Conditions: Methamphetamine-dependence Methamphetamine Abuse
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 61
Healthy volunteers: no

Brief summary:
This Phase 2 study will evaluate the safety and efficacy of monthly intravenous doses of IXT-m200 in treatment-seeking individuals with methamphetamine (METH) use disorder. The hypothesis are that following an initial relapse, IXT-m200 will reduce the occurrence of stimulant-positive saliva samples compared to placebo and improve the signs and symptoms of METH Use Disorder (MUD).

Detailed description:

Arms:
arm 1: Anti-methamphetamine monoclonal antibody, dose levels of 1.5 and 3 g arm 2: Saline

Interventions: intervention 1: IXT-m200 intervention 2: Placebo
Intervention descriptions: intervention 1: IXT-m200 binds METH with high selectivity and affinity. The product contains a murine METH-binding variable region and the constant domains of a human immunoglobulin G (IgG) 2κ. This antibody isotype was chosen because of the lower risk of immune response compared to an IgG1 or IgG3. IXT-m200 targets METH, does not rely on binding to any endogenous target for its action, and has been well-tolerated in previous clinical studies. intervention 2: Saline

Protocol document:
ICF_002.pdf: 
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RESEARCH SUBJECT CONSENT FORM 
 
TITLE: 
OUTLAST: A PHASE 2, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED, MULTIPLE-DOSE STUDY TO 
EVALUATE THE SAFETY AND EFFICACY OF IXT-M200 IN 
TREATMENT-SEEKING INDIVIDUALS WITH 
METHAMPHETAMINE USE DISORDER 
 
PROTOCOL NO.: 
M200C-2201 
 
IRB Protocol #20214728 
 
SPONSOR: 
InterveXion Therapeutics, LLC 
 
FUNDING: 
This trial is funded by the National Institute on Drug Abuse grant 
number DA055481 
 
<<CF-Main Header Block - Investigator>> 
INVESTIGATOR: 
Name 
 
Address 
 
City, State  Zip 
 
Country 
 
STUDY-RELATED 
PHONE NUMBER(S): 
<<CF-Main User Defined #1>> 
 
[24 hour number is required] 
 
 
RESEARCH CONSENT SUMMARY 
You are being asked for your consent to take part in a research study. This document provides a 
concise summary of this research. It describes the key information that we believe most people 
need to decide whether to take part in this research. Later sections of this document will provide 
all relevant details. 
 
InterveXion Therapeutics, LLC is sponsoring this study. The study is being funded by the 
National Institute on Drug Abuse (NIDA), with grant number U01 DA055481, who appreciates 
your involvement in the study. Your study doctor will be paid for his or her work in this study. 
 
What should I know about this research? 
• Someone will explain this research to you<<CF-Main California Bill of Rights>>. 
• Taking part in this research is voluntary. Whether you take part is up to you. 
• If you don’t take part, it won’t be held against you. 
NCT05034874


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• You can take part now and later drop out, and it won’t be held against you 
• If you don’t understand, ask questions. 
• Ask all the questions you want before you decide. 
 
How long will I be in this research? 
We expect that your taking part in this research will last about 8 months. 
 
Why is this research being done? 
The purpose of this research is to determine whether the study drug, IXT-m200, helps to reduce 
methamphetamine (METH) use. We will also learn if multiple doses of IXT-m200 are safe and 
well-tolerated. 
 
What happens to me if I agree to take part in this research? 
If you decide to take part in this research study, the general procedures include receiving 6 
monthly doses of IXT-m200 by intravenous infusion at the study site and then visiting the site 
for monthly checkups for 3 months. At each visit, we will take blood samples for testing and 
check to make sure you are still feeling well. You will be provided with behavioral therapy 
treatment as well. We will also ask you daily about your drug use and expect you to take saliva 
drug tests twice per week. The results of the drug tests will not be reported to authorities and will 
not have any effect on your continuing in the study. You will be treated the same whether they 
are positive or negative for METH. 
 
Could being in this research hurt me? 
The most important risks or discomforts that you may expect from taking part in this research 
include a low risk of a reaction to a dose of IXT-m200 which might appear as an allergic reaction 
with hives or itching, flu-like symptoms, nausea, vomiting, diarrhea, skin rashes, or low blood 
pressure. The study doctor will monitor you for any such potential issues. 
 
Will being in this research benefit me? 
This research may not benefit you at all. However, the most important benefit that you may 
experience from taking part in this research includes a reduction in the number of days or weeks 
that you use METH. 
 
What other choices do I have besides taking part in this research? 
Instead of being in this research, your choices may include getting standard treatment for 
substance use disorder as recommended by your doctor. 
 
What else should I know about this research? 
If you decide to participate in this research, you will be asked to use birth control at all times 
while in the study and not get pregnant or your partner pregnant. You will be asked to report 


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your drug use daily via a smartphone app and to take 2 saliva drug tests each week throughout 
the entire study.  
 
DETAILED RESEARCH CONSENT 
You are being invited to take part in a research study.  A person who takes part in a research 
study is called a research subject, or research participant.  
 
What should I know about this research? 
• Someone will explain this research to you. 
• This form sums up that explanation. 
• Taking part in this research is voluntary. Whether you take part is up to you. 
• You can choose not to take part. There will be no penalty or loss of benefits to which you 
are otherwise entitled. 
• You can agree to take part and later change your mind. There will be no penalty or loss of 
benefits to which you are otherwise entitled. 
• If you don’t understand, ask questions. 
• Ask all the questions you want before you decide. 
 
Why is this research being done? 
The purpose of this research is to determine whether the study drug, IXT-m200, helps people 
with methamphetamine (METH) use disorder to reduce the number of days or weeks they use 
METH. We also want to learn if IXT-m200 will help improve quality of life as a benefit of 
reduced METH use. Finally, we will be studying whether 6 doses of IXT-m200 are safe in 
people with METH use disorder. 
 
About 120 subjects will take part in this research. 
 
We think IXT-m200 may help people stop using METH because it is a monoclonal antibody that 
binds METH in the blood and reduces the amount of METH that reaches the brain where it 
makes you feel high or stimulated. This is expected to reduce or prevent the feelings caused by 
taking METH that lead you to use it again. Combined with therapy, we think IXT-m200 may 
increase the chances that you will quit using METH. 
 
How long will I be in this research? 
We expect that your taking part in this research will last about 8 months. 
 
What happens to me if I agree to take part in this research? 
There are 10 scheduled visits to the study site. The first one is the screening visit, then there will 
be 9 monthly visits if you are enrolled in the study. 
 


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Screening 
During your screening visit, the following procedures will happen: 
• The criteria for study entry will be reviewed. 
• You will be asked about your drug use history including methamphetamine and other 
illicit drugs, nicotine, alcohol, and marijuana 
• Your demographic information (age, sex, race and ethnicity) will be recorded 
• Your weight and height will be measured 
• Your medical history and medications you are taking or have taken in the past year will 
be documented 
• Your vital signs will be taken 
• You will be given a general physical exam 
• You will be asked questions about your mental health, including thoughts of suicide 
• You will be asked to take a urine pregnancy test if female 
• You will be asked to take a drug test that uses oral fluid (saliva) 
• You will be asked to provide blood and urine samples for routine clinical laboratory 
testing (about 3-4 teaspoons of blood) 
• An ECG (which measures how your heart is beating) will be performed. Sticky patches 
will be applied to your chest and extremities. 
• You will be given a questionnaire with 4 questions asking about your quality of life 
called the Treatment Effectiveness Assessment 
 
Enrollment 
If you are eligible and selected to continue in the study, you will be asked to download the 
smartphone app for this study and sign up for a training and welcome video from a representative 
from DynamiCare who provides the app. You will be taught how to use the app and how to take 
the saliva drug tests on your own while recording yourself. You may have to complete the drug 
test multiple times to make sure they are done correctly before you can start the study. 
 
You will be asked to use the smartphone app to report daily drug use through the end of the 
study. The DynamiCare representative will teach you to complete the drug use survey. 
 
You will be asked to complete two saliva drug tests each week after your first dose of study 
drug. The smartphone app will tell you when you should complete those tests. 
 
Throughout the study, you will be asked about any changes in your health. If you feel unwell or 
are seen by another doctor between visits, please tell the study doctor during a visit or by using 
the contact information on the front page of this form. 
 
Dosing Days 
On the first dosing day, the following procedures will be done at the study site. You will be at 
the site for about 5-6 hours. 


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• You will be given a Wellness Check which includes the following: 
• Your medical history and medications will be updated 
• You will be asked about your mental health 
• Your vital signs will be taken and you will be given a brief physical exam 
• You will be given a urine pregnancy test, if female 
• You will be put into a study group by chance (like drawing straws). You have a 2 out of 3 
chance of being placed in the group that receives study drug, and a 1 out of 3 chance of 
being in the group that gets placebo (no drug, just a fluid infusion). You cannot choose 
your study group.  
 
During the research, you and the study doctor will not know which group you are in. (Your study 
doctor can find out in case of an emergency). 
• If you are in the first approximately 60 people enrolled in the study, you will either 
receive 1.5 g of study drug, IXT-m200 or placebo. 
• If you are in the second approximately 60 people enrolled in the study, you will either 
receive 3 g of IXT-m200 or placebo. 
 
IXT-m200 is investigational, which means that it is not approved by the Food and Drug 
Administration (FDA). 
• You will receive the dose of IXT-m200 or placebo by intravenous (IV) infusion which 
will take about 30 min. An IV catheter will be inserted into a vein for study drug 
administration. 
• Blood samples will be taken two times, once before and once 4 hours after the dose of 
study drug to measure the amount of IXT-m200 in your blood (about 1 teaspoon each 
time) and once to perform routine clinical laboratory tests (about 3-4 teaspoons one time). 
A blood sample will also be taken to measure any immune response to the study drug 
(about 1 teaspoon one time). If you have an infusion reaction, your blood will be tested 
for cytokines which help regulate the immune system (about 1 teaspoon up to three 
times). 
• An ECG will be performed shortly after the dosing is completed. 
• While you are at the study site, you will have a therapy session with a trained therapist. 
They will provide cognitive behavioral therapy, a typical type of therapy provided as 
treatment to patients with METH use disorder. 
 
You will return to the study site every 4 weeks for your next dose until you have received 6 total 
doses.  Each visit will take about 5-6 hours and the same procedures will happen. 
 
On the visit of your fourth dose, you will also be asked to complete the Treatment Effectiveness 
Assessment, which is a short survey about how you are doing overall. You will also be asked 
how you think your status has changed since the start of the study. 
 


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Between dosing days, you will have access to a recovery coach. They will be available for 
weekly phone or video calls and by text during working hours. The representative from 
DynamiCare will give you details about this. 
 
Follow-up Visits 
Once you have received all 6 doses, you will return to the study site every 4 weeks for follow-up 
visits. When you have completed 3 follow-up visits, you will have completed the study. Each 
follow-up visit should last about 1-2 hours. During the follow-up visits, the following procedures 
will happen: 
• You will be given a Wellness Check 
• Blood samples (about 1 teaspoon each time) will be taken to measure the amount of study 
drug in your blood and your body’s immune reaction (about 1 teaspoon each time). 
• At some follow-up visits, you will have a therapy session 
• At some follow-up visits, blood (about 3-4 teaspoons) will be taken to perform routine 
clinical laboratory tests  
• At some follow-up visits, you will be asked to complete the Treatment Effectiveness 
Assessment and asked how you think your status has changed since the start of the study. 
 
PK Subset 
If you are asked, and agree, to participate in the 'PK subset’, you will do everything listed above 
plus the following: 
• On the first and last dosing days, you will have one additional blood sample taken (about 
one teaspoon each time) at 1 hour after the dose of study drug. 
• You will return to the study site for additional blood samples (about one teaspoon each 
time) the day after the first dose, then weekly for three weeks. 
• You will also return to the study site for additional blood samples (about one teaspoon 
each time) the day after the last dose, then weekly for three weeks. 
 
There are 8 total extra visits which should not last more than one hour for participating in the PK 
subset. The information collected during these visits will help the sponsor learn more precisely 
about the amount of study drug in your blood over time. 
 
What are my responsibilities if I take part in this research? 
If you take part in this research, you will be responsible to:  
• Comply with the instructions from the study staff 
• Report daily drug use via the smartphone app 
• Complete the saliva drug screens each week when requested by the app 
• Practice an adequate method of birth control, including intrauterine device (IUD); oral, 
dermal ("patch"), implant or injected contraceptives; tubal ligation; barrier methods with 
spermicide; or vasectomized partner throughout the study and until 90 days after 
receiving the last dose of study drug. 


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• Limit alcohol consumption to approximately 1 drink per day for women and 2 drinks per 
day for men while in the study 
• Not participate in any other clinical study or take other investigational drugs or use 
investigational devices 
• Not to donate blood, plasma, platelets, eggs or sperm while in the study 
 
The study drug may change the way drugs similar to METH are eliminated from the body, so 
participants should avoid taking drugs such as amphetamine (including Adderall®, Dexedrine®, 
or Evekeo®) or MDMA (also known as ecstasy) for the duration of study participation. 
 
Could being in this research hurt me? 
IXT-m200 had already been given to over 75 human study participants in four different studies 
when this study started.  We don’t yet know all the risks of taking IXT-m200.  
 
There were no serious adverse reactions in the previous studies. One participant had an infusion 
reaction halfway through the IXT-m200 infusion. The participant had a brief period of 
bronchospasm and wheezing. Bronchospasm is a sudden constriction of the muscles in the walls 
of the bronchioles (airway). The infusion was stopped and the participant was treated. The 
participant fully recovered from the incident. 
 
IXT-m200 is a monoclonal antibody. Risks of taking a monoclonal antibody may include allergic 
reactions such as hives or itching, flu-like symptoms including chills, fatigue, fever, and muscle 
aches and pains, nausea, vomiting, diarrhea, skin rashes, or low blood pressure. 
 
As with taking any drug, there is a risk of allergic reaction. Allergic reactions can be serious 
and/or life threatening and sometimes lead to death. Some symptoms of allergic reactions are 
rash, difficulty breathing, and wheezing, sudden drop in blood pressure, swelling around the 
mouth, throat or eyes, a fast heart rate, and sweating.  Seek treatment and alert the study doctor 
and study staff immediately if you have any of these symptoms. 
 
Risks associated with drawing blood from your veins may include lightheadedness, pain, 
bruising, and bleeding at the site of needle puncture, inflammation of the vein, and sometimes 
infection. 
 
During the placement of an IV catheter into a vein, you may experience pain and/or bruising at 
the site where the IV is placed and blood is taken. In the event the IV fails to work properly, a 
direct needle stick into a vein may be needed to obtain blood for one or more time-points. You 
may experience dizziness, lightheadedness, and/or fainting.  Localized bruising, clotting, and 
infections may occur.  Scarring damage to a vein is also possible. 
 
The loss of confidentiality is a potential risk of being in this study because the study inclusion 
criteria require recreational use of METH. We will protect information about you and your 


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taking part in this research study to the best of our ability. However, absolute confidentiality 
cannot be guaranteed. 
 
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. This means that the researchers cannot release or use information, documents, or samples 
that may identify you in any action or suit unless you say it is okay. They also cannot provide 
them as evidence unless you have agreed.  This protection includes Federal, state, or local civil, 
criminal, administrative, legislative, or other proceedings. An example would be a court 
subpoena. 
 
There are some important things that you need to know.  The Certificate DOES NOT stop 
reporting that Federal, state or local laws require. Some examples are laws that require reporting 
of child or elder abuse, some communicable diseases, and threats to harm yourself or others.  
The Certificate CANNOT BE USED to stop a sponsoring United States Federal or state 
government agency from checking records or evaluating programs. The Certificate DOES NOT 
stop disclosures required by the Federal Food and Drug Administration (FDA). The Certificate 
also DOES NOT prevent your information from being used for other research if allowed by 
Federal regulations. 
 
Researchers may release information about you when you say it is okay. For example, you may 
give them permission to release information to insurers, medical providers or any other persons 
not connected with the research. The Certificate of Confidentiality does not stop you from 
willingly releasing information about your involvement in this research. It also does not prevent 
you from having access to your own information. 
 
If you have any side effects or concerns, you should tell the study doctor or study staff 
immediately. If you don’t tell the study doctor and/or study staff the truth about any side effects 
or concerns, you may harm yourself by being in this study. If it is an emergency or if you cannot 
contact the study staff or study doctor, you should call 911 immediately. 
 
In addition to these risks, taking part in this research may harm you in unknown ways. 
 
Taking part in this research may hurt a pregnancy or fetus in unknown ways. These may be 
minor or so severe as to cause death. 
 
Will it cost me money to take part in this research? 
No, all of the services provided as part of this research will be provided at no cost to you. 
 
Will being in this research benefit me? 
We cannot promise any benefits to you or others from your taking part in this research. However, 
possible benefits to you include a reduction in the number of days or weeks that you use METH 
and a possible reduction in blood pressure increases resulting from METH use. You may also 


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receive a benefit from the therapy provided to all participants, no matter what group you are 
placed in. 
 
What other choices do I have besides taking part in this research? 
Instead of being in this research, your choices may include: 
• Receiving treatment as usual per the recommendations of your doctor. This may include 
behavioral therapy or medications. 
 
What happens to the information collected for this research? 
Your private information and your medical record will be shared with individuals and 
organizations that conduct or watch over this research, including: 
• The research sponsor 
• People who work with the research sponsor, including Syneos Health<<CF-Main SMO 
Company 1>><<CF-Main Affiliated IN Language 1>> and DynamiCare Health 
• Government agencies, such as the Food and Drug Administration and the Department of 
Health and Human Services 
• WCG IRB, the Institutional Review Board (IRB) that reviewed this research 
• Data and safety monitoring committees 
• The National Institute on Drug Abuse who funded this study 
• Other regulatory agencies 
 
We may publish the results of this research. However, we will keep your name and other 
identifying information confidential. 
 
We protect your information from disclosure to others to the extent required by law. We cannot 
promise complete secrecy. 
 
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. 
 
Data or specimens collected in this research might be deidentified and used for future research or 
distributed to another investigator for future research without your consent. 
 
Who can answer my questions about this research? 
If you have questions, concerns, or complaints, or think this research has hurt you or made you 
sick, talk to the research team at the phone number listed above on the first page. 
 
This research is being overseen by WCG IRB. An IRB is a group of people who perform 
independent review of research studies. You may talk to them at 855-818-2289 or 
researchquestions@wcgirb.com if:  


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• You have questions, concerns, or complaints that are not being answered by the research 
team. 
• You are not getting answers from the research team. 
• You cannot reach the research team. 
• You want to talk to someone else about the research. 
• You have questions about your rights as a research subject. 
 
What if I am injured because of taking part in this research? 
If you are injured or get sick because of being in this research, call the study doctor immediately. 
The study doctor will provide emergency medical treatment. Your insurance may be billed for 
this treatment. The sponsor will pay any charges that are not covered by insurance policy or the 
government, provided the injury was not due to your underlying illness or condition and was not 
caused by you or some other third party. No other payment is routinely available from the study 
doctor or sponsor. 
 
Can I be removed from this research without my approval? 
The person in charge of this research can remove you from this research without your approval. 
Possible reasons for removal include: 
• It is in your best interest 
• You have a side effect that requires stopping the research 
• You need a treatment not allowed in this research 
• You become pregnant or have another condition that is not allowed 
• The research is canceled by the FDA or the sponsor 
• You are unable to take the research medication 
• You are unable to keep your scheduled appointments or do not comply with instructions 
from the study staff 
• The Sponsor or investigator request you are removed 
 
We will tell you about any new information that may affect your health, welfare, or choice to 
stay in this research. 
 
What happens if I agree to be in this research, but I change my mind 
later? 
If you decide not to take any further doses of the study drug, please tell the research team. You 
will be asked to continue participating in the other study procedures and assessments. 
 
If you decide to leave this research and not participate any further, contact the research team so 
that the investigator can conduct early termination procedures:  
• You will be given a Wellness Check 


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• Two blood samples (about 1 teaspoon) will be taken to measure the amount of study drug 
in your blood and your body’s immune reaction (about 1 teaspoon). 
• Blood (about 3-4 teaspoons) will be taken to perform routine clinical laboratory tests  
• You will be asked to complete the Treatment Effectiveness Assessment and asked how 
your status has changed since beginning the study. 
 
Will I be paid for taking part in this research? 
<<CF-Main Payment for Part. Paragraph>>For taking part in this research, you may be paid up 
to a total of $[Amount]. Your compensation will be based on the total number of study 
requirements you complete and will not depend on your drug test results. 
Requirement 
Payment per each  
Additional 
payments for PK 
subset 
Screening visit 
$20 
 
Daily drug use questionnaire 
$0.50 
 
Weekly bonus for all questionnaires completed 
$1.50 
 
Saliva test 
$5.00 
 
Study site visit 
$40 
$10 
PK subset visit 
 
$40 
Possible total compensation 
$935 
$1275 
 
Your specimens (even if identifiers are removed) will be transferred to a commercial 
organization for testing and may be used for commercial profit. You will not share in this 
commercial profit. 
<<CF-Main Financial Disclosure>> 


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Statement of Consent:  
Your signature documents your consent to take part in this research. 
 
 
 
Signature of adult subject capable of consent 
 
Date 
 
 
 
Signature of person obtaining consent 
 
Date 
<<CF-Main California HIPAA>> 
 
 
 
Statement of Consent for the PK subset:  
Your signature documents your consent to take part in this research as part of the PK subset. 
 
 
 
Signature of adult subject capable of consent 
 
Date 
 
 
 
Signature of person obtaining consent 
 
Date 


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**For Sites in California** 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR 
RESEARCH PURPOSES  
 
What information may be used and given to others? 
The study doctor will get your personal and medical information.  For example:  
• Past and present medical records 
• Research records 
• Records about phone calls made as part of this research 
• Records about your study visits. 
 
Who may use and give out information about you? 
The study doctor and the study staff.  [They may also share the research information 
with [enter SMO company name], an agent for the study doctor. delete if the site 
does not have an SMO] 
 
Who might get this information? 
The sponsor of this research.  “Sponsor” means any persons or companies that are: 
• working for or with the sponsor, or  
• owned by the sponsor. 
 
Your information may be given to:  
• The U.S. Food and Drug Administration (FDA), 
• Department of Health and Human Services (DHHS) agencies, 
• Governmental agencies in other countries,  
• The institution where the research is being done, 
• Governmental agencies to whom certain diseases (reportable diseases) must be 
reported, and 
• Institutional Review Board (IRB)  
 
Why will this information be used and/or given to others? 
• to do the research,  
• to study the results, and  
• to make sure that the research was done right.   
 


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If the results of this study are made public, information that identifies you will not 
be used. 
 
What if I decide not to give permission to use and give out my health 
information? 
Then you will not be able to be in this research study. 
 
May I review or copy my information? 
Yes, but only after the research is over.  
 
May I withdraw or revoke (cancel) my permission? 
This permission will be good until December 31, 2070. 
 
You may withdraw or take away your permission to use and disclose your health 
information at any time.  You do this by sending written notice to the study doctor.  
If you withdraw your permission, you will not be able to stay in this study. 
 
When you withdraw your permission, no new health information identifying you 
will be gathered after that date.  Information that has already been gathered may 
still be used and given to others.   
 
Is my health information protected after it has been given to others? 
There is a risk that your information will be given to others without your 
permission. 
 
Authorization: 
I have been given the information about the use and disclosure of my health 
information for this research study.  My questions have been answered. 
 
I authorize the use and disclosure of my health information to the parties listed in the 
authorization section of this consent for the purposes described above. 
 
AUTHORIZATION SIGNATURE: 
 
 
 
 
 
 
Signature of Subject 
 
Date 

Prot_000.pdf: 
 
OUTLAST: A PHASE 2, DOUBLE-BLIND, 
RANDOMIZED, PLACEBO-CONTROLLED, 
MULTIPLE-DOSE STUDY TO EVALUATE THE 
SAFETY AND EFFICACY OF IXT-M200 IN 
TREATMENT-SEEKING INDIVIDUALS WITH 
METHAMPHETAMINE USE DISORDER 
Protocol Number: M200C-2201 
National Clinical Trial (NCT) Identified Number: NCT05034874 
IND Sponsor: InterveXion Therapeutics, LLC 
Funded by: NIH/NIDA U01 DA055481 
Version Number:  5 
03 February 2023 
 
 
 


 
OUTLAST: A Phase 2 Study of IXT-m200 in Individuals with Methamphetamine Use Disorder 
Version 5 
M200C-2201 
03 February 2023  
 ii
TABLE OF CONTENTS 
 
TABLE OF CONTENTS ................................................................................................................ ii 
SPONSOR APPROVAL AND SIGNATURE PAGE .................................................................... 1 
STATEMENT OF COMPLIANCE ................................................................................................ 2 
1 PROTOCOL SUMMARY ........................................................................................................ 3 
1.1 Synopsis ........................................................................................................................... 3 
1.2 Schema ............................................................................................................................. 5 
1.3 Schedule of Activities (SoA) ........................................................................................... 6 
1.3.1 
Main Study Participant Schedule ....................................................................... 6 
1.3.2 
PK Subset Participant Schedule ......................................................................... 8 
1.3.3 
Dose Discontinued Participant Schedule ......................................................... 10 
2 INTRODUCTION .................................................................................................................. 11 
2.1 Study Rationale .............................................................................................................. 11 
2.1.1 
Rationale for the Combined Safety and Efficacy Study .................................. 11 
2.1.2 
Rationale for the Selected Population .............................................................. 11 
2.2 Background .................................................................................................................... 11 
2.3 Risk/Benefit Assessment ............................................................................................... 14 
2.3.1 
Known Potential Risks ..................................................................................... 14 
2.3.2 
Known Potential Benefits ................................................................................ 15 
2.3.3 
Assessment of Potential Risks and Benefits .................................................... 15 
3 OBJECTIVES AND ENDPOINTS ........................................................................................ 16 
4 STUDY DESIGN.................................................................................................................... 17 
4.1 Overall Design ............................................................................................................... 17 
4.2 Scientific Rationale for Study Design ........................................................................... 17 
4.3 Justification for Dose ..................................................................................................... 18 
4.4 End of Study Definition ................................................................................................. 18 
5 STUDY POPULATION ......................................................................................................... 18 
5.1 Inclusion Criteria ........................................................................................................... 18 
5.2 Exclusion Criteria .......................................................................................................... 19 
5.3 Lifestyle Considerations ................................................................................................ 20 
5.4 Screen Failures ............................................................................................................... 20 
5.5 Strategies for Recruitment and Retention ...................................................................... 20 
6 STUDY INTERVENTION ..................................................................................................... 21 
6.1 Study Intervention(s) Administration ............................................................................ 21 
6.1.1 
Study Intervention Description ........................................................................ 21 
6.1.2 
Dosing and Administration .............................................................................. 21 
6.2 Preparation/Handling/Storage/Accountability ............................................................... 22 
6.2.1 
Acquisition and accountability ......................................................................... 22 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ....................................... 22 
6.2.3 
Product Storage and Stability ........................................................................... 23 
6.2.4 
Preparation ....................................................................................................... 23 
6.3 Measures to Minimize Bias: Randomization and Blinding ........................................... 23 
6.4 Study Intervention Compliance ..................................................................................... 23 
6.5 Concomitant Therapy .................................................................................................... 24 


 
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7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL............................................................................... 24 
7.1 Discontinuation of Study Intervention ........................................................................... 24 
7.2 Participant Discontinuation/Withdrawal from the Study ............................................... 24 
7.3 Lost to Follow-Up .......................................................................................................... 25 
8 STUDY ASSESSMENTS AND PROCEDURES .................................................................. 25 
8.1 Efficacy Assessments .................................................................................................... 25 
8.1.1 
Quality of Life .................................................................................................. 25 
8.1.2 
Saliva Drug Screens ......................................................................................... 26 
8.1.3 
Self-Report of Drug Use Via App .................................................................... 26 
8.1.4 
Methamphetamine Use Assessments ............................................................... 26 
8.1.5 
Adverse Outcomes Assessment ....................................................................... 26 
8.2 Safety and Other Assessments ....................................................................................... 26 
8.2.1 
Eligibility Criteria ............................................................................................ 27 
8.2.2 
Medical and Medication History ...................................................................... 27 
8.2.3 
Vital Signs ........................................................................................................ 27 
8.2.4 
Physical Exam .................................................................................................. 27 
8.2.5 
Psychiatric Evaluation ...................................................................................... 27 
8.2.6 
Pregnancy Test ................................................................................................. 28 
8.2.7 
Laboratory Tests .............................................................................................. 28 
8.2.8 
Electrocardiograms .......................................................................................... 28 
8.2.9 
Blood for PK, HACA, and Cytokines .............................................................. 28 
8.3 Adverse Events and Serious Adverse Events ................................................................ 29 
8.3.1 
Definition of Adverse Events (AE) .................................................................. 29 
8.3.2 
Definition of Serious Adverse Events (SAE) .................................................. 29 
8.3.3 
Classification of an Adverse Event .................................................................. 30 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ................ 31 
8.3.5 
Adverse Event Reporting ................................................................................. 31 
8.3.6 
Serious Adverse Event Reporting .................................................................... 32 
8.3.7 
Reporting Events to Participants ...................................................................... 32 
8.3.8 
Events of Special Interest ................................................................................. 32 
8.3.9 
Reporting of Pregnancy ................................................................................... 32 
8.4 Unanticipated Problems ................................................................................................. 33 
8.4.1 
Definition of Unanticipated Problems (UP) ..................................................... 33 
8.4.2 
Unanticipated Problem Reporting .................................................................... 33 
8.4.3 
Reporting Unanticipated Problems to Participants .......................................... 33 
9 STATISTICAL CONSIDERATIONS.................................................................................... 34 
9.1 Statistical Hypotheses .................................................................................................... 34 
9.2 Sample Size Determination ........................................................................................... 35 
9.3 Populations for Analyses ............................................................................................... 35 
9.4 Statistical Analyses ........................................................................................................ 36 
9.4.1 
General Approach ............................................................................................ 36 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ................................................. 36 
9.4.3 
Analysis of the Secondary Endpoint(s) ............................................................ 38 
9.4.4 
Safety Analyses ................................................................................................ 39 
9.4.5 
Baseline Descriptive Statistics ......................................................................... 39 
9.4.6 
Planned Interim Analyses ................................................................................ 39 


 
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9.4.7 
Sub-Group Analyses ........................................................................................ 40 
9.4.8 
Tabulation of Individual participant Data ........................................................ 40 
9.4.9 
Exploratory Analyses ....................................................................................... 40 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ......... 41 
10.1 Regulatory, Ethical, and Study Oversight Considerations ............................................ 41 
10.1.1 Informed Consent Process ............................................................................... 41 
10.1.2 Study Discontinuation and Closure .................................................................. 42 
10.1.3 Confidentiality and Privacy ............................................................................. 42 
10.1.4 Future Use of Stored Specimens and Data ....................................................... 43 
10.1.5 Key Roles and Study Governance ................................................................... 43 
10.1.6 Safety Oversight ............................................................................................... 43 
10.1.7 Clinical Monitoring .......................................................................................... 44 
10.1.8 Quality Assurance and Quality Control ........................................................... 44 
10.1.9 Data Handling and Record Keeping ................................................................ 45 
10.1.10 Protocol Deviations .......................................................................................... 46 
10.1.11 Publication and Data Sharing Policy ............................................................... 46 
10.1.12 Conflict of Interest Policy ................................................................................ 46 
10.2 Abbreviations ................................................................................................................. 47 
10.3 Protocol Amendment History ........................................................................................ 49 
11 REFERENCES ....................................................................................................................... 54 
 




 
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STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the National 
Institute on Drug Abuse (NIDA) Terms and Conditions of Award. The investigator will assure that no 
deviation from, or changes to the protocol will take place without prior agreement from InterveXion 
Therapeutics and documented approval from the Institutional Review Board (IRB), except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in the 
conduct of this study have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent using a previously approved consent form. 
 
 
 
 
Investigator Signature/Date: _____________________________________________________________ 


 
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1 
PROTOCOL SUMMARY 
 
1.1 
SYNOPSIS  
Title: 
OUTLAST: A Phase 2, Double-Blind, Randomized, Placebo-Controlled, 
Multiple-Dose Study to Evaluate the Safety and Efficacy of IXT-m200 in 
Treatment-Seeking Individuals with Methamphetamine Use Disorder 
Study Description: 
This Phase 2 study will evaluate the safety and efficacy of monthly 
intravenous doses of IXT-m200 in treatment-seeking individuals with 
methamphetamine (METH) use disorder (MUD). The hypotheses are that 
treatment with IXT-m200 will reduce the occurrence of stimulant-positive 
samples compared to placebo (following an initial grace period during 
which relapses may occur) and improve the signs and symptoms of MUD. 
Objectives: 
 
Primary Objective: To evaluate the efficacy of IXT-m200 in preventing or 
reducing relapse to stimulant use. 
 
Secondary Objectives: To evaluate the efficacy of IXT-m200 in improving 
the signs and symptoms of MUD, increasing the number achieving early 
remission, improving the proportion of participants achieving stimulant 
abstinence, improving participant-rated quality of life, and to evaluate the 
safety of multiple intravenous doses of IXT-m200. 
Endpoints: 
Primary Endpoint:  
• 
Percent of 20 weeks abstinent from stimulants following a 4-week 
grace period (between Week 5 and Week 25) as measured by saliva 
screens and by self-report via smartphone app. 
Secondary Endpoints: 
• 
Proportion of responders at Week 25 as measured by DSM-5 
criteria. A responder is a participant who meets the definition of 
early remission, i.e., ≥3 months and <12 months without meeting 
DSM-5 criteria while disregarding the result for craving.  
• 
Complete abstinence during the last month of study drug treatment 
(between Week 21 and Week 25), as measured by saliva screens 
and by self-report via smartphone app.  
• 
Change from screening in participant-rated quality of life as 
measured by the Treatment Effectiveness Assessment (TEA) at 
Weeks 13, 25, and 33. 
• 
Safety and tolerability of IXT-m200 assessed by physical 
examinations and vital sign, AE, ECG, and clinical laboratory 
testing. 
• 
Number of participants with anti-IXT-m200 antibody levels that 
are confirmed positive and have titers more than three times the 
minimum required dilution. 
Exploratory Endpoints: 
• 
Number of sequential weeks of abstinence from the end of 
treatment visit (Week 25), defined as four weeks after the final 
planned treatment visit (Week 21) as measured by saliva screens 
and by self-report via smartphone app.  
• 
Point-prevalence abstinence (last 7 days) as measured by saliva 
screens and by self-report via smartphone app at Week 25, Week 
29, and Week 33.  


 
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• 
Weekly abstinence from stimulants following a 4-week grace 
period (between Week 5 and Week 25) as measured by saliva 
screens. 
• 
Difference between number of adverse outcomes recorded between 
Week 5 and Week 33. Adverse outcomes include those queried in 
the Adverse Outcomes Assessment and also suicide and overall 
mortality. 
• 
Proportion of responders at Week 33 as measured by DSM-5 
criteria. A responder is a participant who meets the definition of 
early remission, i.e., ≥3 months and <12 months without meeting 
DSM-5 criteria while disregarding the result for craving. 
• 
Difference between groups in Clinical Global Impression of 
Change (CGIC) at Weeks 13, 25, and 33. 
• 
Difference between groups in Patient Global Impression of Change 
(PGIC) at Weeks 13, 25, and 33. 
Study Population: 
Approximately 120 adults seeking treatment for their ongoing METH use 
will be randomized into the study. Approximately 36 of these will be 
included in the PK subset. 
Phase: 
2 
Description of Sites: 
Approximately 10 sites in the US will enroll participants 
Description of Study 
Intervention: 
IXT-m200 is a high-affinity chimeric anti-METH monoclonal antibody that 
is well-tolerated in healthy volunteers and in non-intoxicated participants 
with METH use disorder. It will be administered at a dose of 1.5 g 
(approximately 20 mg/kg) and, depending on the results of an interim 
analysis, up to 3 g (approximately 40 mg/kg). IXT-m200 or placebo 
treatment will be given by intravenous infusion over 30 minutes. Each 
participant will receive 6 doses of either placebo or the same dose level of 
IXT-m200, spaced approximately 4 weeks apart. 
Study Duration: 
Approximately two years 
Participant Duration: 
33 weeks 
 
 


 
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1.2 
SCHEMA 
 
 
 
• Daily self-report of drug use
• Cognitive behavioral therapy 
(Days 1, 29, 57, 85, 113, 141, 197)
• Weekly video sessions with coach 
Random saliva drug screens 
(2X/week)
Screening
(≤15 days before Day 1)
Cohorts 1 and 2 (n=60/cohort) will be enrolled sequentially with an interim 
analysis following cohort 1 (completed through Day 169) to confirm the 
dose for cohort 2. Each participant will be randomized to IXT-m200 or 
placebo and follow the sequence of events indicated below.
Decision to 
Enroll
Dosing
Days 1, 29, 57, 85, 113, 
141 (-2/+7 days)
End of Study Visit
Day 225 
(±3 days)
•Assessments
•Administer IXT-m200 dose by 
IV over 30 min
•Informed consent
•Eligibility criteria
•Assessments
•Smartphone app training
•Recovery coach sessions
Follow-up Visits
Days 169, 197 
(±3 days)
•Assessments
•Assessments


 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
1.3.1 MAIN STUDY PARTICIPANT SCHEDULE 
 
Assessment a 
Screening 
Dosing (-2/+7 days) 
Follow-up (±3 days) 
ET 
Study Week 
≤-1 
1 
5 
9 
13 
17 
21 
25 
29 
33 
NA 
Study Day 
-15 to -1 
1b 
29 
57 
85 
113 
141 
169 
197 
225 
NA 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Initial evaluations p 
Eligibility criteria 
Demographics 
Medical history and medications 
Vital signs c 
Physical exam 
Psychiatric exam (e.g., C-SSRS) 
Urine pregnancy test  
Saliva drug screen 
Drug use assessment via DSM-5 m 
X 
 
 
 
 
 
 
 
 
 
 
Laboratory tests d 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Electrocardiogram (ECG) e 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
App training 
App download and tutorial q 
Saliva drug screens (up to 4) k 
Recovery coaching j 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Outcomes Assessment 
Quality of Life - TEAf 
X 
 
 
 
X 
 
 
X 
 
X 
X 
Quality of Life – PGIC and CGIC f 
 
 
 
 
X 
 
 
X 
 
X 
X 
METH Use Assessments n 
X 
 
 
 
 
 
 
X 
 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Blood for PK g 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for HACA o 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Blood for Cytokines l 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Dose administration h 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Cognitive behavioral therapy 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Wellness check 
Update medical history 
Update medications 
Brief psychiatric evaluation 
Vital signs c 
Targeted physical exam 
Urine pregnancy test 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Continuous events 
AE monitoring i 
Recovery coaching j 
Self-report daily drug use by app 
Random saliva drug screens k 
 
Continuous 
Abbreviations: CGIC – Clinical Global Impression of Change; C-SSRS – Columbia Suicide Severity Rating Scale; ET – early 
termination; HACA – human anti-chimeric antibodies; NA – not applicable; PGIC – Patient Global Impression of Change; PK – 
pharmacokinetic; TEA – Treatment Effectiveness Assessment 
 
a Descriptions of assessments are in Section 8.1 (efficacy) or 8.2 (safety). 
b Study Day -1 is the day prior to the first dose. Study Day 1 is the day of the first dose. 
c Vital sign measurements will be taken on dosing days starting with a pre-dose measurement (≤30 min prior), then 0.25, 0.5, 1, 2, 
and 4 hours (±5 min) after dosing starts, and as needed afterward until normalization. Measurements will be obtained once on 
each non-dosing day. Each test may be repeated once at each time point if the initial result is out of range.  
d Laboratory tests require blood and urine sampling for hematology, serum chemistry, and urinalysis. Samples are to be taken 
2-hr post-dose completion (±10 min) on dose days and once per visit on non-dosing days. 
e ECGs are to be done 30-min post dose completion (±15 min) on dosing days.  


 
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f Quality of Life Assessments include TEA (at Screening, Days 85, 169, & 225), and PGIC and CGIC (on Days 85, 169, & 225). 
These assessments are to be done prior to CBT at the Week 13 visit. 
g PK samples are to be taken pre-dose (≤30 min prior), then 4 hr (±10 min) after the start of each infusion on dosing days. 
Participants should be kept on site until 4 hr post infusion start to collect samples. All other PK samples are to be collected once 
each visit.  
h Doses will be given over 30 min by intravenous (IV) infusion. 
i AEs will be collected by phone call at 1 day and 1 week (±2 days) post-dose throughout the study. 
j Recovery coaching will occur weekly via phone or video. 
k Saliva drug screens will be done remotely and monitored by smartphone app.  
l  Cytokine samples are to be taken pre-dose (≤60 min prior) on each dosing day. If a participant has an infusion reaction, cytokine 
sampling at 1- and 4-hours post-dose (±10 min) should be performed. 
m Drug use assessments at Screening include the DSM5 criteria for any drugs used regularly in the past year and questions about 
route and frequency of METH use.  
n On Days 169 and 225, DSM5 criteria should be used to assess methamphetamine only and for the past 30 days, then for the past 
3 months. 
o HACA samples are to be taken pre-dose (≤60 min prior) on visit Days 1, 57, and 113, and once on Days 169 and 225. 
p If the participant remains eligible at the end of the Screening visit, enroll them in the DynamiCare system as described in the 
DynamiCare Site Guide, and schedule the Day 1 visit. 
q If a participant does not have their phone at the Screening visit, the visit should be rescheduled. 


 
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1.3.2 PK SUBSET PARTICIPANT SCHEDULE 
 
Assessment a 
Screening 
Dosing (-2/+7 days) 
Follow-up  
(±3 days) 
ET 
Study Week 
≤-1 
1 
 
 
 
 
5 
9 
13 
17 
21 
 
 
 
 
25 
29 
33 
NA 
Study Day 
-15 to -1 
1b 
 
 
 
 
29 
57 
85 
113 
141 
 
 
 
 
169 
197 
225 
NA 
PK Sample Collection Day 
 
 
2 
(+1) 
8 
(±2) 
15 
(±3) 
22 
(±3) 
 
 
 
 
 
142 
(+1) 
148 
(±2) 
155 
(±3) 
162 
(±3) 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial evaluations p 
Eligibility criteria 
Demographics 
Medical history and medications 
Vital signs c 
Physical exam 
Psychiatric exam (e.g., C-SSRS) 
Urine pregnancy test  
Saliva drug screen 
Drug use assessment via DSM-5 m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory tests d 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
 
X 
Electrocardiogram (ECG) e 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
App training 
App download and tutorial q 
Saliva drug screens (up to 4) k 
Recovery coaching j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Outcomes Assessment  
Quality of Life Assessments - TEA f 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
Quality of Life – PGIC and CGIC f  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
METH Use Assessments n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for PK g 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for HACA o 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
X 
Blood for Cytokines l 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Dose administration h 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Cognitive behavioral therapy 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
Wellness check 
Update medical history 
Update medications 
Brief psychiatric evaluation 
Vital signs c 
Targeted physical exam 
Urine pregnancy test 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 


 
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Assessment a 
Screening 
Dosing (-2/+7 days) 
Follow-up  
(±3 days) 
ET 
Study Week 
≤-1 
1 
 
 
 
 
5 
9 
13 
17 
21 
 
 
 
 
25 
29 
33 
NA 
Study Day 
-15 to -1 
1b 
 
 
 
 
29 
57 
85 
113 
141 
 
 
 
 
169 
197 
225 
NA 
Continuous events 
AE monitoring i 
Recovery coaching j  
Self-report daily drug use by app 
Random saliva drug screens k 
 
Continuous 
Abbreviations: CGIC – Clinical Global Impression of Change; C-SSRS – Columbia Suicide Severity Rating Scale; ET – early termination; HACA – human anti-chimeric 
antibodies; NA – not applicable; PGIC – Patient Global Impression of Change; PK – pharmacokinetic; TEA – Treatment Effectiveness Assessment 
 
a Descriptions of assessments are in Section 8.1 (efficacy) or 8.2 (safety). 
b Study Day -1 is the day prior to the first dose. Study Day 1 is the day of the first dose. 
c Vital sign measurements will be taken on dosing days starting with a pre-dose measurement (≤30 min prior), then 0.25, 0.5, 1, 2, and 4 hours (±5 min) after dosing starts, and as 
needed afterward until normalization. Measurements will be obtained once on each non-dosing day. Each test may be repeated once at each time point if the initial result is out of 
range.  
d Laboratory tests require blood and urine sampling for hematology, serum chemistry, and urinalysis. Samples are to be taken 2-hr post-dose completion (±10 min) on dose days 
and once per visit on non-dosing days. 
e ECGs are to be done 30-min post dose completion (±15 min) on dosing days.  
f Quality of Life Assessments include TEA (at Screening, Days 85, 169, & 225), and PGIC and CGIC (on Days 85, 169, & 225). These assessments are to be done prior to CBT at 
the Week 13 visit. 
g PK samples are to be taken pre-dose (≤30 min prior), then 4 hr (±10 min) after the start of each infusion on dosing days. Participants should be kept on site until 4 hr post infusion 
start to collect samples. Additional PK samples should be taken on Day 1 and 141 at 1 hr (±10 min) post-start of infusion. All other PK samples are to be collected once each 
visit.  
h Doses will be given over 30 min by intravenous (IV) infusion. 
i AEs will be collected by phone call at 1 day and 1 week (±2 days) post-dose throughout the study. 
j Recovery coaching will occur weekly via phone or video. 
k Saliva drug screens will be done remotely and monitored by smartphone app.  
l  Cytokine samples are to be taken pre-dose (≤60 min prior) on each dosing day. If a participant has an infusion reaction, cytokine sampling at 1- and 4-hours post-dose (±10 min) 
should be performed. 
m Drug use assessments at Screening include the DSM5 criteria for any drugs used regularly in the past year and questions about route and frequency of METH use.  
n On Days 169 and 225, DSM5 criteria should be used to assess methamphetamine only and for the past 30 days, then for the past 3 months. 
o HACA samples are to be taken pre-dose (≤60 min prior) on visit Days 1, 57, and 113, and once on Days 169 and 225. 
p If the participant remains eligible at the end of the Screening visit, enroll them in the DynamiCare system as described in the DynamiCare Site Guide, and schedule the Day 1 
visit.  
q If a participant does not have their phone at the Screening visit, the visit should be rescheduled. 


 
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1.3.3 DOSE DISCONTINUED PARTICIPANT SCHEDULE 
 
This schedule will be followed only when a participant has been enrolled and dosed as normal at least 
once, then dosing is discontinued per section 7.2, but the participant wishes to continue in the study. 
Priority should be placed on those assessments in bold, blue font. 
 
Assessment a 
Site Visit (-2/+7 days) 
Follow-up (±3 days) 
ET 
Study Week 
5 
9 
13 
17 
21 
25 
29 
33 
NA 
Study Day 
29 
57 
85 
113 
141 
169 
197 
225 
NA 
Laboratory tests d 
Once at first visit after dose 
discontinuation 
 
 
X 
Adverse Outcomes Assessment 
Quality of Life - TEAf 
 
 
X 
 
 
X 
 
X 
X 
Quality of Life – PGIC & CGIC f 
 
 
X 
 
 
X 
 
X 
X 
METH Use Assessments n 
 
 
 
 
 
X 
 
X 
X 
Blood for PK g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for HACA o 
 
X 
 
X 
 
X 
 
X 
X 
Cognitive behavioral therapy 
X 
X 
X 
X 
X 
 
X 
 
 
Wellness check 
Update medical history 
Update medications 
Brief psychiatric evaluation 
Vital signs c 
Targeted physical exam 
Urine pregnancy test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Continuous events 
AE monitoring i 
Recovery coaching j 
Self-report daily drug use by app 
Random saliva drug screens k 
Continuous 
Abbreviations: CGIC – Clinical Global Impression of Change; C-SSRS – Columbia Suicide Severity Rating Scale; ET – early 
termination; HACA – human anti-chimeric antibodies; NA – not applicable; PGIC – Patient Global Impression of Change; PK – 
pharmacokinetic; TEA – Treatment Effectiveness Assessment 
 
a Descriptions of assessments are in Section 8.1 (efficacy) or 8.2 (safety). 
c Vital sign measurements will be obtained once on each non-dosing day. Each test may be repeated once at each time point if the 
initial result is out of range.  
d Laboratory tests require blood and urine sampling for hematology, serum chemistry, and urinalysis. Samples are to only be 
taken on the first visit following discontinuation. 
e ECGs are to be done once per visit.  
f Quality of Life Assessments include TEA (at Screening, Days 85, 169, & 225), and PGIC and CGIC (on Days 85, 169, & 225). 
These assessments are to be done prior to CBT at the Week 13 visit. 
g One PK sample should to be taken per visit; mark this as the pre-dose sample in EDC for visits through Week 21.  
j Recovery coaching will occur weekly via phone or video. 
k Saliva drug screens will be done remotely and monitored by smartphone app.  
n On Days 169 and 225, DSM5 criteria should be used to assess methamphetamine only for the past 30 days, then for the past 3 
months. 
o HACA samples are to be taken once each visit. 
 


 
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2 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
2.1.1 RATIONALE FOR THE COMBINED SAFETY AND EFFICACY STUDY 
 
There are no approved medications for the treatment of METH use disorder (MUD); therefore, any 
progress toward development of effective medications for MUD is important. The safety of single doses 
of IXT-m200 has been evaluated in a Phase 1 study of healthy individuals and in a Phase 2 study in 
otherwise healthy non-treatment seeking participants who use METH. No significant safety events 
occurred (no SAEs were reported)1. Furthermore, Good Laboratory Practice (GLP) toxicology studies of 
repeated doses of IXT-m200 in rats at doses well above the proposed doses in this study have not shown 
significant toxicity associated with IXT-m200. However, even though the risk of severe complications 
associated with chimeric monoclonal antibody therapy is low, the risk of infusion reactions is not zero, 
and establishment of safety and tolerability of repeat doses of IXT-m200 in humans is important. Based 
on the clinical experience to date with IXT-m200, gathering these safety data in participants with MUD 
rather than in healthy volunteers is warranted. Given the safety data to date with single doses of 
IXT-m200 in humans, there is no reason to believe that the safety of repeated doses of IXT-m200 will be 
different in otherwise healthy individuals seeking treatment for MUD versus healthy non-drug 
users. Furthermore, the benefit-risk determination of repeat-dose testing of IXT-m200 favors testing in 
people seeking treatment for METH use, because healthy volunteers would not derive any benefit from 
such a study. Finally, the use of a serial study design which first evaluates the safety of a lower dose level 
before proceeding to a higher dose level further decreases any potential safety risk. Therefore, this study 
is a combined safety and efficacy study in otherwise healthy individuals who are seeking treatment for 
MUD.  
 
This protocol is designed to evaluate safety of repeated doses of IXT-m200, to evaluate evidence of 
efficacy in the target population, and to evaluate trends in dose-response relationships for IXT-m200 in 
preventing or reducing relapse to METH use. Compared to placebo, we hypothesize that IXT-m200 will 
decrease relapse to stimulant use, improve the signs and symptoms of MUD, and improve participant-
reported quality of life in treatment-seeking individuals with MUD.  
 
2.1.2 RATIONALE FOR THE SELECTED POPULATION 
 
Treatment-seeking participants with a history of ongoing METH use will be recruited. Because of the use 
of treatment-seeking participants in this study, comprehensive and standardized cognitive behavioral 
therapy (CBT) will be provided to all participants. Persons with MUD, even those who are highly 
motivated to stop their use and receive treatment, are at high risk for recidivism to METH use. Based on 
the observed safety data from our Phase 2 clinical study with IXT-m200 (STAMPOUT), which studied 
non-treatment-seeking participants who use METH and in which participants were given controlled doses 
of METH and then subsequently allowed to resume their habitual METH use, there do not appear to be 
significant safety risks associated with use of IXT-m200 in this population.  
 
2.2 
BACKGROUND  
 
Study Agent 
IXT-m200, also called ch-mAb7F9, binds METH with high selectivity and affinity. The product contains 
a murine METH-binding variable region and the constant domains of a human immunoglobulin G 


 
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(IgG) 2κ. This antibody isotype was chosen because of the lower risk of immune response compared to an 
IgG1 or IgG3. IXT-m200 targets METH, does not rely on binding to any endogenous target for its action, 
and has been well-tolerated in previous clinical studies (see below). 
  
Through the binding of METH in the bloodstream, it is anticipated that IXT-m200 will alter the 
pharmacokinetics (PK) of METH and decrease concentrations of METH reaching its active sites in the 
brain. The presence of IXT-m200 should therefore decrease the perceived pleasurable effects of METH. 
Over the longer term, when combined with behavioral therapy, IXT-m200 should reduce the frequency of 
METH use over time. 
  
Nonclinical IXT-m200 Effectiveness Summary 
A significant body of nonclinical work in rats indicates that IXT-m200 may be effective as a treatment for 
MUD by altering METH central nervous system effects. The potential human efficacy of IXT-m200 is 
demonstrated by multiple important in vivo preclinical studies using the murine version of the antibody, 
called mAb7F9. The studies and results are summarized in the Investigator’s Brochure (IB). 
 
Nonclinical Safety Summary of the Interaction of IXT-m200 with METH 
Four key nonclinical studies were completed in rats to address the potential for IXT-m200 to exacerbate 
METH effects, specifically cardiovascular effects. These studies were designed to identify potential 
toxicities resulting from higher blood concentrations of METH in the presence of IXT-m200, or from 
increased METH consumption by a person in an effort to overcome the reduction of METH effects by the 
antibody.   
 
In each of the 4 studies, rats were acclimated to high doses of METH over a 14-day period to make them 
tolerant to high doses of METH, similar to what occurs in people who chronically use METH. By the last 
day, rats survived three 4 mg/kg doses of METH spaced 4 hours apart. Three days later (Day 17), rats 
were dosed with 0, 5, or 20 mg/kg IXT-m200. The following day, a series of METH binges used to 
simulate attempts to surmount the antibody’s effects was initiated. On Day 18, rats were given 4 doses of 
6 mg/kg METH spaced 2 hours apart. This binge dosing regimen was repeated on Days 21 and 24 for 
certain studies and groups. 
 
The 4 studies (GLP toxicology, cardiovascular effects, METH PK, and METH distribution) collected 
different outcome measurements while using the same METH administration protocol. Results are 
summarized in the IB. There were no adverse effects, as measured by cardiovascular parameters or body 
temperature/activity, attributed to IXT-m200 administration when followed by high doses of METH.  
 
Clinical Research Summary 
A Phase 1 study of the safety of single doses of IXT-m200 in healthy humans has been completed1. In this 
first clinical study, 42 participants (17 females) were dosed in 5 groups (0.2, 0.6, 2, 6, or 20 mg/kg 
IXT-m200), with 10 participants receiving placebo (saline). Pharmacokinetic results indicated that 
IXT-m200 is similar to other IgGs, with an elimination half-life of ~18 days, volume of distribution (Vd) 
of ~5 L and clearance of ~200 mL/d. The disposition of IXT-m200 did not appear to be affected by dose. 
  
There were no serious adverse events (SAEs) or serious adverse reactions during the conduct of the study. 
There were 3 adverse events (AEs) in 2 subjects that were attributed to IXT-m200. A mild infusion 
reaction (Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 Grade 3) and bronchospasm 
(Grade 2) occurred in the same subject. The symptoms included a brief period of bronchospasm with no 
drop in oxygen saturation that resolved with stopping the infusion. A separate subject experienced an AE 
of mild proteinuria (Grade 1). Both subjects were in the same dose group (2 mg/kg IXT-m200).  
  


 
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Samples from all participants were tested for immunogenicity, ie, anti-IXT-m200 antibodies. Samples 
from only 4 (12.5%) IXT-m200 treated participants were confirmed to have low titers. One of these 4 
participants also provided a pre-dose sample that screened positive for anti-IXT-m200 antibodies. The 
development of anti-IXT-m200 antibodies did not appear to be dose-related. 
  
Overall, there were no apparent safety or tolerability concerns identified when IXT-m200 was dosed over 
the range from 0.2 to 20 mg/kg. Therefore, a maximum tolerated dose was not reached. 
  
Following the Phase 1 study, a Phase 2 study of IXT-m200 was conducted (STAMPOUT: Study of 
Antibody for Methamphetamine Outpatient Therapy, NCT03336866). This was a parallel-group, placebo-
controlled, double-blind study in otherwise healthy, non-treatment seeking participants who use METH. 
Participants were required to discriminate METH (30 mg, intravenous) from placebo with a drug effects 
questionnaire (DEQ) to qualify. Those who qualified received single doses of IXT-m200 (6 or 20 mg/kg) 
or placebo followed by weekly METH challenges for up to 4 weeks. The challenges consisted of METH 
(30 mg, intravenous) and placebo, separated by 4 hours. Safety, METH and IXT-m200 PK, and DEQ data 
were collected for up to 126 days. 
 
56 participants were included in the pharmacokinetic and safety sets, with 20 receiving the placebo, 18 
receiving 6 mg/kg IXT-m200, and 18 receiving 20 mg/kg IXT-m200. IXT-m200 was well-tolerated. 
There were no SAEs and all AEs were grades 1 or 2; all resolved as expected. Importantly, IXT-m200 did 
not result in substantial hemodynamic changes when compared with METH alone. IXT-m200 met the 
primary study endpoint, and significantly (p<0.001) altered METH area under the curve (AUC) and 
Cmax with all METH challenges, up to 30-fold and 8-fold respectively, without altering METH renal 
elimination (Figure 1). IXT-m200 decreased METH Vd over 9-fold after the first METH challenge 
(Figure 2). There were favorable trends in DEQ data as well (Figure 3), suggesting that IXT-m200 may 
also have effects on the reinforcing effects of METH use. 
 
Figure 1. METH PK data from STAMPOUT demonstrate IXT-m200 alters METH distribution. 
Area under the curve from time 0 through infinity (AUCinf), maximum METH concentration (Cmax), 
volume of distribution (Vd), and cumulative urinary excretion over 36 hr (Ae) data following the day 5 
challenge are plotted as mean ± SD. IXT-m200 (0, 6, or 20 mg/kg, IV) was administered one day prior to 
METH (30 mg, IV). ****p < 0.0001 


 
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Figure 2. METH volume of distribution is 
significantly reduced by IXT-m200 treatment on 
Day 4 and the effect is still significant 3 weeks later. 
****p < 0.0001 
 
Figure 3. Subject responses on drug 
effects questionnaires indicate a trend 
toward reduction of METH effects 
following an IXT-m200 dose. In this 
example, subjects were asked “Do you LIKE 
any of the effects you are feeling right now?” 
Area under the effect curve data are plotted 
as the change from Day 1 (baseline). 
  
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
General mAb Potential Risks 
Given that there are more than 50 Food and Drug Administration (FDA)-approved mAb medications, and 
several with non-endogenous targets that have been approved (Anthim®, Abthrax®, Synagis®, 
Zinplava®) or are in late-stage clinical trials, risks may be predicted and strategies developed to mitigate 
these risks based on an understanding of the pharmacology of these approved medications. These are 
outlined in the IB along with a summary of the nonclinical toxicology studies of IXT-m200 in absence 
and presence of high-dose METH in rats.  
 
Specific IXT-m200 Potential Risks 
During the Phase 1 study of IXT-m200, there were no SAEs or discontinuations due to treatment-
emergent AEs. Overall, 90% of participants experienced at least 1 AE, but there were no apparent trends 
in the frequency, relatedness, or severity of AEs with increased dose or between active- and placebo-
treated participants1. 
  
There were 3 adverse events in 2 subjects that were attributed to IXT-m200. A mild infusion reaction 
(Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 Grade 3) and bronchospasm (Grade 
2) occurred in the same subject. The symptoms included a brief period of bronchospasm with no drop in 
oxygen saturation that resolved with stopping the infusion. A separate subject experienced an AE of mild 
proteinuria (Grade 1). Both subjects were in the same dose group (2 mg/kg IXT-m200). 
  
Day 5
Day 12
Day 19
Day 26
-15
-10
-5
0
5
AUEC(0-180)
Change from Day 1 (x1000) 
p=0.08
p=0.08
p=0.05


 
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The most frequently reported AEs were increased blood creatine phosphokinase, upper respiratory tract 
infection, decreased hemoglobin, headache, increased aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT), proteinuria, decreased white blood cell (WBC) count, and nasal congestion. 
  
Because IXT-m200 is a mouse-human chimeric antibody, the potential for a human anti-chimeric 
antibody (HACA) response exists. Following single doses of IXT-m200, only 4 of 32 participants were 
confirmed positive for HACA in the Phase 1 study. The development of HACA did not appear to be dose-
related. 
 
In the Phase 2a STAMPOUT study, all AEs were grade 1 or grade 2. Common AEs included palpitations, 
tachycardia, dry mouth, nausea, injection site pain, headache, euphoria, hypervigilance, and 
hyperhidrosis. All of these AEs are expected in people receiving METH, and all participants in this study 
received METH. Of these, only blurred vision, nausea, feeling abnormal, and dry mouth were probably 
related to IXT-m200; each AE was reported by only one subject who received IXT-m200. Furthermore, 
none of the AEs associated with METH appeared to be exacerbated by IXT-m200. For example, an 
analysis of heart rate changes following METH administration demonstrated that average percent heart 
rate increase, and average peak heart rates were not changed in the presence of IXT-m200. Plus, the 
individual maximum attained heart rate in each group was 139 (placebo), 142 (6 mg/kg), and 144 
(20 mg/kg).  
 
Finally, as in the Phase 1 study, samples from all participants were tested for HACA. Only one participant 
in each IXT-m200 dose group had notable titers of anti-IXT-m200 antibodies, and the PK of IXT-m200 
in these participants did not differ from other participants in the dose group. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
IXT-m200 is an investigational product and may convey no benefit to participants. Based on nonclinical 
studies in rodents and clinical data from the STAMPOUT study, it is believed that the product has the 
potential to prevent or reduce the reinforcing properties of METH, or the ‘high’. Further, high doses of 
IXT-m200 may lessen the effects of METH doses on blood pressure.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
The risks of exposing the participants to IXT-m200 are justified to determine its effectiveness. The risks 
are minimized by using a serial cohort design in which the safety of a lower IXT-m200 dose level is 
evaluated before moving to a higher dose level, and by combining the pharmacologic characterization of 
IXT-m200 with standard-of-care cognitive behavioral therapy. 
 
 
 


 
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3 
OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
Primary 
 
To evaluate the efficacy of 
IXT-m200 in preventing or 
reducing relapse to stimulant use 
Percent of 20 weeks abstinent from stimulants following a 4-week 
grace period (between Week 5 and Week 25) as measured by 
saliva screens and by self-report via smartphone app. 
Secondary 
 
To evaluate the efficacy of 
IXT-m200 in increasing the 
number of participants achieving 
early remission 
Proportion of responders at Week 25 as measured by DSM-5 
criteria. A responder is a participant who meets the definition of 
early remission, i.e., ≥3 months and <12 months without meeting 
DSM-5 criteria, while disregarding the result for craving. 
To evaluate the efficacy of 
IXT-m200 in improving the 
proportion of participants 
achieving stimulant abstinence 
Complete abstinence during the last month of study drug treatment 
(between Week 21 and Week 25), as measured by saliva screens 
and by self-report via smartphone app. 
To evaluate the efficacy of 
IXT-m200 in improving 
participant-rated quality of life 
Change from screening in participant-rated quality of life as 
measured by the Treatment Effectiveness Assessment (TEA) at 
Week 13, 25, and Week 33. 
To evaluate the safety of multiple 
intravenous doses of IXT-m200 
Safety and tolerability of IXT-m200 assessed by physical 
examinations and vital sign, AE, ECG, and clinical laboratory 
testing. 
To evaluate the immunogenicity of 
multiple doses of IXT-m200 
Number of participants with anti-IXT-m200 antibody levels that 
are confirmed positive and have titers more than three times the 
minimum required dilution. 
Exploratory  
 
To evaluate the efficacy of 
IXT-m200 in improving the length 
of sustained abstinence  
Number of sequential weeks of abstinence from the end of 
treatment visit (Week 25), defined as four weeks after the final 
planned treatment visit (Week 21) as measured by saliva screens 
and by self-report via smartphone app. 
To evaluate the efficacy of 
IXT-m200 in improving 
post-treatment abstinence 
Point prevalence abstinence (last 7 days) as measured by saliva 
screens and by self-report via smartphone app at Week 25, Week 
29, and Week 33. 
To evaluate the efficacy of 
IXT-m200 in preventing or 
reducing relapse to stimulant use 
Weekly abstinence from stimulants following a 4-week grace 
period (between Week 5 and Week 25) as measured by saliva 
screens. 
To evaluate the efficacy of IXT-
m200 in reducing the adverse 
outcomes associated with MUD 
Difference between number of adverse outcomes recorded 
between Week 5 and Week 33. Adverse outcomes include those 
queried in the Adverse Outcomes Assessment and also suicide and 
overall mortality. 
To evaluate the efficacy of 
IXT-m200 in increasing the 
number of participants achieving 
early remission 
Proportion of responders at Week 33 as measured by DSM-5 
criteria. A responder is a participant who meets the definition of 
early remission, i.e., ≥3 months and <12 months without meeting 
DSM-5 criteria while disregarding the result for craving. 
To evaluate the efficacy of 
IXT-m200 in improving clinician-
rated response to treatment 
Difference between groups in Clinical Global Impression of 
Change (CGIC) at Week 13, 25, and Week 33. 
To evaluate the efficacy of 
IXT-m200 in improving patient-
rated response to treatment 
Difference between groups in Patient Global Impression of 
Change (PGIC) at Week 13, 25, and Week 33. 


 
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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
A Phase 2 double-blind, randomized, placebo-controlled, multiple-dose study will be performed to 
evaluate the safety and efficacy of IXT-m200 in treatment-seeking individuals who use METH. The 
hypotheses are that following an initial relapse, IXT-m200 will reduce the occurrence of stimulant-
positive saliva samples compared to placebo and improve the signs and symptoms of MUD.  
 
Approximately 120 participants will be randomized in two sequential cohorts. In Cohort 1, approximately 
60 participants will be randomized 2:1 to IXT-m200 at 1.5 g or placebo, with approximately 40 
individuals receiving treatment and approximately 20 individuals receiving placebo. An interim analysis 
of data collected through Week 25 will be performed between cohorts to review efficacy data and to 
determine the need for dose escalation. If the interim analysis supports dose escalation, then Cohort 2 will 
randomize approximately 60 participants 2:1 to IXT-m200 at 3 g or placebo. If the interim analysis 
supports dose maintenance or reduction, however, then the sample size for Cohort 2 will be recalculated. 
Randomization will be stratified by self-reported past month METH usage at screening (<18 days per 
month versus ≥18 days per month). 
 
Approximately 18 participants of the 60 per cohort will be enrolled in the PK subset. This subset will 
consist of approximately 12 active and 6 placebo participants in each cohort. Additional PK samples will 
be taken after the first and last doses in order to determine the effect of multiple doses on antibody PK. If 
18 participants have not been enrolled in the PK subset by the time a cohort is filled, the Sponsor will 
determine if additional enrollment is required. 
 
Each participant will receive 6 doses given by IV infusion, with doses given every 4 weeks. Participants 
will also receive concurrent cognitive behavioral therapy during monthly sessions. Saliva drug tests will 
be conducted randomly, with each participant completing two tests each week. 
 
The first four weeks of treatment will be considered a grace period, designed to accommodate the 
likelihood that participants will relapse initially and experience the effects of IXT-m200. It further allows 
participants time to absorb and incorporate some of the skills taught by cognitive behavior therapy. 
METH use endpoints will be analyzed in the weeks following the grace period. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
Use of placebo is justified in this study to create a comparator control group and because there is no 
current established pharmacologic standard of care for MUD. Participants recruited for this study will be 
seeking treatment for their MUD. Because all participants will receive behavioral therapy, which is the 
standard of care, the use of placebo does not place participants at further risk or prevent them from 
receiving a benefit from the antibody medication. 
 
OUTLAST will be the first multiple-dose study of IXT-m200. The first cohort will all be dosed with the 
lower IXT-m200 dose to ensure safety prior to dose escalation (or reduction) in Cohort 2. 
 


 
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4.3 
JUSTIFICATION FOR DOSE 
 
The IXT-m200 doses (1.5 or 3 g) were selected for this study because they are both potentially effective 
in reducing METH effects for several weeks. Nonclinical studies in rats suggest that when the antibody is 
administered several days prior to METH challenge administration, the antibody is effective at reducing 
METH-induced locomotor activity at a ratio of 30 METH molecules per mAb binding site2. (This 
calculation assumes that the METH dose is confined entirely to the blood volume upon administration.) 
Data from our Phase 2 STAMPOUT study demonstrated that IXT-m200 was effective in altering the PK 
of METH in humans for several weeks following a single dose when the total doses of IXT-m200 were 
near or less than the 1.5-g dose and the METH doses were 30 mg. Even with higher doses of METH, we 
predict IXT-m200 doses will reduce METH effects.  
 
IXT-m200 will be administered via IV infusion over 30 min. This is necessary because it is a protein 
medication and would be metabolized to inactive components in the gastrointestinal tract if administered 
orally. The volume that must be given is too large to allow for intramuscular or subcutaneous 
administration based on the current formulation. For the 3-g dose group the dose rate will result in a rate 
of 40 mg/kg/hr in a 75-kg person, which is significantly lower than doses given during a multiple-dose 
GLP toxicology study in which the slowest rate for the high dose was 1800 mg/kg/hr.  
 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if s/he has completed all phases of the study 
including the last visit or last scheduled procedure shown in 1.3. The end of the study is defined as 
completion of the last visit or procedure in the trial globally. 
Participants who have an ongoing AE at the time of study completion will be followed as described in 
8.3.5. Study discontinuation and closure details are in 10.1.2. 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
Eligible participants will:  
1. Be at least 18 years of age at the time of study consent; 
2. Meet DSM-5 criteria for Substance Use Disorder associated with methamphetamine; 
3. Be treatment-seeking methamphetamine users with at least 1 methamphetamine or amphetamine 
positive specimen during the screening period;  
4. Be able and willing to read, comprehend, and give Authorization for Use/Disclosure of Health 
Information (HIPAA) and informed consent; 
5. Be willing to comply with study instructions and dosing, agree to make all appointments, and 
complete the entire course of the study; 
6. Agree to use protocol-specified method(s) of birth control throughout study participation; 
7. Agree to adhere to Lifestyle Considerations throughout study duration (see section 5.3); 
8. Have access to a smartphone or other device capable of supporting the study app;  
9. Successfully complete app-based training program as evidenced by submission of at least 2 valid 
saliva drug screens when randomly assigned during the first two weeks after the Screening visit. 
 


 
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5.2 
EXCLUSION CRITERIA 
 
Eligible participants will NOT:  
1. Have current dependence (past 12 months) Substance Use Disorder, defined by ≥ 2 DSM-5 criteria, 
for any psychoactive substance (i.e., opioids or benzodiazepines), other than methamphetamine or 
nicotine (any severity). Mild severity (2-3 DSM-5 criteria) Substance Use Disorder for alcohol or 
marijuana is allowed; 
2. Be currently taking certain other drugs and medications, including: “designer drugs” (e.g., 3,4-
methylenedioxyMETH (MDMA, Ecstasy, Adam, XTC) and its N-dimethyl metabolite 
methylenedioxyamphetamine (MDA), anti-orexigenic drugs (including over-the-counter medications 
for weight loss), or be chronic users of phenethylamine compounds (e.g., phenylpropanolamine, 
ephedrine, pseudoephedrine, amphetamine, phentermine, phenmetrazine, methylphenidate, 
diethylpropion, and propylhexedrine); 
3. Have a known contraindication or sensitivity to IXT-m200 based on known allergies to other mAbs, 
any inactive ingredient of IXT-m200, or any other products required for the study procedures; 
4. Have a history of severe allergy (rash, hives, breathing difficulty, etc) to any medications; 
5. Have a history of allergic or environmental bronchial asthma within the past 3 years; 
6. Have a current diagnosis of anorexia nervosa or bulimia disorder; 
7. Have a history of unstable cardiovascular disease that is not adequately controlled at the time of 
eligibility determination; 
8. Be mandated by the court to obtain treatment for methamphetamine dependence where such mandate 
required the results of methamphetamine testing to be reported to the court; 
9. Have positive saliva drug screen for psychoactive substances other than amphetamines at the 
screening visit (positive benzodiazepine results are not exclusionary if the participant takes them 
chronically as prescribed and does not appear intoxicated at screening); 
10. Be expected to fail to complete the study protocol due to probable incarceration or relocation from the 
clinic area, or any clinically significant mental or physical illness within a 1-year prior, that would 
impact compliance with trial requirements; 
11. Have clinically significant laboratory values (outside of normal limits). The following specified 
ranges are allowable: 
a. Liver function tests (total, direct, and indirect bilirubin, ALT, AST, gamma-glutamyl transferase, 
lactate dehydrogenase and alkaline phosphatase) <3 times the upper limit of normal, and 
b. Kidney function tests (creatinine and BUN) <2 times the upper limit of normal; 
12. Be considered to be at imminent risk of suicide or have a past-year history of a serious suicide 
attempt (defined as an attempt that results in or requires medical treatment) based on response to 
queries within eligibility screening about suicidal ideation and attempts; 
13. Have an uncontrolled systemic disease or a medical condition that may increase the risk associated 
with study participation or administration of study treatment or that may interfere with the 
interpretation of study results; 
14. Be currently participating or has participated within the last 30 days prior to the start of this study in a 
drug, device, or other interventional research study; unless the study is a COVID-19 study with long-
term follow-ups (participant cannot have received a dose of study drug within the past 30 days); 
15. Be pregnant or lactating; 
16. In the Investigator’s or Sponsor’s (or designee) opinion, be inappropriate for the study, including 
those believed to be attempting to enter the study primarily for financial gain. 
 


 
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5.3 
LIFESTYLE CONSIDERATIONS 
 
IXT-m200 may alter the pharmacokinetics of molecules that are structurally similar to METH; therefore, 
participants should not take drugs such as amphetamine (including Adderall®, Dexedrine®, or Evekeo®) 
or MDMA (also known as ecstasy) for the duration of study participation. 
 
The use of medication-assisted treatment for opioid use disorder is exclusionary, as those medications 
(buprenorphine, methadone, and naltrexone) are psychoactive substances. 
 
Participants are prohibited from the following during the study period: 
• 
Ingesting or using any other investigational drug or device. 
• 
Donating blood, plasma, platelets, eggs or sperm. 
 
Participants will be encouraged to limit their ethanol consumption to approximately 1 drink per day for 
women and 2 drinks per day for men while in the study. 
 
Participants are required to practice an adequate method of birth control, including intrauterine device; 
oral, dermal ("patch"), implant or injected contraceptives; tubal ligation; barrier methods with spermicide; 
or vasectomized partner throughout the study and until 90 days after receiving the last dose of study drug. 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
 
All participants who consent to participate but fail screening will be referred to treatment outside of the 
study per the recommendation of the screening physician. Individuals who do not meet the criteria for 
participation in this trial (screen failure) because of a short term or temporary issue may be rescreened 
(≥30 days later). Sponsor permission for rescreening is required for such cases. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Traditional and non-traditional advertising methods will be utilized to ensure recruitment goals are met. 
This will be accomplished by using advertising such as print, electronic, and/or digital newspapers, flyers, 
mailers, billboards, television, radio, online, social networking, study-branded materials (such as ink pens 
and post-it notes) and other means of communicating with the community that are IRB approved. 
Advertising may also encompass providing materials to potential referrers to assist with recruitment and 
to community agencies to assist in recruiting and retaining participants. 
  
All recruitment materials will refer interested persons to a contact email, website, or telephone number, 
and they will be approached by a study staff member trained to provide the caller with information about 
the study and to schedule interested persons for an in-person interview. Participants will undergo an initial 
screening and those who pass the initial screen will undergo informed consent procedures. 
  


 
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To address retention, we will incorporate procedures used in previous trials, which include frequent 
contact with participants throughout active study periods, incentives to motivate participants to keep study 
visits, and potentially providing travel vouchers for taxis and shared rides to help participants to come to 
clinic. In addition, this study will deliver the vast majority of encounters virtually via smartphone app. We 
believe that this modality will significantly reduce study burden on the participants, will dramatically 
increase study engagement, and will lead to improved study retention compared to studies involving 
primarily in-person visits. 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Study Drug 
IXT-m200 is a chimeric mAb that binds METH with high affinity. The product contains a murine METH-
binding variable region and the constant domains of a human IgG 2κ. This antibody isotype was chosen 
because of the lower risk of immune response compared to an IgG1 or IgG3. IXT-m200 specifically 
targets METH and does not rely on binding to any endogenous target for its action. 
  
By binding METH in the bloodstream and altering METH PK, it is predicted that IXT-m200 decreases 
the amount of METH reaching its active sites in the brain. The presence of IXT-m200 should therefore 
decrease the perceived pleasurable effects of METH. Over the longer term, when combined with behavior 
modification therapy, IXT-m200 should reduce the frequency of METH use. 
 
Cognitive Behavioral Therapy 
All participants in this trial will attend regular cognitive behavioral therapy (CBT) sessions. These 
individual sessions will be conducted by a trained therapist at the study site. CBT generally focuses on the 
following topics: recognizing and changing patterns of use, coping with cravings, changing negative 
thoughts, improving decision making, learning to say no, and improving problem-solving. The content of 
these sessions is prearranged and sequenced using a manualized format.  
 
Other Participant Support 
A smartphone app will be used to engage participants frequently, provide study payments, deliver access 
to a recovery coach, collect daily drug use reports, and conduct video-monitored saliva drug testing. The 
app will provide payment for completion of study-required activities such as clinic visits, saliva testing, 
and self-reports of drug use. The app also connects each participant with a recovery coach who will be 
available for a phone/video call once per week throughout the study. In addition to the scheduled calls, 
the coach will be available by text during working hours. The app will also collect data for two efficacy 
assessments, the saliva drug screens (8.1.2) and self-reported past day drug use (8.1.3). 
 
6.1.2 DOSING AND ADMINISTRATION 
 
Participants will only be randomized and dosed with study drug if they have passed all screening 
requirements before or on Day 1. Participants will be randomized on Day 1. In Cohort 1, participants will 
get 1.5 g IXT-m200 or placebo (2:1). If the interim analysis supports dose escalation, participants will 
receive 3 g IXT-m200 or placebo (2:1) in Cohort 2. If the interim analysis does not support dose 
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size will be recalculated. Each participant will receive 6 doses of assigned study drug, spaced 4 weeks 
apart.   
 
Participants should lie supine or semi-reclined during dose administration. Each dose will be given with 
an infusion pump over 30 minutes with a 50-mL saline flush dispensed after each dose to ensure the entire 
dose is flushed through the infusion set. The study drug infusion start/stop time, infusion rate, infusion 
volume, whether the infusion was completed, if it was stopped, or stopped and restarted will be recorded.  
 
Participants will be asked to eat a light meal prior to arriving at the dosing center but not have anything 
but clear liquids to eat or drink for 1 hour before appointment time. Participants will be offered a light 
meal or snack after dosing completion. 
 
Further doses will not be given to any participant that experiences an SAE that is attributed to the study 
drug (by a causality grading of possibly, probably, or definitely; see section 8.3.3.2), but the participant 
will be followed to completion. No dose adjustments will be made. 
 
All study drug doses will be administered in a blinded manner by the investigator or designee. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Study Intervention: All required IXT-m200 vials will be shipped by Sponsor to the study sites. All unused 
supplies will be checked against the drug accountability records during the study and/or at the end of the 
study. All unused study drug must be disposed of in accordance with applicable requirements.  
  
Placebo: An unblinded pharmacist will be responsible for acquiring commercially available normal saline 
for use as placebo for IXT-m200. 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Study Intervention: IXT-m200 is formulated as a solution containing approximately 20 mg/mL 
IXT-m200 in 10 mM sodium phosphate, pH 6.5, 150 mM sodium chloride, and 0.05% w/v 
polysorbate 80. The product is a clear solution packaged in glass vials with stoppers and flip-off seals. 
Catalent Pharma Solutions manufactures the formulated active pharmaceutical ingredient.  
 
Labels will be similar to the following: 
  
InterveXion Therapeutics® 
Anti-methamphetamine IXT-m200 
18.5-21.5 mg/mL 
Manufactured: DD MMM YYYY 
DP Lot: XXXXXXX 
Catalent Lot: XXXXX 
10 mM sodium phosphate, 150 mM sodium chloride, pH 6.5, with 0.05% Tween 80 
Store refrigerated at 2 to 8°C 
CAUTION: New Drug – Limited by Federal (or United States) law to investigational use only. 
InterveXion Therapeutics, LLC 
4301 W. Markham, Slot 831, Little Rock, AR 72205 


 
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Placebo: Normal saline (0.9% sodium chloride) should be a clear solution for injection. Packaging and 
labeling will be appropriate for use. 
 
Only unblinded personnel will have access to the labeled study drugs.   
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
IXT-m200 vials are single-use and should be stored refrigerated at 2 to 8°C (preferred) or frozen at -20°C. 
The stability of the product is still under investigation and stability protocols will run concurrent to the 
study. A previous lot of IXT-m200 remained stable after 48 months of refrigerated storage when the 
stability protocol was terminated. 
 
6.2.4 PREPARATION 
 
An unblinded member of the study team (i.e., pharmacist) will prepare the study drugs for administration. 
The appropriate amount of IXT-m200 should be administered over 30 min.  Since IXT-m200 is a clear 
solution, it will appear similar to saline placebo. 
  
Placebo: Normal saline requires no preparation prior to administration. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Each potential participant will be assigned a unique number in the screening process (screening number). 
This number will be used to identify the participant throughout the study.  
 
Participants who qualify will be randomized in two sequential cohorts. The dose groups of IXT-m200 or 
placebo will be at a 2:1 ratio in Cohort 1 and, if the interim analysis supports dose escalation, 2:1 in 
Cohort 2. If the interim analysis supports dose maintenance or reduction, then the sample size will be 
recalculated. Placebo participants will be combined for analysis at the end of study. Randomization will 
be stratified by self-reported past-month METH usage at screening (<18 days versus ≥18 days).  
 
Unblinding of treatment assignment during the study is discouraged and should occur only if it is 
absolutely necessary for the investigator, Medical Monitor, Sponsor, or participant to know what he or 
she received for safety reasons. If the Sponsor, the investigator, or Medical Monitor deems identification 
of the study drug to the participant as necessary for the purpose of providing urgent care, the pharmacy 
will inform the investigator of the assignment, who will notify the Medical Monitor, Sponsor, and 
participant. The process of unblinding will be appropriately documented in the investigator file. The date 
and reason for the unblinding must be recorded. When possible, the Medical Monitor and Sponsor should 
be notified prior to unblinding; otherwise, they must be notified within 24 hours after unblinding. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Study drug is administered by intravenous infusion by qualified personnel who are blinded to the 
treatment assignment of the participant. Compliance with dosing will be verified by reference to the 
electronic case report form (eCRF) documentation of dosing. 
 
CBT session attendance will be documented by the site.  
 


 
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6.5 
CONCOMITANT THERAPY 
 
All concomitant medications (i.e., prescription medications, over-the-counter medications, 
non-prescription medications, and supplements) taken during study participation will be recorded on the 
eCRF. For this protocol, a prescription medication is defined as a medication that can be prescribed only 
by a properly authorized/licensed clinician.  
 
In addition, any behavioral therapy sessions with a trained provider outside the protocol will be recorded 
as concomitant therapy. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
The criteria outlined in section 8.3.3.1 will be used to categorize the severity of all AEs. The Sponsor, in 
consultation with the investigator and Medical Monitor, will suspend enrollment until a full safety review 
by the Sponsor and Data and Safety Monitoring Board (DSMB) is performed if any 1 of the following 
events occurs, unless the event was unrelated to study drug administration i.e., causality was graded as 
unrelated or unlikely: 
 
• 
Three (3) participants experience a Grade 3 AE; or, 
• 
One (1) participant experiences a Grade 4 AE; or, 
• 
A death occurs.  
 
Events unrelated to study drug administration include those that are temporally unrelated to study drug 
administration, such as events occurring prior to dosing; or events in which the participant is a passive 
victim, such as a passenger in a motor vehicle crash. 
 
A decision to reinitiate enrollment will be made by the Sponsor following any necessary consultation with 
the appropriate authorities based on the results of the safety review. All other study procedures, including 
dosing, and assessments will continue per protocol during any study pause. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants who withdraw consent for dosing and all future study visits (following early termination 
assessments) will be considered ‘withdrawn’. Participants are free to withdraw at any time upon request; 
they will be asked to complete early termination assessments as soon as possible. 
 
Participants that will no longer be dosed with study drug but agree to continue participation in other study 
procedures and assessments will be considered ‘discontinued’. Participants are free to discontinue at any 
time upon request. Participants will be encouraged to complete study visits, assessments, and therapy 
sessions, even if they elect to discontinue study drug administration. In this case, all study activities will 
be completed per protocol with the exception of dose administrations.  
 
An investigator may discontinue a participant from study drug administration for the following reasons: 
• 
the participant meets an exclusion criterion (either newly developed or not previously recognized) 
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• 
any clinical AE, laboratory abnormality, or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the participant,  
• 
significant non-compliance by the participant, 
• 
if, in the investigator’s opinion, continuation with study drug administration would be detrimental 
to the participant’s well-being,   
• 
at the specific request of Sponsor or the investigator.  
 
Participants who miss dosing days and return to the study at a later point are not automatically 
disqualified from resumption of dosing. Please discuss with Sponsor if two or more consecutive dosing 
visits are missed and the participant later wishes to resume treatment. 
 
In all cases, the reason for withdrawal or discontinuation must be recorded in the eCRF and in the 
participant’s medical records. If the reason is not known, an attempt must be made to follow up with the 
participant to establish whether the reason was an AE, and, if so, this AE must be reported. Once the 
participant has been contacted and expresses their decision to withdraw from further participation in the 
study, the research staff will cease to try to make further contact. 
 
There will be no replacement of participants who withdraw or are discontinued following the first dose of 
study drug. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for the final scheduled visit, 
including an early term visit, and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit, counsel the 
participant on the importance of maintaining the assigned visit schedule, and ascertain if the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
Assessments are to be performed at the time points described in the Schedule of Activities (1.3). 
 
8.1.1 QUALITY OF LIFE 
 
• 
The Treatment Effectiveness Assessment (TEA)5 will be performed at screening and at selected 
subsequent visits per the Schedule of Activities. 
• 
The Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change 
(CGIC) scales will be used at selected time points after the first dose. 


 
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8.1.2 SALIVA DRUG SCREENS 
 
• 
Qualitative saliva drug screens will be used during screening and twice weekly throughout the 
study (Weeks 1-32) to screen for substances of abuse including amphetamine, cocaine, 
methamphetamine, and opiates. Saliva testing will be strictly monitored by performance of a 
specific series of steps recorded by video and reviewed by a trained professional to ensure 
validity of the test results. 
 
8.1.3 SELF-REPORT OF DRUG USE VIA APP 
 
• 
Participants will be required to install an app on their smartphone, tablet, or similar device which 
records daily self-reported drug use from Day 1 through Week 32 or the Early Termination visit. 
The app will query participants daily on their past-day use, upload responses to a database at 
regular intervals, and notify investigators when participants are non-responsive. 
 
8.1.4 METHAMPHETAMINE USE ASSESSMENTS 
 
• 
DSM-5 criteria checklist should be used to assess participants for Methamphetamine Use 
Disorder and the number of criteria met. At screening the checklist should be completed for past 
year history. At each subsequent assessment time point (Week 25 and Week 33), the checklist 
should be completed for the past 30 days AND for the past 3 months, separately. 
• 
Also at Screening, participants should be asked, “What is the main way you take 
methamphetamine?”  Potential answers would be Smoked, Snorted, Intravenous, or Oral.  
• 
Participants should also be asked, “How many days in the past month did you use METH?” 
Answers should be categorized as <18 days or ≥18 days. 
 
8.1.5 ADVERSE OUTCOMES ASSESSMENT 
 
• 
To assess the frequency of adverse outcomes, the following questions should be asked at 
Screening and Weeks 13, 25, and 33. All responses should be counted over the past 3 months. 
• 
Questions: 
o How many unintended encounters with the criminal justice system have occurred? This 
does not include scheduled appointments with parole officers, court dates, or similar 
follow-ups to previous events. However, this does include interactions due to domestic 
disturbance, petty theft, DUI, etc. 
o Have you required emergency medical intervention due to methamphetamine use? This 
might be from a methamphetamine overdose or injury due to use. If yes, how many 
times? 
o Have you tested positive for HIV or Hepatitis where you had not been positive before? 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Assessments are to be performed at the time points described in the Schedule of Activities (1.3). The 
procedures for the collection, handling, and shipping of laboratory samples will be specified in the 
laboratory manual(s) provided to the study site. 
 


 
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8.2.1 ELIGIBILITY CRITERIA 
 
• 
DSM-5 criteria checklist should be used to assess participants for Substance Use Disorders 
(including METH, opioids, alcohol, nicotine, marijuana, etc.) 
 
8.2.2 MEDICAL AND MEDICATION HISTORY 
 
• 
A complete medical history will be obtained by interview and any available medical records at 
screening. Interim medical history will be obtained at all subsequent time points; any new events 
starting after randomization will be recorded as AEs. 
• 
A past-30-days medication history will be obtained by interview and any available medical records 
at screening. Concomitant medications will be updated at all subsequent visits. 
 
8.2.3 VITAL SIGNS 
 
• 
Vital sign measurements (heart rate, blood pressures [systolic and diastolic], respiratory rate, 
temperature [oral], and pulse oximetry readings) will be obtained after the participant has been 
resting supine for at least 5 minutes. 
 
8.2.4 PHYSICAL EXAM 
 
• 
Physical examination (excluding rectal/genital and breast examination) will consist of an 
examination of the following: general appearance, neurological, skin, head, eyes, ears, nose, throat, 
neck, lymph nodes, chest, heart, abdomen, and extremities.  
• 
Targeted physical exams will include heart, lungs, abdomen, skin, and site of injection. Additional 
areas may be targeted if AEs or other complaints require appropriate and more detailed exams. 
• 
Height and weight will be recorded at screening; weight will be recorded at subsequent visits. 
 
8.2.5 PSYCHIATRIC EVALUATION 
 
• 
A complete psychiatric history will be obtained at screening evaluating for (but not limited to) the 
following: major current depression, psychosis, bipolar illness, organic brain disorder, anorexia 
nervosa or bulimia disorder or dementia, which require ongoing medication or which would make 
study compliance difficult in the opinion of the investigator.  
• 
The psychiatric history will be updated at selected subsequent visits.  When updating psychiatric 
history, participants should be asked, “Since your last visit, have you had a serious plan or attempt 
to kill yourself?” 
• 
Suicide-related thoughts and behaviors will be assessed using the Columbia-Suicide Severity 
Rating Scale (C-SSRS) at screening (past year version). The C-SSRS captures the occurrence, 
severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The 
scale includes suggested questions to solicit the type of information needed to determine if a 
suicide-related thought or behavior occurred. The C-SSRS will be administered by appropriately 
trained site personnel. For participants determined to be at imminent risk of suicide, a referral to a 
clinician should be made.  
• 
The C-SSRS may be administered at any time to a participant who indicates, or is suspected to 
have, new suicidal intentions during the study. 
 


 
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8.2.6 PREGNANCY TEST 
 
• 
Urine pregnancy tests will be performed on all females at all visits, unless hysterectomy is reported 
in the medical history. Results from this test should be reviewed prior to dosing. Pregnant 
participants should not receive any further doses, but all other assessments should be completed. 
 
8.2.7 LABORATORY TESTS  
 
The below laboratory tests will be centrally assessed: 
• 
Hematology 
o Erythrocytes: red blood cell (RBC) count, hematocrit, hemoglobin, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, red cell 
distribution width, and reticulocyte count as an absolute value. 
o Leukocytes: WBC and differential (basophils, eosinophils, lymphocytes, monocytes, and 
neutrophils) reported as absolute values. 
o Coagulation: platelet count, prothrombin time measured as international normalized ratio, 
activated partial thromboplastin time. 
• 
Serum Chemistry 
o Liver: alkaline phosphatase, ALT, AST (serum glutamic-oxaloacetic transaminase), bilirubin 
(total, direct, and indirect), gamma-glutamyl transferase, and lactate dehydrogenase. 
o Renal: blood urea nitrogen, creatinine, and uric acid. 
o Electrolytes, sodium, potassium, chloride, and carbon dioxide. 
o General: creatine phosphokinase (CPK), albumin, calcium, magnesium, glucose (fasting), 
phosphate, protein (total), amylase, lipase and prostate specific antigen. 
• 
Urinalysis 
o Samples will be assessed macroscopically first and only if needed, microscopic examination 
will follow. 
o Microscopic: pH, specific gravity, glucose, ketones, leukocyte esterase, nitrites, occult blood, 
and protein, RBCs/hpf, WBCs/hpf, bacteria, casts, epithelial cells, mucous threads, and 
crystals. 
 
8.2.8 ELECTROCARDIOGRAMS 
 
• 
Electrocardiograms (ECG; 12-lead) will be recorded after the participants have been supine for 5 
minutes. Standard ECG parameters including heart rate, QRS, PR, QT, and QTc intervals will be 
measured. The ECGs will be read by a study physician to assess for any abnormalities. Abnormal 
ECG parameters include, but are not limited to ventricular hypertrophy, left axis deviation, atrial or 
ventricular arrhythmias other than sinus, and prolonged QTc (greater than 500 ms). ECGs may be 
repeated if data quality is compromised due to poor lead placement or machine error.  
• 
Confirmed ECG anomalies will be referred for appropriate medical follow-up. 
 
8.2.9 BLOOD FOR PK, HACA, AND CYTOKINES 
 
• 
PK of IXT-m200: A validated enzyme linked immunosorbent assay procedure will be used to 
quantitate IXT-m200 in serum samples. Approximately 1 mL per sample is required. 
• 
HACA: A validated electrochemiluminescent procedure will be used to analyze HACA in serum 
samples. Approximately 1 mL per sample is required. 


 
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• 
Cytokine panel to include at a minimum IL-6, IL-8, and TNFα levels will be determined only if any 
study drug infusion reaction occurs.  
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
An AE is any untoward medical occurrence in a person administered study drug, whether or not 
considered intervention-related. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, 
whether or not related to the IXT-m200.   
 
The AE may be: 
• 
a new illness; 
• 
worsening of a sign or symptom of the condition under treatment or of a concomitant illness; 
• 
an effect of the study medication, including comparator; or 
• 
a combination of 2 or more of these factors. 
 
No causal relationship with IXT-m200 or with the clinical study itself is implied by the use of the term 
“AE”. Pre-existing conditions will not be reported as an AE unless there has been a substantial increase in 
the severity or frequency of the problem which has not been attributed to natural history. 
 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that require 
surgery. The condition for which the surgery is required may be an AE. Planned surgical measures 
permitted by the clinical study protocol and the condition(s) leading to these measures are not AEs. 
 
Adverse events fall into the categories “nonserious” or “serious”. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An SAE is an AE that at any dose: 
 
• 
results in death; 
• 
is life-threatening; 
• 
requires hospitalization or prolongation of existing hospitalization; 
• 
results in persistent or significant disability/incapacity; or 
• 
is a congenital anomaly/birth defect.  
 
The term “life-threatening” in the definition of “serious” refers to an event in which the person was at 
immediate risk of death at the time of the SAE; it does not refer to an SAE which hypothetically might 
have caused death if it were more severe. 
 
Medical and scientific judgment will be exercised in deciding whether other AEs, such as important 
medical events that may not be immediately life-threatening or result in death or hospitalization but in the 
view of the PI require medical or surgical intervention to prevent one of the other outcomes listed above. 
These will also usually be considered serious.  
 


 
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8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 
The general approach outlined by the Club Phase 1 working group in the British Journal of Clinical 
Pharmacology6 will be used to categorize the severity of all AEs. The stopping rules outlined in Section 
7.1 will apply.  
 
The following criteria will be used:  
• 
Grade 1: Transient or mild discomfort; does not interfere with daily activity; no medical 
intervention/treatment required,  
• 
Grade 2: Mild to moderate limitation in activity, some assistance may be needed; no or minimal 
intervention/treatment required, including but not limited to mild analgesics, antacids or 
antibiotics,  
• 
Grade 3: Marked limitation in activity, some assistance usually required; medical 
intervention/treatment required,  
• 
Grade 4: Extreme limitation in activity, significant assistance required; significant medical 
intervention/treatment, likely requiring hospitalization.  
 
For example, if hypotension is not immediately responsive to medications, this will constitute a Grade 3 
reaction and it will be documented as such. Similarly, if bronchospasm (SaO2 < 93% on oxygen) occurs 
and requires medications, this will constitute a Grade 3 reaction, and will be documented as such.  
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below. In a clinical trial, the study 
product must always be suspect.  
 
DEFINITELY – The AE:  
• 
is clearly related to the investigational agent or research intervention;  
• 
has a temporal relationship to the administration of the study drug;  
• 
follows a known pattern of response;  
• 
occurs in the absence of an alternative cause.  
 
PROBABLY – The AE:  
• 
follows a reasonable temporal sequence from study drug administration;  
• 
abates upon discontinuation of the drug;  
• 
cannot be reasonably explained by the known characteristics of the participant’s clinical state.  
 
POSSIBLY – The AE:  
• 
follows a reasonable temporal sequence from study drug administration;  
• 
could have been produced by the participant’s clinical state or by other modes of therapy 
administered to the participant.  
 
UNLIKELY – The AE:  
• 
does not follow a reasonable temporal sequence from study drug administration;  


 
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• 
is readily explained by the participant’s clinical state or by other modes of therapy administered 
to the participant.  
 
UNRELATED – The AE:  
• 
is definitely produced by the participant’s clinical state or by other modes of therapy administered 
to the participant.  
 
8.3.3.3 EXPECTEDNESS  
 
The Sponsor will be responsible for determining whether an AE is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study agent. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-
UP 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care, during engagement of the participant with 
the smartphone app, or upon review by a Study Monitor. All AEs including local and systemic reactions 
not meeting the criteria for SAEs will be captured on the appropriate eCRF. Information to be collected 
includes event description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented appropriately 
regardless of relationship. All AEs will be followed to adequate resolution.  
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study after randomization, it will be recorded as an AE. If changes occur before randomization, 
these should be reported as medical history. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity. All AEs characterized as intermittent require documentation of onset and 
duration of each episode.  
 
The investigator will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for nonserious AEs) or 30 days (for SAEs) after the last day of study 
participation for participants who withdraw. For all events occurring prior to randomization to treatment, 
these events should be recorded on the medical history case report form page. For all events after 
randomization to treatment, these should be recorded on the AE/SAE case report form pages. For all other 
participants, reportable events will be recorded until the last day of study participation. At each study 
visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be 
followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
All AEs (whether serious or nonserious) that occur after the participant has been randomized into a 
treatment group must be documented on the appropriate pages of the eCRF. For all AEs, the investigator 
will provide an assessment of the AE, its treatment and resolution, and its relationship to IXT-m200. 
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symptoms should also be listed below the diagnosis. If only nonspecific signs or symptoms are present, 
then these should be recorded as a diagnosis. 
 
All participants who have AEs, whether considered associated with the use of IXT-m200 or not, will be 
monitored to determine the outcome. The clinical course of the AE will be followed up according to 
accepted standards of medical practice, even after the end of the period of observation to a maximum of 
15 days following the end of study visit. Should the AE result in death, a full pathologist’s report should 
be supplied, if possible. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
The investigator will complete an SAE form within the following timelines:  
• 
All deaths and immediately life-threatening events, whether related or unrelated, will be recorded 
on the designated SAE form and submitted to the medical monitor and Sponsor within 24 hours 
of site awareness.  
• 
Other SAEs regardless of relationship, will be submitted to the medical monitor and Sponsor 
within 48 hours of site awareness.  
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be requested by 
the medical monitor or Sponsor and should be provided as soon as possible.  
 
Information not available at the time of the initial report will be documented on a follow-up SAE form. 
SAE information previously sent to the Sponsor will not be duplicated. When a nonserious event becomes 
serious, details will be forwarded immediately to the Sponsor on the designated SAE report form. 
 
The study Sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the Sponsor's initial receipt of the information.  In addition, the Sponsor must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the Sponsor determines that the information qualifies for reporting. 
 
The NIDA Project Officer (PO) and Science Officer will be notified by the Sponsor within 72 hours of 
the SAE occurrence, and also via NIDA’s online Serious Adverse Event Tracking and Reporting System 
(SAETRS).  
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
It is not anticipated that safety updates, including AEs or SAEs, will be reported to study participants. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
Not applicable. 
 
8.3.9 REPORTING OF PREGNANCY  
 
If a participant is found to be pregnant after they have received study drug, they should complete the 
study, with no further study drug doses administered, and be followed to determine the outcome of the 


 
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pregnancy if the participant is willing. Generally, follow-up will be no longer than 6 to 8 weeks after the 
estimated delivery date. While pregnancy itself is not considered an AE or SAE, any pregnancy 
complications will be recorded as an AE or SAE. 
 
Pregnancies should be reported by the investigator to the Sponsor within 2 days of identification.  
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
Unanticipated problems involving risks to participants or others will include, in general, any incident, 
experience, or outcome that meets all of the following criteria:  
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being 
studied;  
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and  
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized.  
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
Investigators will adhere to the following guidelines for prompt reporting: 
• 
Unanticipated problems that are SAEs should be reported to the IRB within 1 week of the 
investigator becoming aware of the event. 
• 
Any other unanticipated problem should be reported to the IRB within 2 weeks of the investigator 
becoming aware of the problem. 
 
All unanticipated problems should be reported by the Sponsor to the supporting Department of Health and 
Human Services (DHHS) agency head (or designee), and Office for Human Research Protections (OHRP) 
within one month of the IRB’s receipt of the report of the problem from the investigator. 
 
In some cases, the requirement for prompt reporting may be met by submitting a preliminary report to the 
IRB, the supporting DHHS agency head (or designee), and OHRP, with a follow-up report submitted at a 
later date when more information is available.  Determining the appropriate time frame for reporting a 
particular unanticipated problem requires careful judgment by persons knowledgeable about human 
participant protections.  The primary consideration in making these judgments is the need to take timely 
action to prevent avoidable harms to other participants. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
It is not expected that unanticipated problems will be reported to study participants, although appropriate 
study-related actions may be undertaken if determined necessary. 
 


 
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9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
The primary objective of the study is to evaluate the efficacy of IXT-m200 in preventing or reducing 
relapse to stimulant use. The primary efficacy endpoint is percent of 20 weeks abstinent from stimulants 
following a 4-week grace period between Week 5 and Week 25 based on saliva screens and by self-report 
via smartphone app. Each dose group of IXT-m200 will be compared to the placebo group.  
 
For each IXT-m200 dose group, the hypotheses are as follows: 
 
Null Hypothesis (H0): There is no difference between the IXT-m200 group and the placebo 
group in percent weeks abstinent between Week 5 and Week 25. 
 
Alternative Hypothesis (H1): There is a difference between the IXT-m200 group and the 
placebo group percent weeks abstinent between Week 5 and Week 25. 
 
The secondary efficacy objectives are to evaluate the efficacy of IXT-m200 over placebo in the 
proportion of participants achieving early remission, achieving stimulant abstinence, or improving 
participant-rated quality of life as measured by the following endpoints: 
 
• 
Proportion of responders at Week 25 as measured by DSM-5 criteria for early remission. For each 
IXT-m200 dose group, the hypotheses are as follows: 
 
Null Hypothesis (H0): There is no difference between the IXT-m200 group and the placebo 
group in proportion of responders. 
 
Alternative Hypothesis (H1): There is a difference between the IXT-m200 group and the 
placebo group in proportion of responders. 
 
• 
Complete abstinence during the last month of study drug treatment (between Week 21 and Week 
25), as measured by saliva screens and by self-report via smartphone app. For each IXT-m200 
dose group, the hypotheses are as follows: 
 
Null Hypothesis (H0): There is no difference between the IXT-m200 group and the placebo 
group in the proportion of participants achieving stimulant abstinence (responders) between 
Week 21 and Week 25. 
 
Alternative Hypothesis (H1): There is a difference between the IXT-m200 group and the 
placebo group the proportion of participants achieving stimulant abstinence (responders) 
between Week 21 and Week 25. 
 
• 
Change from screening in the Treatment Effectiveness Assessment (TEA) at Week 13, 25, and 
33. For each IXT-m200 dose group and at each timepoint of interest, the hypotheses are as 
follows: 
 
Null Hypothesis (H0): There is no difference between the IXT-m200 group and the placebo 
group in the change from screening Treatment Effectiveness Assessment. 
 


 
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Alternative Hypothesis (H1): There is a difference between the IXT-m200 group and the 
placebo group in the change from screening Treatment Effectiveness Assessment. 
 
The SAP will describe any hypotheses for the exploratory endpoints. The study will use a two-sided Type 
1 error rate (alpha) of 5% for comparing each IXT-m200 arm versus placebo; there will be no multiplicity 
adjustments for multiple comparisons for multiple endpoints and between multiple dose groups. All p-
values reported will be nominal. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
A total of approximately 300 participants are expected to be screened, with a goal of randomizing 
approximately 120 participants (60% screen failure rate).  
 
Approximately 120 participants will be randomized into this study in two sequential cohorts. The first 
cohort will randomize approximately 60 participants 2:1 to IXT-m200 1.5 g or placebo and, if the interim 
analysis supports dose escalation, the second cohort will randomize approximately 60 participants 2:1 to 
IXT-m200 3.0 g or placebo. If the interim analysis supports dose maintenance or reduction, then the 
sample size may be recalculated. Randomization will be stratified by self-reported past-month METH 
usage at screening (<18 days versus ≥ 18 days). Final analyses will compare each IXT-m200 dose group 
to the placebo group pooled over both cohorts. 
 
A sample size of 40 participants in each dose group would provide 90% power to detect a difference in % 
weeks abstinent between Week 5 and Week 25 that is 0.73 times the pooled standard deviation, assuming 
a two-sided 5% alpha. Table 1 presents potential scenarios for the power analyses. For example, if the 
standard deviation is 20%, then the study has 90% power to detect a difference of 14.6% or larger 
between the IXT-m200 group and placebo (approximately 2.92 weeks). 
 
Table 1. Minimum detectable difference between each IXT-m200 group (n=40) versus the placebo 
group (n=40) 
Power 
Detectable 
difference 
Examples of detectable differences with varying pooled SD 
20% 
25% 
30% 
0.80  
0.63 × pooled SD 
12.6% 
15.8% 
18.9% 
0.85 
0.68 × pooled SD 
13.6% 
17.0% 
20.4% 
0.90 
0.73 × pooled SD 
14.6% 
18.3% 
21.9% 
The detectable differences were calculated in PASS using a two-sample t-test assuming 
equal variance a two-sided 5% alpha. SD = standard deviation. 
 
The literature suggests that dropout rates in the study population may be up to 50% 7; the analyses of the 
primary endpoint will account for missing data using imputation.  
 
9.3 
POPULATIONS FOR ANALYSES 
 
The study analysis populations will consist of: 
 
Population 
Description 
Enrolled 
All participants who sign the ICF. 
Intent-to-Treat 
(ITT) 
All randomized participants. Participants will be categorized by their randomized 
treatment assignment. 


 
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Population 
Description 
Modified Intent-
to-Treat (mITT) 
All randomized participants who received at least one dose of study drug. 
Participants will be analyzed according to their randomized treatment assignment. 
Per-Protocol (PP) 
All randomized participants who receive at least one dose of study treatment 
excluding participants with major protocol deviations with the potential to impact 
efficacy assessments. Participants will be analyzed according to the treatment 
which they received (i.e., a participant randomized to placebo who received only 
active study drug in error will be analyzed with active participants, and a 
participant randomized to active who received only placebo will be analyzed with 
the placebo participants). The PP population will exclude participants who 
received some active drug and some placebo. InterveXion will conduct a blinded 
review of the protocol deviations prior to database lock to determine if any 
participant should be excluded from the PP population. 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
A statistical analysis plan (SAP) will document the complete details of the planned statistical analyses and 
will be completed prior to unblinding of the study data. The SAP will include more detail of analysis 
populations, summary strategies, and any amendments to the proposed analyses listed here, if necessary, 
and will supersede the summary statistical descriptions below.  
 
The results of this study will be reported using summary tables, figures, and data listings. Figures, similar 
to heat maps, will be used to depict the testing result at each time point of interest. Cumulative 
distribution functions of percentage of abstinence will also be presented for relevant outcome data. 
 
Unless otherwise indicated, the pre-specified efficacy analyses will be conducted using the ITT 
population. The study will use an overall two-sided Type I error rate of 5%; results will be reported with a 
two-sided 95% confidence interval (CI) and p-value. The SAP will detail the approach to control for 
multiplicity.  
 
Safety, tolerability, and immunogenicity results will be summarized using descriptive statistics. 
Continuous variables will be summarized using appropriate summary statistics (e.g., the number of non-
missing observations (n), mean, standard deviation, median, 25th and 75th percentiles, minimum, and 
maximum; geometric mean, coefficient of variation (CV%), and 95% CIs may also be presented, as 
appropriate). Categorical variables will be summarized with the frequency count and percentage of 
participants with non-missing data.  
 
All summaries will be by treatment group. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary efficacy endpoint is percent of 20 weeks abstinent from stimulants based on saliva screens 
and by self-report via smartphone app during a 20-week period between Week 5 and Week 25, after a 
four-week grace period during which relapses may occur. A combination of self-report and saliva screens 
data and concordance will be used to score each day of the study within these time frames. The primary 
efficacy endpoint analysis will use the ITT population. 


 
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Participants self-report stimulant use on a daily basis; a saliva screen is taken twice a week at two random 
timepoints. Data that contribute to the primary endpoint will be collected from the day after a 
participant’s Week 5 visit through the next 20 weeks. The SAP will detail the visit windows. 
 
A modified combined self-report and pharmacokinetic-1 (SRPHK1) algorithm8 will be used to derive if a 
day is a “use day” or an “abstinent day”. Briefly the rules of the algorithm (as listed in Somoza et al., 
2008 with minor modifications) are: 
  
1. Always label self-reported use days as use days. 
2. Label any day covered by a positive saliva screen as a use day. However, if that day is a 
self-reported no-use day and one of the one or two previous days was self-reported as a use day, 
assign the saliva-based use to the self-reported use day. If self-report is missing for the day prior 
to the positive saliva sample, the day will be considered a use day. 
3. Label as missing any self-reported no-use days not followed by a saliva sample within 7 days. 
Also label as missing any day having a missing self-report and no saliva-based indication of use 
or no use. 
4. Treat all other self-reported no-use days (temporarily) as “unknown”.  
5. Treat “unknown” days as described below: 
a. Calculate the “concordance rate” as follows:  
(1) determine the number of instances in which a day has been assigned a saliva screen 
status of use but the participant reports no use;  
(2) divide this number by the total number of saliva samples;  
(3) subtract the resulting fraction from 1. 
b. If the concordance rate is ≥0.7 (i.e., if we can trust that the participant tells the truth in his 
or her self-report), label all remaining “unknown” days as no-use days; otherwise label all 
remaining “unknown” days as missing. 
6. Weeks with missing values for every day will be imputed as a non-abstinent week. 
 
A visit week with no use days is an abstinent week and a visit week with any use day is a non-abstinent 
week. For each participant, the percent weeks abstinent is the number of weeks (observed or imputed) 
divided by the weeks in the period of interest (i.e., 20 weeks for the primary endpoint).  
 
The primary efficacy analysis is based on a test of the difference between each IXT-m200 dose group and 
the placebo group in percent weeks abstinent, as estimated using an analysis of covariance (ANCOVA). 
The dependent variable in the model is percent weeks abstinent; the independent variables in the model 
will be treatment group assignment and stratification level of past-month METH use at screening.  
 
Adjusted means and standard errors for each treatment group and the estimated difference between the 
groups and associated 95% confidence intervals and two-sided p-values will be reported. 
 
Sensitivity analyses will be described in the SAP and may explore the impact of missing data and 
standard-based imputation with control-based MI. 
 
Details of the primary and sensitivity analyses, including imputation models, will be described in the 
SAP. 
 


 
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9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
The secondary endpoints will be tested using a two-sided alpha of 0.05; no multiplicity adjustment is 
planned, and p-values will be nominal. Secondary endpoint analyses will use the ITT population. 
 
9.4.3.1 PROPORTION OF EARLY REMISSION RESPONDERS AFTER TREATMENT 
 
The first secondary efficacy endpoint is proportion of responders after treatment (measured over the 3 
months prior to the Week 25 visit). A participant will be considered a responder if they meet the 
definition of achieving early remission, which is to report no DSM-5 criteria, while disregarding the result 
for craving, over the past 3 months.  
 
The proportion of participants achieving a response will be compared in each IXT-m200 dose group 
versus the placebo group using a risk difference. The risk difference will be computed using a binomial 
model with an identity link. The independent variables in the model will include treatment group and 
stratification level of past-month METH use at screening. For each comparison and outcome, the 95% 
confidence interval and two-sided p-value will be reported. A sensitivity analysis will be based on a 
logistic regression model testing the null hypothesis that the odds ratio is 1. 
 
If the logistic or binomial regression models fail to converge, the models will be re-run without the 
stratification level variable. If they still fail to converge, a Cochran-Mantel-Haenszel test with an exact 
method will be used to compare the proportion of participants who respond in each group. 
 
Standard errors will be reported for the proportion of responders in each treatment group and the 
estimated difference between the proportion of responders in each group. The estimated difference for the 
proportion of responders in each treatment group, associated 95% confidence intervals, and two-sided 
p-values will also be reported. 
 
9.4.3.2 COMPLETE ABSTINENCE DURING LAST MONTH OF TREATMENT 
 
The second secondary efficacy endpoint is the complete abstinence during the last month of study drug 
treatment (between Week 21 and Week 25), as measured by saliva screens and by self-report via 
smartphone app. A modified SRPHK1 algorithm 8 will be used to derive if a day is a “use day” or an 
“abstinent day” (see Section 9.4.2). A participant will be categorized as fully abstinent if the imputation 
algorithm resolves to zero days of use; otherwise, a participant will be categorized as not abstinent 
(failure). 
 
The proportion of participants achieving complete abstinence will be compared in each IXT-m200 dose 
group versus the placebo group using both an odds ratio and a risk difference. The analysis approach is 
identical to that for the first secondary endpoint as both are binary outcomes.   
 
9.4.3.3 TREATMENT EFFECTIVENESS ASSESSMENT 
 
The third secondary efficacy endpoint is the difference between groups in the change from screening in 
participant-rated quality of life as measured by the Treatment Effectiveness Assessment (TEA) at Weeks 
13, 25, and 33.  
 
The Treatment Effectiveness Assessment includes four items with 10 ordinal response options ranging 
from “not well at all” to “extremely well” (Likert scale), where higher values indicate better quality of 


 
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life 5. The Treatment Effectiveness Assessment score is the sum of the four responses (minimum = 4, 
maximum = 40); the Treatment Effectiveness Assessment score will not be computed if the participant 
did not respond to all four items.  
 
Change from screening in Treatment Effectiveness Assessment scores at each post-screening timepoint 
will be compared in each IXT-m200 group versus the placebo group using a mixed model for repeated 
measures (MMRM), which assumes unobserved values are missing at random. The dependent variable is 
change from screening in Treatment Effectiveness Assessment score. The independent variables in each 
model will include treatment group, stratification level of past-month METH use at screening, screening 
Treatment Effectiveness Assessment score; visit, and treatment group by visit interaction term. In the 
event that the model does not converge, then an ANCOVA model will be fit with the change from 
baseline at the final timepoint as the outcome, baseline outcome value, treatment group, and stratification 
factor as covariates in the model. For each comparison and timepoint, the adjusted means and standard 
errors for each treatment group and the estimated difference between the groups and associated 95% 
confidence intervals and two-sided p-values will be reported. 
 
9.4.4 SAFETY ANALYSES 
 
All safety analyses will be performed on the ITT Population. Descriptive statistics will be used to 
summarize AEs, serious AEs, AEs causing withdrawal from study, AEs judged by the investigator as 
potentially related to study drug, changes in laboratory and vital signs. AEs will be tabulated by Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and preferred term.  
 
Anti-IXT-m200 antibody results will be summarized by treatment group overall and at each timepoint. 
The number and percentage of participants with samples that screened positive or negative for anti-
IXT-m200 antibodies will be presented; for participants with positive screen results whose samples were 
confirmed positive, the number and percentage of participants with each titer category will be presented. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Demographic and baseline characteristics (age, sex, race, ethnicity, body weight, height, BMI, and days 
per month of METH use) will be summarized by treatment group using descriptive statistics for the ITT 
population. 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
The DSMB will review an interim analysis report after the last participant in Cohort 1 has available Week 
25 data (or has previously discontinued) at which time the DSMB will review efficacy in addition to the 
typical safety report content. On the basis of the Week 25 interim analysis, the DSMB may recommend 
whether to proceed to Cohort 2 and which dose to use for the IXT-m200 group (e.g., escalate to 3.0 g, 
continue at 1.5 g, or reduce). If the DSMB recommends continuing dosing at 1.5 g in Cohort 2, the 
sample size will be recalculated. The DSMB may also recommend that the study be stopped early if there 
is sufficient evidence that any of the circumstances in section 10.1.2 apply. 
 
The Sponsor will make the ultimate decision as to whether to accept the DSMB’s recommendation. The 
Sponsor may have access to group-level data but will not have access to unblinded participant-level data 
at the time of the interim analysis. The Sponsor will have ongoing access to individual participant data 
from saliva tests and daily self-reported drug use surveys. 
 


 
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Participants in Cohort 1 will continue the study through Week 33 while the interim analysis is ongoing. 
 
9.4.7 SUB-GROUP ANALYSES 
 
Selected safety and efficacy analyses may be performed in the following subgroups: 
• 
Sex: male versus female 
• 
Gender (as collected on eCRF) 
• 
BMI categorized as under/normal/overweight 
• 
Abstinent during the grace period: abstinent versus not abstinent 
• 
Baseline METH use as randomized: <18 days versus ≥18 days  
• 
Preferred route of administration of METH: smoked, snorted, intravenous, or oral 
• 
Treatment compliance: above versus below median doses of study drug received 
• 
CBT attendance compliance: above versus below median number of sessions attended 
• 
If at least 10% participants are in the mITT population but not the PP population, the PP 
population will be analyzed as a subgroup. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Participant-level listings will include collected data by treatment group and timepoint. 
 
9.4.9 EXPLORATORY ANALYSES 
 
Exploratory analyses will be performed on the ITT population. See Table 2 for planned exploratory 
endpoints and associated analyses; the SAP will describe the methods for summarizing these outcomes. 
Additional exploratory analyses may be described in the SAP.  
 
Table 2. 
Planned exploratory analyses 
Endpoint 
Analysis 
Number of sequential weeks of abstinence from 
the end of treatment visit (Week 25), defined as 
four weeks after the final planned treatment visit 
(Week 21), as measured by saliva screens and by 
self-report via smartphone app. 
“Use day” or “abstinent day” will be derived as 
described for the primary endpoint (see Section 
9.4.2). For each participant, sequential weeks 
abstinent counting backwards from the Week 25 
visit will be calculated based on use/abstinent days, 
for a minimum of 0 weeks and maximum of 24 
weeks of abstinence. 
Point prevalence abstinence (last 7 days) as 
measured by saliva screens and self-report via 
smartphone app at Week 25, Week 29, and Week 
33. 
For each visit of interest, abstinence or use will be 
based on the self-reported use in the previous 7 days 
and saliva screens. A “Use day” or “abstinent day” 
will be derived as described for the primary 
endpoint (see Section 9.4.2). A participant will be 
categorized as fully abstinent if they report no 
stimulant use on all 7 previous days and their saliva 
sample is negative (responder); a participant will be 
categorized as not abstinent if they report any 
stimulant use in the previous 7 days or their saliva 
sample is positive (failure).  


 
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Endpoint 
Analysis 
Weekly abstinence from stimulants following a 
4-week grace period (between Week 5 and Week 
25) as measured by saliva screens. 
For each week, participants will be categorized as 
abstinent or not abstinent based on twice weekly 
saliva samples.   
Difference between number of adverse outcomes 
recorded between Week 5 and Week 33.  
Adverse outcomes include those queried in the 
Adverse Outcomes Assessment and also suicide 
and overall mortality. 
The number of participants reporting each measured 
Adverse Outcome and the total will be reported. 
Proportion of responders at Week 33 as 
measured by DSM-5 criteria. A responder is a 
participant who meets the definition of early 
remission, i.e., ≥3 months and <12 months 
without meeting DSM-5 criteria while 
disregarding the result for craving. 
The number of participants reporting no DSM-5 
criteria, while disregarding the result for craving, 
over the past 3 months will be reported.  
Difference between groups in Clinical Global 
Impression of Change (CGIC) at Week 13, 25, 
and Week 33. 
The comparison between groups will be based on an 
ANCOVA model with CGIC as the outcome and 
treatment group and stratification factor as 
covariates. 
Difference between groups in Patient Global 
Impression of Change (PGIC) at Week 13, 25, 
and Week 33. 
The comparison between groups will be based on an 
ANCOVA model with PGIC as the outcome and 
treatment group and stratification factor as 
covariates. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED 
TO PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting the screening 
process, and subsequently administering study intervention. Other information may be provided to 
potential participants to help describe the nature and objectives of the study and clinical research in 
general, including access to web-based material describing the study. All such participant-facing 
information will be approved in advance by the study’s IRB. 
  
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of participation will be provided to the participants. Consent forms will be IRB-approved and the 
participant will be asked to read and review the document. The investigator or designee will explain the 
research study to the participant and answer any questions that may arise. All participants will receive a 
verbal explanation in terms suited to their comprehension of the purposes, procedures, and potential risks 


 
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of the study and of their rights as research participants. Participants will have the opportunity to carefully 
review the written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with advisors or think about it prior to agreeing to participate. The 
participant will sign the ICF prior to any procedures being done specifically for the study. The 
participants may withdraw consent at any time throughout the course of the trial. A copy of the ICF will 
be given to the participants for their records. The rights and welfare of the participants will be protected 
by emphasizing to them that the quality of their medical care will not be adversely affected if they decline 
to participate in this study. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated at the sole discretion of the Sponsor. 
Written notification, documenting the reason(s) for study suspension or termination, will be provided by 
the Sponsor to investigators, the DSMB, NIDA, and, if necessary, FDA. Investigators will notify 
participants and the IRB. Participants will be contacted, as applicable, and informed of changes to the 
study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants either related to the 
study intervention or unrelated events (such as a national health emergency); 
• 
Demonstration of efficacy that would warrant early termination; 
• 
Insufficient compliance to protocol requirements; 
• 
Data that are not sufficiently complete and/or evaluable; 
• 
Determination that the primary endpoint has been met; 
• 
Determination of futility. 
 
At the discretion of the Sponsor, if temporarily suspended, the Study may resume once any relevant 
concerns have been addressed.  
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality is held strictly in trust by the participating investigators, their staff, and the 
Sponsor and their agents. This confidentiality is extended to cover testing of biological samples in 
addition to the clinical information relating to participants. All personal details of participants will be 
treated as confidential by the investigator and staff, and handling of personal data will be in compliance 
with the Health Insurance Portability and Accountability Act of 1996 and any applicable state laws 
governing the individual study sites. The study participants’ contact information will be securely stored at 
each clinical site for internal use during the study. At the end of the study, all records will continue to be 
kept in a secure location for as long a period as dictated by the reviewing IRB, institutional policies, or 
Sponsor requirements. 
  
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized third 
party without prior written approval from the Sponsor. The Study Monitor or other authorized 
representatives of the Sponsor, IRB or regulatory agencies may inspect any documents maintained by the 
investigator, such as available medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. The clinical study site will permit access to such records. 
  


 
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Certificate of Confidentiality (COC): To further protect the privacy of study participants, a COC is 
granted by the National Institutes of Health (NIH) to all awardees conducting research that collects or 
uses identifiable, sensitive information. This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies by 
helping assure confidentiality and privacy to participants. Investigators are subject to subsection 301(d) of 
the Public Health Service Act. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored as described above. After the study is completed, 
the de-identified, archived data will be maintained as long as regulations require, and will be made 
available by the Sponsor for use by other researchers including those outside of the study via a data 
sharing agreement.  
 
Blood and urine specimens remaining after clinical safety assessments are performed will be stored only 
until the clinical study report is completed. 
  
Blood specimens remaining after PK assessments are performed will be stored for at least 12 months for 
future drug metabolism and PK analysis if needed. 
 
No genetic analysis will be performed. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Sponsor Contact 
Medical Monitor 
W. Brooks Gentry, MD 
Patrick Keenan, MD 
InterveXion Therapeutics, LLC  
Syneos Health  
4301 W. Markham St. #831 
Little Rock, AR 72205 
5707 Southwest Parkway Bldg 2, Suite 200 
Austin, TX 78735 
501 320 7601 
O: 737 484 3018, C: 512 806 4429 
gentrywilliamb@uams.edu 
patrick.keenan@syneoshealth.com 
 
10.1.6 SAFETY OVERSIGHT 
 
There will be a Data and Safety Monitoring Board (DSMB) for this trial, which will regularly review 
unblinded safety data by treatment group from the study.  
 
The DSMB will be composed of individuals with the appropriate expertise, likely including monoclonal 
antibody and methamphetamine clinical pharmacology, psychiatry or behavioral medicine, statistics, and 
a patient advocate or representative. Members of the DSMB should be independent from the study 
conduct and free of conflict of interest, or measures should be in place to minimize perceived conflict of 
interest. The DSMB will meet approximately quarterly to review unblinded data and assess safety data on 
each arm of the study. The DMSB will operate under the rules of an approved charter that will be written 
and reviewed at the organizational meeting of the DSMB. The DSMB will provide its input to the study 


 
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Sponsor and the Sponsor, by the actions of its Medical Expert, will determine whether cohort enrollment 
should continue or if changes should be made.  
 
The DSMB will participate in the Interim Analysis as described in section 9.4.6. 
 
10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of study participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable 
regulatory requirement(s). 
  
Data at clinical sites will be monitored by one or more Study Monitors. Throughout the course of the 
study, the Study Monitor will make frequent contact with the investigator. This will include telephone 
calls and on-site visits. During the on-site visits or through electronic means of viewing both types of 
study records, the Study Monitor will perform source data verification (a comparison of the data in the 
electronic data capture systems with the participant’s medical records including verification of informed 
consent). This will require direct access to all original records for each participant (e.g., clinic charts). 
 
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). The CMP 
describes in detail who will conduct the monitoring, at what frequency monitoring will be done, at what 
level of detail monitoring will be performed, and the distribution of monitoring reports. The Study 
Monitor will also perform drug accountability checks and will request to perform a review of the 
investigator’s study file to assure completeness of documentation in all respects of clinical study conduct. 
  
Upon completion of the study, the Study Monitor will arrange for a final review of the study files, after 
which the files should be secured for the appropriate time period. The investigator, or appointed delegate, 
will meet with the Study Monitor during the on-site visits and will cooperate in providing the documents 
for inspection and responding to inquiries. In addition, the investigator will permit inspection of the study 
files by authorized representatives of the Sponsor or regulatory agencies. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion.  Quality control (QC) procedures will be 
implemented beginning with the data entry system and data QC checks that will be run on the database 
will be generated. Any missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the Study Monitor will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented (recorded), 
and reported in compliance with the protocol, GCP, and other applicable regulatory requirements.  
 
The investigational site will provide direct access to all source data/documents and reports for the purpose 
of monitoring and auditing by the Sponsor, and inspection by local and regulatory authorities. 
 


 
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10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at each site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, legible manner to 
ensure accurate interpretation of data.   
 
Data recorded in the eCRF(s) derived from source documents should be consistent with the data recorded 
on the source documents. Hardcopies of any source document(s) used for recording data for each 
participant enrolled in the study will be filed at the investigative site to be reviewed by the Study Monitor 
for accuracy.  
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into a 21 CFR Part 11-compliant data capture system. The data system 
includes password protection and internal quality checks, such as automatic range checks, to identify data 
that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source 
documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region, or until at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. These documents should be retained for a longer period, however, if 
required by local regulations. No records will be destroyed without the written consent of the Sponsor, if 
applicable. It is the responsibility of the Sponsor to inform the investigator when these documents no 
longer need to be retained.  
 
The following records must be retained by the investigator:  
• 
Signed ICFs for all participants 
• 
Screening log (if applicable), and enrollment log 
• 
Record of official communications between the site and the IRB 
• 
Composition of the IRB or other applicable statement  
• 
Record of all significant communications between the site and Sponsor  
• 
List of sub-investigators and other appropriately qualified persons to whom the investigator has 
delegated significant trial-related duties, together with their roles in the study and their signatures 
• 
Copies of CRFs and of documentation of corrections for all participants 
• 
Drug accountability records 
• 
Record of any body fluids or tissue samples retained 
• 
All other source documents (medical records, hospital record copies, laboratory records, etc) 
• 
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP (Essential 
Documents for the Conduct of a Clinical Trial) 
 
If the investigator is unable to continue to store the study records, s/he must contact the Sponsor to make 
alternative arrangements. Details of these arrangements should be documented. 
 


 
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10.1.10 
PROTOCOL DEVIATIONS  
  
A protocol deviation is any change, divergence, or departure from the study design or procedures defined 
in the protocol; or any noncompliance with the clinical trial protocol, GCP, or study manual requirements. 
The noncompliance may be either on the part of the participant, an investigator, or study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly. All 
deviations will be compiled in a centralized location. 
  
These practices are consistent with ICH E6: 
• 
4.5 Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
• 
5.1 Quality Assurance and Quality Control, Section 5.1.1 
• 
5.20 Noncompliance, Sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the sites to use continuous vigilance to identify and report deviations in a timely 
manner. The investigator will document and explain any deviation from the approved protocol in the 
study source documents and notify the Sponsor. Protocol deviations may need to be sent to the reviewing 
IRB, depending on the nature of the deviation and the IRB guidelines. The investigators and study staff 
are responsible for knowing and adhering to the IRB requirements. 
 
Deviations will be classified by whether or not they meet the definition of important protocol deviations. 
Important protocol deviations are a subset of deviations that might significantly affect the completeness, 
accuracy, and/or reliability of the study data or that might significantly affect a participant's rights, safety, 
or well-being. Deviations will be categorized by type and will be reviewed on an ongoing basis. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
This study will comply with the National Institutes of Health (NIH) Public Access Policy, which ensures 
that the public has access to the published results of NIH-funded research. It requires scientists to submit 
final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
  
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at www.clinicaltrials.gov, and results information 
from this trial will be submitted to www.clinicaltrials.gov. In addition, every attempt will be made to 
publish results in peer-reviewed journals.   
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
Any conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any 
aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of 
interest will be required to have such conflicts managed in a way that is appropriate to their participation 
in the trial. The Sponsor has established policies and procedures to disclose all conflicts of interest and 
will establish a mechanism for the management of all reported dualities of interest. 
 
 


 
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10.2 ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CGIC 
Clinical Global Impression of Change 
CBT 
Cognitive Behavioral Therapy 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
Maximum Concentration 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatine Phosphokinase 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
Coefficient of Variation 
DEQ 
Drug Effects Questionnaire 
DHHS 
Department of Health and Human Services 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ET 
Early termination visit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HACA 
Human Anti-Chimeric Antibodies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICF 
Informed Consent Form 
IgG 
Immunoglobulin G 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
METH 
Methamphetamine 
MDA 
Methylenedioxyamphetamine 
MDMA 
MethylenedioxyMETH 
MI 
Multiple Imputation 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed Model for Repeated Measures 


 
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MUD 
Methamphetamine Use Disorder 
NIH  
National Institutes of Health 
NIDA 
National Institute on Drug Abuse 
OHRP 
Office for Human Research Protections 
OUTLAST 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Multiple-Dose Study to 
Evaluate the Safety and Efficacy of IXT-m200 in Treatment-Seeking Individuals with 
Methamphetamine Use Disorder 
PGIC 
Patient Global Impression of Change 
PK 
Pharmacokinetics 
PO 
Program Officer 
PP 
Per-Protocol 
QC 
Quality Control 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAETRS 
Serious Adverse Event Tracking and Reporting System 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SRPHK1 
Self-Report and Pharmacokinetic-1 Algorithm 
STAMPOUT 
Study of Antibody for Methamphetamine Outpatient Therapy 
TEA 
Treatment Effectiveness Assessment 
US 
United States 
Vd 
Volume of Distribution 
WBC 
White Blood Cell 
 
 
 


 
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10.3 PROTOCOL AMENDMENT HISTORY 
 
Version - Date 
Description of Important Changes  
Brief Rationale 
1 – 03 Sept 2021 
New document 
New protocol  
2 – 29 Nov 2021 
1.1 Updated hypotheses, objectives, and 
list of endpoints  
To improve the trial and align with 
FDA feedback 
1.3 Increased the window size for dosing 
visits, added footnote ‘f’ to specify 
Quality of Life Assessments, added 
Methamphetamine Use Assessments, 
added windows for PK subset samples  
To improve dosing compliance, to 
add clarity and specify visit dates for 
new assessments of 
methamphetamine use 
3 Updated list of objectives and endpoints  
To improve the trial and align with 
FDA feedback 
4.1 Updated hypotheses 
To improve the trial hypotheses 
5.1 Added inclusion criteria 9 
To include a criteria describing the 
minimum criteria for acceptably 
using the study app and successfully 
completing training on both the app 
and saliva test kits 
5.2 Updated exclusion criteria 9 to specify 
a saliva drug screen and what drugs are 
not disqualifying at the screening visit 
To clarify the requirement 
5.2 Updated exclusion criteria 11 to 
include additional liver function tests 
To specify which liver function tests 
are included in the expanded limits 
for eligibility 
5.2 Updated exclusion criteria 12 to note 
past-year history of a serious suicide 
attempt 
To match the time frame of C-SSRS 
(past year version) assessment 
planned 
7.1 Inserted statements clarifying that 
missed doses do not disqualify a 
participant from resuming dosing. 
To clarify that missed doses do not 
preclude further dosing. 
8.1 Inserted clarifying introductory 
comments, updated the saliva drug screen 
panel, and added new sub-section with 
methamphetamine use assessments  
To add clarity and describe added 
assessments of methamphetamine 
use 
8.2 Updated medication history to past 
year, clarified when psychiatric evaluation 
by C-SSRS would lead to a referral, 
removed requirement for quantitative 
urinalysis 
To refine the study requirements and 
better match the eligibility criteria 
8.3.2 Updated description of an SAE that 
is an important medical event 
To add clarity 
8.3.4 Updated the time frame for 
recording reportable AEs 
Limited recording of events to a 
reasonable time frame after last 
doses of IP are given. If a participant 
completes the study, that will be 3 
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Version - Date 
Description of Important Changes  
Brief Rationale 
8.3.5 Reduced the length of time an AE 
would be followed following the end of 
study visit 
Limited following AEs to a 
reasonable time frame after last 
doses of IP are given. 
8.3.6 Reduced the time frame of reporting 
non-expedited SAEs by investigators to 
the medical monitor and Sponsor to 48 
hours 
To allow Sponsor sufficient time to 
report to NIDA by 72 hours 
9.1 Updated hypotheses to match updated 
endpoints 
Required to match updated 
endpoints 
9.4.1 Added description of specific figures 
and cumulative distribution functions to 
be included in the report. 
To provide a data presentation 
requested by FDA 
9.4.2 Added clarifying words and 
sentences 
To clarify that only intermittent 
missing data will be imputed using 
multiple imputation, and to clarify 
that when all data are missing from a 
week the result will be imputed as 
non-abstinent. 
9.4.3 Added section to describe analysis of 
new key endpoint 
To add new required section 
9.4.4 Updated throughout to match the 
updated secondary endpoints 
Required to match updated 
endpoints 
9.4.5 Separated immunogenicity analysis 
and added detail 
To match the separation of 
immunogenicity as its own endpoint 
9.4.7 Updated potential recommendations 
by DSMB to include stopping the study 
early if any circumstances from section 
10.1.2 apply. 
To add clarity 
9.4.8 Added sub-groups for BMI and CBT 
attendance 
To add detail 
9.4.10 – Noted that additional analyses 
will be described in the SAP and include 
added endpoints 
To add clarity  
3 – 20 July 2022 
1.1 Updated study objectives, endpoints, 
and study population description 
To improve the trial and better align 
with FDA feedback 
1.3.1 Added a title to note that the 
schedule applied to all main study 
participants; clarified psychiatric exam 
includes C-SSRS; added line for drug use 
assessment by DSM-5 at Screening; 
inserted Adverse Outcomes Assessment; 
separated Quality of Life assessments; 
separated cytokine sampling by creating a 
new line; provided specific dates for 
assessments in footnotes where multiple 
assessments were on the same line of the 
table; removed reference to the PK subset   
For clarity and to add the new 
Adverse Outcomes Assessment 


 
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Version - Date 
Description of Important Changes  
Brief Rationale 
1.3.2 Added new schedule of activities 
table for PK subset participants 
For clarity 
3 Deleted previous key secondary 
endpoint and reordered secondary and 
exploratory endpoints; added new 
exploratory endpoint analyzing adverse 
outcomes associated with MUD 
To better align with FDA feedback 
4.1 Added paragraph describing the PK 
subset  
To describe the number of 
participants to be included in the PK 
subset and its purpose, and include 
this description in the overall study 
description 
5.3 Added statement that medication-
assisted treatment (MAT) for opioid use 
disorder is not allowed 
To clarify that participants would not 
be eligible if using MAT  
5.4 Added need for Sponsor permission to 
rescreen a potential participant 
To allow the Sponsor to review a 
request for rescreening 
6.1.1 Corrected some details about the 
smartphone app including that it does not 
send participant reminders and that 
recovery coaching will continue 
throughout the trial without tapering and 
stopping 
To correct these details that were 
missed in a previous amendment 
6.1.2 Added causality grades that would 
result in dose discontinuation in a specific 
participant 
To clarify that only SAEs that are 
likely caused by the study drug will 
result in dose discontinuation 
7.1 Added causality grades for AEs that 
would count toward the criteria for 
suspension of enrollment 
To provide clarity that AEs that are 
graded as unrelated or unlikely 
would not count toward the criteria 
for suspending enrollment 
8.1.4 Added questions to be asked at 
Screening related to a participant’s 
methamphetamine use history 
To collect these data for background 
and stratification purposes 
8.1.5 Added the Adverse Outcomes 
Assessment to be administered 
Added questionnaire to allow for 
comparison of the number of adverse 
outcomes in treated and placebo 
groups 
8.2.2 Added phrasing to instruct that new 
events after randomization should be 
recorded as AEs; corrected ‘past-year’ to 
‘past-30-days’ for collection of medical 
history 
To correct the protocol to intended 
language 
8.2.5 Added a question to be asked when 
updating psychiatric history 
To monitor for suicidal ideation and 
attempts in this population 
8.2.6 Added instructions to review 
pregnancy test results prior to dosing and 
that tests are not required after report of 
hysterectomy 
To ensure that pregnant participants 
do not receive further doses of study 
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Version - Date 
Description of Important Changes  
Brief Rationale 
8.2.7 Updated urinalysis description to 
state that macroscopic analysis would be 
done first, followed by microscopic 
analysis only if indicated 
To align with planned analysis 
8.3.4 Added statements indicating that 
AEs prior to randomization should be 
recorded as medical history and any after 
randomization should be recorded as AE 
or SAE as appropriate 
To clarify reporting guidelines since 
the screening period may be several 
weeks 
9.1 Removed descriptions of previous key 
secondary endpoint analysis (related to a 
reduction in DSM-5 criteria), and 
descriptions of analyses of CGIC and 
PGIC endpoints 
To match updated endpoints 
9.4.3 Previous section describing the 
analysis of the prior key secondary 
endpoint was removed and subsequent 
sections renumbered 
To match updated endpoints 
9.4.3.3 (previously numbered 9.4.4.3) 
Removed reference to analysis of CGIC 
and PGIC endpoints 
To match updated endpoints 
9.4.9 Updated Table 2 to match new order 
of endpoints and to include the new 
endpoint related to adverse outcomes  
To match updated endpoints 
4 – 07 Oct 2022 
1.2 Updated schema to include recovery 
coach sessions during screening and to 
shorten the screening period to 15 days 
prior to Day 1 
To match changes throughout the 
protocol 
1.3 Changed the Screening window to 
Study Days -15 to -1; added footnote p; 
clarified only 4 saliva drug screens 
assigned during Screening window; and 
added recovery coaching to the Screening 
window  
To facilitate site operations and 
patient adherence to the early testing 
regimen  
5.1 Changed Inclusion criteria #9 to 
require only 2 valid saliva tests within 2 
weeks for eligibility. 
To increase site and patient 
flexibility in assessing eligibility 
5.2 Appended the parenthetical phrase to 
exclusion criteria #9 
To allow those participants on stable 
benzodiazepine therapy to qualify 
5.2 Appended the statement concerning 
COVID-19 clinical studies 
To allow those patients who are 
participating in the long-term 
follow-up portion of a COVID-19 
study to enroll 
5.4 Removed the term ‘medical’ in the 
second paragraph describing temporary 
issues 
To allow the Sponsor to consider 
giving permission to rescreen a 
participant that did not meet criteria 
other than because of medical issues. 


 
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Version - Date 
Description of Important Changes  
Brief Rationale 
5 – 03 Feb 2023 
1.3.1 and 1.3.2 added footnote q and last 
sentence to footnote f 
To clarify that participants must 
bring a smartphone to the Screening 
visit, or else it should be 
rescheduled, as described in protocol 
clarification letter dated 03 Jan 2023. 
To clarify that certain assessments 
are to be done prior to CBT at Week 
13. 
 
1.3.3 Added new section 
To describe the assessments to be 
done for participants that are dosed 
at least once and then discontinue 
dosing. 
 
5.2 Update exclusion criteria 1  
To clarify that Substance Use 
Disorders are determined over the 
past year as described in the protocol  
clarification letter dated 22 Nov 
2022. 
  
 


 
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Treatment of (+)-Methamphetamine-Induced Locomotor Effects in Rats Using One or a 
Combination of Two High Affinity Anti-Methamphetamine Monoclonal Antibodies. Human 
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3. Kiluk BD, Nich C, Babuscio T, Carroll KM. Quality versus quantity: acquisition of coping 
skills following computerized cognitive–behavioral therapy for substance use disorders. 
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4. Kiluk BD, Nich C, Buck MB, Devore KA, Frankforter TL, LaPaglia DM, Muvvala SB, 
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Treatment and Follow-Up Outcomes. Am J Psychiatry 2018; 175:853–63. 
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7. Cook R, Quinn B, Heinzerling K, Shoptaw S. Dropout in clinical trials of pharmacologic 
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8. Somoza E, Somoza P, Lewis D, Li S-H, Winhusen T, Chiang N, Vocci F, Horn P, Elkashef A. 
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SAP_001.pdf: 
Statistical Analysis Plan Title Page 
Compound Name: 
IXT-m200 
Protocol Title: 
OUTLAST: A Phase 2 Double-Blind, Randomized, Placebo-
Controlled, Multiple-Dose Study to Evaluate the Safety and 
Efficacy of IXT-m200 in Treatment-Seeking Individuals with 
Methamphetamine Use Disorder 
Protocol and Version: 
M200C-2201 V5 
Short Title: 
OUTLAST 
Sponsor Legal Registered Address:  
InterveXion Therapeutics, LLC 
4301 W Markham St #831 
Little Rock, AR 72205 
Regulatory Agency Identifier Number(s) 
Registry 
ID 
ClinicalTrials.gov 
NCT05034874 
Statistical Analysis Plan Version: V5 01MAY2024 
Prepared by:  
 
 
55 Corporate Woods 
9300 West 110th Street, Suite 550 
Overland Park, Kansas 66210 
 
Confidential Information  
 
This document contains confidential information of InterveXion Therapeutics. The information contained within it 
may not be reproduced or otherwise disseminated without the approval of InterveXion Therapeutics.  
 


InterveXion Therapeutics, LLC 
M200C-2201 
IXT-m200 
Statistical Analysis Plan 
 
Version 5 
Confidential 
Page i 
Table of Contents 
Contents 
Statistical Analysis Plan Title Page .............................................................................................. i 
Table of Contents ........................................................................................................................... i 
List of Tables ................................................................................................................................ iii 
Version history ............................................................................................................................. iv 
Abbreviations/Definitions .............................................................................................................v 
SAP Approval Signature Page ................................................................................................... vii 
1. 
Introduction .....................................................................................................................1 
1.1. 
Objectives, Endpoints, and Estimands ...........................................................................1 
1.2. 
Study Design ..................................................................................................................4 
2. 
Statistical Hypotheses and Testing .................................................................................6 
2.1. 
Statistical Hypotheses ....................................................................................................6 
2.2. 
Sample Size Determination............................................................................................6 
2.3. 
Multiplicity Adjustment .................................................................................................7 
2.4. 
Interim Analyses ............................................................................................................7 
2.4.1. 
Data Safety Monitoring Board ....................................................................................8 
3. 
Analysis Sets .....................................................................................................................9 
4. 
Statistical Analyses ........................................................................................................11 
4.1. 
General Considerations ................................................................................................11 
4.1.1. 
Common Statistical Methods and Data Presentations ...............................................11 
4.1.2. 
Other Missing Data, and Data Errors ........................................................................11 
4.1.3. 
Clinical Laboratory LLOQ Values ............................................................................12 
4.1.4. 
Coding of Concomitant Medications and Adverse Events ........................................12 
4.1.5. 
Definition of Study Time Points ................................................................................12 
4.2. 
Participant Accounting.................................................................................................13 
4.3. 
Participant Disposition .................................................................................................13 
4.4. 
Baseline Characteristics and Participant History .........................................................13 
4.5. 
Study Intervention and Concomitant Medications ......................................................13 
4.5.1. 
Extent of Exposure ....................................................................................................13 
4.5.2. 
Treatment Compliance ..............................................................................................13 
4.5.3. 
Concomitant Medications ..........................................................................................13 
4.6. 
Primary Estimand Analysis..........................................................................................14 
4.6.1. 
Main analytical approach ..........................................................................................14 
4.6.2. 
Sensitivity analyses ...................................................................................................16 
4.7. 
Secondary Estimand Analyses .....................................................................................16 
4.8. 
Exploratory Analyses ...................................................................................................18 
4.9. 
Pharmacokinetics Endpoints ........................................................................................25 
4.9.1. 
PK Sampling Schedule ..............................................................................................25 
4.9.2. 
Handling of the Difference between the Scheduled and the Actual Sampling Times
 ...................................................................................................................................25 
4.9.3. 
PK Endpoint ..............................................................................................................26 
4.9.4. 
Presentation of Concentration Data ...........................................................................28 


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4.9.5. 
PK Parameters Derivation .........................................................................................28 
4.10. 
Safety Analyses ............................................................................................................30 
4.10.1. 
Adverse Events ..........................................................................................................30 
4.10.2. 
Clinical Laboratory Analyses ....................................................................................30 
4.10.3. 
Electrocardiograms ....................................................................................................30 
4.10.4. 
Vital Signs .................................................................................................................30 
4.10.5. 
Physical Examination ................................................................................................31 
4.10.6. 
Psychiatric evaluation ................................................................................................31 
4.11. 
Immunogenicity ...........................................................................................................31 
4.12. 
Subgroup analyses .......................................................................................................31 
4.13. 
Changes to Protocol-Planned Analyses .......................................................................31 
5. 
Supporting Documentation ...........................................................................................32 
5.1. 
Appendix 1: Schedule of Events ..................................................................................33 
6. 
References ......................................................................................................................34 
 
 


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List of Tables 
Table 1 
SAP Version History Summary ................................................................................... iv 
Table 2 
Primary and Secondary Efficacy Objectives, Endpoints and Estimands ...................... 2 
Table 3 
Exploratory Efficacy Objectives and Endpoints .......... Error! Bookmark not defined. 
Table 4 
Minimum detectable difference between each IXT-m200 group versus the placebo 
group ........................................................................................................................... 10 
Table 5 
Analysis Populations ..................................................................................................... 9 
 


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Version history 
Table 1 documents the changes to the SAP through all versions. Details regarding protocol 
changes that resulted in changes to the SAP can be found in the respective protocol amendment.  
Table 1 
SAP Version History Summary 
SAP Version 
Approval Date 
Rationale 
Changes to SAP 
1 
24MAY2021 
Original version 
Not Applicable 
2 
01DEC2021 
 
Changes to endpoints 
Addition of pseudo-SAS code for spaghetti plot 
3 
21MAR2023 
The focus of the trial 
has shifted from a 
potentially pivotal trial 
to a purely Phase II, 
information gathering 
trial. 
Change layout of SAP 
Incorporate suggestions from internal and FDA 
discussions, regarding objectives/endpoints and 
analyses. 
Addition of pseudo-R code for plots 
4 
01JUN2023 
Fixing errors in 
endpoints 
Fixed error in exploratory endpoint 
Updated table of contents 
5 
14JUL2023 
 
01MAY2024 
 
Changes to protocol  
 
Adding 
pharmacokinetic 
parameters to the 
analyses 
 
Updated order of endpoints 
Updated study design 
Added pharmacokinetic endpoints 
Fixed discrepancy in endpoint regarding 
imputation of missing data 
 
 


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Abbreviations/Definitions 
 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
app 
application 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CBT 
cognitive behavioral therapy 
CDFs 
cumulative distribution functions 
CI 
confidence interval 
C-SSRS  
Columbia Suicide Severity Rating Scale 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCFR 
electronic case report form 
HIPPA 
Health Insurance Portability and Accountability Act of 1996 
ICH 
International Council for Harmonisation 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IV 
intravenous 
LLOQ 
lower limit of detection 
MedDRA 
Medical Dictionary for Regulatory Activities 
METH 
methamphetamine 
MI 
multiple imputation 
mITT 
modified intent-to-treat 
MMRM 
mixed model repeated measures 
MUD 
methamphetamine use disorder 
PI 
principal investigator 
PK 
pharmacokinetic 


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Abbreviation 
Definition 
PP 
per-protocol 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SPRHK1 
SelfReportPHarmacoKinetic1 


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SAP Approval Signature Page 
PROTOCOL TITLE 
OUTLAST: A Phase 2 Double-Blind, Randomized, Placebo-
Controlled, Multiple-Dose Study to Evaluate the Safety and Efficacy 
of IXT-m200 in Treatment-Seeking Individuals with 
Methamphetamine Use Disorder 
SAP Version, Date 
V5, 01May2024 
SAP AUTHOR 
 
 
 
Michael C. Mosier, PhD 
Director, Biostatistics 
EMB Statistical Solutions, LLC 
Date 
Investigational 
Product 
IXT-m200 
Protocol Number 
M200C-2201 
Protocol Version,  
Date 
5 
03Feb2023 
Signature Statement 
By my signature, I indicate I have reviewed this SAP and find its 
contents to be acceptable. 
Reviewers on behalf of InterveXion Therapeutics, LLC 
 
 
Approver 
Signature 
 
Date  
 
 
 
Misty Stevens, MBA, PhD 
Chief Operating Officer 
Sponsor 
 
 
 


InterveXion Therapeutics, LLC 
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Statistical Analysis Plan 
 
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1. 
Introduction 
The purpose of this SAP is to describe the analysis variables and statistical procedures that will 
be used to analyze and report the results of InterveXion’s protocol M200C-2201.  This study is a 
Phase 2A study evaluating the safety, efficacy, immunogenicity, and pharmacokinetics (PK) of 
IXT-m200, a chimeric anti-methamphetamine monoclonal antibody treatment, in treatment-
seeking individuals with methamphetamine (METH) use disorder (MUD).  This statistical 
analysis plan (SAP) is based on InterveXion’s protocol M200C-2201 version 5, dated 
February 3, 2023. 
The SAP was written in accordance with the recommendations outlined in the International 
Conference on Harmonization (ICH) E9 Guideline entitled “Guidance for Industry: Statistical 
Principles for Clinical Trials” and the ICH-E3 Guideline entitled “Guidance for Industry: 
Structure and Content of Clinical Study Reports”. 
Some of the analyses detailed here may be more explicit or in some respects different from those 
stated in the protocol. In case of differences, this SAP supersedes the statistical sections in the 
protocol. 
Most statistical analyses will be performed using SAS® version 9.4 or later, with SAS program 
code prepared specifically for the project by qualified statisticians and SAS programmers. Other 
validated programs (e.g., S-Plus, R) may be used for graphs or for specialized analyses. 
Changes to the protocol that impact the design, the data collected, or the statistical methods and 
that occur after the finalization of this SAP may require amendment of the approved SAP. 
Similarly, changes to the planned analysis variables and/or statistical methods described in the 
approved SAP may also require amendment of the SAP, so long as the changes were 
implemented prior to database lock. Changes in planned analyses that are decided after database 
lock will be documented in the clinical study report (CSR). 
The formats for the tables, listings, and figures described in this SAP are provided in a 
companion document. Changes to the formats of these reports that are decided after the 
finalization of the SAP will not require an amendment. In addition, any additional supportive or 
exploratory analyses requested after SAP approval will not require amendment of the SAP and 
will instead be described in the CSR.  
Please see the study protocol for details about the study design, procedures, and schedule of 
assessments and see the electronic case report form (eCRF) for details about variables collected 
and their possible values. 
1.1. 
Objectives, Endpoints, and Estimands 
The following Table 2 lists the primary and secondary efficacy objectives of the study, along 
with the endpoints that will be measured, the clinical question to be addressed, as well as the 
estimand.  An estimand is defined in the ICH E9(R1) guidance as “...the target of estimation to 
address the scientific question of interest posed by the trial objective.” 


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Table 2 
Primary and Secondary Efficacy Objectives, Endpoints and Estimands 
Primary 
Objective: 
To evaluate the efficacy of 
IXT-m200 in preventing or 
reducing relapse to 
stimulant use. 
Endpoints:  Percent of 20 weeks abstinent from stimulants following a 
4-week grace period (between Week 5 and Week 25) as measured by 
saliva screens. 
Clinical Question:  Does adding IXT-m200 to standardized cognitive 
behavioral therapy (CBT) program improve the percent of 20 weeks 
abstinent from stimulants following a 4-week grace period, relative to 
the CBT program alone, in treatment-seeking participants, regardless of 
IXT-m200 interruption or discontinuation, for any reason? 
Estimand:  The difference in group means between the IXT-m200 and 
placebo groups for the percent of 20 weeks abstinent from stimulants 
following a 4-week grace period as measured by saliva screens in 
treatment-seeking individuals with MUD. All observations will be used, 
regardless of whether a participant discontinued treatment early. All 
missing values will be imputed assuming the participant is not abstinent. 
Secondary 
Objective: 
To evaluate the efficacy of 
IXT-m200 in improving 
participant-rated quality of 
life. 
Endpoints:  Change from screening in participant-rated quality of life as 
measured by the Treatment Effectiveness Assessment (TEA) at Week 
13, 25, and Week 33. 
Clinical Question:  Does adding IXT-m200 to standardized CBT 
program improve the change from screening in participant-rated quality 
of life relative to the CBT program alone in treatment-seeking 
participants regardless of IXT-m200 interruption or discontinuation, for 
any reason? 
Estimand:  The difference in group medians for the change from 
screening in participant-rated quality of life at Week 13, 25, and 33 
between the IXT-m200 and placebo groups. All observations will be 
used, regardless of whether a participant discontinued treatment early. 
Missing values will not be imputed. 
Objective: 
To evaluate the efficacy of 
IXT-m200 in increasing the 
number of participants 
achieving early remission. 
Endpoints:  Responders at Week 25 as measured by the DSM-5 criteria. 
A responder is a participant who meets the definition of early remission, 
i.e., ≥3 months and <12 months without meeting DSM-5 criteria, while 
disregarding the result for craving. 
Clinical Question:  Does adding IXT-m200 to standardized CBT 
program improve the proportion of participants achieving early 
remission, relative to the CBT program alone in treatment-seeking 
participants regardless of IXT-m200 interruption or discontinuation, for 
any reason? 
Estimand:  The difference in the proportion of responders between the 
IXT-m200 and placebo groups, where a responder is a participant who 
meets the definition of early remission, i.e., ≥3 months and <12 months 
without meeting DSM-5 criteria, other than craving. All observations 
will be used, regardless of whether a participant discontinued treatment 
early. All missing values will be imputed assuming the participant has 
not achieved early remission.  
Objective: 
To evaluate the efficacy of 
IXT-m200 in improving 
Endpoints:  Difference between groups in Clinical Global Impression of 
Change (CGIC) at Week 13, 25, and Week 33. 
 


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clinician-rated response to 
treatment. 
Clinical Question:  Does adding IXT-m200 to standardized CBT 
program improve CGIC at Week 13, 25, and Week 33, relative to the 
CBT program alone in treatment-seeking participants regardless of IXT-
m200 interruption or discontinuation, for any reason? 
Estimand:  The difference in CGIC at Week 13, 25, and Week 33, 
between the IXT-m200 and placebo groups in treatment-seeking 
individuals with MUD. All observations will be used, regardless of 
whether a participant discontinued treatment early. Missing values will 
not be imputed. 
Objective: 
To evaluate the efficacy of 
IXT-m200 in improving 
patient-rated response to 
treatment. 
Endpoints:  Difference between groups in Patient Global Impression of 
Change (PGIC) at Week 13, 25, and Week 33. 
Clinical Question:  Does adding IXT-m200 to standardized CBT 
program improve PGIC at Week 13, 25, and Week 33, relative to the 
CBT program alone in treatment-seeking participants regardless of IXT-
m200 interruption or discontinuation, for any reason? 
Estimand:  The difference in CGIC at Week 13, 25, and Week 33, 
between the IXT-m200 and placebo groups in treatment-seeking 
individuals with MUD. All observations will be used, regardless of 
whether a participant discontinued treatment early. Missing values will 
not be imputed. 
 
Table 3 
Exploratory Efficacy Objectives and Endpoints 
Exploratory Objectives 
Endpoints 
To evaluate the efficacy of IXT-
m200 in increasing the number 
of participants achieving early 
remission. 
Responders at Week 33 as measured by DSM-5 criteria. A 
responder is a participant who meets the definition of early 
remission, i.e., ≥3 months and <12 months without meeting DSM-5 
criteria while disregarding the result for craving. 
To evaluate the efficacy of IXT-
m200 in reducing the number of 
adverse outcomes from the 
Adverse Outcomes Assessment. 
The difference between groups in the number of adverse outcomes 
reported at Week 13, 25, and Week 33. 
To evaluate the efficacy of IXT-
m200 in preventing or reducing 
relapse to stimulant use, as 
measured by self-report 
surveys. 
Percent of days abstinent from stimulants following a 4-week grace 
period (between Week 5 and Week 25) as measured by self-report. 
To evaluate the efficacy of IXT-
m200 in improving the length of 
sustained abstinence. 
Number of sequential weeks of abstinence from the end of 
treatment visit (Week 25), defined as four weeks after the final 
planned dose of study drug (at Week 21), as measured by saliva 
screens. 
To evaluate the efficacy of IXT-
m200 in improving post-
treatment abstinence. 
Point prevalence abstinence (last 7 days) as measured by saliva 
screens at Week 25, Week 29, and Week 33. 
To evaluate the efficacy of 
Complete abstinence during the last month of study drug treatment 
(between Week 21 and Week 25), as measured by saliva screens. 


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IXT-m200 in improving the 
proportion of participants 
achieving stimulant abstinence. 
To evaluate the efficacy of IXT-
m200 in reducing the frequency 
of METH use over time, as 
measured by self-report. 
Difference between groups in the trend over time in the number of 
use days per week, as measured by self-report for Weeks 5 through 
25.   
To evaluate the efficacy of IXT-
m200 in preventing or reducing 
relapse to stimulant use, as 
measured by self-report. 
Proportion of participants with n or fewer use days between Week 
5 and Week 25 measured by self-report. 
To evaluate the efficacy of IXT-
m200 in preventing or reducing 
relapse to stimulant use, as 
measured by saliva screens. 
Proportion of participants with n or fewer use days between Week 
5 and Week 25 measured by saliva screens. 
1.2. 
Study Design 
InterveXion’s protocol M200C-2201 is a Phase 2, double-blind, placebo-controlled, multiple-
dose study of the safety and efficacy of monthly intravenous (IV) doses of IXT-m200 in 
treatment-seeking individuals with METH use disorder. The study was stopped before enrolling 
Cohort 2. As such, any reference to Cohort 2 in this document no longer applies, but has been 
retained for reference.  
The study consists of two cohorts: 
• In Cohort 1, approximately 60 participants will be randomized in a 2:1 ratio to IXT-m200 
1.5 g or placebo (saline). 
• In Cohort 2, approximately 60 participants will be randomized in a 2:1 ratio to the 
recommended dose of IXT-m200 or placebo based on the interim analysis at the end of 
Cohort 1. If the interim analysis recommends maintaining a dose of 1.5 g, then the 
sample size will be recalculated. 
In each cohort, participants will receive either study drug (IXT-m200 at the cohort-specific dose 
or placebo) at the beginning of Weeks 1, 5, 9, 13, 17, and 21. All participants will also 
participate in seven sessions of a standardized cognitive behavioral therapy (CBT) program 
which will be delivered by a trained therapist; the first dose of IXT-m200 or placebo is intended 
to be given on the same day of initiation of CBT. For Cohort 1, the participants will participate in 
the CBT sessions during their monthly visits. For Cohort 2, participants will go to the clinic 
weekly for saliva drug tests and will participate in CBT sessions every two weeks, starting with 
Week 1. Participants will be followed at monthly intervals through Week 33. Cohort 1 will use 
app-based assessments to monitor between visits and Cohort 2 will use TLFB to monitor 
between visits. Schema 1.2 in the protocol displays the schematic of the study design for Cohort 
1, and Appendix 1 shows the schedule of events. The first four weeks of treatment will be 
considered a grace period, designed to accommodate the likelihood that participants will relapse 
initially and experience the effects of IXT-m200. It further allows participants time to absorb and 
incorporate some of the skills taught by cognitive behavior therapy. METH use endpoints will be 
analyzed in the weeks following the grace period. 


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The cohorts will enroll sequentially, beginning with Cohort 1. Once the last participant in Cohort 
1 has available Week 25 data (or has previously discontinued), the Data and Safety Monitoring 
Board (DSMB) will review an interim analysis report that includes efficacy and safety data. 
Based on that interim analysis, the DSMB may recommend whether to proceed to Cohort 2 and 
which dose to use for the IXT-m200 group (e.g., escalate to 3.0 g, continue at 1.5 g, or reduce). 
If the DSMB recommends continuing dosing at 1.5 g in Cohort 2, the sample size will be re-
calculated based on the pooled standard deviation of the observed primary endpoint estimate in 
Cohort 1. The DSMB may also recommend that the study be stopped early if there is sufficient 
evidence that any of the circumstances in protocol section 10.1.2 apply. 
The Sponsor will make the ultimate decision as to whether to accept the DSMB’s 
recommendation. The Sponsor may have access to group-level data but will not have access to 
unblinded participant-level data at the time of the interim analysis. The Sponsor will have 
ongoing access to blinded individual participant data from saliva tests and daily self-reported 
drug use surveys. 
Participants will continue the study in Cohort 1 through Week 33 while the interim analysis is 
ongoing. 


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2. 
Statistical Hypotheses and Testing 
2.1. 
Statistical Hypotheses 
The null hypothesis corresponding to the primary estimand is: 
• Null hypothesis H0: IXT-m200 is not different from placebo with respect to the group 
means for the percent of 20 weeks abstinent from stimulants. 
• Alternative hypothesis H1: There is a difference between IXT-m200 and placebo with 
respect to the group means for the percent of 20 weeks abstinent from stimulants. 
The null and alternative hypotheses for all secondary estimands will be defined similarly, with 
the null hypothesis being “no difference” between groups, and the alternative hypothesis being 
“there is a difference,” (i.e. a two-tailed alternative). 
2.2. 
Sample Size Determination 
As this is an exploratory Phase 2A study, the sample size was not set to power the study to 
statistically detect any particular treatment effect.  Instead, it was chosen to balance the need to 
gather sufficient information regarding treatment effect and variability to plan for Phase 3, while 
not exposing more subjects than necessary to any yet unknown safety concerns. 
Still, an assessment of the potential power of the study for statistical testing is provided in Table 
4. These estimates assume that cohort 2 (if conducted) receives a different dose of IXT-m200, 
and provide the power for comparing each dose group to placebo. The primary endpoint will be 
based on Cohort 2, but cohorts may be pooled to perform additional analyses. 


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Table 4. Minimum detectable difference between each IXT-m200 group versus the 
placebo group  
Power 
Detectable 
difference 
Examples of detectable differences with varying pooled SD 
20% 
25% 
30% 
Cohort 1/Cohort 2 only  
(n1=40 vs n2=20) 
 
 
 
0.80  
0.78 × pooled SD 
15.6% 
(3.1 more weeks) 
19.5% 
(3.9 more weeks) 
23.4% 
(4.7 more weeks) 
0.85 
0.84 × pooled SD 
16.7% 
(3.3 more weeks) 
20.9% 
(4.2 more weeks) 
25.1% 
(5.0 more weeks) 
0.90 
0.90 × pooled SD 
18.1% 
(3.6 more weeks) 
22.5% 
(4.5 more weeks) 
27.1% 
(5.4 more weeks) 
 
 
 
 
 
Cohorts 1 and 2 pooled  
(n1=40 vs n2=40) 
 
 
 
0.80  
0.63 × pooled SD 
12.6%  
(2.5 more weeks) 
15.8% 
(3.2 more weeks) 
18.9% 
(3.8 more weeks) 
0.85 
0.68 × pooled SD 
13.6%  
(2.7 more weeks) 
17.0% 
(3.4 more weeks) 
20.4% 
(4.1 more weeks) 
0.90 
0.73 × pooled SD 
14.6%  
(2.9 more weeks) 
18.3% 
(3.7 more weeks) 
21.9% 
(4.4 more weeks) 
 
 
 
 
 
The detectable differences were calculated in SAS Proc Power using a two-sample t-test assuming equal 
variance a two-sided 5% alpha. SD = standard deviation. 
The literature suggests that dropout rates in the study population may be up to 50%Error! Bookmark 
not defined., and therefore the analyses will account for missing data.  
2.3. 
Multiplicity Adjustment 
As this is an exploratory Phase 2 study, no adjustments for multiplicity will be made. 
2.4. 
Interim Analyses  
An interim analysis will be conducted after the last participant in Cohort 1 has available Week 25 
data (or has previously discontinued).  This interim analysis will include an unblinded review of 
efficacy, in addition to the typical safety report content.   
As a Phase 2 study, there will not be formal statistical stopping rules for efficacy or futility. A 
Data Safety Monitoring Board (DSMB) will review the interim report (see the following Section 
2.4.1 for further details) and provide a non-binding recommendation to the sponsor regarding the 
conduct of the study moving forward.  
 


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2.4.1. 
Data Safety Monitoring Board 
The DSMB will review an interim analysis report after the last participant in Cohort 1 has 
available Week 25 data (or has previously discontinued) at which time the DSMB will review 
efficacy in addition to the typical safety report content. On the basis of the Week 25 interim 
analysis, the DSMB may recommend whether to proceed to Cohort 2, and if proceeding, which 
dose to use for the IXT-m200 group (e.g., escalate to 3.0 g, continue at 1.5 g, or reduce). If the 
DSMB recommends continuing dosing at 1.5 g in Cohort 2, a sample size recalculation will be 
executed using the pooled standard deviation of the primary endpoint in Cohort 1. The DSMB 
may also recommend that the study be stopped early if there is sufficient evidence that any of the 
following circumstances apply. 
• Determination of unexpected, significant, or unacceptable risk to participants either 
related to the study intervention or unrelated events (such as a national health 
emergency); 
• Demonstration of efficacy that would warrant early termination; 
• Insufficient compliance to protocol requirements; 
• Data that are not sufficiently complete and/or evaluable; 
• Determination that the primary endpoint has been met; 
• Determination of futility. 
 
The Sponsor will make the ultimate decision as to whether to accept the DSMB’s 
recommendation. The Sponsor may have access to group-level data but will not have access to 
unblinded participant-level data at the time of the interim analysis. The Sponsor will have 
ongoing access to blinded individual participant data from saliva tests and daily self-reported 
drug use surveys. Participants will continue the study in Cohort 1 through Week 33 while the 
interim analysis is ongoing. 


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3. 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
Table 5 
Analysis Populations 
Participant Analysis Set 
Description 
Intent-to-treat (ITT) 
The intent-to-treat (ITT) population will be comprised of all 
randomized participants categorized by their randomized 
treatment assignment. 
Modified intent-to-treat 
(mITT) 
The modified ITT (mITT) population will be comprised of all 
randomized participants who received at least one dose of study 
drug. Participants will be analyzed according to their randomized 
treatment assignment. 
Per protocol (PP) 
The per-protocol (PP) population will be comprised of 
participants in the mITT population who had no major protocol 
deviations with the potential to impact efficacy assessments. 
Participants will be analyzed according to the treatment which 
they received (i.e., a participant randomized to placebo who 
received only active study drug in error will be analyzed with 
active participants, and a participant randomized to active who 
received only placebo will be analyzed with the placebo 
participants). The PP population will exclude participants who 
received some active drug and some placebo. InterveXion will 
conduct a blinded review of the protocol deviations prior to 
database lock to determine if any participant should be excluded 
from the PP population. 
Safety 
The safety population will be comprised of all randomized 
participants receiving at least one dose of study drug. Subjects 
will be classified according to drug actually received. 
Pharmacokinetic (PK) 
The pharmacokinetic population will include all subjects for 
whom a serum concentration of IXT-m200 is available post-
dose. 
PK Concentration 
This set will include subjects who received at least one dose of 
study drug and have at least one quantifiable serum concentration 
of IXT-m200 post-dose. Subjects with an insufficient number of 
PK samples to derive PK parameters or those not in the PK 
subset will still be used for listing and summary of PK 
concentrations, along with any graphical presentations of 
concentration-time data. 
PK Parameter 
Any subjects in the PK subset for whom the PK profile can be 
adequately characterized. These will be decided by 
Pharmacokinetic Personnel. 
The ITT population will be used to analyze endpoints related to the efficacy objectives, and the 
safety analysis set will be used to analyze all endpoints and assessments related to safety. If less 
than 90% of the ITT population is in the PP population, then efficacy objectives will also be 


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analyzed using the PP population as sensitivity analyses. Immunogenicity will be assessed using 
the mITT population. PK concentrations will be derived using the PK concentration set and PK 
parameters will be derived using the PK parameter set. 
 


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4. 
Statistical Analyses 
4.1. 
General Considerations 
While statistical inference regarding the treatment effect of IXT-m200 on MUD is an important 
aspect of the analysis of this trial, it should be noted that this trial is also intended to gather 
information regarding the feasibility of various endpoints and measures of MUD treatment 
response.  There has been relatively little described in the literature with respect to 
pharmacological treatments, and thus there is a lack of precedence with regard to the most 
efficient measures.  Therefore, this analysis plan incorporates a range of endpoints/estimands and 
sensitivity analyses, from primary through exploratory, which vary the definition of response to 
treatment, and will allow an assessment of the utility of each to measure treatment effect.     
4.1.1. 
Common Statistical Methods and Data Presentations 
Descriptive and inferential statistics will summarize results. Unless otherwise indicated, the pre-
specified efficacy analyses will be conducted using the ITT population. The study will use an 
overall nominal two-sided Type I error rate of 5%; results will be reported with a two-sided 95% 
confidence interval (CI) and nominal p-value. For primary and selected secondary and 
exploratory efficacy outcomes, plots of the cumulative distribution functions (CDFs) will show 
differences by treatment arm.   
Categorical variables will be summarized with the frequency count and percentage of 
participants with non-missing data. Continuous variables will be summarized using appropriate 
summary statistics (e.g., the number of non-missing observations, mean, standard deviation 
(SD), median, 25th and 75th percentiles, minimum, maximum; geometric mean and 95% 
confidence intervals (CIs) may also be presented, as appropriate). 
All summaries will be by treatment group. Tabular presentations will display a separate column 
for each treatment regimen and graphical summaries will color-code each treatment regimen. 
In addition to tabular and graphical summaries, by-participant listings will present all relevant 
electronic case report form (eCRF) data, sorted by treatment group and participant identifier. 
4.1.2. 
Other Missing Data, and Data Errors 
Any missing values for treatment responder endpoints will be imputed as “non-responder.”  
Missing values for global impressions scales will be imputed as the neutral result of “No 
Change.” 
For endpoints related to saliva screens or self-report surveys, if a participant withdraws from the 
study, all remaining days following withdrawal will be imputed as not abstinent. 
Missing values for quality of life, as measured by the Treatment Effectiveness Assessment, will 
not be imputed.  Participants who withdraw or discontinue prior to Week 5, or do not have any 
reported saliva or self-report use data between Weeks 5 and 25 will not be included in the 
analysis.   
In general, missing and partial dates will be displayed as captured in participant listing displays. 
For adverse events: 
 


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• Missing start day: first of the month will be used unless this is before the start date of 
study drug; if the partial date is the same month as the first dose of study drug, the 
treatment start day will be used and the event will be considered treatment-emergent. 
• Missing stop day: the last day of the month will be used.  
• Completely missing start or end dates will remain missing, with no imputation applied. 
Time to onset will be missing, and duration will be considered ongoing. 
For concomitant medications/medical history: 
• If the partial date is a start date, January and 1 will be used for a missing month and 
missing day, respectively. 
• If the partial date is a stop date, December will be used for a missing month, and the end 
of the month will be used for a missing day (i.e., 28/29/30/31 dependent on the month 
and year of the partial date). 
For pharmacokinetic purposes, missing concentration data will be considered as non-informative 
and will not be imputed. No concentration estimates will be provided for missing sample values. 
4.1.3. 
Clinical Laboratory LLOQ Values 
Clinical laboratory results that are below the lower limit of quantification (LLOQ) will be 
imputed as half of the LLOQ. 
4.1.4. 
Coding of Concomitant Medications and Adverse Events 
All adverse events (AEs) will be coded using MedDRA terms. The number and percent of 
participants with any treatment-emergent AE will be presented by MedDRA SOC and PT in 
descending frequency of occurrence. If a participant reports more than one AE that was coded to 
the same SOC or PT, the participant will be counted only once for that specific SOC or PT. 
4.1.5. 
Definition of Study Time Points 
Baseline is the latest pre-dose assessment with a non-missing value on or before the date of 
randomization (Day 1). If time is not collected, Day 1 assessments are assumed to be taken prior 
to first dose and used as baseline. If baseline data are missing, no derivation will be performed, 
and baseline will be set to missing. 
The following conversion factors will be used to convert days to weeks, months, and years: 1 
week = 7 days, 1 month = 30.4375 days, and 1 year = 365.25 days. 
For all randomized participants, Day 1 is the date of randomization. Day 1 is the planned 
timepoint for the first dose administration. Day 1 is also the start of “Week 1”. 
 For assessments on or after the randomization date, time is calculated in days as:  
Study Day = Assessment Date – Randomization Date + 1 (positive number) 
For assessments prior to the randomization date, time is calculated in days as:  
Study Day = Assessment Date – Randomization Date 
For other time variables based on two dates, Duration (days) = End Date – Start Date + 1. 


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4.2. 
Participant Accounting 
The number of subjects who were enrolled, treated with at least one dose of study drug, who 
completed the study, as well as the reasons for withdrawal, will be summarized with counts and 
percentages by treatment group. This table will also include number of screening failures and 
reasons for screening failures. 
4.3. 
Participant Disposition 
The number and percentage of participants who are randomized, receive treatment, complete 
treatment, discontinue treatment early, discontinue study early, and complete study will be 
presented by treatment group. For participants who discontinue study or treatment early, the 
number and percentage discontinuing by reason and most recent dosing visit will be presented. 
The number and percentage of participants in each analysis population will also be presented. 
4.4. 
Baseline Characteristics and Participant History 
Demographic and baseline characteristics (age, sex, race, ethnicity, body weight, height, body 
mass index [BMI], and days per month of METH use) will be summarized by treatment group 
using descriptive statistics. 
4.5. 
Study Intervention and Concomitant Medications 
4.5.1. 
Extent of Exposure 
Study drug exposure will be summarized for all participants by treatment group. Study drug 
exposure will be summarized as the number and percentage of participants receiving at least one 
dose (i.e., in the safety population) using the number randomized as the denominator. In 
addition, the number of participants who completed each dosing visit and the number of doses 
will be summarized by treatment group, using the number in the safety population as the 
denominator. 
4.5.2. 
Treatment Compliance 
Study drug is administered by intravenous infusion by qualified personnel who are blinded to the 
treatment assignment of the participant. Compliance with dosing will be verified by reference to 
the electronic case report form (eCRF) documentation of dosing. CBT session attendance will be 
documented by the site and captured in the eCRF. 
4.5.3. 
Concomitant Medications 
All concomitant medications (i.e., prescription medications, over-the-counter medications, non-
prescription medications, and supplements) taken during study participation will be recorded on 
the eCRF. For this protocol, a prescription medication is defined as a medication that can be 
prescribed only by a properly authorized/licensed clinician. 
 
The use of concomitant medications will be summarized by therapeutic class and generic 
medication name using descriptive statistics. Concomitant medications will include all 
medications taken from randomization through follow-up. 


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In addition, any behavioral therapy sessions with a trained provider outside the protocol will be 
recorded as concomitant therapy. 
4.6. 
Primary Estimand Analysis 
The primary objective of the study is to evaluate the efficacy of IXT-m200 in preventing or 
reducing relapse to stimulant use. 
4.6.1. 
Main analytical approach 
The primary efficacy analysis will use the ITT population and is based on a test of the mean 
difference between each IXT-m200 group and the placebo group in percent weeks abstinent, as 
estimated using an analysis of covariance (ANCOVA). The dependent variable in the model is 
percent weeks abstinent; the independent variables in the model are the following: 
• Treatment group assignment (discrete); and 
• Stratification level of past-month METH use at screening (discrete). 
The data for this primary endpoint will have shown efficacy if the test of mean percent weeks 
abstinent between Week 5 and Week 25 shows nominal statistically significant benefit in any 
IXT-m200 group relative to the placebo group. 
Adjusted means and standard errors for each treatment group and the estimated difference 
between the groups and associated 95% confidence intervals and two-sided p-values will be 
reported. A plot of all saliva screen results for each individual subject throughout the study will 
be provided. Pseudo-R code for the plot is included in Exhibit 2. The data should be divided into 
subsets based on the value of the saliva test value for methamphetamine, including ‘positive’, 
‘negative’, ‘missed’, ‘invalid’. If the result of a saliva screen is not one that is listed, the sponsor 
should be contacted to receive instruction on how to code the value. If a saliva screen test is 
missed, that week will be imputed assuming the participant is not abstinent. If a participant 
withdraws from the study, then all weeks following withdrawal will be assumed as not abstinent. 
For the n subjects, each subject should be assigned a value from 1 to n for the purpose of 
plotting. Participants will be grouped by study treatment. An example plot is available in Exhibit 
3. 
 
Exhibit 2 Pseudo-R Code for Saliva Screen Data Plot 
par(mfrow=c(1,2)) 
par(mar=c(5,4,4,1)) 
plot(NA,NA,xlim=c(0,175),ylim=c(0,25),xlab='Study Day',ylab='Participant',main='Placebo 
Saliva Screen Results', 
        yaxt='n',xaxt='n') 
axis(1, at=seq(0, 175, by=7)) 
axis(2, at=seq(0,25,by=5)) 
 
for(i in 0:15){ 
  polygon(c(14*i+.5,14*i+7.5,14*i+7.5,14*i+.5), c(-5,-
5,75,75),col=rgb(0,0,0,.025),border=rgb(0,0,0,.025)) 


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} 
points(neg_placebo$DAY,neg_placebo$SUBJIDN,col=rgb(0.2,0.7,0.9,1),pch=17,cex=1) 
points(pos_placebo$DAY,pos_placebo$SUBJIDN,col=rgb(1,0.5,0,1),pch=19,cex=1) 
points(miss_placebo$DAY,miss_placebo$SUBJIDN,col=rgb(1,0.5,0,1),pch=4) 
points(inv_placebo$DAY,inv_placebo$SUBJIDN,col=rgb(1,0.5,0,1),pch=5) 
 
par(mar=c(5,1,4,2)) 
plot(NA,NA,xlim=c(0,175),ylim=c(0,50),xlab='Study Day',ylab='',main='IXT-M200 Saliva 
Screen Results', 
        yaxt='n',xaxt='n') 
axis(1, at=seq(0, 175, by=7)) 
axis(2, at=seq(0,50,by=5)) 
 
for(i in 0:15){ 
  polygon(c(14*i+.5,14*i+7.5,14*i+7.5,14*i+.5), c(-5,-
5,75,75),col=rgb(0,0,0,.025),border=rgb(0,0,0,.025)) 
} 
points(neg_trt$DAY,neg_trt$SUBJIDN,col=rgb(0.2,0.7,0.9,1),pch=17,cex=1) 
points(pos_trt$DAY,pos_trt$SUBJIDN,col=rgb(1,0.5,0,1),pch=19,cex=1) 
points(miss_trt$DAY,miss_trt$SUBJIDN-22,col=rgb(1,0.5,0,1),pch=4) 
points(inv_trt$DAY,inv_trt$SUBJIDN,col=rgb(1,0.5,0,1),pch=5) 
 
legend(130, 50, legend=c("Negative Test","Positive Test","Missed Test",'Invalid Test'), 
       col = c(rgb(0.2,0.7,0.9,1),rgb(1,0.5,0,1),rgb(1,0.5,0,1),rgb(1,0.5,0,1)),pch=c(17,19,4,5)) 
 
Exhibit 3 Plot of Saliva Screen Results 
 


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4.6.2. 
Sensitivity analyses 
To assess the robustness of findings from the primary analysis, the following set of sensitivity 
analyses will be performed: 
• Analyses that involve imputing missing values for saliva screens or self-report surveys 
will be repeated without imputing missing values. That is, they will be left as missing, 
and proportions will use the total number non-missing values available as the 
denominator. The primary analysis will be repeated for the PP population as defined in 
Section 3 if less than 90% of the ITT population is in the PP population. 
4.7. 
Secondary Estimand Analyses 
The secondary efficacy objectives are: 
1. To evaluate the efficacy of IXT-m200 in improving participant-rated quality of life. 
2. To evaluate the efficacy of IXT-m200 in increasing the number of participants achieving 
early remission. 
3. To evaluate the efficacy of IXT-m200 in improving clinician-rated response to treatment. 
4. To evaluate the efficacy of IXT-m200 in improving patient-rated response to treatment. 
4.7.1.1. 
Definition of endpoints 
The corresponding secondary endpoints are: 
1. Change from screening in participant-rated quality of life as measured by the Treatment 
Effectiveness Assessment (TEA) at Week 13, 25, and Week 33. 
2. Responders at Week 25 as measured by the DSM-5 criteria. A responder is a participant 
who meets the definition of early remission, i.e., ≥3 months and <12 months without 
meeting DSM-5 criteria, while disregarding the result for craving. 
3. Difference between groups in Clinical Global Impression of Change (CGIC) at Week 13, 
25, and Week 33. 
4. Difference between groups in Patient Global Impression of Change (PGIC) at Week 13, 
25, and Week 33. 
4.7.1.2. 
Main analytical approaches 
All secondary analyses will use the ITT population. 
Quality of life analysis 
A secondary objective is to evaluate the efficacy of IXT-m200 in improving patient-rated quality 
of life, as measured by change from screening in the Treatment Effectiveness Assessment score 
at Week 13, Week 25, and Week 33. 
The Treatment Effectiveness Assessment includes four items with 10 ordinal response options 
ranging from “not well at all” to “extremely well” (Likert scale), where higher values indicate 
better quality of life. The Treatment Effectiveness Assessment score is the sum of the four 
responses (minimum = 4, maximum = 40); the Treatment Effectiveness Assessment score will 
not be computed if the participant did not respond to all four items. 
As the sum of four ordinal items, a nonparametric approach to the analysis will be used since it is 
unlikely the values will meet the necessary normality assumptions for MMRM or ANCOVA 


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methods.  Therefore, the change from screening in Treatment Effectiveness Assessment score at 
each post-screening timepoint will be compared in each IXT-m200 group versus the placebo 
group using a Kruskal-Wallis test.   
For each comparison and timepoint, the Hodges-Lehmann estimate and 95% confidence intervals 
for the difference in group medians, and two-sided p-values will be reported. 
A waterfall plot, depicting the median change from baseline at each timepoint will be provided 
for each treatment group. Pseudo-R code for the plot is included in Exhibit 4. Exhibit 5 contains 
an example of the waterfall plot. 
 
Exhibit 4 Pseudo-R Code for TEA Waterfall Plot 
coltrt <- ifelse(medstrt >= 0,rgb(0.2,0.7,0.9,.75), rgb(1,0.5,0,.75)) 
colplcbo <- ifelse(medsplcbo >= 0,rgb(0.2,0.7,0.9,.75), rgb(1,0.5,0,.75)) 
 
par(mfrow=c(1,2)) 
barplot(medstrt,ylim=c(min(c(medstrt,medsplcbo)),max(c(medstrt,medsplcbo))),col=coltrt,yla
b="Change from Baseline") 
segments(x0=0,x1=4,y0=0,y1=0,lty="dashed") 
 
title('Change from Baseline in TEA Score for IXT-m200 Group') 
axis(1, at=1:3, labels=c("Week 13","Week 25", "Week 33")) 
barplot(medsplcbo,ylim=c(min(c(medstrt,medsplcbo)),max(c(medstrt,medsplcbo))),col=colplc
bo) 
title('Change from Baseline in TEA Score for Placebo Group') 
axis(1, at=1:3, labels=c("Week 13","Week 25", "Week 33")) 
segments(x0=0,x1=4,y0=0,y1=0,lty="dashed") 
Exhibit 5 TEA Waterfall Plot 
 
 


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Proportion of responders meeting early remission criteria 
A secondary objective is the proportion of responders at Week 25 as measured by DSM-5 
criteria. A responder is a participant who meets the definition of early remission, i.e., ≥3 months 
and <12 months without meeting DSM-5 criteria, while disregarding the result for craving. All 
other criteria, 10 in total, will be counted.  Participants that withdraw or discontinue prior to 
Week 5, or do not have any reported saliva or self-report use data between Weeks 5 and 25 will 
not be included in the analysis. 
The proportion of participants achieving a response will be compared in each IXT-m200 dose 
group versus the placebo group using a stratified Mantel-Haenszel statistic with stratification 
level of past-month METH use at screening (discrete). The output will provide the risk 
difference between each IXT-m200 dose group and the placebo group, two-sided p-values, and 
95% confidence intervals using the Miettinen-Nurminen (score) confidence limits4. 
Clinician-rated response to treatment 
A secondary objective is to evaluate the efficacy of IXT-m200 in improving clinician-rated 
response to treatment, as measured by Clinical Global Impression of Change (CGIC) at Week 
13, 25, and Week 33. The CGIC is completed by the clinician and has seven ordinal responses 
(Likert scale) ranging from “very much improved” to “very much worse”. The comparison 
between groups will be conducted using a nonparametric Kruskal-Wallis test.  The percentage of 
subjects in each scale category will be tabulated by treatment group and timepoint, and a 
graphical display using a frequency polygon will be produced for the Week 25 values. 
Patient-rated response to treatment 
Another secondary objective is to evaluate the efficacy of IXT-m200 in improving patient-rated 
response to treatment as measured by the Patient Global Impression of Change (PGIC) at Week 
13, 25, and Week 33. PGIC is completed by the patient and has seven ordinal responses (Likert 
scale) ranging from “very much improved” to “very much worse”. 
The comparison between groups will be conducted using a nonparametric Kruskal-Wallis test. 
The percentage of subjects in each scale category will be tabulated by treatment group and 
timepoint, and a graphical display using a frequency polygon will be produced for the Week 25 
values. 
4.8. 
Exploratory Analyses 
Exploratory analyses will be performed on the ITT population. 
Proportion of responders meeting early remission criteria at Week 33 
An additional exploratory objective is the proportion of responders at Week 33 as measured by 
DSM-5 criteria. A responder is a participant who meets the definition of early remission, i.e., ≥3 
months and <12 months without meeting DSM-5 criteria, while disregarding the result for 
craving. All other criteria, 10 in total, will be counted.  Participants that withdraw or discontinue 
prior to Week 5, or do not have any reported saliva or self-report use data between Weeks 5 and 
25 will not be included in the analysis. 
The proportion of participants achieving a response will be compared in each IXT-m200 dose 
group versus the placebo group using a stratified Mantel-Haenszel statistic with stratification 


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level of past-month METH use at screening (discrete). The output will provide the risk 
difference between each IXT-m200 dose group and the placebo group, two-sided p-values, and 
95% confidence intervals using the Miettinen-Nurminen (score) confidence limits. 
Adverse Outcomes 
An exploratory objective is to evaluate the efficacy of IXT-m200 in reducing the number of 
adverse outcomes from the Adverse Outcome Assessment. The assessment will be conducted at 
Screening, and Weeks 13, 25, and 33. All responses should be counted over the past 3 months. A 
summary table will provided, showing the mean, standard deviation, median, and min and max 
for each treatment group, at each of the given weeks. No formal statistical testing will be 
performed for this endpoint. 
Percent of days abstinent from stimulants between Week 5 and Week 25 
A secondary objective is to evaluate the efficacy of IXT-m200 in preventing or reducing the 
relapse to stimulant use, as measured by the percent of days abstinent from stimulants following 
a 4-week grace period (between Week 5 and Week 25) using self-report surveys via smartphone 
app. 
Participants are to self-report their use/abstinence for each day of the study via the smartphone 
app. Missing survey data will be imputed assuming a use day. The analysis will be repeated 
without the imputation of missing data. 
The difference in percentage of days abstinent from stimulants will be compared in each IXT-
m200 group versus the placebo group using a t-test. For each comparison, the point estimate and 
95% confidence intervals for the difference in group means, and two-sided p-values will be 
reported. 
A plot of all self-report survey results for each individual participant throughout the study will be 
provided. Pseudo-R code for the plot is included in Exhibit 6. Observations should be sorted first 
by the highest study day where the survey was filled out and then by the number of use days. 
Exhibit 6 Pseudo-R Code for Survey Data Plot 
par(mfrow=c(2,1)) 
par(mar=c(3,4,2,1)) 
plot(NA,NA,xlim=c(0,175),ylim=c(0,25),xlab='', 
     ylab='Placebo Participant', 
     main='Meth Survey Responses for Individual Subjects',yaxt='n',xaxt='n') 
axis(1, at=seq(0, 175, by=7)) 
axis(2, at=seq(0,25,by=5)) 
 
for(i in 0:15){ 
  polygon(c(14*i+.5,14*i+7.5,14*i+7.5,14*i+.5), c(-5,-
5,75,75),col=rgb(0,0,0,.025),border=rgb(0,0,0,.025)) 
} 
 
points(nodrug_placebo$DAY,nodrug_placebo$SUBJIDN,col=rgb(0.2,0.7,0.9,1),pch=17,cex=1,yaxt='n') 
points(drug_placebo$DAY,drug_placebo$SUBJIDN,col=rgb(1,0.5,0,1),pch=19,cex=1) 


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points(missed_placebo$DAY,missed_placebo$SUBJIDN,col=rgb(1,0.5,0,1),pch=4,cex=1) 
 
legend(150, 25, legend=c("Answered No","Answered Yes","Missed"), 
       col = c(rgb(0.2,0.7,0.9,1),rgb(1,0.5,0,1),rgb(1,0.5,0,1)),pch=c(17,19,4)) 
 
par(mar=c(5,4,0,1)) 
plot(NA,NA,xlim=c(0,175),ylim=c(0,45),xlab='Study Day',ylab='IXT-M200 Participant', 
     main='',yaxt='n',xaxt='n') 
axis(1, at=seq(0, 175, by=7)) 
axis(2, at=seq(0,45,by=5)) 
 
for(i in 0:15){ 
  polygon(c(14*i+.5,14*i+7.5,14*i+7.5,14*i+.5), c(-5,-
5,75,75),col=rgb(0,0,0,.025),border=rgb(0,0,0,.025)) 
} 
 
points(nodrug_trt$DAY,nodrug_trt$SUBJIDN-22,col=rgb(0.2,0.7,0.9,1),pch=17,cex=1) 
points(drug_trt$DAY,drug_trt$SUBJIDN-22,col=rgb(1,0.5,0,1),pch=19,cex=1) 
points(missed_trt$DAY,missed_trt$SUBJIDN-22,col=rgb(1,0.5,0,1),pch=4,cex=1) 
Sequential weeks of abstinence from the end of treatment visit (Week 25) 
An exploratory objective is to evaluate the efficacy of IXT-m200 in improving the length of 
sustained abstinence. Sequential weeks of abstinence counting backwards from the end of 
treatment visit (Week 25), defined as four weeks after the final planned treatment visit (Week 
21), as measured by saliva screens in each IXT-m200 group will be compared to the placebo 
group. In the event there is no Week 25 visit, then the endpoint is counted from four weeks after 
the last dosing visit attended. 
A “use day” or “abstinent day” will be derived as described for the primary endpoint. For each 
participant, sequential weeks abstinent counting backwards from the Week 25 visit will be 
calculated based on use/abstinent days, for a minimum of 0 weeks and maximum of 24 weeks of 
abstinence.  Participants that withdraw or discontinue prior to Week 5, or do not have any 
reported saliva screen data between Weeks 5 and 25 will not be included in the analysis. 
The difference between each IXT-m200 group and the placebo group in sequential weeks of 
abstinence counting backward from Week 25 will be estimated using an ANCOVA model. The 
independent variables in the model will be treatment group and stratification level of past-month 
METH use at screening. Adjusted means and standard errors for each treatment group and the 
estimated difference between the groups and associated 95% confidence intervals and two-sided 
p-values will be reported. Figures and tables will summarize the outcomes and analysis results. 
This analysis will be repeated with the PP population. 
Point prevalence abstinence (last 7 days) 
One exploratory objective is to evaluate the efficacy of IXT-m200 in improving post-treatment 
abstinence. Point prevalence abstinence (last 7 days) by saliva screens at Week 25, Week 29, and 
Week 33 will be compared between each IXT-m200 group and the placebo group. 


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For each visit of interest, abstinence or use will be based on the saliva screens in the previous 
seven days. A “use day” or “abstinent day” will be derived as described for the primary endpoint. 
A participant will be categorized as fully abstinent if their saliva screens are negative 
(responder); a participant will be categorized as not abstinent if any of their saliva screens are 
positive (failure). The generalized linear mixed model assumes that data are missing at random. 
A generalized linear mixed model regressing binary abstinence on treatment group, visit, 
stratification level of past-month METH use at screening, and a treatment group by visit 
interaction term. For each comparison, the odds ratio, 95% confidence interval, and two-sided p-
value will be reported. Figures and tables will summarize the outcomes and analysis results. 
Within-subject correlations will be modeled using an unstructured covariance structure. If the 
model does not converge (i.e., the study has too few observations for the number of parameters 
estimated), the model will sequentially use the heterogeneous Toeplitz structure, homogeneous 
Toeplitz structure, or compound symmetry structure, each requiring successively fewer 
parameters. 
Complete abstinence between Week 21 and Week 25 responder analysis 
A secondary objective is to evaluate the efficacy of IXT-m200 in improving the proportion of 
participants achieving stimulant abstinence, defined as complete abstinence during the last 
scheduled month of study drug treatment (between Week 21 and Week 25), as measured by 
saliva screens. 
A participant will be categorized as fully abstinent if they have zero days of use (between Week 
21 and Week 25); otherwise, a participant will be categorized as not abstinent (failure).  
Participants who withdraw or discontinue prior to Week 5, or do not have any reported saliva or 
self-report use data between Weeks 5 and 25 will not be included in the analysis. 
The proportion of participants achieving a response will be compared in each IXT-m200 group 
versus the placebo group using a stratified Mantel-Haenszel statistic with stratification level of 
past-month METH use at screening (discrete). The output will provide the risk difference 
between each IXT-m200 dose group and the placebo group, two-sided p-values, and 95% 
confidence intervals using the Miettinen-Nurminen (score) confidence limits.  
Reduction in the frequency of METH use over time 
An additional exploratory objective is to evaluate the efficacy of IXT-m200 in reducing the 
frequency of METH use over time.  For each day from the start of Week 5 through the end of 
Week 25, abstinence or use will be based on the self-reported use in the previous seven days. 
The number of use days in each week will then be determined.   
The weekly total for a subject will be derived by counting the number of use days among the 
non-missing days and normalizing to a seven-day period.  For example, for a subject with 1 use 
day among 4 non-missing days and 3 missing days in a given week, the number of use days (X) 
will be derived as X = (1/4)*7 = 1.75.  No rounding will be performed.  If a subject has all 
missing days in a given week, that week will not be imputed and therefore will not contribute to 
the analysis. 
The number of use days per week will be summarized in a table presenting the mean and 
standard deviation for each treatment group, at each of the weeks from 5 to 25. No formal 
statistical testing will be performed for this endpoint.  A plot of these group means across weeks 
will be provided. 


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A spaghetti plot will also be provided to show the use days per week by subject throughout the 
study.  Pseudo-R code for the plot is included in Exhibit 7, and an example of the plot is included 
in Exhibit 8. 
Exhibit 7 Pseudo-R Code for Weekly Meth Use Days Spaghetti Plot 
survey$DATE <- as.Date(survey$date) 
startday <- aggregate(DATE ~ SUBJID, survey, function(x) min(x)) 
 
### RESPID is response ID, a sequential numbering of the dataset observations 
### SUBJIDN is an integer valued SUBJID, a sequential numbering of unique subjects 
for(i in 1:length(survey$RESPID)) { 
  for(j in 1:max(SUBJIDN)) { 
    if(survey$SUBJID[i]==startday$SUBJID[j]) { 
      survey$DAY[i] <- as.numeric(survey$DATE[i]) - as.numeric(startday$DATE[j]) 
      survey$WEEK[i] <- (as.numeric(survey$DAY[i]) %/% 7)+1 
      survey$METH01[i] <- as.integer(survey$METH[i]=='Methamphetamine') 
      if(is.na(survey$METH01[i])) {survey$METH01[i]=0}  
    } 
  } 
} 
   
setDT(survey) 
weeksdat <- survey[ ,list(usedays=sum(METH01)), by=.(TRT_GRP,SUBJID,WEEK)] 
 
# Add some jittering to be able to distinguish and follow individual participants 
for(i in 1:length(weeksdat$usedays)) { 
  weeksdat$usedays_j[i] = weeksdat$usedays[i]+rnorm(1,mean=0,sd=.05) 
} 
# Spaghetti plot 
plot <-ggplot(data=weeksdat, aes(x=WEEK, y=usedays_j, group=SUBJID))  
plot + 
  geom_line(aes(col = TRT_GRP)) +  
  #geom_point() +# 
  xlim(0,25) + 
  ylim(-.25,7.25) + 
  labs(title = "Spaghetti Plot of Participant Weekly Meth Use Days\n",  
       x="Study Week", y="Number of Meth Use Days", color="Treatment Group\n") + 
  scale_x_continuous(breaks=seq(0,26,2)) + 
  scale_y_continuous(breaks=seq(0,7,1)) 
  theme_bw() 
Exhibit 8 Weekly Meth Use Days Spaghetti Plot 


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Proportion of participants with n or fewer use days between Week 5 and Week 25 
Measured by Self-Report 
The proportion of participants with n or fewer use days between Week 5 and Week 25, where n 
ranges from 0 to 20 will be summarized.  A secondary endpoint is Complete Abstinence during 
the last 4 weeks.  This analysis will expand that to the last 20 weeks and explore a range of use 
days from 0 (complete abstinence) to 20 (an average of one use day a week).   
A “use day” or “abstinent day” will be based on self-report surveys. Missing survey responses 
will be imputed assuming use for that day. The summary will be descriptive only, presenting the 
number and percentage of “responders,” defined as subjects with n or fewer use days between 
Week 5 and Week 25 (Study days 29 to 169).  A continuous responder curve will be produced 
with the number of use days on the horizontal axis and percent of subjects on the vertical axis, 
with a line for each treatment group.  Since the criteria for a responder becomes less strict as n 
increases, both curves would be expected to be near 0% at n=0, and increase as they move to the 
right.  The graph will allow a visual examination of potential separation between treatment 
groups. Pseudo-R code for the plot is included in Exhibit 9. For number of use-days from 0 to 
140 (20 weeks), calculate the proportion of subjects with n use-days or less. Exhibit 10 shows an 
example of the plot. 
Exhibit 9 Pseudo-R Code for Continuous Responder Curve Plot 
plot(NA,NA,xlim=c(0,175),ylim=c(0,1),xaxt='n',yaxt='n',xlab='Number of Use Days', 
ylab='Proportion of Responders',main='Continuous Response Curve') 
for(i in 1:18){ 


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  abline(v=(i-1)*10,col=rgb(0,0,0,0.05)) 
} 
for(i in 1:11){ 
  abline(h=(i-1)/10,col=rgb(0,0,0,0.05)) 
} 
lines(seq(0,max(trt$DAY)),prop_resp_t,col=rgb(0.2,0.7,0.9,1)) 
lines(seq(0,max(placebo$DAY)),prop_resp_c,col=rgb(1,0.5,0,1)) 
axis(1,seq(0,180,10)) 
axis(2,seq(0,1,0.1)) 
 
legend(125, 0.2, legend=c('Treatment','Placebo'), 
       col = c(rgb(0.2,0.7,0.9,1),rgb(1,0.5,0,1)),lwd=c(1,1)) 
 
Exhibit 10 Continuous Responder Curve Plot 
 
Proportion of participants with n or fewer use days between Week 5 and Week 25 
Measured by Saliva Screens 


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The proportion of participants with n or fewer use days between Week 5 and Week 25, where n 
ranges from 0 to 20 will be summarized.  A secondary endpoint is Complete Abstinence during 
the last 4 weeks.  This analysis will expand that to the last 20 weeks and explore a range of use 
days from 0 (complete abstinence) to 20 (an average of one use day a week).   
A “use day” or “abstinent day” will be derived using the following algorithm.  
• If a participant has two positive tests, misses two tests, or has one positive and one 
missing test in a given week, then impute 7 use days for that week. 
• If a participant has one positive/missing test and one negative test, then impute 4 use days 
for that week. 
• If a participant tests negative for both tests, then impute 0 use days for that week. 
The summary will be descriptive only, presenting the number and percentage of “responders,” 
defined as subjects with n or fewer use days between Week 5 and Week 25.  A continuous 
responder curve will be produced with the number of use days on the horizontal axis and percent 
of subjects on the vertical axis, with a line for each treatment group.  Since the criteria for a 
responder becomes less strict as n increases, both curves would be expected to be near 0% at 
n=0, and increase as they move to the right.  The graph will allow a visual examination of 
potential separation between treatment groups. 
4.9. 
Pharmacokinetics Endpoints 
The PK Concentration Set will be used for serum concentration summaries and listings and the 
PK Parameter Set will be used for PK parameter summaries and listings as specified in this 
section. 
PK analyses will be conducted for IXT-m200 by treatment group as described below. The non 
compartmental analysis (NCA) will be performed using appropriate software, i.e., Phoenix™ 
WinNonlin® (Version 8.3 or higher, Certara Corporation). All other analyses will be performed 
using SAS® (Version 9.4 or higher, SAS Institute Inc). 
4.9.1. 
PK Sampling Schedule 
Section 1.3.2 of the protocol contains the full participant schedule for the PK subset. 
• In all main study subjects, blood samples will be taken for analysis of IXT-m200 in 
serum on Day 1, Day 29, Day 57, Day 85, Day 113, and Day 141 at pre-dose (≤30 min 
prior) and 4 hours (±10 min) after the start of dosing, and once each visit on Day 169, 
Day 197, Day 225, and at early termination. 
• In subjects in the PK subset, blood samples will be taken for analysis of IXT-m200 in 
serum on Day 1 and Day 141 at pre-dose (≤30 min prior), 1 hour (±10 min) and 4 hours 
(±10 min) after the start of dosing, and once at each visit on Day 2, Day 8, Day 15, Day 
22, Day 142, Day 148, Day 155, and Day 162. Blood samples will also be taken at pre-
dose and 4 hours after the start of dosing on Day 29, Day 57, Day 85, and Day 113, and 
once each visit on Day 169, Day 197, Day 225, and at early termination. 
4.9.2. 
Handling of the Difference between the Scheduled and the Actual Sampling 
Times 
For all sampling times, the actual sampling times will be calculated as the difference between the 
sample collection actual clock time and the actual clock time of start of dosing. The actual post-


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dose sampling times expressed in hours and rounded off to three decimal digits will be used to 
calculate the PK parameters, except for pre-dose samples occurring prior to dosing (pre-dose), 
which will always be treated as zero (0.000), regardless of the time difference. Scheduled 
sampling times will be presented in concentration tables by treatment group.  
4.9.3. 
PK Endpoint 
Available serum IXT-m200 data up to 28 days after dosing on Day 1 and Day 141 from the PK 
Parameter Set will be used to calculate the PK parameters.  
The following PK parameters will be calculated for Day 1, if the data are sufficient to generate a 
reliable parameter estimate: 
AUC0-t: 
Area under the concentration-time curve from time zero to the last non-zero 
concentration, calculated using the linear up, log down trapezoidal method. 
AUC0-28d: 
Area under the concentration-time curve from time zero to day 28, calculated 
using the linear up, log down trapezoidal method. 
AUC0-inf: 
Area under the concentration-time curve from time zero to infinity 
(extrapolated), calculated as AUC0-t+Ct/Kel, where: Ct = the last observed 
non-zero concentration. 
Cmax: 
Maximum observed concentration.  
Residual area: 
Residual area, calculated as 100*(1- AUC0-t / AUC0-inf). If Residual area is 
>20%, any PK parameters derived from AUC0-inf will be flagged in individual 
listings. 
Tmax: 
Time of observed Cmax. 
t½ : 
Elimination half-life, calculated as log(2)/Kel using the natural logarithm. 
Kel: 
Elimination rate constant. This parameter will be the negative of the 
estimated slope of the linear regression of the ln-transformed serum 
concentration versus time profile in the terminal elimination phase. The Best-
fit method, in Phoenix WinNonlin, will be used to calculate the Kel from at 
least 3 concentration data points excluding the Cmax. Rsq adjusted, the 
goodness of fit statistic for the terminal elimination phase, adjusted for the 
number of points used in the estimation of Kel must be ≥ 0.8. The timepoint 
where ln-linear Kel calculation begins (Kel Lower) and the actual sampling time 
of the last measurable concentration used to estimate the Kel (Kel Upper), as 
well as the Rsq adjusted for the ln-linear regression for the calculation of the 
elimination rate constant will be reported. If the Kel cannot be measured (e.g.: 
fewer than 3 non-zero concentrations in the terminal elimination phase or Rsq 
adjusted <0.8), then elimination related PK parameters (Kel, Kel Lower, Kel Upper, 
AUC0-inf, Rsq adjusted, Residual area, t½, CL and V) will be presented in the 
listing with a flag and excluded from descriptive statistics. 


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CL:  
Clearance, calculated as Dose/AUC0-inf.  
V:  
Volume of distribution, calculated as Dose/(Kel x AUC0-inf).  
The following PK parameters will be calculated for Day 141, if the data are sufficient to generate 
a reliable parameter estimate: 
AUC0-t: 
Area under the concentration-time curve from time zero to the last non-zero 
concentration, calculated using the linear up, log down trapezoidal method. 
AUC0-tau: 
Area under the concentration-time curve over the dosing interval (tau = 28 
days) at steady-state. 
Cmax,ss: 
Maximum observed concentration at steady-state.  
Tmax,ss: 
Time of observed Cmax at steady-state. 
t½ : 
Elimination half-life, calculated as log(2)/Kel using the natural logarithm. 
Kel: 
Elimination rate constant. This parameter will be the negative of the 
estimated slope of the linear regression of the ln-transformed serum 
concentration versus time profile in the terminal elimination phase. The Best-
fit method, in Phoenix WinNonlin, will be used to calculate the Kel from at 
least 3 concentration data points excluding the Cmax. Rsq adjusted, the 
goodness of fit statistic for the terminal elimination phase, adjusted for the 
number of points used in the estimation of Kel must be ≥ 0.8. The timepoint 
where ln-linear Kel calculation begins (Kel Lower) and the actual sampling time 
of the last measurable concentration used to estimate the Kel (Kel Upper), as 
well as the Rsq adjusted for the ln-linear regression for the calculation of the 
elimination rate constant will be reported. If the Kel cannot be measured (e.g.: 
fewer than 3 non-zero concentrations in the terminal elimination phase or Rsq 
adjusted <0.8), then elimination related PK parameters (Kel, Kel Lower, Kel Upper, 
Rsq adjusted, t½, and Vss) will be presented in the listing with a flag and 
excluded from descriptive statistics. 
CLss:  
Clearance at steady-state, calculated as Dose/AUC0-tau.  
Vss:  
Volume of distribution at steady-state, calculated as Dose/(Kel x AUC0-tau).  
RCmax:  
Accumulation ratio based on Cmax, calculated as Cmax on Day 141/Day 1  
RAUC:  
Accumulation ratio based on AUC, calculated as AUC0-tau Day 141/AUC0-28d 
Day 1 


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4.9.4. 
Presentation of Concentration Data 
4.9.4.1. 
Handling of Missing Data 
Missing concentration data will be considered as non-informative and will not be imputed. No 
concentration estimates will be provided for missing sample values. 
4.9.4.2. 
Listing and Presentation of Individual PK Data 
• The sampling time of pre-dose samples relative to dosing is treated as zero for all 
sampling periods separately 
• All concentrations are presented in original units as reported by the Bioanalytical 
laboratory 
• All concentrations that are below the limit of quantification (BLQ) are set to zero 
• Listings of PK sampling times include nominal and actual time elapsed from dose with 
the deviation from the nominal time and measured concentrations of the drug 
• No further imputation will be applied to any missing values 
Individual IXT-m200 concentration data will be listed by subject, visit, timepoint, and treatment 
group.  
An overlay plot (Spaghetti plot) of subjects by treatment group will be presented graphically on 
both linear and semi-logarithmic scales for IXT-m200. 
4.9.4.3. 
Summary of PK Concentration 
For PK concentration summaries, the following applies: 
• All concentrations that are BLQ are set to zero 
• The sampling time of pre-dose samples relative to dosing will be treated as zero 
• Drug concentrations will be summarized by nominal time point 
• Descriptive statistics will be performed 
• No further imputation is applied to any missing values 
• IXT-m200 concentrations will be summarized by treatment group, visit, and time point.  
• Mean (±SD) serum concentration versus time will be presented graphically on both linear 
and semi-logarithmic scales by treatment for IXT-m200. 
4.9.5. 
PK Parameters Derivation 
For the derivation of PK parameters, the following rules will apply: 
• All concentration values below the assay’s lower limit of quantification (BLQ) will be 
treated as zero 
• The sampling time of pre-dose samples relative to dosing will also be treated as zero 
• Actual blood sampling times will be used to derive PK parameters (if the actual blood 
sampling is not present, then that timepoint and concentration will not be considered for 
PK analyses (except for predose, where timepoint as zero will be considered)) 
• No further imputation will be applied to any missing values 
Individual IXT-m200 PK parameters will be listed by subject, visit, and treatment group. 
Additionally, box plots of PK exposure parameters (e.g., AUC, Cmax) and HACA results may be 
presented, as appropriate. 


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4.9.5.1. 
PK Parameters Summarization 
PK parameters and concentrations data will be summarized using the following descriptive 
statistics: 
Variable 
Summarized with: 
PK concentration at 
each nominal time point 
n, number and percentage of subjects with BLQ, 
arithmetic mean, SD, coefficient of variance (CV) 
%, minimum, median, maximum, geometric mean 
and geometric CV% 
AUC0-t, AUC0-28d, 
AUC0-inf, AUC0-tau, Cmax, 
Cmax,ss, CL, CLss, V and 
Vss  
n, arithmetic mean, SD, CV%, minimum, median, 
maximum, geometric mean and geometric CV%  
t1/2, kel and ratios (RCmax 
and RAUC) 
n, arithmetic mean, SD, CV%, minimum, median, 
maximum 
Tmax and Tmax,ss (actual 
time) 
n, minimum, median, and maximum 
Note: CV% = SD/mean in %. n = non-missing No. of observations. 
 
4.9.5.2. 
PK Reporting Precision 
The following precision will be applied to the various descriptive statistics: 
Variables 
Precision 
Minimum; Maximum 
3 significant digits / as needed based on actual measured 
values 
Arithmetic mean; 
Geometric mean; Median 
4 significant digits / as needed based on actual measured 
values 
SD 
5 significant digits / as needed based on actual measured 
values 
CV%; Geometric CV% 
1 decimal place / as needed based on actual measured 
values 
 
For PK concentration and parameter listings, the final reportable results or data will be presented 
by rounding off to 2 decimal digits, except for the following situations (this applies to individual 
data): 
• Kel data, and Rsq adjusted: rounded off to four decimal digits. 
• PK parameters related to time such as Tmax. Tmax,ss, Kel Lower, and Kel Upper must be reported 
with the same precision as the actual sampling time: rounded off to 3 decimal digits. 
• Concentration versus time data: reported as they appear in the corresponding dataset.  
 


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4.10. 
Safety Analyses 
Primary analyses of safety will be summarized for the Safety population. 
4.10.1. Adverse Events 
All adverse events (AEs) will be coded using MedDRA terms. The number and percent of 
participants with any treatment-emergent AE will be presented by MedDRA SOC and PT in 
descending frequency of occurrence. If a participant reports more than one AE that was coded to 
the same SOC or PT, the participant will be counted only once for that specific SOC or PT. 
Summaries of AEs by MedDRA SOC and PT will be provided for the following: 
• AEs (overall and by severity) 
• AEs reported as potentially related to IXT-m200 (including those with missing 
• relatedness designation) (overall and by severity) 
• Serious adverse events (SAEs) 
• AEs leading to study withdrawal 
• AEs leading to treatment discontinuation 
Summaries will be presented by treatment group and for all participants. A listing will include all 
events for each participant, along with study day of onset, duration, severity, seriousness, 
relatedness, action taken (e.g., treatment discontinued, study discontinued, treatment interrupted, 
none), and outcome (e.g., recovered/resolved, recovering/resolving, recovered/resolved with 
sequelae, not recovered/not resolved, fatal, unknown). Separate participant listings of SAEs and 
AEs leading to withdrawal will also be presented. 
If any participant dies during the study, a listing of the fatal AE will also be provided along with 
a participant narrative that will include all relevant information. 
4.10.2. Clinical Laboratory Analyses 
All quantitative centrally reviewed clinical laboratory results other than urinalysis results will be 
presented in standardized units. Both observed values and changes from baseline will be 
summarized for each scheduled timepoint. Figures will be used if appropriate and would include 
shading between the lower and upper limits of normal, as applicable. 
4.10.3. 
Electrocardiograms 
Electrocardiogram (ECG) measurement data will be summarized descriptively by timepoint. 
Both observed values and changes from baseline will be summarized for each scheduled 
timepoint, as well as depicted in figures. Abnormal values will be indicated in listings. 
4.10.4. 
Vital Signs 
Vital signs results (heart rate, diastolic and systolic blood pressure, temperature, and respiratory 
rate) will be summarized descriptively by treatment and planned timepoint. Both observed values 
and changes from baseline will be summarized for each scheduled timepoint and depicted in 
figures. 


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4.10.5. 
Physical Examination 
Physical examination findings will be listed by treatment group, participant, and visit. 
4.10.6. 
Psychiatric evaluation 
Psychiatric evaluation findings will be listed by treatment group, participant, and visit. 
4.11. 
Immunogenicity 
The primary analysis of immunogenicity will be conducted using the ITT population. Secondary 
analyses of immunogenicity will be conducted using the mITT population. The secondary 
endpoint of the number and percentage of participants with anti-IXT-m200 antibody levels that 
are confirmed positive and have titers more than three times the minimum required dilution will 
be summarized by treatment group and overall. For participants with positive screen results 
whose samples underwent immunodepletion, the number and percentage of participants with 
each titer category will be presented. 
4.12. 
Subgroup analyses 
Primary and secondary efficacy analyses may be performed in the following subgroups: 
• Sex: male versus female 
• Gender (as collected on eCRF) 
• BMI categorized as under/normal/overweight 
• Abstinent during the grace period: abstinent versus not abstinent 
• Baseline METH use as randomized: <18 days versus ≥18 days 
• Treatment compliance: above versus below median doses of study drug received 
• Preferred route of administration of methamphetamine 
• CBT attendance compliance: above versus below median number of sessions attended 
• Participants who received additional therapy outside of the study versus those who did 
not 
• If at least 10% participants are in the ITT population but not the PP population, the PP 
population will be analyzed as a subgroup. 
4.13. 
Changes to Protocol-Planned Analyses 
• There are no changes to the analyses planned in the protocol. 
 


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5. 
Supporting Documentation 
 


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5.1. 
Appendix 1: Schedule of Events 
 


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6. 
References 
 
1. International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. Statistical principles for clinical trials (E9). 
International Conference on Harmonization, 1998. 
 
2. International Conference on Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use. Estimands and sensitivity analysis in clinical trials E9 
(R1). International Conference on Harmonization, 2017. 
 
3. Trivedi, M. H., et al. Bupropion and Naltrexone in Methamphetamine Use Disorder. The 
New England Journal of Medicine. 2021, 384: 140-153. 
 
4. Miettinen, O. S., and Nurminen, M. M. (1985). “Comparative Analysis of Two 
Rates.” Statistics in Medicine 4:213–226. 
 
5. Cook R, Quinn B, Heinzerling K, et al. Dropout in clinical trials of pharmacological 
treatment for methamphetamine dependence: the role of initial abstinence. Addiction. 
2017; 112: 1077–1085.