Conditions: Healthy Participants
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 40
Healthy volunteers: yes

Brief summary:
This first in human Phase 1a clinical trial will evaluate the safety, tolerability, and pharmacokinetics of a single IV infusion of PMN310 in healthy volunteers.

Detailed description:
This randomized, double-blind, placebo-controlled study will evaluate the safety, tolerability and pharmacokinetics of single ascending doses of intravenous PMN310 in healthy adult volunteers.

Subjects will be randomly assigned to receive either a single infusion of PMN310 or placebo. After randomization on Day 1, study drug will be administered followed by the collection of safety, tolerability, and PK data.

All dose cohorts will have lumbar punctures (LPs) for PK analysis performed on Day 3 and Day 29. Primary PK and CSF data will be obtained from Day 1 to Day 29. Safety and tolerability will be collected at all visits. The study is an 85-day study with one optional follow up assessment at Day 120.

Arms:
arm 1: PMN310 175mg or placebo administered as a 60-minute infusion. arm 2: PMN310 350mg or placebo administered as a 60-minute infusion. arm 3: PMN310 700mg or placebo administered as a 60-minute infusion. arm 4: PMN310 1400mg or placebo administered as a 60-minute infusion. arm 5: PMN310 2800mg or placebo administered as a 60-minute infusion.

Interventions: intervention 1: PMN310 intervention 2: Placebo
Intervention descriptions: intervention 1: 60-minute intravenous infusion intervention 2: 60-minute intravenous infusion

Protocol document:
Prot_000.pdf: 
Confidential 
 Page 1 
 
CLINICAL STUDY PROTOCOL 
 
A PHASE 1, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, SINGLE ASCENDING DOSE 
STUDY OF THE SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS OF PMN310 INFUSIONS IN 
HEALTHY VOLUNTEERS 
 
 
 
 
Protocol Number: 
PMN310-101 
Protocol Date: 
22 September 2023 
Protocol Version: 
2.0, Amendment 1 
IND Number: 
161194 
Sponsor: 
ProMIS Neurosciences, Inc. 
1 Broadway  
Cambridge, MA 02142 
 
 
Confidentiality Statement 
This study will be performed in compliance with Good Clinical Practices (GCP) and applicable regulatory 
requirements, including the archiving of essential documents.  Information contained in this protocol is 
confidential in nature, and may not be used, divulged, published or otherwise disclosed to others except to the 
extent necessary to obtain approval of the Institutional Review Board or Independent Ethics Committee, or as 
required by law.  Persons to whom this information is disclosed should be informed that this information is 
confidential and may not be further disclosed without the express permission of ProMIS Neurosciences. 
 


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PROTOCOL SIGNATURE PAGE
Protocol Title:
A Phase 1, Double-Blind, Placebo-Controlled, Single Ascending 
Dose Study of the Safety, Tolerability, and Pharmacokinetics of 
PMN310 Infusions in Healthy Volunteers
Protocol Number:
PMN310-101
Protocol Version:
2.0, Amendment 1
Study Phase:
1
Sponsor:
ProMIS Neurosciences, Inc.
Sponsor Representatives
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it 
accurately describes the planned conduct of the study.
Date
 




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with standardized meals provided during inpatient stay.  On Day 1, subjects 
will be randomly assigned to receive either a single infusion of PMN310 or 
placebo (6:2 ratio).  After randomization on Day 1, study drug will be 
administered followed by the collection of safety, tolerability, and PK data 
for 12 weeks postdose (outpatient follow-up period).  Following completion 
of the postdose outpatient follow-up period, subjects may return for an 
optional follow-up visit to evaluate PK, ADA, and exploratory biomarkers, 
if warranted by previous data.  The decision to recommend the optional 
follow-up visit will be made by the Sponsor and communicated to the 
Investigator who will notify the subject about the timing of the optional 
visit. 
All dose cohorts will have lumbar punctures (LPs) performed on Day 3 and 
Day 29.  The timing of additional LPs will be based on available serum PK 
and CSF concentrations of PMN310 from prior cohorts.  The timing of LPs 
will be communicated to the Investigator who will inform the subject.  No 
subject will have more than 3 total LPs. 
Dose Escalation Rules 
Each dose cohort will consist of 8 subjects (6:2; PMN310:placebo).  To 
evaluate the short term safety and tolerability of PMN310, each cohort will 
enroll a sentinel group of 2 subjects (1:1, PMN310:placebo) who will be 
dosed prior to dosing the remaining 6 subjects in the cohort (5:1, 
PMN310:placebo).  The Safety Review Committee (SRC) will review all 
safety data collected through 48 hours postdose from the 2 sentinel subjects 
to determine the acceptability of proceeding with dosing of the remaining 
6 subjects in the cohort. 
Dose escalation to the next cohort will only occur after approval by the 
SRC.  The SRC will determine the acceptability of proceeding with 
enrollment of the next cohort based on review of safety and any available 
PK data at the time of review through 7 days postdose for a minimum of 
6 of 8 subjects per cohort. 
In the event that important safety concerns are observed at any time during 
the study, administration of study drug will be paused, subjects in the 
subsequent cohort(s) will not receive further study drug until further review 
of the safety data has occurred, and subsequent recommendations and 
approval have been provided by the SRC.  
Study Population: 
Inclusion Criteria: 
Subjects must meet all of the following inclusion criteria to be eligible for 
this study: 
1. Male and females, 18 to 65 years of age, inclusive, at time of Screening.
a. Female subjects of childbearing potential must not be breastfeeding 
and must have no plans to become pregnant during the course of the 
study through 120 days after infusion of study drug.  Female 
subjects of childbearing potential who are heterosexual must agree 
to use 1 of the following methods of contraception considered to be 
highly effective (i.e., results in < 1% failure rate when used 
consistently and correctly) from Screening through 120 days after 
the last dose of study drug: 


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Intrauterine device or intrauterine system in place for at least 
3 months prior to first dose. 
 
 4 months prior to participation.  
Vasectomy in the partner is considered to be highly effective 
only if the partner is the sole sexual partner of the female 
subject of child-bearing potential and the vasectomy (as 
communicated to the subject by the vasectomized partner) was 
medically assessed as surgically successful. 
 
Stable hormonal contraception associated with inhibition of 
ovulation (including by not limited to approved oral, 
transdermal, or depot regimen) for at least 3 months prior to 
first dose. 
b. Female subjects of non-childbearing potential must have evidence 
from their medical history indicating that they are not of 
childbearing potential and must not currently be breastfeeding.  
Accepted evidence (self-reported medical history is acceptable) 
includes: 
 
History of sterilization surgery, including tubal ligation, tubal 
occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy. 
 
Postmenopausal status (12 months with no menses and no 
alternative cause).  Postmenopausal status will be confirmed 
with a follicle-stimulating hormone (FSH) test at Screening 
(FSH > 40 mIU/mL).  If there is any doubt about a female 
-menopausal status the subject must use a form of 
highly effective birth control as noted in Inclusion Criterion 1a. 
2. Any non-vasectomized male subjects must agree to use barrier 
contraceptives (male or female partner condom, diaphragm, cervical 
cap, sponges) plus spermicide for 200 days after dosing.  No restrictions 
are required for a vasectomized male provided his vasectomy was 
performed 4 months or more prior to study start.  A male who has been 
vasectomized less than 4 months prior to study start must follow the 
same restrictions as a non-vasectomized male. 
3. Males must not donate sperm for at least 200 days after dosing. 
4. Female subjects must agree not to donate or preserve eggs (ova) for 
120 days after dosing. 
5. Medically healthy with no clinically significant or relevant 
abnormalities in medical history, physical exam, vital signs, ECG, or 
laboratory evaluations (hematology, chemistry, and urinalysis) as 
assessed by the Investigator.  At the I
evaluations may be repeated at Screening or Baseline (pre-dose) to 
assess clinical significance of abnormalities prior to dosing. 
6. Confirmed to have acceptable venous access for blood collections and 
IV dosing administration of study medication. 
7. Has provided written informed consent. 
8. Body mass index is between 18 and 32 kg/m2 (inclusive). 
 
 
 
 
  
  
 
 
 
 
 
 
 
 


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9.
Screening magnetic resonance imaging (MRI) reveals normal 
appearance of the brain parenchyma, normal spacing of ventricular 
system and cisternal spaces and is without any significant abnormality, 
including, but not limited to evidence of prior microhemorrhages, 
lacunar infarcts, hemorrhage, or infarct > 1cm3, cerebral contusion, 
encephalomalacia, aneurysm, vascular malformation, subdural 
hematoma, hydrocephalus, space occupying lesion (e.g., abscess or 
brain tumor such as meningioma). 
Exclusion Criteria: 
Subjects having any of the following exclusion criteria are not eligible for 
this study: 
1. Current or recurrent disease (e.g., cardiovascular, neurological, renal, 
liver, gastrointestinal, malignancy, autoimmune disease, or other 
condition) that could affect the action, absorption or disposition of the 
investigational product, or could affect clinical or laboratory 
assessments. 
2. Clinically significant 12-lead ECG abnormality at Screening.  QT 
interval corrected by Fridericia (QTcF) > 450 milliseconds.  ECG may 
be repeated from the first one collected at Screening.  If repeat ECG is 
subject 
eligibility.  However, if repeat ECG confirms QTcF > 450 msec, the 
subject is not eligible for this study. 
3. Systolic blood pressure > 150 bpm or diastolic blood pressure  
> 90 bpm (measured in supine position after 5 minutes of rest) at 
Screening.  Blood pressure may be repeated from the first assessment 
collected at Screening.  
lood pressure may be 
used to determine subject eligibility. 
4. Experienced a significant systemic illness, as judged by the 
Investigator, within 30 days of the first dose of study drug. 
5. Current or relevant history of physical or psychiatric illness, any 
medical disorder that may require treatment or make the subject 
unlikely to fully complete the study, or any condition that presents 
undue risk from the investigational product or procedures. 
6. Currently using any medication (including over-the-counter or herbal, 
homeopathic preparations) except for acetaminophen as needed for 
miscellaneous aches and pains. 
7. History of alcohol abuse and/or illicit drug use within 12 months prior 
dosing or a smoking history (use of tobacco products). 
8. Unwilling to refrain from ingesting alcohol from Screening through 
Day 15 and unwilling to 
from 
Day 15 for the duration of the study; 1 drink is 5 ounces (150 mL) of 
wine, 12 ounces (360 mL) of beer, or 1.5 ounces (45 mL) of hard 
liquor. 
9. Positive urine drug screen for drugs of abuse or cotinine, or positive 
serum alcohol at Screening or Day -1. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
   
 
 
 








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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
PROTOCOL SYNOPSIS ................................................................................................................3 
1. 
INTRODUCTION ......................................................................................................16 
1.1. 
 ...................................................................................................16 
1.1.1. 
 ............................................16 
1.2. 
PMN310 ......................................................................................................................17 
1.2.1. 
Nonclinical Studies .....................................................................................................17 
1.3. 
Study Rationale ...........................................................................................................19 
1.4. 
Rationale for Dose Selection ......................................................................................19 
1.5. 
Benefit-Risk Assessment ............................................................................................20 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................21 
2.1. 
Study Objectives .........................................................................................................21 
2.1.1. 
Primary Objectives .....................................................................................................21 
2.1.2. 
Secondary Objectives .................................................................................................21 
2.1.3. 
Exploratory Objectives ...............................................................................................21 
2.2. 
Study Endpoints ..........................................................................................................21 
2.2.1. 
Primary Endpoints ......................................................................................................21 
2.2.2. 
Secondary Endpoints ..................................................................................................21 
2.2.3. 
Exploratory Endpoints ................................................................................................21 
3. 
STUDY DESIGN .......................................................................................................22 
3.1. 
Design Characteristics ................................................................................................22 
3.1.1. 
Dose Escalation Rules ................................................................................................22 
3.1.2. 
Safety Review Committee ..........................................................................................24 
4. 
STUDY POPULATION .............................................................................................25 
4.1. 
Inclusion Criteria ........................................................................................................25 
4.2. 
Exclusion Criteria .......................................................................................................26 
5. 
STUDY TREATMENTS............................................................................................28 
5.1. 
Identification and Description of Study Drug ............................................................28 
5.1.1. 
PMN310 ......................................................................................................................28 
5.1.2. 
Placebo ........................................................................................................................28 
5.2. 
Study Drug Preparation and Administration ..............................................................28 
 
 
 
 
 
 
 
 


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5.2.1. 
PMN310 ......................................................................................................................28 
5.2.2. 
Placebo ........................................................................................................................28 
5.3. 
Randomization and Blinding ......................................................................................28 
5.4. 
Unblinding for an Individual Subject .........................................................................29 
5.5. 
Dose Escalation/Stopping Rules .................................................................................29 
5.6. 
Storage, Handling, and Accountability of Study Drug ...............................................29 
5.7. 
Prior and Concomitant Therapy ..................................................................................30 
5.7.1. 
Prohibited Medications ...............................................................................................30 
6. 
STUDY PROCEDURES BY PERIOD ......................................................................31 
6.1. 
Screening Period (Day -28 to Day -1) ........................................................................31 
6.2. 
Inpatient Period (Days -1, 1, 2, 3, and 4) ....................................................................32 
6.2.1.1. 
Day -1 (Day of Admission to the Study Clinic) .........................................................32 
6.2.1.2. 
Day 1 (Day of Study Drug Administration) ...............................................................33 
6.2.1.3. 
Day 2 ...........................................................................................................................33 
6.2.1.4. 
Day 3 ...........................................................................................................................34 
6.2.1.5. 
Day 4 ...........................................................................................................................34 
6.2.2. 
Outpatient Period (Days 8, 15, 29, 43, 57, and 85) ....................................................35 
6.2.2.1. 
Day 8 ...........................................................................................................................35 
6.2.2.2. 
Day 15 .........................................................................................................................35 
6.2.2.3. 
Day 29 .........................................................................................................................36 
6.2.2.4. 
Day 43 .........................................................................................................................36 
6.2.2.5. 
Day 57 .........................................................................................................................37 
6.2.2.6. 
Day 85 .........................................................................................................................37 
6.2.3. 
Optional Follow-Up Visit  Day 120 .........................................................................38 
6.3. 
Early Termination .......................................................................................................38 
7. 
DESCRIPTION OF STUDY PROCEDURES ...........................................................39 
7.1.1. 
Demography and Medical History ..............................................................................39 
7.1.2. 
Columbia-Suicide Severity Rating Scale ....................................................................39 
7.1.3. 
Physical Examination .................................................................................................39 
7.1.4. 
Neurological Exam .....................................................................................................39 
7.1.5. 
Vital Signs ..................................................................................................................40 
7.1.6. 
Body Measurements ...................................................................................................40 
7.1.7. 
Magnetic Resonance Imaging .....................................................................................40 


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7.1.8. 
Electrocardiogram .......................................................................................................40 
7.1.9. 
Laboratory Assessments .............................................................................................40 
7.1.10. 
Pharmacokinetic Sampling .........................................................................................41 
7.1.11. 
Antidrug Antibodies ...................................................................................................41 
7.1.12. 
Exploratory Biomarkers ..............................................................................................41 
7.1.13. 
Lumbar Puncture ........................................................................................................42 
7.1.14. 
Concomitant Medication Use .....................................................................................42 
7.1.15. 
Adverse Events ...........................................................................................................42 
7.1.15.1. 
Definition of a Serious Adverse Event .......................................................................43 
7.1.15.2. 
Assessment of Adverse Event Severity ......................................................................44 
7.1.15.3. 
Assessment of Causality .............................................................................................44 
7.1.15.4. 
Assessment of Expectedness ......................................................................................45 
7.1.15.5. 
Procedures for Eliciting and Recording Adverse Events ...........................................45 
7.1.15.6. 
Reporting Periods for Adverse Events and Serious Adverse Events .........................46 
7.1.15.7. 
Recording Serious Adverse Events ............................................................................46 
7.1.15.8. 
Reporting of Serious Adverse Events .........................................................................47 
7.1.15.9. 
Pregnancy ...................................................................................................................47 
8. 
STUDY TERMINATION AND SUBJECT DISCONTINUATION .........................49 
8.1. 
Study Termination ......................................................................................................49 
8.2. 
Removal or Early Withdrawal of Subjects from Therapy or Assessment ..................49 
8.2.1. 
Removal of Subjects from Therapy or Assessment ....................................................49 
8.2.1.1. 
Potential Criteria for Withdrawal from Study ............................................................49 
8.2.2. 
Definite Criteria for Withdrawal from Study .............................................................50 
8.3. 
Replacement of Study Subjects ..................................................................................50 
9. 
STATISTICAL ANALYSIS PLAN ...........................................................................51 
9.1. 
General Overview .......................................................................................................51 
9.2. 
Determination of Sample Size ....................................................................................51 
9.3. 
Analyzed Population Sets ...........................................................................................51 
9.4. 
Statistical Analyses .....................................................................................................51 
9.4.1. 
Safety Analysis ...........................................................................................................51 
9.4.2. 
Pharmacokinetic Analysis ..........................................................................................51 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................53 
10.1. 
Study Monitoring and Site Audits ..............................................................................53 


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10.2. 
Case Report Forms .....................................................................................................53 
10.3. 
Source Documentation ................................................................................................53 
10.4. 
Data Management .......................................................................................................54 
11. 
ETHICAL CONSIDERATIONS................................................................................55 
11.1. 
Institutional Review Board or Independent Ethics Committee ..................................55 
11.2. 
Ethical Conduct of the Study ......................................................................................55 
11.3. 
Protocol Revisions and/or Deviations ........................................................................55 
11.4. 
Subject Information and Consent ...............................................................................56 
11.5. 
Personal Data Protection .............................................................................................56 
12. 
STUDY ADMINISTRATION ...................................................................................57 
12.1. 
Investigator Site File ...................................................................................................57 
12.2. 
Retention of Study Records ........................................................................................57 
12.3. 
Publication and Disclosure Policy ..............................................................................58 
13. 
REFERENCES ...........................................................................................................59 
14. 
APPENDICES ............................................................................................................61 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................62 
 
 
LIST OF TABLES 
Table 1: 
Classification of Adverse Events by Intensity ............................................................44 
Table 2: 
Timeline for Reporting Serious Adverse Events ........................................................47 
 
 
LIST OF FIGURES 
Figure 1: 
PMN310-101 Study Schema Per Cohort ....................................................................23 
 




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Abbreviation 
Definition 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference for Harmonization 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
LP 
lumbar puncture 
MABEL 
minimal anticipated biological effect level 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NOAEL 
no-observed-adverse-effect level 
PAD 
pharmacologically active dose 
PK 
pharmacokinetic 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QTcF 
QT interval corrected by Fridericia 
SAE 
serious adverse event 
SD 
standard deviation 
SPR 
surface plasma resonance 
SRC 
Safety Review Committee 
t1/2 
terminal half-life 
T2/FLAIR 
T2-weighted fluid-attenuated inversion recovery 
Tmax 
time to Cmax 
Vd 
volume of distribution 
 
 
 






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  Planned doses include 
175 mg, 350 mg, 700 mg, 1400 mg and 2800 mg (optional).  Additional dose levels may be 
added to explore intermediate doses in lieu of the predefined doses.  Any intermediate doses will 
be selected in accordance with the safety and tolerability data reviewed by the Safety Review 
Committee (SRC), and will not exceed a single dose of 2800 mg. 
1.5. 
Benefit-Risk Assessment 
PMN310 has not yet been evaluated in humans and the predicted safety and toxicology findings 
can only be garnered by the completed GLP-compliant toxicology studies in non-human 
primates.  
 
 
 
 
 
 
 
The safety of PMN310 will be assessed throughout the study by monitoring AEs, using criteria 
proposed by Sibille et al., 2010, clinical laboratory assessments, vital sign measurements, 
physical and neurological examinations, 12-lead ECG measurements, and magnetic resonance 
imaging (MRI) evaluations. 
There are no expected direct health benefits to subjects in Study PMN310-101.  The safety, 
tolerability, and PK data collected in Study PMN310-101 will provide initial data supporting the 
evaluation of PMN310 in patients with AD. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
 To assess safety and tolerability of escalating doses of PMN310 when administered as 
a single IV infusion in healthy volunteers 
2.1.2. 
Secondary Objectives 
 To assess the single dose PK of PMN310 
2.1.3. 
Exploratory Objectives 
 To assess the immunogenicity of PMN310 following single dose administration 
 To assess biomarkers in healthy subjects 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoints 
 Adverse events (AEs), clinical laboratory tests (clinical chemistry, hematology, 
urinalysis), physical and neurological examinations, vital signs, and 12-lead ECGs 
2.2.2. 
Secondary Endpoints 
 Serum PK: maximum observed concentration (Cmax), time to Cmax (Tmax), area under 
the curve from Time 0 to last sampling time (AUC0-t), area under the curve from 
Time 0 to infinity (AUC0- ), terminal half-life (t1/2), volume of distribution (Vd), 
clearance (CL) 
 Cerebrospinal fluid (CSF) drug concentrations 
2.2.3. 
Exploratory Endpoints 
 Incidence and titers of ADAs 
 Residual and unused serum and CSF samples will be stored for future use for the 
measurement of biomarkers 
 
 
 
 
 
 
 
 
 
 


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3. 
STUDY DESIGN 
3.1. 
Design Characteristics 
This is a randomized, placebo-controlled, single ascending dose clinical study of PMN310 in 
healthy adult volunteers.  The study aims to establish the safety, tolerability, and PK of a single 
IV infusion of PMN310.  
Subjects who provide written informed consent and meet all eligibility criteria will be admitted 
to the study clinic on Day -1 (i.e., the day prior to dosing with PMN310 or placebo).  Subjects 
will be domiciled for 4 nights with standardized meals provided during inpatient stay.  On Day 1, 
subjects will be randomly assigned to receive either a single infusion of PMN310 or placebo (6:2 
ratio).  After randomization on Day 1, study drug will be administered followed by the collection 
of safety, tolerability, and PK data for 12 weeks postdose (outpatient follow-up period).  
Following completion of the postdose outpatient follow-up period, subjects may return for an 
optional follow-up visit to evaluate PK, ADA, and exploratory biomarkers, if warranted by 
previous data.  The decision to recommend the optional follow-up visit will be made by the 
Sponsor and communicated to the Investigator who will notify the subject about the timing of the 
optional visit. 
All dose cohorts will have lumbar punctures (LPs) performed on Day 3 and Day 29.  The timing 
of additional LPs will be based on available serum PK and CSF concentrations of PMN310 from 
prior cohorts.  The timing of LPs will be communicated to the Investigator who will inform the 
subject.  No subject will have more than 3 total LPs. 
A detailed summary of the schedule of events is available in Appendix 1. 
3.1.1. 
Dose Escalation Rules 
Each dose cohort will consist of 8 subjects (6:2; PMN310:placebo).  To evaluate the short term 
safety and tolerability of PMN310, each cohort will enroll a sentinel group of 2 subjects (1:1, 
PMN310:placebo) who will be dosed prior to dosing the remaining 6 subjects in the cohort (5:1, 
PMN310:placebo).  The first two sentinel subjects for Cohort 1 (age < 50) will have MRIs 
performed and read locally.  The SRC will review all safety data collected through 48 hours 
postdose from the 2 sentinel subjects to determine the acceptability of proceeding with dosing of 
the remaining 6 subjects in the cohort.  Additional details on the SRC are provided in 
Section 3.1.2. 
Dose escalation to the next cohort will only occur after approval by the SRC.  The SRC will 
determine the acceptability of proceeding with enrollment of the next cohort based on review of 
safety and any available PK data at the time of review through 7 days postdose for a minimum of 
6 of 8 subjects per cohort.  Doses to be evaluated are presented in Section 5.2.1. 
In the event that important safety concerns are observed at any time during the study, 
administration of study drug will be paused, subjects in the subsequent cohort(s) will not receive 
further study drug until further review of the safety data has occurred, and subsequent 
recommendations and approval have been provided by the SRC.  Dose escalation/stopping rules 
are detailed in Section 5.5. 
A schematic illustrating the study design is provided in Figure 1. 




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3.1.2. 
Safety Review Committee 
The SRC will be responsible for the review of safety and any available PK data at the time of 
review, and making determinations regarding the acceptability of proceeding with dosing of the 
remaining 6 subjects in a cohort (based on review of sentinel subjects) and dose escalation to the 
next cohort.  The SRC will be comprised of the Study Investigator, Medical Monitor, and 
Sponsor Medical Director.  At a minimum, the SRC will review safety data assessments 
post-dose for a minimum of 6 of 8 subjects per cohort prior to each dose escalation.  The SRC 
charter will specify operational details pertaining to roles and responsibilities, data to be 
reviewed, review frequency, and reporting. 
 
 
 
 
 
 
 
 
 
  
 
 
  
 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for this study: 
1. 
Male and females, 18 to 65 years of age, inclusive, at time of Screening. 
a. Female subjects of childbearing potential must not be breastfeeding and must have no 
plans to become pregnant during the course of the study through 120 days after 
infusion of study drug.  Female subjects of childbearing potential who are 
heterosexual must agree to use 1 of the following methods of contraception 
considered to be highly effective (i.e., results in < 1% failure rate when used 
consistently and correctly) from Screening through 120 days after the last dose of 
study drug: 
 Intrauterine device or intrauterine system in place for at least 3 months prior to 
first dose. 
 Partner has had a vasectomy  4 months prior to participation.  Vasectomy in the 
partner is considered to be highly effective only if the partner is the sole sexual 
partner of the female subject of child-bearing potential and the vasectomy (as 
communicated to the subject by the vasectomized partner) was medically assessed 
as surgically successful. 
 Stable hormonal contraception associated with inhibition of ovulation (including 
by not limited to approved oral, transdermal, or depot regimen) for at least 
3 months prior to first dose. 
b. Female subjects of non-childbearing potential must have evidence from their medical 
history indicating that they are not of childbearing potential and must not currently be 
breastfeeding.  Accepted evidence (self-reported medical history is acceptable) 
includes: 
 History of sterilization surgery , including tubal ligation, tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy. 
 Postmenopausal status (12 months with no menses and no alternative cause).  
Postmenopausal status will be confirmed with a follicle-stimulating hormone 
(FSH) test at Screening (FSH > 40 mIU/mL).  If there is any doubt about a female 
-menopausal status the subject must use a form of highly effective 
birth control as noted in Inclusion Criterion 1a. 
2. 
Any non-vasectomized male subjects must agree to use barrier contraceptives (male or 
female partner condom, diaphragm, cervical cap, sponges) plus spermicide for 200 days 
after dosing.  No restrictions are required for a vasectomized male provided his vasectomy 
was performed 4 months or more prior to study start.  A male who has been vasectomized 
less than 4 months prior to study start must follow the same restrictions as a non-
vasectomized male.  
3. 
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4. 
Female subjects must agree not to donate or preserve eggs (ova) for 120 days after dosing. 
5. 
Medically healthy with no clinically significant or relevant abnormalities in medical 
history, physical exam, vital signs, ECG, or laboratory evaluations (hematology, 
chemistry, and urinalysis) as assessed by the Investigator.  At the I
laboratory evaluations may be repeated at Screening or Baseline (pre-dose) to assess 
clinical significance of abnormalities prior to dosing. 
6. 
Confirmed to have acceptable venous access for blood collections and IV dosing 
administration of study medication. 
7. 
Has provided written informed consent. 
8. 
Body mass index is between 18 and 32 kg/m2 (inclusive). 
9. 
Screening MRI reveals normal appearance of the brain parenchyma, normal spacing of 
ventricular system and cisternal spaces and is without any significant abnormality, 
including, but not limited to evidence of prior microhemorrhages, lacunar infarcts, 
hemorrhage, or infarct > 1cm3, cerebral contusion, encephalomalacia, aneurysm, vascular 
malformation, subdural hematoma, hydrocephalus, space occupying lesion (e.g., abscess 
or brain tumor such as meningioma). 
4.2. 
Exclusion Criteria 
Subjects having any of the following exclusion criteria are not eligible for this study: 
1. 
Current or recurrent disease (e.g., cardiovascular, neurological, renal, liver, 
gastrointestinal, malignancy, autoimmune disease, or other condition) that could affect 
the action, absorption or disposition of the investigational product, or could affect clinical 
or laboratory assessments. 
2. 
Clinically significant 12-lead ECG abnormality at Screening.  QT interval corrected by 
Fridericia (QTcF) > 450 milliseconds.  ECG may be repeated from the first one collected 
 ECG may be used to determine 
subject eligibility.  However, if repeat ECG confirms QTcF > 450 msec, the subject is not 
eligible for this study. 
3. 
Systolic blood pressure > 150 bpm or diastolic blood pressure > 90 bpm (measured in 
supine position after 5 minutes of rest) at Screening.  Blood pressure may be repeated 
from the first assessment collected at Screening.  
ure may be used to 
determine subject eligibility. 
4. 
Experienced a significant systemic illness, as judged by the Investigator, within 30 days 
of the first dose of study drug. 
5. 
Current or relevant history of physical or psychiatric illness, any medical disorder that 
may require treatment or make the subject unlikely to fully complete the study, or any 
condition that presents undue risk from the investigational product or procedures. 
6. 
Currently using any medication (including over-the-counter, herbal or homeopathic 
preparations) except for acetaminophen as needed for miscellaneous aches and pains. 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 


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7. 
History of alcohol abuse and/or illicit drug use within 12 months prior dosing or a 
smoking history (use of tobacco products). 
8. 
Unwilling to refrain from ingesting alcohol from Screening through Day 15 and 
unwilling to 
 from Day 15 for the duration of the 
study; 1 drink is 5 ounces (150 mL) of wine, 12 ounces (360 mL) of beer, or 1.5 ounces 
(45 mL) of hard liquor. 
9. 
Positive urine drug screen for drugs of abuse or cotinine, or positive serum alcohol at 
Screening or Day -1. 
10. 
Any significant concomitant disorder, including active bacterial, fungal, or viral 
infection, incompatible with participation in the study. 
11. 
History of prior malignancy (except adequately treated non melanoma skin cancer or 
carcinoma in-situ of the cervix). 
12. 
Documented history of human immunodeficiency virus (HIV) antibody, or tested positive 
for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody at 
Screening. 
13. 
Donated blood or blood products (e.g., plasma, platelets) within 28 days prior to first 
dose. 
14. 
Received an investigational agent within the last 30 days or 5 half-lives (if known) prior 
to Screening, whichever is longer. 
15. 
Contraindication to brain MRI. 
16. 
Contraindication to undergoing LP including: sensitivity to local anesthetic, international 
normalized ratio (INR) > 1.4 or other coagulopathy, platelet cell count of < 120,000/µL, 
infection at the desired LP site, current use of anti-coagulant medication except for low 
dose aspirin, degenerative arthritis, spinal scoliosis, back surgery, suspected increased 
intracranial pressure on history or neurologic exam, non-communicating hydrocephalus 
or intracranial mass, or prior history of spinal mass or trauma and/or other known 
clinically significant spinal abnormalities. 
17. 
Inability to undergo venipuncture or tolerate venous access. 
18. 
Indication of potential suicidality risk as identified by the following: 
a. 
Lifetime history of recurrent serious or recurrent suicide behavior. 
b. 
to any suicide behavior question on the Columbia-Suicide Severity Rating Scale 
(C-SSRS) Baseline  Screening version. 
c. 
Suicidal ideation with intent or plan wi
response to Item 4 or 5 on the C-SSRS Baseline  Screening version. 
19. 
Any of the following: clinically significant abnormalities on vital signs, physical exam, or 
laboratory testing at Screening and Baseline (pre-dose) per Investigator discretion. 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 


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5. 
STUDY TREATMENTS 
5.1. 
Identification and Description of Study Drug 
5.1.1. 
PMN310 
 
 
 
 
 
 
 
5.1.2. 
Placebo 
Placebo will consist of 100 mL 0.9% NaCl. 
5.2. 
Study Drug Preparation and Administration 
5.2.1. 
PMN310 
Study medication will be prepared at the study clinic by an unblinded pharmacist (or designee) 
IV drug for infusion will be dispensed to staff who will administer study drug.  Specific 
instructions for preparation and administration of study medication will be provided in the 
Pharmacy Manual. 
PMN310 will be administered as a single IV infusion over 60 minutes in 0.9% NaCl, adjusted to 
a total volume of 100 mL, followed by a 15 minute 0.9% NaCl flush.  The complete infusion will 
consist of the IV infusion and the flush following the IV infusion. 
The following dose level cohorts are planned to be evaluated: 175 mg (starting dose level), 
350 mg, 700 mg, 1400 mg, and 2800 mg (optional cohort).  The rationale for selecting these dose 
levels is provided in Section 1.4. 
5.2.2. 
Placebo 
Placebo will be administered as a matching single IV infusion over 60 minutes, followed by a 
15 minute 0.9% NaCl flush.  The complete infusion will consist of the IV infusion and the flush 
following the IV infusion. 
5.3. 
Randomization and Blinding 
Once an eligible subject is at the study site and prepared to receive the study drug, the subject 
will be assigned the treatment allocation according to the randomization sequence.  The 
randomization sequence will be obtained by computer-generated random numbers and provided 
to unblinded study site staff members who will have primary responsibility for drug dispensing.  
Within each cohort, eligible subjects will be randomized to receive PMN310 (N = 6) or placebo 
(N = 2).  Subjects and study personnel will be aware of the dosage level but will be blinded to 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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the study drug administered (PMN310 or placebo).  Only unblinded study site staff members 
assigned to prepare study drug will know whether a subject receives PMN310 or placebo.  To 
maintain appropriate blinding, the unblinded pharmacist will consult the randomization 
acy staff will then 
provide prepared study drug in a blinded fashion to the Investigator (or designee) for infusion. 
5.4. 
Unblinding for an Individual Subject 
In case of an emergency, the Investigator has the sole responsibility of determining if unblinding 
rranted.  Blinding should only be broken in emergency situations 
when knowledge of the treatment assignment is required for the assurance of the safety of the 
subject and the medical management of the subject.  The Sponsor or representative should be 
contacted, when possible, before breaking the blind except in emergency circumstances when the 
Investigator has the sole responsibility for determining the need to unblind.  Upon breaking the 
blind, the reason must be documented, and the Sponsor should be immediately notified.  The 
applicable standard operating procedures (SOPs) will be followed for breaking the blind.  
5.5. 
Dose Escalation/Stopping Rules 
Dose escalation will be paused for review if any of the following occur, Two or more of the 
subjects in a cohort develop Grade  2 AEs in the same category.  
 One or more subjects in a cohort develop Grade  3 AEs. 
 It is determined that the limit of safety and/or tolerability has been reached as 
determined by the SRC.  
The Sponsor or SRC may pause and then stop dosing within a cohort or decide to not dose 
escalate to a higher dose if it is determined that any AE is occurring that is intolerable or poses a 
medically unacceptable safety risk. 
5.6. 
Storage, Handling, and Accountability of Study Drug 
PMN310 will be supplied directly to the study site.  The study site will acknowledge receipt of 
the shipment and record inventory and usage of study drug on a drug disposition form.  Upon 
arrival at the study site, vials will be stored frozen at -25ºC to -15ºC (-13°F to 5°F) inside the 
cartons to minimize exposure to light, with the cartons oriented such that the enclosed vials are 
in the upright position.  An unblinded study monitor will perform reconciliation of the drug 
product. 
Used vi
 
Unused vials will be either destroyed at the study site or returned to the Sponsor, as agreed 
between the site and Sponsor.  Before disposal/destruction of unused vials, final drug 
accountability and reconciliation must be performed by the unblinded study monitor.  
Documentation of destruction of vials of PMN310 must be available for review by the study 
monitor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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5.7. 
Prior and Concomitant Therapy 
5.7.1. 
Prohibited Medications 
All medications, including over-the-counter, herbal, or homeopathic preparations (except for 
acetaminophen as needed for miscellaneous aches and pains), are prohibited during the study, 
unless required to be administered for the treatment of an AE.  Subjects receiving a stable dose 
of medications for high blood pressure or high cholesterol may be included with Sponsor 
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6. 
STUDY PROCEDURES BY PERIOD 
The scheduled assessments for Screening, Inpatient, and Outpatient periods are summarized in 
Appendix 1. 
For each study day described below, when multiple procedures are scheduled at the same 
nominal time relative to dosing, the following chronology of events should be adhered to, where 
possible: 
 Vital signs and ECGs will be obtained as close as possible to the scheduled time (up 
to 45 minutes before PK sampling), but before blood specimen collection. 
 Serum PK samples will be obtained at the scheduled time. 
 After venipuncture, PK samples will be obtained first followed by clinical safety 
laboratory tests. 
In the case of a clinical or laboratory abnormality, the Investigator may apply clinical judgement 
in repeating the measurement if the abnormality is believed likely to be an error. 
6.1. 
Screening Period (Day -28 to Day -1) 
Healthy volunteers will be recruited for this clinical study.  Before initiation of screening 
assessments, the subject must be given a complete explanation of the purpose and procedures 
occurring during the study.  Subsequently, the subject must sign and receive a copy of an 
Institutional Review Board (IRB)-approved informed consent form (ICF) (Section 11.4).  Once 
informed consent has been obtained, screening assessments will be performed and eligibility of 
the subject will be determined based on the inclusion and exclusion criteria.  Subjects who fail 
screening may be rescreened following Sponsor approval. 
Study assessments are described in Section 7. 
 
 Demography and medical history 
 Suicidality evaluation: C-SSRS (Baseline - Screening version) 
 Height 
 Complete physical examination 
 Neurologic examination 
 Vital signs 
 Weight 
 MRI 
 Lumbar x-rays 
puncture) 
 12-lead ECG 
 HBsAg and HCV tests 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 


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 FSH (post-menopausal women only) 
 Pregnancy test (non-post-menopausal women only) 
 Urine drug, urine cotinine, and serum alcohol screen 
 Clinical laboratory tests:  
 Blood chemistry and hematology 
 Urinalysis 
 Coagulation 
 Review of concomitant medications 
 AE assessment of protocol related procedures only, to be performed after informed 
consent is obtained 
The Investigator may use clinical judgment when determining the clinical significance of 
laboratory results throughout the study.  The Medical Monitor may, depending on study criteria, 
be consulted before enrollment of a candidate with abnormal laboratory values. 
6.2. 
Inpatient Period (Days -1, 1, 2, 3, and 4) 
During the inpatient period, standardized breakfast, lunch, and dinner will be provided at fixed 
times.  Meals are to be consumed within 45 minutes.  Evening snacks will be provided at a 
consistent time each day.  Fluids will be allowed liberally. 
6.2.1.1. 
Day -1 (Day of Admission to the Study Clinic) 
On Day 1 eligibility will be confirmed and eligible subjects will be admitted to the study clinic.  
Admission should occur before 6 PM.   
The following assessments will be performed: 
 Complete physical examination 
 Neurologic examination 
 Vital signs 
 Weight 
 12-lead ECG 
 Pregnancy test (non-post-menopausal women only) 
 Urine drug, urine cotinine, and serum alcohol screen 
 Clinical laboratory tests:  
 Blood chemistry and hematology 
 Urinalysis 
 Coagulation 
 ADA serum sampling 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 Residual and unused serum samples will be stored for future use for the measurement 
of biomarkers  
 Review of concomitant medications 
 AE assessment of protocol related procedures only 
The subject will remain in the study clinic overnight. 
6.2.1.2. 
Day 1 (Day of Study Drug Administration) 
Subjects will be randomly assigned to study drug (PMN310 or placebo).  After consumption of a 
standard breakfast, and pre-dosing assessments, study drug will be administered as an IV 
infusion as described in Section 5.2.  After administration of study drug, inpatient follow-up data 
collection will include the following: 
 C-SSRS (Since Last Visit version) 
 Vital signs 
 12-lead ECG 
 PK serum sampling: before infusion, at the end of infusion (see Section 5.2.1 for a 
definition for complete infusion), and at 0.5, 1, 2, 4, 8, and 12 hours after the end of 
infusion. 
 Acceptable windows for PK sampling are as follows (exact time of PK collection 
is to be recorded):  
 Pre-dose sample to be collected within 60 minutes prior to dosing 
 0.5 to 4-hour post-dose samples to be collected ± 5 minutes 
 8 to 12-hour post-dose samples to be collected ± 10 minutes 
 Review of concomitant medications 
 AE assessment 
The subject will remain in the study clinic overnight. 
6.2.1.3. 
Day 2 
On Day 2, subjects will undergo the following assessments: 
 Vital signs  
 12-lead ECG 
 PK serum sampling at 24 and 36 hours from end of Day 1 infusion  
 Acceptable windows for PK sampling are ± 30 minutes (exact time of PK 
collection is to be recorded) 
 Review of concomitant medications 
 AE assessment 
The subject will remain in the study clinic overnight. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2.1.4. 
Day 3 
On Day 3 subjects will undergo the following assessments: 
 Symptom directed physical examination 
 Neurologic examination 
 Vital signs 
 Weight 
 12-lead ECG 
 Clinical laboratory tests:  
 Blood chemistry and hematology 
 Urinalysis 
 Coagulation 
 PK serum sampling 72 hours from end of Day 1 infusion 
 Acceptable window for PK sampling is ± 60 minutes (exact time of PK collection 
is to be recorded) 
 LP. INR/PT/partial thromboplastin time (PTT) and platelet results within 2 days prior 
to the LP must be confirmed and determined to be within normal range before LP. 
 Review of concomitant medications 
 AE assessment 
The subject will remain in the study clinic overnight. 
6.2.1.5. 
Day 4 
On Day 4, subjects will undergo the following assessments: 
 C-SSRS (Since Last Visit version) 
 Vital signs  
 PK serum sampling 96 hours from end of Day 1 infusion 
 Acceptable window for PK sampling is ± 60 minutes (exact time of PK collection 
is to be recorded) 
 Review of concomitant medications 
 AE assessment 
Following the completion of assessments, unless the Investigator feels that a longer period of 
observation is warranted (e.g., due to side effects of the study drug or any study procedure), 
subjects will be discharged from the study clinic. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2.2. 
Outpatient Period (Days 8, 15, 29, 43, 57, and 85) 
Subjects will return to the study site for follow-up outpatient visits on Days 8, 15, 29, 43, 57, and 
85. 
6.2.2.1. 
Day 8 
On Day 8 (±1 day), subjects will undergo the following assessments: 
 Vital signs 
 12-lead ECG 
 Pregnancy test (non-post-menopausal women only) 
 Urine drug, urine cotinine, and serum alcohol screen 
 Clinical laboratory tests:  
 Blood chemistry and hematology 
 Urinalysis 
 Coagulation 
 PK serum sampling 
 Review of concomitant medications 
 AE assessment 
6.2.2.2. 
Day 15 
On Day 15 (±1 day), subjects will undergo the following assessments: 
 Vital signs 
 Clinical laboratory tests:  
 Blood chemistry and hematology 
 Urinalysis 
 Coagulation 
 PK serum sampling 
 Possible LP. INR/ PT/PTT and platelet results within 2 days prior to the LP must be 
confirmed and determined to be within normal range before LP. 
 Post LP, subjects will remain supine for a minimum of 4 hours, and may be kept 
longer for observation at the discretion of the Investigator.  After the 4-hour 
observation period, safety and tolerability will be assessed and subjects will be 
discharged home 
 Review of concomitant medications 
 AE assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2.2.3. 
Day 29 
On Day 29 (±3 days), subjects will undergo the following assessments: 
C-SSRS (Since Last Visit version)
Symptom directed physical examination 
Neurologic examination 
Vital signs  
Weight 
12-lead ECG
Clinical laboratory tests:  
Blood chemistry and hematology 
Urinalysis 
Coagulation 
PK serum sampling 
ADA serum sampling 
Note:  Residual and unused serum and CSF samples will be stored for future use for 
the measurement of biomarkers LP. INR/PT/PTT and platelet results within 2 days 
prior to the LP must be confirmed and determined to be within normal range before 
LP. 
Post LP, subjects will remain supine for a minimum of 4 hours, and may be kept 
longer for observation at the discretion of the Investigator.  After the 4-hour 
observation period, safety and tolerability will be assessed and subjects will be 
discharged home 
Review of concomitant medications 
AE assessment 
6.2.2.4. 
Day 43 
On Day 43 (±3 days), subjects will undergo the following assessments: 
Vital signs 
MRI (subjects > 50 years of age only).  If ARIA is detected, subjects will return for 
additional MRI assessments every 3-4 weeks until the ARIA resolves. 
Clinical laboratory tests:  
Blood chemistry and hematology 
Urinalysis 
Coagulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 PK serum sampling 
 Review of concomitant medications 
 AE assessment 
6.2.2.5. 
Day 57 
On Day 57 (±3 days), subjects will undergo the following assessments: 
 C-SSRS (Since Last Visit version) 
 Vital signs 
 Clinical laboratory tests:  
 Blood chemistry and hematology 
 Urinalysis 
 Coagulation 
 PK serum sampling 
 ADA serum sampling 
 Note:  Residual and unused serum and CSF (if applicable) samples will be stored for 
future use for the measurement of biomarkers Possible LP. INR/ PT/PTT and platelet 
results within 2 days prior to the LP must be confirmed and determined to be within 
normal range before LP. 
 Post LP, subjects will remain supine for a minimum of 4 hours, and may be kept 
longer for observation at the discretion of the Investigator.  After the 4-hour 
observation period, safety and tolerability will be assessed and subjects will be 
discharged home 
 Review of concomitant medications 
 AE assessment 
6.2.2.6. 
Day 85 
On Day 85 (±4 days), subjects will undergo the following assessments: 
 C-SSRS (Since Last Visit version) 
 Symptom directed physical examination 
 Neurologic examination 
 Vital signs 
 Weight 
 12-lead ECG 
 Pregnancy test (non-post-menopausal women only) 
 Urine drug, urine cotinine, and serum alcohol screen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 Clinical laboratory tests:  
 Blood chemistry and hematology 
 Urinalysis 
 Coagulation 
 PK serum sampling 
 ADA serum sampling 
 Note:  Residual and unused serum and CSF samples (if applicable) will be stored for 
future use for the measurement of biomarkers Possible LP. INR/ PT/PTT and platelet 
results within 2 days prior to the LP must be confirmed and determined to be within 
normal range before LP. 
 Post LP, subjects will remain supine for a minimum of 4 hours, and may be kept 
longer for observation at the discretion of the Investigator.  After the 4-hour 
observation period, safety and tolerability will be assessed and subjects will be 
discharged home 
 Review of concomitant medications 
 AE assessment 
6.2.3. 
Optional Follow-Up Visit  Day 120 
The Day 120 visit (± 7 days) is optional.  Subjects who elect to participate in the Day 120 visit 
will undergo the following assessments: 
 PK serum sampling 
 ADA serum sampling 
 Note:  Residual and unused serum samples will be stored for future use for the 
measurement of biomarkers 
6.3. 
Early Termination 
If a subject cannot complete the entire study, efforts will be made to collect all prespecified 
assessments for Day 85 (Appendix 1), if possible.  If a subject withdraws consent before early 
termination no further procedures should be performed and no additional data should be 
collected.  The Sponsor may retain and continue to use any data collected before the withdrawal 
of consent. 
 
 
 
 
 
 
 
 
 


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7.
DESCRIPTION OF STUDY PROCEDURES
Study assessments and procedures are to be performed on the schedule outlined in Appendix 1 
and listed by visit in Section 6. 
Additional details for selected study procedures are provided in the sections below. 
7.1.1. 
Demography and Medical History 
Relevant medical conditions, concomitant illness, surgeries within the 6 months before 
Screening should be documented.  For female subjects, the last menstrual period should be 
recorded. 
7.1.2. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS is an interview with the subject that systematically evaluates suicidal ideation and 
behavior.  The C-SSRS (Baseline - Screening and Since Last Visit versions) will be performed 
by a qualified trained rater. 
At Screening, the C-SSRS will be used to exclude any candidate with a history of suicide 
have experienced suicidal ideation associated with actual intent or plan within 12 months of 
Screening, may have had a history of suicidal behavior within the past 5 years, or had any 
lifetime history of recurrent suicidal behavior, the candidate will be excluded from participation 
in the study. 
After Screening, the C-SSRS will be used to assess ideation and behavior at visits specified in 
Appendix 1.  
stion, a suicidal 
risk assessment must be performed as soon as possible by a qualified mental health practitioner 
(with expertise in evaluation of suicidality) to determine whether it is safe for the subject to 
continue participation in the study. 
7.1.3. 
Physical Examination 
A full physical examination in this study will include the following: skin, eyes, ears, nose, oral 
mucosa, and throat, cardiac, respiratory, abdomen, and extremities.  
A symptom-directed physical examination will include both a full physical examination and a 
directed examination of the affected system related to any reported AE.  
Clinically relevant findings on the physical examination performed at Screening will be recorded 
as medical history.  Any clinically relevant treatment emergent new finding on examination will 
be documented as an AE. 
7.1.4. 
Neurological Exam 
Neurological examinations will include the following: mental status, level of consciousness, 
cranial nerve function, sensory function, motor function, and reflexes. 
Clinically relevant findings from the neurological examination performed at Screening will be 
recorded as medical history.  Any clinically relevant treatment-emergent new finding on 
examination will be documented as an AE. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
  
  
  
  
 
 
 




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 Blood chemistry panel, including blood glucose, calcium, albumin, total protein, 
sodium, potassium, bicarbonate, chloride, magnesium, blood urea nitrogen, 
creatinine, creatine kinase, alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, gamma-glutamyltransferase, bilirubin, lipase, lactate 
dehydrogenase, phosphorus, triglycerides, total cholesterol, high density lipoprotein 
cholesterol, and low-density lipoprotein cholesterol. 
 Urinalysis, including osmolality, creatinine, calcium, sodium, turbidity, color, 
specific gravity, pH, protein, glucose, ketones, bilirubin, blood, urobilinogen, nitrite, 
leukocytes, and microscopic particles.  Urine should not be first morning void.  
Microscopic examination will be performed if urinalysis results are abnormal for 
bacteria, casts, epithelial cells, erythrocytes or leukocytes.  Urine should be collected 
within 1 hour of blood draws for hematology and chemistry panels.  Trace protein 
will be considered positive. 
 Coagulation panel, including (INR, PT, PTT and platelets); results within 2 days prior 
to the LP must be confirmed and determined to be within normal range before LP. 
Other laboratory tests include the following: 
 Viral serology, HBsAg and HCV tests 
 FSH for post-menopausal women only.  Post-menopausal status will be confirmed 
 
 Pregnancy test for non-post-menopausal women only (serum human chorionic 
gonadotropin at Screening and urinary chorionic gonadotropin thereafter).  If a urine 
pregnancy test is positive, a serum pregnancy test must be obtained. 
 Urine drug (amphetamines, methamphetamines, methadone, barbiturates, 
benzodiazepines, cocaine, opiates, methylenedioxymethamphetamine, phencyclidine, 
tetrahydrocannabinol), urine cotinine, and serum alcohol screen 
7.1.10. 
Pharmacokinetic Sampling 
Serum samples (approximately 5 mL) will be collected at the timepoints indicated in Appendix 1 
to assess the serum PK profile of PMN310.  On days when a PK sample is to be drawn and vital 
signs and/or an ECG are to be recorded, the PK sampling should be done shortly after 
completion of the vital signs and ECG.  Details for collection, handling, and shipment of 
specimens are provided in the Laboratory Manual. 
7.1.11. 
Antidrug Antibodies 
Serum samples will be collected to evaluate the levels of ADAs to PMN310 per the schedule in 
Appendix 1.  Details for collection, handling, and shipment of specimens are provided in the 
Laboratory Manual. 
7.1.12. 
Exploratory Biomarkers 
Residual and unused serum and CSF samples will be stored for the measurement of biomarkers 
at the timepoints outlined in Appendix 1.  Retaining surplus samples from scheduled PMN310-
101 study draws and lumbar punctures will be done for all subjects consenting to the study to 
 
 
 
 
 
 
 
 
 
 
  
 
 




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 All AEs (regardless of relationship to study drug) should be recorded from the time of 
informed consent through the follow-up visit at Week 12 (see Section 7.1.15.6).  
Complications that occur in association with any procedure should be recorded as 
AEs with assessed severity whether or not the procedure was protocol mandated. 
 In general, an abnormal diagnostic or laboratory value should not be recorded as an 
AE unless it is associated with clinical signs or symptoms (i.e., assessed as clinically 
significant), requires an intervention, results in an SAE, or results in study 
termination or interruption/discontinuation of study treatment.  When recording an 
AE resulting from a diagnostic or laboratory abnormality, the medical condition or 
diagnosis rather than the abnormality itself should be recorded (e.g., 
 
7.1.15.1. Definition of a Serious Adverse Event 
In this study, an SAE is defined as an AE that meets any of the following criteria: 
 Results in death 
 Is life-threatening:  The term life-threatening in the definition of an SAE refers to an 
event in which the subject was at risk of death at the time of the event.  The term life 
threatening does not refer to an event that, had it occurred in a more severe form, 
might have caused death.  
 Requires hospitalization or a prolongation of an existing hospitalization:  In general, 
hospitalization signifies that the subject has been detained at the hospital or 
emergency ward for observation or treatment that would not have been appropriate in 
ing.  Complications that occur during 
hospitalization are AEs, but not necessarily SAEs.  A medical occurrence or 
complication that prolongs hospitalization is an SAE.  When there is doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered an 
SAE.  Hospitalization for elective treatments of a preexisting condition that did not 
worsen from its original baseline level is not considered an SAE. 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions:  This does not include AEs of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza 
and accidental trauma (e.g., sprained ankle) that may interfere or prevent everyday 
life functions but do not constitute a substantial disruption. 
 A congenital anomaly or birth defect 
 Other important medical event:  Medical or scientific judgment should be exercised 
when deciding whether reporting is appropriate for other important medical events 
that may not result in death, be life-threatening, or require hospitalization but still 
may jeopardize the subject or may require medical intervention to prevent one of the 
outcomes listed in this definition.  These events should also be considered serious.  
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization or in the development of drug dependency or drug abuse.  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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An SAE requires additional detailed reports and follow-up (see Section 7.1.15.8).  The content of 
these detailed reports must address the I
 The Medical Monitor 
will review the SAE to determine if it is an expected SAE (i.e., whether or not the SAE is 
identified in nature, severity, and frequency in the Investigator Brochure). 
7.1.15.2. Assessment of Adverse Event Severity 
The Investigator will assess the intensity of each AE and SAE reported during the study on the 
basis of his or her clinical judgement. 
The classifications in Table 1 should be used in assigning intensity of each AE recorded in the 
CRF. 
Table 1: 
Classification of Adverse Events by Intensity 
Intensity (Grade) 
Definition 
Mild AE (Grade 1) 
An event that is easily tolerated by the subject, 
causing minimal discomfort and not interfering 
with everyday activities. 
Moderate AE (Grade 2) 
Some interference with activity not requiring 
medical intervention 
Severe AE (Grade 3) 
 
Prevents daily activity and requires 
medical intervention 
 
An event that, at the time of occurrence, 
put the subject at risk of death or resulted 
in a persistent or significant disability or 
incapacity.  
 
An event that resulted in death.. 
AE = adverse event 
Any AE that changes in intensity or grade during a single occurrence of an AE will be recorded 
in the CRF at the highest level experienced by the subject. 
An AE that is assessed as severe should not be confused with an SAE.  Severity is a category 
used for rating the intensity of an AE (such as mild, moderate, or severe myocardial infarction).  
An AE, however, may be of relatively minor medical significance (e.g., a severe headache).  
Both AEs and SAEs can be assessed as severe.  An AE is considered serious when it meets 
criteria for one of the predefined outcomes described in Section 7.1.15.1. 
7.1.15.3. Assessment of Causality 
The Investigator must estimate the relationship between study drug and the occurrence of each 
AE or SAE by using his or her best clinical judgment.  Elements to consider for this estimate 
include the history of the underlying disease, concomitant therapy, other risk factors, and the 
temporal relationship of the AE or SAE to exposure to study drug.  The Investigator must also 
 
Because of reporting timelines, the Investigator may have minimal information to include in the 
initial SAE report.  The Investigator, however, must always assess causality for every SAE 
before transmitting the SAE report.  The Investigator may change his or her opinion regarding 
 
 
 
  
 
 
 
 
 
 
  
 
 


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causality in light of follow-up information, with subsequent amendment of the SAE report.  
Causality assessment is 1 of the criteria used to determine regulatory reporting requirements, and 
should not be left blank on the CRF.  The same applies to AEs that are to be processed as SAEs.  
The causal relationship of the study drug to an AE will be rated according to the following 
3-point scale:  
 Unlikely:  Does not follow a reasonable temporal sequence from study drug 
administration; ma
environmental factors or other therapies administered  
 Possible:  Follows a reasonable temporal sequence from study drug administration; 
 environmental factors or 
other therapies administered  
 Probable: Clear temporal association with improvement on cessation of study drug. 
Reappears upon re-challenge or follows a known pattern of response to the study drug  
For regulatory purposes, the following definitions will apply:  
 Related Adverse Event:  
 
 Unrelated Adverse Event: An unrelated AE is an AE with a causality rating of 
 
7.1.15.4. Assessment of Expectedness 
An unexpected adverse drug experience is defined as any adverse drug experience, that is not 
listed in the current Investigator Brochure.  This includes events that may be symptomatically 
and pathophysiologically related to an event listed in the Investigator Brochure but differ from 
the event because of greater severity or specificity.  For example, under this definition, hepatic 
necrosis would be unexpected (by virtue of greater severity) if the Investigator Brochure only 
referred to elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and 
cerebral vasculitis would be unexpected (by virtue of greater specificity) if the Investigator 
Brochure only listed cerebral vascular accidents.  The term unexpected, as used in this definition, 
refers to an adverse drug experience that has not been previously observed (i.e., included in the 
Investigator Brochure) rather than from the perspective of such experience not being anticipated 
from the pharmacological properties of the study drug. 
7.1.15.5. Procedures for Eliciting and Recording Adverse Events 
Investigator and study personnel will report all AEs and SAEs whether elicited during subject 
questioning, or discovered during physical examination, laboratory testing and/or other means 
and should be recorded on the CRF and/or SAE Report Form, as appropriate. 
7.1.15.5.1. Eliciting Adverse Events 
An open-ended or non-directed method of questioning should be used at each study visit to elicit 
the reporting of AEs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 


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7.1.15.5.2. Recording Adverse Events 
The following information should be recorded on the Adverse Events CRF: 
 Description of the event using accepted medical terminology 
 Event onset and resolution dates 
 Whether the AE met serious criteria 
 Severity/grade 
 Relationship to study treatment or other causality 
 Outcome (final outcome) 
 Action taken with study drug 
7.1.15.5.3. Diagnosis vs. Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out of individual symptoms 
(e.g., Dyspnea is a symptom of Pneumonia, therefore, record the reached diagnosis of 
Pneumonia as the event term when determined).  Grouping of symptoms into a diagnosis should 
only be done if each component sign and/or symptom is a medically confirmed component of a 
diagnosis as evidenced by standard medical practice.  If any aspect of a sign or symptom does 
not fit into a classic pattern of the diagnosis, report the individual symptom as a separate AE. 
7.1.15.6. Reporting Periods for Adverse Events and Serious Adverse Events 
The safety reporting period for all AEs and SAEs is from the time of informed consent to the 
follow-up visit at Week 12.  All SAEs that occur after the safety reporting period and are 
considered study treatment-related in the opinion of the Investigator should also be reported to 
the Sponsor. 
Serious adverse events must be followed until significant changes return to baseline levels, the 
event stabilizes (recovering/resolving) or is no longer considered clinically significant by the 
Investigator, or the subject dies or withdraws consent.  All non-serious AEs will be followed 
through the follow-up visit at Week 12.  Certain non-serious AEs of interest should be followed 
until resolution, changes return to baseline levels, or study closure. 
7.1.15.7. Recording Serious Adverse Events 
For SAEs, record the event(s) on both the CRF and an SAE Report Form (paper or electronic).  It 
should be noted that SAEs that occur prior to initiation of study drug (e.g., due to a study 
protocol procedure) will be entered into the clinical database, but not entered into the safety 
database. 
The following should be considered when recording SAEs: 
 Death is an outcome of an event.  The event that resulted in the death should be 
recorded and reported on both an SAE Report Form and CRF. 
 For surgical or diagnostic procedures, the illness leading to the surgical or diagnostic 
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should be captured in the narrative as part of the action taken in response to the 
illness. 
7.1.15.8. Reporting of Serious Adverse Events 
Any SAE occurring after the subject signs the ICF must be reported to pharmacovigilance staff 
by phone, fax, or e-mail within 24 hours of the time the Investigator becomes aware of the SAE 
(Table 2).  Any SAE reported by phone should be immediately followed up with the submission 
of the completed SAE Report Form (Table 2).  Urgent reporting of SAEs is required for the 
following reasons: 
1. 
To enable the Sponsor to fulfill the reporting requirements to the appropriate regulatory 
authority 
2. 
To facilitate discussion between the Sponsor and the Investigator about appropriate 
follow-up measures (if necessary) 
3. 
To facilitate the S
Investigators or sites in a multicenter study 
4. 
To facilitate reporting unanticipated problems involving risk to subjects to the IRB 
Table 2: 
Timeline for Reporting Serious Adverse Events 
Initial SAE Report 
Follow-up SAE Report 
Time Frame 
Document 
Time Frame 
Document 
24 hours 
SAE report 
7 days 
Updated SAE report 
SAE = serious adverse event. 
The SAE report will be completed as thoroughly as possible, including the following: 
 Subject identification information 
 Event term 
 All available details about the SAE 
 Causality of each SAE  
 Signature of the Investigator 
The SAE report will be forwarded to pharmacovigilance staff within designated time frames.  If 
additional information to complete the SAE report is needed, the Investigator will not wait 
before notifying pharmacovigilance staff of the SAE.  The SAE report will be updated by the 
Investigator when additional information is received. 
7.1.15.9. Pregnancy 
All pregnancies or suspected pregnancies occurring in either a female subject or female partner 
of a male subject are immediately reportable events. 
In the event that a pregnancy or suspected pregnancy (including elevated beta-human chorionic 
gonadotropin or positive pregnancy test in a female subject) should occur while the subject is on 
study drug, or within 120 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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immediately reportable event.  The pregnancy, suspected pregnancy, or positive pregnancy test 
must be reported to the study pharmacovigilance group immediately by email using the 
Pregnancy Reporting Form. 
The female subject may be referred to an obstetrician-gynecologist or another appropriate 
healthcare professional for further evaluation. 
The Investigator will follow the female subject until completion of the pregnancy and must 
notify immediately about the outcome of the pregnancy (normal or abnormal outcome) by 
sending to the study pharmacovigilance group using the Pregnancy Follow-up Report Form. 
If the outcome of the pregnancy was abnormal (e.g., spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to the study pharmacovigilance group within 24 hours of 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 30 days that the Investigator suspects is 
related to the in-utero exposure to the study drug should also be reported to the study 
 
Male subjects:  If a female partner of a male subject receiving study drug becomes pregnant, the 
male subject taking study drug should notify the Investigator, and the pregnant female partner 
should be advised to call their healthcare provider immediately. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8. 
STUDY TERMINATION AND SUBJECT DISCONTINUATION 
8.1. 
Study Termination 
If the Sponsor, Investigator, Medical Monitor, or appropriate regulatory officials discover 
conditions arising during the study that indicate that the study should be halted or that the site 
should be terminated, this action may be taken after appropriate consultation among the Sponsor, 
Investigator, and Medical Monitor.  Conditions that may warrant termination of the study 
include, but are not limited to, the following: 
 The discovery of an unexpected, serious, or unacceptable risk to subjects enrolled in 
the study 
 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product 
 A study conducted at a single site in a multicenter study also may warrant termination 
under the following conditions: 
 Failure of the Investigator to enroll subjects into the study at an acceptable rate 
 Failure of the Investigator to comply with pertinent regulations of appropriate 
regulatory authorities 
 Submission of knowingly false information from the site to the Sponsor, Medical 
Monitor, or appropriate regulatory authority 
 Insufficient adherence to protocol requirements 
Study termination and follow-up will comply with conditions set forth in ICH E6, Guideline for 
Good Clinical Practice, Sections 4.12, 4.13, 5.20, and 5.21. 
8.2. 
Removal or Early Withdrawal of Subjects from Therapy or 
Assessment 
8.2.1. 
Removal of Subjects from Therapy or Assessment 
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care. 
The Sponsor or its designee must be notified if a subject is withdrawn from study treatment or 
and CRF.  
Subjects who withdraw from treatment prematurely should complete an Early Termination Visit 
(Section 6.3) as soon as possible. 
8.2.1.1. 
Potential Criteria for Withdrawal from Study 
Any of the following events are possible reasons for subject discontinuation from the study: 
 Subject is noncompliant with the study procedures or medications. 
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 Subject has one or more clinically significant out-of-range laboratory values or 
clinically significant abnormal findings on physical examination. 
The Investigator may contact the Medical Monitor to discuss a potential withdrawal of a subject 
from the study for one of these or other reason. 
8.2.2. 
Definite Criteria for Withdrawal from Study 
Subjects must be discontinued from the study if any of the following events occur: 
 Adverse events (AEs) that are intolerable (as determined by the subject) or that put 
the subject at additional risk as judged by the Investigator 
 Subject develops an illness that would interfere with his or her continued 
participation. 
 Subject withdraws his or her consent. 
 Confirmation of subject pregnancy during the study, as evidenced by a positive 
pregnancy test. 
 
subject. 
 The Sponsor or a regulatory agency terminates the study. 
8.3. 
Replacement of Study Subjects 
Sentinel group subjects who discontinue before Day 7 will be replaced, unless they discontinued 
due to an SAE related to study drug. 
Non-sentinel group subjects who discontinue before Day 7 may be replaced at the discretion of 
the Sponsor and the SRC. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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9. 
STATISTICAL ANALYSIS PLAN 
9.1. 
General Overview 
A formal statistical analysis plan will be developed and finalized prior to unblinding the data.  
This plan will define the healthy population for analysis, outline all data handling conventions, 
and specify all statistical methods to be used for analysis of the data. 
9.2. 
Determination of Sample Size 
A total of 40 subjects will be enrolled across 5 dose cohorts.  Cohort 5 is optional.  Each dose 
cohort will consist of 8 subjects (6 PMN310, 2 placebo).  The sample size of 8 subjects per 
cohort is based on feasibility and precedent for Phase 1 FIH studies.  The sample size of this 
study is not based on statistical considerations; 
 
 
 
9.3. 
Analyzed Population Sets 
 The safety population will include all subjects who receive study drug. 
 The PK population will include all subjects who receive study drug and have at least 
1 sample for PK analysis. 
 The evaluable population will include all subjects who complete at least 1 postdose 
LP. 
9.4. 
Statistical Analyses 
9.4.1. 
Safety Analysis 
Only subjects in the safety population will be included in the safety analysis.  Safety and 
tolerability results including vital signs, MRI if/when indicated, ECGs, laboratory test results, 
physical and neurological examinations, AEs/SAEs, serum ADA, and C-SSRS from this study 
will be assessed using summary statistics by cohort (e.g., n, mean, median, minimum, maximum, 
for continuous endpoints; n and percentages for binary and categorical endpoints).  All placebo 
subjects from the different cohorts will be combined into a single group for summary purposes. 
9.4.2. 
Pharmacokinetic Analysis 
The PK population will be used for the PK analysis.  PMN310 serum concentration data will be 
listed by cohort, subject, and visit/sampling time point.  Descriptive summary statistics will be 
provided by cohort and visit/sampling time point.  Summary statistics will include mean 
(arithmetic and geometric), standard deviation (SD), coefficient of variation (CV) (arithmetic 
and geometric), median, minimum, and maximum.  Concentrations below lower limit of 
quantitation will be treated as zero in summary statistics. 
On the basis of PMN310 concentration -time data, the following PK parameters will be 
estimated using standard noncompartmental methods using Phoenix® WinNonlin® Version 8.0 or 
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 AUC0-t, calculated by using the linear-log trapezoidal rule: linear trapezoidal rule up 
to maximum concentration, and then a log trapezoidal rule for the remainder of the 
curve, where t corresponds to the last measurable time point 
 AUC0-  = AUC0-t + Ct
z, where Ct is the last measurable serum PMN310 
z is the terminal elimination rate constant calculated by using log-
linear regression of the terminal elimination phase of the serum concentration versus 
time curve 
 Cmax of PMN310 from the observed PMN310 concentration-time data 
 Tmax of PMN310 from the observed PMN310 concentration-time data 
 t1/2 
z 
 Vd = volume of distribution during the terminal phase 
 CL = total body clearance 
 
= terminal elimination rate constant  
PK parameters will be summarized by cohort using descriptive statistics (e.g., n, arithmetic 
means, geometric means, SD, %CV, median, minimum, and maximum).  Figures will be created 
to display mean and individual subject PMN310 concentration time curves in serum on both a 
linear and logarithmic scale.   
Dose proportionality of PMN310 will be assessed using a power model.  The PK parameters to 
be analyzed are Cmax and AUClast.  A natural logarithmic transformation will be applied for the 
power model, which implies to a general linear model to the log transformed PK parameter with 
a fixed continuous log-
).  An 
assessment of the relationship between the doses of PMN310 and the PK parameters will be 
obtained from the estimate of the slope and the corresponding 90% confidence interval. 
Cerebrospinal fluid (CSF) PMN310 concentrations will be listed by cohort, participant and 
summarized by cohort.  Summary statistics will include mean (arithmetic and geometric), SD, 
CV (arithmetic and geometric), median, minimum and maximum. 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
   


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10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
 Training of site personnel on all protocol procedures during site initiation visits 
 Routine study site monitoring 
 CRF review against source documents 
 Data management quality control checks 
In addition, the Sponsor or designee may conduct periodic site audits.   
10.1. 
Study Monitoring and Site Audits 
Representatives designated by the Sponsor will monitor the clinical study in accordance with 
current FDA, ICH, national and local regulations and guidelines.  During the clinical study, 
Clinical Monitors will visit the study site(s) on a regular basis to assess and assure satisfactory 
enrollment rates, data recording, maintenance of required regulatory documentation, and 
protocol compliance.  The Investigator must ensure that all requested materials, including subject 
charts, CRFs, source documents, laboratory records, and study drug inventory records are 
available to the Clinical Monitor.  The Investigator must also ensure that he/she and other 
qualified personnel are available at each study site visit to discuss and resolve any study-related 
issues. 
As stipulated by 21 CFR 312.58 and ICH guidelines for Good Clinical Practice (GCP), 
representatives of the Sponsor, the FDA, or other regulatory agencies may conduct periodic 
study site audits.  These representatives must have access to all requested materials, including 
subject charts, CRFs, source documents, laboratory records, and study drug inventory records. 
10.2. 
Case Report Forms 
Authorized site personnel will complete electronic CRFs designed for this study and provided by 
the CRO.  The Investigator will ensure that the CRFs are accurate, complete, legible, and 
completed in a timely fashion.  CRF completion guidelines and instructions for transmitting the 
CRFs to the Sponsor or designee will be provided.   
10.3. 
Source Documentation 
As stipulated by 21 CFR 312.57 and ICH guidelines for GCP, source documentation for this 
clinical study must be maintained to document the treatment and study course of subjects, and to 
substantiate the integrity of the clinical study data submitted for review to the regulatory 
agencies.  Source documentation for clinical studies includes, but is not limited to, the following: 
 Hospital, clinic, or office records documenting study visits, including treatments with 
PMN310 and other treatments or procedures 
 Medical history and physical examination information 
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 Medical consultations 
The Investigator must ensure that source documents that are required to verify the validity and 
completeness of data transcribed on the CRFs are never obliterated or destroyed.  Refer to 
Section 12.2 for record retention requirements. 
The Investigator must ensure that source documentation is accessible to appropriate study 
personnel for purposes of study monitoring and site audits as described in Section 10.1.   
10.4. 
Data Management 
Data will be collected on CRFs as described in Section 10.2, entered into a clinical database, 
reviewed for data quality, completeness, timeliness of data entry, and protocol compliance, and 
analyzed by the Sponsor and its designated representatives.   
 


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11. 
ETHICAL CONSIDERATIONS 
11.1. 
Institutional Review Board or Independent Ethics Committee 
This protocol, the informed consent, Investigator Brochure, and any other relevant supporting 
information (e.g., all advertising materials) must be reviewed and approved by an appropriate 
IRB/Independent Ethics Committee (IEC) before study initiation.  A letter confirming IRB/IEC 
approval of the protocol and informed consent, and a statement that the IRB/IEC is organized 
and operates according to GCP guidelines and the applicable laws and regulations, must be 
provided to Sponsor before screening subjects for the study.  Amendments to the protocol must 
also be approved by the IRB/IEC and local regulatory agency, as appropriate, before the 
implementation of changes in this study (Section 11.3). 
The Investigator is responsible for informing the IRB/IEC of the progress of the clinical study as 
appropriate and updating the IRB/IEC at least annually.  Investigators are required to promptly 
submit Safety Reports or other updated safety information (e.g., amended Investigator Brochure) 
to the IRB/IEC. 
The IRB/IEC may have other specific reporting requirements with which the Investigator is 
expected to comply. 
11.2. 
Ethical Conduct of the Study 
The study will be conducted in accordance with the ethical principles that have their origins in 
the Declaration of Helsinki.   
11.3. 
Protocol Revisions and/or Deviations 
Substantive changes in the protocol include changes that affect the safety of subjects or changes 
that alter the scope of the investigation, the scientific quality of the study, the experimental 
design, dosages, assessment variable(s), the number of subjects treated, or the subject-selection 
criteria.  Such changes must be prepared as a protocol amendment by the Sponsor and 
implemented only upon joint approval of the Sponsor and the Investigator.  A protocol 
amendment must receive IRB/IEC approval before implementation.  In parallel with the 
IRB/IEC approval process, the protocol amendment will be submitted to the appropriate 
regulatory authority as an amendment to the regulatory submission under which the study is 
being conducted.  If a protocol amendment requires changes in the ICF, the revised ICF prepared 
by the Investigator also must be approved by the Sponsor, Medical Monitor, and the IRB/IEC 
before implementation. 
Departures from the protocol are allowed only in situations that eliminate an immediate risk to a 
subject and that are deemed crucial for the safety and wellbeing of that subject.  The Investigator 
or the attending physician also will contact the Medical Monitor as soon as possible in the case 
of such a departure.  These departures do not require preapproval by the IRB; however, the IRB 
and Medical Monitor must be notified in writing as soon as possible after the departure has been 
made.  In addition, the Investigator (
for the protocol deviation and the ensuing events. 
 
 
 
 
 
 
 
 
 
 


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11.4. 
Subject Information and Consent 
The IRB/IEC-approved ICF and Subject Information Sheet, if required, must be provided by the 
Sponsor.  The Investigator or designee must explain to the subject the purpose and nature of the 
study, the study procedures, the possible adverse effects, and all other elements of consent as 
defined in 21CFR Part 50 and other applicable national and local regulations governing ICF.   
Before the performance of any protocol-specific procedures that would not otherwise be done for 
a subject, a written and signed ICF must be obtained from the subject.  The form must be signed 
authorized representative if the subject is 
unable to sign.  A copy of the ICF must be provided to the subject.  If applicable, it can be 
provided in a certified translation into the local language.  Signed ICFs must remain in each 
 must be available for verification by the Medical Monitor or regulatory 
agencies at any time.  
In the United States, subjects must also sign a Health Insurance Portability and Accountability 
Act (HIPAA)-compliant authorization containing the mandated core elements and requirements 
prior to participating in a clinical study. 
11.5. 
Personal Data Protection 
third parties other than those noted below is prohibited.  This information is protected as 
mandated by HIPAA (45 CFR Subpart E) for subjects in the United States.  Further, each subject 
is assigned a unique identification number to correspond to data entered into computer databases 
and used in reports.   
Because of the experimental nature of this treatment, the Investigator agrees to allow the 
IRB/IEC, representatives of the Sponsor, its designated agents and authorized employees of the 
appropriate regulatory agencies to inspect the facilities used in this study and, for purposes of 
verification, allow direct access to the hospital or clinic records of all subjects enrolled into this 
study.  This includes providing de-identified copies of radiology or laboratory results when 
requested by the Sponsor.  A statement to this effect will be included in the informed consent and 
permission form authorizing the use of protected health information. 
physician or other appropriate medical 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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12. 
STUDY ADMINISTRATION 
12.1. 
Investigator Site File 
The following documentation concerning the Investigator and study staff, the IRB/IEC, and the 
institution is required before site initiation: 
 Signed protocol and protocol amendment(s) if applicable 
 Signed statement of Investigator (if required by the regulatory agency) 
 Institutional review board IRB/IEC composition 
 Document indicating IRB/IEC approval of the final protocol and amendment(s) if 
applicable (to include name, address, and chairperson of the IRB/IEC) 
 Document indicating IRB/IEC approval of the final and revised ICF if applicable (to 
include name, address, and chairperson of the IRB/IEC) 
 Blank copy of the IRB/IEC-approved final and revised ICF 
 Document indicating IRB/IEC approval of subject materials study advertisement, if 
applicable (to include name, address, and chairperson of the IRB/IEC) 
 
 
 Laboratory certification or accreditation and normal ranges for tests that are 
performed in the laboratory for study assessments 
 Curricula vitae and if applicable, medical license for the Investigator and 
subinvestigator(s) listed on the Form FDA 1572 of the study 
 Financial disclosure (as required) for the Investigator and subinvestigator(s) listed on 
the Form FDA 1572 of the study 
obligations, the Investigator Brochure, the clinical study protocol and amendments, safety 
information, clinical study material, biological samples, laboratory, Pharmacy Manual, 
monitoring activities, Sponsor/Investigator/Medical Monitor correspondence, will be kept on-site 
in study site specific binders. 
12.2. 
Retention of Study Records 
According to ICH E6, Section 4.9, all CRFs, as well as supporting paper and electronic source 
documentation and administrative records, must be retained by the Investigator until at least 
2 years after the last approval of a marketing application and until there are no pending or 
contemplated marketing applications, or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product in the United States.  
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor.  The Sponsor is responsible for 
informing the Investigator and institution as to when these documents no longer need to be 
retained.  No study documents will be destroyed or moved to a new location without prior 
written approval from the Sponsor.  If the Investigator relocates, retires, or withdraws from the 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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study for any reason, all records required to be maintained for the study should be transferred to 
an agreed-upon designee, such as another Investigator at the institution where the study was 
conducted. 
Audit trails for electronic document must be retained for a period at least as long as the period 
records to which they pertain.  The Investigator must retain 
either the originals of the audit trails or a certified copy of the audit trails. 
12.3. 
Publication and Disclosure Policy 
Sponsor may use the results of this clinical study in registration documents for regulatory 
authorities in the United States or abroad.  Publication of any study results in papers, abstracts, 
posters or other material presented at scientific meetings or published in professional journals 
must be approved by Sponsor. 
 
 
 
 
 






PMN310-101 
Version 2.0; 22 September 2023 
PMN310 
ProMIS Neurosciences 
Confidential 
Page 61 
14. 
APPENDICES 






PMN310-101
Version 1.0, 10 March 2023
PMN310 
ProMIS Neurosciences 
Confidential 
Page 64 
9 FSH will be evaluated for post-menopausal women only.  Post-
 
10 Pregnancy test is not required for post-menopausal women.  Serum human chorionic gonadotropin at Screening and urinary chorionic gonadotropin thereafter.  
If a urine pregnancy test is positive, a serum pregnancy test must be obtained.  Additional details provided in Section 7.1.9. 
11 Pharmacokinetic blood sampling for serum PMN310 concentrations should be performed as follows: 
 
Day 1: before infusion, at the end of infusion, and at 0.5, 1, 2, 4, 8, and 12 hours after the end of infusion 
o 
Acceptable windows for PK sampling are as follows (exact time of PK collection is to be recorded):   
 
Pre-dose sample to be collected within 60 minutes prior to dosing  
 
0.5 to 4-hour post-dose samples to be collected ± 5 minutes  
 
8 to 12-hour post-dose samples to be collected ± 10 minutes 
 
Day 2 (24 and 36 hours) 
o 
Acceptable window for PK sampling is ± 30 minutes (exact time of PK collection is to be recorded) 
 
Day 3 (48 hours) and Day 4 (72 hours) 
o 
Acceptable windows for PK sampling are ± 60 minutes (exact time of PK collection is to be recorded) 
 
Days 8, 15, 29, 43, 57, 85 
12 Note: Residual or unused  serum and CSF samples will be stored for future use for the measurement of biomarkers.  For Day 120, only serum will be stored for 
the measurement of biomarkers since CSF will not be collected at Day 120.  Additional details are provided in Section 7.1.12. 
13 CSF samples will be obtained via lumbar puncture (LP).  All dose cohorts will have LPs on Day 3 and Day 29.  The timing of additional LPs will be based on 
the available serum PK and CSF concentrations of PMN310 from prior cohorts, and may potentially include Day 15, Day 57, or Day 85 (shown in parentheses 
in the Schedule of Assessments).  The timing of LPs will be communicated to the Investigator who will inform the subject.  Coagulation (INR/PT/PTT and 
platelet) results within 2 days prior to the LP must be confirmed and determined to be within normal range before LP.  No subject will have more than 3 total 
LPs.  Post LP, subjects will remain supine for a minimum of 4 hours, and may be kept longer for observation at the discretion of the Investigator.  After the 4-
hour observation period, safety and tolerability will be assessed and subjects will be discharged home. 
14 AE assessment of protocol-related procedures will be performed after informed consent is obtained.  
15 Following completion of the postdose outpatient follow-up period, subjects may return for an optional follow-up visit, if warranted by previous data.  The 
decision to recommend the optional follow-up visit will be made by the Sponsor and communicated to the Investigator who will notify the subject about the 
timing of the optional visit.  Additional details are provided in Section 6.2.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

SAP_001.pdf: 
Study PMN310-101 
ProMIS Neurosciences, Inc
PMN310 
SAP Final v1.0
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Protocol Title: 
A Phase 1, Double-Blind, Placebo-Controlled, Single Ascending 
Dose Study of the Safety, Tolerability, and Pharmacokinetics of 
PMN310 Infusions in Healthy Volunteers 
Protocol Number: 
PMN310-101 
Phase: 
Phase 1 
Sponsor: 
ProMIS Neurosciences, Inc. 
1 Broadway  
Cambridge, MA 02142 
SAP Version 
SAP Final v1.0 
 
SAP Date: 
 
07MAR2024 
 
 
 
 
 
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Study PMN310-101 
ProMIS Neurosciences, Inc
PMN310 
SAP Final v1.0
 
CONFIDENTIAL 
 
Page 4 of 32 
 
1 TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...........................................................................................4 
2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...........................6 
3 
INTRODUCTION ......................................................................................................8 
3.1 
Preface .....................................................................................................................8 
3.2 
Purpose of Analyses ...............................................................................................8 
3.3 
Summary of Statistical Analysis Changes to the Protocol .................................8 
4 
STUDY OBJECTIVES AND ENDPOINTS ............................................................8 
4.1 
Study Objectives.....................................................................................................8 
4.1.1 
Primary Objectives ..........................................................................................8 
4.1.2 
Secondary Objectives.......................................................................................9 
4.1.3 
Exploratory Objectives ....................................................................................9 
4.2 
Study Endpoints .....................................................................................................9 
4.2.1 
Primary Endpoints...........................................................................................9 
4.2.2 
Secondary Endpoints .......................................................................................9 
4.2.3 
Exploratory Endpoints ....................................................................................9 
5 
STUDY METHODS ...................................................................................................9 
5.1 
General Study Design and Plan ............................................................................9 
5.2 
Dose Levels ...........................................................................................................14 
5.3 
Dose Escalation/Stopping Rules .........................................................................14 
5.4 
Subject Replacement Rules .................................................................................14 
5.5 
End of Study Definition .......................................................................................15 
5.6 
Safety Review Committee....................................................................................15 
5.7 
Randomization and Blinding ..............................................................................15 
5.7.1 
Randomization and Blinding ........................................................................15 
5.7.2 
Unblinding for an Individual Subject ..........................................................15 
6 
STATISTICAL CONSIDERATIONS ....................................................................16 
6.1 
Sample Size ...........................................................................................................16 
6.2 
Analysis Populations ............................................................................................16 
6.3 
Covariates and Subgroups ..................................................................................16 
6.4 
Management of Analysis Data ............................................................................17 
6.4.1 
Baseline ...........................................................................................................17 
6.4.2 
Data Handling ................................................................................................17 
6.4.3 
Missing Data ...................................................................................................17 
6.4.3.1 
Handling of Missing Date Values ...........................................................17 
6.4.3.2 
Imputation Methods ................................................................................18 
6.4.4 
Handling of Early Termination Visit Information .....................................18 
6.4.5 
Handling of Clinical Laboratory Results .....................................................18 
6.4.6 
Coding Conventions for Events and Medications .......................................19 
6.4.7 
Analysis Software ...........................................................................................19 
6.4.8 
Study Data ......................................................................................................19 
6.5 
Planned Study Analyses ......................................................................................19 
6.5.1 
Statistical Summaries: Descriptive and Inferential ....................................19 
6.5.2 
Interim Analyses and Data Monitoring .......................................................20 
6.6 
Statistical Tests .....................................................................................................20 
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6.7 
Multiplicity ...........................................................................................................20 
7 
SUMMARY OF STUDY DATA..............................................................................20 
7.1 
Subject Disposition...............................................................................................20 
7.2 
Protocol Deviations ..............................................................................................20 
7.3 
Demographics and Baseline Characteristics .....................................................21 
7.4 
Medical History ....................................................................................................21 
7.5 
Prior and Concomitant Medications ..................................................................21 
7.6 
Treatment Compliance and Exposure ...............................................................22 
8 
PRIMARY ENDPOINTS ANALYSES ..................................................................22 
8.1 
Adverse Events .....................................................................................................22 
8.2 
Serious Adverse Events and Other Significant Adverse Events ......................23 
8.2.1 
Serious Adverse Events .................................................................................23 
8.2.2 
Adverse Events Leading to Discontinuation of Study Drug ......................23 
8.3 
Clinical Laboratory Evaluations ........................................................................23 
8.4 
12-Lead Electrocardiogram (ECG) ....................................................................24 
8.5 
Physical and Neurological Examinations...........................................................24 
8.6 
Vital Signs and Anthropometrics .......................................................................24 
8.7 
Magnetic Resonance Imaging (MRI) .................................................................25 
8.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) ..........................................25 
8.9 
Other Measures ....................................................................................................25 
9 
SECONDARY ENDPOINTS ANALYSES ............................................................25 
9.1 
Serum Pharmacokinetic Analyses ......................................................................26 
9.1.1 
General Considerations .................................................................................26 
9.1.2 
Pharmacokinetic Endpoints ..........................................................................27 
9.1.2.1 
Serum Pharmacokinetic Parameters .....................................................27 
9.1.2.2 
Dose Proportionality ................................................................................29 
9.2 
Cerebrospinal Fluid (CSF) Pharmacokinetic Analyses ...................................29 
10 EXPLORATORY ENDPOINT ANALYSES .........................................................30 
10.1 
Immunogenicity....................................................................................................30 
10.2 
Biomarkers ...........................................................................................................31 
11 REFERENCES .........................................................................................................32 
 
 
LIST OF TABLES 
 
Table 1 
Schedule of Assessments ..........................................................................11 
Table 2 
Planned Study Drug Dose Levels............................................................14 
 
 LIST OF FIGURES 
 
Figure 1 Study Schema Per Cohort ................................................................................10 
 
 
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2 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Only abbreviations and terms relevant to the SAP are repeated herein. The reader is referred to 
the protocol for the complete and comprehensive list of abbreviations and definitions of terms for 
the study.  
Abbreviation 
Definition 
ADA 
antidrug antibody 
ADaM 
Analysis Data Model 
AE 
adverse event 
ARIA 
amyloid-related imaging abnormality 
ATC 
Anatomical Therapeutic Chemical 
AUC0-t 
area under the curve from Time 0 to last sampling time 
AUC0-∞ 
area under the curve from Time 0 to infinity 
AUCextrap 
Area under the curve extrapolated from time t to infinity 
AUClast 
area under the curve to the last timepoint 
BLQ 
Below the limit of quantification 
BMI 
body mass index 
C 
Celsius 
CDISC 
Clinical Data Interchange Standards Consortium 
Cend of infusion 
Concentration at the end of infusion 
CL 
clearance 
Clast 
Concentration corresponding to the time of last measurable 
concentration 
Cmax 
maximum observed concentration 
CRF 
case report form 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
ET 
early termination 
FDA 
Food and Drug Administration 
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Abbreviation 
Definition 
FIH 
first in human 
FSH 
follicle-stimulating hormone 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
IV 
intravenous 
lambda_z (λZ) 
Terminal elimination rate constant 
LLOQ 
Lower limit of quantification 
LP 
lumbar puncture 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCA 
non-compartmental analysis 
PK 
pharmacokinetic 
PT 
preferred term 
QTcF 
QT interval corrected by Fridericia 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SOC 
System organ class 
SOP 
standard operating procedure 
SRC 
Safety Review Committee 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
tlast 
Time of last measurable concentration 
tmax 
time to Cmax 
USA 
United States of America 
Vd 
volume of distribution 
WHO-DD 
World Health Organization – Drug Dictionary 
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3 INTRODUCTION   
3.1 
Preface 
This document presents the statistical analysis plan (SAP) for study PMN310-101 (A Phase 1, 
Double-Blind, Placebo-Controlled, Single Ascending Dose Study of the Safety, Tolerability, and 
Pharmacokinetics of PMN310 Infusions in Healthy Volunteers).   
Reference materials for this statistical plan include the PMN310-101 study protocol v2.0 (dated 
22-September-2023), protocol clarification letter #1 (dated 09-October-2023), protocol 
clarification letter #2 (dated 26-October-2023), protocol clarification letter #3 (dated 16-
November-2023), and Guidance for Industry: E9 Statistical Principles for Clinical Trials (1998).
The SAP described hereafter is an a priori plan. Any changes to this SAP will be finalized and 
approved prior to database lock. Statistical programming may occur as study data accumulate so 
that analysis programs are ready at study completion. Any future amendments made to the 
protocol will not necessitate amendments to the SAP unless changes in the protocol result in 
changes to key analyses.    
3.2 
Purpose of Analyses 
The purposes of the planned analyses described in this SAP are to establish the safety, 
tolerability, and pharmacokinetics (PK) of a single intravenous (IV) infusion of PMN310. 
Results from the analyses completed will be included in the final clinical study report for Study 
PMN310-101 and may also be utilized for regulatory submissions, manuscripts, or other clinical 
development activities. 
Post-hoc exploratory analyses not identified in this SAP may be performed to further examine 
the study data. Exploratory analyses will be clearly identified in the final clinical study report. 
Additional analyses not prospectively identified in this SAP may also be completed for 
publications or regulatory or funding inquiries. These analyses, if performed, may not be 
reported in the clinical study report but will be fully documented in the document containing the 
additional analyses. 
3.3 
Summary of Statistical Analysis Changes to the Protocol 
The analyses described in this analysis plan are consistent with the analyses described in the 
study protocol and protocol clarification letters.  
4 STUDY OBJECTIVES AND ENDPOINTS 
4.1 
Study Objectives 
4.1.1 
Primary Objectives 
•
To assess safety and tolerability of escalating doses of PMN310 when administered as
a single IV infusion in healthy volunteers
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4.1.2 
Secondary Objectives 
• To assess the single dose PK of PMN310 
4.1.3 
Exploratory Objectives 
• To assess the immunogenicity of PMN310 following single dose administration 
• To assess biomarkers in healthy subjects 
4.2 
Study Endpoints 
4.2.1 
Primary Endpoints 
• Adverse events (AEs), clinical laboratory tests (clinical chemistry, hematology, 
urinalysis), physical and neurological examinations, vital signs, and 12-lead 
electrocardiograms (ECGs) 
4.2.2 
Secondary Endpoints 
• Serum PK: maximum observed concentration (Cmax), time to Cmax (tmax), area under 
the curve from Time 0 to last sampling time (AUC0-t), area under the curve from 
Time 0 to infinity (AUC0-∞), terminal half-life (t1/2), volume of distribution (Vd), 
clearance (CL) 
• Cerebrospinal fluid (CSF) drug concentrations 
4.2.3 
Exploratory Endpoints 
• Incidence and titers of antidrug antibodies (ADAs) 
• Residual and unused serum and CSF samples will be stored for future use for the 
measurement of biomarkers 
5 STUDY METHODS 
5.1 
General Study Design and Plan 
This is a randomized, placebo-controlled, single ascending dose clinical study of PMN310 in 
healthy adult volunteers.  The study aims to establish the safety, tolerability, and PK of a single 
IV infusion of PMN310.  
Subjects who provide written informed consent and meet all eligibility criteria will be admitted 
to the study clinic on Day -1 (i.e., the day prior to dosing with PMN310 or placebo).  Subjects 
will be domiciled for 4 nights with standardized meals provided during inpatient stay.  On Day 1, 
subjects will be randomly assigned to receive either a single infusion of PMN310 or placebo (6:2 
ratio).  After randomization on Day 1, study drug will be administered followed by the collection 
of safety, tolerability, and PK data for 12 weeks postdose (outpatient follow-up period).  
Following completion of the postdose outpatient follow-up period, subjects may return for an 
optional follow-up visit to evaluate PK, ADA, and exploratory biomarkers, if warranted by 
previous data.  The decision to recommend the optional follow-up visit will be made by the 
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Table 1 
Schedule of Assessments 
 
Treatment Period 
Screen 
Inpatient 
Outpatient Follow-Up 
Optional 
Follow-Up15 
Week 
-4 
0 
1 
2 
4 
6 
8 
12/ET 
17 
Day 
-28 to -1 
-1 
1 
2 
3 
41 
5 
8 
15 
29 
43 
57 
85 
120 
Window 
na 
na 
na 
na 
na 
na 
na 
± 1 
day 
± 1 
day 
± 3 
days 
± 3 
days 
± 3 
days 
± 4 
days 
± 7 
days 
Informed consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Lumbar x-rays (at investigator 
discretion) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admit to clinical research unit3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization prior to drug 
administration  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Meals and fluids4 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Discharge from clinical research 
unit 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Demography & medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical & neurologic 
examination 
X 
X 
 
 
X5 
 
 
 
 
X5 
 
 
X5 
 
Vital signs6 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
MRI 
X 
 
 
 
 
 
 
 
 
 
X7 
 
 
 
ECG8 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
HBsAg and HCV tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Treatment Period 
Screen 
Inpatient 
Outpatient Follow-Up 
Optional 
Follow-Up15 
Week 
-4 
0 
1 
2 
4 
6 
8 
12/ET 
17 
Day 
-28 to -1 
-1 
1 
2 
3 
41 
5 
8 
15 
29 
43 
57 
85 
120 
Window 
na 
na 
na 
na 
na 
na 
na 
± 1 
day 
± 1 
day 
± 3 
days 
± 3 
days 
± 3 
days 
± 4 
days 
± 7 
days 
FSH9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test10 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
Urine drug, urine cotinine, & 
serum alcohol screen 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
Clinical laboratory tests 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Serum PK collection11 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum ADA collection 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Exploratory biomarkers12 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Lumbar puncture13 
 
 
 
 
X 
 
 
 
(X) 
X 
 
(X) 
(X) 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X14 
X14 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
ADA = antidrug antibodies; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ET = early termination; FSH = follicle-stimulating 
hormone; MRI = magnetic resonance imaging; na = not applicable; PK = pharmacokinetics 
1 Date of discharge from the inpatient study clinic is at the discretion of the Investigator.  It may be extended, if needed, and is dependent on the need for further 
observation and/or care. 
2 Informed consent must be documented before any study-specific screening procedures are performed. 
3 Admission to the study clinic should occur before 6 PM. 
4 Standardized breakfast, lunch, and dinner will be provided at fixed times on each inpatient study day.  Meals are to be consumed within 45 minutes.  Evening 
snacks will be provided at a consistent time each day.  Fluids will be allowed liberally.  
5 Symptom directed physical examination and neurological examination will be performed at the indicated timepoints.  
6 Vital signs should always be collected up to 45 minutes before PK sampling (i.e., nominal time) unless otherwise indicated - before infusion, at the end of 
infusion (see protocol Section 5.2.1 for a definition for complete infusion), and at 0.5, 1, 2, 4, 8, and 12 hours after the end of infusion.  Day 2 (24 and 36 
hours), D3 (48 hours), and Day 4 (72 hours), Days 8, 15, 29, 43, 85.  Subjects should be resting supine for at least 5 minutes before the vital sign assessment; 
the exact time of assessment is to be recorded.  
7 Only subjects ≥ 50 years of age will have MRI assessments at Day 43.  If ARIA is detected, repeat MRIs will be performed every 3-4 weeks until ARIA is 
resolved.    
8 ECGs should always be performed up to 45 minutes before PK Sampling (i.e., nominal time) unless otherwise indicated - before infusion, at the end of 
infusion, and at 1, 2, 4, 8, and 12 hours after the end of infusion.  Day 2 (24 and 36 hours), D3 (48 hours), and Day 4 (72 hours), , 8, 29, and 85.  
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9 FSH will be evaluated for post-menopausal women only.  Post-menopausal status will be confirmed through testing of FSH levels (≥ 40 IU/mL). 
10 Pregnancy test is not required for post-menopausal women.  Serum human chorionic gonadotropin at Screening and urinary chorionic gonadotropin thereafter.  
If a urine pregnancy test is positive, a serum pregnancy test must be obtained.  Additional details provided in protocol Section 7.1.9. 
11 Pharmacokinetic blood sampling for serum PMN310 concentrations should be performed as follows: 
• 
Day 1: before infusion, at the end of infusion, and at 0.5, 1, 2, 4, 8, and 12 hours after the end of infusion 
o 
Acceptable windows for PK sampling are as follows (exact time of PK collection is to be recorded):   
▪ 
Pre-dose sample to be collected within 60 minutes prior to dosing  
▪ 
0.5 to 4-hour post-dose samples to be collected ± 5 minutes  
▪ 
8 to 12-hour post-dose samples to be collected ± 10 minutes 
• 
Day 2 (24 and 36 hours) 
o 
Acceptable window for PK sampling is ± 30 minutes (exact time of PK collection is to be recorded) 
• 
Day 3 (48 hours), Day 4 (72 hours) and Day 5 (96 hours) 
o 
Acceptable windows for PK sampling are ± 60 minutes (exact time of PK collection is to be recorded) 
o Day 5 (96) hours does not require inpatient collection 
• 
Days 8, 15, 29, 43, 57, 85 
12 Note: Residual or unused serum and CSF samples will be stored for future use for the measurement of biomarkers.  For Day 120, only serum will be stored for 
the measurement of biomarkers since CSF will not be collected at Day 120.  Additional details are provided in protocol Section 7.1.12. 
13 CSF samples will be obtained via lumbar puncture (LP).  All dose cohorts will have LPs on Day 3 and Day 29.  The timing of additional LPs will be based on 
the available serum PK and CSF concentrations of PMN310 from prior cohorts, and may potentially include Day 15, Day 57, or Day 85 (shown in parentheses 
in the Schedule of Assessments). The timing of LPs will be communicated to the Investigator who will inform the subject.  Coagulation results within 2 days 
prior to the LP must be confirmed and determined to be within normal range before LP.  No subject will have more than 3 total LPs.  Post LP, subjects will 
remain supine for a minimum of 4 hours, and may be kept longer for observation at the discretion of the Investigator.  After the 4-hour observation period, 
safety and tolerability will be assessed and subjects will be discharged home. 
14 AE assessment of protocol-related procedures will be performed after informed consent is obtained.  
15 Following completion of the postdose outpatient follow-up period, subjects may return for an optional follow-up visit, if warranted by previous data.  The 
decision to recommend the optional follow-up visit will be made by the Sponsor and communicated to the Investigator who will notify the subject about the 
timing of the optional visit.  Additional details are provided in protocol Section 6.2.3. 
 
 
 
 
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5.5 
End of Study Definition 
The end of the study is defined as the date of the last scheduled procedure. If there is an 
unresolved AE or concomitant medication, or an assessment date that is after the end of study, 
the date of study completion will be inclusive of that resolution/assessment date.  
A subject is considered to have completed the study if the subject did not discontinue or 
terminate the study early and has completed the last scheduled procedure as specified in the 
Schedule of Assessments.  
5.6 
Safety Review Committee 
The SRC will be responsible for the review of safety and any available PK data at the time of 
review and making determinations regarding the acceptability of proceeding with dosing of the 
remaining 6 subjects in a cohort (based on review of sentinel subjects) and dose escalation to the 
next cohort.  The SRC will be comprised of the Study Investigator, Medical Monitor, and 
Sponsor Medical Director.  At a minimum, the SRC will review safety data assessments 
collected 48 hours after the sentinel subjects have been dosed in each cohort and ≥ 7 days 
postdose for a minimum of 6 of 8 subjects per cohort prior to each dose escalation.  The SRC 
charter will specify operational details pertaining to roles and responsibilities, data to be 
reviewed, review frequency, and reporting for minutes and decisions. 
5.7 
Randomization and Blinding 
5.7.1 
Randomization and Blinding 
Each subject will be assigned a unique identification number at the screening visit. Once an 
eligible subject is at the study site and prepared to receive the study drug, the subject will be 
assigned the treatment allocation according to the randomization sequence.  The randomization 
sequence will be obtained by computer-generated random numbers and provided to unblinded 
study site staff members who will have primary responsibility for drug dispensing.  Within each 
cohort, eligible subjects will be randomized to receive PMN310 (N = 6) or placebo (N = 2). The 
screening number and randomization number are different numbers. 
Subjects and study personnel will be aware of the dosage level but will be blinded to the study 
drug administered (PMN310 or placebo).  Only unblinded study site staff members assigned to 
prepare study drug will know whether a subject receives PMN310 or placebo.  To maintain 
appropriate blinding, the unblinded pharmacist will consult the randomization sequence, prepare 
the PMN310 or placebo, and label the prepared study drug with the subject’s study identifier and 
the phrase “PMN310 or placebo.”  The unblinded pharmacy staff will then provide prepared 
study drug in a blinded fashion to the Investigator (or designee) for infusion. 
5.7.2 
Unblinding for an Individual Subject 
In case of an emergency, the Investigator has the sole responsibility of determining if unblinding 
of a subject’ treatment is warranted.  Blinding should only be broken in emergency situations when 
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knowledge of the treatment assignment is required for the assurance of the safety of the subject 
and the medical management of the subject.  The Sponsor or representative should be contacted, 
when possible, before breaking the blind except in emergency circumstances when the Investigator 
has the sole responsibility for determining the need to unblind.  Upon breaking the blind, the reason 
must be documented, and the Sponsor should be immediately notified.  
 
 
 
6 STATISTICAL CONSIDERATIONS 
6.1 
Sample Size 
A total of 40 subjects will be enrolled across 5 dose cohorts.  Cohort 5 is optional.  Each dose 
cohort will consist of 8 subjects (6 PMN310, 2 placebo).  The sample size of 8 subjects per 
cohort is based on feasibility and precedent for Phase 1 FIH studies.  
 
 
 
 
6.2 
Analysis Populations 
There will be four (4) analysis populations defined for this study. These analysis populations 
may be further refined, and additional analysis populations may be defined, for example, for the 
analysis of data for a specific assay, based on sample availability and suitability. Any changes 
will be summarized in the Clinical Study Report (CSR). 
• The Safety population will include all subjects who receive study drug.  Subjects will 
be analyzed as treated. 
• The PK population will include all subjects who receive study drug and have at least 
1 post-dose quantifiable concentration for PK analysis.  The PK population will be 
used for the serum PMN310 concentration analyses. Subjects will be analyzed as 
treated. 
• The Evaluable population will include all subjects who complete at least 1 post-dose 
lumbar puncture (LP). The Evaluable population will be used for the cerebrospinal 
fluid (CSF) PMN310 concentrations.  Residual and unused CSF samples will be 
stored for future use for the measurement of exploratory CSF biomarker analyses. 
Subjects will be analyzed as treated. 
• The Randomized population will include all subjects who were randomized. Subjects 
will be analyzed as randomized. 
6.3 
Covariates and Subgroups 
Not applicable. 
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6.4 
Management of Analysis Data 
6.4.1 
Baseline 
Unless otherwise specified, baseline data is defined as the data most recently collected prior to 
the first dose. 
Change from baseline is calculated as:  
Change from baseline = post-baseline visit value – baseline value.  
If either the baseline or visit value is missing, the change from baseline is set to “missing”. 
6.4.2 
Data Handling 
All assessments collected at scheduled and unscheduled days and time points will be included in 
the listings. For parameters that will be summarized by day and time point, the nominal day and 
time point as recorded in the CRF will be used. When the data from a scheduled assessment is 
not available, an unscheduled assessment within the assessment window defined in the Schedule 
of Assessments, if available, will be used to replace the scheduled assessment. If multiple 
unscheduled assessments are present in the assessment window, the unscheduled assessment 
closest to the nominal day and time point will be used. This algorithm will be implemented for 
chemistry, hematology, coagulation, and urinalysis labs, 12-lead ECG, vital signs, PK 
concentrations, ADA results, and exploratory biomarkers.   
Note that blood draws for international normalized ratio/prothrombin time/partial thromboplastin 
time, and platelets may be drawn a day before a scheduled lumbar puncture to ensure results are 
available in time for the lumbar puncture procedure.  The blood draw results that were obtained a 
day early will be analyzed with the scheduled blood draw results.   
6.4.3 
Missing Data 
Unless otherwise specified, there will be no substitutions made to accommodate missing data 
points. 
6.4.3.1 
Handling of Missing Date Values 
Partial or Missing Dates 
The following conventions will be used to impute missing portions of dates for adverse events, 
medical history, and prior and concomitant medications, if warranted. Note that the imputed 
values outlined here may not always provide the most conservative date. In those circumstances, 
the imputed value may be replaced by a date that will lead to a more conservative analysis. 
A. 
Start Dates 
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1)
If the year is unknown, then the date will not be imputed and will be
assigned a missing value.
2)
If the month is unknown, then:
i) If the year matches the first dose date year, then impute the
month and day of the first dose date.
ii) Otherwise, assign ‘January.’
3)
If the day is unknown, then:
i) If the month and year match the first dose date month and
year, then impute the day of the first dose date.
ii) Otherwise, assign the first day of the month.
B.
Stop Dates
1)
If the year is unknown, then the date will not be imputed and will be
assigned a missing value.
2)
If the month is unknown, then assign ‘December.’
3)
If the day is unknown, then assign the last day of the month.
6.4.3.2 
Imputation Methods 
Adverse Events 
If the relationship of an AE is missing, it will be considered treatment related. 
Missing AE severity grade will be coded as 3 (severe). 
For the purpose of final analysis, any imputed AE relationship or severity grade will be 
highlighted with an asterisk (*) in listings. 
PK Concentration and Parameter Estimation 
The rules for imputing concentration data are detailed under Pharmacokinetics (Section 9). 
6.4.4 
Handling of Early Termination Visit Information 
If a subject is terminated early from this study the early termination visit data will be analyzed at 
the closest scheduled visit. If the closest visit has valid data, the early termination data will be 
assigned to the next available visit. 
6.4.5 
Handling of Clinical Laboratory Results 
Multiple laboratories will be utilized in the study.  Prior to analysis, the clinical laboratory results 
and units will be standardized across both laboratories.  Normal ranges and the identification of 
normal/abnormal not clinically significant/abnormal clinically significant/not evaluable results 
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will not be modified, the results from the original laboratory will be used.   Full details will be 
provided in the ADaM Reviewer’s Guide. 
6.4.6 
Coding Conventions for Events and Medications 
All adverse events and medical history will be mapped to the Medical Dictionary for Regulatory 
Activities (MedDRA Version 26.1) system for reporting (preferred term and body system). 
Prior and Concomitant medications will be coded using World Health Organization – Drug 
Dictionary (WHO-DD) (Version 01SEP2022_b3). 
6.4.7 
Analysis Software 
Data manipulation, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher) for 
Windows. PK parameter estimation will be performed using Phoenix® WinNonlin® Version 8.3 
or higher. If the use of other software is warranted, the final clinical study report will detail what 
software was used and for what purposes. 
6.4.8 
Study Data 
All study data will be formulated into regulatory compliant data sets to provide transparency, 
traceability, and integrity of trial analysis results from the collection source. Observed study data 
will be mapped to the CDISC Study Data Tabulation Model (SDTM Implementation Guide v3.3) 
and serve as the source data from the trial. All study analyses will be completed using analysis 
data sets that are derived from the SDTM and follow the CDISC Analysis Data Model (ADaM 
Implementation Guide v1.1) architecture. All planned analyses will be performed using the 
ADaM data sets developed for this study. Controlled Terminology 31 March 2023 or later will 
be used. 
6.5 
Planned Study Analyses 
6.5.1 
Statistical Summaries: Descriptive and Inferential 
Descriptive summaries of variables will be provided as appropriate. In general, for continuous 
variables, the number of non-missing values (n) and the mean, standard deviation (SD), median, 
interquartile range, minimum, and maximum will be tabulated. For PK analyses, coefficient of 
variation (CV%), geometric mean and geometric CV% will also be provided, where appropriate. 
For categorical variables, the count and proportion will be tabulated. Expansion of descriptive 
table categories within and/or across each treatment may occur. 
In general, unless otherwise specified, summaries and analyses will be tabulated by PMN310 
dose level within each cohort, placebo combined into a single group over all cohorts, and overall 
(ex., Cohort 1: 175 mg, Cohort 2: 350 mg, Cohort 3: 700 mg, Cohort 4: 1400 mg, Cohort 5: 2800 
mg, All Placebo, Total).  
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All study related data collected, and all derived data will be presented in listings. Data not 
subject to analysis according to this plan will not appear in any tables or figures but will be 
included in the data listings. 
6.5.2 
Interim Analyses and Data Monitoring 
No formal interim analysis is planned for this study.  
In order to evaluate accumulating safety information and to guide study conduct, a SRC will be 
regularly convened to inform dosing decisions. The SRC membership, responsibilities, operating 
procedures, frequency of meetings, data availability, reporting, and record keeping will be 
described in detail in a separate SRC Charter. Refer to SAP Section 5.6 for more details about 
the SRC. 
6.6 
Statistical Tests 
While confidence intervals will be provided for select analyses, formal statistical hypothesis 
testing is not planned in this SAP.  
6.7 
Multiplicity 
Not applicable. 
7 SUMMARY OF STUDY DATA 
7.1 
Subject Disposition 
A summary of the analysis sets includes the number and percentage of subjects in each treatment 
group for the following categories: subjects screened, subjects in the Randomized population, 
subjects in the Safety population, subjects in the PK population, and subjects in the Evaluable 
population. All percentages will be based on the number of subjects in the Safety population.  
End of trial information will be summarized descriptively for categorical data, including the 
number of subjects completing the study and the number of subjects who prematurely 
discontinued the study with reasons for withdrawal. All percentages will be based on the number 
of subjects in the Safety population. 
For randomized subjects, a listing of eligibility, including any criteria not met and protocol 
version under which each subject was enrolled will be generated. 
Disposition data will be summarized by PMN310 dose level within each cohort, placebo over all 
cohorts, and overall. 
Disposition data will be presented in a by-subject listing. 
7.2 
Protocol Deviations 
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The number of deviations and number and percentage of subjects with protocol deviations, by 
category, will be summarized descriptively for categorical data by PMN310 dose level within 
each cohort, placebo over all cohorts, and overall for the Safety population.  
All protocol deviations will be presented in a by-subject listing. 
7.3 
Demographics and Baseline Characteristics 
Subject demographic data and baseline characteristics will be tabulated and summarized 
descriptively for continuous and categorical data by PMN310 dose level within each cohort, 
placebo over all cohorts, and overall for the Safety population. Data will include age in years, 
sex at birth, race, ethnicity, height, weight, BMI, and childbearing potential.  
Individual subject demographics and baseline characteristics will be presented in by-subject 
listings. 
7.4 
Medical History 
Medical History includes all relevant medical conditions, concomitant illness, surgeries within 
the 6 months before Screening.  For female subjects, the last menstrual period should be 
recorded. 
Medical history will be coded by system organ class (SOC) and preferred term (PT) and 
summarized descriptively for categorical data by PMN310 dose level within each cohort, 
placebo over all cohorts, and overall, for the Safety population. 
Medical history data will be presented in a by-subject listing. 
7.5 
Prior and Concomitant Medications 
All medications, including over-the-counter medications or herbal therapies, given during the 
study as well as any prior medications taken within 4 weeks prior to Screening are to be 
recorded.  
Concomitant medications are defined as any medication taken on or after the day of first dose of 
study drug. Prior medications are defined as any medication that starts and ends prior to the day 
of first dose of study drug. If the start date of a medication is missing/incomplete and the end 
date is prior to the first dose of study drug, the medication will be assumed to be a prior 
medication.  If the start date of a medication is missing/incomplete and the end date is on or after 
the first dose of study drug, the medication will be assumed to be a concomitant medication.  If 
both the start date and end date are missing/incomplete, and it is not clear when the medication 
was taken, the medication will be considered concomitant. 
The number and percentage of subjects with at least 1 concomitant medication will be 
summarized descriptively for categorical data by PMN310 dose level within each cohort, 
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placebo over all cohorts, and overall, Anatomical Therapeutic Chemical (ATC) level 4 and PT. If 
ATC level 4 is missing for a medication a higher (eg, ATC level 3) will be summarized for that 
medication. All summaries will be performed using the Safety population. Subjects will only be 
counted once within each category of medication taken. 
The number and percentages of all prior medications will be summarized similarly to 
concomitant medications in a separate table. 
Prior and concomitant medications data will be presented in a by-subject listing. 
7.6 
Treatment Compliance and Exposure 
The volume of study drug infused (mL), volume of flush used (mL), and total volume infused 
(study drug + flush) (mL) will be summarized descriptively by PMN310 dose level within each 
cohort, placebo over all cohorts, and overall, for the Safety population.  
All dosing information, including derived total exposure to PMN310, will be presented in a by-
subject listing. 
8 PRIMARY ENDPOINTS ANALYSES 
The primary objective of this study is to assess the safety and tolerability of PMN310 of 
escalating doses of PMN310 when administered as a single IV infusion in healthy volunteers.  
All safety summaries will be presented by PMN310 dose level within each cohort, placebo over 
all cohorts, and overall using the Safety population. 
8.1 
Adverse Events 
In general, the number and percentage of subjects with treatment-emergent adverse events 
(TEAEs) will be summarized descriptively for categorical data by SOC and PT. At each level of 
summarization (SOC and PT) subjects are only counted once.    
Only TEAEs will be tabulated, which are defined as any AEs with onset or worsening on or after 
the first dose of the study drug. In general, if a missing/incomplete start date is not clearly prior 
to initiation of treatment, then the AE will be considered a TEAE.  If the AE end date is prior to 
the initiation of treatment, the AE will not be considered a TEAE. 
An overall summary of TEAEs will be provided including the number and percentage of  
• 
Subjects with at least one TEAE,  
• 
Subjects with at least one study drug-related (possible or probably) TEAE,  
• 
Subjects with at least one TEAE with severity Grade 3 (Severe),  
• 
Subjects with at least one treatment-emergent serious adverse events (TESAE),  
• 
Subjects with TEAE leading to treatment discontinuation.  
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The number and percentage of subjects with any TEAEs, and frequency of events, will be 
displayed by SOC and PT. Treatment related (probable or possible relationship to PMN310 
treatment) will be summarized similarly. The number and percentage of subjects with any 
TEAEs, and frequency of events, will also be displayed by PT.   
TEAEs will also be summarized by the greatest reported severity. Counts indicate subjects 
reporting one or more TEAEs that map to the severity grade classification for each PT.  At each 
level of summarization (SOC or PT) subjects are only counted once and the worst severity case 
of repeated instances of the same TEAE will be used in tabulations. Missing severity will be 
considered as Grade 3 (Severe). 
TEAEs will also be summarized by the strongest investigator assessment of relationship to study 
drug in a similar manner to the summary of TEAEs by severity. Missing relationship will be 
considered as probably related. 
All AEs, including those that are not treatment-emergent, will be listed by subject. 
8.2 
Serious Adverse Events and Other Significant Adverse Events 
8.2.1 
Serious Adverse Events 
The number and percentage of subjects with TESAEs, and frequency of events, will be displayed 
by SOC and PT, and relationship to study drug. Within each SOC and PT, subjects will be 
counted only once if they had more than one TESAE event reported.  
All SAEs, including those that are not treatment-emergent, will be included in a by-subject 
listing. 
8.2.2 
Adverse Events Leading to Discontinuation of Study Drug  
The number and percentage of subjects with TEAEs leading to discontinuation of study drug, 
and frequency of events, will be displayed by SOC and PT. Within each SOC and PT, subjects 
will be counted only once if they had more than one TEAE leading to discontinuation of study 
drug.  
All TEAEs leading to discontinuation of study drug will be included in a by-subject listing. 
8.3 
Clinical Laboratory Evaluations 
Chemistry, hematology, coagulation, and urine clinical laboratory results will be summarized 
descriptively for continuous and categorical lab results, as appropriate, by visit for the observed 
value as well as for the change from baseline value (continuous lab results only).  
In addition, laboratory shift summary tables will be provided where normal/abnormal not 
clinically significant/abnormal clinically significant/not evaluable status is collected on the CRF. 
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For each of these lab tests, the shift table will tabulate the number and percentage of subjects that 
shifted from normal/abnormal not clinically significant/abnormal clinically significant/not 
evaluable at Baseline to normal/abnormal not clinically significant/abnormal clinically 
significant/not evaluable at each post-Baseline visit. Percentages will be based on the number of 
subjects with non-missing status at Baseline and each post-Baseline visit. 
Individual laboratory parameters by visit with normal ranges, and abnormal laboratory 
assessments will be included in by-subject listings. 
8.4 
12-Lead Electrocardiogram (ECG) 
Continuous ECG parameter data (heart rate (bpm), PR interval (msec), QRS interval (msec), QT 
interval (msec), and QTcF interval (msec)) will be summarized descriptively for continuous data 
for the observed value as well as for change from baseline value.  
In addition, the number and percentage of subjects with ECG assessments, as reported on the 
CRF, of normal, abnormal not clinically significant, and abnormal clinically significant will be 
summarized categorically. Percentages will be based on the number of subjects with non-missing 
response at each visit and timepoint. 
A categorical summary table describing the n (%) of subjects meeting the below thresholds at 
any post-baseline visit/time point will be generated. 
QTcF Pre-Defined Thresholds 
• 
QTcF > 450 msec 
• 
QTcF > 480 msec 
• 
QTcF > 500 msec 
• 
QTcF increased by > 30 msec from baseline 
• 
QTcF increased by > 60 msec from baseline 
All ECG data will be presented in a by-subject listing. Subjects meeting pre-defined threshold 
values for QTcF will be flagged. 
All abnormal ECG data (abnormal not clinically significant and abnormal clinically significant) 
will be presented in a by-subject listing. Subjects meeting pre-defined threshold values for QTcF 
will be flagged. 
8.5 
Physical and Neurological Examinations 
All physical examination and neurological examination data will be presented in by-subject 
listings. 
8.6 
Vital Signs and Anthropometrics 
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Vital signs data collected include systolic blood pressure (SBP) (mmHg), diastolic blood 
pressure (DBP) (mmHg), pulse rate (bpm), respiratory rate (breaths/min), oral temperature (C), 
weight (kg), and BMI (kg/m2) and will be summarized descriptively for continuous data by visit 
and timepoint for the observed value as well as for the change from baseline value, where 
available.   
A categorical summary table describing the n (%) of subjects meeting the below thresholds at 
any post-baseline visit/timepoint will be generated. 
Vital Sign Pre-Defined Thresholds 
• 
SBP > 180 mmHg (High) 
• 
SBP < 90 mmHg (Low) 
• 
DBP > 110 mmHg (High) 
• 
DBP < 50 mmHg (Low) 
• 
SBP increased by ≥ 30 mmHg from baseline 
• 
SBP decreased by ≥ 30 mmHg from baseline 
• 
DBP increased by ≥ 20 mmHg from baseline 
• 
DBP decreased by ≥ 20 mmHg from baseline 
All vital signs data will be presented in a by-subject listing.  
8.7 
Magnetic Resonance Imaging (MRI) 
MRI results for subjects where amyloid-related imaging abnormalities (ARIA) are detected will 
be presented in a by-subject listing. 
All centrally read MRI data will be presented in a separate by-subject listing. 
8.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
C-SSRS questions since last visit will be summarized descriptively. 
All C-SSRS data will be presented in by-subject listings. 
8.9 
Other Measures 
Urine drug, urine cotinine and alcohol screening; infectious disease tests; meal consumption 
data, and serum and urine pregnancy test data will be presented in by-subject listings. 
If after the study results are reviewed, or Sponsor recommends additional safety parameters or 
analyses be completed, they will be fully described and documented in the final clinical study 
report. The SAP does not need to be amended to complete any other safety measures identified 
as post-hoc. 
9 SECONDARY ENDPOINTS ANALYSES 
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9.1 
Serum Pharmacokinetic Analyses 
9.1.1 
General Considerations 
All PK analysis summaries will be presented using the PK Population. PMN310 serum 
concentration data will be listed by cohort, subject, and visit/sampling time point.  Descriptive 
summary statistics will be provided by cohort and visit/sampling time point. 
Any protocol deviations, concomitant medications, or adverse events which could impact PK 
concentration-data profiles and/or PK parameter estimates will be designated by the Sponsor to 
indicate whether these PK data should be excluded from analysis. All data that are excluded in 
this manner will be listed and the reason for exclusion clearly noted. This review will be done by 
blinded personnel prior to database lock. 
Furthermore, subjects must not have quantifiable pre-dose (prior to the start of infusion) 
concentrations greater than 5% of the corresponding Cmax. All PK data excluded in this manner 
will be evaluated on a case-by-case basis and agreed upon with the Sponsor a priori. 
Serum concentrations of PMN310 will be measured by validated assays and PK parameters will 
be estimated using standard Phoenix® WinNonlin® (Version 8.3, Certara USA) non-
compartmental analysis (NCA) methods and actual blood sampling times relative to dosing (i.e., 
relative to the end of infusion). If the actual collection time is unknown, the nominal collection 
time may be used for the purposes of PK parameter estimation. 
For the calculation of summary statistics and graphical displays of serum concentrations (except 
for plots of geometric mean [geometric CV%]), concentrations that are below the limit of 
quantification (BLQ) will be set to zero (0) for all measurements. In addition, any quantifiable 
concentration observed after at least 2 consecutive BLQ values at the end of a profile will be 
evaluated on a case-by-case basis and may be set to missing along with the BLQ concentrations, 
if warranted. The number and percentage of values missing and the number and percentage of 
values BLQ will be presented with the other summary statistics. If >25% of values at a time 
point within a treatment level are missing or BLQ, no summary statistics will be presented.  
Serum concentration data will be summarized descriptively for continuous data by PMN310 dose 
level and protocol-specified nominal timepoint. Summary statistics for concentration-time data 
will include: n, mean, standard deviation (SD), coefficient of variation (CV%), minimum, 
median, maximum, geometric mean, geometric CV%, and the number and percentage of samples 
that are BLQ and the number and percentage of samples that are missing. All concentration-time 
data and summary statistics will be reported to the same number of decimal places as displayed 
in the bioanalytical data, except for CV%, which will be reported to 1 decimal place. 
Linear-linear and log-linear mean serum concentration-time vs nominal timepoint plots will also 
be presented by dose level, while linear-linear and log-linear individual concentration-time vs 
actual timepoint plots will be presented in a similar manner. 
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All serum concentration data (including actual blood sampling times) will be provided in a by 
subject-listing. 
Serum concentration values that are BLQ will also be imputed as follows for the NCA: 
1. BLQ values at time points prior to any measurable concentration or immediately prior to 
dosing (pre-dose [prior to the start of infusion]) are imputed as 0.  
2. BLQ values between two measurable concentrations will be set to the LLOQ/2. 
3. BLQ values after all measurable concentrations are set to missing. 
Serum PK parameters will be summarized descriptively by PMN310 dose level. Summary 
statistics for the time-related serum PK parameters (tmax, tlast and t1/2) will include: n, mean, SD, 
median, minimum, and maximum while summary statistics for AUCextrap (%) will include n, 
number and percentage of subjects with AUCextrap>20%, mean, SD, median, minimum, and 
maximum. AUC0-∞ values will be considered unreliable estimates if the AUCextrap (%) is greater 
than 20% and will be excluded from summary statistics but will be listed. 
Summary statistics for all other serum PK parameters include: n, mean, SD, CV%, median, 
minimum, maximum, geometric mean, and geometric CV%. 
Except for time-related PK parameters (tmax, tlast, and t1/2), and reporting of CV%, all other PK 
parameters will be reported to 3 significant digits. For tmax, tlast, and t1/2, round all statistics to two 
decimal places. CV% will be reported to 1 decimal place. 
All PK parameter data will be presented in a by-subject listing. 
9.1.2 
Pharmacokinetic Endpoints 
9.1.2.1 
Serum Pharmacokinetic Parameters 
PK parameters will be computed from the individual serum concentrations as data allow. 
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PK Parameter 
Definition 
Study Day 1  
 
AUC0-t (AUClast) 
Area under the serum concentration-time curve from time zero to the last 
measurable concentration 
AUC0-∞ (AUCinf) 
Area under the serum concentration-time curve from time zero extrapolated to 
infinity 
AUCextrap 
Area under the serum concentration-time curve extrapolated from time t to 
infinity as a percentage of total area under the concentration-time curve 
Cend of infusion 
Concentration at the end of the intravenous infusion 
Clast 
Concentration corresponding to the time of last measurable concentration (tlast) 
Cmax 
Maximum observed serum concentration 
tmax 
Time to reach maximum serum concentration 
tlast 
Time of last measurable concentration 
Span 
Time interval used to determine λZ divided by the terminal elimination half-life 
(t1/2) 
Adjusted r2 
Coefficient of determination used as a criteria for the goodness-of-fit 
measurement of a regression analysis 
t1/2 
Terminal elimination half-life 
lambda_z (λZ) 
Terminal elimination rate constant 
CL 
Total body clearance after intravenous infusion 
Vd 
Volume of distribution during the terminal phase 
Additional PK parameters may be estimated as appropriate. 
All AUCs including AUC0-t and AUC0-∞ will be calculated using the linear-up/log-down 
trapezoidal method, using actual sampling times. Missing concentrations will be treated as 
missing and excluded from PK analysis except when they occur at pre-dose (prior to the start of 
infusion), where they will be set to 0. 
AUC0-∞ will be calculated as outlined below:  
AUC0-∞= AUC0-t + (Clast/ lambda_z [λZ]), 
where Clast (defined as the last measurable concentration) is the last temporal quantifiable serum 
concentration. 
Maximum concentration (Cmax), tmax, and tlast will be obtained directly from experimental 
observations. If multiple maxima occur at equal concentrations, the first temporal value will be 
taken. 
The apparent terminal elimination half-life, t1/2, where evaluable, will be calculated as the natural 
log of 2 divided by the terminal elimination rate constant, λz. The number of data points included 
in the regression will be determined by visual inspection, but a minimum of 3 data points in the 
terminal phase, excluding Cmax, is required to estimate λz. In order for λz and λz derived 
DocuSign Envelope ID: BA3AF7D4-E4B6-44A5-AD89-D0AE3B6BC5AB


Study PMN310-101 
ProMIS Neurosciences, Inc
PMN310 
SAP Final v1.0
CONFIDENTIAL 
Page 29 of 32
parameters (AUC0-∞, t1/2, Vd, and CL) to be reported, the adjusted r2 value reported in Phoenix®
WinNonlin® must be ≥0.8. t1/2 should be determined with a span ≥2. If this criterion is not met 
the data will be excluded from descriptive summaries but will be included in the listing of PK 
parameters and flagged. 
Regression parameters for estimation of λz, including the number of time points used, time point 
range used for the regression (minimum time, maximum time), span, and adjusted r2 will be 
listed. 
9.1.2.2 
Dose Proportionality 
Dose proportionality will be analyzed using a power model. The natural log-transformed (ln) 
parameters (Cmax and AUCs: AUC0-t and AUC0-∞) will be fit to a linear model estimating the 
effect of ln(dose) (Gough 1995). The empirical relationship between a PK parameter and dose 
is in the following equation: 
𝑃𝐾 = 𝑒𝛼 ∗ (𝑑𝑜𝑠𝑒)𝛽
Where PK represents the PK parameter AUCs and Cmax. For analysis, this equation is natural 
log-transformed, obtaining the equation below: 
𝐼𝑛𝑃𝐾 = 𝛼 + 𝛽 ∗ 𝐼𝑛(𝑑𝑜𝑠𝑒) 
The slope β measures the dose-proportionality between dose and the PK parameter. 
The confidence interval criteria for assessment of dose proportionality from Smith et al. (2000) 
will be used to test for dose proportionality. The a priori acceptance range for the slope, 
according to Smith, is given by: 
1 + 𝐼𝑛(0.8)/𝐼𝑛(𝑟) < 𝛽 < 1 + 𝐼𝑛(1.25)/𝐼𝑛(𝑟) 
Where 1.25 and 0.8 are the critical a priori values suggested by regulatory authorities for any 
bioequivalence problem after a data log transformation, and r is the ratio of the largest dose to 
the smallest dose. Dose proportionality can be claimed if the 90% confidence interval for the 
slope is entirely contained within this a priori range. 
Dose proportionality will also be explored graphically: regression/scatter plot in the In-In scale 
for the power analysis. 
9.2 
Cerebrospinal Fluid (CSF) Pharmacokinetic Analyses  
All CSF analyses will be conducted using the Evaluable population. 
Descriptive summaries of CSF concentration time data by nominal time point and cohort/dose 
level will be provided. Summary statistics for PMN310 concentration-time data will include the 
DocuSign Envelope ID: BA3AF7D4-E4B6-44A5-AD89-D0AE3B6BC5AB


 
Study PMN310-101 
ProMIS Neurosciences, Inc
PMN310 
SAP Final v1.0
 
 
 
CONFIDENTIAL 
 
Page 30 of 32
 
following: n (number of participants with non-missing values), mean, SD, arithmetic coefficient 
of variation (CV (%)), median, minimum, maximum, geometric mean and 90% confidence 
interval (CI), geometric CV (%), and the number (percentage) of samples are BLQ. All 
concentration-time data and relevant summary statistics will be reported to the same number of 
significant figures as displayed in the bioanalytical data. For calculation of summary statistics, 
concentration values that are BLQ will be set to 0 for all BLQ concentrations. Nominal sampling 
time points relative to the start of dosing will be used for tabulation by time point for summaries 
of concentration-time data. If >25% of values at a time point within a treatment level are missing 
or BLQ, no summary statistics are presented. 
No CSF parameters will be estimated apart from CSF:serum PMN310 ratio. 
CSF PMN310 concentration data and serum PMN310 concentration data will be compared by 
cohort/dose level using summary statistics for nominal time points that have both data points 
available.  Mean (±SD) values may also be plotted, as data permits.    
All CSF data will be presented by timepoint in a by-subject listing. 
10 EXPLORATORY ENDPOINT ANALYSES 
10.1 
Immunogenicity 
All immunogenicity analyses will be conducted using the Safety population. 
Immunogenicity results will be summarized descriptively by PMN310 dose level and visit for 
the number and percentage of subjects who develop detectable levels of anti-PMN310 antibodies 
(ADA). ADA status will be treated as categorical data (positive and negative) and summarized 
descriptively by visit. In addition, a subject will be considered positive for PMN310-induced 
immunogenicity if the subject has at least one confirmed positive ADA response after dosing in 
the study. 
Titer data will also be summarized descriptively for continuous data (n, mean, standard 
deviation, median, minimum, maximum, geometric mean, and geometric CV%) by PMN310 
dose level and visit for the observed value. 
Individual serum and/or CSF concentrations of PMN310 and mean (±SD) PMN310 
concentrations versus time may be presented separately in ADA positive and negative subjects. 
Possible correlation between PK concentrations and any post-dose ADA responses may be 
evaluated using graphical presentation to identify a potential impact of anti-PMN310 antibodies 
on drug exposure. The ADA status is considered in a cumulative manner at each time point (i.e., 
if a subject had a positive sample at any time point of assessment visit that subject would be 
counted as positive throughout the study). 
All immunogenicity data will be presented by timepoint in a by-subject listing. 
DocuSign Envelope ID: BA3AF7D4-E4B6-44A5-AD89-D0AE3B6BC5AB


 
Study PMN310-101 
ProMIS Neurosciences, Inc
PMN310 
SAP Final v1.0
 
 
 
CONFIDENTIAL 
 
Page 31 of 32
 
10.2 
Biomarkers 
Residual and unused serum and CSF samples will be stored for future use for the measurement 
of biomarkers. 
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Study PMN310-101 
ProMIS Neurosciences, Inc
PMN310 
SAP Final v1.0
 
 
 
CONFIDENTIAL 
 
Page 32 of 32
 
11 REFERENCES 
Guidance for Industry: E9 Statistical Principles for Clinical Trials, September 1998. 
FDA Guidance for Industry, Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials (2007). 
K Gough, et al: Assessment of Dose Proportionality: report from the statisticians in the 
pharmaceutical industry/pharmacokinetics UK joint working party. Drug Information Journal 
29:1039-1048 (1995).  
BP Smith, et al: Confidence interval criteria for assessment of dose proportionality. Pharm Res. 
2000 Oct;17(10):1278-83.2000 Oct;17(10):1278-83. 
FDA Guidance for industry, Bioavailability Studies Submitted in NDAs or INDs - General 
Considerations Guidance for Industry (2022). 
FDA Guidance for industry, Immunogenicity Assessment for Therapeutic Protein Products 
(2014). 
FDA Guidance for industry, Immunogenicity Testing of Therapeutic Protein Products — 
Developing and Validating Assays for Anti-Drug Antibody Detection Guidance for Industry 
(2019). 
 
 
 
 
 
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