HEALEY ALS Platform Trial - Regimen C CNM-Au8
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Merit E. Cudkowicz, MD

HEALEY ALS Platform Trial - Regimen C CNM-Au8 
NCT04414345 
Document Date: 22 Nov 2021 

REGIMEN-SPECIFIC APPENDIX C 
 
FOR CNM-Au8  
 
 
Regimen-Specific Appendix Date: 
22 November 2021 
                            Version Number: 
5.0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

HEALEY ALS Platform Trial  
Regimen-Specific Appendix C, CNM-Au8 
 
Version 5.0, 22-NOV-2021 
CONFIDENTIAL 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ---------------------------------------------------------------------------------------------------------- 2 
SIGNATURE PAGE -------------------------------------------------------------------------------------------------------------- 5 
LIST OF ABBREVIATIONS ---------------------------------------------------------------------------------------------------- 6 
REGIMEN-SPECIFIC APPENDIX SUMMARY --------------------------------------------------------------------------- 8 
SCHEDULE OF ACTIVITIES – --------------------------------------------------------------------------------------------- 10 
1. 
INTRODUCTION -------------------------------------------------------------------------------------------------------- 15 
1.1 CNM-Au8 Background Information ------------------------------------------------------------------------------------- 15 
1.2 CNM-Au8 Therapeutic Rationale --------------------------------------------------------------------------------------- 17 
1.2.1 Investigational Product Characteristics --------------------------------------------------------------------------- 17 
1.2.2 Preclinical Data Supporting CNM-Au8 in the Treatment of ALS --------------------------------------------- 18 
1.2.2.1 In vitro ALS Neuroprotection Models-------------------------------------------------------------------- 23 
1.2.2.1.1 CNM-Au8 Protects Primary Rodent Motor Neurons from Excitotoxicity ------------------------ 23 
1.2.2.1.2 CNM-Au8 Protects Normal iPSC Derived Human Motor Neurons From ALS-Participant-
Derived Toxic Astrocytes ------------------------------------------------------------------------------------------ 25 
1.2.2.2 In vivo ALS Neuroprotection Models -------------------------------------------------------------------- 26 
1.2.3 Summary CNM-Au8 Treatment Rationale for ALS ------------------------------------------------------------ 28 
2. 
OBJECTIVES ------------------------------------------------------------------------------------------------------------- 29 
2.1 Study Objectives and Endpoints ----------------------------------------------------------------------------------------- 29 
3. 
RSA DESIGN -------------------------------------------------------------------------------------------------------------- 31 
3.1 Scientific Rationale for RSA Design ------------------------------------------------------------------------------------ 31 
3.2 End of Participation Definition ------------------------------------------------------------------------------------------ 31 
3.3 
End of Regimen Definition ------------------------------------------------------------------------------------------- 31 
4. 
RSA Enrollment ----------------------------------------------------------------------------------------------------------- 33 
4.1 Number of Study Participants -------------------------------------------------------------------------------------------- 33 
4.2 Inclusion and Exclusion Criteria ---------------------------------------------------------------------------------------- 33 
4.2.1 RSA Inclusion Criteria ---------------------------------------------------------------------------------------------- 33 
4.2.2 RSA Exclusion Criteria --------------------------------------------------------------------------------------------- 33 
4.3 Treatment Assignment Procedures -------------------------------------------------------------------------------------- 33 
5. 
INVESTIGATIONAL PRODUCT ------------------------------------------------------------------------------------ 34 
5.1 Investigational Product Manufacturer ---------------------------------------------------------------------------------- 34 
5.2 Labeling, Packaging, and Resupply ------------------------------------------------------------------------------------- 34 
5.3 Acquisition, Storage, and Preparation---------------------------------------------------------------------------------- 35 

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5.4 Study Medication/Intervention, Administration, Escalation, and Duration ---------------------------------------- 35 
5.5 Dosage Adjustment -------------------------------------------------------------------------------------------------------- 36 
5.6 Justification for Dosage -------------------------------------------------------------------------------------------------- 37 
5.6.1. Human Dosing Safety Margins ----------------------------------------------------------------------------------- 37 
5.6.2 Neuroprotection Pharmacologic Exposure Data ----------------------------------------------------------------- 39 
5.7 Participant Compliance -------------------------------------------------------------------------------------------------- 40 
5.8 Overdose -------------------------------------------------------------------------------------------------------------------- 40 
5.9 CNM-Au8 Known Potential Risks and Benefits ----------------------------------------------------------------------- 40 
5.9.1 Known Potential Risks ---------------------------------------------------------------------------------------------- 40 
5.9.1.1 Immediate Risks ---------------------------------------------------------------------------------------------- 40 
5.9.1.2 Long Range Risks -------------------------------------------------------------------------------------------- 41 
5.9.1.3 Summary of Participant Risk ------------------------------------------------------------------------------ 41 
5.9.2 Known Potential Benefits------------------------------------------------------------------------------------------- 41 
5.10 Regimen-Specific Lab Alerts-------------------------------------------------------------------------------------------- 42 
6. 
REGIMEN SCHEDULE ------------------------------------------------------------------------------------------------ 43 
6.1 Regimen-Specific Screening Visit -------------------------------------------------------------------------------------- 44 
6.2 Baseline Visit --------------------------------------------------------------------------------------------------------------- 44 
6.3 Week 2 Telephone Visit -------------------------------------------------------------------------------------------------- 45 
6.4 Week 4 and 8 Visits -------------------------------------------------------------------------------------------------------- 45 
6.5 Week 12 Telephone Visit ------------------------------------------------------------------------------------------------- 45 
6.6 Week 16 Visit --------------------------------------------------------------------------------------------------------------- 45 
6.7 Week 20 Telephone Visit ------------------------------------------------------------------------------------------------- 46 
6.8 
Week 24 Visit or Early Termination Visit ---------------------------------------------------------------------------- 46 
6.9 
Follow-Up Safety Call ------------------------------------------------------------------------------------------------- 46 
6.10 Process for Early Terminations ---------------------------------------------------------------------------------------- 47 
6.11 Open Label Extension -------------------------------------------------------------------------------------------------- 47 
6.11.1 Week 2 OLE Telephone Visit ----------------------------------------------------------------------------------- 48 
6.11.2 
Week 4 OLE Visit ---------------------------------------------------------------------------------------------- 48 
6.11.3 
Week 8 OLE Visit ---------------------------------------------------------------------------------------------- 49 
6.11.4  Week 12 OLE Telephone Visit -------------------------------------------------------------------------------- 49 
6.11.5  Week 16 OLE Visit ---------------------------------------------------------------------------------------------- 49 
6.11.6  Week 20 OLE Telephone Visit -------------------------------------------------------------------------------- 50 
6.11.7  Week 24 OLE Telephone Visit -------------------------------------------------------------------------------- 50 
6.11.8  Week 28 OLE Visit ---------------------------------------------------------------------------------------------- 51 
6.11.9  Week 40 OLE Visit ----------------------------------------------------------- Error! Bookmark not defined. 
6.11.10  Week 52 OLE Visit ---------------------------------------------------------- Error! Bookmark not defined. 
7 
OUTCOME MEASURES AND ASSESSMENTS ------------------------------------------------------------------ 52 
7.1 Voice Analysis ------------------------------------------------------------------------------------------------------------- 52 

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7.2  ALSAQ-40 ----------------------------------------------------------------------------------------------------------------- 52 
7.3  Center for Neurologic Study Bulbar Function Scale --------------------------------------------------------------- 52 
8 
BIOFLUID COLLECTION -------------------------------------------------------------------------------------------- 54 
8.1 Pharmacokinetic (PK) Assessments ------------------------------------------------------------------------------------- 54 
8.1.1 Whole Blood PK Assessments of CNM-Au8 -------------------------------------------------------------------- 54 
8.1.2 Plasma PK Assessments of Riluzole ------------------------------------------------------------------------------ 54 
8.2 Pharmacodynamic (PD) Assessments ---------------------------------------------------------------------------------- 54 
9 
REGIMEN-SPECIFIC STATISTICAL CONSIDERATIONS -------------------------------------------------- 56 
Appendix I: The ALSAQ-40 --------------------------------------------------------------------------------------------------- 57 
Appendix II: The Bulbar Function Scale (CNS-BFS) --------------------------------------------------------------------- 66 
REFERENCES ------------------------------------------------------------------------------------------------------------------- 68 
 

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SIGNATURE PAGE 
 
I have read the attached Regimen-Specific Appendix (RSA) entitled, “REGIMEN C: CNM-Au8” 
dated October 15, 2021 (Version 5.0) and agree to abide by all described RSA procedures.  I 
agree to comply with the International Conference on Harmonisation Tripartite Guideline on 
Good Clinical Practice, applicable FDA regulations and guidelines identified in 21 CFR Parts 11, 
50, 54, and 312, central Institutional Review Board (IRB) guidelines and policies, and the Health 
Insurance Portability and Accountability Act (HIPAA). 
 
By signing the RSA, I agree to keep all information provided in strict confidence and to request 
the same from my staff. Study documents will be stored appropriately to ensure their 
confidentiality. I will not disclose such information to others without authorization, except to the 
extent necessary to conduct the study.  
 
 
 
 
Site Name: 
 
 
 
 
Site Investigator: 
 
 
 
 
Signed: 
 
 
 
 
 
Date: 
 
 

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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ALSAQ-40 
Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 
ASTM 
American Society for Testing and Materials 
ATP 
Adenosine Trinucleotide Phosphate 
Au 
Gold 
AUC 
Area under the curve 
AUC(0-24) 
Area under the curve for 24 hours  
CNM-Au8 
Aqueous suspension of clean surfaced nanocrystals consisting of gold atoms self-organized into 
crystals of various faceted, geometrical shapes  
CNS 
Central nervous system 
CNS-BFS 
Center for Neurologic Study Bulbar Function Scale 
CSF 
Cerebrospinal fluid or cerebral spinal fluid 
fALS 
Familial ALS 
FVC 
Forced Vital Capacity 
HED 
Human equivalent dose 
HDPE 
High density polyethylene 
hr 
Hour 
ICP-MS 
Inductively Coupled Plasma Mass Spectrometry 
IP 
Investigational Product 
K2EDTA 
Dipotassium ethylenediaminetetraacetic acid 
kg 
Kilogram 
m 
meter 
MAD 
Multiple ascending dose 
mg 
Milligram 
mL 
Milliliter 
MRS 
Magnetic Resonance Spectroscopy 
mRNA 
Messenger Ribonucleic acid (RNA) 
MTD 
Maximum tolerated dose 
NAD+ 
Oxidized form of nicotinamide adenine dinucleotide 
NADH 
Reduced form of nicotinamide adenine dinucleotide 
NADPH 
Reduced form of nicotinamide adenine dinucleotide phosphate 
NaHCO3 
Sodium bicarbonate (baking soda) 

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Abbreviation 
Definition 
ng 
nanogram 
nm 
nanometer 
NOAEL 
No observed adverse effect level 
OLE 
Open Label Extension 
PD 
Pharmacodynamic 
PPP 
Pentose phosphate pathway 
RSA 
Regimen-Specific Appendix 
SAE 
Serious adverse event 
SOD1 
Superoxide dismutase 
SVC 
Slow Vital Capacity 
TEM 
Transmission electron microscopy 
TK 
Toxicokinetic 
USP 
United States Pharmacopeia 
VC 
Vital Capacity 
 
 
 
 
 
 
 
 
 
 
 
 

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REGIMEN-SPECIFIC APPENDIX SUMMARY 
Regimen-Specific Appendix C 
For CNM-Au8  
 
Rationale and RSA Design 
 
CNM-Au8 is a suspension of clean-surfaced, faceted gold nanocrystals whose catalytic activity 
independently impacts energetic, metabolic, and redox pathways, resulting in significant 
neuroprotection from oxidative and excitotoxic insults.  
 
CNM-Au8 is a nanocatalyst that is administered orally, penetrates the blood brain barrier, and 
has a unique mechanism of action involving: (1) the catalytic production of nicotinamide adenine 
dinucleotide (NAD), a key co-factor in the ATP-generating pathways of all cells, (2) catalytic 
anti-oxidative activity resulting in cellular protection from oxidative stress, and (3) catalytic 
stimulation of the pentose phosphate pathway, influencing both anti-oxidative as well as anabolic 
processes. Importantly, CNM-Au8 demonstrated significant neuroprotection of healthy human 
motor neurons from cell death induced by toxic ALS-participant derived astrocytes, and of 
primary rat motor neurons from glutamatergic excitotoxicity. Oral delivery of CNM-Au8 to a 
mouse model of ALS resulted in the recovery of functional behaviors and significant extension 
of lifespan.  
 
Given the involvement of cellular bioenergetic failure in the pathogenesis of ALS, the 
development of a disease modifying therapeutic that addresses the energetic dysregulation 
underlying the progressive accumulation of oxidative stress and dysregulated RNA processing is 
a rational therapeutic strategy.  
 
This clinical protocol will test CNM-Au8 at doses of 30 mg and 60 mg versus placebo in a 
randomized, double-blind manner, to determine if CNM-Au8 can demonstrate sufficient efficacy 
and safety on accepted clinical and paraclinical outcomes for the treatment of ALS. The 
investigation of two doses of the study drug is based on counsel from the FDA recommending 
including a dose finding strategy in the study.  The 30 mg and 60 mg doses of CNM-Au8 
selected for the study achieve at least comparable AUC exposure in humans as those shown to 
demonstrate neuroprotection efficacy in nonclinical animals studies, and demonstrated minimal 
treatment emergent adverse events in the Phase 1 First-In-Human study in healthy volunteers. 
 
Allocation to Treatment Regimens 
Participants must first be screened under the Master Protocol before they are randomized to an 
RSA.  
 

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As soon as pre-defined criteria for futility for the RSA are met, or the target number of 
randomized participants has been reached, enrollment will stop in the RSA.   
 
Number of Planned Participants and Treatment Groups 
The number of planned participants for this regimen is approximately160.   
 
There are 2 treatment groups for this regimen, active and placebo. Participants will be 
randomized in a 3:1 ratio to active treatment or placebo (i.e., 120 active: 40 placebo).  Half of the 
active treatment group will receive CNM-Au8 30mg/day and the other half will receive 
60mg/day (i.e., 60 at 30mg/day: 60 at 60mg/day). 
 
Planned Number of Sites 
Research participants will be enrolled from approximately 60 centers in the US.   
 
Treatment Duration 
The maximum duration of the placebo-controlled treatment portion is 24 weeks.  
 
Follow-up Duration 
At the conclusion of the 24-week placebo-controlled Treatment Period of the study, all 
participants will either schedule a 28-day follow up phone call and end their participation in the 
regimen or have the option to receive CNM-Au8 in the Open Label Extension (OLE) phase of 
the study.  
In the OLE, CNM-Au8 will be provided by Clene Nanomedicine, until the primary results of the 
24 week double-blind portion of the study are available, or Clene or sponsor terminate support or 
development of CNM-Au8 for ALS. 
   
Total Planned Trial Duration 
For participants completing the placebo-controlled Treatment Period of the Study, the planned 
amount of time for a participant in the trial is up to 34 weeks, or about 8 months.  This duration 
assumes a 6-week screening window, a 24-week placebo-controlled treatment period, and a 4-
week safety follow-up period for those participants who do not enter the Open Label Extension. 
Participants will complete approximately 10 study visits during the placebo-controlled treatment 
period of the study.  
 
 

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SCHEDULE OF ACTIVITIES – PLACEBO-CONTROLLED PERIOD14  
 
As per the Schedule of Activities (SOA) below, visits must occur every 4 weeks and will be alternatively clinic-, phone-, or 
telemedicine-based, as applicable.  There is a maximum 24-week duration of placebo-controlled treatment for a Regimen. 
 
Activity (page 1 of 2) 
Master 
Protocol or 
Regimen-
Specific 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Baseline 
Week 2 
Week 
416, 17 
Week 
816, 17 
Week 12 
Week 
1617 
Week 20 
Week 
24 or 
Early 
Term. 
Visit14, 
16 
Follow-Up 
Safety Call11, 
14 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
-42 to -1 
Days 
-41 to 0 
Day 
Day 0 
Day 14 
±3 
Day 28 
±7 
Day 56 
±7 
Day 84 
±3 
Day 112 
±7 
Day 140 
±3 
Day 168 
±7 
28 days after 
last dose 3 
days 
Written Informed Consent2 
Master 
X 
X 
 
 
 
 
 
 
 
 
 
Written Informed Consent - OLE 
Master 
 
 
 
 
 
 
 
X 
 
 
 
Inclusion/Exclusion Review 
Master 
X 
X3 
 
 
 
 
 
 
 
 
 
ALS & Medical History 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Neurological Exam 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs4 
Master 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Slow Vital Capacity 
Master 
X18 
 
X 
 
 
X 
 
X 
 
X 
 
Home Spirometry 
Regimen 
X18 
 
X 
 
 
X 
 
X 
 
X 
 
Muscle Strength Assessment  
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
ALSFRS-R 
Master 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
ALSAQ-40 
Regimen 
 
 
X 
 
 
 
 
 
 
X 
 
CNS Bulbar Function Scale 
Regimen 
 
 
X 
 
 
X 
 
X 
 
X 
 
12-Lead ECG 
Master 
X 
 
 
 
 
 
 
 
 
X 
 
Clinical Safety Labs5 
Master 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
PK/PD Biomarker Blood 
Collection12 
Regimen 
 
 
X 
 
X 
X 
 
 
 
X 
 
Biomarker PD Urine Collection 
Regimen 
 
 
X 
 
 
 
 
 
 
X 
 

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Biomarker Blood Collection 
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
Activity (page 2 of 2) 
Master 
Protocol or 
Regimen-
Specific 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Baseline 
Week 2 
Week 
416, 17 
Week 
816, 17 
Week 12 
Week 
1617 
Week 20 
Week 
24 or 
Early 
Term. 
Visit14, 
16 
Follow-Up 
Safety Call11, 
14 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
-42 to -1 
Days 
-41 to 0 
Day 
Day 0 
Day 14 
±3 
Day 28 
±7 
Day 56 
±7 
Day 84 
±3 
Day 112 
±7 
Day 140 
±3 
Day 168 
±7 
28 days after 
last dose 3 
days 
Biomarker Urine Collection 
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
DNA Collection7 (optional) 
Master 
 
 
X 
 
 
 
 
 
 
 
 
CSF Collection (optional) 
Master 
 
 
X 
 
 
 
 
X15 
 
 
 
Concomitant Medication 
Review 
Master 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event Review6 
Master 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia-Suicide Severity 
Rating Scale 
Master 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Install Smartphone App19 
Regimen 
 
 
X 
 
 
 
 
 
 
 
 
Voice Recording9 
Regimen 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Uninstall Smartphone App 
Regimen 
 
 
 
 
 
 
 
 
 
X 
 
Assignment to the Regimen 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Randomization within the 
Regimen 
Master 
 
X 
 
 
 
 
 
 
 
 
Administer/Dispense 
Investigational product 
Master 
 
 
X8 
 
 
X 
 
X 
 
X10 
 
Study Drug 
Accountability/Compliance 
Master 
 
 
 
X20 
X 
X 
X20 
X 
X20 
X 
 
Exit Questionnaire 
Master 
 
 
 
 
 
 
 
 
 
X 
 
Vital Status Determination13 
Master 
 
 
 
 
 
 
 
 
 
X 
 
 
1 Master Protocol Screening procedures must be completed within 42 days to 1 day prior to the Baseline Visit. The Regimen-Specific Screening Visit and Baseline Visit should be 
combined, if possible.    

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2 During the Master Protocol Screening Visit, participants will be consented via the Master Protocol informed consent form (ICF). After a participant is randomized to a regimen, 
participants will be consented a second time via the regimen-specific ICF.  
3 At the Regimen Specific Screening Visit, participants will have regimen-specific eligibility criteria assessed.   
4 Vital signs include weight, systolic and diastolic pressure, respiratory rate, heart rate and temperature.  Height measured at Master Protocol Screening Visit only. 
5 Clinical safety labs include hematology (CBC with differential), complete chemistry panel, thyroid function and urinalysis. Serum pregnancy testing will occur in women of 
child-bearing potential at the Master Protocol Screening Visit and as necessary during the study. Pregnancy testing is only repeated as applicable if there is a concern for 
pregnancy. 
6 Adverse events that occur after signing the consent form will be recorded.  
7 The DNA sample can be collected after baseline if a baseline sample is not obtained or the sample is not usable. 
8 Administer first dose of investigational product only after Baseline Visit procedures are completed. 
9 In addition to study visits outlined in the SOA, participants will be asked to complete twice weekly voice recordings at home.  
10 Drug will only be dispensed at this visit if the participant continues in the OLE. 
11 Participants will only have a Follow-Up Safety Call at this time if they do not continue on in the OLE.  Participants who continue into OLE will have a Follow-Up Safety Call 
after their last dose of study drug during the OLE phase. 
12 Whole blood and plasma will be collected prior to administration of the daily dose at the Baseline and Week 24 visit.  Plasma will be collected prior to administration of the 
daily dose at the Week 4 and Week 8 visits.  Refer to the RSA laboratory manual for collection and processing parameters.  
13 Vital status, defined as a determination of date of death or death equivalent or date last known alive, will be determined for each randomized participant at the end of the 
placebo-controlled portion of their follow-up (generally the Week 24 visit, as indicated). If at that time the participant is alive, his or her vital status should be determined again at 
the time of the last patient last visit (LPLV) of the placebo-controlled portion of a given regimen. We may also ascertain vital status at later time points by using publicly available 
data sources as described in section 8.15 of the Master Protocol. 
14 The maximum window between study visits during the placebo-controlled period may not exceed 64 days.  
15 If the CSF collection is unable to be performed for logistical reasons, such as scheduling, at the Week 16 Visit, it may be performed at the Week 24 Visit. 
16 Participants should be instructed to hold the study drug on the day of the study visit. Study drug should not be taken until after study visit procedures are complete. 
17 Visit may be conducted via phone or telemedicine with remote services instead of in-person if this is needed to protect the safety of the participant due to a pandemic, or other 
reason.  
18 If required due to pandemic-related restrictions, Forced Vital Capacity (FVC) performed by a Pulmonary Function Laboratory evaluator or with a study-approved home 
spirometer, or sustained phonation using a study approved method may be used for eligibility (Master Protocol Screening ONLY).    
19 Two smartphone apps should be installed on the participant’s phone, one to collect the voice recordings and one to collect home spirometry.   
20 Drug accountability will not be done at phone visits. A drug compliance check-in must be held during phone visits to ensure participant is taking drug per dose regimen and to 
note any report of missed doses.  
 
 

 
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SCHEDULE OF ACTIVITIES – REGIMEN SPECIFIC OPEN LABEL EXTENSION PHASE (OPTIONAL) 
Activity (page 1 of 1) 
Master 
Protocol or 
Regimen-
Specific 
 
Open Label Extension (Optional)5 
Week 2 
Week 
49 
Week 
89 
Week 
12 
Week 
168,9 
Week 20 
 
Week 
24  
Week 28 and Q12 
Weeks8,9,11  
 
Follow-Up Safety Call6 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Phone 
Day 14 
+3 
 
 
 
Day 28 
±7 
 
 
 
Day 56 
±7 
Day 84 
±3 
Day 112 
±7 
Day 140 
±3 
 
 
 
Day168 
±3 
Day 196 ± 14  
 
 
 
28±7 days after last dose 
Vital Signs1 
Master 
 
X 
X 
 
X 
 
 
X 
 
Slow Vital Capacity 
Master 
 
X 
X 
 
X 
 
 
X 
 
Home Spirometry 
Regimen 
 
X 
X 
 
X 
 
 
X 
 
ALSFRS-R 
Master 
 
X 
X 
X 
X 
X 
X 
X 
 
ALSAQ-40 
Regimen 
 
 
 
 
 
 
 
X 
 
CNS Bulbar Function Scale 
Regimen 
 
 
X 
 
X 
 
 
X 
 
Clinical Safety Labs2 
Master 
 
X 
X 
 
X 
 
 
X 
 
PK/PD Biomarker Blood 
Collection11 
Regimen 
 
 
 
 
X 
 
 
X11 
 
Biomarker PD Urine 
Collection11 
Regimen 
 
 
 
 
X 
 
 
X11 
 
Biomarker Blood 
Collection11 
Master 
 
 
 
 
X 
 
 
X11 
 
Biomarker Urine 
Collection11 
Master 
 
 
 
 
X 
 
 
X11 
 
Concomitant Medication 
Review 
Master 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event Review3 
Master 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
Columbia-Suicide Severity 
Rating Scale 
Master 
 
X 
X 
 
X 
 
 
X 
 

 
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Administer/Dispense 
Investigational product 
Master 
 
 
X 
 
X 
 
 
X 
 
Drug 
Accountability/Compliance 
Master 
X10 
X 
X 
X10 
X 
X10 
X10 
X 
 
1 Vital signs include weight, systolic and diastolic pressure, respiratory rate, heart rate and temperature.  Height in cm measured at Master Protocol Screening Visit only. 
2 Clinical safety labs include hematology (CBC with differential), complete chemistry panel, liver function tests, thyroid function and urinalysis. Serum pregnancy testing will 
occur in women of child-bearing potential at the Master Protocol Screening Visit and as necessary during the study. Pregnancy testing is only repeated as applicable if there is a 
concern for pregnancy. 
3 Adverse events that occur after signing the consent form will be recorded.  
4 Participants who continue into OLE will have a Follow-Up Safety Call (as described in the body of this RSA) after their last dose of study drug during the OLE phase. 
5 The duration of the OLE is until the primary results of the 24 week double-blind portion of the study are available, or Clene or sponsor terminates support or development of 
CNM-Au8 for ALS. 
6 Participants who continue into the OLE and then withdraw consent or early terminate will be asked to complete an Early Termination Visit and Follow-Up Safety Call as 
described in the body of this RSA.  
7 The maximum window between study visits during the OLE may not exceed 64 days for the Week 8 and Week 16 visits; and 96 days for the Week 28, Week 40, and Week 52 
visits.  
8 Participants should be instructed to hold the study drug on the day of the study visit. Study drug should not be taken until after study visit procedures are complete. 
9 Visit may be conducted via phone or telemedicine with remote services instead of in-person if this is needed to protect the safety of the participant due to a pandemic or other 
reasons.  
10 Drug accountability will not be done at phone visits. A drug compliance check-in must be held during phone visits to ensure participant is taking drug per dose regimen and to 
note any report of missed doses 
11 Blood and urine biomarker collection in OLE phase will only occur at week 16, 28, and 52 
 
 

 
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1. INTRODUCTION 
Regimen C: CNM-Au8  
 
1.1 CNM-Au8 Background Information 
Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal neurodegenerative disease affecting 
motor neurons with an incidence of approximately 1 in 100,000. Most ALS cases are sporadic, 
with 5–10% of cases being familial ALS (Zarei et al., 2015). Both sporadic and familial ALS are 
associated with degeneration and loss of cortical and spinal motor neurons, resulting in muscle 
wasting and weakness, eventually leading to respiratory failure and death. The etiology of ALS 
remains unknown. Emerging research has discovered interconnecting pathophysiological 
mechanisms amongst the seemingly disparate genetic mutations, implicated in both familial 
(fALS) and sporadic (sALS) ALS.  Importantly, these emerging data suggest that impairments 
related to oxidative stress and mitochondrial function appear to be common across many 
underlying genetic abnormalities. Genetic mutations in superoxide dismutase (SOD1), regulation 
of RNA processing and metabolism (represented by mutations in FUS, TDP43 and several more 
genes) all appear to result in both oxidative stress and RNA dysregulation, indicative of an 
underlying bioenergetic failure in ALS. Bioenergetic dysfunction affects not only motor neurons 
themselves but also astrocytes and oligodendrocytes that provide crucial energetic support to 
motor neuron survival.  Postmortem analyses of brain tissues from both fALS and sALS 
participants exhibit evidence of widespread accumulation of oxidative damage to proteins, lipids, 
and DNA. Transgenic mice expressing mutant SOD1 forms have evidence of nerve and spinal 
cord tissue damage that recapitulates key aspects of ALS and demonstrates clear evidence of 
excessive protein and lipid oxidation (D’Amico et al., 2013b). Oxidative stress also leads to the 
accumulation of protein aggregates such as TDP43 (Bozzo et al., 2017a), which are invariably 
found in ALS motor neurons, and which indicate failures of protein degradation systems such as 
autophagy (Blokhuis et al., 2013). 
 
Elevated oxidative stress has been shown to impact the processing of gene transcripts important 
for motor neuron survival.  This observation connecting oxidative stress to RNA processing was 
demonstrated when paraquat, a well-known inducer of oxidative stress, was shown to induce 
striking changes in RNA splicing in neuroblastoma cells (Maracchioni et al., 2007). Two of the 
pre-mRNAs whose splicing was shown to be altered in this study are transcripts of genes known 
to be important for motor neuron survival, Survival Motor Neuron (SMN) and Apoptotic 
Peptidase Activating Factor 1 (APAF1) (Maracchioni et al., 2007). The mis-localization of the 
RNA-binding protein TDP43 in ALS is further evidence of the connection between oxidative 
stress and RNA dysmetabolism.  In general, TDP43 is involved in pre-RNA processing in the 
nucleus, where it functions in transcriptional control.  However, oxidative stress causes the 

 
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TDP43 to translocate to the cytoplasm, where it accumulates in stress granules, as protein 
aggregates. Sequestration of an RNA regulator such as TDP43 in the cytoplasm and away from 
the nucleus is thought to prevent it from carrying out its normal functions and thereby can lead to 
dysregulation of RNA processing and transcription.  The converse relationship has similarly 
been shown, namely that mis-regulation of RNA metabolism increases oxidative stress within 
the CNS. Mutations in RNA regulators FUS and TDP43 cause disruptions in the expression of 
key nuclear-encoded mitochondrial genes (Zhang et al., 2014) as well as in the expression of 
energy metabolism regulators such as PGC-1 alpha and oxidative stress reducers such as 
MnSOD and catalase (Sanchez-Ramos et al., 2011). Therefore, the pathophysiologic disease 
mechanism of ALS appears to involve a positive feedback cycle of oxidative stress and protein 
aggregation impacting RNA regulation which in turn leads to a sustained increased oxidative 
stress disease state, ending in motor neuron death (Bozzo et al., 2017b).  
 
Unifying both themes of RNA dysregulation and oxidative stress is the concept that ALS is a 
disease of energetic dysmetabolism (Dupuis et al., 2011; Tefera and Borges, 2016; Vandoorne et 
al., 2018). Motor neurons consume high amounts of energy  to function and are therefore 
exquisitely sensitive to apoptosis if their energetic demands cannot be met. The main energy-
producing organelle of the cell, the mitochondria, exhibit dysfunction in ALS on multiple levels. 
For example, overall there are fewer mitochondria, as measured by mitochondrial DNA, in the 
spinal cords of both fALS and sALS participants (Wiedemann et al., 2002). Presynaptic 
mitochondrial swelling in motor neurons has been observed in both ALS participants (Siklos et 
al., 1996), as well as in a SOD1 transgenic mouse model prior to disease onset (Manfredi and 
Xu, 2005). Swollen and vacuolarized mitochondria are indicative of impaired mitochondrial 
function (Siklos et al., 1996), which is corroborated by studies showing that there is decreased 
activity of the electron transport chain in spinal cord mitochondria of ALS participants 
(Wiedemann et al., 2002). Because reduced respiration and reduced ATP synthesis preceded 
clinical symptom onset in SOD1G93A mice (Jung et al., 2002; Mattiazzi et al., 2002; 
Szelechowski et al., 2018), energetic dysmetabolism appears to play an important role in the 
etiology of this disease. Overexpression of PGC-1 alpha, which stimulates mitochondrial 
biogenesis, improved survival, motor neuron function and motor neuron survival in mutant 
SOD1G93A mice (Zhao et al., 2011), indicating that improving mitochondrial function and/or 
efficiency may be a successful therapeutic strategy for ALS (Vandoorne et al., 2018). 
 
Energetic dysmetabolism in ALS is further underscored by studies uncovering carbohydrate 
metabolism abnormalities and ATP deficits in ALS motor neurons (Vandoorne et al., 2018). 
FDG-PET imaging has demonstrated a correlation between reduced ALS brain glucose uptake 
and cognitive impairment (Canosa et al., 2016) as well as overall disease severity (Dalakas et al., 
1987). Some groups who conducted FDG-PET studies showing reduced glucose uptake in ALS 
participant brains suggested CNS hypometabolism can be used as an early diagnostic indication 

 
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of ALS (Van Laere et al., 2014; Van Weehaeghe et al., 2016). While it is difficult to determine 
whether lowered glucose utilization detected in imaging studies is due to reduced neuronal 
catabolism of glucose or due to motor neuron loss, there are further lines of evidence to suggest 
energetic dysmetabolism in ALS cells. A proteomic study of ALS participant fibroblasts 
indicated a significant reduction in key enzymes involved in glycolysis (Szelechowski et al., 
2018), and expression profiling of sALS participant motor cortexes showed downregulation of 
glycolytic genes (Lederer et al., 2007). A GWAS analysis involving 12577 cases and 23475 
controls identified glycolysis/gluconeogenesis as among the top seven biological pathways 
represented by the genes identified as associated with ALS (Du et al., 2018). Because glia 
preferentially utilize glycolysis, these results may indicate a dysfunction of glia in providing 
energetic support to motor neurons in ALS participants. Energetic stress on motor neurons may 
increase their levels of oxidative stress, as observed in post-mortem brain samples of ALS 
participants (Ferrante et al., 1997), and lead to motor neuron death.  
 
1.2 CNM-Au8 Therapeutic Rationale 
CNM-Au8 is a concentrated aqueous suspension of clean-surfaced nanocrystals consisting solely 
of Au atoms organized into clean surfaced crystals of highly faceted, substantially uniform 
geometrical shapes that act as nanocatalysts, supporting cellular bioenergetic reactions.  
 
CNM-Au8 is supplied for dosing orally in sodium bicarbonate buffered USP purified water. 
Each mL of CNM-Au8 suspension at 500 μg/mL is estimated to contain between 100 - 500 
trillion highly faceted Au nanocrystals. IP will consist of 60 mL high density polyethylene 
(HDPE) bottles containing CNM-Au8 at concentrations of 250 μg/mL (15 mg)  or 500 μg/mL 
(30 mg), or placebo, administered orally, once daily in the morning, at least 30 minutes prior to 
food intake.  Study participants will consume two (2) bottles of IP each morning for total daily 
intake of 120 mL equivalent to CNM-Au8 30mg or 60mg, or placebo. 
 
1.2.1 Investigational Product Characteristics 
The median diameter of CNM-Au8 nanocrystals is approximately 13 nm, as determined by 
transmission electron microscopy (TEM).  Based upon the distributed range (Dn5 – Dn95: 6.5 – 
15.8 nm) of measured nanocrystal diameters and approximate geometrical shapes (e.g., low 
volume estimate: disc-like approximation, aspect ratio of 0.2; maximum volume estimate: 
spheroid, aspect ratio of 1.0), each Au nanocrystal has an approximate composition ranging from 
13,000 – 66,000 Au atoms per nanocrystal at the 13 nm median diameter with a corresponding 
molar mass ranging between 2.7 x 103 kDA to 1.3 x 104 kDA. Summary estimates for CNM-Au8 
mass, volume, and particle characteristics are described below in Table 1.  Each mL of CNM-
Au8 suspension at 500 μg/mL is estimated to contain between 100 - 500 trillion highly faceted 
Au nanocrystals. 

 
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Table 1. Estimated Volume, Mass, and Particle Characteristics of CNM-Au8 
Metric 
(CNM-Au8 500 μg/mL, 60 mL Dose) 
Disc-Like 
Approximation 
Minimum 
(Aspect 0.2) 
Spherical 
Approximation 
Maximum 
(Aspect 1.0) 
Median Au Nanocrystal Diameter (nm) 
13 
Au Nanocrystal Volume (nm3) 
2.3 x 10^2 
1.2 x 10^3 
Au Nanocrystal Surface Area (nm2) 
3.2 x 10^2 
5.3 x 10^2 
Au Atoms per Nanocrystal (count) 
1.4 x 10^4 
6.8 x 10^4 
Au Nanocrystal Molecular Weight (kDa) 
2.7 x 10^3 
1.3 x 10^4 
Total Au Nanocrystal Surface Area per mL (cm2) 
3.6 x10^2 
1.2 x10^2 
Au Nanocrystals per mL CNM-Au8 (count) 
1.1 x 10^14 
2.3 x 10^13 
Au Nanocrystals per 60 mL Dose (count) 
3.4 x 10^15 
6.8 x 10^14 
 
1.2.2 Preclinical Data Supporting CNM-Au8 in the Treatment of ALS  
CNM-Au8 passes into the systemic circulation via intestinal absorption.  Cellular uptake of 
CNM-Au8, following oral administration, has been demonstrated in a variety of cells and tissue 
matrices including macrophages, oligodendrocytes, neurons, and brain tissue, utilizing 
Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and high resolution TEM 
visualization of nanocrystals.   
 
Preclinical characterization of the in vitro and in vivo properties of CNM-Au8 demonstrated that 
it acts to protect neuronal populations from chemical, inflammatory, and hypoxic insults through 
a series of unique catalytic mechanisms involving 1) the nicotine adenine dinucleotide redox 
couple (NAD+/NADH) to boost glycolytic energy production, 2) the nicotine adenine 
dinucleotide phosphate redox couple (NADP+/NADPH) to influence anabolic processes 
associated with differentiation, and 3) the SOD-like inactivation of reactive oxygen species and 
nitric oxide to protect cells from oxidative damage and mitochondrial dysfunction.  
The nicotinamide adenine dinucleotide redox couple (NAD+, NADH) plays a central role in the 
energy metabolism of all living cells. NAD+, NADH and their relative intracellular ratio 
(NAD+/NADH) are linked to regulation of energy homeostasis, neuroprotection, immune 
function, chromosome stability, DNA repair mechanisms, sleep and circadian rhythms, and 
longevity (Canto et al., 2015; Imai, 2010a, b; Nikiforov et al., 2015; Ying, 2008).   

 
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Fundamentally, NAD+ and NADH are essential coenzymes in the adenosine triphosphate (ATP)-
generating reactions driving both glycolysis and oxidative phosphorylation.  More specifically, 
in aerobic glycolysis, NAD+ availability is integral to the enzymatic cascade from 
glyceraldehyde 3-phosphate via glyceraldehyde phosphate dehydrogenase to 1,3-
bisphosphoglyceric acid.  Similarly, two electrons are removed via NADH oxidation in Complex 
I of the electron transport chain during oxidative phosphorylation, resulting in NAD+, and 
ultimately these electrons are transferred to a lipid-soluble carrier, ubiquinone. 
In addition, NAD+ and its metabolites act as binding substrates for a wide range of proteins 
including the metabolic and transcription-regulating sirtuins, the poly-ADP-ribose polymerases 
(PARPs) involved in DNA repair, and the cyclic ADP-ribose synthases (cADPRs) such as CD38 
that serve to regulate Ca2+ signaling involved in cell cycle control and insulin signaling (Canto 
et al., 2015). In the Wallerian Degeneration Slow Dominant Mutant Mouse, heightened 
expression of NMNAT1, resulting in increased NAD+, has been attributed to protect against the 
axonal degeneration, otherwise observed in these mice (Sasaki et al., 2009).   
 
Quantitative measurement of regional brain area NAD+ concentrations and redox states in 
humans has recently been demonstrated using a novel 31P-Magnetic Resonance Spectroscopy 
(MRS) imaging technique (Chouinard et al., 2017; Lu et al., 2016). In people, brain 
NAD+/NADH redox potential is inversely correlated with age. 31P-MRS of the visual cortex of 
young (21-26 year old), middle-aged (33-36 year old), and aged (59-68 year old) healthy 
individuals demonstrated a linear decline of NAD+ redox potential with increasing age (Zhu et 
al., 2015). This age-related decrease in cerebral energy metabolism is believed to be associated 
with the bioenergetic failure underlying many neurodegenerative diseases, because 
NAD+/NADH redox potential is essential for fundamental ATP-generating processes such as 
glycolysis and mitochondrial oxidative phosphorylation. These bioenergetic processes power all 
cellular processes including ‘housekeeping’ functions that are responsible for maintaining overall 
cellular health including processes of autophagy, apoptosis, and the unfolded protein response 
(UPR) (Canto et al., 2015; Chua and Tang, 2013a; Villanueva-Paz et al., 2016). Boosting brain 
NAD+ levels in a mouse model of AD reduced DNA damage, neuroinflammation, and apoptosis 
while improving cognitive function in multiple behavioral tests and restored hippocampal 
synaptic plasticity (Hou et al., 2018).  
 
The first demonstration of catalyzed oxidation of NADH to NAD+ by gold nanoparticles was 
demonstrated by Huang et al. (2005) using a simple cell-free assay. In order to compare the 
catalytic oxidation rate of clean-surfaced CNM-Au8 against similarly-sized gold nanoparticles 
made using citrate reduction, the same cell-free assay utilized by Huang et al. was repeated 
comparing gold nanoparticles sourced from the U.S. National Institutes of Standards and 
Technology (NIST).  The resulting change in the 339 nm NADH absorbance peak was assessed 

 
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while investigating each of the gold nanoparticles at the same concentrations.  In all cases, 
CNM-Au8 nanocrystals consistently showed significantly superior catalytic activities regardless 
of size and/or method of preparation of the comparator gold nanoparticles. 
 
Figure 1. CNM-Au8 NADH Catalysis Rates 
 
Figure 1A.  CNM-Au8 Catalytic Effects vs. NIST 
Standard Citrated AuNP 
Figure 1B. Relative NADH Oxidation Rates vs. 
NIST Citrated AuNP 
CNM-Au8 treatment of rodent central nervous system cells in vitro also significantly increases 
levels of both NAD+ and NADH (Figure 2). 
 
Figure 2.  Effects of CNM-Au8 on NAD Levels in Primary Rodent Mesencephalic 
Cultures 
Figure 2A. Effect of CNM-Au8 on NAD+ 
Levels 
Figure 2B. Effect of CNM-Au8 on NADH 
Levels 
 
 
The redox couple NADP+/NADPH, similar to NAD+/NADH, plays a fundamental role in 
energy homeostasis, anabolic processes, and protection against oxidative stress. NADP+ and 
NADPH function in the pentose phosphate pathway (PPP), serves to provide precursors for 
nucleotide and amino acid biosynthesis (Stincone et al., 2015). In addition, NADP+ and NADPH 
0
5
10
15
20
25
30
0.10
0.12
0.14
0.16
0.18
0.20
0.22
0.24
NADH control, no GNPs
NIST 30nm
NIST 10nm
CNM-Au8
26 M NADH in 5.7 mM NaHCO3 with 3.4 g/mL Au
absorbance at 339nm, cm
-1
time, min
CNM-Au8
NIST 10nm
NIST 30nm
0
1
2
3
4
5
6
7
8
9
10
26 M NADH in 5.7 mM NaHCO3
NADH oxidation rate, a.u.
GNPs at [Au] ~ 3.4 g/mL
co n tro l
C N M -A u 8  (1 0  n g /m l)
C N M -A u 8  (1 0 0  n g /m l)
C N M -A u 8  (1  µ g /m l)
C N M -A u 8  (1 0  µ g /m l)
B D N F  (5 0  n g /m l)
0
10
20
30
40
50
60
70
80
90
Q u an tity  o f N A D +  (n M )
*
*
*
* p < 0 .0 5  v s c o n tro l c o n d itio n  O n e -W a y  A N O V A  fo llo w e d  b y  D u n n e tt's te st
co n tro l
C N M -A u 8  (1 0  n g /m l)
C N M -A u 8  (1 0 0  n g /m l)
C N M -A u 8  (1  µ g /m l)
C N M -A u 8  (1 0  µ g /m l)
B D N F  (5 0  n g /m l)
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
Q uantity of N A D H  (nM )
*
*
*
*p< 0.05 vs control condition O ne-W ay A N O V A  follow ed by D unnett's test
*

 
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serve as the redox equivalents for both the thioredoxin and glutathione systems (Grant, 2008; 
Pollak et al., 2007), which in turn serve as the cell’s primary defenses against oxidative stress.  
CNM-Au8 catalyzes the oxidation of NADPH to NADP+ (Figure 3). While the time course of 
catalysis of NADPH to NADP+ is longer than that observed for conversion of NADH to NAD+, 
the magnitude of the effect is similar. Thus, CNM-Au8 plays an important role in providing 
NADP+ to the enzyme glucose 6-phosphate dehydrogenase for the conversion of 6-
phosphogluconate to ribulose 5-phosphate and NADPH + CO2, which represents the rate-
limiting step of the oxidative branch of the PPP. 
 
 Figure 3.  Effects of CNM-Au8 on NADPH Oxidation  
 
 
Excessive reactive oxygen exposure disrupts cellular redox homeostasis, damages intracellular 
organelles as well as DNA and proteins, and may also underpin pathophysiologic mechanisms of 
ALS.  Super oxide dismutases (SODs) evolved as a component of the cell’s antioxidant defense 
system to regulate the levels of reactive oxygen species (ROS) and prevent damage from 
oxidative stress. SOD enzymes are found in the cytoplasm and mitochondria where they convert 
oxygen radicals to O2 or H2O2, which can in turn be converted to water and O2 by catalases.  A 
dose-dependent reduction of ROS levels was observed in differentiating oligodendrocyte 
precursor cells in primary culture with CNM-Au8 treatment. 
 
 
 

 
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Figure 4 . Effects of CNM-Au8 on SOD and ROS Generation 
Figure 4A. Effects on SOD Activity Assay  
 
Figure 4B.  Effects on ROS Generation in Purified Murine OPC 
cultures 
Figure 4C.  Effects on ROS Generation in 
Murine OPC Cultures Plus Rotenone 
 
Demonstration of SOD-like catalytic activity with CNM-Au8 treatment has several important 
implications. First, neurons and glial cells are energetically demanding and generate large 
amounts of ROS as byproducts of the energetic processes necessary for their function. Theories 
of aging and neurodegeneration suggest that as CNS cells age, they are less able to efficiently 
remove ROS and thereby succumb to the consequences of long-term ROS exposure. As CNS 
cells are exquisitely sensitive to ROS, they are among the first cell types to degenerate, leading 
to the cognitive, psychomotor, and movement impairments observed in diseases such as ALS, 
Alzheimer’s disease, and Parkinson’s disease (Angelova and Abramov, 2018). In addition, 
SOD1 may act not only as a regulator of ROS but also as a part of a glucose-oxygen sensing 
mechanism of a cell to determine whether the cell utilizes oxidative phosphorylation or aerobic 
glycolysis for ATP production (Reddi and Culotta, 2013). A study of oligodendrocyte (OL) 
energetics showed that human OLs preferentially use aerobic glycolysis during differentiation 
and myelination (Rone et al., 2016).  Data with CNM-Au8 demonstrate that treatment switches 
OPCs from proliferation to differentiation, while simultaneously stimulating aerobic glycolysis 

 
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production of ATP likely through NADH oxidation. Stimulation of SOD-like activity therefore is 
consistent with a role for CNM-Au8 in regulating cellular bioenergetics.  
 
Figure 5. Effect of CNM-Au8 on OPC Differentiation and ATP Production 
 
 
Effect of CNM-Au8 on a) OPC differentiation (O4+ cells) in isolated murine OPCs and b) ATP production in 
MO3.13 oligodendrocytes (72hr). Statistical analysis performed using one-way ANOVA (p < 0.05). 
 
 
Nonclinical Summary of In Vitro and In Vivo ALS Neuroprotection Studies 
1.2.2.1 In vitro ALS Neuroprotection Models 
 
CNM-Au8 exhibits neuroprotective effects in a broad range of neural cell types in in vitro and in 
vivo preclinical models of ALS. 
1.2.2.1.1 CNM-Au8 Protects Primary Rodent Motor Neurons from Excitotoxicity 
Excitotoxicity is the pathological process by which neuronal death occurs as a result of excessive 
stimulation of receptors at excitatory synapses such as the NMDA receptor. Excitotoxicity has 
been implicated in acute neurological damage from ischemia and traumatic brain injury and in 
the chronic neurodegeneration in Huntington's disease. Glutamate excitoxicity is also believed to 
be a significant contributor to motor neuron death in ALS.  Excitotoxic neuronal death via over-
activation of NMDA receptors contributes to excessive flux of calcium (Ca2+) into the cell. This 
triggers a range of responses resulting in cell death, including increased oxidative stress, 
inappropriate activation of proteases such as calpain, dysregulation of Ca2+-related pathways, 
mitochondrial damage, and the apoptotic cascade.  
 
Determination of the neuroprotective effects of  CNM-Au8 on motor neurons in an in vitro 
glutamate challenge model was carried out in ventral spinal cord cultures from E14 rat embryos 
(Martinou et al., 1992). On Day 11 after seeding, cultures were pre-treated with CNM-Au8 or 

 
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vehicle. The positive control riluzole was added for 1 hour of pre-treatment before glutamate 
addition. On Day 13, glutamate was added to the cultures for 20 minutes, followed by treatment 
of riluzole or CNM-Au8 for another 48 hours before cells were fixed and stained. Cultures were 
stained with anti-MAP-2 to assess motor neuron survival and neurite lengths, and also with TDP-
43 and Hoechst stain to assess extranuclear TDP43. CNM-Au8 dose-dependently protects motor 
neurons from glutamate-induced cell death (Figure 6A) while also preserving neurite length 
(Figure 6B). CNM-Au8 also outperformed riluzole on neurite network preservation.  In addition, 
CNM-Au8 treatment prevented the accumulation of cytoplasmic TDP-43, a hallmark of ALS 
cytotoxicity (Figure 6D).  
 
Figure 6 . Neuroprotection of Motor Neurons from Glutamate Excitotoxicity by CNM-
Au8 
Figure 6A. Motor Neuron Survival 
Figure 6B. Motor Neuron Neurtie Network Area 
 
 
Figure 6B. Effect Of CNM-Au8 on MAP-2 Staining in Rat Hippocampal Neurons Following Glutamate 
Excitotoxicity Injury 

 
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Figure 6D. Reduction in Cytoplasmic TDP43 
 
1.2.2.1.2 CNM-Au8 Protects Normal iPSC Derived Human Motor Neurons From ALS-
Participant-Derived Toxic Astrocytes 
Astrocytes from both sporadic and familial ALS participants display toxicity against normal 
human motor neurons (MN) in co-culture (Meyer et al., 2014a). Toxic ALS-participant-derived 
astrocytes appear to secrete an unidentified toxic factor; and when co-cultured with human MNs, 
the MNs die (Meyer et al., 2014a). Similar studies have shown that astrocytes from sporadic 
participants also exhibit toxicity against healthy MNs, likely by similar mechanisms (Haidet-
Phillips et al., 2011; Meyer et al., 2014b; Qian et al., 2017). To determine whether CNM-Au8 
protects MNs from toxic ALS-participant-derived astrocytes, healthy human iPSC-derived MNs 
were plated with SOD1A4V astrocytes for 14 days in the presence of various doses of CNM-
Au8 or vehicle. Neuroprotection was assessed by quantification of the expression of neuronal 
markers (Tuj1, Isl1/2, and ChAT) compared to vehicle treated control. Measurement of primary 
neurite lengths and a neurite network complexity Sholl analysis was also conducted (Sholl, 
1953). As shown in Figure 7 below significant neuroprotective dose-dependent effects of CNM-
Au8 treatment were consistently observed on survival in the presence of SOD1A4V participant-
derived toxic astrocytes.  
 
 
 
 
 
 
 

 
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Figure 7. CNM-Au8 Protects Normal iPSC Derived Human Motor Neurons From ALS-
Participant-Derived Toxic Astrocytes 
 
 
 
 
1.2.2.2 In vivo ALS Neuroprotection Models 
 
To demonstrate the efficacy of CNM-Au8 treatment in an in vivo model of ALS, two studies 
were conducted in separate SOD1G93A mouse model strains. These included the rapidly 
progressive SOD1G93A transgenic line on a mixed SJL/C57BL6 background (Heiman-Patterson 
et al., 2005) and the more slowly progressive SOD1G93A transgenic line on a congenic C57Bl/6 
background (Lutz, 2018) with lifespans of ~157 days compared to ~129 days, respectively. The 
study using rapidly progressing SOD1G93A animals showed only minor improvement in clinical 
onset (p=0.13, Mantel-Cox test), as well as significant lack of brainstem atrophy (p<0.05, 
unpaired t-test) in the CNM-Au8-treated group (N=15 animals per group;); all other functional 
measures were not significant (data not shown).  In the study of the slower progressing 
SOD1G93A (N=20 female mice, 10 per group), four-week-old female SOD1 mice were randomly 
assigned one of two groups with each group balanced for weight.  
 
Beginning at four weeks of age, mice were provided either CNM-Au8 or vehicle ad libitum in 
their drinking water. Beginning at Week 8 of age each mouse was tested weekly for strength and 
motor coordination utilizing several measures including the triple horizontal bar hang time test, 
static rod orientation test, inverted screen hang time test, weight hold test, and home cage wheel 
activity (average speed) in addition to standard ALS clinical scoring (Deacon, 2013a, 2013b; 
Hatzipetros et al., 2015). The CNM-Au8-treated group significantly outperforms the vehicle 
treated group at virtually all timepoints across these tests (Figure 8).   In addition, survival 
benefits have been observed through Week 22 of the study (Figure 9). 
 
Taken together, these preliminary data from an ongoing study in a transgenic ALS mouse model 
demonstrate preservation of motor function following chronic treatment with CNM-Au8. 
 

 
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Figure 8. Locomotor Functional Efficacy of CNM-Au8 in an SOD1G93A (C57Bl/6 
congenic strain) Murine Study 
 
A. ALS TDI Neuro Score 
 
B. Weights Hold Test 
C. Horizontal Bar Test 
 
 
D. Home Wheel Velocity  
E. Home Wheel Velocity By Period 
 
 
 
 

 
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Figure 9. Effect of CNM-Au8 on Survival in a Murine SOD1G93A Model 
 
 
1.2.3 Summary CNM-Au8 Treatment Rationale for ALS 
 
CNM-Au8-treated motor neurons are protected against cell death by glutamate excitotoxicity in a 
dose-dependent manner in a primary rat neural-glial co-culture where cytoplasmic levels of 
TDP-43 are significantly reduced. Aberrant cytoplasmic localization and aggregation of TDP-43 
has been observed in over 90% of cases of ALS in humans (Neumann et al. 2006).  Further, 
results from these multiple iPSC human motor neuron studies derived from sporadic, familial, 
and healthy lines indicate that CNM-Au8 is neuroprotective to MNs challenged with multiple 
different ALS disease related stressors, namely, excitotoxic and toxic astrocytic stress.  Results 
from the SOD1G93A-overexpression mouse study demonstrate significant improvements in 
locomotor performance of CNM-Au8-treated mice with a significant survival benefit. 
In summary, CNM-Au8 has demonstrated neuroprotection across a range of neuronal cell types, 
antioxidant activity to counteract the accumulation of ROS in ALS, and preservation of motor 
function in an ALS mouse model. CNM-Au8 therefore represents an important therapeutic 
candidate for ALS. 
 
 

 
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2. OBJECTIVES 
2.1 Study Objectives and Endpoints  
Primary Efficacy Objective: 
To evaluate the efficacy CNM-Au8 as compared to placebo on ALS disease progression.  
 
Secondary Efficacy Objective: 
• To evaluate the effect of CNM-Au8 on selected secondary measures of disease 
progression, including survival. 
 
Safety Objective: 
• To evaluate the safety of CNM-Au8 for ALS. 
 
Exploratory Efficacy Objective: 
• To evaluate the effect of CNM-Au8 on selected biomarkers and endpoints. 
 
Primary Efficacy Endpoint: 
Change in disease severity as measured by the ALS Functional Rating Scale-Revised (ALSFRS-
R) total score using a Bayesian repeated measures model that accounts for loss to follow-up due 
to mortality.  
 
Secondary Efficacy Endpoints: 
• Change in respiratory function as assessed by slow vital capacity (SVC). 
• Change in muscle strength as measured isometrically using hand-held dynamometry 
(HHD) and grip strength. 
• Survival. 
 
Safety Endpoints: 
• Treatment-emergent adverse and serious adverse events. 
• Changes in laboratory values and treatment-emergent and clinically significant laboratory 
abnormalities. 
• Changes in ECG parameters and treatment-emergent and clinically significant ECG 
abnormalities. 
• Treatment-emergent suicidal ideation and suicidal behavior. 
 
Exploratory Efficacy Endpoints: 
• Changes in quantitative voice characteristics. 
• Difference in the proportion of patients experiencing a  6-point decline in the ALSFRS-
R between active treatment and placebo from Baseline to Week 24. 
• Changes in biofluid biomarkers of neurodegeneration. 

 
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• Changes in patient reported outcomes.  
• Change in respiratory function as assessed by home spirometry. 
 
 
 
 

 
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3. RSA DESIGN 
This study is a multi-center, randomized, placebo-controlled trial, testing two active doses of 
CNM-Au8 (30 mg, 60 mg), given orally daily versus color-matched placebo. Participants will be 
randomized 3:1 active (CNM-Au8): placebo.  Participants randomized to active will be equally 
allocated between the CNM-Au8 30 mg and 60 mg doses. 
  
3.1 Scientific Rationale for RSA Design 
The comparator for this study is placebo. Placebo will consist of a sodium bicarbonate solution 
in USP water, color matched to active CNM-Au8. Placebo was chosen as the comparator 
because there are no highly effective, disease-modifying therapies currently available for people 
with ALS. Both riluzole and edaravone, the only two therapies currently approved for ALS, are 
available to participants as concomitant therapy during this study. In this manner, participants are 
not sacrificing any potential benefit from currently approved therapies  to participate in this 
study. 
 
3.2 End of Participation Definition 
A participant is considered to have ended his or her participation in the placebo-controlled period 
of the Regimen if they: 
•  Complete planned placebo-controlled period visits, as described in the SOA, including 
participants on or off study drug 
• Early terminate from the study and complete the Early Termination Visit and Follow-Up 
Phone call as described in Section 6.1.11 
• Withdraw consent to continue participation in the study, or are lost to follow-up 
.  
If a participant initiates open-label study drug in the OLE period, he or she is considered to have 
completed his or her participation in the OLE period of the Regimen if they choose to 
discontinue participation or if all planned OLE period visits, including the last visit or the last 
scheduled procedure shown in the SOA, have been completed.  
3.3    End of Regimen Definition 
 
The end of the placebo-controlled period in a Regimen occurs when all randomized participants 
have completed their participation in the placebo-controlled period as defined in section 3.2. 

 
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The end of the OLE period in a Regimen occurs when all participants who initiated open-label 
study drug in the OLE period have completed their participation in the OLE period as defined in 
section 3.2. 
 
 
 

 
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4. RSA ENROLLMENT 
4.1 Number of Study Participants 
Approximately one hundred-sixty (160) participants will be randomized for this Regimen.   
 
4.2 Inclusion and Exclusion Criteria 
In order to be randomized to an RSA, participants must meet the Master Protocol eligibility 
criteria.  In addition, participants meeting all of the following inclusion and exclusion criteria 
will be allowed to enroll in this Regimen:  
 
4.2.1 RSA Inclusion Criteria 
Per the Master Protocol. 
 
4.2.2 RSA Exclusion Criteria  
1. History of allergy to gold, gold salts, or colloidal gold preparations.  
 
4.3 Treatment Assignment Procedures 
Each participant who meets all eligibility criteria for the RSA will be randomized to receive 
either CNM-Au8 or placebo for approximately 24-weeks of double-blind treatment.  An 
additional period of open-label treatment may be offered to participants following completion of 
the placebo-controlled portion of the study. 
 
 
 

 
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5. INVESTIGATIONAL PRODUCT  
5.1 Investigational Product Manufacturer 
Manufacturing, testing, product characterization, release of CNM-Au8 will be carried out at the 
Sponsor’s facility at 500 Principio Parkway West, Suite 400, North East, MD 21901, USA.  
 
Table 2.  CNM-Au8 Investigational Product Dosing Administration 
 
Description 
CNM-Au8 30 mg 
CNM-Au8 60 mg 
Matched Placebo 
Total Daily Dosage 
30 mg 
60mg 
NA 
Concentration 
250 μg/mL 
500 μg/mL 
NA 
Volume per Bottle 
60 mL 
60 mL 
60 mL 
Bottles per Day 
2 
2 
2 
Daily Volume 
120 mL 
120 mL 
120 mL 
Route of 
Administration 
Oral 
Oral 
Oral 
Time and 
Frequency 
Once Daily; Same 
Time Each Day  
(± 1 hour) 
Once Daily; Same 
Time Each Day  
(± 1 hour) 
Once Daily; Same 
Time Each Day  
(± 1 hour) 
 
The investigational product components and quality standards are described in Table 6 below. 
 
Table 3.  CNM-Au8 Components and Quality Standards 
 
Description 
Quality Standard 
CNM-
Au8 
30 mg 
CNM-
Au8 
60 mg 
Matched 
Placebo 
NaHCO3 (mg) per 
bottle 
ACS, USP identity 
32.8 mg 
32.8 mg 
32.8 mg 
Au (mg) per Bottle 
Conforms with ASTM B562-95 and USP 
<233>  
15 mg 
30 mg 
NA 
USP Purified Water 
USP for total organic carbon, and 
conductivity 
60 mL 
60 mL 
60 mL 
 
  
5.2 Labeling, Packaging, and Resupply 
All investigational drug products will be labeled according to applicable local and legislative 
requirements. Label text will be approved according to the Sponsor’s agreed procedures, and a 

 
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copy of the labels will be made available to the study site upon request. For all study drugs, a 
system of numbering in accordance with all requirements of Good Manufacturing Practice 
(GMP) will be used, ensuring that each dose of study drug can be traced back to the respective 
bulk ware of the ingredients. The Sponsor’s Quality Assurance group will maintain lists linking 
all numbering levels.  A complete record of batch numbers and expiry dates of all study 
treatment as well as the labels will be maintained in the Sponsor study file. 
 
Study drug label may include, but is not limited to, the following information: 
• Batch number 
• Storage information 
• Unique number/code 
  
5.3 Acquisition, Storage, and Preparation 
Investigational product will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and GMP requirements and will be inaccessible to unauthorized personnel. A 
complete record of batch numbers and expiry dates can be found in the regimen industry partner 
study file; the site-relevant elements of this information will be available in the Investigator site 
file. The responsible site personnel will confirm receipt of IP via the interactive web response 
system (IWRS) and will use the IP only within the framework of this clinical study and in 
accordance with this protocol. Receipt, distribution, return and destruction (if any) of the IP must 
be properly documented according to the Sponsor’s agreed and specified procedures. 
 
All IP must be kept in a locked area with limited access and stored at 15°- 25°C (59°- 77°F). 
Mean kinetic temperature should not to exceed 25°C. Excursions between 15°C and 30°C (59° 
and 86° F) that may be experienced in pharmacies, hospitals, or warehouses, and during shipping 
are allowed. 
 
5.4 Study Medication/Intervention, Administration, Escalation, and Duration 
 
Participants will either receive CNM-Au8 30 mg, 60 mg, or color-matched placebo in the study.  
The Investigational Product (IP) will be self-administered by participants who will be directed to 
take the IP each day in the morning at approximately the same time, at home at least thirty (30) 
minutes prior to food intake. The drug formulations will be identical in appearance (size, shape, 
volume, color) and smell. The packaging and labeling will be designed to maintain blinding to 
the Site Investigator’s team and to participants. There are no visible differences between CNM-
Au8 30 mg, 60 mg, and placebo dosing units.  
 

 
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Participants may take the study drug by mouth or through a gastric tube.  Participants taking 
study drug by gastric tube should be directed to first flush the tube with approximately 20-30 mL 
of distilled water, administer study drug, and then flush the tube post-study drug administration 
with another 20-30 mL of distilled water. 
 
Based on the supply of the IP provided, the maximum window between in-clinic study visits 
during the placebo-controlled period may not exceed 64 days. The maximum window between 
in-clinic study visits during the Open Label Extension period may not exceed may not exceed 64 
days for the first 16 weeks, and may not exceed 96 days for the duration of the OLE study 
period. 
 
5.5 Drug Returns and Destruction  
At each in person visit the steps outlined in Manual of Procedures must be followed for study 
drug accountability and compliance, as well as study drug return and destruction.  
 
Prior to study drug destruction, all used and unused IP requires a second accountability 
verification to be completed by a different study team member, and both verifications should be 
documented on the study destruction logs. No study drug may be destroyed on-site until written 
approval is provided by the study monitoring team. Sites should follow their local drug 
destruction policies. 
 
 

 
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5.5 Dosage Adjustment 
 
No dosage adjustments are anticipated during the placebo-controlled period of the study. If 
participants have difficulty tolerating IP, the Investigator may permit the participants to reduce 
the daily dose by one (1) bottle. Potential tolerability issues may include gastrointestinal 
disturbances, headache, somnolence, or other treatment emergent adverse events are not 
otherwise explained.  
 
Down titration of IP to one (1) bottle daily will only be allowed to address tolerability issues and 
only with Medical Monitor approval. After a participant has been down titrated to, he/she may be 
allowed to retry two (2) bottle dose (re-challenge), after a discussion with and approval by the 
Site Investigator and Medical Monitor. Any dosing changes must be appropriately documented 
including start date(s) and re-challenge date(s). If the participant cannot tolerate the re-challenge, 
he/she may remain at the lower dose of one (1) bottle daily. Drug holidays (e.g., treatment-free 
periods) are not permitted. 
 
During the Open Label Extension, participants will maintain their current blinded dose. 
Participants previously randomized to placebo during the placebo-controlled period of the study 
will be re-randomized to receive CNM-Au8 30 mg or 60 mg for the Open Label Extension. All 
dosing assignments will remain blinded throughout the Open Label Extension. IP tolerability 
issues encountered during the Open Label Extension will be managed on a case-by-case basis by 
the Site Investigator in coordination with the Medical Monitor. 
 
5.6 Justification for Dosage  
Dosage selection has been made based on human safety margins from nonclinical toxicology 
studies and the exposure data from pharmacology studies that demonstrated neuroprotection 
benefits. 
 
5.6.1. Human Dosing Safety Margins 
Based upon the maximum doses (mg/kg/day) evaluated in the nonclinical GLP repeat-dose 21-
day toxicokinetic studies, the completed first-in-human Phase 1 study (AU8.1000-14-01) doses 
of 15, 30, 60, 90 mg provided a safety margin to the NOAEL based on dose ratios (mg/m2) 
ranging from 26x – 4x in rodents, and 195x – 32x in canines, as described in the tables below.  
Therefore, at the top dose of 90 mg tested in humans, there was a minimum 4x safety margin to 
the NOAEL in rats.  
 

 
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Table 4. Summary of CNM-Au8 Conversion of Animal 21-Day Repeat Doses To Human 
Equivalent Dose (HED) Based On Body Surface Area (mg/m2) for 60 kg Human 
 
Further, when evaluating Au exposure based on the end of study Day 21 AUC(0-24) (ng*hr/mL) 
in the canine, and rodent studies in comparison with the human 21-day MAD study, the human 
doses provided an exposure safety margin ranging from 3.3x – 1.6x  compared with rodents, and 
18.5x – 9.0x compared with canines, as described in the Table 3 below. 
 
Table 5. Summary of CNM-Au8 Exposure Safety Margin Based on End of Study AUC(0-
24) ng*hr/mL. Ratio of Animal Toxicokinetic to Human Pharmacokinetic AUC Results 
From 21-Day Repeat Dose Studies.  
 
CNM-Au8 exposure at the NOAEL at the end of the chronic toxicokinetic studies in the 9-Month 
canine and 6-Month rodent chronic dosing studies, provided an exposure safety margin ranging 
from 6.5x – 3.2x, and 13.6x – 6.7x in rodents and canines, respectively in comparison with the 
human exposures in the 21-day MAD study, as described below in Table 4. 
 
 
 
Species 
21-Day 
NOAEL 
Dose 
(mg/kg/day) 
21-Day 
NOAEL 
Dose 
(mg/m2) 
Safety Margin Based on Dosing Ratios (mg/m2) 
(For 21-Day dosing Studies) 
15 mg 
(9.3 
mg/m2) 
30 mg 
(18.5 
mg/m2) 
60 mg 
(37.0 
mg/m2) 
90 mg 
(55.5 
mg/m2) 
Rat 
40 
240 
25.9 
13.0 
6.5 
4.3 
Canine 
90 
1800 
194.6 
97.3 
48.6 
32.4 
 
Species 
 
21-Day 
NOAEL 
Dose 
(mg/kg/day) 
Animal 
End of 
Study 
AUC(0-24) 
(ng*hr/mL)a 
Safety Margin Based on Animal/Human  
AUC(0-24) Ratio (For 21-Day Dosing Studies) 
Human 
15 mg 
AUC 
(32.3 
ng*hr/mL) 
Human 
30 mg 
AUC 
(41.4 
ng*hr/mL) 
Human 
60 mg 
AUC 
(50.3 
ng*hr/mL) 
Human 
90 mg 
AUC 
(66.0 
ng*hr/mL) 
Rat 
40 
106 
3.3 
2.6 
2.1 
1.6 
Canine 
90 
596 
18.5 
14.4 
11.8 
9.0 
Notes: a Average of Male and Female AUC(0-24) ng*hr/mL values at End of Study 

 
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Table 6.  Summary of CNM-Au8 Exposure Safety Margin Based on End of Study AUC(0-
24) ng*hr/mL Ratio of Chronic Animal Toxicokinetic 6 and 9-Month Rodent and Canine 
Repeat Dose Studies to Human 21-Day Pharmacokinetic Results  
 
 
5.6.2 Neuroprotection Pharmacologic Exposure Data 
Based on the blood gold exposure observed in rodent toxicokinetic (TK) studies where 
significant remyelination and neuroprotection benefits were observed in preclinical 
neuroprotection models at mean AUC value of 30.6 (hr*ng/mL), which suggests a minimum 
human equivalent exposure to achieve a positive bioenergetic response to CNM-Au8 of 15 – 30 
mg.  Increased AUC exposure of 50.3 (hr*ng/mL) was observed at the CNM-Au8 60 mg dose.   
 
Figure 10. 21-Day AUC Exposure Ranges Between Rodent Toxicokinetic Studies, 
Preclinical Efficacy Models, and First-In-Human Dosing 
 
 
 
Species (Study) 
 
NOAEL  
Chronic 
Dosing 
(mg/kg/day) 
Animal 
End of 
Study 
AUC(0-
24) 
(ng*hr/m
L)a 
Safety Margin Based on Chronic Animal End-of-Study/ 
Human 21-Day AUC(0-24) Ratio 
Human 
15 mg AUC 
(32.3 
ng*hr/mL) 
Human 
30 mg AUC 
(41.4 
ng*hr/mL) 
Human 
60 mg AUC 
(50.3 
ng*hr/mL) 
Human 
90 mg AUC 
(66.0 
ng*hr/mL) 
Rat (6-Month) 
40 
209 
6.5 
5.0 
4.2 
3.2 
Canine  
(9-Month) 
10 
440 
13.6 
10.6 
8.7 
6.7 
a Average of Male and Female AUC(0-24) ng*hr/mL values  at End of Study 

 
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In conclusion, based on CNM-Au8 exposures at the NOAELs in the chronic rodent and canine 
studies along with observed CNM-Au8 exposures in 21-day multiple dosing in humans while 
also considering safety and tolerability, the dosage chosen for this study in participants with ALS 
will be CNM-Au8 30 mg/day and 60 mg/day.   
 
5.7 Participant Compliance 
Participants will be requested to return any unused IP including empty packaging and used 
bottles at each study visit. Treatment compliance will be assessed at in clinic study visits through 
bottle counts and will be documented and summarized by a drug-dispensing log for each 
participant. During phone visits, drug compliance check-in will be held to ensure participant is 
taking drug per dose regimen and to note any report of missed doses. Overall treatment 
compliance with IP intake for the per protocol analysis set should be between 80% and 120% of 
the planned dose and will be assessed at specified study visits. In the event participants are not 
compliant within this range, discontinuation may be considered by the Site Investigator in 
consultation with the Medical Monitor or designee. 
 
The date of dispensing the IP to the participant will be documented in the eCRF. Changes in IP 
dosing for tolerability issues will also be documented in the eCRF. 
 
If a dose of IP is missed, the participant should take the dose that day and continue with the 
planned dosing interval for the following day. The dose should not be doubled to make up for a 
missed dose within the same day.  
 
5.8 Overdose 
In the event of overdose, study staff should monitor the study participant and provide supportive 
care as needed. The SI should also contact the Medical Monitor within twenty-four (24) hours.  
No prior experience has been documented regarding overdosage in humans.  
5.9 Prohibited Medications 
There are no prohibited medications for this regimen.  
5.10 CNM-Au8 Known Potential Risks and Benefits 
5.10.1 Known Potential Risks 
5.10.1.1 Immediate Risks  
 
• There has been limited human exposure to clean-surfaced Au nanocrystals. There could be 
unexpected adverse effects from 24 weeks of exposure to 30 mg or 60 mg of CNM-Au8. 
These risks have been mitigated by an extensive preclinical toxicology program in multiple 

 
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species demonstrating No-Adverse-Effect-Levels (NOAEL) at the highest doses studied (up 
to 10 mg/kg/day in canines; 40 mg/kg/day in rats). Therefore, no Maximum Tolerated Dose 
(MTD) could be established in these nonclinical studies. In addition, single and multiple 
ascending dose studies have been performed in healthy human volunteers, which showed no 
significant adverse events (SAEs) or safety issues. CNM-Au8 was well tolerated at the doses 
studied up to 90 mg per day over twenty-one days of consecutive dosing. 
 
• There have been no clinical trials of CNM-Au8 in humans with ALS. There is a risk that 
CNM-Au8 may not be effective and a very small risk that CNM-Au8 could make participants 
worse. These risks have been mitigated by a robust preclinical program, demonstrating that 
CNM-Au8 is effective in multiple models of protection from neurodegeneration. 
 
5.10.1.2 Long Range Risks 
 
There has been limited human exposure to CNM-Au8. There could be unexpected adverse 
effects from chronic exposure to 30 mg or 60 mg of CNM-Au8. Based on rodent and canine 
toxicokinetic data, when taken orally with daily administration, CNM-Au8 can be expected to be 
absorbed, and eliminated, relatively slowly with increasing blood and tissue concentrations 
accumulating over time.  
 
The risks of long-term exposure to CNM-Au8 are mitigated by toxicology studies with chronic 
dosing, demonstrating no significant toxicities or maximum-tolerated dose. 
 
5.10.1.3 Summary of Participant Risk 
 
Given the potential benefits of CNM-Au8 demonstrated in pre-clinical models of ALS, the safety 
of CNM-Au8 demonstrated in preclinical toxicology studies and Phase 1 clinical trials in healthy 
controls, overall, the benefit-risk of CNM-Au8 is positive for participants with ALS.  
 
5.10.2 Known Potential Benefits 
As described previously, in preclinical models of ALS, CNM-Au8 has demonstrated efficacy in 
several relevant models of neurodegeneration.  CNM-Au8 has been shown to protect neuronal 
populations from chemical, inflammatory, and hypoxic insults through a series of unique 
catalytic mechanisms involving 1) the nicotine adenine dinucleotide redox couple 
(NAD+/NADH) to boost glycolytic energy production, 2) the nicotine adenine dinucleotide 
phosphate redox couple (NADP+/NADPH) to influence anabolic processes associated with 
differentiation, and 3) the SOD-like inactivation of reactive oxygen species and nitric oxide to 
protect cells from oxidative damage and mitochondrial dysfunction. These data suggest that 

 
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CNM-Au8 could improve participant functioning and/or prolong life in participants with ALS. 
The safety of CNM-Au8, at the doses to be tested in this study have been shown to be safe and 
well tolerated in preclinical toxicology and Phase 1 clinical trials in healthy controls. 
 
5.11 Regimen-Specific Lab Alerts 
Site Investigators and the Medical Monitor will receive an alert from the Central Lab for certain 
lab changes.  (See below.)  These alerts are informative only, and they do not mean a participant 
must reduce drug dosage or discontinue study drug. These alerts indicate that the Site 
Investigator and Medical Monitor should follow up with additional testing and management as 
clinically indicated. Discontinuation of any participant on the basis of abnormal laboratory 
findings will be at the discretion of the Site Investigator. 
 
Chemistry Panel Test 
Name 
Outlier Criteria Warranting Further 
Investigation 
ALT and AST 
>3x ULN 
Creatinine 
>1.5 x Baseline 
Hematology Panel Test 
Name 
Outlier Criteria Warranting Further 
Investigation 
Platelet count 
<75,000/mm3 
 

 
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6. REGIMEN SCHEDULE  
In addition to procedures in the Master Protocol, the following regimen-specific procedures will 
be conducted during the study: 
 
• Home Spirometry 
o Note: Home spirometry should be collected within the visit window but will occur 
while the participant is not in the clinic (at home or other remote location)e.  
• ALSAQ-40 
• CNS Bulbar Function Scale 
• Voice recording 
• Smartphone installation and removal 
• Whole blood collection for PK and PD analyses 
• Plasma collection for PK and PD analyses 
• Urine collection for PD analyses 
 
Modifications to Regimen Schedule  
 
Designated visits in the Schedule of Activities (i.e., Week 4, Week 8, and Week 16) may be 
conducted via telemedicine (or phone if telemedicine is not available) with remote services 
instead of in-person if needed to protect the safety of the participant due to a pandemic or other 
reason. If a planned in-clinic visit is conducted via telemedicine (or phone if telemedicine is not 
available) with remote services, only selected procedures will be performed. Instructions on how 
to document missed procedures are included in the MOP.  
 
In addition to the procedures in the Master Protocol that should be conducted during the phone or 
telemedicine and remote visits, the following regimen-specific procedures should be completed:  
 
• Home Spirometry (Week 8 and 16 only) 
• Voice Recording 
• CNS Bulbar Function Scale (Week 8 and 16 only)  
 
Details on collection of the CNS Bulbar Function Scale, dispensing IP during remote visits, and 
documenting participants’ willingness to participate in OLE are described in the MOP. 
 
Blood samples for PK and PD analyses are not collected during the remote visits by the home 
health agency and this should be recorded as such in the applicable source documentation and 
EDC.  

 
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6.1 Regimen-Specific Screening Visit 
This visit will take place in-person after the Master Protocol randomization to a regimen. There 
are no regimen-specific procedures for this visit. For this regimen, the Regimen-Specific 
Screening Visit and Baseline Visit should be combined, if possible. 
Participants may be required to reconsent to the regimen if new procedures or information is 
added in the future. Should a participant need to reconsent, this should occur during the 
participant’s next in-person visit. If the participant’s next in-clinic visit is conducted remotely, 
reconsent may also be completed remotely using the following procedures: 
 
1. The site staff sends copy of the informed consent form to the participant.  
2. The participant reads through the consent form but does not sign.  
3. The Site Investigator, or other study staff member approved and delegated to obtain informed 
consent, contacts the participant and reviews the informed consent form with the participant. 
4. The participant signs the informed consent form and returns the original signed consent form 
back to the site. 
5. Once received at the site, the individual who consented the participant signs the informed 
consent form. 
 
6.2 Baseline Visit 
This visit will take place on Day 0.  The following procedures will be performed for the regimen 
schedule: 
 
• ALSAQ-40 
• CNS Bulbar Function Scale 
• Install smartphone app 
• Home Spirometry 
• Voice recording 
• Whole blood collection for PK and PD analyses 
• Plasma collection for PK and PD analyses 
• Urine collection for PD analyses 
• Dispense IP 
• Administer first dose of IP in clinic after all Baseline procedures have been completed 
• Remind participant to bring in investigational product to the next visit 
 
 

 
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6.3 Week 2 Telephone Visit 
 
This visit will take place 14 ± 3 days after the Baseline Visit via telephone.  No regimen-specific 
procedures will be performed at this visit. 
 
6.4 Week 4 and 8 Visits 
Participants should be instructed to hold study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
 
These visits will take place on Days 28 ± 7 and 56 ± 7 days, respectively.  The following 
procedures will be performed for the regimen schedule: 
 
• Home Spirometry [Week 8 Only] 
• CNS Bulbar Function Scale [Week 8 only] 
• Voice recording 
• Plasma collection for PK analyses 
• Dispense IP (Week 8 only)  
• Remind participant to bring in investigational product to the next visit 
 
6.5 Week 12 Telephone Visit 
 
This visit will take place 84 ± 3 days after the Baseline Visit via telephone.  No regimen-specific 
procedures will be performed at this visit. 
 
6.6 Week 16 Visit  
This visit will take place on Day 112 ± 7 days.  The following procedures will be performed for 
the regimen schedule: 
• Home Spirometry 
• ALSAQ-40 
• CNS Bulbar Function Scale 
• Voice Recording 
• Dispense IP 
• Document participant’s willingness to participate in the OLE 
o 
If OLE consent is not obtained at Week 16, it may be obtained at Week 24. 
 
• Remind participant to bring in investigational product to the next visit 

 
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6.7 Week 20 Telephone Visit 
 
This visit will take place 140 ± 3 days after the Baseline Visit via telephone. No regimen-specific 
procedures will be performed at this visit. 
 
6.8 Week 24 Visit or Early Termination Visit 
Participants should be instructed to hold study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
 
This visit will take place on Day 168 ± 7 days.  The following procedures will be performed for 
the regimen schedule: 
• Home Spirometry 
• ALSAQ-40 
• CNS Bulbar Function Scale 
• Voice recording  
• Uninstall smartphone app 
• Whole blood collection for PK and PD analyses 
• Plasma collection for PD analyses 
• Urine collection for PD analyses 
• Dispense IP [See note below.] 
• Remind participant to bring investigational product to the next visit (only if continuing in 
OLE) 
 
Note: Drug is only dispensed at this visit if the participant is continuing in the Open Label 
Extension. 
 
6.9 Follow-Up Safety Call 
Participants will have a Follow-Up Safety Call 28±3 days after their last dose of study drug.  
Only those participants NOT continuing on in the Open Label Extension will have the Follow-
Up Safety Call at the end of their participation in the placebo-controlled portion of the trial.  The 
following procedures will be performed: 
 
• Assess and document AEs 
 

 
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6.10 Process for Early Terminations  
Participants who early terminate from the study and do not complete the protocol per ITT will be 
asked to be seen for an in-person Early Termination Visit and complete a Follow-Up Safety Call. 
If a participant is not able to be seen in-person, safety assessments and others that can be 
conducted remotely should be performed. 
 
 
The in-person Early Termination Visit should be scheduled as soon as possible after a participant 
early terminates. If the participant early terminates or withdraws consent during the placebo-
controlled portion of the Regimen, all assessments that are collected at the Week 24 in-clinic 
visit should be conducted. If the participant early terminates or withdraws consent during the 
OLE phase, all assessments that are collected at the OLE Week 52 in-clinic visit should be 
conducted. The Follow-Up Safety Call should be completed approximately 28 days after the last 
dose of study drug.   
 
If the Early Termination Visit occurs approximately 28±3 days after the last dose of study drug, 
the information for the Follow-Up Safety Call can be collected during the Early Termination 
Visit, and a separate Follow-Up Safety Call does not need to be completed. If the in-person Early 
Termination Visit does not occur within 28±3 days of the last dose of study drug, the Follow-Up 
Safety Call should occur approximately 28 days after the last dose of study drug and the Early 
Termination Visit will be completed after the Follow-Up Safety Call.  
 
If a participant decides to discontinue study drug, but will complete the protocol, an in-person 
Early Termination Visit and Follow-Up Safety Call is not necessary. 
 
6.11 Open Label Extension  
 
Participants who have completed the placebo-controlled portion of the trial on drug. will be 
eligible to continue in the Open Label Extension (OLE) as outlined in the SOA. Participants will 
first be asked about their desire to continue in the OLE at the Regimen-Specific Screening Visit.  
They will also be asked to re-confirm whether they want to continue in the OLE at the Week 16 
Visit of the placebo-controlled period. The OLE, CNM-Au8 will be provided by Clene 
Nanomedicine, until the primary results of the 24 week double-blind portion of the study are 
available, or Clene or sponsor terminate support or development of CNM-Au8 for ALS. 
 
Modifications to OLE Schedule  
Designated visits in the Schedule of Activities for the OLE (i.e. Week 4, Week 8, Week 16, 
Week 28, and Week 40) may be conducted via telemedicine (or phone if telemedicine is not 
available) with remote services instead of in-person if needed to protect the safety of the 

 
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participant due to a pandemic or other reason. If a planned in-clinic visit is conducted via 
telemedicine (or phone if telemedicine is not available) with remote services, only selected 
procedures will be performed. Instructions on how to document missed procedures are included 
in the Manual of Procedures.  
 
In addition to the procedures in the Master Protocol that should be conducted during the phone or 
telemedicine and remote visits, the following regimen-specific procedures should be completed:  
 
• Home Spirometry 
• CNS Bulbar Function Scale (Not done at OLE Week 4).  
 
Blood and urine samples for PK and PD analysis are not collected during the remote visits by the 
home health agency, and this should be recorded as such in the applicable source documentation 
and EDC.  
 
6.11.1 Week 2 OLE Telephone Visit 
 
This visit will take place via telephone 14 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Drug Compliance Check-In 
• 
Remind participant to bring investigational product to the next visit 
 
6.11.2 Week 4 OLE Visit 
 
This visit will take place in-person 28 ± 10 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Collect vital signs including weight 
• 
Perform SVC 
• 
Collect Home Spirometry  
• 
Administer ALSFRS-R questionnaire 
• 
Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  

 
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• 
Perform investigational product compliance 
• 
Remind participant to bring investigational product to the next visit 
 
6.11.3 Week 8 OLE Visit 
 
This visit will take place in-person at 56 ± 7 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Collect vital signs including weight 
• 
Perform SVC 
• 
Collect Home Spirometry 
• 
Administer ALSFRS-R questionnaire 
• 
CNS Bulbar Function Scale 
• 
Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  
• 
Dispense investigational product to participant  
• 
Perform investigational product compliance 
• 
Remind participant to bring investigational product to the next visit 
 
6.11.4  Week 12 OLE Telephone Visit 
 
This visit will take place via telephone at 84 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Administer ALSFRS-R questionnaire 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Drug Compliance Check-In 
• 
Remind participant to bring investigational product to the next visit 
 
6.11.5  Week 16 OLE Visit 
 
Participants should be instructed to hold study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
 

 
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This visit will take place in-person at 112 ± 7 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Collect vital signs including weight 
• 
Perform SVC 
• 
Collect Home Spirometry 
• 
Administer ALSFRS-R questionnaire 
• 
CNS Bulbar Function Scale 
• 
Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  
• 
Collect urine sample biomarker analyses 
• 
Collect blood sample for biomarker analyses 
• 
Whole blood PK and PD collection  
• 
Plasma PD collection 
• 
PD urine collection 
• Dispense investigational product to participant  
• 
Perform investigational product compliance 
• 
Remind participant to bring investigational product to the next visit 
 
6.11.6  Week 20 OLE Telephone Visit 
 
This visit will take place via telephone at 140 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Administer ALSFRS-R questionnaire 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Drug Compliance Check-In 
• 
Remind participant to bring investigational product to the next visit 
 
 
6.11.7  Week 24 OLE Telephone Visit 
 
This visit will take place via telephone at 168 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Administer ALSFRS-R questionnaire 
• 
Review concomitant medications 

 
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• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Drug Compliance Check-In 
• 
Remind participant to bring investigational product to the next visit 
 
6.11.8  Week 28 and Q12 Week OLE Visits 
 
Participants should be instructed to hold study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
 
The Week 28 OLE Visit will take place in-person 196 ± 14 days after the Week 24 Visit of the 
placebo-controlled portion of the trial. The procedures listed in the SoA should be performed and 
participants should be provided with 8 weeks of drug and instructions for dosing. Following the 
Week 28 OLE Visit, visit will occur every 12 weeks ± 14 days. 

 
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7 OUTCOME MEASURES AND ASSESSMENTS 
For all assessments listed below, please refer to the Manual of Procedures for detailed 
instructions. 
 
7.1 Voice Analysis 
In addition to the scheduled in clinic voice recordings, voice samples will be collected twice per 
week, using an app installed on either an android or iOS based smartphone.  The app 
characterizes ambient noise, then asks patients to perform a set of speaking tasks: reading 
sentences -- 5 fixed and 5 chosen at random from a large sentence bank-- repeating a consonant-
vowel sequence, producing a sustained phonation, and counting on a single breath. Voice signals 
are uploaded to a HIPAA-compliant web server, where an AI-based analysis identifies relevant 
vocal attributes. Quality control (QC) of individual samples will occur by evaluation of voice 
records by trained personnel. 
 
The voice analysis app is only available in English, therefore participants who do not speak 
English should not complete the voice recording. Caregivers cannot provide language assistance 
when the participant is completing the voice recording. 
 
7.2  ALSAQ-40 
 
The Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 (ALSAQ-40) is a patient self-
report health status patient-reported outcome. The ALSAQ-40 consists of forty questions that are 
specifically used to measure the subjective well-being of patients with ALS and motor neuron 
disease. 
 
Participants will be handed the questionnaire and asked to write their answers themselves.  
Caregivers can also help, if needed. 
 
7.3  Center for Neurologic Study Bulbar Function Scale 
 
The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) is a patient self-report scale 
that has been developed for use as an endpoint in clinical trials and as a clinical measure for 
evaluating and following ALS patients. The CNS-BFS consists of three domains (swallowing, 
speech, and salivation), which are assessed with a 21-question, self-report questionnaire. 
 

 
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Participants will be handed the questionnaire and asked to write their answers themselves.  
Caregivers can also help, if needed. 
 
Instructions on administering the questionnaire during a phone or telemedicine visit will be 
included in the MOP. 
 
7.4 Home Spirometry 
 
Remote/home-based forced vital capacity will be measured with the MIR Spirobank Smart 
spirometer. Instructions for use will be provided to the participant.  The participant will perform 
the vital capacity maneuver at home (or other remote location) with real time video coaching (or 
phone coaching, if video is not available) by the evaluator.  Three to five vital capacity 
maneuvers will be performed, consistent with the manner vital capacity is obtained in clinic.   
 
 
 

 
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8 BIOFLUID COLLECTION 
8.1 Pharmacokinetic (PK) Assessments 
8.1.1 Whole Blood PK Assessments of CNM-Au8 
Samples for the measurement of whole blood concentrations of Au will be collected before (pre-
dose) administration of investigational product per the Schedule of Assessments.  PK collection 
and processing parameters are specified in the RSA laboratory manual.   
 
PK analyses of CNM-Au8 will be specified in a separate PK analysis plan. 
 
PK blood samples will be shipped to and analyzed under the responsibility of the Clene 
Nanomedicine, Inc.’s bioanalytical laboratory at: 
 
Clene Nanomedicine, Inc. 
Bioanalytics Laboratory 
500 Principio Parkway West, Suite 400 North East, MD 21901-2912 
USA 
 
8.1.2 Plasma PK Assessments of Riluzole 
Samples for the measurement of plasma concentrations of riluzole will be collected before (pre-
dose) administration of both riluzole and the IP per the Schedule of Assessments.  Riluzole 
plasma PK collection and processing parameters are specified in the laboratory manual. 
 
Population PK analyses of riluzole will be specified in the separate PK analysis plan. The first 
forty (40) participants taking riluzole and randomized to Regimen C (CNM-Au8) to reach the 
Week 8 visit will be evaluated by the DSMB, or unblinded DSMB PK designee, to determine 
whether there are any changes in riluzole population PK parameters following treatment with 
CNM-Au8 versus placebo at the Week 4 and Week 8 timepoints.  The unblinded riluzole 
population PK analyses and designee will be implemented as per the DSMB charter. 
 
Riluzole PK plasma samples will be shipped to and analyzed under the responsibility of Covance 
Central Laboratory Services LP. 
 
8.2 Pharmacodynamic (PD) Assessments 
Plasma, whole blood, and urine samples for pharmacodynamic measurements will be collected 
before (pre-dose) administration of the investigational product per the Schedule of 
Assessments.  PD collection and processing parameters are specified in the laboratory manual. 

 
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PD plasma, whole blood, and urine samples will be shipped to the Clene Nanomedicine, Inc.’s 
bioanalytical laboratory at the address noted above for long-term storage. PD analyses will be 
conducted with external vendors and specified in a separate PD analysis plan. 
 
 

 
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9 
REGIMEN-SPECIFIC STATISTICAL CONSIDERATIONS 
9.1  Deviations from the Default Master Protocol Trial Design 
 
The statistical design for this regimen will be in accordance with the default statistical design 
described in Appendix I of the master protocol with only one deviation. This regimen will not 
include interim analyses for early success.  
 
9.2  Regimen Specific Operating Characteristics  
 
Clinical trial simulation is used to quantify operating characteristics for this regimen (refer to the 
regimen SAP for further details).   
 
9.3  Sharing of Controls from other Regimens 
 
The primary analysis of this regimen will include sharing of all controls from the other 
regimens.  This is justified by the minor differences in inclusion/exclusion criteria of the RSA, 
such that there are no expected systematic differences in the primary endpoint between the 
controls across regimens.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX I: THE ALSAQ-40

 
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APPENDIX II: THE BULBAR FUNCTION SCALE (CNS-BFS) 
BULBAR FUNCTION SCALE (CNS-BFS) 
SIALORRHEA 
Does 
Not 
Apply 
(1) 
Applies 
Rarely 
(2) 
   Applies 
Occasionally 
(3) 
Applies 
Frequently  
(4) 
Applies 
Most of 
the Time 
(5) 
 
1. Excessive saliva is a concern to 
me. 
 
 
 
 
 
2. I take medication to control 
drooling. 
 
 
 
 
 
3. Saliva causes me to gag or 
choke. 
 
 
 
 
 
4. Drooling causes me to be 
frustrated or embarrassed. 
 
 
 
 
 
5. In the morning I notice saliva on 
my pillow. 
 
 
 
 
 
6. My mouth needs to be dabbed to 
prevent drooling. 
 
 
 
 
 
7. My secretions are not 
manageable. 
 
 
 
 
 
  
TOTAL Sialorrhea Score: _____ 
SPEECH 
Does 
Not 
Apply 
(1) 
Applies 
Rarely 
(2) 
   Applies 
Occasionally 
(3) 
Applies 
Frequently  
(4) 
Applies 
Most of 
the Time 
(5) 
Unable to 
Communicate 
by Speaking 
(6) 
1. My speech is difficult to 
understand. 
 
 
 
 
 
 
2. To be understood I repeat myself. 
 
 
 
 
 
 
3. People who understand me tell 
other people what I said.  
 
 
 
 
 
 
4. To communicate I write things 
down or use devices such as a 
computer. 
 
 
 
 
 
 
5. I am talking less because it takes 
so much effort to speak. 
 
 
 
 
 
 

 
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6. My speech is slower than usual. 
 
 
 
 
 
 
7. It is hard for people to hear me. 
 
 
 
 
 
 
  
TOTAL Speech Score: _____ 
SWALLOWING 
Does 
Not 
Apply 
(1) 
Applies 
Rarely 
(2) 
   Applies 
Occasionally 
(3) 
Applies 
Frequently  
(4) 
Applies 
Most of 
the Time 
(5) 
  
    Feeding tube is in place 
1. Swallowing is a problem. 
 
 
 
 
 
2. Cutting my food makes it easier 
to chew and swallow. 
 
 
 
 
 
3. To get food down I have 
switched to a soft diet. 
 
 
 
 
 
4. After swallowing I gag or choke. 
 
 
 
 
 
5. It takes longer to eat. 
 
 
 
 
 
6. My weight is dropping because I 
can't eat normally. 
 
 
 
 
 
7. Food gets stuck in my throat. 
 
 
 
 
 
  
TOTAL Swallowing Score: _____ 
OVERALL SCORE: _____ 
 
 
 
 
 
 
 
 

 
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