 
ANS 6637-
200 mg 
1, 2, 3, 4, 
5 
x 
x 
x 
x 
x 
x 
x 
xx 
xx 
 
ANS 6637-
600 mg 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 24: Drug Accountability – Safety Subjects 
Subject ID 
Treatment Group 
Bottle # 
Date 1st Dispensed 
Date Returned 
# Tablets Returned 
xxx 
ANS 6637-200 mg 
1, 2, 3 
ddmmmyyyy 
ddmmmyyyy 
xx 
 
ANS 6637-600 mg 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
178    
 
 
 
Listing 25: Take Control – mITT Subjects 
 
 
Dates Modules Viewed 
Subject 
ID 
Treatment Group 
1 
2 
3 
4 
5 
6 
7 
xxx 
ANS 6637-200 mg 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
 
ANS 6637-600 mg 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
179    
 
Listing 26: Adverse Events – Safety Subjects 
 
Notes: Day is relative to Study Day 0. 
 Severity: 1=Mild; 2=Moderate; 3=Severe; 4=Potentially Life-threatening. 
 Relationship: 1= Unrelated; 2=Unlikely; 3=Possibly; 4=Probably; 5=Definitely 
 Action Taken Due to AE: 1=None; 2=Treated with Drugs; 3=Non-drug treatment; 4=ER/Outpatient visit; 5=Hospitalization; 6=Referral for treatment 
 Outcome: 1=Resolved; 2=Recovered with sequelae; 3=Ongoing; 4=Required treatment; 5=Unknown 
 
Programmer’s Note: If “Were any AEs reported?” checkbox=No, then display “None Reported” in the Adverse Event column and SOC/PT column. If an AE 
started and stopped the same day, the duration is 1 day. 
 
 
Subject 
ID 
Treatment 
Group 
Adverse 
Event 
(Verbatim) 
S: SOC 
P: PT 
Term 
Start Date/ 
Day 
Stop Date/ 
Day 
 
Duration 
in Days 
Severity 
Relation
-ship 
Actions 
Taken 
Outcome 
Seri
ous 
xxx 
ANS 6637-
200 mg 
Verbatim 
ddmmmyyyy/ 
xx  
ddmmmyyyy/ 
xx 
 
1 
1 
1 
1 
Yes 
 
ANS 6637-
600 mg 
S: xxxx 
xx 
xx 
 
2 
2 
2 
2 
No 
 
Placebo 
P: xxxx 
 
 
 
3 
3 
3 
3 
 
 
 
 
 
 
 
4 
4 
4 
4 
 
 
 
 
 
 
 
 
5 
5 
5 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
180    
 
Listing 27: Adverse Events – Subjects Taking CYP3A Substrate 
Notes: Day is relative to Study Day 0. 
 Severity: 1=Mild; 2=Moderate; 3=Severe; 4=Potentially Life-threatening. 
 Relationship: 1= Unrelated; 2=Unlikely; 3=Possibly; 4=Probably; 5=Definitely 
 Action Taken Due to AE: 1=None; 2=Treated with Drugs; 3=Non-drug treatment; 4=ER/Outpatient visit; 5=Hospitalization; 6=Referral for treatment 
 Outcome: 1=Resolved; 2=Recovered with sequelae; 3=Ongoing; 4=Required treatment; 5=Unknown 
 
Programmer’s Note: If “Were any AEs reported?” checkbox=No, then display “None Reported” in the Adverse Event column and SOC/PT column. If an AE 
started and stopped the same day, the duration is 1 day. 
Subject 
ID 
Treatment 
Group 
Adverse 
Event 
(Verbatim) S: 
SOC 
P: PT 
Term 
Start Date/ 
Day 
Stop Date/ 
Day 
 
Duration 
in Days 
Severity 
Relation-
ship 
Actions 
Taken 
Outcome 
Serious 
xxx 
ANS 6637-
200 mg 
Verbatim 
ddmmmyyyy 
ddmmmyyyy 
 
1 
1 
1 
1 
Yes 
 
ANS 6637-
600 mg 
S: xxxx 
xx 
xx 
 
2 
2 
2 
2 
No 
 
Placebo 
P: xxxx 
 
 
 
3 
3 
3 
3 
 
 
 
 
 
 
 
4 
4 
4 
4 
 
 
 
 
 
 
 
 
5 
5 
5 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
181    
 
Listing 28: Serious Adverse Events – Safety Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
SAE 
Verbatim 
S: SOC 
P: PT 
Start Date/ 
Day 
Stop Date/ 
Day 
SAE Category 
SAE 
Description 
Relevant 
tests/ 
laboratory 
data 
 
 
 
 
 
 
 
 
xxx 
ANS 6637-
200 mg 
Verbatim 
ddmmmyyyy 
ddmmmyyyy 
Results in Death 
 
xxxxxx 
 
ANS 6637-
600 mg 
S: XXX 
Xx 
Xx 
Life-threatening 
 
 
 
Placebo 
P: XX 
 
 
Requires or Prolongs 
Hospitalization 
 
 
 
 
 
 
 
Disability 
 
 
 
 
 
 
 
Congenital Anomaly/Birth 
Defect 
 
 
 
 
 
 
 
Required Intervention to 
Prevent 
Persistant or Significant 
Disability / Incapacity 
 
 
 
 
 
 
 
Other 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
182    
 
 
 
 
 
 
 
 
Subject 
ID 
SAE 
Date of death 
Cause of death 
Hospitalization 
Date/Discharge 
Date 
Comments 
 
 
 
 
 
 
xxx 
Verbatim 
ddmmmyyyy 
xxxxxx 
ddmmmyyyy 
xxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
ddmmmyyyy 
 
 
 
 
 
 
 
 Notes: Day is relative to Study Day 0. 
Severity: 1=Mild; 2=Moderate; 3=Severe; 4=Potentially Life-threatening. 
Relationship: 1= Unrelated; 2=Unlikely; 3=Possibly; 4=Probably; 5=Definitely 
Outcome: 1=Recovered/Resolved; 2=Recovering/Resolving; 3=Not Recovered/Not Resolved; 4=Recovered/Resolved With Sequelae; 5=Fatal (Date of Death) 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
183    
 
Listing 29: Elicited Adverse Events – Safety Subjects 
Subject 
ID  
Treatment Group 
Date 
Changes in appetite 
Heat sensation (flushing 
or feeling hot) 
Increased heart rate 
or heart palpitations 
xxx 
ANS 6637-200 mg 
ddmmmyyyy 
Yes 
Yes 
Yes 
 
ANS 6637-600 mg 
 
No 
No 
No 
 
Placebo 
 
 
 
 
 
 
Listing 30: POMS Scores – mITT Subjects 
 
 
 
Scores 
Subject 
ID 
Treatment 
Group 
Week 
Total Mood 
Disturbance  
Tension  
Depressio
n  
Anger 
Fatigue 
Confusion  
Vigor  
 
 
 
 
 
 
 
 
 
 
xxx 
ANS 6637-
200 mg 
 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
ANS 6637-
600 mg 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
184    
 
Listing 31. Columbia-Suicide Severity Scale – Safety Subjects 
 
 
 
 
Response to Question: 
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Visit Date 
Study 
Week 
Q1 
Q2 
Q3 
Q4 
Q5 
Q6 
Q7 
Q8 
Q9 
Q10 
Q11 
Q12 
Q13 
xxx 
ANS 6637-
200 mg 
ddmmmyyyy 
 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Type 1 
1 
1 
0 
0 
0 
Yes 
 
ANS 6637-
600 mg 
 
 
No 
No 
No 
No 
No 
No 
Type 2 
2 
2 
1 
1 
1 
No 
 
Placebo 
 
 
 
 
 
 
 
 
Type 3 
3 
3 
2 
2 
2 
 
 
 
 
 
 
 
 
 
 
 
Type 4 
4 
4 
3 
3 
3 
 
 
 
 
 
 
 
 
 
 
 
Type 5 
5 
5 
4 
4 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
5 
5 
 
Suicide Ideation 
1. Have you wished you were dead or wished you could go to sleep and not wake up? 
2. Have you actually had any thoughts of killing yourself? 
3. Have you been thinking about how you might do this? 
4. Have you had these thoughts and had some intention of acting on them? 
5. Have you started to work out or worked out the details of how to kill yourself? 
6. Do you intend to carry out this plan? 
Intensity of Ideation 
7. The following features should be rated with respect to the most severe type of ideation (i.e. 1-5 with 1 being the least severe and 5 being the 
most severe) 
8. How many times have you had these thoughts?1=Less than once a week; 2=Once a week;  3=2-5 times a week;  4=Daily or almost;  
5=Many times each day 
9. When you have the thoughts, how long do they last? 1=Fleeting-few seconds or minutes; 2=Less than 1 hr-some of the time;  3=1-4 hrs/a lot of 
time;  4=4-8 hrs/most of day;  5=More than 8 hours/persistent or continuous 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
185    
 
10. Could/can you stop thining about killing yourself or wanting to die if you want to?  1=Easily; 2=Little Difficulty; 3=Some Difficulty; 
4=Lot of Difficulty;  5=Unable to control; 0=Does not attempt to control 
11. Are there things that stop you from wanting to die or acting on thoughts of committing suicide? 1=Definite deterrents; 2=Probably Deterrents;  
3=Uncertain Deterrents; 4=Unlikely Deterrents; 5=No Deterrents; 0=Does not apply 
12. What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end pain or stop the way you were feeling or 
to get attention, revenge or reaction from others 1=Completely to get attention or revenge or reaction; 2=Mostly to get attention or revenge or 
reaction; 3=Equally to get attention or revenge or reaction and stop pain; 4=Mostly to stop pain; 5=Completely to stop pain; 0=Does not apply 
Suicidal Behavior 
13. Have you made a suicide attempt? 
 
 
 
Response to Question: 
 
 
 
 
 
 
 
Subject 
ID 
Treatment 
Group 
Study 
Week 
Q14 
Q15 
Q16 
Q17 
Q18 
Q19 
Q20 
Q21 
Q22 
Q23 
Q24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxx 
ANS 6637-
200 mg 
 
xx 
Yes 
Yes 
xx 
Yes 
xx 
Yes 
Yes 
Yes 
0 
0 
 
ANS 6637-
600 mg 
 
 
No 
No 
 
No 
 
No 
No 
No 
1 
1 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
2 
2 
 
 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 (date ddmmmyyyy) 
 
14. Number of attempts 
15. Has the subject engaged in non-suicidal self-injurious behavior? 
16. Has there been a time when you started to do something to end your life but someone or something stopped you before actually did anything? 
17. Number interrupted 
18. Has there been a time when you stared to do something to try to end your life but you stopped yourself before you actually did anything? 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
186    
 
19. Number aborted 
20. Have you taken any step towards making a suicide attempt or preparing to kill yourself? 
21. Suicidal behavior was present during the assessment period 
22. Completed suicide? 
23. Actual Lethality/Medical Damage;  0=No physical damage; 1=Minor physical damage; 2=Moderate physical Damage; 3=Moderately severe 
physical damage; 4=Severe physical damage; 5=Death 
24. Potential Lethality;  0=Behavior not likely to result in injury; 1=Behavior likely to result in injury, but not death; 2=Behavior likely to result in 
death 
 
Listing 32: Blood Chemistries and Thyroid Results – Safety Subjects 
Subject 
ID  
Treatment Group 
Visit Date 
Test Name 
Result 
Units 
Flag 
Evaluation 
xxxx 
ANS 6637-200 mg 
ddmmmyyyy 
Creatinine 
x.xx 
mg/dL 
H (high) 
WNL 
 
ANS 6637-600 mg 
 
Total Bilirubin 
xxx 
mg/dL 
L (low) 
Abnormal, NCS 
 
Placebo 
 
ALT 
xx.x 
U/L 
 
Abnormal, CS 
 
 
 
AST 
x.xx 
U/L 
 
 
 
 
 
Creatinine Clearance 
xxx.xx 
mL/min 
 
 
 
 
 
Akaline Phosphate 
xxx.x 
U/L 
 
 
 
 
 
Albumin 
xx.x 
g/dL 
 
 
 
 
 
GGT 
xx.x 
U/L 
 
 
 
 
 
TSH 
xx.xx 
 
 
 
 
 
 
Thyroxine 
xx.xx 
 
 
 
 
 
 
Free Thyroxine 
xx.xx 
 
 
 
 
 
 
Triiodothyronine 
xx.xx 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
187    
 
Listing 33: Hematology – Safety Subjects 
Subject 
ID  
Treatment 
Group 
Visit Date 
Test Name 
Result 
Units 
xxxx 
ANS 6637-
200 mg 
ddmmmyyyy 
Hematocrit 
xxx.xx 
% 
 
ANS 6637-
600 mg 
 
Hemoglobin 
xxx 
g/dL 
 
Placebo 
 
RBC 
xx.x 
mil/uL 
 
 
 
WBC 
x.xx 
thous/uL 
 
 
 
Platelets 
xxx.xx 
thous/uL 
 
 
 
Neutrophils 
xxx.x 
% 
 
 
 
Monocytes 
xx.x 
% 
 
 
 
Eosinophils 
xx.x 
% 
 
 
 
Basophils 
xx.x 
% 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
188    
 
Listing 34: Urinalysis – Safety Subjects 
Subject 
ID  
Treatment 
Group 
Visit Date 
Study 
Week 
pH 
Specific 
Gravity 
Glucose 
Glucose 
Result 
(mg/dL) 
Protein 
Ketones 
Blood 
Nitrites 
Bilirubin 
Leukocyte 
Esterase 
xxx 
ANS 6637-
200 mg 
ddmmmyyyy 
Screen 
xx.x 
x.xxx 
Negative 
xxxx 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
 
ANS 6637-
600 mg 
 
x 
 
 
Positive 
 
Trace 
Trace 
Trace 
Positive 
Trace 
Trace 
 
Placebo 
 
 
 
 
 
 
1+ 
1+ 
1+ 
 
1+ 
1+ 
 
 
 
 
 
 
 
 
2+ 
2+ 
2+ 
 
2+ 
2+ 
 
 
 
 
 
 
 
 
3+ 
3+ 
3+ 
 
3+ 
3+ 
 
 
 
 
 
 
 
 
4+ 
4+ 
4+ 
 
4+ 
4+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
189    
 
Listing 35: Urinalysis Microscopy1 – Safety Subjects 
Subject 
ID  
Treatment 
Group 
Visit Date 
Test Name 
Result (cells/HPF) 
xxxx 
ANS 6637-200 mg 
ddmmmyyyy 
Microscopic RBC 
xx 
 
ANS 6637-600 mg 
 
Microscopic WBC 
xx 
 
Placebo 
 
Epithelial Cells 
xx 
 
 
 
Hyaline Casts 
xx 
1Only subjects that had microscopy 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
190    
 
Listing 36: Pregnancy Test/Birth Control Data – Safety Subjects 
Subject 
ID  
Treatment Group 
Gender 
Pregnancy Test 
Performed? 
 
Pregnancy Test / 
Visit Date 
Pregnancy Result 
Methods of birth control 
xxx 
ANS 6637-200 mg 
Male 
Not Done 
ddmmmyyyy 
Negative 
Oral Contraceptive 
 
ANS 6637-600 mg 
Female 
Yes 
 
Positive 
Contraceptive Sponge 
 
Placebo 
 
 
 
 
Contraceptive Skin Patch 
 
 
 
 
 
 
Double Barrier 
 
 
 
 
 
 
Intrauterine 
 
 
 
 
 
 
Etonogestrel implant 
 
 
 
 
 
 
Medroxyprogesterone 
 
 
 
 
 
 
Complete Abstinence 
 
 
 
 
 
 
Hormonal Viginal contraceptive Ring  
 
 
 
 
 
 
Surgically Sterile 
 
 
 
 
 
 
Postemopausal 
 
 
 
 
 
 
Partner surgically Sterile 
 
 
 
 
 
 
Other : xxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
  Programming note: Only indicate birth control methods that were indicated as Yes 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
191    
 
Listing 37: Blood Alcohol Concentration – Safety Subjects 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Visit Date 
Study 
Week 
BAC 
Performed 
Time of 
BAC 
BAC % 
 
 
 
 
 
 
 
xxx 
ANS 6637-200 
mg 
ddmmmyyyy 
x 
Done  
hh:mm 
x.xxx 
 
ANS 6637-600 
mg 
 
 
Not Done  
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 38. Urine Drug Screen – Safety Subjects 
Subject ID  
Treatment 
Group 
Visit Date 
Study 
Week 
AMP1 
Benzos2 
Coc3 
Bup4 
Meth5 
Methadone 
Opioids 
THC 
Barb6 
MDMA 
EtG7 
xxx 
ANS 6637-
200 mg 
ddmmmyyyy 
Screen 
Neg 
Neg 
Neg 
Neg 
Neg 
Neg 
Neg 
Neg 
Neg 
Neg 
Neg 
 
ANS 6637-
600 mg 
 
x 
Pos 
Pos 
Pos 
Pos 
Pos 
Pos 
Pos 
Pos 
Pos 
Pos 
Pos 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
1AMP = Amphetamine; 2Benzos = Benzodiazapines; 3 Coc = Cocaine; 4 Bup = Buprenorphine; 5 Methamphetamine; 6Barb = Barbituates; 
7 EtG = Ethyl Glucuronide; Note: Neg=negative; Pos=positive 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
192    
 
 
Listing 39: Vital Signs and Body Weights– Safety Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject ID  
Treatment 
Group 
Visit Date 
Study 
Week 
Weight (Kg) 
Heart Rate 
(beats/min) 
Systolic Pressure 
(mmHg) 
Diastolic Pressure 
(mmHg) 
 
 
 
 
 
 
 
 
xxx 
ANS 6637-200 
mg 
ddmmmyyyy 
Screening  
xxx 
xxx 
xxx 
xxx 
 
ANS 6637-600 
mg 
 
x 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
193    
 
 
Listing 40. ECG – Safety Subjects 
 
 
 
 
 
 
Subject ID  
Treatment Group 
Visit Date 
Study 
Week 
Result 
If abnormal, specify finding  
 
 
 
 
 
 
xxx 
ANS 6637-200 
mg 
ddmmmyyyy 
Screen 1 
Normal 
xxxxxxxxxxx 
 
ANS 6637-600 
mg 
 
x 
Abnormal, NCS 
 
 
Placebo 
 
 
Abnormal, CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
194    
 
Listing 41. Prior and Concomitant Medications – Safety Subjects 
Subject 
ID 
Treatment 
Group  
Special 
Med 
Class 
Verbatin Med  
Indication 
Route  
Frequency 
Dose  
Start Date/ 
Stop Date  
Study Day  
Continuing?  
xxx 
ANS 
6637-200 
mg 
Yes  
xxx  
xxxxxx 
xxxxxx  
xxxxxx 
xxxxxx  
ddmmmyyyy 
xxx 
Yes  
 
ANS 
6637-600 
mg 
 
 
 
 
 
 
 
 
 
 
Placebo 
No  
xxx  
 
 
 
 
 
 
No  
A special med is one that has potential for drug-drug interactions. Classes of these medications include proton pump inhibitors, histamine-
2 antagonists,. OATP1B1 and OATP1B3 transporters, OAT1 and OAT3 transporters, MATE1, MATE-2K, and OCT2 transporters, P-gp 
transporter tnhibitors, and BCRP transporters. 
Listing 42: Blood for Drug Concentrations – Safety Subjects 
Subject 
ID 
Treatment 
Group  
Sample 
Collected? 
PK Sampling 
Date  
PK Sampling Time 
Sampling 
Problems?  
GS-548351 
Plasma Level 
(ng/mL) 
Comments 
xxx 
ANS 6637-
200 mg 
Yes  
ddmmmyyyy 
hh:mm 
Yes 
 
xxxxxx 
 
ANS 6637-
600 mg 
No 
 
 
No 
 
 
 
Placebo 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol HLAB-002, Version 1.0  Dated: 16Mar2020 
195    
 
Listing 43: Comments – Safety Subjects 
 
 
 
Subject ID 
Treatment Group 
Comments  
 
 
 
xxx 
ANS 6637-200 mg 
 xxxxxxxxxxxxxx 
 
ANS 6637-600 mg 
 
 
Placebo 
 
 
 


 
 
196 
 
12.3. 
Figures 
 
 


 
 
197 
 
 
Figure 1: 
Percentage of Subjects No Heavy Drinking Days Weeks 2-5  
 
Programmer note: Use percent on y-axis, bar graph of PSNHDD add Cohen’s h, * a significant p-value, put values on graph 
 
Figure 2: 
Percentage of Subjects Abstinent Weeks 2-5  
 
Programmer note: bar graph of PSA add Cohen’s h, * a significant p-value, put values on graph 
 
 
Figure 3: 
Weekly Percentage of Subjects No Heavy Drinking Days (mITT) 
Programmer note: graph of estimates out to 5 weeks. Include 95% confidence intervals for each estimate and * on statistically significant differences 
between treatment groups. 
Figure 4: 
Weekly Percentage of Subjects Abstinent (mITT) 
 
Figure 5: 
Weekly Percentage WHO 1-Level Decrease in Alcohol Consumption (mITT) 
Figure 6: 
Weekly Percentage WHO 2-Level Decrease in Alcohol Consumption No Imputation (mITT) 
Figure 7: 
Percentage Days Abstinent per Week Least Squares Means – (mITT) 
Figure 8: 
Percent Heavy Drinking Days per Week Lease Squares Means –(mITT) 
Figure 9: 
Mean Drinks per Week Lease Squares Means – (mITT) 
Figure 10: 
Mean Drinks per Drinking Day by Week Least Squares Means –  (mITT) 
Figure 11: 
Weekly Number of Cigarettes Smoked in Smokers Over Entire Treatment Period – Least Squares Means 
(mITT) 
Figure 12: 
Clinical Chemistry, Urinalysis, and Hematology Values Over Time