Conditions: Methamphetamine Intoxication (Disorder)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

Brief summary:
The hypothesis of this multisite Phase 2a study is that IXT-m200 will be well-tolerated in patients with acute mild to moderate METH toxicity. A randomized, open label design will be used in which one dose of IXT-m200 will be compared to treatment-as-usual (TAU). Approximately 40 participants will be enrolled in 4 cohorts. A dose escalation approach will be used so that progressively higher IXT-m200 doses will be evaluated in each cohort. In conjunction with safety monitoring, this design assures the opportunity to observe early safety findings before any participants are exposed to the next higher dose. The randomization ratio for IXT-m200 versus TAU is defined as 4:1 for each cohort so that the number of participants receiving TAU equals the number receiving each dose of IXT-m200 at the end of the study.

Agitation scales and vital signs will be recorded to track effect of the antibody treatment versus TAU over time on agitation associated with METH use. While in the emergency department (ED), detailed and pertinent medical and psychiatric histories, and physical exam will be obtained, along with laboratory assessments and ECGs. In the ED, participants will give blood samples for analysis of METH and IXT-m200 concentrations and followed for development of adverse events. Participants will be evaluated at 2 days and 4 weeks after discharge from the ED for adverse events and drug use history. Cohort escalation reviews will be performed by the Sponsor, Medical Monitor, and Data and Safety Monitoring Board (DSMB) between cohorts and the next group will not start until after completion of this review.

Detailed description:

Arms:
arm 1: IXT-m200 is a high-affinity chimeric anti-METH monoclonal antibody that is well-tolerated in healthy volunteers and in non-intoxicated people with METH use disorder. The total dose will be given over 10 min for the 0.5-g dose and over 20 min for the 1-, 1.5-, and 2-g doses. arm 2: Lorazepam is a benzodiazepine that is safe and commonly used to treat agitation and dysphoria in the emergency setting. Haloperidol is commonly used to treat agitation due to psychosis.

Interventions: intervention 1: IXT-m200 intervention 2: Lorazepam intervention 3: Haloperidol
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: Lorazepam is a benzodiazepine that is safe and commonly used to treat agitation and dysphoria in the emergency setting. intervention 3: Haloperidol is commonly used to treat agitation due to psychosis.

Protocol document:
ICF_002.pdf: 
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INFORMED CONSENT FORM- INITIAL CONSENT AND HIPAA AUTHORIZATION 
 
For use with participants with capacity to consent only 
 
For use with cohort 3 only 
 
TITLE: 
METH-OD: A PHASE 2A STUDY OF IXT-M200 IN 
PATIENTS WITH TOXICITY FROM METHAMPHETAMINE 
OVERDOSE 
 
PROTOCOL NO.: 
M200C-2101 
 
WCG IRB Protocol # 20210895 
 
SPONSOR: 
InterveXion Therapeutics, LLC 
 
INVESTIGATOR: 
Name 
 
Address 
 
City, State  Zip 
 
Country 
 
STUDY RELATED 
PHONE NUMBER(S): 
Phone Number 
 
Phone Number (24 hours) 
 
[24 hour number is required] 
 
Taking part in this research is voluntary.  You may decide not to participate, or you may 
leave the study at any time.  Your decision will not result in any penalty or loss of 
benefits to which you are otherwise entitled. 
 
If you have any questions, concerns, or complaints or think this research has hurt you, 
talk to the research team at the phone number(s) listed in this document. 
 
In this consent form “you” generally refers to the research subject.  
 
You are invited to take part in a research study because you have mild to moderate 
toxicity (undesirable or harmful effect of a drug) from a methamphetamine overdose. 
Your participation is voluntary and requires your written consent. If you decide not to 
take part in this study, you can continue with your current medical care. 
 
Participating in a research study is not the same as getting regular medical care. The 
goal of a research study is to collect information about a medical treatment; the goal of 
regular medical care is to improve your health. Being in this study does not replace your 
regular medical care, but you may have additional evaluations or changes in your 
treatments during the study. 


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Sponsor: InterveXion Therapeutics, LLC 
 
InterveXion Therapeutics, LLC is sponsoring this study. The study is being funded by 
the National Institute on Drug Abuse (NIDA), with grant number U01 DA053043, who 
appreciates your involvement in the study. Your study doctor will be paid for his or her 
work in this study.  
 
The study will take place at approximately 5 centers in the United States with about 24 
people with mild to moderate toxicity from a methamphetamine overdose participating. 
 
The study has been reviewed by an Institutional Review Board (IRB). An IRB is a group 
of scientists and non-scientists who review the ethics of research. The goal of the IRB is 
to protect the rights and welfare of study subjects. 
 
Before agreeing to be in this study, it is important that you read and understand this 
form. It describes the goal, procedures, benefits, risks, discomforts, and precautions of 
the study. It also describes different procedures that are available to you and your right 
to withdraw from the study at any time. Please read this information carefully and ask 
the study doctor or study staff for an explanation if you have any questions. 
 
If you choose to participate in this study, you will be asked to read and sign this initial 
consent document. You will receive a copy of this signed and dated form to keep. 
 
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. 
 
Why is this study being done? 
InterveXion Therapeutics, LLC has begun a study of an investigational drug (also known 
as the “study drug”) called IXT-m200 as a possible treatment for mild to moderate 
methamphetamine toxicity. An investigational drug is one that has not been approved 
by regulatory agencies, such as the United States (US) Food and Drug Administration 
(FDA), European Union (EU) European Medicines Agency (EMA), or others. 
 
The goal of this study is to learn how well different doses of the study drug work and 
how safe the study drug is in participants with a methamphetamine overdose. 
 
The study has enrolled enough participants dosed with IXT-m200, but still needs 
additional participants who are given treatment-as-usual for comparison. 
 
How long will my participation in this study last? 
You will be in this study for approximately 28 days. You will be treated in the emergency 
department, then asked to return for a check-up 2 days later and again after 4 weeks. 
 


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What will happen during this study?  
The study is divided into 3 periods: a screening period, a treatment period, and a follow-
up period. During each study period, you will have 1 or more visits with your study 
doctor. You will need to stay in the emergency department initially for at least 2 hours 
after receiving the study drug. How long you stay in the emergency department will 
depend on the treatment you get and how you respond to the treatment. It is expected 
you will be ready to leave in a few hours, but it may be 8 hours or more before you are 
ready to leave the emergency department. It is also possible that you will be admitted to 
the hospital as an inpatient after your emergency department treatment. All other visits 
should not take more than 1 to 2 hours. 
 
Before any study-related tests and procedures can be done, you will be asked to read 
and sign this informed consent form. The goal of the screening period is to determine 
whether you meet the requirements to take part in this study. If you do not meet the 
requirements, the study doctor will explain why and will discuss other treatment options 
with you. 
 
If the study doctor determines that you meet all of the requirements to be in the study, 
you will be assigned to receive the following treatments:  
• treatment as usual, which will be up to 4 mg of lorazepam (Ativan), up to 5 mg of 
haloperidol (Haldol), or a combination of both. 
 
You will receive up to 4 mg of lorazepam by IV and/or up to 5 mg of haloperidol by 
intramuscular injection (injection into a muscle) into your arm or buttocks or by IV. 
Lorazepam and haloperidol are drugs commonly used to treat methamphetamine 
toxicity symptoms. 
 
Description of the procedures and tests 
The following tests and procedures will occur as shown in the picture below. 
 
• Physical and neurological (relating to your nervous system) examinations: A 
check-up of your health, which will include examining your head, ears, eyes, 
nose, throat, neck, heart, chest, lungs, abdomen, arms and legs, skin, and any 
other physical conditions of note. Your height and weight will also be measured.  
• Medical, medication, and psychiatric history: You will be asked some questions 
about your health, including allergies or other illnesses, any medications you 
have taken, and if you have used methamphetamine in the past 24 hours.  
• Vital signs: Your heart and breathing rate, blood pressure, body temperature, and 
blood oxygen levels will be measured. 
• Mental health: You will be asked some questions about if you think about killing 
yourself or have tried to kill yourself. 
• You will be asked questions about your drug use and how it felt after participating 
in the study. 


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• You will be asked if you agree to have an IV line inserted so that you can be 
given study medications and if you agree to have blood drawn several times. 
• You will be assessed for agitation or sleepiness frequently. 
• Electrocardiogram (ECG): A technician will place patches (sticky pads) on your 
chest that will be connected by wires to a machine. The machine will record the 
electrical activity of your heart. 
• You will be given a Breathalyzer test to check for alcohol. 
• Laboratory tests: Blood and urine samples will be collected. 
o A blood sample will be taken to measure the methamphetamine in your 
blood. About 10 mL (1-2 teaspoons) of blood will be taken. 
o A blood sample will be taken for various blood tests to evaluate your 
general health (the cells and chemicals in your blood, etc.). About 10 ml 
(1-2 teaspoons) of blood will be taken at least 30 minutes after you receive 
the study drug and again 2 days later. 
o A urine sample will be taken to test your health and to perform a drug test. 
▪ If you are a female who is able to have children, a urine sample 
will be collected to test whether or not you are pregnant. 
 
The following picture shows what procedures and assessments will occur at which 
visit(s). In addition to the visits described below, the study doctor may do some 
additional tests, if necessary for your safety. 
 


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Study Outline 
  
Abbreviations: IM, intramuscular; IV, intravenous; min, minutes. 
 
Triage
Consent
Decision 
to Enroll
Administer lorazepam 
(≤4 mg) by IV, 
haloperidol (≤5 mg) 
by IM or IV, or both
Follow and observe 
for AEs
Outpatient follow-ups 
on Days 3 and 28
Subject 
participation 
concluded
•Vitals and agitation scores taken at 0.5, 1, 
2, 3, 4, 6, and 8 hr post-dose
•Sample for clinical labs and UDS, and do 
ECG as soon as feasible >0.5 hr post-dose
•Perform UPT and breathalyzer as soon as 
feasible
•Take PK samples
• Eligibility criteria
• Agreement with procedures
• Focused history and physical exam
• Vitals
• Agitation scores
•Repeat informed consent (Day 3)
•Clinical labs and UDS (Day 3)
Discharge 
or admit


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What do I have to do? 
During the study, you will have the following responsibilities: 
• 
Follow the study instructions given by the study staff and doctor. 
• 
Tell the study doctor of any illnesses or injuries, side effects, or other problems that 
occur during your participation in this study. 
• 
Tell the study doctor or staff of any new medications (prescription or over-the-
counter) that you start taking after signing this consent form. 
• 
Return to the clinic as instructed by the study staff and doctor. 
• 
You should continue to make regular visits to your family/personal doctor or any 
other special doctors you were seeing before starting the study because being in the 
study does not replace regular medical care. 
• 
Contact the study doctor if you find you have any questions about the study after you 
sign this form. 
 
What are the risks and possible discomforts? 
Any study has risks, which may include things that could make you sick, make you feel 
uncomfortable, or harm you. You might experience side effects while participating in the 
study. All participants in the study will be watched carefully for any side effects. The 
study team may give you medicines to help reduce side effects. These side effects may 
be mild or serious. In some cases, these side effects might be long lasting or permanent 
and may even be life-threatening. 
 
In this research study, you will receive lorazepam and/or haloperidol. 
 
Possible risks/side effects associated with lorazepam include: 
• Lorazepam is a benzodiazepine that is approved by the US FDA for short-term 
relief of anxiety symptoms. Lorazepam is often given to relieve anxiety or to 
cause sedation. This is a medication that is commonly used to treat non–life-
threatening symptoms of a methamphetamine overdose. 
• Side effects of lorazepam include drowsiness, tiredness, amnesia (memory loss), 
and loss of balance. 
• It is possible that lorazepam may increase the risk of respiratory depression 
(slow ineffective breathing), especially if combined with another sedative 
medication. 
 
Possible risks/side effects associated with haloperidol include: 
• Haloperidol is approved to treat some mental or mood disorders. Haloperidol is 
often given to help you think more clearly, feel less nervous, and reduce 
aggression. This medication is commonly used to treat non–life-threatening 
symptoms of a methamphetamine overdose. 
• Side effects of single doses of haloperidol given over a short period of time 
include dizziness, lightheadedness, drowsiness, difficulty urinating, sleep 
disturbances, headache, and anxiety. 
 


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Other risks include: 
• Blood samples: Over the whole study, you may have approximately 30 ml (2 
tablespoons) of blood taken. You might feel lightheaded, pain, or have bruising or 
bleeding when blood samples are taken (infection rarely happens). 
• ECG: Skin irritation is rare but could occur during an ECG from the electrode 
patches (which are sticky) or gel that is used. 
• You will have a catheter inserted (IV line) to be dosed with medications if 
needed. There is a small risk of infection from the IV insertion. 
 
Confidentiality risks include:  
• To enroll in this study, you must admit to using methamphetamine. We will 
protect the information about you and your taking part in this research study to 
the best of our ability, but there is a risk of loss of confidentiality. 
• 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 US federal or state government agency from checking records 
or evaluating programs. The Certificate DOES NOT stop disclosures required by 
the US 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. 
 
In addition to these risks, taking part in this research may harm you in unknown ways. 
 
What are the benefits of being in this study? 
There is no guarantee that you will receive any benefits. However, you will be helping 
others by contributing to medical research. Possible benefits to others include the 
continued development of a medication to treat a methamphetamine overdose. Your 
condition will be checked as long as your participation in the study lasts. However, 
services provided and evaluations carried out as part of the study should not be seen as 


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a substitute for a careful evaluation, ongoing medical care, or follow-up by your 
family/personal doctor. 
 
You have the right to be informed of the overall results of the study. 
 
What other options are available if I do not take part in this study? 
You do not have to take part in the study to treat your mild to moderate 
methamphetamine toxicity. Instead of being in this research study, your choices may 
include the following: 
 
• You may choose to be treated by the emergency department doctor as he or she 
would normally do if you were not in the study. This may include treatment with 
lorazepam, haloperidol, or other similar drugs to calm or sedate you. Other drugs 
to reduce blood pressure may be added as needed. 
• You may also choose to not have further treatment for your symptoms. 
 
Your study doctor will discuss these options, and their risks and benefits, with you. 
 
What if I get harmed or injured during the study? 
If you require medical treatment for an illness or injury that is a direct result of 
participating in the study, call the study doctor immediately. The study doctor will 
provide emergency medical treatment or refer you for treatment. Your insurance may be 
billed for this treatment. The Sponsor will pay any charges that are not covered by your 
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. 
 
What are the costs for participation? 
You will not be charged for any study doctor visits, laboratory work, tests, or procedures 
that are needed for the study. You or your insurance company will have to pay for 
routine care you would receive whether or not you are in the study.  You may talk to the 
study staff and your insurance company about what is covered. 
 
Will I be paid? 
[You will receive no direct payment for taking part. However, you will be compensated 
for your time and reimbursed for transportation or parking payments related to visiting 
the study center. 
 
OR You will receive $XX for each completed study visit. 
 
OR You will not receive any payment for taking part in this research study.] 
 


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Do I have to take part in the study? 
Taking part in this study is voluntary. You can choose not to participate or you can 
withdraw later at any time for any reason. Your decision not to participate or to stop 
study participation will not result in any penalty or loss of benefits to which you are 
otherwise entitled. Your regular medical care will not be affected.  
 
If you are considering or have already decided to leave the study, you should contact 
the study doctor to discuss the safest way to leave the study. This may involve 
completing some final tests and examinations. You should also contact your 
primary/family doctor so he or she can provide you with the best course of continuing 
care. 
 
New information 
If new findings that would affect your safety and willingness to participate in the study 
are identified while you are in the study, you will be told as soon as possible so you can 
decide whether to leave the study or continue. If you decide to continue, you will be 
required to sign a new informed consent form. 
 
Could I be withdrawn from the study? 
Sometimes the study doctor or InterveXion Therapeutics, LLC may decide it best for 
you to stop your participation and remove you from the study (even if you do not agree). 
The study doctor will discuss this with you. Possible reasons for doing so include the 
following: 
• It is in your best interest. 
• You have a side effect that requires stopping the research. 
• You do not follow the instructions given by the study staff or doctors. 
• You no longer qualify after further questioning or testing. 
• Your blood samples do not contain any methamphetamine.  
• The research is canceled by the US FDA or the Sponsor. 
• You are unable to keep your scheduled appointments. 
 
What medical care will I receive when my participation in this study stops? 
After your participation in this research study, you will no longer have access to the 
study. If you return to the emergency department with a methamphetamine overdose, 
you will be treated as usual. You cannot enroll in the study more than once. 
 
What will happen to the samples that I provide? 
Data or specimens collected in this research might be deidentified (your personal 
information is removed) and used for future research or distributed to another 
investigator for future research without your consent. The blood and urine samples that 
you provide may be transferred to a commercial organization for testing and storage; 
however, the samples will be deidentified first. This commercial organization will have 
ownership of the research results and may file patents or otherwise protect and 


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commercialize any research results; you will not benefit from any future 
commercialization. 
 
What happens with my data and other personal information? 
All data collected on Day 1 will be used in the study analyses. However, no data will be 
collected on Day 3 or Day 28 if consent is not obtained from the participant on Day 3. 
 
All information that you give will be kept strictly confidential.  The information collected 
about you usually will not directly identify you (for example, by name, address, or social 
security number).  Instead, a coded identification number will be used for your 
information.   
 
Your records may be reviewed by: 
• Study Sponsor (the sponsor) and its affiliates 
• Individuals and/or companies that act on the Sponsor’s behalf, including 
Syneos Health. 
• The Institutional Review Board (IRB). 
• Data safety monitoring committees 
• Accrediting agencies that monitoring the accuracy and completeness of the 
research data 
• The U.S. Food and Drug Administration (FDA) 
• Department of Health and Human Services (DHHS) agencies 
• NIDA 
• Other regulatory agencies 
 
These people may look at your records to make sure the study has been done the right 
way.  They also want to make sure that your health information has been collected the 
right way, or for other reasons that are allowed under the law. 
 
If information about this study is published, you will not be identified. 
 
A detailed description of what will happen to your data and other personal information is 
included in the HIPAA Authorization that you should read and sign to be able to 
participate in this study. 
 
Whom should I reach if I have a question? 
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(s) listed above on the 
first page. 
 


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This research is being overseen by an Institutional Review Board (“IRB”). An IRB is a 
group of people who perform independent review of research studies. You may talk to 
them at 1-855-818-2289 or Researchquestions@wcgirb.com if: 
• 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. 
 
Participant Consent to Participate 
 
By signing this informed consent form, I agree to the following: 
• I have read and I understand this informed consent form.  
• I have been given the chance to ask any questions that I had about the study, and 
all questions that I asked were answered to my satisfaction.  
• I understand the risks of taking part in this study as described in this informed 
consent form.  
• I freely consent to be treated under the study doctor’s care. I understand that there 
is no guarantee that I will receive any benefits from taking part in this study.  
• I understand that I am free to withdraw from the study at any time for any reason. I 
will tell the study doctor if I decide to withdraw so that participation may end in an 
orderly manner and my future care can be discussed. I understand that the study 
doctor can stop my participation in the study at any time. 
• I understand that I will be told of any new information that might relate to my 
willingness to continue in the study. 
• I understand that I cannot participate in another research study while taking part in 
this one. 
• I understand that I will receive a signed and dated copy of this informed consent 
form for my records. 
 


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My consent to participate in this study does not take away any legal rights in the case of 
negligence (carelessness) or other legal fault of anyone who is involved with this study. 
 
 
_______________________________________ 
Name of participant (print) 
 
 
_______________________________________ 
_________________ 
Signature of participant 
Date (dd/Mmm/yyyy) 
 
I confirm that all the contents of this informed consent form were discussed and that any 
questions have been answered. I confirm that this participant was found capable of 
consent by administration of the UCSD Brief Assessment of Capability to Consent. 
 
 
___________________________________ 
Name of study doctor or person administering consent (print) 
 
 
____________________________________ 
_________________ 
Signature of study doctor or person administering 
Date (dd/Mmm/yyyy) 
consent 
 
Impartial Witness  
I am an impartial witness, and I confirm I was present during the entire informed 
consent discussion. I attest that the information in this informed consent form was 
accurately explained, apparently understood, that the consent to participate was given 
freely by the participant. 
 
 
_______________________________________ 
Name of impartial witness (print) 
 
 
_______________________________________ 
_________________ 
Signature of impartial witness 
Date (dd/Mmm/yyyy) 
 
An impartial witness is: 
• a person who is independent of the trial,  
• who cannot be unfairly influenced by people involved with the trial, 
• who attends the informed consent process, and  
• who reads the informed consent form and any other written information supplied 
to the participant if necessary. 
 


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HIPAA AUTHORIZATION TO USE AND/OR DISCLOSE PERSONAL 
HEALTH INFORMATION 
 
In this form, the terms “you” and “your” refers to the research subject. 
 
Federal laws and regulations give you certain rights related to “protected 
health information” or which might identify you.  These include the right to 
know who will receive your protected health information and how it will be 
used. The study doctor must obtain your authorization (permission) to use 
or share any of your protected health information. This authorization form, 
which is attached to your consent for participation in the research study, 
helps explain to you how your protected health information collected in the 
Study will be used and shared with others. 
 
Data to Be Collected and Processed: The study staff will collect, use and 
share protected health data about you for the study. This data may include 
your name or initials, date of birth, gender, contact details, and information 
needed for payment processing. In addition, the following sensitive 
personal data about you may be collected: health, ethnicity, and race. 
 
Except when required by law, you will not be identified by name, address, 
telephone number or other facts that could identify the health information 
as yours. 
 
Examples of the information that may be used are: 
• Medical records (from any doctor, hospital or other healthcare 
provider) 
• Information created or collected during the research.  This could 
include your medical history, and dates or results from any physical 
exams, laboratory tests or other tests. 
 


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IRB Version 1.0 
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Sponsor: InterveXion Therapeutics, LLC 
Who May Receive Your Personal Health Information: The study doctor 
and study staff will receive your protected health information. Additionally, 
individuals from the following organizations may also receive your 
protected health information: 
• Study Sponsor (the sponsor) and its affiliates 
• Individuals and/or companies that act on the Sponsor’s behalf, 
including Syneos Health. 
• Institutional Review Board (IRB) 
• Data safety monitoring committees 
• Accrediting agencies that monitoring the accuracy and completeness 
of the research data 
• The U.S. Food and Drug Administration (FDA) 
• Department of Health and Human Services (DHHS) agencies 
• NIDA 
• Other regulatory agencies 
 
The sponsor and the groups above will use your health information: 
• to complete this research 
• to evaluate the results of the study 
• to check that the study is being done properly 
• to obtain marketing approval for new products resulting from this 
research 
 
The information that is shared with those listed above may no longer be 
protected by federal privacy rules or this authorization form and may be 
released without your permission. 
 
With your permission, the study doctor will tell your primary doctor about 
your role in this study. In unusual cases, the study doctor may be required 
to release your protected health information in response to an order from a 
court of law. 
 
How Your Personal Data Will Be Used: The protected health information 
collected about you will be recorded in your study file by the study staff to 
run the study and to monitor your safety as a participant. Your protected 
health information may be processed on a computer, on paper, or both. 
The collection of this data is necessary to conduct the study and comply 


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with applicable laws. You will not be able to participate in the study if you 
fail or refuse to provide your information. 
 
If you do not consent to the collection and use of your personal information, 
you will not be able to be in the study. 
 
Results of this study may be presented at meetings or in publications; 
however, your identity will never be shared. Your personal data will not be 
used for any direct marketing purposes. 
 
Storage of Your Personal Data: Your personal health information will be 
stored in the study databases and/or paper files for whichever time period 
is longer, as required by applicable laws: 
• at least 30 years after the study ends, OR 
• at least 2 years after the drug being studied has received its last 
approval for sale, OR 
• at least 2 years after the drug’s development has stopped. 
 
Confidentiality: To keep your identity private, all data that is sent or 
provided outside of the study center will show only a coded identification 
number instead of your name. Only the study doctor and authorized 
personnel will be able to connect this code to your name. They will use a 
list that will be kept in a secure place to link this code to your name in case 
of an emergency. 
 
You may not be able to review some of your records related to the study 
until after the study is over. When the study is over, you may contact the 
study doctor to see your health data from the study and to correct any 
errors. 
 
Right to Refuse Use of Protected Health Information: Your 
authorization to disclose your protected health information for this research 
study is voluntary.  However, if you do not authorize the use of such 
protected health information, you will not be allowed to participate in this 
study.  If you withdraw your authorization during the study, you will be 
removed from the study. 
 


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Right to Revoke or Withdraw Use of Your Protected Health 
Information: You may withdraw the authorization for use of your protected 
health information at any time or choose not to participate. Neither decision 
will result in any penalty or loss of benefits to which you are otherwise 
entitled.  If you wish to withdraw your authorization for use of your 
protected health information, you must inform the study doctor in writing. 
 
If you stop participating in or are removed from the study, no new 
information about you will be collected for the study unless you have a side 
effect related to the study. Any protected health information already 
recorded as a result of your participation in the study may continue to be 
used and disclosed by the study doctor for the purposes outlined above. 
 
If you withdraw from the study but do not withdraw your Authorization, new 
health information may be collected until this study ends. 
 
If you do not withdraw this Authorization, it will remain in effect. 
 
If the research site is located in California, Delaware, Indiana, Washington, 
or Wisconsin this authorization will expire on 31Dec2070. 
 
There is no expiration of this authorization except for research conducted in 
the states listed above. 
 


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AUTHORIZATION 
By signing this form, I allow the use or disclosure of my health information.  
I will receive a signed and dated copy of this Authorization. 
 
 
_______________________________________ 
Name of participant (print) 
 
 
_______________________________________ _________________ 
Signature of participant 
Date (dd/Mmm/yyyy) 
 
Impartial Witness (when applicable*) 
I am an impartial witness, and I confirm I was present during the entire 
Authorization discussion. I attest that the information in this form was 
accurately explained, apparently understood, that Authorization was given 
freely by the participant. 
 
 
_______________________________________ 
Name of impartial witness (print) 
 
 
_______________________________________ _________________ 
Signature of impartial witness 
Date (dd/Mmm/yyyy) 
 
An impartial witness is: 
• a person who is independent of the trial,  
• who cannot be unfairly influenced by people involved with the trial, 
• who attends the Authorization process, and  
• who reads the Authorization and any other written information 
supplied to the participant if necessary. 
 

Prot_000.pdf: 
METH-OD: A PHASE 2A STUDY OF IXT-M200 IN 
PATIENTS WITH TOXICITY FROM 
METHAMPHETAMINE OVERDOSE 
Protocol Number: M200C-2101 
National Clinical Trial (NCT) Identified Number:  NCT04715230 
IND Sponsor: InterveXion Therapeutics, LLC 
Funded by: NIH/NIDA U01 DA053043 
Version Number: 5 
22 Aug 2022 


  
 
 
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 .......................................................................................................................................... 4 
1.3. Schedule of Activities (SoA)......................................................................................................... 5 
2. INTRODUCTION ................................................................................................................................... 6 
2.1. Study Rationale ............................................................................................................................. 6 
2.2. Background ................................................................................................................................... 6 
2.3. Risk/Benefit Assessment ............................................................................................................... 9 
2.3.1. 
Known Potential Risks ................................................................................................... 9 
2.3.2. 
Known Potential Benefits............................................................................................... 9 
2.3.3. 
Assessment of Potential Risks and Benefits .................................................................. 9 
3. OBJECTIVES AND ENDPOINTS ...................................................................................................... 10 
4. STUDY DESIGN .................................................................................................................................. 10 
4.1. Overall Design............................................................................................................................. 10 
4.2. Scientific Rationale for Study Design ......................................................................................... 11 
4.3. Justification for Dose .................................................................................................................. 11 
4.4. End of Study Definition .............................................................................................................. 12 
5. STUDY POPULATION ....................................................................................................................... 12 
5.1. Description of and Rationale for the Selected Population .......................................................... 12 
5.2. Inclusion Criteria ......................................................................................................................... 13 
5.3. Exclusion Criteria ........................................................................................................................ 13 
5.4. Lifestyle Considerations .............................................................................................................. 14 
5.5. Screen Failures ............................................................................................................................ 14 
5.6. Strategies for Recruitment and Retention ................................................................................... 15 
5.6.1. 
Strategies for Recruitment ............................................................................................ 15 
5.6.2. 
Strategies for Retention and Follow-Up....................................................................... 15 
6. STUDY INTERVENTION ................................................................................................................... 15 
6.1. Study Intervention Administration .............................................................................................. 15 
6.1.1. 
Study Intervention Description .................................................................................... 15 
6.1.2. 
Dosing and Administration .......................................................................................... 16 
6.2. Preparation/Handling/Storage/Accountability ............................................................................ 16 
6.2.1. 
Acquisition and Accountability .................................................................................... 16 
6.2.2. 
Formulation, Appearance, Packaging, and Labeling ................................................... 16 
6.2.3. 
Product Storage and Stability ....................................................................................... 17 
6.2.4. 
Preparation ................................................................................................................... 17 
6.3. Measures to Minimize Bias: Randomization and Blinding ........................................................ 17 
6.4. Study Intervention Compliance ................................................................................................... 17 
6.5. Concomitant Therapy and Risk Mitigation plan ......................................................................... 18 
6.5.1. 
Rescue Medicines ......................................................................................................... 18 
6.5.2. 
Risk Mitigation ............................................................................................................. 18 
7. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................. 19 


  
 
 
iii 
7.1. Discontinuation of Study Intervention ........................................................................................ 19 
7.2. Participant Discontinuation/Withdrawal from the Study ............................................................ 19 
7.3. Lost to Follow-Up ....................................................................................................................... 20 
8. STUDY ASSESSMENTS AND PROCEDURES ................................................................................ 20 
8.1. Efficacy Assessments .................................................................................................................. 20 
8.2. Safety and Other Assessments .................................................................................................... 21 
8.3. Adverse Events and Serious Adverse Events .............................................................................. 23 
8.3.1. 
Definition of Adverse Events (AE) .............................................................................. 23 
8.3.2. 
Definition of Serious Adverse Events (SAE) ............................................................... 23 
8.3.3. 
Classification of an Adverse Event .............................................................................. 24 
8.3.4. 
Time Period and Frequency for Event Assessment and Follow-Up ............................ 25 
8.3.5. 
Adverse Event Reporting ............................................................................................. 25 
8.3.6. 
Serious Adverse Event Reporting ................................................................................ 26 
8.3.7. 
Reporting Events to Participants .................................................................................. 26 
8.3.8. 
Events of Special Interest ............................................................................................. 26 
8.3.9. 
Reporting of Pregnancy ................................................................................................ 27 
8.4. Unanticipated Problems .............................................................................................................. 27 
8.4.1. 
Definition of Unanticipated Problems.......................................................................... 27 
8.4.2. 
Unanticipated Problem Reporting ................................................................................ 27 
8.4.3. 
Reporting Unanticipated Problems to Participants ...................................................... 28 
9 
STATISTICAL CONSIDERATIONS .................................................................................................. 28 
9.1. Statistical Hypotheses ................................................................................................................. 28 
9.2. Sample Size Determination ......................................................................................................... 28 
9.3. Populations for Analyses ............................................................................................................. 29 
9.4. Statistical Analyses ..................................................................................................................... 29 
9.4.1. 
General Approach ........................................................................................................ 29 
9.4.2. 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 29 
9.4.3. 
Analysis of the Secondary Endpoint(s) ........................................................................ 29 
9.4.4. 
Safety Analyses ............................................................................................................ 30 
9.4.5. 
Baseline Descriptive Statistics ..................................................................................... 31 
9.4.6. 
Planned Interim Analyses............................................................................................. 31 
9.4.7. 
Exploratory Analyses ................................................................................................... 31 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 31 
10.1. Regulatory, Ethical, and Study Oversight Considerations .......................................................... 31 
10.1.1. Informed Consent Process ............................................................................................ 31 
10.1.2. Study Discontinuation and Closure .............................................................................. 33 
10.1.3. Confidentiality and Privacy .......................................................................................... 34 
10.1.4. Future Use of Stored Specimens and Data ................................................................... 34 
10.1.5. Key Roles and Study Governance ................................................................................ 35 
10.1.6. Safety Oversight ........................................................................................................... 35 
10.1.7. Clinical Monitoring ...................................................................................................... 35 
10.1.8. Quality Assurance and Quality Control ....................................................................... 36 
10.1.9. Data Handling and Record Keeping ............................................................................. 36 
10.1.10. Protocol Deviations ...................................................................................................... 37 
10.1.11. Publication and Data Sharing Policy ............................................................................ 38 
10.1.12. Conflict of Interest Policy ............................................................................................ 38 
10.2. Abbreviations .............................................................................................................................. 39 
10.3. Protocol Amendment History...................................................................................................... 41 
11 REFERENCES ...................................................................................................................................... 45 


  
 
 
iv 
12 DATA AND SAFETY MONITORING PLAN .................................................................................... 47 
12.1. Summary of the Protocol............................................................................................................. 48 
12.1.1. Study Design ................................................................................................................ 48 
12.1.2. Primary and Secondary Objectives and Outcome Measures........................................ 50 
12.1.3. Inclusion Criteria .......................................................................................................... 50 
12.1.4. Exclusion Criteria ......................................................................................................... 51 
12.1.5. Power Calculation and Sample Size............................................................................. 51 
12.2. Trial Management ....................................................................................................................... 52 
12.2.1. Participating Clinics ..................................................................................................... 52 
12.2.2. Planned Enrollment Timetable ..................................................................................... 53 
12.2.3. Target Population Distribution ..................................................................................... 53 
12.3. Data Management and Analysis .................................................................................................. 54 
12.3.1. Data Acquisition and Transmission ............................................................................. 54 
12.3.2. Data Entry Methods ..................................................................................................... 54 
12.3.3. Data Security and Plan for Protecting Confidentiality ................................................. 54 
12.3.4. Data Analysis Plan ....................................................................................................... 55 
12.4. Quality Assurance and Quality Control ...................................................................................... 55 
12.4.1. Procedures in Place to Ensure the Validity and Integrity of the Data .......................... 55 
12.4.2. Procedures to Guarantee the Accuracy and Completeness of the Data During Data 
Collection, Entry, Transmission, and Analysis ........................................................................... 55 
12.5. Regulatory Issues ........................................................................................................................ 56 
12.5.1. Reporting of SAEs ....................................................................................................... 56 
12.5.2. Reporting of IRB Actions to NIDA ............................................................................. 57 
12.5.3. Report of Changes or Amendments to the Protocol ..................................................... 57 
12.6. Trial Safety .................................................................................................................................. 57 
12.6.1. Potential Risks and Benefits for Participants ............................................................... 57 
12.6.2. Risk Mitigation Plan..................................................................................................... 58 
12.6.3. Trial Stopping Rules..................................................................................................... 58 
12.6.4. Process of AE/SAE Collection, Assessment, and Reporting ....................................... 59 
12.6.5. AE/SAE Follow-Up Plan ............................................................................................. 60 
12.7. Trial Efficacy............................................................................................................................... 60 
12.7.1. Plans for Interim Analysis of Efficacy Data ................................................................ 60 
12.8. DSM Plan Administration ........................................................................................................... 60 
12.8.1. Responsibility for Data and Safety Monitoring ........................................................... 60 
12.8.2. Persons Responsible for Monitoring the Trial ............................................................. 60 
12.8.3. Disclosure of Any Conflict of Interest in the DSM ..................................................... 61 
12.8.4. Frequency of DSM ....................................................................................................... 61 
12.8.5. Content of DSM Report ............................................................................................... 61 
12.9. DSM Board Plan ......................................................................................................................... 61 
12.9.1. Members and Affiliation .............................................................................................. 61 
12.9.2. Conflict of Interest ....................................................................................................... 61 
12.9.3. Frequency of Meetings ................................................................................................. 62 
12.9.4. Protection of Confidentiality ........................................................................................ 62 
12.9.5. Monitoring Activities (Initial and Ongoing Study Review)......................................... 62 
12.9.6. Communication Plan to IRB, NIDA, and FDA ........................................................... 62 


MET-M--D 
Meth-OD: A Phase 2a Study of!XT-m200 in Patients with Toxicity from Methamphetamine Overdose 
M200C-2101 
Chief Medical Officer 
Chief Operating Officer 
Version 5 
22 Aug2022 


 
Meth-OD: A Phase 2a Study of IXT-m200 in Patients with Toxicity from Methamphetamine Overdose 
Version 5 
M200C-2101 
22 Aug 2022 
 
 
2 
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: _____________________________________________________________ 


 
Meth-OD: A Phase 2a Study of IXT-m200 in Patients with Toxicity from Methamphetamine Overdose 
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22 Aug 2022 
 
 
3 
1.  
PROTOCOL SUMMARY 
1.1. SYNOPSIS  
Title: 
Meth-OD: A Phase 2a Study of IXT-m200 in Patients with Toxicity from 
Methamphetamine Overdose 
Study Description: 
The proposed study is a randomized, open-label Phase 2a study of 
IXT-m200 versus treatment-as-usual (TAU) in which patients with mild to 
moderate methamphetamine (METH) toxicity will be treated with 
IXT-m200 or lorazepam and/or haloperidol. The hypothesis is that 
IXT-m200 will be well-tolerated in patients with acute mild to moderate 
METH toxicity. 
Objectives: 
 
Primary Objective: To evaluate the safety and tolerability of IXT-m200 in 
patients with mild to moderate METH toxicity. 
 
Secondary Objectives: To determine the time course and degree of 
normalization of agitation and vital signs, and to determine the percentage 
of participants in each group requiring rescue medications for psychiatric or 
cardiovascular manifestations of METH intoxication.   
Endpoints: 
Primary Endpoint:   
• 
Safety and tolerability of IXT-m200 as measured by physical 
examinations and vital sign, adverse event (AE), electrocardiogram 
(ECG), and clinical laboratory testing. 
Secondary Endpoints: 
• 
Agitation/sedation scores over time as measured with the ACES 
(Agitation/Calmness Evaluation Scale);  
• 
Vital signs including blood pressure, heart rate and temperature 
over time;  
• 
Need for rescue medications to treat: 
o agitation, dysphoria, or psychosis (CNS signs/symptoms) 
o hypertension, tachycardia, or other cardiovascular 
instability (CV signs/symptoms). 
Exploratory Endpoints: 
• 
Emergency department (ED) length of stay as measured by 
disposition order time minus triage time, and by disposition order 
time minus start of treatment time, with log transformation. 
Study Population: 
Approximately 24 males and females aged 18-45, presenting to an ED 
setting with mild to moderate METH toxicity who request treatment for 
symptoms related to their METH use will be recruited. 
Phase: 
2a 
Description of Sites 
Enrolling Participants: 
Approximately 5 ED 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 people with 
METH use disorder. The total dose will be given over 10 min for the 0.5-g 
dose and over 20 min for higher doses. Lorazepam is a benzodiazepine that 
is safe and commonly used to treat agitation and dysphoria in the 
emergency setting. Haloperidol is commonly used to treat agitation due to 
psychosis.  
Study Duration: 
Approximately one year 
Participant Duration: 
28 days 


 
Meth-OD: A Phase 2a Study of IXT-m200 in Patients with Toxicity from Methamphetamine Overdose 
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1.2. SCHEMA 
 


 
Meth-OD: A Phase 2a Study of IXT-m200 in Patients with Toxicity from Methamphetamine Overdose 
Version 5 
M200C-2101 
22 Aug 2022 
 
 
5 
1.3. SCHEDULE OF ACTIVITIES (SOA) 
 
Assessment 
Triage 
Screening 
Dosing and Assessments f 
Follow-upa 
Study Day 
1 
1 
1 
Day not 
specified 
3 
(+2) 
28 
(±7) 
Hour 
NA 
<0 
<0 
0 
0.25 
0.5 
0.75 
1 
1.5 
2 
3 
4 
6 
8 
>8, <Discharge 
from ED 
Discharge 
from ED 
NA 
NA 
Focused history and physical 
exam b, c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Focused review of systems b, c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Medication history 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Detailed and pertinent 
psychiatric history c, d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs c 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
As needed 
X 
X 
X 
Agitation score c 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
As needed 
 
 
 
Informed consent and 
UBACC 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Eligibility criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samples d 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
Dose administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Observe for AEs 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
As needed 
X 
X 
X 
Assess for rescue meds 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
As needed 
X 
 
 
Clinical labs and ECG 
 
 
 
 
 
Once, as soon as feasible 
 
 
 
 
X 
 
UDS, UPT, Breathalyzer  
 
 
Once, as soon as feasible 
 
 
 
 
 
 
Detailed and pertinent 
medical history e 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
DSM5 SUD checklist 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Drug use assessment and 
Meth Perception Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
AE – adverse event; UDS – urine drug screen; UPT – urine pregnancy test; ECG – electrocardiogram; DSM5 SUD – Diagnostic and Statistical Manual of Mental Disorders 5 for 
Substance Use Disorders; NA – not applicable; UBACC – UCSD Brief Assessment of Capacity to Consent 
a If participants do not return for a follow-up visit, a phone call will be attempted to assess any AEs. 
b Focused history, physical exam and review of systems based on main complaint, related details from other parts of the medical history and physical exam, and eligibility criteria.  
c Assessments will be obtained as either part of triage or screening, depending on the site. PANSS-EC will be done at screening only; ACES will be done at each time point as 
marked. 
d PK samples will be drawn for both IXT-m200 and METH per section 8.2. 
e Detailed and pertinent history includes pertinent past medical, family and social histories in addition to focused history. Detailed physical exam to be completed if indicated by 
detailed and pertinent medical history.  
f Subjects may be discharged at any time point after the 2-hr assessments are completed if the subject is deemed medically eligible; assessments at Day 1, Hours 3-8 may be 
skipped if discharged. Assessments assigned for the time of discharge from ED should be completed for all subjects. 


 
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2.  
INTRODUCTION 
2.1. STUDY RATIONALE  
 
No direct antagonists have been approved, or even clinically evaluated, for treatment of METH overdose. 
In fact, no medications have been approved for any form of METH Use Disorder (MUD) 1. Emergency 
care providers use a variety of medications to manage patients with METH toxicity based on the primary 
presenting symptoms and their individual and institutional experience. Mild to moderate agitation and 
dysphoria may be treated with benzodiazepines or antipsychotic medications 2. Severe CNS agitation and 
delirium are treated with combinations of benzodiazepines, antipsychotics, and other sedatives (e.g., 
ketamine) 2. The cardiovascular and cerebrovascular effects of METH overdose are treated with 
combinations of vasodilators, beta and calcium channel blockers, and anti-arrhythmic medications 3. 
Altogether, given the lack of targeted therapies, ED management of patients presenting with METH 
toxicity is symptomatic at best, intended only to reduce and/or mask the acute physiologic effects of 
METH until it can be cleared by metabolism and excretion. Furthermore, patients with METH toxicity 
may be hypersomnolent during metabolism of METH and repletion of monoamines and adenosine 
triphosphate. These sedative effects, especially when combined with sedative effects of benzodiazepines 
or other sedatives, may delay ED discharge and increase length of stay 4 at best, and may result in 
compromise of ventilation at worst. A single pharmacokinetic antagonist medication that results in a 
calmer, cooperative patient without sedation would offer a clear advantage over current 
pharmacologic approaches for the management of agitation associated with METH overdose. 
 
IXT-m200, a chimeric monoclonal antibody (mAb) that binds METH with high affinity, has been 
evaluated in a Phase 2a study in non-treatment-seeking people who use METH (NCT03336866). Data 
from multiple studies in rats show that METH effects, such as increased locomotor activity, are quickly 
reduced following treatment with anti-METH antibodies 5,6.This is accompanied by reductions in brain 
METH concentrations. Preliminary results from the Phase 2a study in otherwise healthy people with 
MUD indicate that IXT-m200 greatly reduces METH volume of distribution by sequestering METH in 
the blood, as expected based on animal data. The antibody also appears to be well-tolerated in healthy 
people who do and do not use METH. Together, these results suggest that IXT-m200, a specific METH 
pharmacokinetic (PK) antagonist, could be an effective treatment for METH overdose. 
 
2.2. BACKGROUND  
 
Study Intervention 
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 (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) 7,8. 
  
Through the binding of METH in the bloodstream, it is anticipated that IXT-m200 will alter the PK of 
METH and decrease concentrations of METH in its active sites in the brain. IXT-m200 may therefore 
decrease both the CNS and hemodynamic effects of METH 5,6.  
  
Nonclinical IXT-m200 Effectiveness Summary 
A significant body of nonclinical work in rats indicates that anti-METH antibodies quickly reduce METH 
effects and brain concentrations after administration. The potential human efficacy of IXT-m200 is 


 
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7 
demonstrated by several 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) 5,6,9. 
 
Nonclinical Safety Summary of the Interaction of IXT-m200 with METH 
A series of nonclinical studies was 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 self-administration (SA) in an effort to overcome the reduction of METH effects by the 
antibody.   
 
In each of the studies, rats were acclimated 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 a patient’s attempts to 
surmount the antibody’s effects was initiated. On Day 18, rats were given 4 doses of METH at 6 mg/kg 
spaced 2 hours apart. This binge dosing regimen was repeated on Days 21 and 24 for certain studies and 
groups. 
 
The 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 completed 10. In 
this study, 42 subjects (17 females) were dosed in 5 groups (0.2, 0.6, 2, 6, and 20 mg/kg IXT-m200, 
which are approximately 15 – 1500 mg in an average 75-kg subject), with 10 subjects receiving placebo 
(saline). Pharmacokinetic results indicate that IXT-m200 is similar to other IgGs, with an elimination 
half-life of ~18 days, volume of distribution (Vd) of ~5 L, and elimination clearance of ~200 mL/day. 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. 
Only 1 AE was definitely attributed to IXT-m200. A single subject experienced a Common Terminology 
Criteria for Adverse Events (CTCAE v.4.0) Grade 3 infusion reaction half-way through the IXT-m200 
infusion. The subject experienced a brief period of bronchospasm, in which the subject and investigator 
heard a single expiratory wheeze. The infusion was stopped and the subject was treated with solumedrol 
and diphenhydramine. No further symptoms were noted. The subject required outpatient therapy later for 
bronchitis. Because the infusion reaction and bronchitis were mild and short-lived, the study continued 
with no protocol changes. 
  
Samples from all subjects were tested for immunogenicity (i.e., anti-IXT-m200 antibodies). Samples from 
only 4 (12.5%) IXT-m200 treated subjects were confirmed to have low titers. One of these 4 subjects 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 
a range from 0.2 to 20 mg/kg. Therefore, a maximum tolerated dose was not reached. 
  
A Phase 2a study of the effect of IXT-m200 on METH pharmacokinetics and METH pharmacodynamics 
has been completed in otherwise healthy people who use METH. The primary goals of this study, called 


 
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STAMPOUT (Study of Antibody for Methamphetamine Outpatient Therapy, NCT03336866), were to 
show that IXT-m200 alters the PK of METH and reduces the reinforcing subjective effects that perpetuate 
METH use. In addition, the safety and tolerability of the effect of single IV doses of IXT-m200 (6 or 20 
mg/kg, which were up to 2000 mg) were determined in this population.  In STAMPOUT, non-treatment-
seeking people who had MUD received a single dose of IXT-m200 followed by weekly METH 
challenges. Serial blood samples and urine collections were analyzed to determine METH PK changes 
due to the antibody dose. Drug effects questionnaires were given after METH challenges to quantify the 
impact of IXT-m200 on the subjective effects of METH.  
 
In a pre-specified interim analysis of PK and safety data, METH PK parameters were estimated and 
summarized by treatment group, which showed clear dose-dependent changes in METH disposition in the 
presence of IXT-m200 (Figure 1). Dose-dependent changes in METH plasma PK parameters, including 
area under the curve (AUC), maximum concentration (Cmax), and volume of distribution (Vd) were 
evident at the first METH challenge, and were maintained through the entire inpatient period. These data 
show that IXT-m200 redistributes METH in a dose-dependent manner. Importantly, METH was excreted 
in the urine at similar levels across treatment groups, demonstrating that IXT-m200 does not impair renal 
elimination of METH. There were no SAEs or AEs of greater severity than Grade 2 (mild or moderate 
only) in STAMPOUT. This includes all events recorded following the dose of IXT-m200 and the 
subsequent weekly METH challenges. Furthermore,  some STAMPOUT participants used METH after 
release without apparent safety complications, further illustrating the safety of combinations of IXT-m200 
and METH. These data suggest that IXT-m200 will be well-tolerated in people who have taken METH 
prior to treatment in an ED setting. 
 
A second Phase 1 study of single 3-g doses of IXT-m200 in healthy volunteers is ongoing 
(NCT05027451) with no safety issues identified to date.  In this study, 9 healthy volunteers were 
randomized to 3 g IXT-m200 or placebo at a 7:2 ratio. Each received their dose as a 30-min intravenous 
infusion, then remained at the study site overnight to complete Day 1 and Day 2 assessments (e.g., 
electrocardiogram (ECG), laboratory assessments, blood draws, and vital signs). Following discharge on 
Day 2, participants return to the clinic for follow-up pharmacokinetic (PK) and safety assessments on Day 
8, then every 1-3 weeks thereafter until Day 127. Dosing has been completed with > 4 months of safety 
data collected to date, with no SAEs. 
AUCinf
0
20000
40000
60000
METH AUCinf (hr*ng/mL)
Cmax
0
200
400
600
800
1000
METH Cmax (ng/mL)
Vd
0
100
200
300
400
500
METH Vd (L)
Urine AE
0
5
10
15
METH Excreted (mg)
0
6
20
Figure 1. METH PK data from STAMPOUT interim analysis 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 (Urine 
AE) data are plotted as group means ± SD. IXT-m200 (0, 6, or 20 mg/kg, IV) was administered one day 
prior to METH (30 mg, IV). 


 
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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 completed Phase 1 study of IXT-m200, there were no SAEs or discontinuations due to 
treatment-emergent AEs. Overall, 90% of subjects 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 subjects 10. 
  
Only 1 AE was definitely attributed to IXT-m200. A single subject experienced a CTCAE v.4.0 Grade 3 
infusion reaction half-way through the IXT-m200 infusion. The subject experienced a brief period of 
bronchospasm, in which the subject and investigator heard a single expiratory wheeze. The infusion was 
stopped and the subject was treated with solumedrol and diphenhydramine. No further symptoms were 
noted. The subject required outpatient therapy later for bronchitis. 
  
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 subjects were 
confirmed positive for HACA in the completed Phase 1 study. The development of HACA did not appear 
to be dose-related 10. 
2.3.2. KNOWN POTENTIAL BENEFITS  
 
IXT-m200 is an investigational product and may convey no benefit to patients. Based on nonclinical 
studies in rodents 7,11, 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 tolerability and 
effectiveness.  IXT-m200 was not associated with significant safety issues in healthy individuals (Phase 
1) and in otherwise healthy non-treatment seeking people with MUD (Phase 2a). The general safety of 
antibody-based medications is outlined above in section 2.3.1 and in the IB. The risks of treatment with 
IXT-m200 will be minimized by selection of participants who desire treatment for their mild to moderate 
METH toxicity, but who are not in extremis. The risks are further mitigated by the selection of 


 
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participants who do not have significant concomitant illness (Section 5.2). Given the mechanism of action 
and the safety record, IXT-m200 has the potential to be useful in the treatment of METH toxicity, 
justifying its use.  
 
3. OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
Primary 
 
 
To evaluate the safety and 
tolerability of IXT-m200 in 
patients with mild to moderate 
METH toxicity 
Safety and tolerability of 
IXT-m200 as measured by 
physical examinations and vital 
sign, AE, ECG, and clinical 
laboratory testing 
Safety must be systematically 
evaluated of IXT-m200 when 
given to patients with ongoing 
METH toxicity for the first time  
Secondary 
 
 
To determine the time course 
and degree of normalization of 
agitation and vital signs 
Agitation/sedation scores over 
time as measured by ACES 12  
Agitation is a significant CNS 
component of METH toxicity and 
a cause for hospital admission  
Vital signs including blood 
pressure, heart rate and 
temperature over time 
Elevated or depressed 
hemodynamics are a component of 
CV toxicity 
To determine the percentage 
of participants requiring 
rescue medications for 
psychiatric or cardiovascular 
manifestations of METH 
toxicity  
Need for rescue medications to 
treat: 
- agitation, dysphoria, or 
psychosis (CNS toxicity) 
- hypertension, tachycardia, or 
other cardiovascular 
instability (CV toxicity) 
An evaluation of IXT-m200 
effects on requirement of rescue 
medications is needed 
Tertiary/Exploratory  
 
 
To determine how long 
patients with METH toxicity 
stay in the ED 
ED length of stay as measured 
by disposition order time minus 
triage time, and as measured by 
disposition order time minus 
start of treatment time, with log 
transformation 
Prolonged wait times are 
associated with a number of 
negative outcomes, including 
patient dissatisfaction, increased 
hospitalization rate, poor quality of 
care, and increased mortality 13 
 
4. STUDY DESIGN  
4.1. OVERALL DESIGN 
 
The hypothesis of this multisite Phase 2a study is that IXT-m200 will be well-tolerated in patients with 
acute mild to moderate METH toxicity. A randomized, open label design will be used in which one dose 
of IXT-m200 will be compared to treatment-as-usual (TAU). Approximately 24 participants will be 
enrolled in 3 cohorts. A dose escalation approach will be used so that progressively higher IXT-m200 
doses will be evaluated in each of the first two cohorts. In conjunction with safety monitoring, this design 
assures the opportunity to observe early safety findings before any participants are exposed to the next 
higher dose. The randomization ratio for IXT-m200 versus TAU is defined as 4:1 for each of cohorts 1 
and 2, with up to an additional 4 TAU participants in cohort 3 so that the number of participants receiving 
TAU equals the number receiving each dose of IXT-m200 at the end of the study.  
 


 
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Cohort 
IXT-m200  
dose (g) 
IXT-m200:TAU 
subject numbers 
1 
0.5 
8:2 
2 
2 
8:2 
3 
0 
0:4 
 
Agitation scales and vital signs will be recorded to track effect of the antibody treatment versus TAU over 
time on agitation associated with METH use. While in the ED, detailed and pertinent medical and 
psychiatric histories, and physical exam will be obtained, along with laboratory assessments and ECGs. In 
the ED, participants will give blood samples for analysis of METH and IXT-m200 concentrations and 
followed for development of adverse events. Participants will be evaluated at 2 days and 4 weeks after 
discharge from the ED for adverse events and drug use history. Cohort escalation review will be 
performed by the Sponsor, Medical Monitor, and Data and Safety Monitoring Board (DSMB) after cohort 
1 and the next group will not start until after completion of this review.  
 
4.2. SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
Because the participants in this study present requesting treatment for METH toxicity, but because 
IXT-m200 has not been administered in an acute setting to agitated patients, the open-label TAU 
comparison offers an early assessment of the utility of IXT-m200 for use to treat METH toxicity. A 
placebo control is not ethical because these patients present to the ED requesting treatment. The study 
design also includes rescue medications to ensure that in the event of worsening of the symptoms, which 
may be due to progression of the intoxication or due to either treatment, the patients may be treated in a 
timely fashion. The dose escalation in subsequent groups with safety evaluation between cohorts 1 and 2 
is designed is ensure that an effective dose is tested. 
 
While lorazepam and haloperidol are commonly used to treat agitation in the ED, there is no consensus on 
the ideal sedative for acute agitation in the ED 1. The goal of sedation in the ED is to calm a patient so 
he/she is not a danger to him/herself or others, and can be more accurately assessed by physicians. METH 
causes release of monoamines from nerve terminals and blocks their reuptake; chronic and binge METH 
use severely alters monoamine homeostasis. The adrenergic reserves of METH overdose patients are 
therefore atypical, making their responses to sedative medications difficult to predict. Even with careful 
titration of sedatives, patients may experience profound and prolonged somnolence, increasing their 
length of ED stays 14. For agitation due to overdose or intoxication, benzodiazepines and/or first-
generation antipsychotics, such as haloperidol, are often recommended 2 but sufficient doses of these 
drugs to reduce agitation may sedate patients for hours. This approach results in at best prolonged ED 
stays, and at worst the masking of other symptoms (physical or psychiatric) that may need more timely 
attention.  
 
4.3. JUSTIFICATION FOR DOSE 
 
IXT-m200 will be given via IV administration because this will provide immediate effects and provide 
for reliable pharmacokinetic analysis. The IXT-m200 doses selected for this study may include the range 
tested in Phase 1 (0.2 to 20 mg/kg or 3-g) and Phase 2a (6 and 20 mg/kg) studies of IXT-m200. 
Converting doses for a 75-kg person shows that the 0.5-g dose = 6.67 mg/kg and a 1.5-g dose = 20 mg/kg. 
2-g doses have been given to participants weighing 100 kg without complication in the Phase 2a study 
and 3-g doses were given to all active participants (n=7) in the second Phase 1 study. Importantly, it is not 
necessary to reduce METH brain concentrations to “zero” to demonstrate a clinically useful effect in this 


 
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study, so we do not anticipate that markedly higher doses will be required. Rather, the pharmacological 
goal is to redistribute enough METH from the CNS into the systemic circulation so that symptoms are 
reduced sufficiently to allow patients to be discharged or referred for further treatment. In rodent studies, 
IXT-m200 acutely reduces CNS effects when present in a ratio of less than 30 molecules of METH per 
mAb binding site 15. Given that there is no way to predict body burden or previous METH intake by 
people presenting to an ED, this study uses unit doses (e.g., 0.5 and 2 g) to facilitate dosing, establish 
safety, and determine dose response for agitation.  
 
The rate of IXT-m200 administration is justified to obtain rapid resolution of symptoms of METH 
toxicity, commensurate with that obtained by lorazepam and/or haloperidol. The infusion rate for the 
0.5-g dose is 33 mg/kg/hr (assuming a 75-kg person) and those for the 2-g doses are 80 mg/kg/hr. In prior 
studies, the highest infusion rate was 80 mg/kg/hr. Importantly, the infusion rates in two GLP toxicology 
studies greatly exceed the proposed rates for this study. In the first, rats were given 200 mg/kg/hr for a 
total single dose of 400 mg/kg, and in a second completed study, 300 mg/kg was given in 10 min or less 
each week for six months for a repeating rate of 1800 mg/kg/hr. There were no reported safety issues with 
these infusion rates in rats. Furthermore, it appears unlikely that there have been infusion rate-related AEs 
in human studies.  
 
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 the Schedule of Activities (SoA; section 1.3). 
Participants with an ongoing AE at the time of study completion will be followed until the event resolves, 
the Sponsor and the investigator agree that further follow-up is not medically necessary, or until they are 
lost to follow-up.  
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA. 
 
5. STUDY POPULATION 
5.1. DESCRIPTION OF AND RATIONALE FOR THE SELECTED POPULATION 
 
Qualified participants will present seeking emergent treatment for unpleasant symptoms related to their 
recent METH use. They may also have taken other abused drugs or medications such as opioids and still 
qualify. They may display signs of mild to moderate METH toxicity such as dysphoria, agitation, mild 
paranoia, or a feeling of being unsafe. Participants will be agreeable to general study procedures (e.g., 
placement of an IV, repeated measurement of vital signs and agitation assessments, repeated blood 
draws).  
 
People with mild to moderate symptoms have been selected for this initial study in an ED setting because 
while they need rapid treatment, the need for rescue sedative medications will be lower and less urgent 
than in people suffering from acute, severe intoxication or other major health issues. Recruiting lower 
severity participants will allow time to determine/observe the effects of IXT-m200 doses prior to, or 
without the need to add, additional medications which could obscure the effects of the antibody. This 
initial study will establish safety and efficacy in a controlled population prior to expanding in future 
studies to a greater risk, more vulnerable population who may need more intensive intervention for their 
acute METH intoxication. 
 


 
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Criteria for diagnosing METH toxicity are adapted from the DSM-5 criteria for stimulant intoxication and 
include: 
• 
Recent (last 24 hour) use of methamphetamine or amphetamine 
• 
Clinically significant problematic behavioral or psychological changes 
o e.g., euphoria or affective blunting; changes in sociability; hypervigilance; interpersonal 
sensitivity; anxiety, tension or anger; stereotyped behaviors; impaired judgement that 
developed during or shortly after METH use 
• 
Two or more of the following 
o Bradycardia or tachycardia (<40 or >100 beats per minute) 
o Hypertension or hypotension (>140/90 or < 90/60) 
o Pupillary dilatation 
o Perspiration or chills 
o Nausea or vomiting 
o Psychomotor agitation or retardation 
o Muscular weakness, respiratory depression, chest pain, or cardiac arrhythmias 
o Confusion, seizures, dyskinesias, dystonias, or coma 
• 
The symptoms are not due to a general medical condition and are not better accounted for by 
another mental disorder 
 
5.2. INCLUSION CRITERIA 
 
Eligible participants will:  
1. Be aged 18 to 45 years, inclusive; 
2. Present to the ED with METH toxicity as defined in protocol; 
3. Have a PANSS-EC score of 14-28, inclusive; 
4. Have or agrees to have an intravenous (IV) line placed; 
5. Give a history of METH use in the past 24 hours, with participant or observer attribution of 
symptoms to METH, or have a positive METH drug screen; 
6. Be accompanied or readily represented by a legally authorized representative (surrogate) who can 
consent to participation on behalf of the participant if participant is found not able to consent for 
themselves using the UCSD Brief Assessment of Capacity to Consent (UBACC); and 
7. Consent or assent to participation in the study. 
 
5.3. EXCLUSION CRITERIA 
 
Eligible participants will NOT:  
1. Present with concomitant opioid overdose requiring ventilatory support; 
2. Be self-reported to be pregnant or lactating; 
3. Be considered to have significant concomitant medical illness or trauma, or symptoms of severe 
METH toxicity including  
a. sepsis or febrile illness;  
b. myocardial infarction, cardiac decompensation or arrhythmias including tachycardia that 
is not sinus; severe hypertension (>180/110 mmHg); inadequately treated hypertension 
on chronic medication; history of vasculitis; 
c. coma, stroke or severe head injury; new or ongoing seizure activity 
d. acute pulmonary decompensation or severe chronic obstructive pulmonary disease;  


 
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e. any hepatic impairment and/or acute hepatitis or renal impairment due to concomitant 
medical illness; or 
f. 
current, or history of, neuroleptic malignant syndrome;  
4. Be considered to be at imminent risk of suicide or have disqualifying answers to the following 
two questions. Disqualifying answers would be 1b2 or 2b. 
 
1. In the past 30 days, have you considered killing yourself? 
a) No 
b) Yes – if Yes, how often? 
B1) Not often (twice or less) 
b2) Somewhat often (more than twice) 
 
2. In the past year, have you attempted to kill yourself? 
a) No 
b) Yes 
 
5. Be considered to be at imminent risk of injury or danger to self, others or property; 
6. Have a history of severe allergy (rash, hives, breathing difficulty, etc.) to both lorazepam and 
haloperidol, or known hypersensitivity or infusion reaction to any antibody medications; or 
7. Be judged by the treating ED physician, investigator, or Sponsor (or designee) to be inappropriate 
for the study, including people whom the investigator determines cannot reasonably be consulted 
for assent to participation. 
 
5.4. 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. 
 
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. 
 
Subjects are required to 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 dose of study drug. 
 
5.5. 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 SAEs. 
 


 
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All participants who consent but fail screening will be referred to treatment in the ED outside of the study 
per the recommendation of the screening physician. Subjects may be rescreened at any future presentation 
to the ED. 
5.6. STRATEGIES FOR RECRUITMENT AND RETENTION 
5.6.1. STRATEGIES FOR RECRUITMENT  
 
Generally speaking, recruitment strategies are based on appropriate site selection (sufficient numbers of 
potential participants) and education of ED staff to look for possible participants. 
 
The recruitment of vulnerable participants is necessary because the study is designed to determine if 
IXT-m200 is well-tolerated and works to reverse METH toxicity in an emergency setting. While people 
under the influence of METH and other drugs may be vulnerable because they may lack full consent 
capacity, participants will still provide assent, and their legally authorized representative will provide 
consent at the time of the study start if the participant is found lacking the capacity to consent for 
themselves using the UBACC assessment. No participant will be enrolled in the study who does not 
provide consent or assent. On Day 3, when participants return for their first follow-up visit, informed 
consent will be obtained, or repeated, from them.  
 
Participants will be compensated based on local precedent, which may be different at each site.  
5.6.2. STRATEGIES FOR RETENTION AND FOLLOW-UP  
 
Retention strategies are based on education of the participant and discussion of the importance of follow-
up to good health. Specifically, this includes the opportunity to follow up on any medical findings from 
the ED stay, and to further discuss opportunities for treatment for MUD if the person desires. 
 
Phone calls, text messages, and emails will be sent as reminders to the participants to follow up. 
Transportation will be provided if needed to the follow-up visits, and referral for treatment of psychiatric 
and medical issues will be arranged.  
 
6. STUDY INTERVENTION 
6.1. STUDY INTERVENTION ADMINISTRATION 
6.1.1. STUDY INTERVENTION DESCRIPTION 
 
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. 
 
The mechanism of action of IXT-m200 is via high-affinity binding to METH, which either prevents 
METH from reaching its sites of action in the CNS, or removes it from those sites of action 7,8. Because 
anti-METH antibody medications significantly alter the distribution and tissue concentration of METH, 
their mechanism of action is PK antagonism. IXT-m200 was developed from a murine anti-METH 


 
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antibody and preclinical studies have shown that both the murine and chimeric antibodies bind METH 
and alter its PK in a similar way 7,8,16. Further information on IXT-m200 may be found in the IB.  
6.1.2. DOSING AND ADMINISTRATION 
 
Participants in cohorts 1 and 2 will be randomized to TAU or IXT-m200 after consenting to participate. 
Participants in cohort 3 will receive TAU. An IV line will be started and a balanced salt solution (e.g., 
PlasmaLyte®) will be administered at a rate of 75 mL/hr. IXT-m200 will be given over 10 min (for 0.5 g) 
or 20 min (for higher doses) per dosing guidelines. The IXT-m200 infusion start/stop time, infusion rate, 
infusion volume, whether the infusion was completed, if it was stopped, or stopped and restarted will be 
recorded in the eCRF. Participants will be asked to remain semi-reclined during dose administration and 
to refrain from strenuous activity from dosing through 24 hours after. If randomized to TAU, one of the 
following three choices will be administered as determined by the treating physician: 1) up to 4 mg 
lorazepam by IV push, 2) up to 5 mg haloperidol by IM or IV injection, or 3) a combination of up to 4 mg 
lorazepam by IV push and up to 5 mg haloperidol by IM or IV injection. IV fluids will be given as 
tolerated for up to 4 hours after dosing with either IXT-m200 or TAU, at which point the IV will be 
capped and preserved during the remainder of the ED stay. When the ED staff determine it is appropriate, 
a regular diet may be started. If there is an adverse reaction to study drug, the participant will be treated as 
outlined in Section 6.5. 
 
6.2. PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1. ACQUISITION AND ACCOUNTABILITY 
 
Study Intervention: Sponsor will provide the required number of vials of IXT-m200. IXT-m200 vials will 
be shipped to the study sites prior to study initiation. 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.  
  
The investigator at each site will be responsible for acquiring commercially available TAU and rescue 
medications for use in the study. 
6.2.2. FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Study Intervention: IXT-m200 is formulated as an injection 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. The University 
of Iowa Pharmaceuticals produces the vialed drug product. 
 
Labels will be similar to the following:  
InterveXion Therapeutics® 
Anti-methamphetamine IXT-m200 
18.5-21.5 mg/mL 
Manufactured: DD MMM YYYY 
UIP Lot: XXXIXXXX 
Catalent Lot: XXXXX 
10 mM sodium phosphate, 150 mM sodium chloride, pH 6.5, with 0.05% Tween 80 


 
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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 
6.2.3. PRODUCT STORAGE AND STABILITY 
 
IXT-m200 vials are single-use and should be stored refrigerated at 2 to 8°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 
 
The appropriate total dose of IXT-m200 will be prepared for IV administration. No dilution of the drug 
product is required. For calculation purposes, the concentration of the drug product is 20 mg/mL. 
 
Dose level (g) Volume to be dosed (mL) 
0.5 
25 
2 
100 
  
TAU and rescue medications: These are obtained and provided by the local pharmacy in appropriate 
doses and delivery devices. Lorazepam will be given by slow IV push as the participant tolerates. 
Haloperidol is given via an intramuscular injection in the deltoid or gluteal muscles or by slow IV push as 
tolerated.  
 
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 in cohorts 1 and 2 will be randomized to IXT-m200 or TAU after consenting to participate. 
Those who qualify will be randomized at a 4:1 ratio. Randomization codes will be generated by the 
randomization statistician and will be implemented by interactive voice/web response system (IXRS). 
This will be the same system for all sites so that there is no site bias to dosing. Participants will be 
randomized in the order they are enrolled. Participants in cohort 3 will receive TAU. 
 
This is an open-label study, in which the Sponsor and the investigators are aware of treatment 
assignments on an ongoing basis to facilitate efficient dose escalation while comparing study agent to 
treatment as usual. While participants in cohorts 1 and 2 will not be actively informed of their group 
assignment, no active measures will be taken to blind participants to treatment assignment. 
 
6.4. STUDY INTERVENTION COMPLIANCE 
 
IXT-m200 and TAU are administered by the IV or IM routes by qualified personnel. Compliance with 
dosing will be verified by reference to the eCRF documentation of dosing. 


 
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6.5. CONCOMITANT THERAPY AND RISK MITIGATION PLAN 
 
All concomitant medications (i.e., those given in the ED, prescription medications, over-the-counter 
medications, non-prescription medications, and supplements) taken during study participation will be 
recorded on the eCRF.  
6.5.1. RESCUE MEDICINES 
 
Lorazepam or haloperidol will be used as first-line rescue medications in all participants, regardless of 
treatment assignment, for agitation or dysphoria (lorazepam) or psychosis (haloperidol) 2,14,17. If further 
rescue medications are needed, the choice and doses of the rescue medications will be at the discretion of 
the treating ED physician. To allow time for maximum effects of the initial treatments to evolve, rescue 
medications should not be given for 30 min after initiation of IXT-m200 or TAU dosing; however, timing 
is ultimately at the discretion of the treating physician. 
 
Hypertension or tachycardia may be treated at the discretion of the treating physician with labetalol, 
hydralazine, or other similar approaches. Other cardiovascular instability (e.g., hypotension with blood 
pressure less than approximately 80/50 mmHg or less than approximately 90/60 mmHg with symptoms of 
dizziness, near syncope, or nausea, for example) will be treated initially with a fluid bolus14. If 
hypotension persists, it will be treated with incremental doses of the direct acting vasopressors 
phenylephrine, norepinephrine, or dopamine (starting at alpha adrenergic doses >10 µg/kg/min), or other 
appropriate medications at the discretion of the treating ED physician.  
6.5.2. RISK MITIGATION  
 
The following risk mitigation strategies have been designed based on other studies in people who use 
METH, on the problems posed specifically by enrolling participants in an emergency setting, on the 
clinical pharmacology of METH, and on the known pharmacology of IXT-m200: 
1. Selection of a specific participant group. As stipulated in the protocol, participants who are 
relatively healthy with no significant medical or surgical illness will be recruited. 
2. IXT-m200 dosing. IXT-m200 will be administered in escalating dose groups so that the lowest 
IXT-m200 dose (0.5 g) will be evaluated before the higher doses, in subsequent cohorts. This will 
allow determination of the effects of IXT-m200 at a low predicted effective IXT-m200 dose, 
before effects are assessed following a high predicted effective IXT-m200 dose.  
3. Treatment in an Emergency Department. A crash cart will be available in the ED and personnel 
trained in CPR are always available in the ED setting. Oxygen and emergency ventilation 
equipment are immediately available. Normal saline will be used as the IV fluid and fluid boluses 
can be administered if any hypotension is seen. In the event of serious medical complications, a 
code may be called. 
4. Frequent safety review. A formal safety review will be done between cohorts, and at any point 
needed based on the severity of AEs. This would include Grade 3 AEs related to worsening of 
METH effects in the presence of IXT-m200.  
 
All of the study sites are EDs and therefore have all medications that might be needed to treat mAb 
toxicity, which may manifest as hypotension and bradycardia or tachycardia; bronchospasm with or 
without hypoxemia; or flushing, pruritis, and urticaria. Hospital-maintained crash carts, and oxygen and 
emergency ventilation equipment (Ambubags) are always available. Advanced Cardiovascular Life 
Support-certified providers and code teams are always available to treat life-threatening events.  
 


 
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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.  
Enrollment and study drug administration will be immediately paused if any 1 of the following events 
occurs, unless the event was clearly unrelated to study drug administration, or the event is an expected 
sequelae of untreated METH toxicity: 
• 
Three (3) participants experience a Grade 3 AE.  
• 
Two (2) participants experience a Grade 3 AE related to increased agitation, aggression, or 
anxiety. 
• 
One (1) participant experiences a Grade 4 AE.  
• 
A death occurs.  
 
Expected sequelae of untreated METH toxicity which will not be considered grounds for a study pause 
include: 
• 
Hypertension/tachycardia 
• 
Euphoria 
• 
Agitation 
• 
Insomnia 
• 
Anxiety 
• 
Seizures 
• 
Mania/aggression 
 
Worsening of any of the above following administration of study drug will be considered an AE and 
subject to the rules for study pause above. 
If any of the pause conditions are met, the Sponsor, in consultation with the investigator and Medical 
Monitor, will suspend enrollment until a full safety review by both the Sponsor and DSMB is performed. 
A decision to reinitiate enrollment will be made following relevant consultation with the appropriate 
authorities based on the results of the safety review. 
7.2. PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants may be withdrawn from the study at any time before IXT-m200 administration for reasons 
including the following: 
• 
at their own request or at the request of their legally authorized representative, 
• 
the participant meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation, 
• 
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, 
• 
if, in the investigator’s opinion, continuation in the study would be detrimental to the participant’s 
well-being, or 
• 
at the specific request of InterveXion (Sponsor) or clinical site. 
 
Once participants receive IXT-m200, every reasonable effort will be made to have them attend the Day 3 
and 28 follow-up appointments.  
 


 
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In all cases, the reason for withdrawal must be recorded in the electronic Case Report Form (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 discontinue from further participation in 
the study, the research staff will cease further contact attempts. 
 
Participants who consent and are randomized but do not receive the study intervention may be replaced 
and will not be included in any data set.   
 
Participants who consent and are randomized and do receive the study intervention, but leave the ED 
prior to medical discharge and/or are not positive for METH by UDS or blood testing will be included in 
the safety set and ITT. Additional subjects may be recruited to ensure that both cohorts 1 and 2 contain 8 
subjects dosed with IXT-m200 and 2 subjects dosed with TAU who complete the protocol through 
discharge from the ED and are positive for METH based on UDS or blood testing.  
 
Participants will not be replaced if they complete through discharge from the ED, but do not return for 
Day 3 or 28 visits. 
 
7.3. LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if s/he fails to return for the Day 3 and 28 scheduled 
visits 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 as soon as possible 
and 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  
 
Study procedures to evaluate agitation include: 
• 
The PANSS-EC (Positive and Negative Syndrome Scale – Excited Component) is used commonly 
as an assessment tool for clinical studies of pharmacotherapy for agitation. It includes 5 items 
(excitement, poor impulse control, tension, hostility, and uncooperativeness) which are each rated 
from 1 (absent) to 7 (extremely severe). A score of 14-28 is consistent with clinically significant 
psychomotor agitation of mild to moderate severity 18–20. It will be administered only at screening as 
part of eligibility determination.  
• 
The ACES (Agitation-Calmness Evaluation Scale) is a single-item, 9-point scale to differentiate 
agitated, calm, and sleep states. It has been used to assess the effects of pharmacotherapy on 


 
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agitation 12. This assessment will be performed at all time points marked in the Schedule of 
Activities table to determine the impact of IXT-m200 versus TAU on agitation. 
• 
Vital sign measurements over time including heart rate, blood pressure, temperature.  
• 
Need for rescue medications to treat CNS symptoms of agitation, dysphoria, or psychosis; and CV 
symptoms of hypertension, tachycardia, or other cardiovascular instability. 
 
8.2. SAFETY AND OTHER ASSESSMENTS 
 
UCSD Brief Assessment of Capacity to Consent (UBACC) 
• 
A 10-item list of questions focused on understanding and appreciation of the description of the 
research study 21. This assessment will be used to screen potential participants for the capacity to 
consent for themselves. A score of 20 will be required to be eligible to consent without an LAR. 
 
Safety evaluations include the following: 
 
Medical and Medication Histories  
• 
Medical history: A focused medical history will be obtained at triage/screening by interview and 
any available medical records. A detailed and pertinent medical history will be obtained after 
IXT-m200 dosing or TAU is complete and the participant is cooperative.  
• 
Medication history: A medication history will be obtained at triage/screening by interview and any 
available medical records. This will be reviewed and supplemented if needed after IXT-m200 or 
TAU dosing is complete and the participant is cooperative. The medication history will be reviewed 
at the 2 scheduled study visits.  
 
Physical Examination, Vital Sign Measurement, Height, and Weight  
• 
A focused physical examination (excluding rectal/genital and breast examination) will be 
performed at triage/screening. The physical examination may consist of vital signs and an 
examination of the following: general appearance, neurological, skin, head, eyes, ears, nose, throat, 
neck, chest, heart, abdomen, and extremities.  
o A detailed physical examination (excluding rectal/genital and breast examination) will be 
performed after IXT-m200 or TAU dosing is complete and the patient is cooperative. 
o Focused exams will be performed during the two follow-up appointments and as otherwise 
necessary.  
• 
Vital sign measurements (heart rate, blood pressures [systolic and diastolic], respiratory rate, 
temperature [oral], and pulse oximetry readings) will be obtained. Measurements will be taken at 
triage and screening, and as outlined in the Schedule of Activities table.  
• 
Height and weight will be obtained on Day 1 after dosing with IXT-m200 or TAU. 
 
Evaluations of Drug and Alcohol Use 
• 
DSM-5 criteria will be used at the Day 3 follow-up visit to assess for Substance Use Disorders 
(including METH, opioids, alcohol, nicotine, marijuana, etc.).  
• 
Qualitative urine drug screen (UDS; including amphetamines, MDMA, barbiturates, 
benzodiazepines, cocaine, opiates, THC, and phencyclidine) and alcohol breath testing will be 
performed once. This testing may be done before or after initial treatment so that the agitation may 
be treated as quickly as possible.  
• 
Administer standard drug assessment of METH and other drug use since last visit on Days 3 and 28 
• 
The METH Perceptions Assessment is the following list of questions intended to determine whether 
IXT-m200 affects how subjects perceive subsequent doses of METH. 


 
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o Note to administrator, if subject has reported multiple instances of METH use since last 
visit, instruct them to recall their first time of use since last visit.  Ask the following 
questions: 
“Did you take your typical dose of METH as you normally would before you started the 
study?” Answer: Yes or No 
If No, “Did you try more or less than normal?”  Answer: More or Less 
“How was the high compared to what you typically get from that dose?”  Answer: Scale of 
1-5; 1 = Less than expected, 3 = Just as expected, 5 = Better than expected 
If 1 or 2, “Did you take more METH to get the high you wanted?” Answer: Yes or No 
If Yes, “Did that get the result you wanted?”  Answer: Yes or No 
 
Psychiatric Evaluation  
• 
A detailed and pertinent psychiatric history will be obtained at triage/screening evaluating for (but 
not limited to) the following: major current depression, psychosis, bipolar illness, organic brain 
disorder, or dementia, which would make study compliance difficult in the opinion of the 
investigator.  
• 
Subjects will be queried about their history of suicide attempts and suicide ideation by the 
following two questions and any others the investigator deems necessary.  
 
1. In the past 30 days, have you considered killing yourself? 
a) No 
b) Yes - if Yes, how often? 
b1) Not often (twice or less) 
b2) Somewhat often (more than twice) 
 2. In the past year, have you attempted to kill yourself? 
a) No 
b) Yes 
 Disqualifying answers would be 1b2 or 2b. 
 
Electrocardiogram  
• 
An electrocardiogram (ECG; 12-lead) will be recorded after IXT-m200 or TAU dosing is complete 
and the participant is cooperative. 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).  
 
Biological Specimen and Laboratory Evaluations  
• 
Blood samples will be taken for analysis of IXT-m200 in serum on Day 1 (pre-dose, 4 hours after 
dosing, and at discharge), Day 3, and Day 28 from subjects who were randomized to receive 
IXT-m200 only. 
• 
Blood samples will be taken for analysis of METH and amphetamine in plasma on Day 1 (pre-dose, 
4 hours after dosing, and at discharge). 
• 
Blood will be taken for clinical laboratory studies which will include complete blood count, blood 
urea nitrogen/creatinine, serum glucose, electrolytes, liver function tests (AST, ALT, gamma-
glutamyl transferase, alkaline phosphatase, total and direct bilirubin), and creatinine phosphokinase. 
These tests will be performed on Day 1 after dosing is completed and repeated on Day 3.  
• 
Urine samples will be taken for UDS, urinalysis, and urine pregnancy tests. These tests will be 
performed on Day 1; results are not required prior to dosing. 
 


 
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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 participant administered IXT-m200 or TAU, 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 
IXT-m200 or TAU, whether or not related to IXT-m200 or TAU.   
 
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, TAU, 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 admission to the hospital; 
• 
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 participant 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 22 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.  
 
Regarding vital sign AEs, Section 6.5.1 defines blood pressure criteria for treatment with fluids and 
medications. 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 (O2 saturation < 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 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.   
 
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 to the study drug;  
• 
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 or for the participant’s underlying medical condition. 
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, 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, it will be recorded as an AE.  
 
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 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 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. Every attempt 
should be made to describe the AE in terms of a diagnosis. If appropriate, component 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 


 
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accepted standards of medical practice, even after the end of the period of observation, until a satisfactory 
explanation is found or the investigator considers it medically justifiable to terminate follow-up. Should 
the AE result in death, a full pathologist’s report should be supplied, if possible. 
 
Adverse events will be reviewed by the Sponsor, Medical Monitor and DSMB between cohorts. If an 
investigator decides it necessary, AEs may be reviewed at any time by consultation with the investigator, 
Medical Monitor, and Sponsor. 
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 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 Sponsor will be responsible for notifying the 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 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.  
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  
 
As a dose-escalation safety trial, safety will be monitored closely and dose escalation will occur only 
when available safety data warrant. On the other hand, the proposed trial by nature involves a population 
in significant duress, sufficient to merit a visit to the ED and meet the required eligibility criteria, and 
these participants will display a range of expected AEs due to their concomitant METH toxicity.  
 


 
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To balance these important requirements of trial conduct and patient protection, the study will capture any 
AEs underway at the time of presentation to the ED that can be attributed to METH toxicity. These 
include:  
• 
 Hypertension/tachycardia  
• 
 Euphoria  
• 
 Agitation  
• 
 Insomnia  
• 
 Anxiety  
• 
 Seizures  
• 
 Mania/aggression  
 
These AEs will not be considered as study participation-related, and will not be included in consideration 
of dose escalation or study stopping criteria, unless they newly emerge or worsen after administration of 
investigational product.  If they worsen, and reach sufficient severity, they will be considered as a part of 
the trial stopping criteria. 
8.3.9. REPORTING OF PREGNANCY  
 
If a participant is found to be pregnant after they have received IXT-m200 and before day 28, they should 
complete the study, with no further IXT-m200 doses administered, and be followed to determine the 
outcome of the 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 
 
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. 


 
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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 
subject 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. 
 
9 
STATISTICAL CONSIDERATIONS  
 
A statistical analysis plan (SAP) will be prepared after the protocol is approved. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to address 
all study objectives. The SAP will serve as a complement to the protocol and supersedes it in case of 
differences. 
 
The statistical evaluation will be performed using SAS® software version 9.4 or higher (SAS Institute, 
Cary, NC). All data will be listed, and summary tables will be provided. Summary statistics will be 
summarized and presented by treatment group, i.e., dose level of IXT-m200 and TAU, whereby the TAU 
patients from all cohorts will be pooled. For continuous variables, data will be summarized with the 
number of subjects (N), mean, standard deviation, median, minimum, and maximum by treatment group. 
For categorical variables, data will be tabulated with the number and proportion of subjects for each 
category by treatment group. 
 
9.1. STATISTICAL HYPOTHESES 
 
This is a descriptive study for evaluation of safety and tolerability as the primary objective. Descriptive 
summaries will be performed for tabulation and comparison of safety and efficacy endpoints. Descriptive 
statistical tests will be applied for the pairwise statistical comparison of efficacy endpoints in IXT-m200 
dose levels versus TAU using a two-sided alpha level of 5%. 
 
9.2. SAMPLE SIZE DETERMINATION 
 
No formal sample size estimation has been performed. A sample size of 8 IXT-m200 and approximately 8 
TAU patients is considered adequate to assess the safety and tolerability of IXT-m200 compared to TAU. 
Data from TAU patients from each cohort will be pooled for summaries. 
 


 
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9.3. POPULATIONS FOR ANALYSES 
 
The enrolled population will include all patients who sign the informed consent. 
 
The safety population will include all randomized patients who receive any dose of study drug. The 
treatment group assignment in this population will be defined by the treatment actually received. This 
population will be used for the analysis of safety. 
 
The Intent-to-Treat (ITT) population will include all randomized participants. The treatment group 
assignment in this population will be defined by the randomized treatment. This population will be used 
for the analysis of efficacy. 
 
The Full Analysis Set (FAS) population will include those in the ITT population who receive any dose of 
study drug and were positive for methamphetamine by UDS or blood testing during the ED stay. The 
treatment group assignment in this population will be defined by the randomized treatment. This 
population will be used for the analysis of efficacy. 
 
The Per-Protocol (PP) population will include all of the FAS who completed the Day 1 assessments, stay 
through discharge from the ED, and do not have any major protocol deviation impacting the efficacy 
assessments. The treatment group assignment in this population will be defined by the randomized 
treatment. This population will be used for the analysis of efficacy. 
 
The PK Population will include all subjects for whom a PK concentration is available post-dose. 
 
9.4. STATISTICAL ANALYSES 
9.4.1. GENERAL APPROACH 
 
This is a descriptive study for evaluation of safety and tolerability as the primary objective. The 
comparison of safety endpoints and of efficacy endpoints between the treatment groups will be performed 
using descriptive summaries and descriptive confidence intervals (CI) and statistical tests. 
9.4.2. ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Not applicable. 
9.4.3. ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Summary tables with descriptive statistics for actual values and changes from baseline will be provided 
for the ACES score for each scheduled timepoint by treatment group. Descriptive pairwise t-tests will be 
performed for the comparison of the changes from baseline of each IXT-m200 dose versus TAU. The 
time course of actual ACES scores and of change from baseline ACES scores will be presented by 
treatment group in a figure using mean values and 95% CIs. 
 
The time to normalization of agitation using ACES will be defined as the time until the ACES score 
climbs to ≥4 the first time, in subjects for which the score remains in the range of 4-6 for the remaining 
time points. If the ACES score rises to the range of 7-9 during the ED stay, then normalization will be 


 
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defined as the time until the score is reduced to within the range of 4-6 following the end of the sedated 
period. This time will be presented by Kaplan-Meier estimates and figure by treatment group, and will be 
pairwise compared between each IXT-m200 dose versus TAU by the logrank test. 
 
The time course of actual values of vital sign parameters and of changes from baseline will be presented 
by treatment group in a figure using mean values and 95% CIs. A shift table of post-baseline vital sign 
parameter values compared to baseline values will be provided by treatment group presenting the number 
and percentage of subjects below normal range / within normal range / above normal range. The time to 
normalization (i.e., returning to normal range) of vital sign parameters is defined as the first time the vital 
sign parameter is in normal range and remains in normal range for the remaining time-points. This time 
will be presented by Kaplan-Meier estimates and figure by treatment group, and will be pairwise 
compared between each IXT-m200 dose versus TAU by the logrank test. 
  
Number and percentage of patients with any rescue medication (from start of study treatment until 
discharge) will be provided by treatment group and overall IXT-m200 and total. Additionally, separate 
tables with the number and percentage of subjects with rescue medications for psychiatric manifestations 
and for cardiovascular manifestations, will be provided by treatment group, overall IXT-m200 and total. 
 
PK concentrations of IXT-m200 and METH will be summarized by timepoint and by treatment group. 
Additionally, change from baseline of METH concentration will be summarized for each post-dose 
timepoint by treatment group. The change from baseline in METH concentration will be presented 
graphically. 
9.4.4. SAFETY ANALYSES 
 
All reported AEs will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA). The incidence of treatment-emergent AEs (TEAEs; events with onset dates on or 
after the administration of the study drug) will be included in incidence tables. Events with missing onset 
dates will be included as treatment-emergent. If a subject experiences more than one occurrence of the 
same AE, the occurrence with the greatest severity and the closest association with the study drug will be 
used in the summary tables. An overall summary by treatment group, overall IXT-m200 and total will be 
presented with the number and percentage of subjects experiencing any TEAE, any TEAE by severity, 
any related TEAE, any serious AE (SAE), any related SAE, any AESI, and any TEAE leading to death. 
Summary tables by system organ class and preferred term will be provided for treatment group, overall 
IXT-m200 and total for TEAEs, TEAEs by maximum severity, TEAEs by maximum relationship to study 
treatment, treatment-related TEAEs, serious TEAEs, and AESIs. All AEs will be listed by patient, along 
with information regarding onset, duration, relationship and severity to study drug, action taken with 
study drug, treatment of event, and outcome. 
 
Vital signs will be summarized using descriptive statistics: actual values and changes from baseline will 
be presented for each scheduled assessment time point by treatment group, overall IXT-m200 and total. 
Weight and BMI will be summarized by treatment group, overall IXT-m200 and total.  
 
Physical examination results will be presented by number and percentage of patients in each category and 
scheduled time point by treatment group, overall IXT-m200 and total.  
 
Clinical laboratory data (continuous parameters) will be summarized using descriptive statistics for each 
scheduled assessment time point by treatment group. Categorical laboratory data and urinary drug screen 
results will be presented by number and percentage of patients in each category and scheduled time point 


 
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by treatment group. Additionally, for laboratory data, frequency tables with number and percentage of 
patients of scheduled time point will be provided using the categories above/within/below normal range. 
 
Extent of exposure will be summarized by a frequency table of number and percentage of patients by 
treatment group who received the total amount of the planned infusion, and who received the infusion 
partly. 
9.4.5. BASELINE DESCRIPTIVE STATISTICS 
 
Demographic and baseline characteristics will be summarized by treatment group, overall IXT-m200 and 
total. 
9.4.6. PLANNED INTERIM ANALYSES  
 
No interim analyses are planned. 
9.4.7. EXPLORATORY ANALYSES 
 
The duration of the stay in the ED, calculated as starting from triage time and also as starting from 
treatment start time, will be summarized by descriptive statistics by treatment group and overall 
IXT-m200. The descriptive pairwise comparison of IXT-m200 dose levels versus TAU will be performed 
by a t-test using log-transformed durations. 
 
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 if required, a legally authorized representative (LAR; surrogate or substitute decision 
maker) and written documentation of informed consent and/or assent from the participant is required prior 
to starting the screening process, and subsequently administering study intervention.   
 
 
 


 
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10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Given that METH use can cause agitation, delirium, and psychosis, only people who are found able to 
consent for themselves using the UBACC, or for whom a LAR who can consent for the participant can be 
identified will be recruited. The LAR may provide consent in accordance with local regulations, as 
described in 0.  
 
Specifics will vary depending the clinical site, but patients identified with symptoms of METH toxicity 
will be approached by the investigator or designated and trained study personnel about participation in the 
study. Patients will be asked if they would like to participate in the study and if they have a LAR to 
provide consent for them. If the answer is yes to both questions, or they are found able to give consent for 
themselves, informed consent will be sought using IRB-approved consent forms and processes. No one 
will participate without providing written consent or assent by signature of the participant recorded on the 
ICF. 
 
The process for consent is outlined in the following figure. 
 
 
Written informed consent, or reconsent, from the participant will be obtained before any procedures are 
conducted on Day 3.  
 
 
Potential participant 
identified
Can 
participant 
consent for 
themselves?
Initiate study 
procedures
Review Day 1 ICF
Yes
No
Perform UBACC 
assessment
Follow steps to secure 
written LAR consent 
on Day 1 ICF
Complete Day 1 ICF 
with written participant 
consent
Ensure participant 
signs ICF for written 
assent


 
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10.1.1.2.1 LAR CONSENT PROCEDURES 
 
The following steps will be conducted to obtain consent from the LAR on Day 1, when a subject is found 
unable to consent for themselves by using the UBACC: 
 
1. The informed consent form (ICF) will be sent to the potential LAR by email, fax, or other 
electronic means. 
2. The person obtaining consent will connect with the LAR by phone, video, or other means and 
will confirm they are speaking with the correct individual. 
a. The conversation requires a witness to be present starting with Step 2, preferably a 
member of the site staff so that signatures can be easily obtained. 
3. The date and version number of the consent will be confirmed between the person obtaining 
consent and the LAR. 
4. The consenting process will proceed as usual with the person obtaining consent verbally going 
over the informed consent and answering any questions. 
5. The person obtaining consent will ask for verbal informed consent to conduct screening 
assessments. 
6. The person obtaining consent will document the conversation in the subject file or progress notes 
recording at a minimum: 
a. Date and time of the conversation 
b. How it occurred (e.g., telephone or video conference) 
c. Name of the witness and any other participants 
d. Confirmation that the LAR received the ICF 
e. Confirmation of verbal informed consent to conduct screening 
7. The LAR will sign the ICF.  This may be documented in many ways, including: 
a. The LAR may print the ICF, sign it and return a scan or picture of the form 
electronically. The LAR must be informed that there is a small risk of email being 
intercepted in route. 
b. The LAR may use an electronic signature. Some options include: 
i. Adobe Sign 
ii. Apple Pen 
iii. DocuSign 
8. Documentation of the LAR signature must be received, and all other steps in the informed 
consent process completed, prior to any therapeutic intervention. 
9. The final ICF must be filed in the designated investigator/research file location and a copy given 
to the LAR and participant. 
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 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. Sponsor will provide the reason(s) for the termination or suspension. 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; 


 
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• 
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 
subjects in this study. The clinical study site will permit access to such records. 
  
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 in the Statistical Considerations 
(Section 9) and Data Handling (Section 10.1.9) sections of this protocol. 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. 
  


 
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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 
 
 
Safety oversight will be under the direction of a DSMB composed of individuals with the appropriate 
expertise, likely including clinical trial oversight, monoclonal antibody and methamphetamine clinical 
pharmacology, acute care medicine (cardiovascular and/or emergency), psychiatry or behavioral 
medicine, statistics, and a patient advocate or representative. Members of the DSMB will be independent 
from the study conduct and free of conflict of interest, or measures will be enacted to minimize real or 
perceived conflicts of interest.  The DSMB will meet at the conclusion of cohort 1 to assess safety data 
and intermittently as necessary. 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 Sponsor. 
 
Cohort escalation review will be performed by the Sponsor, Medical Monitor, and DSMB between 
cohorts 1 and 2 and the next group will not start until after completion of this review. This review will be 
scheduled to occur approximately two weeks after the last enrollee in the cohort has completed the Day 3 
visit so that all Day 3 data available are considered. Safety data to be reviewed include vital signs, ECG, 
AEs, clinical laboratory values (serum and urine), and UDS. 
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 by electronic means of viewing both 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 


 
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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. 
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 adverse events (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 


 
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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 investigator and the IRB 
• 
Composition of the IRB or other applicable statement  
• 
Record of all significant communications between the investigator 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 eCRFs and of documentation of corrections for all participants 
• 
Drug accountability records 
• 
Record of any body fluids or tissue samples retained 
• 
All other source documents (patient 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, he must contact the Sponsor to make 
alternative arrangements. Details of these arrangements should be documented. 
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 manual of procedures 
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 subject's rights, safety, or 
well-being. Deviations will be categorized by type and will be reviewed on an ongoing basis. 


 
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10.1.11. 
PUBLICATION AND DATA SHARING POLICY 
 
This study will comply with the 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 
ACES 
Agitation/Calmness Evaluation Scale 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
AUCinf 
Area Under the Curve from Time 0 Through Infinity 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
Maximum Concentration 
CMP 
Clinical Monitoring Plan 
CNS 
Central Nervous System 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Cardiovascular 
DHHS 
Department of Health and Human Services 
DSM5  
Diagnostic and Statistical Manual of Mental Disorders 5  
DSM5 SUD 
Diagnostic and Statistical Manual of Mental Disorders 5 for Substance Use Disorders 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Forms 
ED 
Emergency Department 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HACA 
Human Anti-Chimeric Antibody 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
IgG 
Immunoglobulin G 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
IV 
Intravenous 
IXRS 
Interactive Voice/Web Response System 
LAR 
Legally Authorized Representative 
mAb 
Monoclonal Antibody  
MedDRA 
Medical Dictionary for Regulatory Activities 
METH 
Methamphetamine 
MUD 
Methamphetamine Use Disorder 
N 
Number 
NA 
Not Applicable 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIDA 
National Institute on Drug Abuse 
OHRP 
Office for Human Research Protections 


 
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PANSS-EC 
Positive and Negative Syndrome Scale – Excited Component 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
QC 
Quality Control 
SA 
Self-Administration 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SoA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
STAMPOUT Study of Antibody for Methamphetamine Outpatient Therapy, NCT03336866 
TAU 
Treatment As Usual 
TEAE 
Treatment-Emergent Adverse Event 
UBACC 
UCSD Brief Assessment of Capacity to Consent 
UDS 
Urine Drug Screen 
UPT 
Urine Pregnancy Test 
Urine AE 
Cumulative Urinary Excretion 
US 
United States 
Vd 
Volume of Distribution 
WBC 
White Blood Cell 
 
 
 


 
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10.3. PROTOCOL AMENDMENT HISTORY 
 
Version/Date 
Description of Change  
Brief Rationale 
V2 
23Mar2021 
Updates throughout to 
allow dosing of haloperidol 
up to 5 mg by IM or IV 
TAU may include 5 mg haloperidol. IV dosing option 
added to allow physicians the choice. 
1.3 Clarified SOA to match 
section 8 for UDS. 
Clarification updates only. 
5.2 Updated inclusion 
criteria 3 with upper bound 
of 25 for PANSS-EC score. 
To ensure that severely METH intoxicated patients are 
not enrolled. 
6.5.1 Added dopamine (and 
other medications) as 
option for rescue 
medication for hypotension 
at specified starting dose. 
To include additional rescue medications. 
7.1 Added study halting 
rule for two Grade 3 AEs 
related to agitation, 
aggression, or anxiety. 
Increased METH toxicity signs could indicate treatment 
failure. It is important to pause the study for review in 
the case of toxicity-related AEs. 
8.2 Changed Day 3 clinical 
labs from ‘repeat if needed’ 
to ‘required’. 
It is likely that the Day 1 lab results would not be 
available in order to determine necessity of repeat lab 
data by Day 3. 
10.1.1.2 Clarified consent 
process. 
To note that a box will be checked if LAR consent is 
obtained by phone. 
12.9.1 Added DSMB 
member names and 
affiliations.  
To add names and affiliations. 
V3 
15Nov2021 
1.2 Updated schema. 
To remove references to time frames. 
1.3 Added collection of 
ACES score at time 0 and 
broadened the window for 
collection of UDS, UPT, 
and breathalyzer. 
To ensure an ACES score is captured proximate to 
dosing initiation and to allow UDS, UPT, and 
breathalyzer to occur before or after dosing. 
5.2 Revised inclusion 
criteria 3 to increase the 
upper limit of the PANSS-
EC assessment to 28.  
To more accurately reflect moderate severity agitation, 
which could include a score of “4” on all 7 dimensions.  
5.2 Revised inclusion 
criteria 5 to include a 
positive METH drug 
screen. 
To allow a positive METH drug screen rather than 
participant or observer attribution of symptoms to 
METH use. 
5.3 Revised exclusion 
criteria 1 to remove the 
exclusion of those requiring 
naloxone treatment. 
Removed as unnecessary. 
5.3 Revised exclusion 
criteria 3c to remove the 
Removed as unnecessary. 


 
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Version/Date 
Description of Change  
Brief Rationale 
exclusion of agitation 
requiring restraint. 
5.3 Revised exclusion 
criteria 4 to include 
suicidality questions asked 
and modify the time frame 
of the questions asked. 
To include the specific questions to be asked and the 
disqualification criteria in the list with other criteria. 
The time frames for reported suicidal ideation and 
suicide attempt were reduced to allow those with 
adolescent or >1 year ago suicide attempts to enroll. It 
is considered that participants who have not attempted 
suicide again in the past year and have also not been 
thinking much about it in the past month are stable 
enough for study enrollment. 
6.2.3 Removed the frozen 
IP storage option. 
To clarify the preferred storage condition of 
refrigerated. 
7.2 Clarified recruitment of 
additional subjects. 
To clarify that additional subjects may, not will, be 
recruited to complete the cohorts with those testing 
positive for METH. 
8.1 Updated the rationale 
for the PANSS-EC range. 
To clarify the change to inclusion criteria 3. 
8.2 Updated the 
Evaluations of Drug and 
Alcohol Use to remove 
propoxyphene and change 
time frame for UDS and 
breathalyzer 
To remove propoxyphene testing as unnecessary and 
broaden the time frame for collecting UDS and 
breathalyzer tests to before or after dosing. 
8.2 Updated the Psychiatric 
Evaluation section to 
modify the time frame used 
for questions about suicide 
attempts and ideation. 
The time frames for reported suicidal ideation and 
suicide attempt were reduced to allow those with 
adolescent or >1 year ago suicide attempts to enroll. It 
is considered that participants who have not attempted 
suicide again in the past year and have also not been 
thinking much about it in the past month are stable 
enough for study enrollment. Removed reference to 
IXT Suicidal Ideation Questionnaire as unnecessary. 
8.2 Added bilirubin to 
laboratory evaluations 
Test was previously omitted. 
8.2 Changed time frame for 
UDS, urinalysis, and UPT 
To broaden the time frame for collecting urine samples 
to before or after dosing. 
8.3.2 Clarified wording to 
define a medically 
important event classified 
as an SAE. 
To clarify the definition of a medically important event 
that should be considered an SAE. 
8.3.6 Reduced the time 
frame of reporting of SAEs 
to Sponsor and Medical 
Monitor that are not life 
threatening to 48 hours. 
To allow time for reporting to NIDA by 72 hours post-
event occurrence. 
9.4.3 Removed requirement 
for two consecutive time 
points following a return to 
To allow subjects to be discharged faster rather than 
waiting on an additional time point after a return to 
normal. 


 
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Version/Date 
Description of Change  
Brief Rationale 
normal for the ACES 
assessment. 
9.4.3 Removed requirement 
to report ratio of IXT-m200 
to METH. 
Removed as unnecessary. 
10.1.1.2 Clarified consent 
process by adding wording 
from Protocol Clarification 
Letter dated 07 April 2021. 
Removed unnecessary wording and added section 
10.1.1.2.1 describing IRB-approved consent procedures 
for LAR. 
10.1.7 Added option for 
electronic SDV as needed. 
To clarify that SDV could be done via electronic means 
if necessary and possible, and not only during an on-site 
visit. 
V4 
09Mar2022 
Updates throughout to 
change dose level for 
cohort 2 to 2-g doses  
To update the dose level for cohort 2 to 2-g doses. Dose 
levels for cohorts 3 and 4 will be updated by future 
amendment. 
1.3 Inserted UBACC in 
SOA 
To note that the UBACC should be performed along 
with Informed Consent processes 
2.2 Noted that the 
STAMPOUT study was 
complete and a Phase 1 
study is ongoing 
To provide updated background information in support 
of the protocol change. 
4.1 Updated table of cohort 
dose levels  
To update the dose levels for cohorts 2-4. 
4.3 Updated dose levels and 
added supporting 
information  
To remove unnecessary dose information for 1- and 1.5-
g doses, and provide calculated dose administration 
rates that are supportive of the protocol change. 
5.2 Added phrase to IC#6 
To allow an exception to the requirement for an LAR if 
the participant is capable of consenting for themselves 
as determined by the UBACC 
5.2 Added consent or to 
IC#7 
To clarify that participants must consent or assent, the 
choice of which will depend on whether they have the 
capacity to consent for themselves 
5.3 Adjusted EC#6 wording To allow participants with an allergy to one of the two 
TAU medications to participate, so long as they are not 
allergic to both 
5.6.1 Updated phrasing for 
consistency 
To note that a LAR is required only if a participant is 
found unable to consent for themselves 
6.2.4 Removed 1- and 1.5-g 
doses 
To remove reference to doses that are now unplanned 
8.2 Added description of 
the UBACC 
To provide a description of the UBACC and clarify its 
use 
9.4.6 Revised the purpose 
of the Interim Analysis 
To change the purpose of the Interim Analysis slightly 
by determining the appropriate cohorts 3 and 4 doses 
rather than confirming their pre-specified levels are 
appropriate. 


 
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Version/Date 
Description of Change  
Brief Rationale 
10.1.1 Updated Informed 
Consent process 
Entire section updated to allow participants to consent 
for themselves if found to have the capacity to consent 
by the UBACC. If unable to consent, a LAR may be 
used for consent along with the written assent of the 
participant. All participants are to provide consent, 
again if they originally consented for themselves, on 
Day 3. 
10.1.3 Added Investigator 
responsibility 
To specify that Investigators have certain 
responsibilities due to the Certificate of Confidentiality. 
V5 
22Aug2022 
1.1 Updated number of 
anticipated participants 
Changed number from 40 to 24 in order to complete the 
study with equal number of participants in the low, 
high, and TAU groups. 
4.1 Updated number of 
anticipated participants, 
number of cohorts, and 
timing of DSMB reviews 
Changed number from 40 to 24 participants, reduced 
the number of cohorts required, and the timing of 
DSMB meetings. 
4.2 Removed comment that 
lowest effective dose would 
be identified 
Intermediate doses have been removed from the 
protocol, thus the lowest effective dose may not be 
identified 
6.2 Clarified randomization 
Required update to match cohort dose revisions 
6.3 Clarified randomization 
Required update to match cohort dose revisions 
7.2 Updated replacement of 
participant 
Required update to match cohort dose revisions 
9 Removed reference to 4 
cohorts 
Required update to match cohort dose revisions 
9.2 Clarified number of 
TAU patients needed is 8  
Required update to match cohort dose revisions 
9.4.6 Removed plan for 
interim analysis 
An interim analysis is no longer necessary following 
cohort 2 as the treatment for cohort 3 is TAU. 
10.1.6 Updated DSMB 
meeting schedule 
Required update to match cohort dose revisions 
 
 


 
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11 REFERENCES  
 
1. Klein LR, Driver BE, Miner JR, Martel ML, Hessel M, Collins JD, Horton GB, Fagerstrom E, Satpathy 
R, Cole JB. Intramuscular midazolam, olanzapine, ziprasidone, or haloperidol for treating acute agitation 
in the emergency department. Ann Emerg Med 2018; 72:374–85. 
2. Wilson MP, Pepper D, Currier GW, Holloman GH, Feifel D. The psychopharmacology of 
agitation: consensus statement of the American Association for Emergency Psychiatry project 
BETA psychopharmacology workgroup. West J Emerg Medicine 2012; 13:26–34. 
3. Schwarzbach V, Lenk K, Laufs U. Methamphetamine‐related cardiovascular diseases. ESC 
Heart Failure 2020; 7:407–14. 
4. Richards JR, Hamidi S, Grant CD, Wang CG, Tabish N, Turnipseed SD, Derlet RW. 
Methamphetamine use and emergency department utilization: 20 years later. J Addict 2017; 
2017:1–8. 
5. Byrnes-Blake KA, Laurenzana EM, Landes RD, Gentry WB, Owens SM. Monoclonal IgG 
affinity and treatment time alters antagonism of (+)-methamphetamine effects in rats. Eur J 
Pharmacol 2005; 521:86–94. 
6. Byrnes-Blake KA, Laurenzana EM, Carroll FI, Abraham P, Gentry WB, Landes RD, Owens 
SM. Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-
methamphetamine in rats. Eur J Pharmacol 2003; 461:119–28. 
7. Laurenzana EM, Stevens MW, Frank JC, Hambuchen MD, Hendrickson HP, White SJ, 
Williams DK, Owens SM, Gentry WB. Pharmacological effects of two anti-methamphetamine 
monoclonal antibodies. Supporting data for lead candidate selection for clinical development. 
Hum Vaccin Immunother 2014; 10:2638–47. 
8. Stevens MW, Tawney RL, West CM, Kight AD, Henry RL, Owens SM, Gentry WB. 
Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use. 
mAbs 2014; 6:547–55. 
9. White SJ, Hendrickson HP, Atchley WT, Laurenzana EM, Gentry WB, Williams DK, Owens 
SM. Treatment with a monoclonal antibody against methamphetamine and amphetamine reduces 
maternal and fetal rat brain concentrations in late pregnancy. Drug Metab Dispos 2014; 42:1285–
91. 
10. Stevens MW, Henry RL, Owens SM, Schutz R, Gentry WB. First human study of a chimeric 
anti-methamphetamine monoclonal antibody in healthy volunteers. mAbs 2014; 6:1649–56. 
11. Owens SM, Atchley WT, Hambuchen MD, Peterson EC, Gentry WB. Monoclonal antibodies 
as pharmacokinetic antagonists for the treatment of (+)-methamphetamine addiction. CNS 
Neurol Disord Drug Targets [Internet] 2011; 10:892–8. Available from: 


 
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https://www.researchgate.net/publication/221733100_Monoclonal_Antibodies_as_Pharmacokine
tic_Antagonists_for_the_Treatment_of_-Methamphetamine_Addiction 
12. Battaglia J, Lindborg SR, Alaka K, Meehan K, Wright P. Calming versus sedative effects of 
intramuscular olanzapine in agitated patients. Am J Emerg Medicine 2003; 21:192–8. 
13. Zhu JM, Singhal A, Hsia RY. Emergency department length-of-stay for psychiatric visits 
was significantly longer than for nonpsychiatric visits, 2002–11. Health Affair 2017; 35:1698–
706. 
14. Richards JR, Hawkins JA, Acevedo EW, Laurin EG. The care of patients using 
methamphetamine in the emergency department: Perception of nurses, residents, and faculty. 
Subst Abus 2018; :1–31. 
15. Hambuchen MD, Rüedi-Bettschen D, Williams DK, Hendrickson H, Owens SM. Treatment 
of rats with an anti-(+)-methamphetamine monoclonal antibody shortens the duration of action of 
repeated (+)-methamphetamine challenges over a one month period. Vaccine 2014; 32:6213–9. 
16. Laurenzana EM, Byrnes-Blake KA, Milesi-Hallé A, Gentry WB, Williams DK, Owens SM. 
Use of anti-(+)-methamphetamine monoclonal antibody to significantly alter (+)-
methamphetamine and (+)-amphetamine disposition in rats. Drug Metab Dispos 2003; 31:1320–
6. 
17. Chiang M, Lombardi D, Du J, Makrum U, Sitthichai R, Harrington A, Shukair N, Zhao M, 
Fan X. Methamphetamine-associated psychosis: Clinical presentation, biological basis, and 
treatment options. Hum Psychopharmacol 2019; 34:e2710. 
18. Sacchetti E, Amore M, Sciascio GD, Ducci G, Girardi P, Mauri M, Tortorella A, Matteis 
LMD, Menacci C. Psychomotor agitation in psychiatry: an Italian expert consensus. Evidence-
based Psychiatric Care 2017; 1:1–24. 
19. Montoya A, Valladares A, Lizán L, San L, Escobar R, Paz S. Validation of the Excited 
Component of the Positive and Negative Syndrome Scale (PANSS-EC) in a naturalistic sample 
of 278 patients with acute psychosis and agitation in a psychiatric emergency room. Health Qual 
Life Out 2011; 9:18. 
20. Kay SR, Fiszbein A, Opfer LA. The Positive and Negative Syndrome Scale (PANSS) for 
Schizophrenia. Schizophrenia Bull 1987; 13:261–76. 
21. Jeste DV, Palmer BW, Appelbaum PS, Golshan S, Glorioso D, Dunn LB, Kim K, Meeks T, 
Kraemer HC. A New Brief Instrument for Assessing Decisional Capacity for Clinical Research. 
Arch Gen Psychiat 2007; 64:966–74. 
22. Sibille M, Patat A, Caplain H, Donazzolo Y. A safety grading scale to support dose 
escalation and define stopping rules for healthy subject first-entry-into-man studies. Br J Clin 
Pharmacol 2010; 70:736–48.  


 
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12 DATA AND SAFETY MONITORING PLAN 
 
U01 DA 053043 (PD/PI: Gentry, William B. and Stevens, Misty) 
 
Meth-OD: A Phase 2A Study of IXT-m200 in Patients with Toxicity from 
Methamphetamine Overdose 
 
Protocol Number: M200C-2101 
 
Medical Monitor: Patrick Keenan, MD 
 
 
August 22, 2022 
 
 
This Data and Safety Monitoring Plan (DSMP) is forward looking and may not be amended in real time 
to reflect changes in study status, participant enrollment, etc. In the event of a conflict between the DSMP 
and the clinical protocol, the current clinical protocol shall be followed. 
 
 


 
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12.1. SUMMARY OF THE PROTOCOL 
12.1.1. STUDY DESIGN 
 
Refer to protocol section 4 for further details. 
 
The hypothesis of this multisite Phase 2a study is that IXT-m200 will be well-tolerated in patients with 
acute mild to moderate METH toxicity. A randomized, open label design will be used in which one dose 
of IXT-m200 will be compared to treatment-as-usual (TAU). Approximately 24 participants will be 
enrolled in 3 cohorts. A dose escalation approach will be used so that progressively higher IXT-m200 
doses will be evaluated in each of the first two cohorts. In conjunction with safety monitoring, this design 
assures the opportunity to observe early safety findings before any participants are exposed to the next 
higher dose. The randomization ratio for IXT-m200 versus TAU is defined as 4:1 for each of cohorts 1 
and 2, with up to an additional 4 TAU participants in cohort 3 so that the number of participants receiving 
TAU equals the number receiving each dose of IXT-m200 at the end of the study.  
 
Cohort 
IXT-m200  
dose (g) 
IXT-m200:TAU 
subject numbers 
1 
0.5 
8:2 
2 
2 
8:2 
3 
0 
0:4 
 
Agitation scales and vital signs will be recorded to track effect of the antibody treatment versus TAU over 
time on agitation associated with METH use. While in the ED, detailed and pertinent medical and 
psychiatric histories, and physical exam will be obtained, along with laboratory assessments and ECGs. In 
the ED, participants will give blood samples for analysis of METH and IXT-m200 concentrations and 
followed for development of adverse events. Participants will be evaluated at 2 days and 4 weeks after 
discharge from the ED for adverse events and drug use history. Cohort escalation review will be 
performed by the Sponsor, Medical Monitor, and Data and Safety Monitoring Board (DSMB) after cohort 
1 and the next group will not start until after completion of this review.  
 
The next page shows the Schedule of Activities. 
 


 
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Assessment 
Triage 
Screening 
Dosing and Assessments f 
Follow-upa 
Study Day 
1 
1 
1 
Day not 
specified 
3 
(+2) 
28 
(±7) 
Hour 
NA 
<0 
<0 
0 
0.25 
0.5 
0.75 
1 
1.5 
2 
3 
4 
6 
8 
>8, <Discharge 
from ED 
Discharge 
from ED 
NA 
NA 
Focused history and physical 
exam b, c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Focused review of systems b, c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Medication history 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Detailed and pertinent 
psychiatric history c, d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs c 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
As needed 
X 
X 
X 
Agitation score c 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
As needed 
 
 
 
Informed consent and 
UBACC 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Eligibility criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samples d 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
Dose administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Observe for AEs 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
As needed 
X 
X 
X 
Assess for rescue meds 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
As needed 
X 
 
 
Clinical labs and ECG 
 
 
 
 
 
Once, as soon as feasible 
 
 
 
 
X 
 
UDS, UPT, Breathalyzer  
 
 
Once, as soon as feasible 
 
 
 
 
 
 
Detailed and pertinent 
medical history e 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
DSM5 SUD checklist 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Drug use assessment and 
Meth Perception Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
AE – adverse event; UDS – urine drug screen; UPT – urine pregnancy test; ECG – electrocardiogram; DSM5 SUD – Diagnostic and Statistical Manual of Mental Disorders 5 for 
Substance Use Disorders; NA – not applicable; UBACC – UCSD Brief Assessment of Capacity to Consent 
a If participants do not return for a follow-up visit, a phone call will be attempted to assess any AEs. 
b Focused history, physical exam and review of systems based on main complaint, related details from other parts of the medical history and physical exam, and eligibility criteria.  
c Assessments will be obtained as either part of triage or screening, depending on the site. PANSS-EC will be done at screening only; ACES will be done at each time point as 
marked. 
d PK samples will be drawn for both IXT-m200 and METH per section 8.2. 
e Detailed and pertinent history includes pertinent past medical, family and social histories in addition to focused history. Detailed physical exam to be completed if indicated by 
detailed and pertinent medical history.  
f Subjects may be discharged at any time point after the 2-hr assessments are completed if the subject is deemed medically eligible; assessments at Day 1, Hours 3-8 may be 
skipped if discharged. Assessments assigned for the time of discharge from ED should be completed for all subjects. 


 
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12.1.2. PRIMARY AND SECONDARY OBJECTIVES AND OUTCOME MEASURES 
Refer to protocol section 3. 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
Primary 
 
 
To evaluate the safety and 
tolerability of IXT-m200 in 
patients with mild to moderate 
METH toxicity 
Safety and tolerability of IXT-
m200 as measured by physical 
examinations and vital sign, 
AE, ECG, and clinical 
laboratory testing 
Safety must be systematically 
evaluated of IXT-m200 when 
given to patients with ongoing 
METH toxicity for the first time  
Secondary 
 
 
To determine the time course 
and degree of normalization of 
agitation and vital signs 
Agitation/sedation scores over 
time as measured by ACES 12  
Agitation is a significant CNS 
component of METH toxicity and 
a cause for hospital admission  
Vital signs including blood 
pressure, heart rate and 
temperature over time 
Elevated or depressed 
hemodynamics are a component of 
CV toxicity 
To determine the percentage 
of participants requiring 
rescue medications for 
psychiatric or cardiovascular 
manifestations of METH 
toxicity  
Need for rescue medications to 
treat: 
- agitation, dysphoria, or 
psychosis (CNS toxicity) 
- hypertension, tachycardia, or 
other cardiovascular 
instability (CV toxicity) 
An evaluation of IXT-m200 
effects on requirement of rescue 
medications is needed 
Tertiary/Exploratory  
 
 
To determine how long 
patients with METH toxicity 
stay in the ED 
ED length of stay as measured 
by disposition order time minus 
triage time, and as measured by 
disposition order time minus 
start of treatment time, with log 
transformation 
Prolonged wait times are 
associated with a number of 
negative outcomes, including 
patient dissatisfaction, increased 
hospitalization rate, poor quality of 
care, and increased mortality 13 
12.1.3. INCLUSION CRITERIA 
Refer to protocol section 5.2. 
Eligible participants will:  
1. Be aged 18 to 45 years, inclusive; 
2. Present to the ED with METH toxicity as defined in protocol; 
3. Have a PANSS-EC score of 14-28, inclusive; 
4. Have or agrees to have an intravenous (IV) line placed; 
5. Give a history of METH use in the past 24 hours, with participant or observer attribution of 
symptoms to METH or have a positive METH drug screen; 
6. Be accompanied or readily represented by a legally authorized representative (surrogate) who can 
consent to participation on behalf of the participant if participant is found not able to consent for 
themselves using the UCSD Brief Assessment of Capacity to Consent (UBACC); and 
7. Consent or assent to participation in the study. 


 
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12.1.4. EXCLUSION CRITERIA 
Refer to protocol section 5.3. 
Eligible participants will NOT:  
1. Present with concomitant opioid overdose requiring ventilatory support; 
2. Be self-reported to be pregnant or lactating; 
3. Be considered to have significant concomitant medical illness or trauma, or symptoms of severe 
METH toxicity including  
a. sepsis or febrile illness;  
b. myocardial infarction, cardiac decompensation or arrhythmias including tachycardia that 
is not sinus; severe hypertension (>180/110 mmHg); inadequately treated hypertension 
on chronic medication; history of vasculitis 
c. coma, stroke or severe head injury; new or ongoing seizure activity 
d. acute pulmonary decompensation or severe chronic obstructive pulmonary disease;  
e. any hepatic impairment and/or acute hepatitis or renal impairment due to concomitant 
medical illness; or 
f. 
current, or history of, neuroleptic malignant syndrome  
4. Be considered to be at imminent risk of suicide or have disqualifying answers to the following 
two questions. Disqualifying answers would be 1b2 or 2b. 
 
1. In the past 30 days, have you considered killing yourself? 
a) No 
b) Yes - if Yes, how often? 
b1) Not often (twice or less) 
b2) Somewhat often (more than twice) 
 
2. In the past year, have you attempted to kill yourself? 
a) No 
b) Yes 
 
5. Be considered to be at imminent risk of injury or danger to self, others or property; 
6. Have a history of severe allergy (rash, hives, breathing difficulty, etc.), to both lorazepam and 
haloperidol, or known hypersensitivity or infusion reaction to any antibody medications; or 
7. Be judged by the treating ED physician, investigator, or Sponsor (or designee) to be inappropriate 
for the study, including people whom the investigator determines cannot reasonably be consulted 
for assent to participation. 
12.1.5. POWER CALCULATION AND SAMPLE SIZE 
Refer to protocol section 9 and the SAP for further detail on statistical analysis. 
Because Meth-OD is mainly a safety study, the sample size for this study is not based on statistical 
hypotheses. The number of participants within each dose group was chosen based on feasibility, as well 
as historical experience with initial safety and tolerability trials. From the perspective of tolerability 
assessment, the probability that a given adverse event would not be observed in a group of participants 
administered an assigned dose was analyzed for various true population incidence rates was computed 
(Table 1).  


 
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Table 1. Probability of Not Observing an Adverse Event for Various True Incidence Rates  
 
Probability of Not Observing an AE in Varying Group Sizes 
True incidence rate 4 subjects 6 subjects 8 subjects 9 subjects 12 subjects 18 subjects 
0.10 
0.66 
0.53 
0.43 
0.387 
0.28 
0.150 
0.20 
0.41 
0.26 
0.17 
0.134 
0.069 
0.018 
0.30 
0.24 
0.12 
0.058 
0.040 
0.014 
0.002 
0.40 
0.13 
0.047 
0.017 
0.010 
0.002 
< 0.001 
0.50 
0.063 
0.016 
0.004 
0.002 
< 0.001 
< 0.001 
The probability of not observing an AE under each sample size and true incidence rate scenario was 
calculated using an exact test for binomial proportion assuming a two-sided Type I error (alpha) of 0.05 
and near-zero null proportion of 0.000001. The values reported in the table are the Type 2 error. Analyses 
were conducted in SAS® 9.4. 
Based on the nature of this study, the proposed sample size of 8 participants in each IXT-m200-
containing treatment group adequately allows for the detection of clinically meaningful rates of adverse 
events with the probability of not observing an AE for true incidence rates. 
12.2. TRIAL MANAGEMENT 
12.2.1. PARTICIPATING CLINICS 
 
Dr. Michael Wilson 
University of Arkansas for Medical Sciences 
4301 W. Markham St., Little Rock, AR 72205 
 
Dr. Thomas Robey 
Providence Community Hospital 
1330 Rockefeller Ave Suite 440, Everett, WA 98201 
 
Dr. Cameron Crandall 
University of New Mexico 
MSC11 6025 1 UNM, Albuquerque, NM 87131 
 
Dr. David McClellan 
Sacred Heart Medical Center/Providence Medical Research Center 
105 W 8th Avenue, Suite 532C, Spokane, WA 99204 
 


 
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12.2.2. PLANNED ENROLLMENT TIMETABLE 
 
12.2.3. TARGET POPULATION DISTRIBUTION 
 
TARGETED/PLANNED ENROLLMENT: Number of Participants 
 
Not Hispanic or Latino 
Hispanic or Latino 
 
Racial Categories 
Female 
Male 
Female 
Male 
Total 
American Indian/ 
Alaska Native 
0 
1 
0 
0 
1 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian or  
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
1 
2 
0 
0 
3 
White 
4 
7 
1 
3 
15 
More than One Race 
1 
1 
1 
1 
4 
Total 
6 
12 
2 
4 
24 
 
 
 


 
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12.3. DATA MANAGEMENT AND ANALYSIS 
12.3.1. DATA ACQUISITION AND TRANSMISSION 
Refer to protocol section 10.1.9.1. 
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 adverse events (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. 
12.3.2. DATA ENTRY METHODS 
All data will be collected on source documents and then entered in the eCRFs. 
12.3.3. DATA SECURITY AND PLAN FOR PROTECTING CONFIDENTIALITY 
 
Refer to protocol section 10.1.3. 
 
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 
subjects in this study. The clinical study site will permit access to such records. 
  
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 


 
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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. 
12.3.4. DATA ANALYSIS PLAN 
 
Refer to protocol section 9 for further details. 
 
A statistical analysis plan (SAP) will be prepared after the protocol is approved. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to address 
all study objectives. The SAP will serve as a complement to the protocol and supersedes it in case of 
differences. 
12.4. QUALITY ASSURANCE AND QUALITY CONTROL 
12.4.1. PROCEDURES IN PLACE TO ENSURE THE VALIDITY AND INTEGRITY OF 
THE DATA 
Refer to protocol section 10.1.8. 
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. 
12.4.2. PROCEDURES TO GUARANTEE THE ACCURACY AND COMPLETENESS OF 
THE DATA DURING DATA COLLECTION, ENTRY, TRANSMISSION, AND 
ANALYSIS 
Refer to protocol section 10.1.7. 
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). 
  


 
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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 by electronic means of viewing both 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. 
 
12.5. REGULATORY ISSUES 
12.5.1. REPORTING OF SAES 
Refer to protocol section 8.3.6. 
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 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 Sponsor will be responsible for notifying the 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. 
 


 
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The NIDA Project Officer (PO) and Project Scientist (PS) 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.  
12.5.2. REPORTING OF IRB ACTIONS TO NIDA 
InterveXion will be responsible for reporting IRB actions to the NIDA PO. 
12.5.3. REPORT OF CHANGES OR AMENDMENTS TO THE PROTOCOL 
InterveXion will be responsible for reports of protocol changes or amendments to the NIDA PO and PS 
and the FDA. Significant protocol changes will be approved by NIDA prior to implementation, unless 
there is an immediate safety concern for participants. 
12.6. TRIAL SAFETY 
12.6.1. POTENTIAL RISKS AND BENEFITS FOR PARTICIPANTS 
Refer to protocol section 2.3. 
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 subjects 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 
subjects 10. 
  
Only 1 AE was definitely attributed to IXT-m200. A single subject experienced a CTCAE v.4.0 Grade 3 
infusion reaction half-way through the IXT-m200 infusion. The subject experienced a brief period of 
bronchospasm, in which the subject and investigator heard a single expiratory wheeze. The infusion was 
stopped and the subject was treated with solumedrol and diphenhydramine. No further symptoms were 
noted. The subject required outpatient therapy later for bronchitis. 
  
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 subjects were 
confirmed positive for HACA in the Phase 1 study. The development of HACA did not appear to be dose-
related 10. 
 


 
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IXT-m200 is an investigational product and may convey no benefit to patients. Based on nonclinical 
studies in rodents 7,11, 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.  
12.6.2. RISK MITIGATION PLAN 
Refer to protocol section 6.5.2. 
The following risk mitigation strategies have been designed based on other studies in people who use 
METH, on the problems posed specifically by enrolling participants in an emergency setting, on the 
clinical pharmacology of METH, and on the known pharmacology of IXT-m200: 
1. Selection of a specific participant group. As stipulated in the protocol, participants who are 
relatively healthy with no significant medical or surgical illness will be recruited. 
2. IXT-m200 dosing. IXT-m200 will be administered in escalating dose groups so that the lowest 
IXT-m200 dose (0.5 g) will be evaluated before the higher doses), in subsequent cohorts. This 
will allow determination of the effects of IXT-m200 at a low predicted effective IXT-m200 dose, 
before effects are assessed following a high predicted effective IXT-m200 dose.  
3. Treatment in an Emergency Department. A crash cart will be available in the ED and personnel 
trained in CPR are always available in the ED setting. Oxygen and emergency ventilation 
equipment are immediately available. Normal saline will be used as the IV fluid and fluid boluses 
can be administered if any hypotension is seen. In the event of serious medical complications, a 
code may be called. 
4. Frequent safety review. A formal safety review will be done between cohorts, and at any point 
needed based on the severity of AEs. This would include Grade 3 AE’s related to worsening of 
METH effects in the presence of IXT-m200.  
 
All of the study sites are EDs and therefore have all medications that might be needed to treat mAb 
toxicity, which may manifest as hypotension and bradycardia or tachycardia; bronchospasm with or 
without hypoxemia; or flushing, pruritis, and urticaria. Hospital-maintained crash carts, and oxygen and 
emergency ventilation equipment (Ambubags) are always available. Advanced Cardiovascular Life 
Support-certified providers and code teams are always available to treat life-threatening events.  
12.6.3. TRIAL STOPPING RULES 
Refer to protocol section 7.1. 
Enrollment and study drug administration will be immediately paused if any 1 of the following events 
occurs, unless the event was clearly unrelated to study drug administration, or the event is an expected 
sequelae of untreated METH toxicity: 
• 
Three (3) participants experience a Grade 3 AE.  
• 
Two (2) participants experience a Grade 3 AE related to increased agitation, aggression, or 
anxiety. 
• 
One (1) participant experiences a Grade 4 AE.  
• 
A death occurs.  
 
Expected sequelae of untreated METH toxicity which will not be considered grounds for a study pause 
include: 
• 
Hypertension/tachycardia 
• 
Euphoria 


 
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• 
Agitation 
• 
Insomnia 
• 
Anxiety 
• 
Seizures 
• 
Mania/aggression 
 
Worsening of any of the above following administration of study drug will be considered an AE and 
subject to the rules for study pause above. 
If any of the pause conditions are met, the Sponsor, in consultation with the investigator and Medical 
Monitor, will suspend enrollment until a full safety review by both the Sponsor and DSMB is performed. 
A decision to reinitiate enrollment will be made following relevant consultation with the appropriate 
authorities based on the results of the safety review. 
Also refer to protocol section 10.1.2. 
This study may be temporarily suspended or prematurely terminated at the sole discretion of the Sponsor. 
Written notification, documenting the reason 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. Sponsor will provide the reason(s) for the termination or suspension. 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. 
12.6.4. PROCESS OF AE/SAE COLLECTION, ASSESSMENT, AND REPORTING 
Refer to protocol section 8.3. 
All AEs (whether serious or nonserious) that occur after the participant has been randomized 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. Every attempt 
should be made to describe the AE in terms of a diagnosis. If appropriate, component 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, until a satisfactory 
explanation is found or the investigator considers it medically justifiable to terminate follow-up. Should 
the AE result in death, a full pathologist’s report should be supplied, if possible. 
 


 
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Adverse events will be reviewed by the Sponsor, Medical Monitor and DSMB between cohorts. If an 
investigator decides it necessary, AEs may be reviewed at any time by consultation with the investigator, 
Medical Monitor, and Sponsor. 
Refer to DSMP section 12.5.1 for details on SAEs. 
12.6.5. AE/SAE FOLLOW-UP PLAN 
Refer to DSMP section 12.6.4. 
12.7. TRIAL EFFICACY 
12.7.1. PLANS FOR INTERIM ANALYSIS OF EFFICACY DATA 
Refer to protocol section 9.4.6. 
No interim analyses are planned. 
12.8. DSM PLAN ADMINISTRATION 
12.8.1. RESPONSIBILITY FOR DATA AND SAFETY MONITORING 
Refer to protocol section 10.1.6. 
Safety oversight will be under the direction of a DSMB composed of individuals with the appropriate 
expertise, likely including clinical trial oversight, monoclonal antibody and methamphetamine clinical 
pharmacology, acute care medicine (cardiovascular and/or emergency), psychiatry or behavioral 
medicine, statistics, and a patient advocate or representative. Members of the DSMB will be independent 
from the study conduct and free of conflict of interest, or measures will be enacted to minimize real or 
perceived conflicts of interest.  The DSMB will meet at the conclusion of cohort 1 to assess safety data 
and intermittently as necessary. 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 Sponsor. 
 
Cohort escalation review will be performed by the Sponsor, Medical Monitor, and DSMB between 
cohorts 1 and 2 and the next group will not start until after completion of this review. This review will be 
scheduled to occur approximately two weeks after the last enrollee in the cohort has completed the Day 3 
visit so that all Day 3 data available are considered. Safety data to be reviewed include vital signs, ECG, 
AEs, clinical laboratory values (serum and urine), and UDS. 
12.8.2. PERSONS RESPONSIBLE FOR MONITORING THE TRIAL 
Safety monitoring will be the responsibility of the investigators, Medical Monitor and the DSMB. Each 
investigator and the Medical Monitor will provide recommendations to the Sponsor based on their 
perspectives. The Sponsor, by the actions of its Chief Medical Officer, W. Brooks Gentry, will then 
determine whether cohort enrollment should continue or if changes should be made.  


 
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12.8.3. DISCLOSURE OF ANY CONFLICT OF INTEREST IN THE DSM 
Employees at the selected trial sites have no financial interests in InterveXion, and therefore the 
monitoring done at the study sites and by the clinical monitor will not be conflicted. As described above, 
the DSMB will be recruited to have no serious conflicts of interest and any unavoidable conflicts will be 
properly disclosed. 
Dr. Gentry maintains an active conflict management plan with UAMS. A component of this plan is that 
human studies related to InterveXion are to be performed by a contract research organization (CRO) in 
which safety can be assessed by the CRO. Dr. Gentry is not involved in any way with subject recruitment 
or with the day-to-day management of the trial. All safety decisions will be made with the input of the 
investigator, Medical Monitor, and DSMB. 
InterveXion also maintains records on conflicts for its investigators. 
12.8.4. FREQUENCY OF DSM 
Refer to DSMP section 12.4.2 for clinical monitoring frequency and section 12.8.1 for DSMB meeting 
frequency. 
12.8.5. CONTENT OF DSM REPORT 
Content of DSM report (to be submitted to NIDA PO and PS annually at the same time as the RPPR is 
due) 
• 
Brief description of the trial and progress 
• 
Enrollment update and baseline sociodemographic characteristics 
• 
Retention and disposition of study participants (active, completed, and terminated/withdrawn) 
• 
Regulatory Issues (amendment, deviations, IRB report, QA issues) 
• 
AEs and SAEs listings 
12.9. DSM BOARD PLAN 
12.9.1. MEMBERS AND AFFILIATION 
 
• 
Keith Coffee, MD (Chair) – Medical and Scientific Operations, Peachtree Bioresearch Solutions 
• 
Lauren Whiteside, MD – Dept of Emergency Medicine, University of Washington 
• 
Travis Rieder, PhD – Berman Institute of Bioethics, Johns Hopkins University 
• 
Lukas Makris, PhD – Statistical Consultant, Stathmi, Inc. 
• 
Theodore Treese, MD, MBA – Psychiatrist and Principal Investigator, Adaptive Clinical Research, 
Inc. 
12.9.2. CONFLICT OF INTEREST 
Refer to DSMP section 12.8.1. 


 
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12.9.3. FREQUENCY OF MEETINGS 
Refer to DSMP section 12.8.1. 
12.9.4. PROTECTION OF CONFIDENTIALITY 
The DSMB members will be required to sign confidentiality agreements prior to participation. 
12.9.5. MONITORING ACTIVITIES (INITIAL AND ONGOING STUDY REVIEW) 
The Board will meet to review the protocol, monitor recruitment, adverse events, data quality, and overall 
study performance.  Details of the monitoring activities will be outlined in the DSMB Charter. 
12.9.6. COMMUNICATION PLAN TO IRB, NIDA, AND FDA 
The DSMB’s recommendations following interim reviews will be reported to InterveXion as Sponsor. If 
the recommendation is other than that the study should continue as designed, and if study changes are 
made as a result, InterveXion will promptly report to the IRB, NIDA, and FDA if necessary, according to 
applicable regulations and ICH Guidance. 
 
 


METH-OD: A PHASE 2A STUDY OF IXT-M200 IN 
PATIENTS WITH TOXICITY FROM 
METHAMPHETAMINE OVERDOSE 
Protocol Number: M200C-2101 
National Clinical Trial (NCT) Identified Number:  NCT04715230 
IND Sponsor: InterveXion Therapeutics, LLC 
Funded by: NIH/NIDA U01 DA053043 
Version Number: 5 
22 Aug 2022 


  
 
 
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 .......................................................................................................................................... 4 
1.3. Schedule of Activities (SoA) ......................................................................................................... 5 
2. INTRODUCTION ................................................................................................................................... 6 
2.1. Study Rationale ............................................................................................................................. 6 
2.2. Background ................................................................................................................................... 6 
2.3. Risk/Benefit Assessment ............................................................................................................... 9 
2.3.1. 
Known Potential Risks ................................................................................................... 9 
2.3.2. 
Known Potential Benefits ............................................................................................... 9 
2.3.3. 
Assessment of Potential Risks and Benefits .................................................................. 9 
3. OBJECTIVES AND ENDPOINTS ...................................................................................................... 10 
4. STUDY DESIGN .................................................................................................................................. 10 
4.1. Overall Design ............................................................................................................................. 10 
4.2. Scientific Rationale for Study Design ......................................................................................... 11 
4.3. Justification for Dose .................................................................................................................. 11 
4.4. End of Study Definition .............................................................................................................. 12 
5. STUDY POPULATION ....................................................................................................................... 12 
5.1. Description of and Rationale for the Selected Population .......................................................... 12 
5.2. Inclusion Criteria ......................................................................................................................... 13 
5.3. Exclusion Criteria ........................................................................................................................ 13 
5.4. Lifestyle Considerations .............................................................................................................. 14 
5.5. Screen Failures ............................................................................................................................ 14 
5.6. Strategies for Recruitment and Retention ................................................................................... 15 
5.6.1. 
Strategies for Recruitment ............................................................................................ 15 
5.6.2. 
Strategies for Retention and Follow-Up ....................................................................... 15 
6. STUDY INTERVENTION ................................................................................................................... 15 
6.1. Study Intervention Administration .............................................................................................. 15 
6.1.1. 
Study Intervention Description .................................................................................... 15 
6.1.2. 
Dosing and Administration .......................................................................................... 16 
6.2. Preparation/Handling/Storage/Accountability ............................................................................ 16 
6.2.1. 
Acquisition and Accountability .................................................................................... 16 
6.2.2. 
Formulation, Appearance, Packaging, and Labeling ................................................... 16 
6.2.3. 
Product Storage and Stability ....................................................................................... 17 
6.2.4. 
Preparation ................................................................................................................... 17 
6.3. Measures to Minimize Bias: Randomization and Blinding ........................................................ 17 
6.4. Study Intervention Compliance ................................................................................................... 17 
6.5. Concomitant Therapy and Risk Mitigation plan ......................................................................... 18 
6.5.1. 
Rescue Medicines ......................................................................................................... 18 
6.5.2. 
Risk Mitigation ............................................................................................................. 18 
7. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................. 19 


  
 
 
iii 
7.1. Discontinuation of Study Intervention ........................................................................................ 19 
7.2. Participant Discontinuation/Withdrawal from the Study ............................................................ 19 
7.3. Lost to Follow-Up ....................................................................................................................... 20 
8. STUDY ASSESSMENTS AND PROCEDURES ................................................................................ 20 
8.1. Efficacy Assessments .................................................................................................................. 20 
8.2. Safety and Other Assessments .................................................................................................... 21 
8.3. Adverse Events and Serious Adverse Events .............................................................................. 23 
8.3.1. 
Definition of Adverse Events (AE) .............................................................................. 23 
8.3.2. 
Definition of Serious Adverse Events (SAE) ............................................................... 23 
8.3.3. 
Classification of an Adverse Event .............................................................................. 24 
8.3.4. 
Time Period and Frequency for Event Assessment and Follow-Up ............................ 25 
8.3.5. 
Adverse Event Reporting ............................................................................................. 25 
8.3.6. 
Serious Adverse Event Reporting ................................................................................ 26 
8.3.7. 
Reporting Events to Participants .................................................................................. 26 
8.3.8. 
Events of Special Interest ............................................................................................. 26 
8.3.9. 
Reporting of Pregnancy ................................................................................................ 27 
8.4. Unanticipated Problems .............................................................................................................. 27 
8.4.1. 
Definition of Unanticipated Problems .......................................................................... 27 
8.4.2. 
Unanticipated Problem Reporting ................................................................................ 27 
8.4.3. 
Reporting Unanticipated Problems to Participants ...................................................... 28 
9 
STATISTICAL CONSIDERATIONS .................................................................................................. 28 
9.1. Statistical Hypotheses ................................................................................................................. 28 
9.2. Sample Size Determination ......................................................................................................... 28 
9.3. Populations for Analyses ............................................................................................................. 29 
9.4. Statistical Analyses ..................................................................................................................... 29 
9.4.1. 
General Approach ........................................................................................................ 29 
9.4.2. 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 29 
9.4.3. 
Analysis of the Secondary Endpoint(s) ........................................................................ 29 
9.4.4. 
Safety Analyses ............................................................................................................ 30 
9.4.5. 
Baseline Descriptive Statistics ..................................................................................... 31 
9.4.6. 
Planned Interim Analyses ............................................................................................. 31 
9.4.7. 
Exploratory Analyses ................................................................................................... 31 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 31 
10.1. Regulatory, Ethical, and Study Oversight Considerations .......................................................... 31 
10.1.1. Informed Consent Process ............................................................................................ 31 
10.1.2. Study Discontinuation and Closure .............................................................................. 33 
10.1.3. Confidentiality and Privacy .......................................................................................... 34 
10.1.4. Future Use of Stored Specimens and Data ................................................................... 34 
10.1.5. Key Roles and Study Governance ................................................................................ 35 
10.1.6. Safety Oversight ........................................................................................................... 35 
10.1.7. Clinical Monitoring ...................................................................................................... 35 
10.1.8. Quality Assurance and Quality Control ....................................................................... 36 
10.1.9. Data Handling and Record Keeping ............................................................................. 36 
10.1.10. Protocol Deviations ...................................................................................................... 37 
10.1.11. Publication and Data Sharing Policy ............................................................................ 38 
10.1.12. Conflict of Interest Policy ............................................................................................ 38 
10.2. Abbreviations .............................................................................................................................. 39 
10.3. Protocol Amendment History ...................................................................................................... 41 
11 REFERENCES ...................................................................................................................................... 45 


  
 
 
iv 
12 DATA AND SAFETY MONITORING PLAN .................................................................................... 47 
12.1. Summary of the Protocol ............................................................................................................. 48 
12.1.1. Study Design ................................................................................................................ 48 
12.1.2. Primary and Secondary Objectives and Outcome Measures ....................................... 50 
12.1.3. Inclusion Criteria .......................................................................................................... 50 
12.1.4. Exclusion Criteria ......................................................................................................... 51 
12.1.5. Power Calculation and Sample Size ............................................................................. 51 
12.2. Trial Management ....................................................................................................................... 52 
12.2.1. Participating Clinics ..................................................................................................... 52 
12.2.2. Planned Enrollment Timetable ..................................................................................... 53 
12.2.3. Target Population Distribution ..................................................................................... 53 
12.3. Data Management and Analysis .................................................................................................. 55 
12.3.1. Data Acquisition and Transmission ............................................................................. 55 
12.3.2. Data Entry Methods ..................................................................................................... 55 
12.3.3. Data Security and Plan for Protecting Confidentiality ................................................. 55 
12.3.4. Data Analysis Plan ....................................................................................................... 56 
12.4. Quality Assurance and Quality Control ...................................................................................... 56 
12.4.1. Procedures in Place to Ensure the Validity and Integrity of the Data .......................... 56 
12.4.2. Procedures to Guarantee the Accuracy and Completeness of the Data During Data 
Collection, Entry, Transmission, and Analysis ........................................................................... 56 
12.5. Regulatory Issues ........................................................................................................................ 57 
12.5.1. Reporting of SAEs ....................................................................................................... 57 
12.5.2. Reporting of IRB Actions to NIDA ............................................................................. 58 
12.5.3. Report of Changes or Amendments to the Protocol ..................................................... 58 
12.6. Trial Safety .................................................................................................................................. 58 
12.6.1. Potential Risks and Benefits for Participants ............................................................... 58 
12.6.2. Risk Mitigation Plan ..................................................................................................... 59 
12.6.3. Trial Stopping Rules ..................................................................................................... 59 
12.6.4. Process of AE/SAE Collection, Assessment, and Reporting ....................................... 60 
12.6.5. AE/SAE Follow-Up Plan ............................................................................................. 61 
12.7. Trial Efficacy ............................................................................................................................... 61 
12.7.1. Plans for Interim Analysis of Efficacy Data ................................................................ 61 
12.8. DSM Plan Administration ........................................................................................................... 61 
12.8.1. Responsibility for Data and Safety Monitoring ........................................................... 61 
12.8.2. Persons Responsible for Monitoring the Trial ............................................................. 61 
12.8.3. Disclosure of Any Conflict of Interest in the DSM ..................................................... 62 
12.8.4. Frequency of DSM ....................................................................................................... 62 
12.8.5. Content of DSM Report ............................................................................................... 62 
12.9. DSM Board Plan ......................................................................................................................... 62 
12.9.1. Members and Affiliation .............................................................................................. 62 
12.9.2. Conflict of Interest ....................................................................................................... 63 
12.9.3. Frequency of Meetings ................................................................................................. 63 
12.9.4. Protection of Confidentiality ........................................................................................ 63 
12.9.5. Monitoring Activities (Initial and Ongoing Study Review) ......................................... 63 
12.9.6. Communication Plan to IRB, NIDA, and FDA ........................................................... 63 


 
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SPONSOR APPROVAL AND SIGNATURE PAGE 
 
 
 
 
W. Brooks Gentry, M.D. 
Chief Medical Officer 
 
 
 
 
 
Misty Stevens, Ph.D., M.B.A. 
Chief Operating Officer 
 
 


 
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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: 
Meth-OD: A Phase 2a Study of IXT-m200 in Patients with Toxicity from 
Methamphetamine Overdose 
Study Description: 
The proposed study is a randomized, open-label Phase 2a study of 
IXT-m200 versus treatment-as-usual (TAU) in which patients with mild to 
moderate methamphetamine (METH) toxicity will be treated with 
IXT-m200 or lorazepam and/or haloperidol. The hypothesis is that 
IXT-m200 will be well-tolerated in patients with acute mild to moderate 
METH toxicity. 
Objectives: 
 
Primary Objective: To evaluate the safety and tolerability of IXT-m200 in 
patients with mild to moderate METH toxicity. 
 
Secondary Objectives: To determine the time course and degree of 
normalization of agitation and vital signs, and to determine the percentage 
of participants in each group requiring rescue medications for psychiatric or 
cardiovascular manifestations of METH intoxication.   
Endpoints: 
Primary Endpoint:   
• 
Safety and tolerability of IXT-m200 as measured by physical 
examinations and vital sign, adverse event (AE), electrocardiogram 
(ECG), and clinical laboratory testing. 
Secondary Endpoints: 
• 
Agitation/sedation scores over time as measured with the ACES 
(Agitation/Calmness Evaluation Scale);  
• 
Vital signs including blood pressure, heart rate and temperature 
over time;  
• 
Need for rescue medications to treat: 
o agitation, dysphoria, or psychosis (CNS signs/symptoms) 
o hypertension, tachycardia, or other cardiovascular 
instability (CV signs/symptoms). 
Exploratory Endpoints: 
• 
Emergency department (ED) length of stay as measured by 
disposition order time minus triage time, and by disposition order 
time minus start of treatment time, with log transformation. 
Study Population: 
Approximately 40 24 males and females aged 18-45, presenting to an ED 
setting with mild to moderate METH toxicity who request treatment for 
symptoms related to their METH use will be recruited. 
Phase: 
2a 
Description of Sites 
Enrolling Participants: 
Approximately 5 ED 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 people with 
METH use disorder. The total dose will be given over 10 min for the 0.5-g 
dose and over 20 min for higher doses. Lorazepam is a benzodiazepine that 
is safe and commonly used to treat agitation and dysphoria in the 
emergency setting. Haloperidol is commonly used to treat agitation due to 
psychosis.  
Study Duration: 
Approximately one year 
Participant Duration: 
28 days 


 
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1.2. SCHEMA 
 


 
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1.3. SCHEDULE OF ACTIVITIES (SOA) 
 
Assessment 
Triage 
Screening 
Dosing and Assessments f 
Follow-upa 
Study Day 
1 
1 
1 
Day not 
specified 
3 
(+2) 
28 
(±7) 
Hour 
NA 
<0 
<0 
0 
0.25 
0.5 
0.75 
1 
1.5 
2 
3 
4 
6 
8 
>8, <Discharge 
from ED 
Discharge 
from ED 
NA 
NA 
Focused history and physical 
exam b, c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Focused review of systems b, c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Medication history 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Detailed and pertinent 
psychiatric history c, d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs c 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
As needed 
X 
X 
X 
Agitation score c 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
As needed 
 
 
 
Informed consent and 
UBACC 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Eligibility criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samples d 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
Dose administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Observe for AEs 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
As needed 
X 
X 
X 
Assess for rescue meds 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
As needed 
X 
 
 
Clinical labs and ECG 
 
 
 
 
 
Once, as soon as feasible 
 
 
 
 
X 
 
UDS, UPT, Breathalyzer  
 
 
Once, as soon as feasible 
 
 
 
 
 
 
Detailed and pertinent 
medical history e 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
DSM5 SUD checklist 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Drug use assessment and 
Meth Perception Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
AE – adverse event; UDS – urine drug screen; UPT – urine pregnancy test; ECG – electrocardiogram; DSM5 SUD – Diagnostic and Statistical Manual of Mental Disorders 5 for 
Substance Use Disorders; NA – not applicable; UBACC – UCSD Brief Assessment of Capacity to Consent 
a If participants do not return for a follow-up visit, a phone call will be attempted to assess any AEs. 
b Focused history, physical exam and review of systems based on main complaint, related details from other parts of the medical history and physical exam, and eligibility criteria.  
c Assessments will be obtained as either part of triage or screening, depending on the site. PANSS-EC will be done at screening only; ACES will be done at each time point as 
marked. 
d PK samples will be drawn for both IXT-m200 and METH per section 8.2. 
e Detailed and pertinent history includes pertinent past medical, family and social histories in addition to focused history. Detailed physical exam to be completed if indicated by 
detailed and pertinent medical history.  
f Subjects may be discharged at any time point after the 2-hr assessments are completed if the subject is deemed medically eligible; assessments at Day 1, Hours 3-8 may be 
skipped if discharged. Assessments assigned for the time of discharge from ED should be completed for all subjects. 


 
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2.  
INTRODUCTION 
2.1. STUDY RATIONALE  
 
No direct antagonists have been approved, or even clinically evaluated, for treatment of METH overdose. 
In fact, no medications have been approved for any form of METH Use Disorder (MUD) 1. Emergency 
care providers use a variety of medications to manage patients with METH toxicity based on the primary 
presenting symptoms and their individual and institutional experience. Mild to moderate agitation and 
dysphoria may be treated with benzodiazepines or antipsychotic medications 2. Severe CNS agitation and 
delirium are treated with combinations of benzodiazepines, antipsychotics, and other sedatives (e.g., 
ketamine) 2. The cardiovascular and cerebrovascular effects of METH overdose are treated with 
combinations of vasodilators, beta and calcium channel blockers, and anti-arrhythmic medications 3. 
Altogether, given the lack of targeted therapies, ED management of patients presenting with METH 
toxicity is symptomatic at best, intended only to reduce and/or mask the acute physiologic effects of 
METH until it can be cleared by metabolism and excretion. Furthermore, patients with METH toxicity 
may be hypersomnolent during metabolism of METH and repletion of monoamines and adenosine 
triphosphate. These sedative effects, especially when combined with sedative effects of benzodiazepines 
or other sedatives, may delay ED discharge and increase length of stay 4 at best, and may result in 
compromise of ventilation at worst. A single pharmacokinetic antagonist medication that results in a 
calmer, cooperative patient without sedation would offer a clear advantage over current 
pharmacologic approaches for the management of agitation associated with METH overdose. 
 
IXT-m200, a chimeric monoclonal antibody (mAb) that binds METH with high affinity, has been 
evaluated in a Phase 2a study in non-treatment-seeking people who use METH (NCT03336866). Data 
from multiple studies in rats show that METH effects, such as increased locomotor activity, are quickly 
reduced following treatment with anti-METH antibodies 5,6.This is accompanied by reductions in brain 
METH concentrations. Preliminary results from the Phase 2a study in otherwise healthy people with 
MUD indicate that IXT-m200 greatly reduces METH volume of distribution by sequestering METH in 
the blood, as expected based on animal data. The antibody also appears to be well-tolerated in healthy 
people who do and do not use METH. Together, these results suggest that IXT-m200, a specific METH 
pharmacokinetic (PK) antagonist, could be an effective treatment for METH overdose. 
 
2.2. BACKGROUND  
 
Study Intervention 
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 (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) 7,8. 
  
Through the binding of METH in the bloodstream, it is anticipated that IXT-m200 will alter the PK of 
METH and decrease concentrations of METH in its active sites in the brain. IXT-m200 may therefore 
decrease both the CNS and hemodynamic effects of METH 5,6.  
  
Nonclinical IXT-m200 Effectiveness Summary 
A significant body of nonclinical work in rats indicates that anti-METH antibodies quickly reduce METH 
effects and brain concentrations after administration. The potential human efficacy of IXT-m200 is 


 
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demonstrated by several 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) 5,6,9. 
 
Nonclinical Safety Summary of the Interaction of IXT-m200 with METH 
A series of nonclinical studies was 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 self-administration (SA) in an effort to overcome the reduction of METH effects by the 
antibody.   
 
In each of the studies, rats were acclimated 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 a patient’s attempts to 
surmount the antibody’s effects was initiated. On Day 18, rats were given 4 doses of METH at 6 mg/kg 
spaced 2 hours apart. This binge dosing regimen was repeated on Days 21 and 24 for certain studies and 
groups. 
 
The 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 completed 10. In 
this study, 42 subjects (17 females) were dosed in 5 groups (0.2, 0.6, 2, 6, and 20 mg/kg IXT-m200, 
which are approximately 15 – 1500 mg in an average 75-kg subject), with 10 subjects receiving placebo 
(saline). Pharmacokinetic results indicate that IXT-m200 is similar to other IgGs, with an elimination 
half-life of ~18 days, volume of distribution (Vd) of ~5 L, and elimination clearance of ~200 mL/day. 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. 
Only 1 AE was definitely attributed to IXT-m200. A single subject experienced a Common Terminology 
Criteria for Adverse Events (CTCAE v.4.0) Grade 3 infusion reaction half-way through the IXT-m200 
infusion. The subject experienced a brief period of bronchospasm, in which the subject and investigator 
heard a single expiratory wheeze. The infusion was stopped and the subject was treated with solumedrol 
and diphenhydramine. No further symptoms were noted. The subject required outpatient therapy later for 
bronchitis. Because the infusion reaction and bronchitis were mild and short-lived, the study continued 
with no protocol changes. 
  
Samples from all subjects were tested for immunogenicity (i.e., anti-IXT-m200 antibodies). Samples from 
only 4 (12.5%) IXT-m200 treated subjects were confirmed to have low titers. One of these 4 subjects 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 
a range from 0.2 to 20 mg/kg. Therefore, a maximum tolerated dose was not reached. 
  
A Phase 2a study of the effect of IXT-m200 on METH pharmacokinetics and METH pharmacodynamics 
has been completed in otherwise healthy people who use METH. The primary goals of this study, called 


 
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STAMPOUT (Study of Antibody for Methamphetamine Outpatient Therapy, NCT03336866), were to 
show that IXT-m200 alters the PK of METH and reduces the reinforcing subjective effects that perpetuate 
METH use. In addition, the safety and tolerability of the effect of single IV doses of IXT-m200 (6 or 20 
mg/kg, which were up to 2000 mg) were determined in this population.  In STAMPOUT, non-treatment-
seeking people who had MUD received a single dose of IXT-m200 followed by weekly METH 
challenges. Serial blood samples and urine collections were analyzed to determine METH PK changes 
due to the antibody dose. Drug effects questionnaires were given after METH challenges to quantify the 
impact of IXT-m200 on the subjective effects of METH.  
 
In a pre-specified interim analysis of PK and safety data, METH PK parameters were estimated and 
summarized by treatment group, which showed clear dose-dependent changes in METH disposition in the 
presence of IXT-m200 (Figure 1). Dose-dependent changes in METH plasma PK parameters, including 
area under the curve (AUC), maximum concentration (Cmax), and volume of distribution (Vd) were 
evident at the first METH challenge, and were maintained through the entire inpatient period. These data 
show that IXT-m200 redistributes METH in a dose-dependent manner. Importantly, METH was excreted 
in the urine at similar levels across treatment groups, demonstrating that IXT-m200 does not impair renal 
elimination of METH. There were no SAEs or AEs of greater severity than Grade 2 (mild or moderate 
only) in STAMPOUT. This includes all events recorded following the dose of IXT-m200 and the 
subsequent weekly METH challenges. Furthermore,  some STAMPOUT participants used METH after 
release without apparent safety complications, further illustrating the safety of combinations of IXT-m200 
and METH. These data suggest that IXT-m200 will be well-tolerated in people who have taken METH 
prior to treatment in an ED setting. 
 
A second Phase 1 study of single 3-g doses of IXT-m200 in healthy volunteers is ongoing 
(NCT05027451) with no safety issues identified to date.  In this study, 9 healthy volunteers were 
randomized to 3 g IXT-m200 or placebo at a 7:2 ratio. Each received their dose as a 30-min intravenous 
infusion, then remained at the study site overnight to complete Day 1 and Day 2 assessments (e.g., 
electrocardiogram (ECG), laboratory assessments, blood draws, and vital signs). Following discharge on 
Day 2, participants return to the clinic for follow-up pharmacokinetic (PK) and safety assessments on Day 
8, then every 1-3 weeks thereafter until Day 127. Dosing has been completed with > 4 months of safety 
data collected to date, with no SAEs. 
AUCinf
0
20000
40000
60000
METH AUCinf (hr*ng/mL)
Cmax
0
200
400
600
800
1000
METH Cmax (ng/mL)
Vd
0
100
200
300
400
500
METH Vd (L)
Urine AE
0
5
10
15
METH Excreted (mg)
0
6
20
Figure 1. METH PK data from STAMPOUT interim analysis 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 (Urine 
AE) data are plotted as group means ± SD. IXT-m200 (0, 6, or 20 mg/kg, IV) was administered one day 
prior to METH (30 mg, IV). 


 
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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 completed Phase 1 study of IXT-m200, there were no SAEs or discontinuations due to 
treatment-emergent AEs. Overall, 90% of subjects 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 subjects 10. 
  
Only 1 AE was definitely attributed to IXT-m200. A single subject experienced a CTCAE v.4.0 Grade 3 
infusion reaction half-way through the IXT-m200 infusion. The subject experienced a brief period of 
bronchospasm, in which the subject and investigator heard a single expiratory wheeze. The infusion was 
stopped and the subject was treated with solumedrol and diphenhydramine. No further symptoms were 
noted. The subject required outpatient therapy later for bronchitis. 
  
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 subjects were 
confirmed positive for HACA in the completed Phase 1 study. The development of HACA did not appear 
to be dose-related 10. 
2.3.2. KNOWN POTENTIAL BENEFITS  
 
IXT-m200 is an investigational product and may convey no benefit to patients. Based on nonclinical 
studies in rodents 7,11, 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 tolerability and 
effectiveness.  IXT-m200 was not associated with significant safety issues in healthy individuals (Phase 
1) and in otherwise healthy non-treatment seeking people with MUD (Phase 2a). The general safety of 
antibody-based medications is outlined above in section 2.3.1 and in the IB. The risks of treatment with 
IXT-m200 will be minimized by selection of participants who desire treatment for their mild to moderate 
METH toxicity, but who are not in extremis. The risks are further mitigated by the selection of 


 
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participants who do not have significant concomitant illness (Section 5.2). Given the mechanism of action 
and the safety record, IXT-m200 has the potential to be useful in the treatment of METH toxicity, 
justifying its use.  
 
3. OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
Primary 
 
 
To evaluate the safety and 
tolerability of IXT-m200 in 
patients with mild to moderate 
METH toxicity 
Safety and tolerability of 
IXT-m200 as measured by 
physical examinations and vital 
sign, AE, ECG, and clinical 
laboratory testing 
Safety must be systematically 
evaluated of IXT-m200 when 
given to patients with ongoing 
METH toxicity for the first time  
Secondary 
 
 
To determine the time course 
and degree of normalization of 
agitation and vital signs 
Agitation/sedation scores over 
time as measured by ACES 12  
Agitation is a significant CNS 
component of METH toxicity and 
a cause for hospital admission  
Vital signs including blood 
pressure, heart rate and 
temperature over time 
Elevated or depressed 
hemodynamics are a component of 
CV toxicity 
To determine the percentage 
of participants requiring 
rescue medications for 
psychiatric or cardiovascular 
manifestations of METH 
toxicity  
Need for rescue medications to 
treat: 
- agitation, dysphoria, or 
psychosis (CNS toxicity) 
- hypertension, tachycardia, or 
other cardiovascular 
instability (CV toxicity) 
An evaluation of IXT-m200 
effects on requirement of rescue 
medications is needed 
Tertiary/Exploratory  
 
 
To determine how long 
patients with METH toxicity 
stay in the ED 
ED length of stay as measured 
by disposition order time minus 
triage time, and as measured by 
disposition order time minus 
start of treatment time, with log 
transformation 
Prolonged wait times are 
associated with a number of 
negative outcomes, including 
patient dissatisfaction, increased 
hospitalization rate, poor quality of 
care, and increased mortality 13 
 
4. STUDY DESIGN  
4.1. OVERALL DESIGN 
 
The hypothesis of this multisite Phase 2a study is that IXT-m200 will be well-tolerated in patients with 
acute mild to moderate METH toxicity. A randomized, open label design will be used in which one dose 
of IXT-m200 will be compared to treatment-as-usual (TAU). Approximately 40 24 participants will be 
enrolled in 4 3 cohorts. A dose escalation approach will be used so that progressively higher IXT-m200 
doses will be evaluated in each of the first two cohorts. In conjunction with safety monitoring, this design 
assures the opportunity to observe early safety findings before any participants are exposed to the next 
higher dose. The randomization ratio for IXT-m200 versus TAU is defined as 4:1 for each of cohorts 1 
and 2, with up to an additional 4 TAU participants in cohort 3 so that the number of participants receiving 
TAU equals the number receiving each dose of IXT-m200 at the end of the study.  
 


 
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Cohort 
IXT-m200  
dose (g) 
IXT-m200:TAU 
subject numbers 
1 
0.5 
8:2 
2 
2 
8:2 
3 
To be determined by amendment; ≤30 
80:24 
4 
To be determined by amendment; ≤3 
8:2 
 
Agitation scales and vital signs will be recorded to track effect of the antibody treatment versus TAU over 
time on agitation associated with METH use. While in the ED, detailed and pertinent medical and 
psychiatric histories, and physical exam will be obtained, along with laboratory assessments and ECGs. In 
the ED, participants will give blood samples for analysis of METH and IXT-m200 concentrations and 
followed for development of adverse events. Participants will be evaluated at 2 days and 4 weeks after 
discharge from the ED for adverse events and drug use history. Cohort escalation reviews will be 
performed by the Sponsor, Medical Monitor, and Data and Safety Monitoring Board (DSMB) between 
after cohort 1s and the next group will not start until after completion of this review.  
 
4.2. SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
Because the participants in this study present requesting treatment for METH toxicity, but because 
IXT-m200 has not been administered in an acute setting to agitated patients, the open-label TAU 
comparison offers an early assessment of the utility of IXT-m200 for use to treat METH toxicity. A 
placebo control is not ethical because these patients present to the ED requesting treatment. The study 
design also includes rescue medications to ensure that in the event of worsening of the symptoms, which 
may be due to progression of the intoxication or due to either treatment, the patients may be treated in a 
timely fashion. The dose escalation in subsequent groups with safety evaluation between cohorts 1 and 2 
is designed is ensure that an effective dose is tested, and to identify the lowest effective dose of mAb. 
 
While lorazepam and haloperidol are commonly used to treat agitation in the ED, there is no consensus on 
the ideal sedative for acute agitation in the ED 1. The goal of sedation in the ED is to calm a patient so 
he/she is not a danger to him/herself or others, and can be more accurately assessed by physicians. METH 
causes release of monoamines from nerve terminals and blocks their reuptake; chronic and binge METH 
use severely alters monoamine homeostasis. The adrenergic reserves of METH overdose patients are 
therefore atypical, making their responses to sedative medications difficult to predict. Even with careful 
titration of sedatives, patients may experience profound and prolonged somnolence, increasing their 
length of ED stays 14. For agitation due to overdose or intoxication, benzodiazepines and/or first-
generation antipsychotics, such as haloperidol, are often recommended 2 but sufficient doses of these 
drugs to reduce agitation may sedate patients for hours. This approach results in at best prolonged ED 
stays, and at worst the masking of other symptoms (physical or psychiatric) that may need more timely 
attention.  
 
4.3. JUSTIFICATION FOR DOSE 
 
IXT-m200 will be given via IV administration because this will provide immediate effects and provide 
for reliable pharmacokinetic analysis. The IXT-m200 doses selected for this study may include the range 
tested in Phase 1 (0.2 to 20 mg/kg or 3-g) and Phase 2a (6 and 20 mg/kg) studies of IXT-m200. 
Converting doses for a 75-kg person shows that the 0.5-g dose = 6.67 mg/kg and a 1.5-g dose = 20 mg/kg. 
2-g doses have been given to participants weighing 100 kg without complication in the Phase 2a study 
and 3-g doses were given to all active participants (n=7) in the second Phase 1 study. Importantly, it is not 


 
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necessary to reduce METH brain concentrations to “zero” to demonstrate a clinically useful effect in this 
study, so we do not anticipate that markedly higher doses will be required. Rather, the pharmacological 
goal is to redistribute enough METH from the CNS into the systemic circulation so that symptoms are 
reduced sufficiently to allow patients to be discharged or referred for further treatment. In rodent studies, 
IXT-m200 acutely reduces CNS effects when present in a ratio of less than 30 molecules of METH per 
mAb binding site 15. Given that there is no way to predict body burden or previous METH intake by 
people presenting to an ED, this study uses unit doses (e.g., 0.5 and 2 g) to facilitate dosing, establish 
safety, and determine dose response for agitation.  
 
The rate of IXT-m200 administration is justified to obtain rapid resolution of symptoms of METH 
toxicity, commensurate with that obtained by lorazepam and/or haloperidol. The infusion rate for the 
0.5-g dose is 33 mg/kg/hr (assuming a 75-kg person) and those for the 2-g doses are 80 mg/kg/hr. In prior 
studies, the highest infusion rate was 80 mg/kg/hr. Importantly, the infusion rates in two GLP toxicology 
studies greatly exceed the proposed rates for this study. In the first, rats were given 200 mg/kg/hr for a 
total single dose of 400 mg/kg, and in a second completed study, 300 mg/kg was given in 10 min or less 
each week for six months for a repeating rate of 1800 mg/kg/hr. There were no reported safety issues with 
these infusion rates in rats. Furthermore, it appears unlikely that there have been infusion rate-related AEs 
in human studies.  
 
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 the Schedule of Activities (SoA; section 1.3). 
Participants with an ongoing AE at the time of study completion will be followed until the event resolves, 
the Sponsor and the investigator agree that further follow-up is not medically necessary, or until they are 
lost to follow-up.  
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA. 
 
5. STUDY POPULATION 
5.1. DESCRIPTION OF AND RATIONALE FOR THE SELECTED POPULATION 
 
Qualified participants will present seeking emergent treatment for unpleasant symptoms related to their 
recent METH use. They may also have taken other abused drugs or medications such as opioids and still 
qualify. They may display signs of mild to moderate METH toxicity such as dysphoria, agitation, mild 
paranoia, or a feeling of being unsafe. Participants will be agreeable to general study procedures (e.g., 
placement of an IV, repeated measurement of vital signs and agitation assessments, repeated blood 
draws).  
 
People with mild to moderate symptoms have been selected for this initial study in an ED setting because 
while they need rapid treatment, the need for rescue sedative medications will be lower and less urgent 
than in people suffering from acute, severe intoxication or other major health issues. Recruiting lower 
severity participants will allow time to determine/observe the effects of IXT-m200 doses prior to, or 
without the need to add, additional medications which could obscure the effects of the antibody. This 
initial study will establish safety and efficacy in a controlled population prior to expanding in future 
studies to a greater risk, more vulnerable population who may need more intensive intervention for their 
acute METH intoxication. 


 
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Criteria for diagnosing METH toxicity are adapted from the DSM-5 criteria for stimulant intoxication and 
include: 
• 
Recent (last 24 hour) use of methamphetamine or amphetamine 
• 
Clinically significant problematic behavioral or psychological changes 
o e.g., euphoria or affective blunting; changes in sociability; hypervigilance; interpersonal 
sensitivity; anxiety, tension or anger; stereotyped behaviors; impaired judgement that 
developed during or shortly after METH use 
• 
Two or more of the following 
o Bradycardia or tachycardia (<40 or >100 beats per minute) 
o Hypertension or hypotension (>140/90 or < 90/60) 
o Pupillary dilatation 
o Perspiration or chills 
o Nausea or vomiting 
o Psychomotor agitation or retardation 
o Muscular weakness, respiratory depression, chest pain, or cardiac arrhythmias 
o Confusion, seizures, dyskinesias, dystonias, or coma 
• 
The symptoms are not due to a general medical condition and are not better accounted for by 
another mental disorder 
 
5.2. INCLUSION CRITERIA 
 
Eligible participants will:  
1. Be aged 18 to 45 years, inclusive; 
2. Present to the ED with METH toxicity as defined in protocol; 
3. Have a PANSS-EC score of 14-28, inclusive; 
4. Have or agrees to have an intravenous (IV) line placed; 
5. Give a history of METH use in the past 24 hours, with participant or observer attribution of 
symptoms to METH, or have a positive METH drug screen; 
6. Be accompanied or readily represented by a legally authorized representative (surrogate) who can 
consent to participation on behalf of the participant if participant is found not able to consent for 
themselves using the UCSD Brief Assessment of Capacity to Consent (UBACC); and 
7. Consent or assent to participation in the study. 
 
5.3. EXCLUSION CRITERIA 
 
Eligible participants will NOT:  
1. Present with concomitant opioid overdose requiring ventilatory support; 
2. Be self-reported to be pregnant or lactating; 
3. Be considered to have significant concomitant medical illness or trauma, or symptoms of severe 
METH toxicity including  
a. sepsis or febrile illness;  
b. myocardial infarction, cardiac decompensation or arrhythmias including tachycardia that 
is not sinus; severe hypertension (>180/110 mmHg); inadequately treated hypertension 
on chronic medication; history of vasculitis; 
c. coma, stroke or severe head injury; new or ongoing seizure activity 
d. acute pulmonary decompensation or severe chronic obstructive pulmonary disease;  


 
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e. any hepatic impairment and/or acute hepatitis or renal impairment due to concomitant 
medical illness; or 
f. 
current, or history of, neuroleptic malignant syndrome;  
4. Be considered to be at imminent risk of suicide or have disqualifying answers to the following 
two questions. Disqualifying answers would be 1b2 or 2b. 
 
1. In the past 30 days, have you considered killing yourself? 
a) No 
b) Yes – if Yes, how often? 
B1) Not often (twice or less) 
b2) Somewhat often (more than twice) 
 
2. In the past year, have you attempted to kill yourself? 
a) No 
b) Yes 
 
5. Be considered to be at imminent risk of injury or danger to self, others or property; 
6. Have a history of severe allergy (rash, hives, breathing difficulty, etc.) to both lorazepam and 
haloperidol, or known hypersensitivity or infusion reaction to any antibody medications; or 
7. Be judged by the treating ED physician, investigator, or Sponsor (or designee) to be inappropriate 
for the study, including people whom the investigator determines cannot reasonably be consulted 
for assent to participation. 
 
5.4. 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. 
 
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. 
 
Subjects are required to 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 dose of study drug. 
 
5.5. 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 SAEs. 
 


 
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All participants who consent but fail screening will be referred to treatment in the ED outside of the study 
per the recommendation of the screening physician. Subjects may be rescreened at any future presentation 
to the ED. 
5.6. STRATEGIES FOR RECRUITMENT AND RETENTION 
5.6.1. STRATEGIES FOR RECRUITMENT  
 
Generally speaking, recruitment strategies are based on appropriate site selection (sufficient numbers of 
potential participants) and education of ED staff to look for possible participants. 
 
The recruitment of vulnerable participants is necessary because the study is designed to determine if 
IXT-m200 is well-tolerated and works to reverse METH toxicity in an emergency setting. While people 
under the influence of METH and other drugs may be vulnerable because they may lack full consent 
capacity, participants will still provide assent, and their legally authorized representative will provide 
consent at the time of the study start if the participant is found lacking the capacity to consent for 
themselves using the UBACC assessment. No participant will be enrolled in the study who does not 
provide consent or assent. On Day 3, when participants return for their first follow-up visit, informed 
consent will be obtained, or repeated, from them.  
 
Participants will be compensated based on local precedent, which may be different at each site.  
5.6.2. STRATEGIES FOR RETENTION AND FOLLOW-UP  
 
Retention strategies are based on education of the participant and discussion of the importance of follow-
up to good health. Specifically, this includes the opportunity to follow up on any medical findings from 
the ED stay, and to further discuss opportunities for treatment for MUD if the person desires. 
 
Phone calls, text messages, and emails will be sent as reminders to the participants to follow up. 
Transportation will be provided if needed to the follow-up visits, and referral for treatment of psychiatric 
and medical issues will be arranged.  
 
6. STUDY INTERVENTION 
6.1. STUDY INTERVENTION ADMINISTRATION 
6.1.1. STUDY INTERVENTION DESCRIPTION 
 
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. 
 
The mechanism of action of IXT-m200 is via high-affinity binding to METH, which either prevents 
METH from reaching its sites of action in the CNS, or removes it from those sites of action 7,8. Because 
anti-METH antibody medications significantly alter the distribution and tissue concentration of METH, 
their mechanism of action is PK antagonism. IXT-m200 was developed from a murine anti-METH 


 
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antibody and preclinical studies have shown that both the murine and chimeric antibodies bind METH 
and alter its PK in a similar way 7,8,16. Further information on IXT-m200 may be found in the IB.  
6.1.2. DOSING AND ADMINISTRATION 
 
Participants in each cohorts 1 and 2 will be randomized to TAU or IXT-m200 after consenting to 
participate. Participants in cohort 3 will receive TAU. An IV line will be started and a balanced salt 
solution (e.g., PlasmaLyte®) will be administered at a rate of 75 mL/hr. IXT-m200 will be given over 10 
min (for 0.5 g) or 20 min (for higher doses) per dosing guidelines. The IXT-m200 infusion start/stop time, 
infusion rate, infusion volume, whether the infusion was completed, if it was stopped, or stopped and 
restarted will be recorded in the eCRF. Participants will be asked to remain semi-reclined during dose 
administration and to refrain from strenuous activity from dosing through 24 hours after. If randomized to 
TAU, one of the following three choices will be administered as determined by the treating physician: 1) 
up to 4 mg lorazepam by IV push, 2) up to 5 mg haloperidol by IM or IV injection, or 3) a combination of 
up to 4 mg lorazepam by IV push and up to 5 mg haloperidol by IM or IV injection. IV fluids will be 
given as tolerated for up to 4 hours after dosing with either IXT-m200 or TAU, at which point the IV will 
be capped and preserved during the remainder of the ED stay. When the ED staff determine it is 
appropriate, a regular diet may be started. If there is an adverse reaction to study drug, the participant will 
be treated as outlined in Section 6.5. 
 
6.2. PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1. ACQUISITION AND ACCOUNTABILITY 
 
Study Intervention: Sponsor will provide the required number of vials of IXT-m200. IXT-m200 vials will 
be shipped to the study sites prior to study initiation. 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.  
  
The investigator at each site will be responsible for acquiring commercially available TAU and rescue 
medications for use in the study. 
6.2.2. FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Study Intervention: IXT-m200 is formulated as an injection 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. The University 
of Iowa Pharmaceuticals produces the vialed drug product. 
 
Labels will be similar to the following:  
InterveXion Therapeutics® 
Anti-methamphetamine IXT-m200 
18.5-21.5 mg/mL 
Manufactured: DD MMM YYYY 
UIP Lot: XXXIXXXX 
Catalent Lot: XXXXX 
10 mM sodium phosphate, 150 mM sodium chloride, pH 6.5, with 0.05% Tween 80 


 
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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 
6.2.3. PRODUCT STORAGE AND STABILITY 
 
IXT-m200 vials are single-use and should be stored refrigerated at 2 to 8°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 
 
The appropriate total dose of IXT-m200 will be prepared for IV administration. No dilution of the drug 
product is required. For calculation purposes, the concentration of the drug product is 20 mg/mL. 
 
Dose level (g) Volume to be dosed (mL) 
0.5 
25 
2 
100 
  
TAU and rescue medications: These are obtained and provided by the local pharmacy in appropriate 
doses and delivery devices. Lorazepam will be given by slow IV push as the participant tolerates. 
Haloperidol is given via an intramuscular injection in the deltoid or gluteal muscles or by slow IV push as 
tolerated.  
 
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 in each cohorts 1 and 2 will be randomized to IXT-m200 or TAU after consenting to 
participate. Those who qualify will be randomized at a 4:1 ratio. Randomization codes will be generated 
by the randomization statistician and will be implemented by interactive voice/web response system 
(IXRS). This will be the same system for all sites so that there is no site bias to dosing. Participants will 
be randomized in the order they are enrolled. Participants in cohort 3 will receive TAU. 
 
This is an open-label study, in which the Sponsor and the investigators are aware of treatment 
assignments on an ongoing basis to facilitate efficient dose escalation while comparing study agent to 
treatment as usual. While participants in cohorts 1 and 2 will not be actively informed of their group 
assignment, no active measures will be taken to blind participants to treatment assignment. 
 
6.4. STUDY INTERVENTION COMPLIANCE 
 
IXT-m200 and TAU are administered by the IV or IM routes by qualified personnel. Compliance with 
dosing will be verified by reference to the eCRF documentation of dosing. 


 
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6.5. CONCOMITANT THERAPY AND RISK MITIGATION PLAN 
 
All concomitant medications (i.e., those given in the ED, prescription medications, over-the-counter 
medications, non-prescription medications, and supplements) taken during study participation will be 
recorded on the eCRF.  
6.5.1. RESCUE MEDICINES 
 
Lorazepam or haloperidol will be used as first-line rescue medications in all participants, regardless of 
treatment assignment, for agitation or dysphoria (lorazepam) or psychosis (haloperidol) 2,14,17. If further 
rescue medications are needed, the choice and doses of the rescue medications will be at the discretion of 
the treating ED physician. To allow time for maximum effects of the initial treatments to evolve, rescue 
medications should not be given for 30 min after initiation of IXT-m200 or TAU dosing; however, timing 
is ultimately at the discretion of the treating physician. 
 
Hypertension or tachycardia may be treated at the discretion of the treating physician with labetalol, 
hydralazine, or other similar approaches. Other cardiovascular instability (e.g., hypotension with blood 
pressure less than approximately 80/50 mmHg or less than approximately 90/60 mmHg with symptoms of 
dizziness, near syncope, or nausea, for example) will be treated initially with a fluid bolus14. If 
hypotension persists, it will be treated with incremental doses of the direct acting vasopressors 
phenylephrine, norepinephrine, or dopamine (starting at alpha adrenergic doses >10 µg/kg/min), or other 
appropriate medications at the discretion of the treating ED physician.  
6.5.2. RISK MITIGATION  
 
The following risk mitigation strategies have been designed based on other studies in people who use 
METH, on the problems posed specifically by enrolling participants in an emergency setting, on the 
clinical pharmacology of METH, and on the known pharmacology of IXT-m200: 
1. Selection of a specific participant group. As stipulated in the protocol, participants who are 
relatively healthy with no significant medical or surgical illness will be recruited. 
2. IXT-m200 dosing. IXT-m200 will be administered in escalating dose groups so that the lowest 
IXT-m200 dose (0.5 g) will be evaluated before the higher doses, in subsequent cohorts. This will 
allow determination of the effects of IXT-m200 at a low predicted effective IXT-m200 dose, 
before effects are assessed following a high predicted effective IXT-m200 dose.  
3. Treatment in an Emergency Department. A crash cart will be available in the ED and personnel 
trained in CPR are always available in the ED setting. Oxygen and emergency ventilation 
equipment are immediately available. Normal saline will be used as the IV fluid and fluid boluses 
can be administered if any hypotension is seen. In the event of serious medical complications, a 
code may be called. 
4. Frequent safety review. A formal safety review will be done between cohorts, and at any point 
needed based on the severity of AEs. This would include Grade 3 AEs related to worsening of 
METH effects in the presence of IXT-m200.  
 
All of the study sites are EDs and therefore have all medications that might be needed to treat mAb 
toxicity, which may manifest as hypotension and bradycardia or tachycardia; bronchospasm with or 
without hypoxemia; or flushing, pruritis, and urticaria. Hospital-maintained crash carts, and oxygen and 
emergency ventilation equipment (Ambubags) are always available. Advanced Cardiovascular Life 
Support-certified providers and code teams are always available to treat life-threatening events.  
 


 
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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.  
Enrollment and study drug administration will be immediately paused if any 1 of the following events 
occurs, unless the event was clearly unrelated to study drug administration, or the event is an expected 
sequelae of untreated METH toxicity: 
• 
Three (3) participants experience a Grade 3 AE.  
• 
Two (2) participants experience a Grade 3 AE related to increased agitation, aggression, or 
anxiety. 
• 
One (1) participant experiences a Grade 4 AE.  
• 
A death occurs.  
 
Expected sequelae of untreated METH toxicity which will not be considered grounds for a study pause 
include: 
• 
Hypertension/tachycardia 
• 
Euphoria 
• 
Agitation 
• 
Insomnia 
• 
Anxiety 
• 
Seizures 
• 
Mania/aggression 
 
Worsening of any of the above following administration of study drug will be considered an AE and 
subject to the rules for study pause above. 
If any of the pause conditions are met, the Sponsor, in consultation with the investigator and Medical 
Monitor, will suspend enrollment until a full safety review by both the Sponsor and DSMB is performed. 
A decision to reinitiate enrollment will be made following relevant consultation with the appropriate 
authorities based on the results of the safety review. 
7.2. PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants may be withdrawn from the study at any time before IXT-m200 administration for reasons 
including the following: 
• 
at their own request or at the request of their legally authorized representative, 
• 
the participant meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation, 
• 
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, 
• 
if, in the investigator’s opinion, continuation in the study would be detrimental to the participant’s 
well-being, or 
• 
at the specific request of InterveXion (Sponsor) or clinical site. 
 
Once participants receive IXT-m200, every reasonable effort will be made to have them attend the Day 3 
and 28 follow-up appointments.  
 


 
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In all cases, the reason for withdrawal must be recorded in the electronic Case Report Form (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 discontinue from further participation in 
the study, the research staff will cease further contact attempts. 
 
Participants who consent and are randomized but do not receive the study intervention may be replaced 
and will not be included in any data set.   
 
Participants who consent and are randomized and do receive the study intervention, but leave the ED 
prior to medical discharge and/or are not positive for METH by UDS or blood testing will be included in 
the safety set and ITT. Additional subjects may be recruited to ensure that each both cohorts 1 and 2 
contains 8 subjects dosed with IXT-m200 and 2 subjects dosed with TAU who complete the protocol 
through discharge from the ED and are positive for METH based on UDS or blood testing.  
 
Participants will not be replaced if they complete through discharge from the ED, but do not return for 
Day 3 or 28 visits. 
 
7.3. LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if s/he fails to return for the Day 3 and 28 scheduled 
visits 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 as soon as possible 
and 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  
 
Study procedures to evaluate agitation include: 
• 
The PANSS-EC (Positive and Negative Syndrome Scale – Excited Component) is used commonly 
as an assessment tool for clinical studies of pharmacotherapy for agitation. It includes 5 items 
(excitement, poor impulse control, tension, hostility, and uncooperativeness) which are each rated 
from 1 (absent) to 7 (extremely severe). A score of 14-28 is consistent with clinically significant 
psychomotor agitation of mild to moderate severity 18–20. It will be administered only at screening as 
part of eligibility determination.  
• 
The ACES (Agitation-Calmness Evaluation Scale) is a single-item, 9-point scale to differentiate 
agitated, calm, and sleep states. It has been used to assess the effects of pharmacotherapy on 


 
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agitation 12. This assessment will be performed at all time points marked in the Schedule of 
Activities table to determine the impact of IXT-m200 versus TAU on agitation. 
• 
Vital sign measurements over time including heart rate, blood pressure, temperature.  
• 
Need for rescue medications to treat CNS symptoms of agitation, dysphoria, or psychosis; and CV 
symptoms of hypertension, tachycardia, or other cardiovascular instability. 
 
8.2. SAFETY AND OTHER ASSESSMENTS 
 
UCSD Brief Assessment of Capacity to Consent (UBACC) 
• 
A 10-item list of questions focused on understanding and appreciation of the description of the 
research study 21. This assessment will be used to screen potential participants for the capacity to 
consent for themselves. A score of 20 will be required to be eligible to consent without an LAR. 
 
Safety evaluations include the following: 
 
Medical and Medication Histories  
• 
Medical history: A focused medical history will be obtained at triage/screening by interview and 
any available medical records. A detailed and pertinent medical history will be obtained after 
IXT-m200 dosing or TAU is complete and the participant is cooperative.  
• 
Medication history: A medication history will be obtained at triage/screening by interview and any 
available medical records. This will be reviewed and supplemented if needed after IXT-m200 or 
TAU dosing is complete and the participant is cooperative. The medication history will be reviewed 
at the 2 scheduled study visits.  
 
Physical Examination, Vital Sign Measurement, Height, and Weight  
• 
A focused physical examination (excluding rectal/genital and breast examination) will be 
performed at triage/screening. The physical examination may consist of vital signs and an 
examination of the following: general appearance, neurological, skin, head, eyes, ears, nose, throat, 
neck, chest, heart, abdomen, and extremities.  
o A detailed physical examination (excluding rectal/genital and breast examination) will be 
performed after IXT-m200 or TAU dosing is complete and the patient is cooperative. 
o Focused exams will be performed during the two follow-up appointments and as otherwise 
necessary.  
• 
Vital sign measurements (heart rate, blood pressures [systolic and diastolic], respiratory rate, 
temperature [oral], and pulse oximetry readings) will be obtained. Measurements will be taken at 
triage and screening, and as outlined in the Schedule of Activities table.  
• 
Height and weight will be obtained on Day 1 after dosing with IXT-m200 or TAU. 
 
Evaluations of Drug and Alcohol Use 
• 
DSM-5 criteria will be used at the Day 3 follow-up visit to assess for Substance Use Disorders 
(including METH, opioids, alcohol, nicotine, marijuana, etc.).  
• 
Qualitative urine drug screen (UDS; including amphetamines, MDMA, barbiturates, 
benzodiazepines, cocaine, opiates, THC, and phencyclidine) and alcohol breath testing will be 
performed once. This testing may be done before or after initial treatment so that the agitation may 
be treated as quickly as possible.  
• 
Administer standard drug assessment of METH and other drug use since last visit on Days 3 and 28 
• 
The METH Perceptions Assessment is the following list of questions intended to determine whether 
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o Note to administrator, if subject has reported multiple instances of METH use since last 
visit, instruct them to recall their first time of use since last visit.  Ask the following 
questions: 
“Did you take your typical dose of METH as you normally would before you started the 
study?” Answer: Yes or No 
If No, “Did you try more or less than normal?”  Answer: More or Less 
“How was the high compared to what you typically get from that dose?”  Answer: Scale of 
1-5; 1 = Less than expected, 3 = Just as expected, 5 = Better than expected 
If 1 or 2, “Did you take more METH to get the high you wanted?” Answer: Yes or No 
If Yes, “Did that get the result you wanted?”  Answer: Yes or No 
 
Psychiatric Evaluation  
• 
A detailed and pertinent psychiatric history will be obtained at triage/screening evaluating for (but 
not limited to) the following: major current depression, psychosis, bipolar illness, organic brain 
disorder, or dementia, which would make study compliance difficult in the opinion of the 
investigator.  
• 
Subjects will be queried about their history of suicide attempts and suicide ideation by the 
following two questions and any others the investigator deems necessary.  
 
1. In the past 30 days, have you considered killing yourself? 
a) No 
b) Yes - if Yes, how often? 
b1) Not often (twice or less) 
b2) Somewhat often (more than twice) 
 2. In the past year, have you attempted to kill yourself? 
a) No 
b) Yes 
 Disqualifying answers would be 1b2 or 2b. 
 
Electrocardiogram  
• 
An electrocardiogram (ECG; 12-lead) will be recorded after IXT-m200 or TAU dosing is complete 
and the participant is cooperative. 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).  
 
Biological Specimen and Laboratory Evaluations  
• 
Blood samples will be taken for analysis of IXT-m200 in serum on Day 1 (pre-dose, 4 hours after 
dosing, and at discharge), Day 3, and Day 28 from subjects who were randomized to receive 
IXT-m200 only. 
• 
Blood samples will be taken for analysis of METH and amphetamine in plasma on Day 1 (pre-dose, 
4 hours after dosing, and at discharge). 
• 
Blood will be taken for clinical laboratory studies which will include complete blood count, blood 
urea nitrogen/creatinine, serum glucose, electrolytes, liver function tests (AST, ALT, gamma-
glutamyl transferase, alkaline phosphatase, total and direct bilirubin), and creatinine phosphokinase. 
These tests will be performed on Day 1 after dosing is completed and repeated on Day 3.  
• 
Urine samples will be taken for UDS, urinalysis, and urine pregnancy tests. These tests will be 
performed on Day 1; results are not required prior to dosing. 
 


 
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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 participant administered IXT-m200 or TAU, 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 
IXT-m200 or TAU, whether or not related to IXT-m200 or TAU.   
 
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, TAU, 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 admission to the hospital; 
• 
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 participant 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 22 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.  
 
Regarding vital sign AEs, Section 6.5.1 defines blood pressure criteria for treatment with fluids and 
medications. 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 (O2 saturation < 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 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.   
 
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 to the study drug;  
• 
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 or for the participant’s underlying medical condition. 
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, 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, it will be recorded as an AE.  
 
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 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 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. Every attempt 
should be made to describe the AE in terms of a diagnosis. If appropriate, component 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 


 
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accepted standards of medical practice, even after the end of the period of observation, until a satisfactory 
explanation is found or the investigator considers it medically justifiable to terminate follow-up. Should 
the AE result in death, a full pathologist’s report should be supplied, if possible. 
 
Adverse events will be reviewed by the Sponsor, Medical Monitor and DSMB between cohorts. If an 
investigator decides it necessary, AEs may be reviewed at any time by consultation with the investigator, 
Medical Monitor, and Sponsor. 
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 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 Sponsor will be responsible for notifying the 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 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.  
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  
 
As a dose-escalation safety trial, safety will be monitored closely and dose escalation will occur only 
when available safety data warrant. On the other hand, the proposed trial by nature involves a population 
in significant duress, sufficient to merit a visit to the ED and meet the required eligibility criteria, and 
these participants will display a range of expected AEs due to their concomitant METH toxicity.  
 
To balance these important requirements of trial conduct and patient protection, the study will capture any 
AEs underway at the time of presentation to the ED that can be attributed to METH toxicity. These 
include:  


 
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• 
 Hypertension/tachycardia  
• 
 Euphoria  
• 
 Agitation  
• 
 Insomnia  
• 
 Anxiety  
• 
 Seizures  
• 
 Mania/aggression  
 
These AEs will not be considered as study participation-related, and will not be included in consideration 
of dose escalation or study stopping criteria, unless they newly emerge or worsen after administration of 
investigational product.  If they worsen, and reach sufficient severity, they will be considered as a part of 
the trial stopping criteria. 
8.3.9. REPORTING OF PREGNANCY  
 
If a participant is found to be pregnant after they have received IXT-m200 and before day 28, they should 
complete the study, with no further IXT-m200 doses administered, and be followed to determine the 
outcome of the 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 
 
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. 
 


 
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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 
subject 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. 
 
9 
STATISTICAL CONSIDERATIONS  
 
A statistical analysis plan (SAP) will be prepared after the protocol is approved. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to address 
all study objectives. The SAP will serve as a complement to the protocol and supersedes it in case of 
differences. 
 
The statistical evaluation will be performed using SAS® software version 9.4 or higher (SAS Institute, 
Cary, NC). All data will be listed, and summary tables will be provided. Summary statistics will be 
summarized and presented by treatment group, i.e., dose level of IXT-m200 and TAU, whereby the TAU 
patients from all 4 cohorts will be pooled. For continuous variables, data will be summarized with the 
number of subjects (N), mean, standard deviation, median, minimum, and maximum by treatment group. 
For categorical variables, data will be tabulated with the number and proportion of subjects for each 
category by treatment group. 
 
9.1. STATISTICAL HYPOTHESES 
 
This is a descriptive study for evaluation of safety and tolerability as the primary objective. Descriptive 
summaries will be performed for tabulation and comparison of safety and efficacy endpoints. Descriptive 
statistical tests will be applied for the pairwise statistical comparison of efficacy endpoints in IXT-m200 
dose levels versus TAU using a two-sided alpha level of 5%. 
 
9.2. SAMPLE SIZE DETERMINATION 
 
No formal sample size estimation has been performed. A sample size of 8 IXT-m200 and approximately 
28 TAU patients per dose cohort is considered adequate to assess the safety and tolerability of IXT-m200 
compared to TAU. Data from TAU patients from each cohort will be pooled for summaries. 
 


 
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9.3. POPULATIONS FOR ANALYSES 
 
The enrolled population will include all patients who sign the informed consent. 
 
The safety population will include all randomized patients who receive any dose of study drug. The 
treatment group assignment in this population will be defined by the treatment actually received. This 
population will be used for the analysis of safety. 
 
The Intent-to-Treat (ITT) population will include all randomized participants. The treatment group 
assignment in this population will be defined by the randomized treatment. This population will be used 
for the analysis of efficacy. 
 
The Full Analysis Set (FAS) population will include those in the ITT population who receive any dose of 
study drug and were positive for methamphetamine by UDS or blood testing during the ED stay. The 
treatment group assignment in this population will be defined by the randomized treatment. This 
population will be used for the analysis of efficacy. 
 
The Per-Protocol (PP) population will include all of the FAS who completed the Day 1 assessments, stay 
through discharge from the ED, and do not have any major protocol deviation impacting the efficacy 
assessments. The treatment group assignment in this population will be defined by the randomized 
treatment. This population will be used for the analysis of efficacy. 
 
The PK Population will include all subjects for whom a PK concentration is available post-dose. 
 
9.4. STATISTICAL ANALYSES 
9.4.1. GENERAL APPROACH 
 
This is a descriptive study for evaluation of safety and tolerability as the primary objective. The 
comparison of safety endpoints and of efficacy endpoints between the treatment groups will be performed 
using descriptive summaries and descriptive confidence intervals (CI) and statistical tests. 
9.4.2. ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Not applicable. 
9.4.3. ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Summary tables with descriptive statistics for actual values and changes from baseline will be provided 
for the ACES score for each scheduled timepoint by treatment group. Descriptive pairwise t-tests will be 
performed for the comparison of the changes from baseline of each IXT-m200 dose versus TAU. The 
time course of actual ACES scores and of change from baseline ACES scores will be presented by 
treatment group in a figure using mean values and 95% CIs. 
 
The time to normalization of agitation using ACES will be defined as the time until the ACES score 
climbs to ≥4 the first time, in subjects for which the score remains in the range of 4-6 for the remaining 
time points. If the ACES score rises to the range of 7-9 during the ED stay, then normalization will be 


 
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defined as the time until the score is reduced to within the range of 4-6 following the end of the sedated 
period. This time will be presented by Kaplan-Meier estimates and figure by treatment group, and will be 
pairwise compared between each IXT-m200 dose versus TAU by the logrank test. 
 
The time course of actual values of vital sign parameters and of changes from baseline will be presented 
by treatment group in a figure using mean values and 95% CIs. A shift table of post-baseline vital sign 
parameter values compared to baseline values will be provided by treatment group presenting the number 
and percentage of subjects below normal range / within normal range / above normal range. The time to 
normalization (i.e., returning to normal range) of vital sign parameters is defined as the first time the vital 
sign parameter is in normal range and remains in normal range for the remaining time-points. This time 
will be presented by Kaplan-Meier estimates and figure by treatment group, and will be pairwise 
compared between each IXT-m200 dose versus TAU by the logrank test. 
  
Number and percentage of patients with any rescue medication (from start of study treatment until 
discharge) will be provided by treatment group and overall IXT-m200 and total. Additionally, separate 
tables with the number and percentage of subjects with rescue medications for psychiatric manifestations 
and for cardiovascular manifestations, will be provided by treatment group, overall IXT-m200 and total. 
 
PK concentrations of IXT-m200 and METH will be summarized by timepoint and by treatment group. 
Additionally, change from baseline of METH concentration will be summarized for each post-dose 
timepoint by treatment group. The change from baseline in METH concentration will be presented 
graphically. 
9.4.4. SAFETY ANALYSES 
 
All reported AEs will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA). The incidence of treatment-emergent AEs (TEAEs; events with onset dates on or 
after the administration of the study drug) will be included in incidence tables. Events with missing onset 
dates will be included as treatment-emergent. If a subject experiences more than one occurrence of the 
same AE, the occurrence with the greatest severity and the closest association with the study drug will be 
used in the summary tables. An overall summary by treatment group, overall IXT-m200 and total will be 
presented with the number and percentage of subjects experiencing any TEAE, any TEAE by severity, 
any related TEAE, any serious AE (SAE), any related SAE, any AESI, and any TEAE leading to death. 
Summary tables by system organ class and preferred term will be provided for treatment group, overall 
IXT-m200 and total for TEAEs, TEAEs by maximum severity, TEAEs by maximum relationship to study 
treatment, treatment-related TEAEs, serious TEAEs, and AESIs. All AEs will be listed by patient, along 
with information regarding onset, duration, relationship and severity to study drug, action taken with 
study drug, treatment of event, and outcome. 
 
Vital signs will be summarized using descriptive statistics: actual values and changes from baseline will 
be presented for each scheduled assessment time point by treatment group, overall IXT-m200 and total. 
Weight and BMI will be summarized by treatment group, overall IXT-m200 and total.  
 
Physical examination results will be presented by number and percentage of patients in each category and 
scheduled time point by treatment group, overall IXT-m200 and total.  
 
Clinical laboratory data (continuous parameters) will be summarized using descriptive statistics for each 
scheduled assessment time point by treatment group. Categorical laboratory data and urinary drug screen 
results will be presented by number and percentage of patients in each category and scheduled time point 


 
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by treatment group. Additionally, for laboratory data, frequency tables with number and percentage of 
patients of scheduled time point will be provided using the categories above/within/below normal range. 
 
Extent of exposure will be summarized by a frequency table of number and percentage of patients by 
treatment group who received the total amount of the planned infusion, and who received the infusion 
partly. 
9.4.5. BASELINE DESCRIPTIVE STATISTICS 
 
Demographic and baseline characteristics will be summarized by treatment group, overall IXT-m200 and 
total. 
9.4.6. PLANNED INTERIM ANALYSES  
 
Between cohorts 2 and 3, a review of the efficacy data, i.e., all secondary endpoints, will be undertaken to 
determine the dose levels for cohorts 3 and 4. The Medical Monitor and DSMB will provide their 
recommendations to the Sponsor for a final decision.  
 
A protocol amendment will incorporate the adjustments. Further details will be provided in the DSMB 
Charter and the SAP.No interim analyses are planned. 
9.4.7. EXPLORATORY ANALYSES 
 
The duration of the stay in the ED, calculated as starting from triage time and also as starting from 
treatment start time, will be summarized by descriptive statistics by treatment group and overall 
IXT-m200. The descriptive pairwise comparison of IXT-m200 dose levels versus TAU will be performed 
by a t-test using log-transformed durations. 
 
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 if required, a legally authorized representative (LAR; surrogate or substitute decision 
maker) and written documentation of informed consent and/or assent from the participant is required prior 
to starting the screening process, and subsequently administering study intervention.   
 
 
 


 
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10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Given that METH use can cause agitation, delirium, and psychosis, only people who are found able to 
consent for themselves using the UBACC, or for whom a LAR who can consent for the participant can be 
identified will be recruited. The LAR may provide consent in accordance with local regulations, as 
described in 0.  
 
Specifics will vary depending the clinical site, but patients identified with symptoms of METH toxicity 
will be approached by the investigator or designated and trained study personnel about participation in the 
study. Patients will be asked if they would like to participate in the study and if they have a LAR to 
provide consent for them. If the answer is yes to both questions, or they are found able to give consent for 
themselves, informed consent will be sought using IRB-approved consent forms and processes. No one 
will participate without providing written consent or assent by signature of the participant recorded on the 
ICF. 
 
The process for consent is outlined in the following figure. 
 
 
Written informed consent, or reconsent, from the participant will be obtained before any procedures are 
conducted on Day 3.  
 
 
Potential participant 
identified
Can 
participant 
consent for 
themselves?
Initiate study 
procedures
Review Day 1 ICF
Yes
No
Perform UBACC 
assessment
Follow steps to secure 
written LAR consent 
on Day 1 ICF
Complete Day 1 ICF 
with written participant 
consent
Ensure participant 
signs ICF for written 
assent


 
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10.1.1.2.1 LAR CONSENT PROCEDURES 
 
The following steps will be conducted to obtain consent from the LAR on Day 1, when a subject is found 
unable to consent for themselves by using the UBACC: 
 
1. The informed consent form (ICF) will be sent to the potential LAR by email, fax, or other 
electronic means. 
2. The person obtaining consent will connect with the LAR by phone, video, or other means and 
will confirm they are speaking with the correct individual. 
a. The conversation requires a witness to be present starting with Step 2, preferably a 
member of the site staff so that signatures can be easily obtained. 
3. The date and version number of the consent will be confirmed between the person obtaining 
consent and the LAR. 
4. The consenting process will proceed as usual with the person obtaining consent verbally going 
over the informed consent and answering any questions. 
5. The person obtaining consent will ask for verbal informed consent to conduct screening 
assessments. 
6. The person obtaining consent will document the conversation in the subject file or progress notes 
recording at a minimum: 
a. Date and time of the conversation 
b. How it occurred (e.g., telephone or video conference) 
c. Name of the witness and any other participants 
d. Confirmation that the LAR received the ICF 
e. Confirmation of verbal informed consent to conduct screening 
7. The LAR will sign the ICF.  This may be documented in many ways, including: 
a. The LAR may print the ICF, sign it and return a scan or picture of the form 
electronically. The LAR must be informed that there is a small risk of email being 
intercepted in route. 
b. The LAR may use an electronic signature. Some options include: 
i. Adobe Sign 
ii. Apple Pen 
iii. DocuSign 
8. Documentation of the LAR signature must be received, and all other steps in the informed 
consent process completed, prior to any therapeutic intervention. 
9. The final ICF must be filed in the designated investigator/research file location and a copy given 
to the LAR and participant. 
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 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. Sponsor will provide the reason(s) for the termination or suspension. 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; 


 
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• 
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 
subjects in this study. The clinical study site will permit access to such records. 
  
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 in the Statistical Considerations 
(Section 9) and Data Handling (Section 10.1.9) sections of this protocol. 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. 
  


 
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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 
 
 
Safety oversight will be under the direction of a DSMB composed of individuals with the appropriate 
expertise, likely including clinical trial oversight, monoclonal antibody and methamphetamine clinical 
pharmacology, acute care medicine (cardiovascular and/or emergency), psychiatry or behavioral 
medicine, statistics, and a patient advocate or representative. Members of the DSMB will be independent 
from the study conduct and free of conflict of interest, or measures will be enacted to minimize real or 
perceived conflicts of interest.  The DSMB will meet at the conclusion of each cohort 1 to assess safety 
data and intermittently as necessary. 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 Sponsor. 
 
Cohort escalation reviews will be performed by the Sponsor, Medical Monitor, and DSMB between 
cohorts 1 and 2 and the next group will not start until after completion of this review. Thisese reviews 
will be scheduled to occur approximately two weeks after the last enrollee in the cohort has completed the 
Day 3 visit so that all Day 3 data available are considered. Safety data to be reviewed include vital signs, 
ECG, AEs, clinical laboratory values (serum and urine), and UDS. 
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 by electronic means of viewing both 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 


 
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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. 
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 adverse events (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 


 
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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 investigator and the IRB 
• 
Composition of the IRB or other applicable statement  
• 
Record of all significant communications between the investigator 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 eCRFs and of documentation of corrections for all participants 
• 
Drug accountability records 
• 
Record of any body fluids or tissue samples retained 
• 
All other source documents (patient 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, he must contact the Sponsor to make 
alternative arrangements. Details of these arrangements should be documented. 
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 manual of procedures 
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 subject's rights, safety, or 
well-being. Deviations will be categorized by type and will be reviewed on an ongoing basis. 


 
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10.1.11. 
PUBLICATION AND DATA SHARING POLICY 
 
This study will comply with the 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 
ACES 
Agitation/Calmness Evaluation Scale 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
AUCinf 
Area Under the Curve from Time 0 Through Infinity 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
Maximum Concentration 
CMP 
Clinical Monitoring Plan 
CNS 
Central Nervous System 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Cardiovascular 
DHHS 
Department of Health and Human Services 
DSM5  
Diagnostic and Statistical Manual of Mental Disorders 5  
DSM5 SUD 
Diagnostic and Statistical Manual of Mental Disorders 5 for Substance Use Disorders 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Forms 
ED 
Emergency Department 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HACA 
Human Anti-Chimeric Antibody 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
IgG 
Immunoglobulin G 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
IV 
Intravenous 
IXRS 
Interactive Voice/Web Response System 
LAR 
Legally Authorized Representative 
mAb 
Monoclonal Antibody  
MedDRA 
Medical Dictionary for Regulatory Activities 
METH 
Methamphetamine 
MUD 
Methamphetamine Use Disorder 
N 
Number 
NA 
Not Applicable 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIDA 
National Institute on Drug Abuse 
OHRP 
Office for Human Research Protections 


 
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PANSS-EC 
Positive and Negative Syndrome Scale – Excited Component 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
QC 
Quality Control 
SA 
Self-Administration 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SoA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
STAMPOUT Study of Antibody for Methamphetamine Outpatient Therapy, NCT03336866 
TAU 
Treatment As Usual 
TEAE 
Treatment-Emergent Adverse Event 
UBACC 
UCSD Brief Assessment of Capacity to Consent 
UDS 
Urine Drug Screen 
UPT 
Urine Pregnancy Test 
Urine AE 
Cumulative Urinary Excretion 
US 
United States 
Vd 
Volume of Distribution 
WBC 
White Blood Cell 
 
 
 


 
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10.3. PROTOCOL AMENDMENT HISTORY 
 
Version/Date 
Description of Change  
Brief Rationale 
V2 
23Mar2021 
Updates throughout to 
allow dosing of haloperidol 
up to 5 mg by IM or IV 
TAU may include 5 mg haloperidol. IV dosing option 
added to allow physicians the choice. 
1.3 Clarified SOA to match 
section 8 for UDS. 
Clarification updates only. 
5.2 Updated inclusion 
criteria 3 with upper bound 
of 25 for PANSS-EC score. 
To ensure that severely METH intoxicated patients are 
not enrolled. 
6.5.1 Added dopamine (and 
other medications) as 
option for rescue 
medication for hypotension 
at specified starting dose. 
To include additional rescue medications. 
7.1 Added study halting 
rule for two Grade 3 AEs 
related to agitation, 
aggression, or anxiety. 
Increased METH toxicity signs could indicate treatment 
failure. It is important to pause the study for review in 
the case of toxicity-related AEs. 
8.2 Changed Day 3 clinical 
labs from ‘repeat if needed’ 
to ‘required’. 
It is likely that the Day 1 lab results would not be 
available in order to determine necessity of repeat lab 
data by Day 3. 
10.1.1.2 Clarified consent 
process. 
To note that a box will be checked if LAR consent is 
obtained by phone. 
12.9.1 Added DSMB 
member names and 
affiliations.  
To add names and affiliations. 
V3 
15Nov2021 
1.2 Updated schema. 
To remove references to time frames. 
1.3 Added collection of 
ACES score at time 0 and 
broadened the window for 
collection of UDS, UPT, 
and breathalyzer. 
To ensure an ACES score is captured proximate to 
dosing initiation and to allow UDS, UPT, and 
breathalyzer to occur before or after dosing. 
5.2 Revised inclusion 
criteria 3 to increase the 
upper limit of the PANSS-
EC assessment to 28.  
To more accurately reflect moderate severity agitation, 
which could include a score of “4” on all 7 dimensions.  
5.2 Revised inclusion 
criteria 5 to include a 
positive METH drug 
screen. 
To allow a positive METH drug screen rather than 
participant or observer attribution of symptoms to 
METH use. 
5.3 Revised exclusion 
criteria 1 to remove the 
exclusion of those requiring 
naloxone treatment. 
Removed as unnecessary. 
5.3 Revised exclusion 
criteria 3c to remove the 
Removed as unnecessary. 


 
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Version/Date 
Description of Change  
Brief Rationale 
exclusion of agitation 
requiring restraint. 
5.3 Revised exclusion 
criteria 4 to include 
suicidality questions asked 
and modify the time frame 
of the questions asked. 
To include the specific questions to be asked and the 
disqualification criteria in the list with other criteria. 
The time frames for reported suicidal ideation and 
suicide attempt were reduced to allow those with 
adolescent or >1 year ago suicide attempts to enroll. It 
is considered that participants who have not attempted 
suicide again in the past year and have also not been 
thinking much about it in the past month are stable 
enough for study enrollment. 
6.2.3 Removed the frozen 
IP storage option. 
To clarify the preferred storage condition of 
refrigerated. 
7.2 Clarified recruitment of 
additional subjects. 
To clarify that additional subjects may, not will, be 
recruited to complete the cohorts with those testing 
positive for METH. 
8.1 Updated the rationale 
for the PANSS-EC range. 
To clarify the change to inclusion criteria 3. 
8.2 Updated the 
Evaluations of Drug and 
Alcohol Use to remove 
propoxyphene and change 
time frame for UDS and 
breathalyzer 
To remove propoxyphene testing as unnecessary and 
broaden the time frame for collecting UDS and 
breathalyzer tests to before or after dosing. 
8.2 Updated the Psychiatric 
Evaluation section to 
modify the time frame used 
for questions about suicide 
attempts and ideation. 
The time frames for reported suicidal ideation and 
suicide attempt were reduced to allow those with 
adolescent or >1 year ago suicide attempts to enroll. It 
is considered that participants who have not attempted 
suicide again in the past year and have also not been 
thinking much about it in the past month are stable 
enough for study enrollment. Removed reference to 
IXT Suicidal Ideation Questionnaire as unnecessary. 
8.2 Added bilirubin to 
laboratory evaluations 
Test was previously omitted. 
8.2 Changed time frame for 
UDS, urinalysis, and UPT 
To broaden the time frame for collecting urine samples 
to before or after dosing. 
8.3.2 Clarified wording to 
define a medically 
important event classified 
as an SAE. 
To clarify the definition of a medically important event 
that should be considered an SAE. 
8.3.6 Reduced the time 
frame of reporting of SAEs 
to Sponsor and Medical 
Monitor that are not life 
threatening to 48 hours. 
To allow time for reporting to NIDA by 72 hours post-
event occurrence. 
9.4.3 Removed requirement 
for two consecutive time 
points following a return to 
To allow subjects to be discharged faster rather than 
waiting on an additional time point after a return to 
normal. 


 
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Version/Date 
Description of Change  
Brief Rationale 
normal for the ACES 
assessment. 
9.4.3 Removed requirement 
to report ratio of IXT-m200 
to METH. 
Removed as unnecessary. 
10.1.1.2 Clarified consent 
process by adding wording 
from Protocol Clarification 
Letter dated 07 April 2021. 
Removed unnecessary wording and added section 
10.1.1.2.1 describing IRB-approved consent procedures 
for LAR. 
10.1.7 Added option for 
electronic SDV as needed. 
To clarify that SDV could be done via electronic means 
if necessary and possible, and not only during an on-site 
visit. 
V4 
09Mar2022 
Updates throughout to 
change dose level for 
cohort 2 to 2-g doses  
To update the dose level for cohort 2 to 2-g doses. Dose 
levels for cohorts 3 and 4 will be updated by future 
amendment. 
1.3 Inserted UBACC in 
SOA 
To note that the UBACC should be performed along 
with Informed Consent processes 
2.2 Noted that the 
STAMPOUT study was 
complete and a Phase 1 
study is ongoing 
To provide updated background information in support 
of the protocol change. 
4.1 Updated table of cohort 
dose levels  
To update the dose levels for cohorts 2-4. 
4.3 Updated dose levels and 
added supporting 
information  
To remove unnecessary dose information for 1- and 1.5-
g doses, and provide calculated dose administration 
rates that are supportive of the protocol change. 
5.2 Added phrase to IC#6 
To allow an exception to the requirement for an LAR if 
the participant is capable of consenting for themselves 
as determined by the UBACC 
5.2 Added consent or to 
IC#7 
To clarify that participants must consent or assent, the 
choice of which will depend on whether they have the 
capacity to consent for themselves 
5.3 Adjusted EC#6 wording To allow participants with an allergy to one of the two 
TAU medications to participate, so long as they are not 
allergic to both 
5.6.1 Updated phrasing for 
consistency 
To note that a LAR is required only if a participant is 
found unable to consent for themselves 
6.2.4 Removed 1- and 1.5-g 
doses 
To remove reference to doses that are now unplanned 
8.2 Added description of 
the UBACC 
To provide a description of the UBACC and clarify its 
use 
9.4.6 Revised the purpose 
of the Interim Analysis 
To change the purpose of the Interim Analysis slightly 
by determining the appropriate cohorts 3 and 4 doses 
rather than confirming their pre-specified levels are 
appropriate. 


 
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Version/Date 
Description of Change  
Brief Rationale 
10.1.1 Updated Informed 
Consent process 
Entire section updated to allow participants to consent 
for themselves if found to have the capacity to consent 
by the UBACC. If unable to consent, a LAR may be 
used for consent along with the written assent of the 
participant. All participants are to provide consent, 
again if they originally consented for themselves, on 
Day 3. 
10.1.3 Added Investigator 
responsibility 
To specify that Investigators have certain 
responsibilities due to the Certificate of Confidentiality. 
V5 
22Aug2022 
1.1 Updated number of 
anticipated participants 
Changed number from 40 to 24 in order to complete the 
study with equal number of participants in the low, 
high, and TAU groups. 
4.1 Updated number of 
anticipated participants, 
number of cohorts, and 
timing of DSMB reviews 
Changed number from 40 to 24 participants, reduced 
the number of cohorts required, and the timing of 
DSMB meetings. 
4.2 Removed comment that 
lowest effective dose would 
be identified 
Intermediate doses have been removed from the 
protocol, thus the lowest effective dose may not be 
identified 
6.2 Clarified randomization 
Required update to match cohort dose revisions 
6.3 Clarified randomization 
Required update to match cohort dose revisions 
7.2 Updated replacement of 
participant 
Required update to match cohort dose revisions 
9 Removed reference to 4 
cohorts 
Required update to match cohort dose revisions 
9.2 Clarified number of 
TAU patients needed is 8  
Required update to match cohort dose revisions 
9.4.6 Removed plan for 
interim analysis 
An interim analysis is no longer necessary following 
cohort 2 as the treatment for cohort 3 is TAU. 
10.1.6 Updated DSMB 
meeting schedule 
Required update to match cohort dose revisions 
 
 


 
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11 REFERENCES  
 
1. Klein LR, Driver BE, Miner JR, Martel ML, Hessel M, Collins JD, Horton GB, Fagerstrom E, Satpathy 
R, Cole JB. Intramuscular midazolam, olanzapine, ziprasidone, or haloperidol for treating acute agitation 
in the emergency department. Ann Emerg Med 2018; 72:374–85. 
2. Wilson MP, Pepper D, Currier GW, Holloman GH, Feifel D. The psychopharmacology of 
agitation: consensus statement of the American Association for Emergency Psychiatry project 
BETA psychopharmacology workgroup. West J Emerg Medicine 2012; 13:26–34. 
3. Schwarzbach V, Lenk K, Laufs U. Methamphetamine‐related cardiovascular diseases. ESC 
Heart Failure 2020; 7:407–14. 
4. Richards JR, Hamidi S, Grant CD, Wang CG, Tabish N, Turnipseed SD, Derlet RW. 
Methamphetamine use and emergency department utilization: 20 years later. J Addict 2017; 
2017:1–8. 
5. Byrnes-Blake KA, Laurenzana EM, Landes RD, Gentry WB, Owens SM. Monoclonal IgG 
affinity and treatment time alters antagonism of (+)-methamphetamine effects in rats. Eur J 
Pharmacol 2005; 521:86–94. 
6. Byrnes-Blake KA, Laurenzana EM, Carroll FI, Abraham P, Gentry WB, Landes RD, Owens 
SM. Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-
methamphetamine in rats. Eur J Pharmacol 2003; 461:119–28. 
7. Laurenzana EM, Stevens MW, Frank JC, Hambuchen MD, Hendrickson HP, White SJ, 
Williams DK, Owens SM, Gentry WB. Pharmacological effects of two anti-methamphetamine 
monoclonal antibodies. Supporting data for lead candidate selection for clinical development. 
Hum Vaccin Immunother 2014; 10:2638–47. 
8. Stevens MW, Tawney RL, West CM, Kight AD, Henry RL, Owens SM, Gentry WB. 
Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use. 
mAbs 2014; 6:547–55. 
9. White SJ, Hendrickson HP, Atchley WT, Laurenzana EM, Gentry WB, Williams DK, Owens 
SM. Treatment with a monoclonal antibody against methamphetamine and amphetamine reduces 
maternal and fetal rat brain concentrations in late pregnancy. Drug Metab Dispos 2014; 42:1285–
91. 
10. Stevens MW, Henry RL, Owens SM, Schutz R, Gentry WB. First human study of a chimeric 
anti-methamphetamine monoclonal antibody in healthy volunteers. mAbs 2014; 6:1649–56. 
11. Owens SM, Atchley WT, Hambuchen MD, Peterson EC, Gentry WB. Monoclonal antibodies 
as pharmacokinetic antagonists for the treatment of (+)-methamphetamine addiction. CNS 
Neurol Disord Drug Targets [Internet] 2011; 10:892–8. Available from: 


 
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https://www.researchgate.net/publication/221733100_Monoclonal_Antibodies_as_Pharmacokine
tic_Antagonists_for_the_Treatment_of_-Methamphetamine_Addiction 
12. Battaglia J, Lindborg SR, Alaka K, Meehan K, Wright P. Calming versus sedative effects of 
intramuscular olanzapine in agitated patients. Am J Emerg Medicine 2003; 21:192–8. 
13. Zhu JM, Singhal A, Hsia RY. Emergency department length-of-stay for psychiatric visits 
was significantly longer than for nonpsychiatric visits, 2002–11. Health Affair 2017; 35:1698–
706. 
14. Richards JR, Hawkins JA, Acevedo EW, Laurin EG. The care of patients using 
methamphetamine in the emergency department: Perception of nurses, residents, and faculty. 
Subst Abus 2018; :1–31. 
15. Hambuchen MD, Rüedi-Bettschen D, Williams DK, Hendrickson H, Owens SM. Treatment 
of rats with an anti-(+)-methamphetamine monoclonal antibody shortens the duration of action of 
repeated (+)-methamphetamine challenges over a one month period. Vaccine 2014; 32:6213–9. 
16. Laurenzana EM, Byrnes-Blake KA, Milesi-Hallé A, Gentry WB, Williams DK, Owens SM. 
Use of anti-(+)-methamphetamine monoclonal antibody to significantly alter (+)-
methamphetamine and (+)-amphetamine disposition in rats. Drug Metab Dispos 2003; 31:1320–
6. 
17. Chiang M, Lombardi D, Du J, Makrum U, Sitthichai R, Harrington A, Shukair N, Zhao M, 
Fan X. Methamphetamine-associated psychosis: Clinical presentation, biological basis, and 
treatment options. Hum Psychopharmacol 2019; 34:e2710. 
18. Sacchetti E, Amore M, Sciascio GD, Ducci G, Girardi P, Mauri M, Tortorella A, Matteis 
LMD, Menacci C. Psychomotor agitation in psychiatry: an Italian expert consensus. Evidence-
based Psychiatric Care 2017; 1:1–24. 
19. Montoya A, Valladares A, Lizán L, San L, Escobar R, Paz S. Validation of the Excited 
Component of the Positive and Negative Syndrome Scale (PANSS-EC) in a naturalistic sample 
of 278 patients with acute psychosis and agitation in a psychiatric emergency room. Health Qual 
Life Out 2011; 9:18. 
20. Kay SR, Fiszbein A, Opfer LA. The Positive and Negative Syndrome Scale (PANSS) for 
Schizophrenia. Schizophrenia Bull 1987; 13:261–76. 
21. Jeste DV, Palmer BW, Appelbaum PS, Golshan S, Glorioso D, Dunn LB, Kim K, Meeks T, 
Kraemer HC. A New Brief Instrument for Assessing Decisional Capacity for Clinical Research. 
Arch Gen Psychiat 2007; 64:966–74. 
22. Sibille M, Patat A, Caplain H, Donazzolo Y. A safety grading scale to support dose 
escalation and define stopping rules for healthy subject first-entry-into-man studies. Br J Clin 
Pharmacol 2010; 70:736–48.  


 
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12 DATA AND SAFETY MONITORING PLAN 
 
U01 DA 053043 (PD/PI: Gentry, William B. and Stevens, Misty) 
 
Meth-OD: A Phase 2A Study of IXT-m200 in Patients with Toxicity from 
Methamphetamine Overdose 
 
Protocol Number: M200C-2101 
 
Medical Monitor: Patrick Keenan, MD 
 
 
August 22, 2022 
 
 
This Data and Safety Monitoring Plan (DSMP) is forward looking and may not be amended in real time 
to reflect changes in study status, participant enrollment, etc. In the event of a conflict between the DSMP 
and the clinical protocol, the current clinical protocol shall be followed. 
 
 


 
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12.1. SUMMARY OF THE PROTOCOL 
12.1.1. STUDY DESIGN 
 
Refer to protocol section 4 for further details. 
 
The hypothesis of this multisite Phase 2a study is that IXT-m200 will be well-tolerated in patients with 
acute mild to moderate METH toxicity. A randomized, open label design will be used in which one dose 
of IXT-m200 will be compared to treatment-as-usual (TAU). Approximately 40 24 participants will be 
enrolled in 4 3 cohorts. A dose escalation approach will be used so that progressively higher IXT-m200 
doses will be evaluated in each of the first two cohorts. In conjunction with safety monitoring, this design 
assures the opportunity to observe early safety findings before any participants are exposed to the next 
higher dose. The randomization ratio for IXT-m200 versus TAU is defined as 4:1 for each of cohorts 1 
and 2, with up to an additional 4 TAU participants in cohort 3 so that the number of participants receiving 
TAU equals the number receiving each dose of IXT-m200 at the end of the study.  
 
Cohort 
IXT-m200  
dose (g) 
IXT-m200:TAU 
subject numbers 
1 
0.5 
8:2 
42 
2 
8:2 
3 
0 
0:4 
 
Agitation scales and vital signs will be recorded to track effect of the antibody treatment versus TAU over 
time on agitation associated with METH use. While in the ED, detailed and pertinent medical and 
psychiatric histories, and physical exam will be obtained, along with laboratory assessments and ECGs. In 
the ED, participants will give blood samples for analysis of METH and IXT-m200 concentrations and 
followed for development of adverse events. Participants will be evaluated at 2 days and 4 weeks after 
discharge from the ED for adverse events and drug use history. Cohort escalation reviews will be 
performed by the Sponsor, Medical Monitor, and Data and Safety Monitoring Board (DSMB) between 
after cohort 1s and the next group will not start until after completion of this review.  
 
The next page shows the Schedule of Activities. 
 


 
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Assessment 
Triage 
Screening 
Dosing and Assessments f 
Follow-upa 
Study Day 
1 
1 
1 
Day not 
specified 
3 
(+2) 
28 
(±7) 
Hour 
NA 
<0 
<0 
0 
0.25 
0.5 
0.75 
1 
1.5 
2 
3 
4 
6 
8 
>8, <Discharge 
from ED 
Discharge 
from ED 
NA 
NA 
Focused history and physical 
exam b, c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Focused review of systems b, c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Medication history 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Detailed and pertinent 
psychiatric history c, d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs c 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
As needed 
X 
X 
X 
Agitation score c 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
As needed 
 
 
 
Informed consent and 
UBACC 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Eligibility criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samples d 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
Dose administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Observe for AEs 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
As needed 
X 
X 
X 
Assess for rescue meds 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
As needed 
X 
 
 
Clinical labs and ECG 
 
 
 
 
 
Once, as soon as feasible 
 
 
 
 
X 
 
UDS, UPT, Breathalyzer  
 
 
Once, as soon as feasible 
 
 
 
 
 
 
Detailed and pertinent 
medical history e 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
DSM5 SUD checklist 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Drug use assessment and 
Meth Perception Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
AE – adverse event; UDS – urine drug screen; UPT – urine pregnancy test; ECG – electrocardiogram; DSM5 SUD – Diagnostic and Statistical Manual of Mental Disorders 5 for 
Substance Use Disorders; NA – not applicable; UBACC – UCSD Brief Assessment of Capacity to Consent 
a If participants do not return for a follow-up visit, a phone call will be attempted to assess any AEs. 
b Focused history, physical exam and review of systems based on main complaint, related details from other parts of the medical history and physical exam, and eligibility criteria.  
c Assessments will be obtained as either part of triage or screening, depending on the site. PANSS-EC will be done at screening only; ACES will be done at each time point as 
marked. 
d PK samples will be drawn for both IXT-m200 and METH per section 8.2. 
e Detailed and pertinent history includes pertinent past medical, family and social histories in addition to focused history. Detailed physical exam to be completed if indicated by 
detailed and pertinent medical history.  
f Subjects may be discharged at any time point after the 2-hr assessments are completed if the subject is deemed medically eligible; assessments at Day 1, Hours 3-8 may be 
skipped if discharged. Assessments assigned for the time of discharge from ED should be completed for all subjects. 


 
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12.1.2. PRIMARY AND SECONDARY OBJECTIVES AND OUTCOME MEASURES 
Refer to protocol section 3. 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
Primary 
 
 
To evaluate the safety and 
tolerability of IXT-m200 in 
patients with mild to moderate 
METH toxicity 
Safety and tolerability of IXT-
m200 as measured by physical 
examinations and vital sign, 
AE, ECG, and clinical 
laboratory testing 
Safety must be systematically 
evaluated of IXT-m200 when 
given to patients with ongoing 
METH toxicity for the first time  
Secondary 
 
 
To determine the time course 
and degree of normalization of 
agitation and vital signs 
Agitation/sedation scores over 
time as measured by ACES 12  
Agitation is a significant CNS 
component of METH toxicity and 
a cause for hospital admission  
Vital signs including blood 
pressure, heart rate and 
temperature over time 
Elevated or depressed 
hemodynamics are a component of 
CV toxicity 
To determine the percentage 
of participants requiring 
rescue medications for 
psychiatric or cardiovascular 
manifestations of METH 
toxicity  
Need for rescue medications to 
treat: 
- agitation, dysphoria, or 
psychosis (CNS toxicity) 
- hypertension, tachycardia, or 
other cardiovascular 
instability (CV toxicity) 
An evaluation of IXT-m200 
effects on requirement of rescue 
medications is needed 
Tertiary/Exploratory  
 
 
To determine how long 
patients with METH toxicity 
stay in the ED 
ED length of stay as measured 
by disposition order time minus 
triage time, and as measured by 
disposition order time minus 
start of treatment time, with log 
transformation 
Prolonged wait times are 
associated with a number of 
negative outcomes, including 
patient dissatisfaction, increased 
hospitalization rate, poor quality of 
care, and increased mortality 13 
12.1.3. INCLUSION CRITERIA 
Refer to protocol section 5.2. 
Eligible participants will:  
1. Be aged 18 to 45 years, inclusive; 
2. Present to the ED with METH toxicity as defined in protocol; 
3. Have a PANSS-EC score of 14-28, inclusive; 
4. Have or agrees to have an intravenous (IV) line placed; 
5. Give a history of METH use in the past 24 hours, with participant or observer attribution of 
symptoms to METH or have a positive METH drug screen; 
6. Be accompanied or readily represented by a legally authorized representative (surrogate) who can 
consent to participation on behalf of the participant if participant is found not able to consent for 
themselves using the UCSD Brief Assessment of Capacity to Consent (UBACC); and 
7. Consent or assent to participation in the study. 


 
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12.1.4. EXCLUSION CRITERIA 
Refer to protocol section 5.3. 
Eligible participants will NOT:  
1. Present with concomitant opioid overdose requiring ventilatory support; 
2. Be self-reported to be pregnant or lactating; 
3. Be considered to have significant concomitant medical illness or trauma, or symptoms of severe 
METH toxicity including  
a. sepsis or febrile illness;  
b. myocardial infarction, cardiac decompensation or arrhythmias including tachycardia that 
is not sinus; severe hypertension (>180/110 mmHg); inadequately treated hypertension 
on chronic medication; history of vasculitis 
c. coma, stroke or severe head injury; new or ongoing seizure activity 
d. acute pulmonary decompensation or severe chronic obstructive pulmonary disease;  
e. any hepatic impairment and/or acute hepatitis or renal impairment due to concomitant 
medical illness; or 
f. 
current, or history of, neuroleptic malignant syndrome  
4. Be considered to be at imminent risk of suicide or have disqualifying answers to the following 
two questions. Disqualifying answers would be 1b2 or 2b. 
 
1. In the past 30 days, have you considered killing yourself? 
a) No 
b) Yes - if Yes, how often? 
b1) Not often (twice or less) 
b2) Somewhat often (more than twice) 
 
2. In the past year, have you attempted to kill yourself? 
a) No 
b) Yes 
 
5. Be considered to be at imminent risk of injury or danger to self, others or property; 
6. Have a history of severe allergy (rash, hives, breathing difficulty, etc.), to both lorazepam and 
haloperidol, or known hypersensitivity or infusion reaction to any antibody medications; or 
7. Be judged by the treating ED physician, investigator, or Sponsor (or designee) to be inappropriate 
for the study, including people whom the investigator determines cannot reasonably be consulted 
for assent to participation. 
12.1.5. POWER CALCULATION AND SAMPLE SIZE 
Refer to protocol section 9 and the SAP for further detail on statistical analysis. 
Because Meth-OD is mainly a safety study, the sample size for this study is not based on statistical 
hypotheses. The number of participants within each dose group was chosen based on feasibility, as well 
as historical experience with initial safety and tolerability trials. From the perspective of tolerability 
assessment, the probability that a given adverse event would not be observed in a group of participants 
administered an assigned dose was analyzed for various true population incidence rates was computed 
(Table 1).  


 
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Table 1. Probability of Not Observing an Adverse Event for Various True Incidence Rates  
 
Probability of Not Observing an AE in Varying Group Sizes 
True incidence rate 4 subjects 6 subjects 8 subjects 9 subjects 12 subjects 18 subjects 
0.10 
0.66 
0.53 
0.43 
0.387 
0.28 
0.150 
0.20 
0.41 
0.26 
0.17 
0.134 
0.069 
0.018 
0.30 
0.24 
0.12 
0.058 
0.040 
0.014 
0.002 
0.40 
0.13 
0.047 
0.017 
0.010 
0.002 
< 0.001 
0.50 
0.063 
0.016 
0.004 
0.002 
< 0.001 
< 0.001 
The probability of not observing an AE under each sample size and true incidence rate scenario was 
calculated using an exact test for binomial proportion assuming a two-sided Type I error (alpha) of 0.05 
and near-zero null proportion of 0.000001. The values reported in the table are the Type 2 error. Analyses 
were conducted in SAS® 9.4. 
Based on the nature of this study, the proposed sample size of 8 participants in each IXT-m200-
containing treatment group adequately allows for the detection of clinically meaningful rates of adverse 
events with the probability of not observing an AE for true incidence rates. 
12.2. TRIAL MANAGEMENT 
12.2.1. PARTICIPATING CLINICS 
 
Dr. Michael Wilson 
University of Arkansas for Medical Sciences 
4301 W. Markham St., Little Rock, AR 72205 
 
Dr. Thomas Robey 
Providence Community Hospital 
1330 Rockefeller Ave Suite 440, Everett, WA 98201 
 
Dr. Cameron Crandall 
University of New Mexico 
MSC11 6025 1 UNM, Albuquerque, NM 87131 
 
Dr. David McClellan 
Sacred Heart Medical Center/Providence Medical Research Center 
105 W 8th Avenue, Suite 532C, Spokane, WA 99204 
 


 
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12.2.2. PLANNED ENROLLMENT TIMETABLE 
 
12.2.3. TARGET POPULATION DISTRIBUTION 
 
TARGETED/PLANNED ENROLLMENT: Number of Participants 
 
Not Hispanic or Latino 
Hispanic or Latino 
 
Racial Categories 
Female 
Male 
Female 
Male 
Total 
American Indian/ 
Alaska Native 
0 
1 
0 
0 
1 
Asian 
0 
21 
0 
0 
21 
Native Hawaiian or  
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
21 
42 
0 
0 
63 
White 
74 
127 
1 
63 
2615 
More than One Race 
1 
1 
1 
21 
54 
Total 
106 
2012 
2 
84 
4024 
Meth-OD study overview
Grant start
Pre-study 
Site selection/contracting
Investigator's meeting
Site activations
Cohort 1
10 subjects (0.5 p/s/m)
Last Subject through Day 28
Cohort Escalation Review
Cohort 2
10 subjects (0.67 p/s/m)
Last Subject through Day 28
Cohort Escalation Review and Interim Analysis
Cohort 3
10 subjects (0.67 p/s/m)
Last Subject through Day 28
Cohort Escalation Review
Cohort 4
10 subjects (0.67 p/s/m)
Last Subject through Day 28
Study Closeout
Database lock
Stats analysis and TLFs
Draft Clinical Study Report
Final Study Report
Feb Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
Jan
Feb
Meth-OD study overview
Grant start
Pre-study 
Site selection/contracting
Investigator's meeting
Site activations
Cohort 1
10 subjects (~2/mo)
Last Subject through Day 28
Cohort Escalation Review
Cohort 2
10 subjects
Last Subject through Day 28
Cohort 3
4 subjects
Last Subject through Day 28
Study Closeout
Database lock
Stats analysis and TLFs
Draft Clinical Study Report
Final Study Report
Feb Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun Jul


 
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12.3. DATA MANAGEMENT AND ANALYSIS 
12.3.1. DATA ACQUISITION AND TRANSMISSION 
Refer to protocol section 10.1.9.1. 
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 adverse events (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. 
12.3.2. DATA ENTRY METHODS 
All data will be collected on source documents and then entered in the eCRFs. 
12.3.3. DATA SECURITY AND PLAN FOR PROTECTING CONFIDENTIALITY 
 
Refer to protocol section 10.1.3. 
 
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 
subjects in this study. The clinical study site will permit access to such records. 
  
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 


 
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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. 
12.3.4. DATA ANALYSIS PLAN 
 
Refer to protocol section 9 for further details. 
 
A statistical analysis plan (SAP) will be prepared after the protocol is approved. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to address 
all study objectives. The SAP will serve as a complement to the protocol and supersedes it in case of 
differences. 
12.4. QUALITY ASSURANCE AND QUALITY CONTROL 
12.4.1. PROCEDURES IN PLACE TO ENSURE THE VALIDITY AND INTEGRITY OF 
THE DATA 
Refer to protocol section 10.1.8. 
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. 
12.4.2. PROCEDURES TO GUARANTEE THE ACCURACY AND COMPLETENESS OF 
THE DATA DURING DATA COLLECTION, ENTRY, TRANSMISSION, AND 
ANALYSIS 
Refer to protocol section 10.1.7. 
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). 
  


 
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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 by electronic means of viewing both 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. 
 
12.5. REGULATORY ISSUES 
12.5.1. REPORTING OF SAES 
Refer to protocol section 8.3.6. 
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 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 Sponsor will be responsible for notifying the 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. 
 


 
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The NIDA Project Officer (PO) and Project Scientist (PS) 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.  
12.5.2. REPORTING OF IRB ACTIONS TO NIDA 
InterveXion will be responsible for reporting IRB actions to the NIDA PO. 
12.5.3. REPORT OF CHANGES OR AMENDMENTS TO THE PROTOCOL 
InterveXion will be responsible for reports of protocol changes or amendments to the NIDA PO and PS 
and the FDA. Significant protocol changes will be approved by NIDA prior to implementation, unless 
there is an immediate safety concern for participants. 
12.6. TRIAL SAFETY 
12.6.1. POTENTIAL RISKS AND BENEFITS FOR PARTICIPANTS 
Refer to protocol section 2.3. 
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 subjects 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 
subjects 10. 
  
Only 1 AE was definitely attributed to IXT-m200. A single subject experienced a CTCAE v.4.0 Grade 3 
infusion reaction half-way through the IXT-m200 infusion. The subject experienced a brief period of 
bronchospasm, in which the subject and investigator heard a single expiratory wheeze. The infusion was 
stopped and the subject was treated with solumedrol and diphenhydramine. No further symptoms were 
noted. The subject required outpatient therapy later for bronchitis. 
  
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 subjects were 
confirmed positive for HACA in the Phase 1 study. The development of HACA did not appear to be dose-
related 10. 
 


 
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IXT-m200 is an investigational product and may convey no benefit to patients. Based on nonclinical 
studies in rodents 7,11, 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.  
12.6.2. RISK MITIGATION PLAN 
Refer to protocol section 6.5.2. 
The following risk mitigation strategies have been designed based on other studies in people who use 
METH, on the problems posed specifically by enrolling participants in an emergency setting, on the 
clinical pharmacology of METH, and on the known pharmacology of IXT-m200: 
1. Selection of a specific participant group. As stipulated in the protocol, participants who are 
relatively healthy with no significant medical or surgical illness will be recruited. 
2. IXT-m200 dosing. IXT-m200 will be administered in escalating dose groups so that the lowest 
IXT-m200 dose (0.5 g) will be evaluated before the higher doses), in subsequent cohorts. This 
will allow determination of the effects of IXT-m200 at a low predicted effective IXT-m200 dose, 
before effects are assessed following a high predicted effective IXT-m200 dose.  
3. Treatment in an Emergency Department. A crash cart will be available in the ED and personnel 
trained in CPR are always available in the ED setting. Oxygen and emergency ventilation 
equipment are immediately available. Normal saline will be used as the IV fluid and fluid boluses 
can be administered if any hypotension is seen. In the event of serious medical complications, a 
code may be called. 
4. Frequent safety review. A formal safety review will be done between cohorts, and at any point 
needed based on the severity of AEs. This would include Grade 3 AE’s related to worsening of 
METH effects in the presence of IXT-m200.  
 
All of the study sites are EDs and therefore have all medications that might be needed to treat mAb 
toxicity, which may manifest as hypotension and bradycardia or tachycardia; bronchospasm with or 
without hypoxemia; or flushing, pruritis, and urticaria. Hospital-maintained crash carts, and oxygen and 
emergency ventilation equipment (Ambubags) are always available. Advanced Cardiovascular Life 
Support-certified providers and code teams are always available to treat life-threatening events.  
12.6.3. TRIAL STOPPING RULES 
Refer to protocol section 7.1. 
Enrollment and study drug administration will be immediately paused if any 1 of the following events 
occurs, unless the event was clearly unrelated to study drug administration, or the event is an expected 
sequelae of untreated METH toxicity: 
• 
Three (3) participants experience a Grade 3 AE.  
• 
Two (2) participants experience a Grade 3 AE related to increased agitation, aggression, or 
anxiety. 
• 
One (1) participant experiences a Grade 4 AE.  
• 
A death occurs.  
 
Expected sequelae of untreated METH toxicity which will not be considered grounds for a study pause 
include: 
• 
Hypertension/tachycardia 
• 
Euphoria 


 
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• 
Agitation 
• 
Insomnia 
• 
Anxiety 
• 
Seizures 
• 
Mania/aggression 
 
Worsening of any of the above following administration of study drug will be considered an AE and 
subject to the rules for study pause above. 
If any of the pause conditions are met, the Sponsor, in consultation with the investigator and Medical 
Monitor, will suspend enrollment until a full safety review by both the Sponsor and DSMB is performed. 
A decision to reinitiate enrollment will be made following relevant consultation with the appropriate 
authorities based on the results of the safety review. 
Also refer to protocol section 10.1.2. 
This study may be temporarily suspended or prematurely terminated at the sole discretion of the Sponsor. 
Written notification, documenting the reason 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. Sponsor will provide the reason(s) for the termination or suspension. 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. 
12.6.4. PROCESS OF AE/SAE COLLECTION, ASSESSMENT, AND REPORTING 
Refer to protocol section 8.3. 
All AEs (whether serious or nonserious) that occur after the participant has been randomized 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. Every attempt 
should be made to describe the AE in terms of a diagnosis. If appropriate, component 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, until a satisfactory 
explanation is found or the investigator considers it medically justifiable to terminate follow-up. Should 
the AE result in death, a full pathologist’s report should be supplied, if possible. 
 


 
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Adverse events will be reviewed by the Sponsor, Medical Monitor and DSMB between cohorts. If an 
investigator decides it necessary, AEs may be reviewed at any time by consultation with the investigator, 
Medical Monitor, and Sponsor. 
Refer to DSMP section 12.5.1 for details on SAEs. 
12.6.5. AE/SAE FOLLOW-UP PLAN 
Refer to DSMP section 12.6.4. 
12.7. TRIAL EFFICACY 
12.7.1. PLANS FOR INTERIM ANALYSIS OF EFFICACY DATA 
Refer to protocol section 9.4.6. 
Between cohorts 2 and 3, a review of the efficacy data, i.e., all secondary endpoints, will be undertaken to 
determine the dose levels for cohorts 3 and 4. The Medical Monitor and DSMB will provide their 
recommendations to the Sponsor for a final decision.  
 
A protocol amendment will incorporate the adjustments. Further details will be provided in the DSMB 
Charter and the SAP.No interim analyses are planned. 
12.8. DSM PLAN ADMINISTRATION 
12.8.1. RESPONSIBILITY FOR DATA AND SAFETY MONITORING 
Refer to protocol section 10.1.6. 
Safety oversight will be under the direction of a DSMB composed of individuals with the appropriate 
expertise, likely including clinical trial oversight, monoclonal antibody and methamphetamine clinical 
pharmacology, acute care medicine (cardiovascular and/or emergency), psychiatry or behavioral 
medicine, statistics, and a patient advocate or representative. Members of the DSMB will be independent 
from the study conduct and free of conflict of interest, or measures will be enacted to minimize real or 
perceived conflicts of interest.  The DSMB will meet at the conclusion of each cohort 1 to assess safety 
data and intermittently as necessary. 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 Sponsor. 
 
Cohort escalation reviews will be performed by the Sponsor, Medical Monitor, and DSMB between 
cohorts 1 and 2 and the next group will not start until after completion of this review. Thiese reviews will 
be scheduled to occur approximately two weeks after the last enrollee in the cohort has completed the 
Day 3 visit so that all Day 3 data available are considered. Safety data to be reviewed include vital signs, 
ECG, AEs, clinical laboratory values (serum and urine), and UDS. 
12.8.2. PERSONS RESPONSIBLE FOR MONITORING THE TRIAL 
Safety monitoring will be the responsibility of the investigators, Medical Monitor and the DSMB. Each 
investigator and the Medical Monitor will provide recommendations to the Sponsor based on their 


 
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perspectives. The Sponsor, by the actions of its Chief Medical Officer, W. Brooks Gentry, will then 
determine whether cohort enrollment should continue or if changes should be made.  
12.8.3. DISCLOSURE OF ANY CONFLICT OF INTEREST IN THE DSM 
Employees at the selected trial sites have no financial interests in InterveXion, and therefore the 
monitoring done at the study sites and by the clinical monitor will not be conflicted. As described above, 
the DSMB will be recruited to have no serious conflicts of interest and any unavoidable conflicts will be 
properly disclosed. 
Dr. Gentry maintains an active conflict management plan with UAMS. A component of this plan is that 
human studies related to InterveXion are to be performed by a contract research organization (CRO) in 
which safety can be assessed by the CRO. Dr. Gentry is not involved in any way with subject recruitment 
or with the day-to-day management of the trial. All safety decisions will be made with the input of the 
investigator, Medical Monitor, and DSMB. 
InterveXion also maintains records on conflicts for its investigators. 
12.8.4. FREQUENCY OF DSM 
Refer to DSMP section 12.4.2 for clinical monitoring frequency and section 12.8.1 for DSMB meeting 
frequency. 
12.8.5. CONTENT OF DSM REPORT 
Content of DSM report (to be submitted to NIDA PO and PS annually at the same time as the RPPR is 
due) 
• 
Brief description of the trial and progress 
• 
Enrollment update and baseline sociodemographic characteristics 
• 
Retention and disposition of study participants (active, completed, and terminated/withdrawn) 
• 
Regulatory Issues (amendment, deviations, IRB report, QA issues) 
• 
AEs and SAEs listings 
12.9. DSM BOARD PLAN 
12.9.1. MEMBERS AND AFFILIATION 
 
• 
Pedro Delgado, MD (Chair) – Saint Maarten Campus, American University of the Caribbean School 
of Medicine 
• 
Keith Coffee, MD (Chair) – Medical and Scientific Operations, Peachtree Bioresearch Solutions 
• 
Lauren Whiteside, MD – Dept of Emergency Medicine, University of Washington 
• 
Travis Rieder, PhD – Berman Institute of Bioethics, Johns Hopkins University 
• 
Lukas Makris, PhD – Statistical Consultant, Stathmi, Inc. 
• 
Theodore Treese, MD, MBA – Psychiatrist and Principal Investigator, Adaptive Clinical Research, 
Inc. 


 
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12.9.2. CONFLICT OF INTEREST 
Refer to DSMP section 12.8.1. 
12.9.3. FREQUENCY OF MEETINGS 
Refer to DSMP section 12.8.1. 
12.9.4. PROTECTION OF CONFIDENTIALITY 
The DSMB members will be required to sign confidentiality agreements prior to participation. 
12.9.5. MONITORING ACTIVITIES (INITIAL AND ONGOING STUDY REVIEW) 
The Board will meet to review the protocol, monitor recruitment, adverse events, data quality, and overall 
study performance.  Details of the monitoring activities will be outlined in the DSMB Charter. 
12.9.6. COMMUNICATION PLAN TO IRB, NIDA, AND FDA 
The DSMB’s recommendations following interim reviews will be reported to InterveXion as Sponsor. If 
the recommendation is other than that the study should continue as designed, and if study changes are 
made as a result, InterveXion will promptly report to the IRB, NIDA, and FDA if necessary, according to 
applicable regulations and ICH Guidance. 
 
 

SAP_001.pdf: 
 
 
 
This document is confidential. 
SAP Version: SAP 2.0 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 1 of 41 
Statistical Analysis Plan  
SAP Text Version Number: 2.0 
SAP Text Date: 17-Feb-2023 
 
Sponsor Name: InterveXion Therapeutics, LLC 
 
Protocol Number: M200C-2101 
 
Protocol Title: Meth-OD: A Phase 2a Study of IXT-m200 in Patients with Toxicity from 
Methamphetamine Overdose 
 
Protocol Version and Date: 5.0, 22 August 2022 
 
Syneos Health Project Code: 7013570  
 
Authors: Andy Torres, Senior Biostatistician 
Caleb Wagner, Senior Pharmacokineticist 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to InterveXion Therapeutics, LLC. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of InterveXion 
Therapeutics, LLC. However, this document may be disclosed to appropriate Institutional Review Board 
and Ethics Committees or duly authorized representatives of a national regulatory authority under the 
condition that they are requested to keep it confidential. In the event of an actual or suspected breach of 
this obligation, Syneos Health should be notified promptly. 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: InterveXion Therapeutics, LLC; Protocol No.: M200C-2101 
This document is confidential. 
SAP Version: SAP 2.0 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 2 of 41 
Revision History 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
0.1 
19-May-2021 
Andy Torres 
Initial Release Version  
0.2 
12-Aug-2021 
Andy Torres 
Revisions based on sponsor comments 
1.0 
27-Oct-2021 
Andy Torres 
Revisions based on sponsor comments 
2.0 
017-Feb-2023 
Andy Torres 
Revisions based on Protocol version number 4 and 5, 
and sponsor comments 


Statistical Analysis Plan for Interventional Studies
Sponsor: InterveXion Therapeutics, LLC; Protocol No.: M200C-2101
This document is confidential.
SAP Version: SAP 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
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I confirm that I have reviewed this document and agree with the content.
Approvals
Syneos Health Approval
Andy Torres, Senior Biostatistician
Name, Title
Lead Biostatistician
Signature
Date (DD-Mmm-
YYYY)
Raven Reavis, Associate Director, 
Biostatistics
Name, Title
Senior Reviewing Biostatistician 
Signature
Date (DD-Mmm-
YYYY)
Caleb Wagner, Senior Pharmacokineticist
Name, Title
Pharmacokineticist
Signature
Date (DD-Mmm-
YYYY)
InterveXion Therapeutics, LLC Approval
Misty Stevens, MBA, PhD, Chief 
Operating Officer
Name, Title
Sponsor Contact
Signature
Date (DD-Mmm-
YYYY)


Statistical Analysis Plan for Interventional Studies
Sponsor: InterveXion Therapeutics, LLC; Protocol No.: M200C-2101
This document is confidential.
SAP Version: SAP 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
Page 4 of 41
Table of Contents
Revision History..........................................................................................................................2
Approvals ..................................................................................................................................3
Glossary of Abbreviations...................................................................................................7
Purpose..............................................................................................................................9
Study Objectives ..............................................................................................................10
Study Details/Design........................................................................................................11
Endpoints .........................................................................................................................13
Analysis Sets....................................................................................................................14
General Aspects for Statistical Analysis ...........................................................................15


Statistical Analysis Plan for Interventional Studies
Sponsor: InterveXion Therapeutics, LLC; Protocol No.: M200C-2101
This document is confidential.
SAP Version: SAP 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
Filing requirements: TMF
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Demographic, Other Baseline Characteristics and Medication .........................................18
Efficacy ............................................................................................................................20
Pharmacokinetics.............................................................................................................24


Statistical Analysis Plan for Interventional Studies
Sponsor: InterveXion Therapeutics, LLC; Protocol No.: M200C-2101
This document is confidential.
SAP Version: SAP 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
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Safety...............................................................................................................................27
Interim Analyses...............................................................................................................30
Changes from Analysis Planned in Protocol.....................................................................31
Reference List ..................................................................................................................32
Programming Considerations ...........................................................................................33
Quality Control .................................................................................................................38
Appendix ..........................................................................................................................39


Statistical Analysis Plan for Interventional Studies
Sponsor: InterveXion Therapeutics, LLC; Protocol No.: M200C-2101
This document is confidential.
SAP Version: SAP 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
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Glossary of Abbreviations
Abbreviation
Description
ACES
Agitation-Calmness Evaluation Scale
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass index
CI
Confidence Interval
CRF
Case Report Form
ECG
Electrocardiogram
ED
Emergency department
DSMB
Data and Safety Monitoring Board
ICH
International Conference on Harmonization
IV
Intravenous
IXRS
Interactive Voice/Web Response System
MedDRA
Medical Dictionary for Regulatory Activities
METH
methamphetamine
N/A
Not Applicable
NA
Not Applicable
PANSS-EC
Positive and Negative Syndrome Scale 
Excited Component
PCS
Potentially clinically significant
PDNCMP
Protocol Deviation and Non-Compliance Management Plan
PT
Preferred Term
QTc
Corrected QT Interval
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SOC
System Organ Class
SOP
Standard Operating Procedure
SYNH
Syneos Health
TAU
Treatment-as-usual


Statistical Analysis Plan for Interventional Studies
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SAP Version: SAP 2.0 
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Abbreviation 
Description 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
Table, Figure and Listing 
UBACC 
UCSD Brief Assessment of Capacity to Consent 
UDS 
urine drug screen 
WHO-DD 
World Health Organization Drug Dictionary 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: InterveXion Therapeutics, LLC; Protocol No.: M200C-2101
This document is confidential.
SAP Version: SAP 2.0
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020
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Purpose
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies which will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives.
Responsibilities
Syneos Health will perform the statistical analyses and is responsible for the production and quality 
control of all tables, figures and listings. Pharmacokinetics (PK) analysis will be carried out by Syneos 
Health.
Timings of Analyses
The primary analysis of safety and efficacy and/or pharmacokinetics is planned after all subjects complete 
the final study visit or terminate early from the study. Unless otherwise specified, the analysis includes all 
data collected in the database through the time of the database lock.
An independent Data and Safety Monitoring Board (DSMB) will review descriptive summaries of 
accumulating safety, subject disposition and limited efficacy data at the conclusion of cohort 1 and 
intermittently as necessary. Further description of the DSMB analyses can be found in the DSMB charter. 
No interim analyses are planned.


Statistical Analysis Plan for Interventional Studies
Sponsor: InterveXion Therapeutics, LLC; Protocol No.: M200C-2101
This document is confidential.
SAP Version: SAP 2.0
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Study Objectives
Primary Objective
To evaluate the safety and tolerability of IXT-m200 in patients with mild to moderate methamphetamine 
(METH) toxicity.
Secondary Objectives
To determine the time course and degree of normalization of agitation and vital signs.
To determine the percentage of participants requiring rescue medications for psychiatric or 
cardiovascular manifestations of METH intoxication.
Exploratory Objective
To determine how long patients with METH toxicity stay in the emergency department (ED).


Statistical Analysis Plan for Interventional Studies
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SAP Version: SAP 2.0
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Study Details/Design
Brief Description
The hypothesis of this multisite Phase 2a study is that IXT-m200 will be well-tolerated in subjects with
acute mild to moderate METH toxicity. A randomized, open-label design will be used in which one dose of 
IXT-m200 will be compared to treatment-as-usual (TAU). Approximately 24 participants will be enrolled in
3 cohorts. A dose escalation approach will be used so that progressively higher IXT-m200 doses will be 
evaluated in each of the first two cohorts. In conjunction with safety monitoring, this design assures the
opportunity to observe early safety findings before any participants are exposed to the next higher dose. 
The randomization ratio for IXT-m200 versus TAU is defined as 4:1 for each of cohorts 1 and 2, with up to 
an additional 4 TAU participants in cohort 3 so that the number of participants receiving TAU equals the 
number receiving each dose of IXT-m200 at the end of the study.
Table 4.1: Cohort Design
Cohort
IXT-m200 dose (g)
IXT-m200:TAU
subject numbers
1
0.5
8:2
2
2
8:2
3
0
0:4
Agitation scales and vital signs will be recorded to track effect of the antibody treatment versus TAU over 
time on agitation associated with METH use. While in the ED, detailed and pertinent medical and 
psychiatric histories, and physical exam results will be obtained, along with laboratory assessments and 
electrocardiogram (ECGs). In the ED, participants will give blood samples for analysis of METH and 
IXT-m200 concentrations and will be followed for development of adverse events. Participants will be 
evaluated at 2 days and 4 weeks after discharge from the ED for adverse events and drug use history. 
Cohort escalation reviews will be performed by the Sponsor, Medical Monitor, and Data and Safety 
Monitoring Board (DSMB) after cohort 1 and the next group will not start until after completion of this 
review.
Subject Selection
Qualified participants will present seeking emergent treatment for unpleasant symptoms related to their
recent METH use. They may also have taken other abused drugs or medications such as opioids and still
qualify. They may display signs of mild to moderate METH toxicity such as dysphoria, agitation, mild
paranoia, or a feeling of being unsafe. Participants will be agreeable to general study procedures (e.g.,
placement of an intravenous [IV] line, repeated measurement of vital signs and agitation assessments, 
repeated blood draws).
People with mild to moderate symptoms have been selected for this initial study in an ED setting because
while they need rapid treatment, the need for rescue sedative medications will be lower and less urgent
than in people suffering from acute, severe intoxication or other major health issues. Recruiting lower
severity participants will allow time to determine/observe the effects of IXT-m200 doses prior to, or without 
the need to add, additional medications which could obscure the effects of the antibody. This initial study 
will establish safety and efficacy in a controlled population prior to expanding in future studies to a greater 


Statistical Analysis Plan for Interventional Studies
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This document is confidential.
SAP Version: SAP 2.0
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Page 12 of 41
risk, more vulnerable population who may need more intensive intervention for their acute METH 
intoxication.
The criteria for diagnosing METH toxicity is specified in section 5.1 of the protocol. The full list of inclusion 
and exclusion criteria is provided in sections 5.2 and 5.3 of the protocol.
Determination of Sample Size
No formal sample size estimation has been performed. A sample size of 8 IXT-m200 and approximately 8 
TAU subjects is considered adequate to assess the safety and tolerability of IXT-m200 compared to TAU. 
Data from TAU subjects from each cohort will be pooled for summaries. 
Treatment Assignment and Blinding
The treatment allocation ratio will be 8:2, IXT-m200 to TAU for cohort 1 and 2, with up to an additional 4 
TAU participants in cohort 3. Interactive voice/web response system (IXRS) will be used to assign 
subjects to treatment using a list of randomization codes generated by a randomizing statistician. No 
stratification factors will be used.
Interactive Voice/Web Response System will be the same system for all sites so that there is no site bias 
to dosing. Participants will be randomized in the order they are enrolled. 
This is an open-label study, in which the Sponsor and the Investigators are aware of treatment 
assignments on an ongoing basis to facilitate efficient dose escalation while comparing study drug to 
treatment as usual. While participants in cohorts 1 and 2 will not be actively informed of their group 
assignment, no active measures will be taken to blind participants to treatment assignment.
Administration of Study Medication
An IV line will be started and a balanced salt solution (e.g., PlasmaLyte®) will be administered at a rate of 
75 mL/hr. IXT-m200 will be given over 10 min (for 0.5 g) or 20 min (for higher doses) per dosing 
guidelines. The IXT-m200 infusion start/stop time, infusion rate, infusion volume, whether the infusion 
was completed, if it was stopped, or stopped and restarted will be recorded in the electronic Case Report 
Form (eCRF). Participants will be asked to remain semi-reclined during dose administration and to refrain 
from strenuous activity from dosing through 24 hours after. If randomized to TAU, one of the following 
three choices will be administered as determined by the treating physician: 1) up to 4 mg lorazepam by IV 
push, 2) up to 5 mg haloperidol by IM or IV injection, or 3) a combination of up to 4 mg lorazepam by IV 
push and up to 5 mg haloperidol by IM or IV injection. IV fluids will be given as tolerated for up to 4 hours 
after dosing with either IXT-m200 or TAU, at which point the IV will be capped and preserved during the 
remainder of the ED stay. When the ED staff determine it is appropriate, a regular diet may be started. If 
there is an adverse reaction to study drug, the participant will be treated as outlined in protocol 
Section 6.5.
Study Procedures and Flowchart
The study procedures to be performed as summarized in the Schedule of Assessments, is provided in the 
protocol Section 1.3, Schedule of Activities. 


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Endpoints
Primary Endpoint
Safety and tolerability of IXT-m200 as measured by physical examinations and vital sign, adverse 
event (AE), ECG, and clinical laboratory testing
Secondary Endpoints
Agitation/sedation scores over time as measured by Agitation-Calmness Evaluation Scale 
(ACES)
Vital signs including blood pressure, heart rate and temperature over time
Need for rescue medications to treat: 
o
agitation, dysphoria, or psychosis (central nervous system [CNS] toxicity) 
o
hypertension, tachycardia, or other cardiovascular instability (CV toxicity)
Exploratory Endpoints
ED length of stay as measured by disposition order time minus triage time, and as measured by 
disposition order time minus start of treatment time, with log transformation


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Analysis Sets
Enrolled Population
The enrolled population will include all subjects who signed an informed consent.
Safety Population
The Safety Population will include all randomized subjects who receive any dose of study drug. The 
treatment group assignment in this population will be defined by the treatment actually received. This 
population will be used for the analysis of safety.
Intent-to-Treat (ITT) Population
The Intent-to-Treat (ITT) population will include all randomized subjects. The treatment group assignment 
in this population will be defined by the randomized treatment. This population will be used for the 
analysis of efficacy.
Full Analysis Set (FAS) Population
The Full Analysis Set (FAS) population will include those in the ITT population who receive any dose of 
study drug and were positive for methamphetamine by urine drug screen (UDS) or blood testing during 
the ED stay. UDS results from data vendor Q2 Solutions or local lab will be used to derive FAS 
Amphetamines
.
or the 
result for both lab tests are missing but have a quantifiable Day 1 pre-dose blood test for 
Methamphetamine will also be included in the FAS population. The treatment group assignment in this 
population will be defined by the randomized treatment. This population will be used for the analysis of 
efficacy.
Per-Protocol Population
The Per-Protocol (PP) population will include all of FAS who completed the Day 1 assessments, stay 
through discharge from the ED, and do not have any major protocol deviation impacting the efficacy
assessments. The treatment group assignment in this population will be defined by the randomized 
treatment. This population will be used for the analysis of efficacy. 
Pharmacokinetic (PK) Population
The PK Population will include all subjects for whom a serum concentration of IXT-m200 is available 
post-dose. Serum (IXT-m200) and plasma (METH) concentrations are listed for all subjects in the PK 
population. 
Protocol Deviations
Protocol deviation management is described in the Protocol Deviation and Non-compliance Management
Plan (PDNCMP). Deviations will be classified by whether or not they meet the definition of major protocol 
deviations. Major 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 subject's 
rights, safety, or well-being. Deviations will be categorized by type and will be reviewed on an ongoing 
basis. A protocol deviation listing will be provided. Deviations will be classified as either major (or critical) 
or minor if the non-compliance adversely affects the study or process. 


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General Aspects for Statistical Analysis
General Methods
All analyses and summaries will be produced using Statistical Analysis System (SAS®) version 9.4 or 
higher. All SAS programs used to generate analytical results will be developed and validated according to 
Syneos Health (SYNH) programming standards and SAS validation procedures. Summaries will be 
presented by treatment group and overall unless otherwise specified. Each active treatment cohort will be 
labeled in the outputs by its cohort number and dose level, e.g., Cohort 1 (IXT-m200 0.5 g). Additionally, 
overall IXT-m200 and overall TAU (treatment-as-usual) will be presented. 
Unless otherwise noted, continuous variables will be summarized using the number of non-missing 
observations (n), arithmetic mean (mean), standard deviation (SD), median, minimum, and maximum 
values as summary statistics. The minimum and maximum will be displayed to the precision with which 
the data were collected. The mean, median and quartiles will be displayed to one additional decimal place 
and the SD will be displayed to two additional decimal places, where applicable.
Descriptive statistics for categorical/qualitative data will include frequency counts and percentages. The 
total number of subjects with a non-missing value for the given variable will be used as the denominator 
for percent calculations, unless stated otherwise. All percentages will be presented with one decimal, 
unless otherwise specified. Percentages equal to 100 will be presented as 100, and percentages will not 
be presented for zero frequencies.
All relevant subject data will be included in listings. All subjects entered into the database will be included 
in subject data listings.
Key Definitions
Baseline
Unless otherwise specified, baseline is defined as the last non-missing observation prior to the first dose of 
IXT-m200 or TAU. 
Study Hour
The hour of first dose of study drug administration is defined as study Hour 0. Subsequent hours are 
numbered consecutively (Hour 1, Hour 2, etc.). Prior to the hour of first dose of study drug administration, 
study hours are numbered sequentially with negative values (i.e., Hour -1, Hour -2, etc.).
Study Day
The day of first dose of study drug administration is defined as study Day 1. Subsequent days are numbered 
consecutively (Day 2, Day 3, etc.). Prior to the day of first dose of study drug administration, study days are 
numbered sequentially with negative values (i.e., Day -1, Day -2, etc.). There is no Day 0.
Missing Data
In general, missing data will not be imputed. All analyses will be based on observed cases. Sections 7.3.1 
and 7.3.2 note the situations where missing data will be imputed.
Handling of Missing Dates/Months/Years for Prior/Concomitant Therapies
If a medication cannot be classified into concomitant or prior status due to incomplete start and/or stop 
date, the rules below will be applied for the classification.


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For start date,
If the year and month are observed but the day is missing, the first day of the month will be used
unless month and year are the same as month and year of first dose date then impute using the 
day of first dose date.
If the year is observed but the month and day are missing, the first day of the year, 01 Jan, will be 
used unless year is the same as first dose date then the first dose date will be used.
If the start date is completely missing, the medication will be considered concomitant unless the 
stop date is before study drug administration.
If the start and stop dates are both completely missing, a therapy will be considered concomitant.
For end date,
If the year and month are observed but the day is missing, the last day of the month will be used
unless month and year are the same as month and year of last dose date, then impute the last 
dose date.
If the year is observed but the month and day are missing, the last day of the year, 31 Dec, will be 
used unless year is the same as last dose date then the last dose date will be used.
If the end date is completely missing, if medication is still ongoing, then missing end date is not 
supposed to be imputed. If the medication is not ongoing and the start date is prior to first dose 
date, the end date will be imputed using 1st dose date. 
If both start and end dates are completely missing, medication will be considered concomitant.
The original partial or missing date will be shown in listings for all prior and concomitant medications.
Adverse Events Dates
For AEs with incomplete dates, the following rules will be used to impute start and/or stop dates for the sole 
purpose of determining if an AE is treatment-emergent. Imputed dates will not appear in the data listings.
For partial start dates:
If the month and year of AE onset are provided but day is missing
o
If the month and year match the month and the year of the date of first dosing 
administration, then the date of first dosing administration will be used and the AE will be 
considered treatment-emergent. 
o
Otherwise, the first day of the month will be used. 
If the year of AE onset is provided, but the month and day are missing
o
If the year matches the year of the first dosing administration, then the date of first dosing 
administration will be used. 
o
Otherwise, 01 Jan will be used.
o
If the stop date is not missing and the imputed onset date is after the stop date, then the 
stop date will be used.
o
If the onset date is completely missing and the stop date is on or after the date of first dose, 
the event will be considered a treatment-emergent adverse event (TEAE).
o
If both onset date and stop date are missing, the event will be considered a TEAE. Partial 
stop dates will not be imputed in this instance.


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Visit Windows
There will be no derivation for visit windows in terms of summary assessments. Nominal visits will be used 
for by-visit tables.
Pooling of Centers
Data from all sites will be summarized together for analyses.
Subgroups
No subgroup analyses are planned for the study.


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Demographic, Other Baseline Characteristics and Medication
Subject Disposition and Withdrawals
A summary table will be produced detailing the number of subjects screened and screen failed, the 
number and percentage of all subjects in each analysis population, subjects who completed or who 
prematurely discontinued the study. In addition, reasons leading to discontinuation from study will be 
summarized for each treatment group and overall. A listing of subject disposition will also be provided.
Screened subjects are defined as all subjects with a non-missing informed consent date. 
Demographic and Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics will be presented by each treatment 
group and overall for the Safety Population. The characteristics being summarized which include: age at 
screening (in years), gender, race, ethnicity, height (cm), weight (kg), body mass index (BMI) (kg/m2), and 
for females, childbearing potential. Baseline characteristics include Agitation-Calmness Evaluation Scale 
(ACES), Positive and Negative Syndrome Scale 
Excited Component (PANSS-EC), systolic blood
pressure (mmHg), diastolic blood pressure (mmHg), heart rate (beats/min), and temperature (C).
Height (in cm) = height (in inches) * 2.54
Weight (in kg) = weight (in lbs) * 0.4536
BMI (kg/m2) = Weight(kg)/[Height(m)2]
Demographics and Baseline characteristics will be listed by subject for the Safety Population.
Medical and Psychiatric History
Medical History will be summarized for the Safety Population using Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class (SOC) and preferred term (PT). The reported medical history 
terms will be coded using MedDRA Version 23.0 or higher. The number of subjects with any medical or 
surgical history will also be summarized. A subject experiencing a medical history within more than one 
SOC and PT will be counted only once within that SOC and PT, respectively.
Medical history and psychiatric history findings will be listed by subject using the Safety Population.
Medication
Medications will be classified as prior and concomitant. All prior and concomitant medications will be 
classified using the Anatomical Therapeutic Chemical (ATC) classification codes and preferred drug names 
from the World Health Organization Drug Dictionary (WHO-DD), March 2021.
Summaries of prior, concomitant, and rescue medications will be presented separately in tabular form 
using the ATC 4 level term as an upper classification level and the preferred drug name as a lower 
classification level. All medications will be summarized by descending frequency of ATC level 4 and
preferred drug name within a given ATC level 4 term. The summary will consist of the frequency and 
percent of safety subjects who used the medication at least once. 
For each subject, the medication will be counted only once within a level 4 ATC and only once within a 
given preferred drug name level. A subject may appear more than once if he/she has more than one 


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concomitant medication coded under different ATC categories; however, the subject will be counted only 
once in the overall category. 
A by-subject listing with coded terms will also be provided using the Safety Population.
Prior Medication
Any medication that started prior and did not continue past the first dose of study treatment will be 
classified as prior.
Concomitant Medication
Concomitant medications are defined as all medications taken during the study treatment period, 
including those which started before study treatment, but were reported ongoing at the first 
administration.
Rescue Medication
Rescue medications will be identified in the Prior and Concomitant medications CRF and are limited to 
those reported prior to discharge from the ED on Day 1. Central nervous system rescue medications 
include lorazepam (Ativan) and haloperidol (Haldol). Cardiovascular rescue medications include labetalol,
hydralazine, or other similar approaches. There is no standardized list of rescue medications as hospitals 
will use a wide variety. A review of the list of medications that are marked as rescue medication on the 
CRF page Prior and Concomitant Medications will be conducted in order to classify as either 
cardiovascular or psychiatric manifestations of METH intoxication. It is advised that this review will be 
held at the end of each cohort prior to the cohort escalation meeting. 
Extent of Exposure
The following summaries will be provided for the IXT-m200 treatment groups for the Safety Population:
Number and percentage of subjects who received the complete planned IXT-m200 infusion
Total volume administered (mL)
Number and percentage of subjects who received an incomplete infusion and reasons for 
incomplete administered, 
Number and percentage of subjects with a dose interruption and re-start and reasons for 
interruption
The following summaries will be provided for the TAU treatment group:
Number and percentage of subjects receiving each dose level of TAU
Total Lorazepam administered (mg)
Total Haloperidol administered (mg)
If combination of Lorazepam and Haloperidol were administered, then total dose administered of 
Lorazepam (mg) and Haloperidol (mg)
Route of Administration, Haloperidol (mg)
IXT-m200 and TAU infusion details will be listed by subject using the Safety Population.


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Efficacy
The comparison of efficacy endpoints between the treatment groups will be performed using descriptive 
summaries and descriptive confidence intervals (CI) and statistical tests. All efficacy parameters will be 
summarized and presented in tables based on the Intent-to-Treat (ITT) population, Full Analysis Set 
(FAS) population, and the Per-Protocol (PP) population.
Agitation/Sedation Scores Over Time as Measured by Agitation-Calmness Evaluation 
Scale (ACES)
ACES is a single-item scale where 1 = marked agitation; 2 = moderate agitation; 3 = mild agitation; 4 = 
normal; 5 = mild calmness; 6 = moderate calmness; 7 = marked calmness; 8 = deep sleep; and 9 = 
unable to be aroused.
Summary tables with descriptive statistics for actual values and changes from baseline will be provided
for the ACES score for each scheduled timepoint by treatment group. Descriptive pairwise t-tests will be
performed for the comparison of the changes from baseline of each IXT-m200 dose versus TAU using a 
two-sided alpha level of 5%. 
The hypotheses for the t-test comparing mean change from baseline of each IXT-m200 dose group 
versus TAU is expressed as:
H0: µ1 - µ2 = 0 ("the difference in mean change from baseline is equal to 0")
H1: µ1 -
he difference in mean change from baseline is not 0")
where µ1 and µ2 are the population mean change from baseline for IXT-m200 and TAU,
respectively. 
The following general form of the SAS PROC TTEST procedure will be used:
PROC TTEST DATA=dataset-name ALPHA=0.05;
  VAR CHG;
   CLASS TRTP;
RUN;
where CHG is the mean change from baseline of the ACES score, and TRTP is the planned 
treatment.  
Shift tables will be generated for change in ACES score from baseline to all scheduled post-baseline 
visits. The proportions of subjects who shifted ACES score categories will be summarized by treatment 
group, using the following categories: Agitated (ACES 1-2), Normal (3-5), or Sedated (6-9). 
In addition, analysis of ACES scores will be performed using a proportional odds model or an ordinal 
logistic regression for repeated measures with planned treatment , baseline ACES score category, 
timepoint (Day 1 
0.5 hour, Day 1 
1 hour, Day 1 
2 hours), and planned treatment by timepoint 
interaction as independent variables. ACES category Sedated (6-9) category will be used as the 
reference response category. The odds ratio for this model is consistent with the ratio of one-unit increase 
in the ACES score category odds comparing the treatment groups. For instance, IXT-m200 may have a 
1.2x higher odds of increasing from normal to agitated compared to TAU.


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Interpretation of odds ratio value: 
OR=1 Exposure (treatment group) does not affect odds of outcome (ACES score) 
OR>1 Exposure associated with higher odds of an increase in ACES score category in group 1 
vs group 2. 
OR<1 Exposure associated with lower odds of an increase (or higher odds of a decrease) in 
ACES score category in group 1 vs group 2. 
 
Treatment effects will be expressed as the estimated odds ratio (OR) of each active treatment over TAU. 
Estimated ORs, together with the associated two-sided 95% confidence interval and p-value will be 
calculated. Results will be plotted using a Forest plot. The following general form of the SAS PROC 
GENMOD procedure will be used: 
PROC GENMOD DATA=ADQS;  
  CLASS TRTP BASE VISIT SUBJID /PARAM=GLM;  
  MODEL ACES = TRTP VISIT TRTP*VISIT  BASE/ DIST=MULTINOMIAL LINK=CLOGIT; 
  REPEATED SUBJECT = SUBJID / TYPE=IND; 
RUN; 
 
where ACES is the categorized ACES score at the specified timepoint, BASE is the baseline 
categorized ACES score, TRTP is the planned treatment, VISIT is the scheduled timepoint.   
 
The below are the estimate statements for Day 1  0.5 Hour as an example and similar logic will be 
applied for Day 1 -1 hour and Day 1  2 hour visits: 
 
   estimate 'Odds (agitated) of Cohort 1 Day 1 - 0.5 Hour' intercept 1 0 TRTP 1 0 0 AVISITN 1 0 0 
TRTP*VISIT 1 0 0 0 0 0 0 0 0 BASECAT1 0 1/ exp;  
   estimate 'Odds (normal) of Cohort 1 Day 1 - 0.5 Hour' intercept 0 1 TRTP 1 0 0 AVISITN 1 0 0 
TRTP*VISIT 1 0 0 0 0 0 0 0 0 BASECAT1 0 1/ exp;  
   estimate 'Odds (agitated)of Cohort 2 Day 1 - 0.5 Hour' intercept 1 0 TRTP 0 1 0 AVISITN 1 0 0 
TRTP*VISIT 0 0 0 1 0 0 0 0 0 BASECAT1 0 1/ exp;  
   estimate 'Odds (normal) of Cohort 2 Day 1 - 0.5 Hour' intercept 0 1 TRTP 0 1 0 AVISITN 1 0 0 
TRTP*VISIT 0 0 0 1 0 0 0 0 0 BASECAT1 0 1/ exp;  
   estimate 'Odds (agitated) of Cohort 3 Day 1 - 0.5 Hour' intercept 1 0 TRTP 0 0 1 AVISITN 1 0 0 
TRTP*VISIT 0 0 0 0 0 0 1 0 0 BASECAT1 0 1/  exp;  
   estimate 'Odds (normal) of Cohort 3 Day 1 - 0.5 Hour' intercept 0 1 TRTP 0 0 1 AVISITN 1 0 0 
TRTP*VISIT 0 0 0 0 0 0 1 0 0 BASECAT1 0 1/  exp;  
   estimate 'Odds (agitated) of Pooled IXT Day 1 - 0.5 Hour' intercept 1 0 TRTP 5 .5 0 AVISITN 1 0 0 
TRTP*VISIT .5 0 0 .5 0 0 0 0 0 BASECAT1 0 1/ exp;  
   estimate 'Odds (normal) of Pooled IXT Day 1 - 0.5 Hour' intercept 0 1 TRTP .5 .5 0 AVISITN 1 0 0 
TRTP*VISIT .5 0 0 .5 0 0 0 0 0 BASECAT1 0 1/ exp;  
 
   lsmestimate TRTP*VISIT 'Odds Ratio C1 Versus TAU' 1 0 0 0 0 0 -1 0 0 / exp cl; 
   lsmestimate TRTP*VISIT 'Odds Ratio C2 Versus TAU' 0 0 0 1 0 0 -1 0 0 / exp cl; 
   lsmestimate TRTP*VISIT 'Odds Ratio Pooled IXT Versus TAU' .5 0 0 .5 0 0 -1 0 0 / exp cl; 
 
In addition, figures will be provided including by-subject plots of ACES scores over time, the mean 
observed ACES score and standard deviation for each treatment group over time, and mean change from 
baseline and standard deviation for each treatment group over time.  
 


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Vital Signs including Blood Pressure and Heart Rate
The time course of actual values of vital sign parameters and of changes from baseline will be presented 
by treatment group in a figure using mean values and standard deviation. A shift table of post-baseline 
vital sign parameter values compared to baseline values will be provided by treatment group presenting 
the number and percentage of subjects below normal range / within normal range / above normal range.
The ranges will be derived programmatically using the values specified in Table 9.2.1.
Table 9.2.1:
Normal Range for Vital Signs Parameters
Vital Signs
Parameter
Below 
Normal Range
Within 
Normal Range
Above 
Normal Range
Heart Rate (beats/min)   <40
40-100
>100
Systolic Blood 
Pressure (mmHg)
<90
90-140
>140
Diastolic Blood 
Pressure (mmHg)
<60
60-90
>90
Temperature (F)
NA
<100.4
>=100.4
The time to normalization (i.e., returning to normal range) of vital sign parameters is defined as the time 
from start of dosing of either IXT-m200 or TAU to first time the vital sign parameter is in normal range and 
remains in normal range for the remaining time-points. This time will be presented by Kaplan-Meier 
estimates and figure by treatment group and will be pairwise compared between each IXT-m200 dose 
versus TAU by the log-rank test. 
The following general form of the SAS PROC LIFETEST procedure will be used:
PROC LIFETEST DATA=dataset-name NOTABLE;
  TIME AVAL*CENSOR(1);
   STRATA TRTP / test = LOGRANK adjust = sidak diff=control('TAU');
RUN;
where AVAL is the time (hours) to normalization of vital sign parameters; CENSOR is the 
censoring variable (1=censoring, 0=event), TRTP is the planned treatment which the subject was 
randomized to, and diff=control('TAU') requests comparisons of the control curve, TAU, with all 
other curves.
A plot of the Kaplan-Meier estimate of the survival distribution function over time will be presented. In 
addition, figures will be provided including by-subject plots over time, the mean observed value and 95% 
confidence interval for each treatment group over time, and mean change from baseline and 95% 
confidence interval for each treatment group over time. 
Need for Rescue Medications
Number and percentage of subjects with any rescue medication (from start of study treatment until 
discharge) will be provided by timepoint and by treatment group, overall IXT-m200 and overall TAU. 
Additionally, separate tables with the number and percentage of subjects with rescue medications for 
psychiatric manifestations and for cardiovascular manifestations, described in section 8.4.3, will be 


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provided by treatment group, overall IXT-m200 and overall TAU. The proportion of subjects with any 
rescue medication will be compared between the IXT-m200 treatment groups (Cohorts 1-2 and overall 
IXT-m200) and overall TAU using a Fisher
exact test. 
Emergency Department (ED) Length of Stay
ED length of stay as measured by discharge time minus triage time, and as measured by discharge time 
minus start of treatment time, observed values and with log transformation (natural logarithm (ln), log to 
the base e), will be summarized. A two-sample t-test will be used to test if the mean difference between 
each IXT-m200 dose versus TAU is significantly different from zero at a 5% significance level. In the two-
sample t-test, we assume the differences in the log time between the two groups to be normally 
distributed. These assumptions will be checked using quantile-quantile (Q-Q) plots and if not satisfied, 
then a non-parametric Wilcoxon signed-rank test will be performed.
The following general form of the SAS PROC TTEST procedure will be used to perform a two-sample t-
test:
PROC TTEST DATA=dataset-name;
   CLASS TRTP;
   VAR AVAL;
RUN;
where AVAL is the log transformation of ED length of stay, and TRTP is the planned treatment.  
The following general form of the SAS PROC NPAR1WAY will be used to perform a Wilcoxon rank sum 
test, if necessary:
PROC NPAR1WAY DATA=dataset-name WILCOXON;
   CLASS TRTP;
   VAR AVAL;
RUN;


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Pharmacokinetics
The PK Population will be used for the analyses specified in this section. Concentration for METH and 
amphetamine, if available, will be summarized as described below but no further PK analysis will be
conducted.
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.,
WinNonlin® (Version 8.0 or higher, Certara Corporation). All other analyses will be performed using SAS®
(Version 9.4 or higher, SAS Institute Inc.)
PK Sampling Schedule
Blood samples will be taken for analysis of IXT-m200 in serum on Day 1 (pre-dose, 4 hours after 
dosing, and at discharge) and on Days 3 and 28.
Blood samples will be taken for analysis of METH, and amphetamine in plasma on Day 1 
(pre-dose, 4 hours after dosing, and at discharge).
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 (doses will be given over varying 
times). The actual post-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.
PK Endpoint
Available serum IXT-m200 data will be used to calculate pharmacokinetic parameters 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 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 plasma concentration versus time 
profile in the terminal elimination phase.  Due to the limited number of PK sample 
time points, manual selection using the Day 28 follow-up visit and 1 other
concentration data point will be used to calculate Kel. 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 


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reported. If the Kel cannot be measured (e.g.: fewer than 2 non-zero concentrations 
in the terminal elimination phase or missing visit Day 28 follow-up sample), then 
elimination related PK parameters (Kel, Kel Lower, Kel Upper, AUC0-inf, Rsq adjusted,
Residual area, t½, CL and V) will not be reported for PK profiles.
CL: 
Clearance, calculated as Dose/AUC0-inf. 
V: 
Volume of distribution, calculated as Dose/(Kel x AUC0-inf). 
Presentation of Concentration Data
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.
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, METH, and amphetamine concentration data will be listed by subject, 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 and METH. Furthermore, an overlay plot (Spaghetti plot) of 
subjects by treatment group will be presented graphically on both linear and semi-logarithmic scales for 
change from baseline concentration of METH.
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 and METH concentrations will be summarized by treatment group, analyte, and time point, 
using descriptive statistics including n, number and percentage of subjects with BLQ, arithmetic mean, 
geometric mean, SD, arithmetic and geometric coefficient of variation (CV) %, minimum, median and 
maximum. The following precision will be applied to the various descriptive statistics:


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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
PK Parameters Derivation
For the derivation of PK parameters, the following rules will apply:
All concentration 
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
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):
PK parameters related to time such as Tmax 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.
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, arithmetic mean, SD, coefficient of variance (CV) %, 
minimum, median and maximum
AUCs, Cmax, CL, and V 
n, arithmetic mean, SD, CV%, minimum, median, 
maximum, geometric mean and geometric CV% 
t1/2, kel
n, arithmetic mean, SD, CV%, minimum, median, 
maximum
tmax (actual time)
n, minimum, median, and maximum
Note: CV% = SD/mean in %. n = non-missing No. of observations.
Interim PK Analysis
No interim PK analyses are planned for this study. 


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Safety
The population used for safety analyses will be the Safety Population. Safety will be assessed based on 
adverse event (AE), clinical laboratory data (hematology and clinical chemistry), physical examinations, 
vital signs, and extent of exposure. Table summaries will be presented by treatment group (each 
IXT-m200 treatment group, overall IXT-m200, and TAU).
Adverse Events
All adverse events will be classified by System Organ Class (SOC) and Preferred Term (PT) using 
MedDRA version 23.0.
A TEAE is defined as any event not present before exposure to study treatment or any event already 
present that worsens in either intensity or frequency after exposure to study treatment. In addition, events 
with missing onset dates will be included as treatment-emergent.
An overall summary of TEAEs will be tabulated across all treatment groups, including the number and 
percent of subjects reporting:
TEAEs
TEAEs by Severity Grade
Study Treatment-related TEAEs
Serious TEAEs
Study Treatment-related Serious TEAEs
TEAEs of Special Interest
TEAEs leading to Discontinuation of Study Treatment
TEAEs leading to Death  
A summary table of TEAEs (number and percentage of subjects who experienced an AE) grouped by 
primary SOC and PT will be presented across all treatment groups for the following categories of events:
All TEAEs
All TEAEs by maximum severity grade
All TEAEs by maximum relationship to study treatment
All Study Treatment-related TEAEs
All TEAEs leading to discontinuation of study treatment
All TEAEs leading to death
All Serious TEAEs
All TEAEs of Special Interest 
AEs are assessed with respect to relationship status by the investigator, as unrelated, unlikely related, 
possibly related, probably related, and definitely related. An AE would be categorized in statistical 
-
probably 
related, or definitely related.  
AEs of Special Interest include the following events:
Hypertension/tachycardia
Euphoria
Agitation
Insomnia


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Anxiety
Seizures
Mania/aggression
A subject with more than one occurrence of the same AE in a particular SOC and PT will be counted only 
once in the total of subjects experiencing AEs in that particular SOC and PT, respectively. If a subject 
experiences the same AE at more than one severity, or with more than one relationship category, the 
most severe rating or the stronger causal relationship will be reported.
Any missing relationship of an A
-
. Any missing severity grade of 
an AE will be included in the Grade 3 - Severe category.
The tables will be sorted by descending frequency of SOC and then, within a SOC, by descending 
frequency of PT based on the subject count for the overall IXT-m200 treatment group.
All AEs will be listed by subject and chronologically by date and time of AE onset. This listing will include 
all data collected in the eCRF and the coded variables. Additional listings of SAEs, treatment-related 
TEAEs, AEs leading to discontinuation of study treatment, and deaths will be provided.
Laboratory Evaluations
Clinical laboratory data (continuous parameters) will be summarized using descriptive statistics for each 
scheduled assessment time point by treatment group. Categorical laboratory data and urinary drug screen 
results will be presented by number and percentage of subjects in each category and scheduled time point 
by treatment group. Additionally, for laboratory data, frequency tables with number and percentage of 
subjects of scheduled time point will be provided using the categories above/within/below normal range.
Laboratory results will be displayed using standard units for all summaries and listings. Laboratory results 
collected in conventional units will be converted to International System of Units (SI) for all summaries 
and listings.
Potentially clinically significant values will be identified for Hematology and Chemistry parameters using the 
reference range values specified in the Q2 Solutions Range Chart V01, 27 Apr 2021. The reference ranges 
are included in Appendix 18.1.
All laboratory values (including values, reference ranges, and possible flags (low, high)) will be presented 
in the subject data listings.
Vital Signs 
Vital signs will be summarized using descriptive statistics: actual values and changes from baseline will be 
presented for each scheduled assessment time point by treatment group, overall IXT-m200 and overall 
TAU.
Vital sign measurements that will be summarized include blood pressure (systolic and diastolic, mmHg), 
heart rate (beats per minute [bpm]), re
Fahrenheit), pulse 
oximetry (%), weight (kg), and BMI (kg/m2). Summary statistics for vital sign measurements will be 
presented for each scheduled time point and for the change from baseline to each time point.
Vital signs data will be listed chronologically by subject and time points for each vital sign parameter. 


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Potentially clinically significant values will be identified for vital sign parameters as outlined below.
Table 12.3.1:
Potentially Clinically Significant Values for Vital Signs
Vital Sign
Parameter
Units
Criteria for PCS Values (Observed 
values)
High 
Low 
Heart rate
Beats/min
>120 
<40 
Systolic Blood 
Pressure 
mmHg 
>180
<90 
Diastolic Blood 
pressure 
mmHg 
>110
<50 
Oxygen Saturation
%
NA
<92
12-Lead ECG
An electrocardiogram (ECG; 12-lead) will be recorded after IXT-m200 or TAU dosing is complete and the 
participant is cooperative. Standard ECG parameters including heart rate, QRS (ms), PR (ms), QT (ms),
and QTc intervals (ms) 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).
An ECG will be performed 
; table in 
Section 1.3 of the protocol.
Potentially clinically significant values will be identified for ECG parameters as outlined below.
Table 12.4.1:
Potentially Clinically Significant Values for QT (ms), QTc intervals (ms)
ECG Parameter
Units
Criteria for PCS Values (Observed 
values)
High 
Low 
QT, QTc 
intervals
ms
>450 but <=480
>480 but <=500
>500
NA
12-Lead ECG results will be provided in a data listing.
Physical Examination
Physical examination results will be listed by subject and summarized by number and percentage of 
subjects in each body system category and scheduled time point. 


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Interim Analyses
No interim analyses are planned. 


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Changes from Analysis Planned in Protocol
Several instances in the protocol describe summaries by treatment group, overall IXT-m200 and total. 
Unless otherwise stated, all analyses will be summarized by treatment group, overall IXT-m200 and 
overall TAU.
Section 9.4.3 of the protocol indicates that secondary endpoint Agitation/sedation scores over time as 
measured by ACES will be analyzed by time to normalization of agitation using ACES. Instead, this 
secondary endpoint will be analyzed using methods specified in Section 9.1 of this SAP.
Section 3 of the protocol includes Tertiary/Exploratory endpoint: Emergency Department (ED) length of 
stay as measured by disposition order time minus triage time, and as measured by disposition order time 
minus start of treatment time, with log transformation. Upon evaluation of results for disposition order time 
minus triage time, it was determined that discharge time minus triage time is the preferred estimate for ED 
length of stay. Discharge time minus start of treatment time will also be applied.


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Reference List
Protocol No. M200C-2101. Meth-OD: A Phase 2a Study of IXT-m200 in Patients with Toxicity from
Methamphetamine Overdose. Version Number: 5. 22 August 2022.


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Programming Considerations
All TFLs and statistical analyses will be generated using SAS for Windows, Release 9.4 (SAS Institute Inc., 
Cary, NC, USA). Computer-generated TFL output will adhere to the following specifications.  
General Considerations
One SAS program can create several outputs
Each output will be stored in a separate file
Output files will be delivered in Word format or portable document format (pdf)
Numbering of TFLs will follow ICH E3 guidance 
Table, Figure, and Listing Format
General
All TFLs will be produced in landscape format on A4/American letter size, unless otherwise 
specified.
All TFLs will be produced using the Courier New font, size 8 which is the smallest acceptable point 
size for the Regulatory Authorities
The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides.
Headers and footers for figures will be in Courier New font, size 8 which is the smallest acceptable 
point size for the Regulatory Authorities
Legends will be used for all figures with more than one variable, group, or item displayed
TFLs will be in black and white (no color), unless otherwise specified
Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used
Only standard keyboard characters will be used in the TFLs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
2, Cmax) will be 
employed on a case-by-case basis
Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate
Headers
All output should have the following header at the top left of each page:
InterveXion Therapeutics, LLC
Protocol: M200C-2101


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All output will have Page n of N at the top or bottom right corner of each page. TFLs are internally 
paginated in relation to the total length (i.e., the page number will appear sequentially as page n of 
N, where N is the total number of pages in the table)
The date the output was generated will appear along with the program name as a footer on each 
page
Display Titles
Each TFL is identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 numbering is 
strongly recommended, but sponsor preferences are obtained before final determination. A decimal 
system (x.y and x.y.z) are used to identify TFLs with related contents. The title is centered. The 
analysis set are identified on the line immediately following the title. The title and table designation 
are single spaced. A solid line spanning the margins will separate the display titles from the body.
Table x.y.z
First Line of Title
Second Line of Title if Needed
(ITT Analysis Set)
Column Headers
Column headings are displayed immediately below the solid line described above in initial upper-
case characters.
In the case of efficacy tables, the variable (or characteristic) column is on the far left followed by the 
treatment group columns and total column (if applicable). P-values may be presented under the 
total column or in separate p-value column (if applicable). Within-treatment comparisons may have 
p-values presented in a row beneath the summary statistics for that treatment
For numeric variables, include unit in column or row heading when appropriate
Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or 
in the row headings,
representing the number of subjects in the analysis set
The order of treatments in the tables and listings will be Cohort 1 (IXT-m200 0.5 g), Cohort 2 
(IXT-m200 2 g), Overall IXT-m200, and Overall TAU. 
Body of the Data Display
15.2.5.1.
General Conventions
Data in columns of a table or listing are formatted as follows:
Alphanumeric values will be left-justified;
Whole numbers (e.g., counts) will be right-justified; and
Numbers containing fractional portions will be decimal aligned.


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15.2.5.2. 
Table Conventions 
 Units will be included where available 
 For categorical parameters, all categories will be presented in the table, even if n=0 for all 
treatment groups in a given category. For example, the frequency distribution for symptom severity 
would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be presented and so counts 
of 0 will be presented as 0 and not as 0 (0%). 
 An Unknown or Missing category will be added to each parameter for which information is not 
available for 1 or more subjects 
 Unless otherwise specified, the estimated mean and median for a set of values will be printed out 
to 1 more significant digit than the original values, and standard deviations (SD) will be printed out 
to 2 more significant digits than the original values. The minimum and maximum will report the 
same significant digits as the original values. For example, systolic blood pressure will be 
presented as follows: 
N 
 XX 
Mean 
XXX.X 
SD 
   X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
 
 P-values will be output in the format: 0.xxx , where xxx is the value rounded to 3 decimal places. 
Every p-value less than 0.001 will be presented as <0.001. If the p-value is less than 0.0001, then 
present as <0.0001. If the p-value is returned as >0.999, then present as >0.999 
 Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8%), 13 (5.4%)). Unless otherwise noted, for all percentages, the 
number of subjects in the analysis set for the treatment group who have an observation will be the 
denominator. Percentages after zero counts should not be displayed and percentages equating to 
100% are presented as 100%, without decimal places.  
 Tabular display of data for medical history, prior/concomitant medications, and all tabular displays 
of adverse event data will be presented by the body system, treatment class, or SOC with the 
highest occurrence in the overall IXT-m200 treatment group in decreasing order, assuming all 
terms are coded. Within the body system, drug class and SOC, medical history (by preferred term), 
drugs (by ATC1 code), and adverse events (by preferred term) will be displayed in decreasing 


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order. If incidence for more than 1 term is identical, they will then be sorted alphabetically. Missing 
descriptive statistics or p-values which cannot be estimated will be reported as -
The percentage of subjects will normally be calculated as a proportion of the number of subjects 
assessed in the relevant treatment group (or overall) for the analysis set presented. However, 
careful consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed. Details will be described in 
footnotes or programming notes, as necessary
For categorical summaries (number and percentage of subjects) where a subject can be included 
in more than one category, a footnote or programming note will be added describing whether the 
subject is included in the summary statistics for all relevant categories or just 1 category as well as
the selection criteria
Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by (cont) at the top of each subsequent page. The 
overall summary statistics for the subheading should only be output on the first relevant page
15.2.5.3.
Listing Conventions
Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time
Missing data will be represented on subject listings as either a hyphen ( - ) with a corresponding 
footnote ( - = unknown or not evaluated ), or as N/A , with the footnote N/A = not applicable , 
whichever is appropriate
Dates will be printed in SAS DATE9.format ( DD_MMM_YYYY : 01JUL2000). Missing portions of 
dates will be represented on subject listings as dashes (--JUL2000). Dates that are missing 
because they are not applicable for the subject will be output as N/A , unless otherwise specified
All observed time values will be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study
Units will be included where available
15.2.5.4.
Figure Conventions
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis
Footnotes
A solid line spanning the margins will separate the body of the data display from the footnotes. 
All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display
Footnotes will always begin with Note: if an informational footnote, or 1, 2, 3, etc. if a reference 
footnote. Each new footnote will start on a new line, where possible
Subject specific footnotes are avoided, where possible


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Footnotes will be used sparingly and add value to the TFL. If more than six lines of footnotes are 
planned, then a cover page is strongly recommended to be used to display footnotes, and only 
those essential to comprehension of the data will be repeated on each page 
 The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, the date the program was run, and the listing source 
  
 
 Sources and/or cross-references in footnotes will use the keyword prefix (in singular form) for each 
reference and will be separated by a comma when multiple cross-references are displayed 
Example 
Listing source: Listing 16.2.4.1.1, Listing 16.2.4.1.2, Listing 16.2.4.2.1 


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Quality Control
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses. An overview of the development of programs is detailed in Syneos 
Health Developing Statistical Programs SOP (3907).
Syneos Health Developing Statistical Programs SOP (3907), Conducting the Transfer of Biostatistical 
Deliverables SOP (3908) and the SAS Programming and Validation Plan describes the quality control 
procedures that are performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs produce the output by 
checking for their logic, efficiency and commenting and by review of the produced output.


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Appendix
Q2 Solutions Range Chart
Range Values
Analyte
Sex
Age
Reference
Units
Haematology
WBC
Both
>=16Y
4.1-12.3
x10E3/uL
Haemoglobin
Female
12-65Y
11.6-16.2
g/dL
Male
18-65Y
13.0-17.5
g/dL
Haematocrit
Female
12-65Y
35.0-47.0
%
Male
18-65Y
40.0-52.0
%
RBC
Female
12-65Y
3.8-5.5
X10E6/uL
Male
12-65Y
4.1-5.9
X10E6/uL
MCV
Female
3-110Y
79-98
fL
Male
3-110Y
79-97
fL
MCH
Both
1-110Y
26-34
pg/cell
MCHC
Both
>=0Y
31-37
g/dL
RDW
Both
0-110Y
11.6-14.8
%
Platelet count
Both
0-110Y
140-450
X10E3/uL
Neutrophils
Both
>=16Y
40.9-77.0
%
Lymphocytes
Both
>=16Y
15.5-46.6
%
Monocytes
Both
>=16Y
3.1-12.5
%
Eosinophils
Both
>=16Y
0.0-6.0
%
Basophils
Both
>=16Y
0.0-2.4
%
Blasts
Both
0-110Y
0-0
%
Promyelocytes
Both
0-110Y
0-0
%
Myelocytes
Both
0-110Y
0-0
%
Metamyelocytes
Both
0-110Y
0-0
%
Bands
Both
0-110Y
0.0-5.0
%
Prolymphocytes
Both
0-110Y
0-0
%
Atypical lymphocytes
Both
0-110Y
0-3
%
Neutrophils Absolute
Both
>=16Y
2.03-8.36
x10E3/uL
Lymphocytes Absolute
Both
>=16Y
1.02-3.36
x10E3/uL
Monocytes Absolute
Both
>=16Y
0.18-0.90
x10E3/uL
Eosinophils Absolute
Both
>=16Y
0.00-0.56
x10E3/uL


Statistical Analysis Plan for Interventional Studies
Sponsor: InterveXion Therapeutics, LLC; Protocol No.: M200C-2101 
This document is confidential. 
SAP Version: SAP 2.0 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 40 of 41 
Basophils Absolute
Both
>=16Y
0.00-0.17
x10E3/uL
Blasts Absolute 
Both
0-110Y
0.00-0.00
x10E3/uL
Promyelocytes Abs
Both
0-110Y
0.00-0.00
x10E3/uL
Myelocytes Absolute
Both
0-110Y
0.00-0.00
x10E3/uL
Metamyelocytes Absolute 
Both
0-110Y
0.00-0.00
x10E3/uL
Bands Absolute
Both
0-110Y
0.00-0.50
x10E3/uL
Prolymphocytes Absolute
Both
0-110Y
0.00-0.00
x10E3/uL
Atypical lymphocytes Absolute
Both
0-110Y
0.00-0.30
x10E3/uL
Nucleated RBC 
Both
0-110Y
0-0
/100
WBC 
Plasma cells Absolute 
Both
0-110Y
0.00-0.00
x10E3/uL
Plasma cells
Both
0-110Y
0-0
% 
 
Range Values 
 
Analyte
Sex 
Age
Reference
Units
Chemistry 
 
Sodium
Both 
>=0Y
135-147
mEq/L
Potassium
Both 
0-109Y
3.3-5.1
mEq/L
Chloride
Both 
1-90Y
97-110
mEq/L
Bicarbonate
Both 
16-109Y
19-29 
mEq/L
BUN/Urea 
Both 
18-60Y
6-20
mg/dL
Creatinine 
Female 
>=16Y
0.51-0.95 
mg/dL
Male
>=16Y
0.67-1.17 
mg/dL
Glucose 
Both 
16-59Y
74-106
mg/dL
Calcium
Both 
12-65Y
8.4-10.3
mg/dL
ALT
Female 
>=17Y
<=33
U/L
Male
>=17Y
<=41
U/L
AST
Female 
>=16Y
<=31
U/L
Male
>=16Y
<=37
U/L
GGT
Female 
>=16Y
5-36
U/L
Male
>=16Y
8-61
U/L
Alkaline Phosphatase 
Female 
>=18Y
35-104
U/L
Male
>=18Y
40-129
U/L
CPK 
Female 
16-110Y
26-192
U/L
Male
16-110Y
39-308
U/L
 


Statistical Analysis Plan for Interventional Studies
Sponsor: InterveXion Therapeutics, LLC; Protocol No.: M200C-2101 
This document is confidential. 
SAP Version: SAP 2.0 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 41 of 41 
Range Values 
 
Analyte
Sex 
Age
Reference
Units
Urinalysis 
 
Urine dipstick blood 
Both 
>=0Y
NEGATIVE
Urine dipstick leukocyte esterase 
Both 
>=0Y
NEGATIVE
Urine dipstick protein
Both 
>=0Y
NEGATIVE
Urine microscopy
Both 
>=0Y
NORMAL
Urinalysis RBC 
Male
>=0Y
0-5/HPF
Female 
11-110Y
0-8/HPF
Urinalysis WBC 
Male
0-110Y
0-3/HPF
Female 
13-110Y
0-12HPF 
Range Values 
 
 
 
 
Analyte
Sex 
Age
Reference
Units
Urine Drug Screen
 
Amphetamines
Both 
>=0Y
Negative
Barbiturates
Both 
>=0Y
Negative
Benzodiazepines 
Both 
>=0Y
Negative
Cocaine 
Both 
>=0Y
Negative
Marijuana Metabolites 
Both 
>=0Y
Negative
Opiates 
Both 
>=0Y
Negative
Phencyclidine (PCP)
Both 
>=0Y
Negative
 
Tested at QD Nichols Institute, Valencia , CA
Propoxyphene
Both 
>=0Y
NEGATIVE