A 3-arm, Multicenter, Double-blind, Placebo-controlled, Randomized Study to Assess the Efficacy and Safety of ADS-5102 Amantadine Extended Release Capsules in Multiple Sclerosis Patients With Walking Impairment
Phase: PHASE3
Conditions: Walking Impairment, Multiple Sclerosis
Sponsor: Adamas Pharmaceuticals, Inc.

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
1 
1. 
TITLE PAGE 
ADS-AMT-MS301 
 
A 3-ARM, MULTICENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
RANDOMIZED STUDY TO ASSESS THE EFFICACY AND SAFETY OF ADS-5102 
AMANTADINE EXTENDED RELEASE CAPSULES IN MULTIPLE SCLEROSIS 
PATIENTS WITH WALKING IMPAIRMENT 
 
 
Investigational Product:  
ADS-5102 (amantadine Extended Release Capsules) 
 
                                                US IND Number: 125,381 
 
Sponsor:   
 
 
 
 
Adamas Pharmaceuticals, Inc. 
1900 Powell Street, Suite 750 
Emeryville, California 94608 
United States of America 
 
Telephone: +1 (510) 450-3500 
Facsimile: +1 (510) 428-0519 
 
Medical Monitor:  
 
 
Robert Elfont, MD 
 
Document Date:   
 
 
28 February 2018 
 
Version:   
 
 
 
 
Amendment 1 
 
 
 
 
 THIS DOCUMENT IS CONFIDENTIAL AND CONTAINS PROPRIETARY INFORMATION OF ADAMAS 
PHARMACEUTICALS, INC., WHICH MAY NOT BE DISCLOSED WITHOUT EXPRESS PRIOR WRITTEN 
PERMISSION OF ADAMAS PHARMACEUTICALS, INC. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
3 
2. 
SYNOPSIS 
Name of Sponsor/Company: Adamas Pharmaceuticals, Inc. 
Name of Investigational Product: ADS-5102 (Amantadine Extended Release Capsules) 
Name of Active Ingredient: amantadine 
Title of Study: A 3-Arm, Multicenter, Double-Blind, Placebo-Controlled, Randomized Study to 
Assess the Efficacy and Safety of ADS-5102 Amantadine Extended Release Capsules in Multiple 
Sclerosis Patients with Walking Impairment   
(Protocol ADS-AMT-MS301) 
Study Centers: Approximately 80 sites 
Number of Subjects (Planned): Approximately 570 subjects are to be enrolled in the Single-Blind 
Placebo Run-In Period to ensure that 540 subjects complete the Single-Blind Placebo Run-In Period 
and are eligible to be randomized into the Double-Blind Treatment Period. 
Studied period: Approximately 18 months (from 
randomization of first subject to last subject last visit)  
Estimated Date First Subject Enrolled: March 2018 
Phase of development: 3 
Objectives:  
Primary: 
• 
To evaluate the efficacy of 274 mg ADS-5102 in subjects with multiple sclerosis (MS) with 
walking impairment as measured by the Timed 25-foot Walk (T25FW, feet/second) at 
Week 16. 
Secondary: 
 
Key: 
• 
To evaluate the efficacy of 274 mg ADS-5102 in subjects with MS and walking impairment 
as measured by the T25FW, Timed Up and Go (TUG) test, and the 2-Minute Walk Test 
(2MWT) at Week 16. 
• 
To evaluate the efficacy of 137 mg ADS-5102 in subjects with MS and walking impairment 
as measured by the T25FW, the TUG test, and the 2MWT at Week 16.  
 
Supportive: 
• 
To evaluate the efficacy of 274 mg ADS-5102 and 137 mg ADS-5102 in subjects with MS 
and walking impairment as measured by the T25FW, the TUG, and the 2MWT across all 
study visits.  
• 
To evaluate the efficacy of 274 mg ADS-5102 and 137 mg ADS-5102 in subjects with MS 
and walking impairment as measured by the Multiple Sclerosis Walking Scale-12 
(MSWS-12) in subjects treated with 274 mg ADS-5102 and subjects treated with 137 mg 
ADS-5102. 
Safety: 
• 
To evaluate the safety and tolerability of 274 mg and 137 mg of ADS-5102 in subjects with 
MS and walking impairment. 
 
 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
4 
Study Design:  
This is a multicenter, 3-arm, randomized, placebo-controlled, double-blind, parallel-group study of 
ADS-5102 (amantadine extended release [ER] capsules) in MS patients with walking impairment, 
incorporating a Single-Blind Placebo Run-In Period prior to randomization, and forced up-titration 
for the high-dose group. 
Eligibility for inclusion in this study will require all subjects to be on a stable medication regimen for 
at least 30 days prior to screening, and to continue the same dosing regimen for the duration of their 
study participation. Subjects may not have been treated with dalfampridine within 30 days prior to 
screening. 
Consented subjects who complete the up to 3-week screening period will undergo a 4-week 
Single-Blind Placebo Run-In Period during which subjects will receive placebo as 2 capsules once 
daily at bedtime. 
Subjects who complete the Single-Blind Placebo Run-In Period and continue to meet study eligibility 
criteria will be randomized with equal probability to 1 of 3 treatment groups: placebo or ADS-5102 at 
137 mg or 274 mg per dose. Study drugs will be administered as 2 capsules once daily at bedtime.  
Subjects who are randomized to placebo will receive placebo capsules throughout the 12-week 
Double-Blind Treatment Period.  
Subjects who are randomized to 137 mg of ADS-5102 will receive 137 mg of ADS-5102 throughout 
the Double-Blind Treatment Period.  
Subjects who are randomized to 274 mg of ADS-5102 will receive 137 mg for the first week, 
205.5 mg for the second week, and 274 mg for the remainder of the 12-week Double-Blind Treatment 
Period. 
During the Double-Blind Treatment Period, subjects will return to the clinic for safety and efficacy 
assessments at Weeks 6, 8, 12, and 16. In addition, telephone visits for safety assessments will be 
conducted at Weeks 5 and 7.  
Subjects who complete the study through the Week 16 visit will be eligible to enter an optional  
open-label extension (OLE) study, protocol ADS-AMT-MS303. Subjects who withdraw from the 
study prior to completion of the Week 16 visit will have an early termination visit that includes safety 
follow-up and efficacy assessments. Subjects who complete 12 weeks of double-blind treatment and 
elect not to participate in the OLE study will have a final post-treatment safety and efficacy 
assessment 2 weeks after their Week 16 visit. The end of study (EOS) is defined as when a subject 
completes the Week 16 visit (if electing to enter the OLE study) or the safety follow-up visit (if 
electing not to enter the OLE study). 
All study visits and efficacy assessments should be scheduled to occur at approximately the same 
time of day for each individual subject. To the extent practicable, study visits and efficacy 
assessments should be scheduled to occur when a subject is not likely to be experiencing acute side 
effects from a concomitant medication (e.g., flu-like side effects following interferon-beta injection). 
Efficacy assessments should be conducted in following sequence: MSWS-12; T25FW; TUG; 2MWT. 
Subjects using an assistive device during the walking assessments at Screening should use the same 
assistive device for all subsequent walking tests. Each subject’s efficacy assessment should be 
performed by the same clinical rater, if possible. 
Adverse events (AEs) and concomitant medications will be recorded beginning with the first dose of 
study drug during the Single-Blind Placebo Run-In Period and continuing through the last study visit. 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
5 
Diagnosis and Eligibility Criteria:  
Inclusion Criteria: 
1. Signed a current IRB-approved informed consent form 
2. Male or female subjects between 18 and 70 years of age, inclusive, at the time of Screening 
3. Confirmed diagnosis of MS according to the 2017 McDonald criteria (Thompson et al., 2017) 
4. Current medication regimen must be stable for at least 30 days prior to screening, and subject 
must be willing to continue the same dosing regimen for the duration of study participation 
5. Maximum Expanded Disability Status Scale (EDSS) score during screening of 6.5 
6. Sufficient ambulatory ability (ambulatory aids acceptable if used consistently) to complete two 
trials of the Timed 25-Foot Walk (T25FW) at the screening visit, with the two trials completed 
within 5 minutes of each other in accordance with the specific instructions provided by the 
National MS Society Functional Composite Manual 
7. Stable physical activity level (inclusive of prescribed physical therapy) for at least 30 days prior 
to screening and willing to continue without change for the duration of study participation 
8. A score on each of two completed screening T25FW tests between 8 and 45 seconds, inclusive 
Exclusion Criteria: 
1. Documented inability to tolerate amantadine 
2. History of hypersensitivity or allergic reaction to amantadine, rimantadine, or memantine, or to 
any of the excipients used in the study drug capsules (refer to Table 2) 
3. Clinically significant MS relapse with onset less than 30 days prior to screening 
4. Presence of neurologic dysfunction or medical condition, the severity of which, in the judgement 
of the investigator, would preclude the ability to perform walking tests safely 
5. Receipt of systemic corticosteroids (intravenous [IV] or oral) or ACTHAR gel within 30 days 
prior to screening 
6. Receipt of dalfampridine (or any 4-aminopyridine or 2,4-diaminopyridine preparation) or 
amantadine within 30 days prior to screening 
7. History of other neurological or medical condition that, in the opinion of the investigator, would 
affect study outcome assessments 
8. History of seizures within 3 years prior to screening 
9. History of hallucinations (visual, auditory, or any other type) within 3 years prior to screening 
10. History of bipolar disorder, schizophrenia, or psychosis, regardless of treatment 
11. For subjects with a history of major depressive disorder, the presence of active depressive 
symptoms that, in the opinion of the investigator, would affect the subject’s ability to complete 
study assessments, or which would not be in the subject’s best interest to participate in the study 
12. History of suicide attempt 
13. History of suicidal ideation within 3 years of screening, or presence of suicidal ideation at 
screening, as detected by the Columbia Suicidality Scale (C-SSRS)  
14. History of cognitive impairment sufficient, in the clinical judgement of the investigator, to affect 
the subject’s ability to consent or complete study assessments, or to render it not in the subject’s 
best interest to participate in the study 
15. History of alcohol or substance dependence or abuse within 2 years prior to screening 
16. History of stroke, transient ischemic attack (TIA), or myocardial infarction (MI) within 2 years 
prior to screening 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
6 
17. History of cancer within 5 years prior to screening, with the following exceptions: adequately 
treated non-melanomatous skin cancers, localized bladder cancer, non-metastatic prostate cancer, 
in situ cervical cancer, or other definitively treated cancer that is considered cured 
18. Presence of orthostatic hypotension at screening: a decrease in systolic blood pressure (at least 
20 mm Hg) or diastolic blood pressure (at least 10 mm Hg) within 3 minutes of the subject 
standing up, compared to pressures obtained while sitting 
19. Any laboratory test results outside of the central laboratory’s normal range at screening that are 
assessed by the investigator to be clinically significant. Documentation by the investigator of 
clinical significance or insignificance must accompany out of range laboratory test results at 
screening 
20. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) screening laboratory 
results > 2 times the upper limit of normal 
21. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (per Modification of Diet in 
Renal Disease [MDRD] calculation) 
22. Inability to swallow oral capsules, or a history of gastrointestinal malabsorption that would 
preclude the use of oral medication 
23. If female, is pregnant or lactating 
24. If a sexually active female, is not surgically sterile or at least 2 years post-menopausal, or does 
not agree to utilize a highly effective hormonal method of contraception (an IUD, or 
vasectomized male partner is also acceptable), in combination with a barrier method, from 
screening through at least 4 weeks after the completion of study treatment. If a sexually active 
male, does not agree to utilize condoms from screening through at least 4 weeks after the 
completion of study treatment. 
25. Received live attenuated influenza vaccine within 2 weeks prior to randomization or planning to 
receive live attenuated influenza vaccine during the duration of the study (amantadine may 
interfere with the efficacy of live attenuated vaccine) 
26. Current treatment with medications that may affect urinary pH: carbonic anhydrase inhibitors, 
sodium bicarbonate, urinary acidification agents, quinine, quinidine, triamterene, or trimethoprim 
27. Treatment with an investigational drug or device within 30 days prior to screening 
28. Treatment with an investigational biologic within 6 months or 5 half-lives, whichever is longer, 
prior to screening 
29. Current participation in another clinical trial 
30. Prior or current participation in an Adamas clinical trial 
31. Planned elective surgery, with the exception of minor dermatological procedures, during study 
participation 
Investigational Product, Dosage and Mode of Administration:  
All subjects are to continue their current (prior to screening visit) MS medications and regimens, 
without change, for the duration of their study participation, to the extent compatible with good 
neurological care. 
Consented subjects who complete screening and the Single-Blind Placebo Run-In Period and meet 
study eligibility criteria will be randomized with equal probability to 1 of 3 treatment groups: placebo, 
137 mg ADS-5102, or 274 mg ADS-5102. 
ADS-5102 (amantadine ER capsules) will be administered orally, as 2 capsules once daily at bedtime 
for the 12-week Double-Blind Treatment Period. 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
7 
The dosing regimens for the 2 active treatment arms are: 
• 
137 mg/d (1 x 137 mg capsule + 1 placebo capsule) for 12 weeks for the 137 mg ADS-5102 
group 
• 
137 mg/d for 1 week (1 x 137 mg capsule + 1 placebo capsule), followed by 205.5 mg/d 
(1 x 137 mg capsule + 1x 68.5 mg capsule) for 1 week, followed by 274 mg/d (2 x 137 mg 
capsules) for 10 weeks for the 274 mg ADS-5102 group 
Reference Therapy, Dosage and Mode of Administration:  
Placebo capsules (indistinguishable from ADS-5102 capsules) will be administered orally as 
2 capsules once daily at bedtime for the 4-week Single-Blind Placebo Run-In Period for all subjects 
and for the 12-week Double-Blind Treatment Period for subjects randomized to the placebo arm. 
Duration of Treatment: Maximum duration of subject participation is up to approximately 21 weeks 
and will include a 3-week (maximum) screening period, 4-week Single-Blind Placebo Run-In Period, 
a 12-week Double-Blind Treatment Period for all subjects, and a 2-week post-treatment safety  
follow-up period for subjects who choose not to participate in the OLE study. 
Criteria for Evaluation: 
Primary Efficacy Measure: T25FW (measured in seconds but calculated to a feet/sec measurement) 
Secondary Efficacy Measures: TUG (seconds), 2MWT (meters), and MSWS-12 
Safety Measures: Adverse events (AEs), clinical laboratory evaluations (hematology, clinical 
chemistry, urinalysis, serum pregnancy tests for females of child bearing potential), vital signs, and 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Statistical Methods: 
Primary Efficacy Endpoint and Sample Size Determination:  
The primary efficacy endpoint is the proportion of responders in each treatment group (see definition 
details below).  
Based on the results from the Phase 2 study, responder rates of 24% and 33% were observed at 
Week 4 for subjects treated with placebo and 274 mg ADS-5102, respectively, in the modified  
intent-to-treat (MITT) analysis set. In this study, it is anticipated that the placebo response rate at 
Week 16 will be no greater than 20% and response rate among subjects treated with 274 mg or  
137 mg ADS-5102 will be at least 33%. Using these estimates, 180 randomized subjects per active 
treatment group and placebo will be needed for the test of differences in proportions (Farrington-
Manning approach for the Miettimen-Nurminen [MN] test.) to have 80% power at the 2-sided 5% 
significance level to detect this 13% difference favoring ADS-5102. Assuming a 5% dropout rate 
during the 4-week placebo run-in period, 570 subjects will be enrolled in the study to randomize 540. 
For this sample size of 180 randomized subjects per group, power will be at least 80% to detect 
treatment differences (ADS-5102 versus placebo) of -2.7 seconds and 5.0 meters in the changes from 
baseline at Week 16 in the TUG test and 2MWT when the standard deviation of the changes from 
baseline is no greater than 6.0 sec and 14.9 meters, respectively, and the dropout rate is not greater 
than 20%. 
Analysis Sets: 
The safety analysis set will include all randomized subjects who receive at least one dose of  
double-blind study drug and will be analyzed according to the treatment actually received. 
The intent-to-treat (ITT) analysis set will include all randomized subjects who receive at least one 
dose of study drug, and will be analyzed according to the randomized treatment assignment. This 
population will be used for the efficacy analyses including the analyses of primary and key secondary 
endpoints. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
8 
The per-protocol (PP) analysis set will include all randomized and dosed subjects who provide 
Week 16 efficacy data and do not have any major protocol deviations that could confound this 
assessment. This population will also be used for efficacy analyses. 
Efficacy Analyses 
Primary Efficacy: The primary efficacy endpoint is the proportion of responders in the 274 mg 
ADS-5102 treatment group relative to the placebo group, where a responder is defined as a subject 
who has a ≥ 20% increase from Baseline to Week 16 in walking speed measured using the T25FW 
(average of two measurements 5 minutes apart). This analysis will be done using the ITT analyses set. 
Subjects who fail to have an increase of at least 20% at Week 16 in the T25FW (feet/seconds) will be 
considered non-responders. Subjects who do not have an observation at Week 16 for whatever reason 
will be considered to have an indeterminate outcome and will also be included in the denominators, 
effectively counting them as non-responders for the purpose of treatment comparisons. However, 
tabulations of each response category will be provided. For this endpoint, baseline will be defined as 
the average walking speed (feet/seconds) from the T25FW at Weeks 0 and 2 (prior to randomization).  
The objective of the primary efficacy analysis is to test for superiority of the 274 mg ADS-5102 
group compared to the placebo group in terms of the difference (active minus placebo) in the 
proportion of responders at Week 16 using the ITT analysis set. This test of proportions will be done 
using the MN test at the 2-sided 5% level. Both the 2-sided p-value and the 95% confidence interval 
(CI) for the difference will be obtained. Superiority will be concluded if the lower limit of the 95% CI 
is greater than zero (equivalently 2-sided p-value < 0.05). 
Key Secondary Efficacy: Provided superiority of 274 mg ADS-5102 versus placebo is shown in the 
primary analysis, the key secondary objectives will be evaluated using a gatekeeping strategy to 
control the overall Type I error rate at 5%. Using this approach, the following research hypotheses 
will be evaluated sequentially in the order given using the ITT analyses set: (1) superiority of 274 mg 
ADS-5102 compared to placebo in mean change from baseline at Week 16 in the T25FW 
(feet/second) test; (2) superiority of 274 mg ADS-5102 compared to placebo in mean change from 
baseline at Week 16 in the TUG (sec) test; (3) superiority of 274 mg ADS-5102 compared to placebo 
in mean change from baseline at Week 16 in the 2MWT (m); (4) superiority of 137 mg ADS-5102 
compared to placebo in terms of the proportion of T25FW responders at Week 16; (5) superiority of 
137 mg ADS-5102 compared to placebo in mean change from baseline at Week 16 in the T25FW 
(feet/second) test; (6) superiority of 137 mg ADS-5102 compared to placebo in mean change from 
baseline at Week 16 in the TUG test; and (7) superiority of 137 mg ADS-5102 compared to placebo 
in mean change from baseline at Week 16 in the 2MWT. For each hypothesis, if a non-significant 
result (p > 0.05) is obtained, no further inferential conclusions will be drawn and any statistically 
significant result will be declared supportive of efficacy only. 
The test of superiority of 137 mg ADS-5102 versus placebo in terms of the proportion of responders 
at Week 16 will be done using the same approach as for the primary analyses.  
The tests of superiority of 274 mg ADS-5102 and of 137 mg ADS-5102 versus placebo in terms of 
the mean change from baseline in the T25FW (feet/second), TUG test (sec), and the 2MWT (m) will 
be done using t-tests derived from the corresponding linear mixed model with repeated measurement 
(MMRM) model with the change from baseline (i.e. T25FW, TUG, or 2MWT) as the dependent 
variable and fixed effects of treatment group, study week, and treatment by study week interaction. 
The baseline value will be included as a covariate and an unstructured variance-covariance matrix 
will be used for the within-subject residual variability. For the T25FW, TUG test, and the 2MWT, 
baseline will be the average of Weeks 0 and 2 (prior to randomization).  
Secondary Supportive Endpoints: Each active dose will be compared to placebo in terms of the 
mean change from baseline at each study visit in the T25FW (feet/sec), TUG test (sec)and the 2MWT 
(m). These analyses will be done using the MMRM model described earlier. The T25FW (sec) will be 
evaluated in a similar manner. 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
9 
Safety and Tolerability Analyses 
Adverse events will be recorded starting from the date/time of first dose during the Single-Blind 
Placebo Run-In Period through the EOS Visit. The time periods of AE recording will be divided into 
AEs with onset during the Single-Blind Placebo Run-In Period and AEs during the Double-Blind 
Treatment Period (i.e., treatment-emergent AEs [TEAEs]). All AEs will be listed by subject and 
period. 
For AEs during double-blind treatment, standard incidence rates will be summarized by treatment 
group, system organ class (SOC), and preferred term (PT) within SOC in the safety analysis set.  
Clinical laboratory test parameters will be listed for individual subjects and values outside of the 
reference ranges will be flagged. The incidence of potentially clinically significant changes in 
laboratory parameters will be tabulated by treatment group. Vital signs measurements at each 
timepoint will be listed by subject. The incidence of potentially clinically significant changes at each 
study visit will be summarized.  
Descriptive statistics for the mean and mean changes in the C-SSRS will be generated by treatment 
group and visit. Results will also be graphically depicted. 
 
 
 
 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
10 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
APPROVALS: .................................................................................................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............10 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................15 
5. 
INTRODUCTION ......................................................................................................17 
5.1. 
Walking Impairment in Multiple Sclerosis .................................................................17 
5.2. 
ADS-5102 for Walking Impairment in Multiple Sclerosis .........................................17 
5.3. 
Product (Formulation) Rationale ................................................................................18 
5.4. 
Dose Selection ............................................................................................................19 
5.5. 
Dosing Regimen and Titration ....................................................................................19 
5.6. 
Rationale for ADS-AMT-MS301 Study Design ........................................................20 
5.7. 
Population to be Studied .............................................................................................21 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................22 
6.1. 
Primary Objective .......................................................................................................22 
6.2. 
Secondary Objectives .................................................................................................22 
6.2.1. 
Key ..............................................................................................................................22 
6.2.2. 
Supportive ...................................................................................................................22 
6.2.3. 
Safety ..........................................................................................................................22 
7. 
INVESTIGATIONAL PLAN .....................................................................................23 
7.1. 
Overall Study Design ..................................................................................................23 
7.2. 
Number of Subjects ....................................................................................................24 
7.3. 
Treatment Assignment ................................................................................................24 
7.4. 
Dose Adjustment Criteria ...........................................................................................24 
7.4.1. 
Dose Adjustment for Renal Impairment .....................................................................24 
7.4.2. 
Dose Adjustment for Adverse Events .........................................................................24 
7.5. 
Criteria for Study Termination ...................................................................................25 
7.6. 
Duration of Subject Participation ...............................................................................25 
7.7. 
Estimated Study Duration ...........................................................................................25 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................26 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
11 
8.1. 
Subject Inclusion Criteria ...........................................................................................26 
8.2. 
Subject Exclusion Criteria ..........................................................................................26 
8.3. 
Subject Withdrawal Criteria .......................................................................................28 
8.4. 
Subject Enrollment .....................................................................................................28 
8.5. 
Discontinuation of Study Drug ...................................................................................28 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................30 
9.1. 
Study Drug ..................................................................................................................30 
9.2. 
Study Drug Packaging and Labeling ..........................................................................30 
9.3. 
Study Drug Storage .....................................................................................................31 
9.4. 
Administration ............................................................................................................31 
9.5. 
Study Drug Accountability .........................................................................................31 
9.6. 
Study Drug Handling and Disposal ............................................................................32 
9.7. 
Prohibited Medications and Restrictions ....................................................................32 
9.8. 
Concomitant Medications ...........................................................................................33 
9.9. 
Treatment Compliance ................................................................................................33 
9.10. 
Randomization and Blinding ......................................................................................33 
10. 
ASSESSMENT OF EFFICACY ................................................................................34 
11. 
ASSESSMENT OF SAFETY .....................................................................................35 
11.1. 
Physical Assessments Relating to Safety ...................................................................35 
11.1.1. 
Scheduled Physical Assessments Relating to Safety ..................................................35 
11.1.2. 
Unscheduled Physical Assessments Relating to Safety ..............................................36 
11.2. 
Clinical Laboratory Tests ...........................................................................................36 
11.3. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................37 
12. 
EVALUATIONS BY VISIT ......................................................................................37 
12.1. 
Screening/Day -21 to -1 ..............................................................................................37 
12.2. 
Single-Blind Placebo Run-In Period/Week 0 to Week 2 ............................................38 
12.3. 
Baseline/Week 4 .........................................................................................................38 
12.4. 
Double-Blind Treatment Period: Telephone Visits at Weeks 5 and 7 ........................39 
12.5. 
Double-Blind Treatment Period: Week 6 Visit ..........................................................39 
12.6. 
Double-Blind Treatment Period: Week 8 Visit ..........................................................39 
12.7. 
Double-Blind Treatment Period: Week 12 Visit ........................................................40 
12.8. 
Double-Blind Treatment Period: Week 16 Visit ........................................................40 
12.9. 
Early Termination Visit ..............................................................................................40 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
12 
12.10. 
Safety Follow-Up/End of Study Visit .........................................................................41 
12.11. 
Unscheduled Study Visit ............................................................................................41 
13. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND ADVERSE 
EVENTS OF SPECIAL INTEREST ..........................................................................42 
13.1. 
Definition of Adverse Events .....................................................................................42 
13.1.1. 
Adverse Event (AE) Definition ..................................................................................42 
13.1.2. 
Serious Adverse Event (SAE) Definition ...................................................................43 
13.1.2.1. 
Clarification of SAE Definition ..................................................................................44 
13.1.2.2. 
Clarification of Subject Deaths ...................................................................................44 
13.1.3. 
Adverse Event of Special (AESI) ...............................................................................45 
13.1.4. 
Assessment of Adverse Events ...................................................................................45 
13.1.5. 
Type of Adverse Events (AE, SAE, or AESI) ............................................................45 
13.1.6. 
Severity of Adverse Events ........................................................................................45 
13.1.7. 
Relationship to Study Drug ........................................................................................46 
13.1.8. 
Follow-up of Adverse Events and Serious Adverse Events .......................................46 
13.2. 
Recording Adverse Events .........................................................................................47 
13.2.1. 
Adverse Event Recording ...........................................................................................47 
13.2.2. 
Serious Adverse Event Recording ..............................................................................48 
13.2.3. 
Adverse Event of Special Interest Recording .............................................................48 
13.3. 
Reporting Adverse Events ..........................................................................................48 
13.3.1. 
Investigator Reporting Requirements .........................................................................49 
13.3.2. 
Post-Study Reporting Responsibility ..........................................................................49 
13.3.3. 
Pregnancy ...................................................................................................................49 
14. 
STATISTICS ..............................................................................................................50 
14.1. 
Primary Efficacy Endpoint and Sample Size Determination .....................................50 
14.2. 
Analysis Sets ...............................................................................................................50 
14.3. 
Handling of Missing Data ...........................................................................................50 
14.4. 
Efficacy Analyses .......................................................................................................50 
14.4.1. 
Primary Efficacy Analyses .........................................................................................50 
14.4.2. 
Key Secondary Efficacy Analyses ..............................................................................51 
14.4.3. 
Secondary Supportive Analyses .................................................................................51 
14.5. 
Safety and Tolerability ...............................................................................................52 
14.6. 
Demographics and Baseline Characteristics ...............................................................52 
14.7. 
Prior and Concomitant Medications ...........................................................................53 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
13 
14.8. 
Completion of the Study and Withdrawals .................................................................53 
14.9. 
Protocol Deviations ....................................................................................................53 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................54 
15.1. 
Study Monitoring ........................................................................................................54 
15.2. 
Audits and Inspections ................................................................................................54 
15.3. 
Subject Confidentiality ...............................................................................................54 
15.4. 
Case Report Forms .....................................................................................................55 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................56 
17. 
ETHICS ......................................................................................................................57 
17.1. 
Ethics Review .............................................................................................................57 
17.2. 
Ethical Conduct of the Study ......................................................................................57 
17.3. 
Written Informed Consent ..........................................................................................57 
17.4. 
Changes in the Conduct of the Study or Planned Analyses ........................................58 
17.5. 
Emergency Contact with Investigator ........................................................................58 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................59 
18.1. 
Inspection of Records .................................................................................................59 
18.2. 
Retention of Records ..................................................................................................59 
19. 
INFORMATION DISCLOSURE AND INVENTIONS ............................................59 
19.1. 
Ownership ...................................................................................................................59 
19.2. 
Confidentiality ............................................................................................................60 
20. 
PUBLICATION POLICY ..........................................................................................61 
21. 
LIST OF REFERENCES ............................................................................................62 
22. 
APPENDICES ............................................................................................................65 
APPENDIX A. SCHEDULE OF EVENTS ................................................................................66 
APPENDIX B. STUDY DESIGN SCHEMATIC ......................................................................68 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
14 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................15 
Table 2: 
Clinical Formulations for Study ADS-AMT-MS301 .................................................30 
Table 3: 
Randomization Groups for Study ADS-AMT-MS301 ...............................................31 
Table 4: 
Efficacy Assessments .................................................................................................34 
Table 5: 
Physical Examination Assessments Relating to Safety ..............................................35 
Table 6: 
Clinical Laboratory and Other Assessments ...............................................................36 
  
 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
15 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol.  
Table 1: 
Abbreviations and Specialist Terms  
Abbreviation  
Explanation 
2MWT 
2-Minute Walk Test 
2,4-DAP 
2,4-diaminopyridine 
4-AP 
4-aminopyridine 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase  
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CNS 
Central nervous system 
CRF 
Case report form (paper and/or electronic) 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
ECG 
Electrocardiogram 
EDSS 
Expanded Disability Status Scale 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
ER 
Extended release 
ET 
Early termination 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent ethics committee 
IR 
Immediate release 
IRB 
Institutional review board 
IRT 
Interactive response technology 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
IWRS 
Interactive web response system 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
16 
Table 1: 
Abbreviations and Specialist Terms (Continued) 
MDRD 
Modification of Diet in Renal Disease 
MI 
Myocardial infarction 
MMRM 
Mixed model repeated measurement 
MN 
Miettimen-Nurminen 
MS 
Multiple sclerosis 
MSWS-12 
Multiple Sclerosis Walking Scale-12 
OLE 
Open-label extension 
PD 
Parkinson’s disease 
PI 
Principal Investigator 
PP  
Per-protocol 
REB 
Research ethics board 
SAE 
Serious adverse event 
T25FW 
Timed 25-Foot Walk  
TEAE 
Treatment-emergent adverse event 
TIA 
Transient ischemic attack 
tmax 
Time to maximum observed concentration 
TUG 
Timed Up and Go 
US 
United States  
WBC 
White blood cell(s); leukocyte(s) 
 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
17 
5. 
INTRODUCTION 
5.1. 
Walking Impairment in Multiple Sclerosis 
Adamas is developing ADS-5102, an extended-release (ER) capsule formulation of amantadine 
hydrochloride (HCl), as a treatment to improve walking in patients with multiple sclerosis (MS).  
MS is a chronic, usually progressive, autoimmune-mediated disorder of the central nervous 
system (CNS). The prevalence of MS in the United States (US), based on recently reported 
analyses of healthcare databases, is on the order of 400,000 to 675,000 individuals 
(Dilokthornsakul et al., 2016; Wallin, 2017). Patients generally become symptomatic early in 
adulthood and continue to accumulate disability throughout most of their lives. The autoimmune 
assault in MS can involve any part of the CNS, and by definition, affects multiple regions over 
time (Schumacher, 1950; Kantarci and Wingerchuk, 2006). This feature of MS makes 
neurological functions that depend on the integration of multiple CNS systems particularly 
susceptible to disability. Walking, which depends on the coordinated functioning of multiple 
CNS motor and sensory systems, is frequently impaired in MS. About 50% of MS patients 
become dependent on some form of walking aid after 15 years with the disease 
(Kantarci and Wingerchuk, 2006). 
While there are now numerous drugs approved to reduce inflammation, and slow the progression 
of disability in MS, there are limited options available for the treatment of frequent, and often 
persistent, neurological deficits, with only one drug, dalfampridine (4-aminopyridine [4-AP]; 
Ampyra®) currently approved to treat walking impairment. Dalfampridine was approved in 2010 
as a treatment to improve walking in patients with MS, as demonstrated by an increase in 
walking speed. However, this product appears to benefit only a subset of patients, comprising 
some 30%-60% (Goodman et al., 2009; Goodman et al., 2010; Prugger and Berger, 2013; 
Ruck et al., 2013; Korsen et al., 2016) of those who try it. Consequently, there remains an unmet 
medical need for additional therapies to treat impaired mobility in MS patients. 
5.2. 
ADS-5102 for Walking Impairment in Multiple Sclerosis 
Amantadine has been reported to possess multiple pharmacological activities. The precise 
mechanism through which amantadine may exert its beneficial effects in MS has not been 
completely elucidated, and multiple pharmacological activities may contribute to amantadine’s 
effects in this indication. Amantadine is known to be a low affinity, uncompetitive inhibitor of 
the N-methyl-D-aspartate (NMDA) receptor (Kornhuber et al., 1991; Bresink et al., 1995; 
Parsons et al., 1995, Parsons et al., 1996). Nonclinical studies have demonstrated that 
amantadine decreases neuronal toxicity associated with excessive glutamate release  
(Danysz et al., 1997) and improves cognitive function (Wang et al., 2014). Amantadine has been 
shown to increase the action potential duration in rat atria to a similar degree as dalfampridine 
(Northover, 1994), which suggested that amantadine may also block potassium channels. Studies 
conducted by Adamas with amantadine in rat coronal brain slices demonstrated that amantadine 
blocked neuronal potassium channels over a wide concentration range (10-1000 μM). Blockade 
of potassium channels is the putative mechanism by which dalfampridine is believed to exert its 
clinical benefit in MS walking (Ampyra package insert). In addition, amantadine has been shown 
to modulate cholinergic signaling (Albuquerque, et al., 1978), affect serotonin levels  
(Wesemann et al., 1979), inhibit microglial activation, and increase the release of glial cell-
derived nerve growth factor (Ossola et al., 2011). 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
18 
Adamas conducted a Phase 2 study of ADS-5102 in MS patients, Study ADS-AMT-MS201, to 
assess the safety and tolerability of ADS-5102 in patients with MS. Secondary objectives were to 
assess the potential benefit of ADS-5102 on walking speed, functional mobility, walking 
distance, fatigue, depression, and cognition of patients with MS. Walking speed was prespecified 
as the key secondary outcome, and trial participants were screened for the presence of walking 
impairment on the basis of performing the Timed 25-Foot Walk (T25FW) test in 8 to 45 seconds, 
inclusive. 
This 4-week, placebo-controlled, proof-of-concept study showed a manageable safety and 
tolerability profile for ADS-5102 in participants with MS. The safety data were similar to the 
previously published results in Parkinson’s disease (PD) (Pahwa et al., 2015; Pahwa et al., 2017). 
The types of AEs reported were also consistent with the known safety profile of immediate-
release amantadine.  
A statistically significant effect on the percent change in walking speed from baseline was 
observed and a greater proportion of ADS-5102-treated participants experienced a ≥ 20% 
improvement. Trends suggesting benefit, which did not reach statistical significance, were 
observed for the Timed Up and Go (TUG) test, and less so on the 2-Minute Walk Test (2MWT). 
Previous studies indicate these tests are less sensitive, requiring longer follow-up and larger 
sample size to demonstrate benefit (Hobart, 2017). Results on participant-reported walking 
ability, measured by the MSWS-12 over 4 weeks, did not demonstrate benefit. The short 
duration of the study may not have provided sufficient time to detect a treatment effect on this 
patient-reported outcome, as the recall period for the questionnaire is 2 weeks. 
The goal of the Phase 3 study, ADS-AMT-MS301, is, therefore, to confirm the efficacy, safety, 
and tolerability of ADS-5102 as a treatment to improve walking in the patients with MS that was 
suggested in the Phase 2 study.  
5.3. 
Product (Formulation) Rationale 
The ADS-5102 investigational drug product is a capsule containing ER coated pellets of 
amantadine HCl. The rationale for a formulation that slows the release of amantadine is based 
upon the nature and timing of the CNS side effects associated with immediate release (IR) 
amantadine relative to dosing, as well as observations with other CNS active drugs. Immediate 
release formulations of amantadine HCl have a short tmax of 2-4 hours (Aoki and Sitar, 1988), 
and the most commonly reported side effects are CNS-related, including dizziness 
(lightheadedness), agitation, hallucinations, and insomnia, which can occur within a few hours of 
dosing (Jackson et al., 1967; Hayden et al., 1981). The AEs reported with amantadine therapy in 
MS (Murray, 1985; Canadian MS Research Group 1987; McEvoy et al., 1987; Rosenberg and 
Appenzeller, 1988; Chiba et al., 1992; Krupp et al., 1995; Ashtari et al., 2009; Berger, 2011) are 
overall similar to those observed with amantadine treatment in PD. The increased frequency of 
AEs at higher doses, in particular CNS events and sleep disturbances, limits the routine use of 
amantadine IR at doses of 300 mg/day or higher. The pharmacologic rationale for improved 
tolerability of an ER formulation of amantadine is that the reduction in the rate of rise in plasma 
concentration may reduce the CNS adverse effects.  
Recent preclinical experiments have shown that the rate of rise in amantadine plasma 
concentrations may contribute to CNS impairment, with a more rapid rise in plasma 
concentrations resulting in greater CNS impairment. Studies conducted by Adamas have 
demonstrated that rapid bolus infusion with amantadine resulted in greater CNS impairment, as 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
19 
determined by time balancing on a rotating rod (Rotarod, a validated model of safety 
pharmacology in rodents), whereas as a slower rate of infusion reaching the same final plasma 
concentration produced no discernible CNS side-effects. These results are consistent with 
favorable tolerability profile of ADS-5102 as demonstrated in clinical studies supporting the 
dyskinesia indication in patients with Parkinson’s disease. 
5.4. 
Dose Selection 
Two dosages of ADS-5102 are being tested in Study ADS-AMT-MS301, 137 mg/d and  
274 mg/d, to adequately characterize the dose-response curve.  
The 274 mg dose was selected because this was the dose that was tested in the Phase 2 study, 
Study ADS-AMT-MS201, and showed a statistically significant effect on walking speed in the 
T25FW test. Additionally, the 274 mg dose showed a clearly positive trend toward significance 
in the TUG test in the Phase 2 study. With respect to the safety and tolerability of the 274 mg 
dose, the overall AE profile and the AE-related dropout rate observed in Study 
ADS-AMT-MS201 support entering Phase 3 in MS, with the preliminary expectation that 
acceptable safety and tolerability will be confirmed. The AE profile was qualitatively similar to 
the AE profile discernible from the published studies of amantadine IR in MS (Canadian MS 
Research Group 1987; Chiba et al., 1992; Krupp et al., 1995; Ashtari et al., 2009; Berger, 2011) 
and to the AE profile observed in the clinical studies of ADS-5102 in PD, as reflected in the 
GOCOVRI™ prescribing information.   
Although the 137 mg dose was not evaluated as a separate treatment arm in the Phase 2 study, 
the data suggest that this dose may confer some effect on walking speed. A separation in the least 
squared (LS) mean walking speeds between the ADS-5102 and placebo groups was evident at 
the first post-baseline T25FW test, which was performed after 2 weeks of dosing. As the first 
2 weeks of dosing constituted a 1-step titration, with subjects in the active-therapy arm receiving 
ADS-5102 at 137 mg/d for the first week, it is plausible that the time spent at the 137 mg dose 
could have contributed to the efficacy signal at study Week 2. The low dropout rates during the 
first week of dosing suggest that the 137 mg dose is tolerable. Even if the 137 mg dose of 
ADS-5102 should prove to be only minimally effective, it could still provide a valuable 
alternative to patients who may be intolerant of a higher dose of amantadine. 
5.5. 
Dosing Regimen and Titration 
ADS-5102 is to be taken once daily at bedtime. The tmax for ADS-5102 is expected to occur at 
12 to 14 hours post dose. ADS-5102 is designed to maintain high concentrations throughout 
most of the waking day, with concentrations decreasing in the evening. This pharmacokinetic 
profile could enable higher daily doses to be tolerated with a once-nightly ER preparation than 
are typically reported for dosing with an amantadine IR formulation. The once daily at bedtime 
dosing regimen may also provide enhanced convenience and improve compliance. 
The 12-week Double-Blind Treatment Period of the study includes a 2-step, forced titration 
phase for subjects randomized to the 274 mg/d ADS-5102 arm of the study, followed by a 
maintenance phase of approximately 10 weeks. The titration occurs over approximately the first 
2 weeks of the study, with dosing in the first week at 137 mg/d, and in the second week at 
205.5 mg/d. Subjects randomized to the 137 mg/d arm will undergo a sham titration, but will, in 
fact, be continuing on a daily dose of 137 mg/d throughout the titration and maintenance periods. 
Similarly, subjects randomized to the placebo arm of the study will undergo a sham titration, but 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
20 
will, in fact, be continuing on placebo throughout the titration and maintenance periods. The 
sham titrations are included to preserve blinding. No down-titration will be permitted.  
Although it is anticipated that the slow absorption of the ER formulation will facilitate the ability 
of patients to tolerate higher dose of amantadine than historically reported as use in MS, the 
titration phase is being included for the 274 mg dose to further ensure its tolerability. When a 
1-step forced titration, from 137 to 274 mg, was employed in Adamas’ clinical studies of 
ADS-5102 in PD, premature discontinuation rates were still higher during the earlier, as 
compared to the later, times on-study. Moving from a 1-step to a 2-step titration should serve to 
further limit early discontinuation of study drug.  
5.6. 
Rationale for ADS-AMT-MS301 Study Design 
The overall objectives of this Phase 3 study are to establish the efficacy of ADS-5102, an ER 
form of amantadine, in improving walking performance, and to characterize its safety and 
tolerability at a dosage of 137 or 274 mg/d, administered once daily at bedtime, in MS patients 
with walking impairment. A multicenter, 3-arm, randomized, placebo-controlled, double-blind, 
parallel-group study, incorporating a Single-Blind Placebo Run-In Period prior to randomization 
and forced up-titration for the high-dose group, is an appropriate design to accomplish these 
objectives. 
The duration of the Double-Blind Treatment Period of the study, 12 weeks, should be adequate 
to demonstrate an effect of ADS-5102 on walking ability, as a positive effect on walking was 
observed after 4 weeks of treatment in the Phase 2 study. Obtaining serial efficacy measures at 
multiple timepoints throughout the 12-week duration should indicate whether any observed 
effect is diminishing, increasing, or holding steady over time. If, as in PD, a positive effect is 
observed with active study drug early after its initiation, and the effect holds relatively constant 
through to the last efficacy assessment, then it is likely that the 12-week duration will be 
assessed to have been adequate to establish the durability of the drug effect over time. 
Incorporating into the study design a Single-Blind Placebo Run-In Period for all eligible subjects 
prior to randomization to their assigned treatment group in the double-blind phase of the study 
provides several potential advantages over starting double-blind treatment immediately 
following the initial screening period. By allowing subjects the opportunity to discontinue 
treatment while only receiving placebo, AEs related to study participation, but not to study drug, 
per se (e.g., AEs related to anxiety about receiving an experimental therapy), in subjects who 
might be prone to experiencing such AEs, may be reduced in the safety and tolerability data 
obtained by study’s end and provide a truer reflection of the drug’s safety and tolerability profile. 
Also, it is generally believed that for many outcome measures, the durability of the placebo 
response diminishes over time. The addition of the pre-randomization placebo run-in period 
provides additional time for any potential contribution of a placebo response to have decreased 
by the time of the final efficacy evaluation. Lastly, by performing efficacy assessments during 
the placebo run-in period, the impact of practice effects on the variability of efficacy measures 
can be diminished. 
The duration of the Single-Blind Placebo Run-In Period, 4 weeks, is considered long enough to 
permit realization of its potential benefits without being so long as to substantially increase the 
overall burden of study participation. It is also consistent with the duration of the placebo run-in 
periods employed in other drug studies in walking impairment in MS (Goodman et al., 2009; 
Goodman et al., 2010).  

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
21 
As amantadine is not currently known, or widely held, to be a disease modifying treatment for 
MS, i.e., is generally considered to be a symptomatic therapy, no irreparable harm is considered 
likely to result from withholding the experimental treatment in the subjects randomized to 
receive placebo. 
5.7. 
Population to be Studied 
Subjects with MS who are experiencing impaired walking will be randomized into the study. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
22 
6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
• To evaluate the efficacy of 274 mg ADS-5102 in subjects with multiple sclerosis 
(MS) with walking impairment as measured by the Timed 25-foot Walk (T25FW, 
feet/second) at Week 16 
6.2. 
Secondary Objectives 
6.2.1. 
Key  
• To evaluate the efficacy of 274 mg ADS-5102 in subjects with MS and walking 
impairment as measured by the T25FW, Timed Up and Go (TUG) test, and the  
2-Minute Walk Test (2MWT) at Week 16. 
• To evaluate the efficacy of 137 mg ADS-5102 in subjects with MS and walking 
impairment as measured by the T25FW, the TUG test, and the 2MWT at Week 16.  
6.2.2. 
Supportive  
• To evaluate the efficacy of 274 mg ADS-5102 and 137 mg ADS-5102 in subjects 
with MS and walking impairment as measured by the T25FW, the TUG, and the 
2MWT across all study visits.  
• To evaluate the efficacy of 274 mg ADS-5102 and 137 mg ADS-5102 in subjects 
with MS and walking impairment as measured by the Multiple Sclerosis Walking 
Scale-12 (MSWS-12) in subjects treated with 274 mg ADS-5102 and subjects treated 
with 137 mg ADS-5102. 
6.2.3. 
Safety  
• To evaluate the safety and tolerability of 274 mg and 137 mg of ADS-5102 in 
subjects with MS and walking impairment. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
23 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a multicenter, 3-arm, randomized, placebo-controlled, double-blind, parallel-group study 
of ADS-5102 (amantadine ER capsules) in MS subjects with walking impairment, incorporating 
a Single-Blind Placebo Run-In Period prior to randomization, and forced up-titration for the 
high-dose group.  
All subjects will have received a stable regimen of MS medications, both disease modifying and 
symptomatic, for at least 30 days prior to screening, and will continue the same doses and 
regimens for the duration of their study participation, to the extent compatible with good 
neurological care. Subjects will not have used amantadine, dalfampridine, or any 4-AP or 
2,4-diaminopyridine (2,4-DAP) preparation within 30 days prior to screening. 
Consented subjects who complete the up to 3-week screening period will undergo a 4-week 
Single-Blind Placebo Run-In Period during which they will administer placebo as 2 capsules 
once daily at bedtime. 
Subjects who complete the Single-Blind Placebo Run-In Period and continue to meet study 
eligibility criteria will be randomized with equal probability to 1 of 3 treatment groups: placebo 
or ADS-5102 at a final dosage of either 137 or 274 mg/d (treatment groups are identified by their 
final dosage). Study drugs will be administered as 2 capsules once daily at bedtime. 
Subjects who are randomized to placebo will receive placebo capsules throughout the 12-week 
Double-Blind Treatment Period, including the 2-week forced titration and 10-week maintenance 
phases.  
Subjects who are randomized to 137 mg of ADS-5102 will receive 137 mg of ADS-5102 
throughout the 12-week Double-Blind Treatment Period, including the 2-week forced titration 
and 10-week maintenance phases.  
Subjects who are randomized to 274 mg of ADS-5102 will receive 137 mg for the first week 
(Week 1 of the forced titration phase of the Double-Blind Treatment Period), 205.5 mg for the 
second week (Week 2 of the forced titration phase of the Double-Blind Treatment Period), and 
274 mg for the remaining 10 weeks of the 12-week Double-Blind Treatment Period. 
Subjects will return to the clinic for safety and efficacy assessments at Week 0 and Week 2 prior 
to randomization and at Weeks 4 (randomization and baseline visit), 6 (only safety), 8, 12, and 
16 after randomization. In addition, telephone visits for safety assessments will be conducted at 
Weeks 5 and 7. Subjects who withdraw from the study before Week 16 will have an early 
termination visit that includes safety follow-up and efficacy assessments, as appropriate.   
Subjects who complete 12 weeks of double-blind treatment (16 weeks total treatment, including 
placebo run-in) without significant protocol deviations, as assessed by the investigator and the 
sponsor, will be eligible to enter an optional open-label extension (OLE) study, protocol ADS-
AMT-MS303. The Week 16 visit of Study ADS-AMT-MS301 will serve as the first study visit 
of Study ADS-AMT-MS303 for those subjects who consent to participate. 
Subjects who complete 12 weeks of double-blind treatment (16 weeks total treatment, including 
placebo run-in) but elect not to participate in the OLE study will return to the clinic for a final 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
24 
post-treatment safety and efficacy assessment 2 weeks after their Week 16 visit (Week 18), i.e., 
after being off treatment for approximately 2 weeks. 
The End of Study (EOS) is defined as when a subject completes the Week 16 visit (if electing to 
enter the OLE study) or the Safety Follow-Up Visit (if electing not to enter the OLE study). 
All study visits and efficacy assessments should be scheduled at approximately the same time of 
day for an individual subject. To the extent practicable, study visits and efficacy assessments 
should be scheduled to occur when a subject is not likely to be experiencing acute side effects 
from a concomitant medication (e.g., flu-like side effects following interferon-beta injection). 
Efficacy assessments should be conducted in following sequence: MSWS-12; T25FW; TUG; 
2MWT. Subjects using an assistive device during the walking assessments at Screening should 
use the same assistive device for all subsequent walking tests. Each efficacy assessment for an 
individual should be performed by the same clinical rater, if possible. 
Adverse events and concomitant medications will be recorded beginning with the first dose of 
study drug and continuing through the last study visit. 
The schedule of assessments is provided in Appendix A. 
7.2. 
Number of Subjects 
Approximately 570 subjects are to be enrolled in the Single-Blind Placebo Run-In Period at 
approximately 80 study sites to ensure that 540 subjects complete the Single-Blind Placebo 
Period and are eligible to be randomized into the Double-Blind Treatment Period (approximately 
180 enrolled in each treatment group: placebo, 137 mg ADS-5102, and 274 mg ADS-5102). 
7.3. 
Treatment Assignment 
Consented subjects who complete screening, meet study eligibility criteria, and complete the 
Single-Blind Placebo Run-In Period will be randomized with equal probability to 1 of the 
3 treatment groups to receive placebo, 137 mg ADS-5102, or 274 mg ADS-5102. 
7.4. 
Dose Adjustment Criteria 
7.4.1. 
Dose Adjustment for Renal Impairment 
Subjects whose estimated glomerular filtration rate (eGFR) falls below 60 mL/min/1.73 m2, 
confirmed by repeat testing, should discontinue study drug (see Section 8.5). 
7.4.2. 
Dose Adjustment for Adverse Events 
Study drug may only be withheld for the evaluation or treatment of an AE. If, in the judgement 
of the investigator, study drug should be withheld for the evaluation or treatment of an AE, the 
investigator may have the subject do so for up to 3 consecutive days, and is then to have the 
subject resume dosing at the same dose level. If, in the judgement of the investigator, study drug 
needs to be withheld for more than 3 consecutive days, the investigator must contact one of the 
study’s Medical Monitors to determine whether drug may be withheld for a longer period or the 
subject should be permanently discontinued from study drug. Study drug may not be down-
titrated. This procedure applies to the withholding of study drug throughout the study with the 
exception of the titration phase of the Double-Blind Treatment Period. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
25 
In the special case of study drug being withheld for the evaluation or treatment of an AE 
occurring during the titration phase of the Double-Blind Treatment Period (i.e., Week 4 to 
Week 6), the investigator may have the subject do so for up to 3 consecutive days, and is then 
have the subject resume dosing at same dose level. The subject is to finish the remaining 
capsules in the blister card (see Section 9.2), i.e., including the 2-dose overage. The subject must 
return to the clinic to receive his or her next blister pack without missing any additional doses. If, 
in the judgement of the investigator, study drug needs to be withheld for more than 3 consecutive 
days the subject is to be permanently discontinued from study drug. 
7.5. 
Criteria for Study Termination 
The sponsor reserves the right to discontinue the trial at any time; reasons will be provided if this 
occurs. The Principal Investigator (PI) reserves the right to discontinue participation in the study 
for safety or other reasons at any time in collaboration with the sponsor. The investigator should 
notify the institutional review board (IRB) in writing of the trial’s completion or early 
termination and provide a copy of the notification to the sponsor. 
7.6. 
Duration of Subject Participation 
Maximum duration of subject participation is up to approximately 21 weeks and will include a 
3-week (maximum) screening period, a 4-week Single-Blind Placebo Run-In Period, a 12-week 
Double-Blind Treatment Period for all subjects (including a 2-week forced up-titration and a 
10-week maintenance phase for subjects in the high-dose group), and a 2-week post-treatment 
safety follow-up period for subjects who choose not to participate in the OLE study. 
7.7. 
Estimated Study Duration 
The estimated study duration is approximately 18 months, from randomization of the first subject 
to the last subject’s EOS visit. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
26 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
1. Signed a current IRB-approved informed consent form 
2. Male or female subjects between 18 and 70 years of age, inclusive, at the time of 
Screening 
3. Confirmed diagnosis of MS according to the 2017 McDonald criteria  
(Thompson et al., 2017) 
4. Current medication regimen must be stable for at least 30 days prior to screening, and 
subject must be willing to continue the same dosing regimen for the duration of study 
participation 
5. Maximum Expanded Disability Status Scale (EDSS) score during screening of 6.5 
6. Sufficient ambulatory ability (ambulatory aids acceptable if used consistently) to 
complete two trials of the Timed 25-Foot Walk (T25FW) at the screening visit, with the 
two trials completed within 5 minutes of each other in accordance with the specific 
instructions provided by the National MS Society Functional Composite Manual 
7. Stable physical activity level (inclusive of prescribed physiotherapy) for at least 30 days 
prior to screening and willing to continue without change for the duration of study 
participation 
8. A score on each of two completed screening T25FW tests between 8 and 45 seconds, 
inclusive 
8.2. 
Subject Exclusion Criteria 
1. Documented inability to tolerate amantadine 
2. History of hypersensitivity or allergic reaction to amantadine, rimantadine, or memantine, 
or to any of the excipients used in the study drug capsules (refer to Table 2) 
3. Clinically significant MS relapse with onset less than 30 days prior to screening 
4. Presence of neurologic dysfunction or medical condition, the severity of which, in the 
judgement of the investigator, would preclude the ability to perform walking tests safely 
5. Receipt of systemic corticosteroids (intravenous [IV] or oral) or ACTHAR gel within 
30 days prior to screening 
6. Receipt of dalfampridine (or any 4-aminopyridine or 2,4-diaminopyridine preparation) or 
amantadine within 30 days prior to screening 
7. History of other neurological or medical condition that, in the opinion of the investigator, 
would affect study outcome assessments 
8. History of seizures within 3 years prior to screening 
9. History of hallucinations (visual, auditory, or any other type) within 3 years prior to 
screening 
10. History of bipolar disorder, schizophrenia, or psychosis, regardless of treatment 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
27 
11. For subjects with a history of major depressive disorder, the presence of active depressive 
symptoms that, in the opinion of the investigator, would affect the subject’s ability to 
complete study assessments, or which would not be in the subject’s best interest to 
participate in the study 
12. History of suicide attempt 
13. History of suicidal ideation within 3 years of screening, or presence of suicidal ideation at 
screening, as detected by the Columbia Suicidality Scale (C-SSRS) 
14. History of cognitive impairment sufficient, in the clinical judgement of the investigator, 
to affect the subject’s ability to consent or complete study assessments, or to render it not 
in the subject’s best interest to participate in the study 
15. History of alcohol or substance dependence or abuse within 2 years prior to screening 
16. History of stroke, transient ischemic attack (TIA), or myocardial infarction (MI) within 
2 years prior to screening 
17. History of cancer within 5 years prior to screening, with the following exceptions: 
adequately treated non-melanomatous skin cancers, localized bladder cancer, 
non-metastatic prostate cancer, in situ cervical cancer, or other definitively treated cancer 
that is considered cured 
18. Presence of orthostatic hypotension at screening: a decrease in systolic blood pressure (at 
least 20 mm Hg) or diastolic blood pressure (at least 10 mm Hg) within 3 minutes of the 
subject standing up, compared to pressures obtained while sitting 
19. Any laboratory test results outside of the central laboratory’s normal range at screening 
that are assessed by the investigator to be clinically significant. Documentation by the 
investigator of clinical significance or insignificance must accompany out of range 
laboratory test results at screening 
20. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) screening 
laboratory results > 2 times the upper limit of normal 
21. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (per Modification of 
Diet in Renal Disease [MDRD] calculation) 
22. Inability to swallow oral capsules, or a history of gastrointestinal malabsorption that 
would preclude the use of oral medication 
23. If female, is pregnant or lactating 
24. If a sexually active female, is not surgically sterile or at least 2 years post-menopausal, or 
does not agree to utilize a highly effective hormonal method of contraception (an IUD, or 
vasectomized male partner is also acceptable), in combination with a barrier method, 
from screening through at least 4 weeks after the completion of study treatment. If a 
sexually active male, does not agree to utilize condoms from screening through at least 4 
weeks after the completion of study treatment. 
25. Received live attenuated influenza vaccine within 2 weeks prior to randomization or 
planning to receive live attenuated influenza vaccine during the duration of the study 
(amantadine may interfere with the efficacy of live attenuated vaccine) 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
Confidential and Proprietary 
28 
26. Current treatment with medications that may affect urinary pH: carbonic anhydrase
inhibitors, sodium bicarbonate, urinary acidification agents, quinine, quinidine,
triamterene, or trimethoprim
27. Treatment with an investigational drug or device within 30 days prior to screening
28. Treatment with an investigational biologic within 6 months or 5 half-lives, whichever is
longer, prior to screening
29. Current participation in another clinical trial
30. Prior or current participation in an Adamas clinical trial
31. Planned elective surgery, with the exception of minor dermatological procedures, during study
participation
8.3. 
Subject Withdrawal Criteria 
Subjects will be advised that they are free to withdraw from the study at any time. Reasons that 
subjects may be withdrawn from the study include the following: 
•
Subject discontinued study drug (see Section 8.5) and wishes to withdraw
•
Subject consent is withdrawn
•
Sponsor decision, after discussion with the investigator
If a subject is withdrawn from the study, all efforts will be made to complete the early 
termination visit that includes efficacy assessments and safety follow-up. In addition, women of 
childbearing potential will have a post-study pregnancy test performed at the early termination 
visit. 
All information, including the reason for withdrawal, should be reported on the applicable pages 
of the case report form (CRF). 
For subjects who are lost to follow-up, three documented attempts will be made to contact the 
subject for follow-up information, including reason for discontinuation and follow-up of AEs. 
Subjects who withdraw from the study will not be replaced. 
8.4. 
Subject Enrollment 
All subjects must sign and date an IRB-approved informed consent form (ICF) before any study 
procedures, including screening procedures, are performed. Subjects will be considered enrolled 
into the study after they have signed the ICF and have met all study-mandated 
inclusion/exclusion criteria.  
8.5. 
Discontinuation of Study Drug  
Subjects should discontinue study drug if judged necessary by the investigator or sponsor, and 
reasons may include any of the following: 
•
eGFR falls below 60 mL/min/1.73 m2, confirmed by repeat testing (see Section 7.4.1)
•
Need to take a medication that is excluded or that may interfere with study
measurements

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
29 
 Subjects requiring MS treatment adjustment due to disease exacerbation or 
progression should be discussed with one of the Medical Monitors 
• Intolerable or unacceptable AEs 
• Positive pregnancy test 
Subjects who discontinue study drug will be encouraged to complete the study. If the subject 
decides to withdraw from the study, he or she will have an early termination visit that includes 
efficacy assessments and safety follow-up. 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
30 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Study Drug 
The clinical supplies will include 137 mg and 68.5 mg ADS-5102 capsules and matching 
placebo capsules. All capsules provided during the study are indistinguishable in size and 
appearance. 
Amantadine is designated generically as amantadine hydrochloride and chemically as 
1-adamantanamine hydrochloride. 
The clinical formulations are shown in the table below. 
Table 2: 
Clinical Formulations for Study ADS-AMT-MS301 
 
Placebo 
ADS-5102 
137 mg and 68.5 mg 
Formulation 
Microcrystalline cellulose pellets in 
an oral capsule 
Extended release coated pellets of 
amantadine in an oral capsule 
Dose Strength 
Not applicable 
137 mg amantadine per capsule 
68.5 mg amantadine per capsule 
Description 
White to off-white pellets filled in 
white opaque/white opaque colored 
hard gelatin capsule, size 0.  
White to off-white pellets filled in white 
opaque/white opaque colored hard 
gelatin capsule, size 0.  
Excipients 
Microcrystalline cellulose, NF/EP 
Magnesium stearate, USP/NF/EP 
Microcrystalline cellulose, NF/EP 
Hypromellose, USP/EP 
Copovidone, NF/EP 
Talc, USP/EP 
Ethyl cellulose, USP/NF/EP  
Povidone, USP/EP  
Medium chain triglycerides, 
USP/EP/NF  
Magnesium stearate, USP/NF/EP 
USP: United States Pharmacopeia; NF: National Formulary; EP: European Pharmacopoeia. 
 
9.2. 
Study Drug Packaging and Labeling 
The study drug will be packaged in child-resistant blister wallets, each containing a total of  
36 capsules (2 capsules per dose, allowing a 2-week supply plus 2 extra doses per week). All 
blister wallets will be labeled with, at a minimum, the protocol number, route of administration, 
number of capsules to be administered, lot number, storage conditions, sponsor’s name and 
address, investigator ‘s name, subject number, and applicable investigational drug caution 
statements. 
The study drug will be assigned by an interactive response technology (IRT) system per the 
assigned dosing schedule and titration scheme at designated study visits. Details of the 
dispensation schedule will be included in the IRT user manual. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
31 
9.3. 
Study Drug Storage 
All study drugs must be stored at 25oC (77oF) with excursions permitted to 15-30°C (59-86°F) in 
a secured location with access limited to authorized personnel. 
An authorized pharmacist or designated staff member will dispense the study drug. The 
dispensing and administration will be recorded in a drug accountability log. 
9.4. 
Administration 
Table 3: 
Randomization Groups for Study ADS-AMT-MS301 
TREATMENT GROUP 
274 mg ADS-5102 
137 mg ADS-5102 
Placebo 
Single-Blind Placebo Run-In Period 
Week 0 to Week 4 
2 x placebo capsules 
2 x placebo capsules 
2 x placebo capsules 
Double-Blind Treatment Period, Forced Titration Phase 
Week 4 to Week 5 
1 x 137 mg ADS-5102 capsule 
1 x placebo capsule 
1 x 137 mg ADS-5102 
capsule 
1 x placebo capsule 
2 x placebo capsules 
Week 5 to Week 6 
1 x 137 mg ADS-5102 capsule 
1 x 68.5 mg ADS-5102 
capsule 
1 x 137 mg ADS-5102 
capsule 
1 x placebo capsule 
2 x placebo capsules 
Double-Blind Treatment Period, Maintenance Phase 
Week 6 to Week 16 
2 x 137 mg ADS-5102 capsule 
1 x 137 mg ADS-5102 
capsule 
1 x placebo capsule 
2 x placebo capsules 
 
Each dose will be administered as 2 oral capsules once daily at bedtime. 
Capsules are to be swallowed intact, and can be taken with any nonalcoholic beverage, with or 
without food.  
While taking study drug, concomitant use with alcohol is not recommended, as it may increase the 
potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension 
and may result in dose-dumping 
Dosing will continue through Week 16. 
9.5. 
Study Drug Accountability 
All study drug supplied is for use only in this clinical study and must not be used for any other 
purpose. The investigator is responsible for the study drug accountability, reconciliation and 
record maintenance at the investigational site. In accordance with all applicable regulatory 
requirements, the investigator or designated site staff must maintain study drug accountability 
records throughout the course of the study. This person will document the amount of study drug 
received and the amount supplied and/or administered to and returned by subjects, if applicable. 
Copies of all packing slips for the study drug shipments must be retained. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
32 
A Study Drug Accountability Record must be kept current and will contain at a minimum the 
following information: 
• The identification of the subject to whom the drug was dispensed 
• The date(s) and quantity of the drug dispensed to the subject 
• Any product accidentally or deliberately destroyed 
• Current quantity of total study drug supply 
Subjects will be instructed to return all used and unused blister cards of study drug for drug 
accountability purposes. All used and unused blister cards must be saved for reconciliation by 
the sponsor’s study monitor or an assigned designee. 
During the study, the study drug and all shipment, accountability and dispensing records must be 
available for inspection by the study monitor. Drug supply reconciliation is required at the end of 
the study by the study monitor. 
9.6. 
Study Drug Handling and Disposal 
After reconciliation, all unused drug supplies will be disposed of according to instructions 
provided by the sponsor. Records shall be maintained by the investigator of any such disposition 
of the study drug, which must show the identification and quantity of each unit returned. 
9.7. 
Prohibited Medications and Restrictions 
The following medications are prohibited during study participation: 
• Amantadine, other than provided study drug 
• Dalfampridine, or any formulations of 4-AP (or 2,4-DAP) 
• Live attenuated influenza vaccine 
• Medications that may affect urinary pH: carbonic anhydrase inhibitors, sodium 
bicarbonate, urinary acidification agents, quinine, quinidine, triamterene, or 
trimethoprim 
Products with anticholinergic properties may potentiate the anticholinergic-like side effects of 
amantadine. Subjects should be monitored for anticholinergic effects. The investigator should 
consider reducing the dose of anticholinergic drugs, if atropine-like effects appear when these drugs 
are used concurrently.  
While taking study drug, it is recommended as a general safety precaution when evaluating a 
CNS-active agent that subjects should avoid alcohol consumption. 
No new medications should be initiated during the course of the study, except as deemed 
necessary by the investigator to treat an AE. No new MS medications should be initiated during 
study participation, unless there is an urgent medical need. If this occurs, please inform the 
Medical Monitor. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
33 
9.8. 
Concomitant Medications 
Information regarding medications taken by the subject within 30 days prior to the screening 
visit and throughout the study will be collected and recorded on the Prior/Concomitant 
Medications CRF. This information will include the name of the medication, dosage information 
(including frequency and route of administration), dates taken, reason for use, and stop date, if 
available. 
All subjects will have received a stable regimen of MS medications for at least 30 days prior to 
screening, and will continue the same doses and regimens for the duration of their study 
participation. Subjects will not have used amantadine, dalfampridine, or any 4-AP or 2,4-DAP 
preparation within 30 days prior to screening. 
Any other current and allowed prescription/non-prescription medications and/or nutritional 
supplements must have been at a stable dose and frequency for at least 30 days prior to 
screening, and subjects must be willing to continue those doses and regimens during the placebo-
controlled, double-blind period of the study. (This criterion does not apply to medications that 
are taken on an as-needed basis only). 
9.9. 
Treatment Compliance 
Subjects will be instructed to return all used/unused blister cards at the next study visit, when the 
designated study site staff will review the number of returned capsules to assess subject 
compliance. 
9.10. 
Randomization and Blinding 
A subject is considered randomized at Baseline/Week 0, when the site confirms the 
randomization event via a centralized randomization system (interactive web response system 
[IWRS]). Complete instructions on the use of the system are provided in the IWRS manual. 
Following completion of the 4-week Single-Blind Placebo Run-in Period, consented subjects 
meeting all eligibility criteria will be randomly assigned in equal probability to 1 of 3 treatment 
groups: placebo, 137 mg ADS-5102, or 274 mg ADS-5102. 
The identity of the treatment assigned to individual subjects can be revealed in an emergency 
only. Details of the process to be followed are provided in the study and IWRS manuals. The PI 
is responsible for ensuring that the instructions on how to request unblinding of treatment are 
stored safely, that their location is known, and that access is readily available to the relevant staff 
in case of an emergency. 
A subject’s treatment assignment should only be unblinded when knowledge of the treatment is 
essential for the safety of the subject. Unblinding for any other reason will be considered a 
protocol deviation. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
34 
10. 
ASSESSMENT OF EFFICACY 
Evaluations relating to efficacy to be performed during the study are described in the following 
table. Full details on how efficacy assessments are to be performed will be provided in the study 
manual. 
Table 4: 
Efficacy Assessments 
Assessment 
Study Visit 
Description 
Timed 25-Foot 
Walk (T25FW) 
Screening 
Week 0, Week 2 
Baseline/Week 4 
Week 8 
Week 12 
Week 16 (or ET) 
Safety Follow-Up 
The T25FW is a measure of lower extremity function. 
The subject is directed to a clearly marked 25-foot 
course and is instructed to walk 25 feet as quickly as 
possible, but safely. The task is immediately 
administered again by having the subject walk back the 
same distance. The result is reported as time to 
complete (seconds) or speed (feet per second). 
Improvement is indicated by a decrease in time or an 
increase in speed. 
Timed Up and 
Go (TUG)  
Week 0, Week 2 
Baseline/Week 4 
Week 8 
Week 12 
Week 16 (or ET)  
Safety Follow-Up 
The TUG is a measure of lower extremity strength, 
balance, and coordination. The subject stands up from a 
chair, walks 3 meters then turns around and walks back 
to the chair to sit down. The result is reported in 
seconds. Improvement is indicated by negative change 
scores. 
2-Minute Walk 
Test (2MWT) 
Week 0, Week 2 
Baseline/Week 4 
Week 8 
Week 12 
Week 16 (or ET) 
Safety Follow-Up 
The 2MWT is a measure of lower extremity function. 
The subject is instructed to walk as far as possible in 
2 minutes, and the distance is measured in meters. 
Improvement is indicated by positive change scores. 
Multiple 
Sclerosis 
Walking Scale-
12 (MSWS-12) 
Week 0, Week 2 
Baseline/Week 4 
Week 8 
Week 12 
Week 16 (or ET) 
Safety Follow-Up 
The MSWS-12 is a 12-item walking scale that is a 
measure of subject-reported walking ability during the 
past 2 weeks. Each item is scored on a 1 to 5 scale. A 
total score can be generated and transformed to a 0 to 
100 scale. Improvement is indicated by negative 
change scores. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
35 
11. 
ASSESSMENT OF SAFETY 
11.1. 
Physical Assessments Relating to Safety 
11.1.1. 
Scheduled Physical Assessments Relating to Safety 
Physical examinations relating to safety to be performed during the study are described in the 
following table. 
Table 5: 
Physical Examination Assessments Relating to Safety 
Assessment  
Study Visit  
Description  
Complete physical 
examination 
Screening 
Week 16 (or ET) 
Physical examination including: skin, head-neck, 
eyes-ears-nose-throat, lungs-chest, heart, abdomen, 
extremities. 
Symptom-directed 
physical examination, 
as needed 
Baseline/Week 4 
Week 8 
Week 12 
Safety Follow-Up  
Physical examination adequate to evaluate fully the 
diagnosis and severity of an AE or AEs having 
occurred up to the date of the visit. 
Height 
Screening 
Height will be measured at screening only and 
recorded in centimeters.  
Weight 
Screening 
Week 16 (or ET) 
Weight will be recorded in kilograms. Subjects may 
be weighed in their undergarments or in light 
clothing (no jackets or shoes). Measuring weight 
must be done consistently, using the same set of 
weighing scales when possible. 
Vital signs 
Screening 
Week 0, Week 2 
Baseline/Week 4 
Week 8 
Week 12 
Week 16 (or ET) 
Safety Follow-Up  
Systolic and diastolic blood pressures, heart rate, 
and body temperature should be recorded after the 
subject has been seated quietly for at least 
5 minutes. Blood pressure, respiratory rate, heart 
rate, and temperature will be measured once each 
day assessed. During screening only, after the 
seated blood pressure has been obtained, the 
measurement will be repeated within 3 minutes of 
the subject standing up. This procedure may be 
repeated, if appropriate, following hydration. If 
repeated, a total of two additional pairs of blood 
pressure assessments (sitting/standing) should be 
obtained, and the results of the last attempt should 
be reported. 
Electrocardiogram 
(ECG) 
Screening 
A 12-lead ECG (25 or 50 mm/sec) with a 10-second 
rhythm strip will be recorded after the subject has 
rested supine or semi-recumbent for at least 5 
minutes. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
36 
11.1.2. 
Unscheduled Physical Assessments Relating to Safety 
If, at a scheduled or unscheduled study visit, a subject reports experiencing or having 
experienced an AE or is observed to be having an AE, the investigator should perform those 
examinations necessary to evaluate fully the diagnosis and severity of the AE. 
If the AE is one of dizziness, lightheadedness, pre-syncope, syncope, or a related event, the 
examination must include, at a minimum, testing for orthostatic hypotension, as described above. 
11.2. 
Clinical Laboratory Tests 
The clinical laboratory and other tests relating to safety to be performed during the study are 
described in the following table. The estimated total blood volume collected throughout the study 
(for clinical laboratory tests) is expected to be approximately 30 mL for safety serum chemistry 
and hematology laboratory evaluations. 
Table 6: 
Clinical Laboratory and Other Assessments 
Assessment 
Study Visit 
Description 
Hematology  
Screening 
Week 16 (or ET) 
Blood samples (5 mL) will be collected. Hematology 
parameters include: hemoglobin, hematocrit, mean 
corpuscular volume (MCV), mean corpuscular 
hemoglobin concentration (MCHC), red blood cell 
(RBC) count, white blood cell (WBC) count, WBC 
differential count, and platelet count. Hematology will 
be conducted by a central laboratory. 
Serum Chemistry  Screening 
Week 16 (or ET) 
Blood samples (10 mL) will be collected (fasting is 
not required). Routine serum chemistry parameters 
include alkaline phosphatase, albumin, blood urea 
nitrogen, calcium, carbon dioxide, chloride, 
creatinine, γ-glutamyl transferase, glucose, inorganic 
phosphorus, potassium, alanine aminotransferase, 
lactate dehydrogenase, aspartate aminotransferase, 
sodium, total bilirubin, and total protein. 
Urinalysis  
Screening 
Week 16 (or ET) 
Urinalysis will be performed using sponsor-supplied 
dipsticks, including leukocytes, specific gravity, pH, 
protein, ketones, glucose, nitrite, blood, urobilinogen, 
and bilirubin. If nitrite, blood, or protein tests are 
positive, a microscopic examination will be 
performed. 
Serum pregnancy 
test (if 
applicable) 
Screening 
Week 16 (or ET) 
Safety Follow-Up  
Serum pregnancy test will be performed for all female 
subjects of childbearing potential. 
Urine pregnancy 
test (if 
applicable) 
Week 0, Week 2 
Baseline/Week 4 
Urine pregnancy test will be performed for all female 
subjects of childbearing potential. 
Estimated glomerular filtration rate (eGFR) will be calculated by the central laboratory using MDRD. 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
37 
11.3. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be performed at every visit. Full details on how this assessment is to be 
performed will be provided separately. 
While the C-SSRS can provide valuable information as to the presence and intensity of suicidal 
ideation; determining the need for, and appropriate level of, therapeutic intervention depends on 
clinical judgment. The Joint Commission has published guidelines for treating suicidal ideation, 
“Sentinel Event Alert 56: Detecting and treating suicide ideation in all settings,” along with other 
resources that may prove useful to the investigator, available at: 
www.jointcommission.org/sea_issue_56/. 
Subjects should be also be monitored for depression, depressed mood, confusional state, and/or 
apathy, as well as suicidal ideation or behavior. New or worsening depression should be captured 
as an adverse event and treated appropriately per the Investigator’s obligation and judgement. 
12. 
EVALUATIONS BY VISIT 
A schedule of study evaluations is provided in Appendix A. 
Study visits should occur on the day scheduled. There is a (+/-) 2 day window for Visit 3 through 
Visit 18. 
12.1. 
Screening/Day -21 to -1 
During screening, potential subjects for the study will be fully informed about the nature of the 
study and possible AEs. Subjects who wish to participate in the study must read and understand 
the consent form and sign the document after the investigator has answered all questions to the 
candidate’s satisfaction. Further procedures can begin only after the consent form has been 
signed. 
The screening visit must be conducted within 21 days prior to the Week 0 visit. Potential study 
subjects will be evaluated for entry into the study according to the stated inclusion and exclusion 
criteria. Individuals who are identified during this screening as not eligible for study enrollment 
need not complete all screening procedures. The reason for ineligible status is to be documented. 
The following procedures will be performed to establish each subject’s qualifications for 
enrollment into the study: 
• The subject is fully informed about the study and gives written informed consent to 
participate in the study 
• Confirm commitment of caregiver and/or study partner, if applicable 
• Review inclusion/exclusion criteria and evaluate initial subject eligibility 
 Administer the EDSS (administration instructions and forms will be provided 
separately) 
 Administer the screening T25FW (administration instructions and forms will be 
provided in the study manual) 
• Record demographic information 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
38 
• Medical history with an emphasis on the subject’s MS and walking impairment, and 
past treatments for these conditions; alcohol and drug use, other neurological 
diseases, psychiatric disorders including Major Depressive Disorder or symptom 
(e.g., hallucinations, agitation, paranoia, suicidal ideation), history of seizures, stroke 
or TIA; history of MI or congestive heart failure (CHF); and history of cancer 
• Record all medications currently taken or taken in the previous 30 days  
• Complete physical examination 
• Obtain subject weight in kilograms and height in centimeters 
• Vital signs (blood pressure, respiratory rate, heart rate, and temperature), including 
assessment of orthostatic hypotension 
• Blood sample for central laboratory analysis including hematology, serum chemistry 
and eGFR 
• ECG (12-lead) 
• Urinalysis 
• Blood sample for serum pregnancy test in females of childbearing potential. 
• Administer the C-SSRS (administration instructions and forms will be provided in the 
study manual) 
Full details on how individual efficacy assessments are to be performed will be provided in the 
study manual. 
12.2. 
Single-Blind Placebo Run-In Period/Week 0 to Week 2 
The following procedures will be performed at the Week 0 and Week 2 visits: 
• Review inclusion/exclusion criteria and assess continued subject eligibility 
• Assess and record concomitant medications 
• Assess and record AEs 
• Vital signs (blood pressure, respiratory rate, heart rate, and temperature) 
• Urine sample for urine pregnancy test in females of childbearing potential 
• Efficacy assessments 
• C-SSRS 
• Dispense placebo (4-week supply) for eligible subjects (Week 0 only)  
• Collect used/unused blister cards and evaluate compliance (Week 2 only)  
12.3. 
Baseline/Week 4 
• Review inclusion/exclusion criteria and determine subject eligibility 
• Assess and record any changes in concomitant medications since screening 
• Assess and record AEs 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
39 
• Symptom-direct physical examination, as needed 
• Vital signs (blood pressure, respiratory rate, heart rate, and temperature)  
• Urine sample for urine pregnancy test in females of childbearing potential 
• Efficacy assessments (see Section 10) 
• C-SSRS 
• Collect used/unused blister cards and evaluate compliance 
• Randomize the subject to treatment via the interactive system 
• Dispense double-blind study drug (2-week supply) 
12.4. 
Double-Blind Treatment Period: Telephone Visits at Weeks 5 and 7  
• Review dosing instructions 
• Assess and record any changes in concomitant medications since screening 
• Assess and record AEs 
12.5. 
Double-Blind Treatment Period: Week 6 Visit 
• Assess and record concomitant medications  
• Assess and record AEs 
• C-SSRS 
• Collect used/unused blister cards and evaluate compliance 
• Dispense double-blind study drug (2-week supply)  
12.6. 
Double-Blind Treatment Period: Week 8 Visit  
• Assess and record concomitant medications  
• Assess and record AEs 
• Symptom-direct physical examination, as needed  
• Vital signs (blood pressure, respiratory rate, heart rate, and temperature)  
• Efficacy assessments  
• C-SSRS  
• Collect used/unused blister cards and evaluate compliance  
• Dispense double-blind study drug (4-week supply)  
 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
40 
12.7. 
Double-Blind Treatment Period: Week 12 Visit  
• Assess and record concomitant medications  
• Assess and record AEs 
• Symptom-direct physical examination, as needed  
• Vital signs (blood pressure, respiratory rate, heart rate, and temperature)  
• Efficacy assessments  
• C-SSRS  
• Collect used/unused blister cards and evaluate compliance  
• Dispense double-blind study drug (4-week supply)  
12.8. 
Double-Blind Treatment Period: Week 16 Visit  
• Assess and record concomitant medications  
• Assess and record AEs 
• Complete physical exam  
• Vital signs (blood pressure, respiratory rate, heart rate, and temperature)  
• Obtain subject weight in kilograms  
• Blood sample for central laboratory analysis including hematology, serum chemistry, 
and eGFR  
• Urinalysis  
• Blood sample for serum pregnancy test in females of childbearing potential  
• Efficacy assessments  
• C-SSRS  
• Collect used/unused blister cards and evaluate compliance  
12.9. 
Early Termination Visit 
• Assess and record concomitant medications 
• Assess and record AEs 
• Complete physical examination 
• Blood sample for central laboratory analysis including hematology, serum chemistry, 
and eGFR 
• Urinalysis 
• Vital signs (blood pressure, respiratory rate, heart rate, and temperature)  
• Obtain subject weight in kilograms  
• Blood sample for serum pregnancy test in females of childbearing potential 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
41 
• Efficacy assessments  
• C-SSRS 
• Collect used/unused blister cards and evaluate compliance 
• Completion of Early Termination Visit CRF, including reason for early 
discontinuation. (If early termination is due to AE, then a brief narrative of the AE 
will be recorded in the allocated section of the Early Termination Visit CRF) 
12.10. 
Safety Follow-Up/End of Study Visit 
This will be the final post-treatment safety and efficacy visit for subjects who complete 12 weeks 
of double-blind treatment but elect not to participate in the OLE study. Subjects will return to the 
clinic 2 weeks after their Week 16 visit (Week 18), i.e., after being off treatment for 
approximately 2 weeks and the following will be performed: 
• Assess and record concomitant medications  
• Assess and record AEs  
• Symptom-directed physical examination, as needed  
• Vital signs (blood pressure, respiratory rate, heart rate, and temperature)  
• Efficacy assessments  
• Blood sample for serum pregnancy test in females of childbearing potential 
• C-SSRS  
12.11. 
Unscheduled Study Visit 
• Assess and record concomitant medications  
• Assess and record AEs  
• Symptom-directed physical examination, as needed  
• Vital signs (blood pressure, respiratory rate, heart rate, and temperature) 
 
 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
42 
13. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND 
ADVERSE EVENTS OF SPECIAL INTEREST 
During the study, the investigator or study site personnel will be responsible for querying and 
recording adverse events (AEs) and serious adverse events (SAEs), as detailed in this section of 
the protocol. In this study AEs and SAEs will be reported from the time of study drug 
administration until the last study visit or death, or whichever occurs first. 
13.1. 
Definition of Adverse Events 
An adverse event (AE) is any untoward medical occurrence, including the deterioration of a 
pre-existing medical condition, that occurs in conjunction with the use of a medicinal product in 
humans, whether or not considered to have a causal relationship to the medicinal product. An AE 
can, therefore, be any unfavorable or unintended sign (including a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
In clinical studies, the temporal association of an AE with the use of a medicinal product, study 
drug, may be difficult to ascertain; an AE can include an untoward medical occurrence 
happening at any time, including baseline or washout periods, even if no study treatment has 
been administered. 
13.1.1. 
Adverse Event (AE) Definition 
Any medical condition or clinically significant laboratory abnormality with an onset date before 
the first date of study drug administration is usually considered to be pre-existing, and should not 
be documented in the CRF as an AE. 
An AE does include: 
• an exacerbation of a pre-existing illness; 
• an increase in frequency or intensity of a pre-existing episodic event or condition; 
• a condition detected or diagnosed after study drug administration even though it may 
have been present prior to the start of the study; 
• persistent disease or symptoms present at baseline which worsen following the start of 
the study. 
An AE does not include: 
• medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
Note: in this case, the condition that led to the procedure is an AE; 
• pre-existing diseases or conditions present or detected prior to start of study drug 
administration, which do not worsen; 
• the disease or disorder being studied or a sign or symptom associated with that disease 
(i.e., signs or symptoms associated with lack of efficacy will generally be considered to 
reflect underlying disease, rather than AEs); 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
43 
o In this study, walking ability is an efficacy parameter and changes in this measure 
(both positive and negative) will be reported as efficacy outcomes. Worsening of 
other MS-associated parameters should be reported as AEs 
• situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, elective abortion, social, and/or convenience admissions); 
• overdose of either study drug or concomitant medication without any signs or symptoms. 
(Dosing details will be recorded on the appropriate CRF(s)). 
• pregnancy - Pregnancy in itself is not regarded as an AE unless there is a suspicion that 
an investigational product may have interfered with the effectiveness of a contraceptive 
medication (see Section 13.3.3). 
All AEs must be fully and completely documented on the AE page of the CRF and in the 
subject’s medical notes. The following attributes must be assigned: description of AE, dates and 
times of onset and resolution (or whether ongoing), severity (Section 13.1.6), relationship to 
study drug (Section 13.1.7), whether an SAE or not (Section 13.1.2, and action taken (i.e., no 
action taken; study drug interrupted; study drug discontinued; other). 
In the event that a subject is withdrawn from the study because of an AE, it must be recorded on 
the CRF. The subject should be followed and treated by the investigator until the AE has 
resolved or a new chronic baseline has been established. 
The investigator must report all directly observed AEs and all spontaneously reported AEs. At 
each visit the investigator will ask the subject a nonspecific question (e.g., “Have you noticed 
anything different since your last visit?”) to assess whether any AEs have occurred since the last 
report or visit. AEs will be identified and documented on the AE page of the CRF in appropriate 
medical terminology. 
13.1.2. 
Serious Adverse Event (SAE) Definition 
A serious adverse event (SAE) is any AE occurring during any study phase (i.e., baseline, 
treatment, washout, or follow-up), and at any dose of the investigational product, or placebo, that 
fulfils one or more of the following: 
• results in death; 
• is life-threatening (subject is at immediate risk of death at the time of the event); 
• requires inpatient hospitalization or results in prolongation of existing hospitalization; 
• results in persistent or significant disability/incapacity; 
• is a congenital anomaly/birth defect in the offspring of a subject who received study drug; 
• is a significant or important medical event, i.e., an event that, based upon appropriate 
medical judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the above-mentioned criteria (examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse). 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
44 
When a causality assessment is provided for an SAE, it is important to include a rationale for the 
assessment so that a better understanding of the reported event can be compiled. The rationale 
should be accompanied by all available supporting evidence, including relevant laboratory tests, 
histopathology evaluations, and the results of other diagnostic procedures. The investigator’s 
rationale with supporting evidence is valuable when the sponsor performs a cumulative analysis 
of similar events. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs.   
13.1.2.1. Clarification of SAE Definition 
“Occurring at any dose” does not imply that the subject is receiving study drug at the time of the 
event. Dosing may have been interrupted temporarily prior to the onset of the SAE, but may have 
contributed to the event. 
“Life-threatening” means that the subject was at immediate risk of death from the event as it 
occurred. This does not include an event that might have led to death, had it occurred with 
greater severity. 
Complications that occur during hospitalizations are AEs. If a complication prolongs 
hospitalization, it is an SAE. 
“Inpatient hospitalization” does not imply that the subject must have had an overnight stay in the 
hospital. If the subject was admitted to the hospital for less than a day for the purpose of 
treatment or observation, the definition of “inpatient hospitalization” is met. Brief treatment in an 
outpatient clinic or Emergency department does not constitute “inpatient hospitalization.” 
The term “severe” is often used to describe the intensity (severity) of a specific event (see 
Section 13.1.6); the event itself, however, may be of relatively minor medical significance (such 
as severe headache). This is not the same as “serious,” which is based on event outcome or 
action criteria usually associated with events that pose a threat to a subject’s life or functioning. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
An SAE is considered “unexpected” if it is not listed in the Investigator’s Brochure or is not 
listed at the specificity or severity that has been observed. It is the responsibility of the sponsor to 
make this determination. 
13.1.2.2. Clarification of Subject Deaths 
All subject deaths (regardless of relationship to study drug) should be reported within 24 hours 
for subjects while on study protocol up to and including the safety follow-up visit. This should 
be recorded on the subject CRF and the SAE form. 
Death is an outcome of an AE and not an AE in itself. All reports of subject death should include 
an AE term for the cause of the death unless the protocol provides other specific instructions 
(e.g., mortality related to underlying disease is an efficacy endpoint). For all reports in which an 
AE term is not provided (other than “Death”), follow-up for the cause of death will be required. 
Only in the rare occurrence that no verbatim description of an AE can be obtained from the 
investigative site, then “Death – Unknown Cause” will be used as the event term. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
Confidential and Proprietary 
45 
13.1.3. 
Adverse Event of Special (AESI) 
There are two AEs of special interest (AESIs) in this study: 
•
Hallucinations (including visual, auditory, or other sensory modality)
•
Suicidality (including suicidal ideation and attempted suicide)
For either AESI, a specific AESI CRF page will be filled out at the time the investigator becomes 
aware of the event, including a brief narrative summary of the event. 
Additional AESIs may also be identified by the Medical Monitor. Significant AEs of particular 
clinical importance, other than SAEs, AESIs pre-specified above, and those AEs leading to 
discontinuation of a subject from the study, may also be classified at or by study’s end as AESIs. 
For each such AESI, additional information may be requested from the investigator so that a 
brief narrative of the event may be written and included in the Clinical Study Report. 
13.1.4. 
Assessment of Adverse Events 
The investigator should attempt to establish a diagnosis of the event based on the signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be documented 
as the AE (and SAE if serious) and not the individual signs/symptoms.  
13.1.5. 
Type of Adverse Events (AE, SAE, or AESI) 
An investigator must make the determination as to whether an AE qualifies as an SAE or an 
AESI. If an investigator is uncertain as to whether an SAE has occurred, the investigator should 
contact the Medical Monitor. 
13.1.6. 
Severity of Adverse Events 
The severity of each AE/SAE should be classified into one of three defined categories as 
follows: 
•
Mild:  there is awareness of a sign or symptom, but the AE is easily tolerated by the
subject, causes minimal discomfort, and does not interfere in a significant manner with
the subject’s normal functioning level or activities;
•
Moderate:  the AE is sufficiently uncomfortable to interfere with normal everyday
activities, but is not hazardous to health;
•
Severe:  the AE produces significant impairment of functioning or incapacitation, with
inability to perform normal activities, and is a definite hazard to the subject’s health.
These three categories are based on the investigator’s clinical judgment, which in turn depends 
on consideration of various factors such as the subject’s reports, the physician’s observations, 
and the physician’s prior experience. The severity of the AE should be recorded in the 
appropriate section on the AE page of the CRF. 
The evaluation of severity must be distinguished from the evaluation of “seriousness”; severity is 
a measure of intensity whereas seriousness is defined by the criteria under Section 13.1.6. A 
severe event might not meet the criteria for seriousness and a serious event might be evaluated as 
mild or moderate. For example, a subject might have a severe headache that does not require 
hospitalization and is consequently not serious; or a subject might have a mild myocardial 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
46 
infarction that requires hospitalization and is therefore serious. It is important to distinguish 
between serious and severe AEs.   
13.1.7. 
Relationship to Study Drug 
An investigator must make the determination of relationship to the investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If no 
valid reason exists for suggesting a relationship, then the AE should be classified as “not 
related.” If there is any valid reason, even if undetermined, for suspecting a possible cause-and-
effect relationship between the investigational product and the occurrence of the AE, then the AE 
should be considered “related.” 
The relationship or association of the AE/SAE to study drug will be characterized as “related” 
or “not related”. An AE/SAE will be considered to be not related to the use of the study drug if 
any of the following criteria are met: 
• An unreasonable temporal relationship between administration of the product and the 
onset on the AE (e.g., the event occurred either before, or too long after administration of 
the product for it to be considered product-related); 
• A causal relationship between the product and the AE is biologically implausible (e.g., 
death as a passenger in an automobile accident); 
• A clearly more likely alternative explanation for the AE is present (e.g., typical adverse 
reaction to a concomitant drug). 
Adverse events will be considered “related” to the use of the study drug if none of the “not 
related” criteria are met. 
The investigator will use clinical judgment to determine the relationship of the AE/SAE to study 
drug. An AE/SAE may be related to the study drug, other concomitant medications, intercurrent 
illness, a procedure performed in the course of the study, or another reason. Among the potential 
etiologies, the investigator should make a determination based on the most likely causal 
relationship. Alternative causes, such as the natural history of any underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the study 
drug should be considered. The investigator will also take into account the Investigator’s 
Brochure (or Prescribing Information, if applicable) in the causality assessment. 
There may be situations when an SAE has occurred and the investigator has minimal information 
to include in the initial report to the sponsor. However, it is very important that the investigator 
always makes an assessment of causality prior to transmission of the SAE report to the sponsor, 
as the causality assessment is one of the criteria used when determining regulatory reporting 
requirements. The investigator may change the causality assessment in light of follow-up 
information, by amending the SAE report accordingly. 
13.1.8. 
Follow-up of Adverse Events and Serious Adverse Events 
All AEs and SAEs must be followed until resolution (or return to baseline status), or until the 
condition stabilizes or is otherwise explained, or until the subject dies or is lost to follow-up. The 
investigator is responsible for ensuring that follow-up includes any supplemental investigations  

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
47 
as may be indicated to elucidate as completely as practical the nature and/or causality of the 
AE/SAE. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations. If a subject dies during participation in the study or during a 
recognized follow-up period, the investigator should provide the sponsor with a copy of any 
post-mortem findings, including histopathology. 
13.2. 
Recording Adverse Events 
13.2.1. 
Adverse Event Recording 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. Any AE (i.e., a new event or an exacerbation of a pre-existing condition) 
with an onset date after start of study drug administration up to and including the designated 
follow-up safety visit should be recorded as an AE on the CRF.  
Information about all AEs, including SAEs, that occur after a subject has been enrolled, whether 
before treatment, during treatment, or within 14 days following the cessation of treatment must 
be recorded. AEs occurring after a subject has begun study drug are designated as treatment-
emergent adverse events (TEAEs) to distinguish these from AEs occurring after enrollment, but 
before treatment. For the purposes of this trial, AEs occurring during the Single-Blind Placebo 
Rin-in Period will be recorded, but will not be considered TEAEs.   
All AEs must be recorded on the AE CRF regardless of the severity or relationship to study drug. 
It is important that investigators also report all AEs that result in permanent discontinuation of 
the study drug being studied, whether serious or non-serious. 
Out of range clinical laboratory findings (e.g., clinical chemistry, hematology) or findings on 
other assessments (e.g., electrocardiogram, X-rays, vital signs) per se are not reported as AEs. 
However, if the out of range finding is deemed clinically significant or is associated with signs 
and/or symptoms, the finding must be recorded as an AE (and additionally as an SAE if it meets 
the criteria of being serious; see Section 13.1.2), as described above. 
The investigator should exercise medical and scientific judgment in deciding whether an out of 
range clinical laboratory finding or finding on other assessment is clinically significant. Usually, 
the abnormality should be associated with a clinically evident sign or symptom, or be likely to 
result in an evident sign or symptom in the near term, in order to be considered clinically 
significant. A clinically significant laboratory abnormality in the absence of clinical symptoms 
may jeopardize the subject and may require intervention to prevent immediate consequences. For 
example, a markedly low serum glucose concentration may not be accompanied by coma or 
convulsions, yet be of a magnitude to require glucose administration to prevent such sequelae. 
For each AE, the investigator will evaluate and report the onset (date and time), resolution (date 
and time), intensity, causality, action taken, serious outcome (if applicable), and whether or not it 
caused the subject to discontinue the study. 
Pregnancy is not an AE; should a pregnancy occur, it must be recorded on a separate pregnancy 
form and reported as detailed below.   

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
48 
13.2.2. 
Serious Adverse Event Recording 
If an AE is determined to be an SAE, in addition to recording the appropriate information on the 
AE CRF page, the information will also be recorded on an SAE CRF page. Additionally, the 
basis for determining an AE to be an SAE will be recorded on the SAE CRF. A brief narrative of 
the SAE must be provided in the allocated section of the SAE CRF page. Follow-up information 
regarding the SAE, as it becomes available, will also be recorded on the SAE CRF page(s).  
13.2.3. 
Adverse Event of Special Interest Recording 
If an AE is determined to be an AESI, in addition to recording the appropriate information on the 
AE CRF page, the information will also be recorded on the appropriate AESI CRF page. Specific 
questions pertaining to the AESI will be answered on the AESI CRF page. A brief narrative of 
the AESI must be provided in the allocated section of the AESI CRF page. Follow-up 
information regarding the AESI, as it becomes available, will also be recorded on the AESI CRF 
page(s).  
13.3. 
Reporting Adverse Events 
The sponsor has requirements for reporting SAEs to both the local regulatory authority and other 
regulatory agencies regarding the safety of a drug under clinical investigation. The sponsor or 
designee must be notified within 24 hours once the investigator determines that an AE meets the 
protocol definition of an SAE. The procedures for reporting serious adverse events are as 
follows: 
• Complete the “Serious Adverse Event Report”; 
• Contact the pharmacovigilance staff member identified on the SAE Report Form and 
report the Serious Adverse Event within 24 hours of the investigator’s knowledge of the 
event; 
• For fatal or life-threatening events, also fax copies of hospital case reports, autopsy 
reports, and other documents when requested and applicable. 
The investigator must verify the accuracy of the information recorded on the SAE pages with the 
corresponding source documents, and complete, sign and date the SAE pages. 
The sponsor or designee may request additional information from the investigator to ensure the 
timely completion of accurate safety reports. 
Any fatal or life-threatening events should also be reported immediately by telephone to the 
sponsor’s designee. 
The investigator, or responsible person according to local requirements, must comply with the 
applicable local regulatory requirements concerning the reporting of SAEs to all applicable 
regulatory authorities and IRBs. Investigators will also be notified of all unexpected, serious, 
drug-related events (7/15 Day Safety Reports) that occur during the clinical trial. Each site is 
responsible for notifying its IRB or IEC of these additional SAEs. 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
49 
13.3.1. 
Investigator Reporting Requirements 
When an investigative site receives an initial or follow-up notification of an SAE or other safety 
information (e.g., revised Investigator’s Brochure) from the sponsor, the responsible person, 
according to local requirements, must submit this information to the local IRB and keep a copy 
in their files. 
13.3.2. 
Post-Study Reporting Responsibility 
All SAEs, regardless of cause or relationship, which occur from the time of study drug 
administration up to and including the safety follow-up visit, must be reported to the sponsor or 
designee. If the investigator learns at any time after a subject has been discharged from the study 
of an untoward medical occurrence that would have qualified as an SAE during the study, and 
such event is reasonably related to previous study drug exposure, the investigator should 
promptly notify the sponsor or designee. 
13.3.3. 
Pregnancy 
A pregnancy is not an AE. If a subject becomes pregnant while enrolled in the study following 
administration of study drug, the sponsor or designee must be notified within 24 hours of the 
investigator learning of the pregnancy. Administration of study drug will be discontinued 
immediately and the subject will be followed through the outcome of the pregnancy. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. If pregnancy occurs in a female partner of a male subject, they will 
be asked to be consented to obtain additional information regarding the pregnancy.  The 
investigator will be required to complete a Pregnancy Information Form and fax the information 
to the sponsor or designee. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
50 
14. 
STATISTICS 
14.1. 
Primary Efficacy Endpoint and Sample Size Determination 
The primary efficacy endpoint is the proportion of responders in each treatment group (see 
definition details below).  
Based on the results from the Phase 2 study, responder rates of 24% and 33% were observed at 
Week 4 for subjects treated with placebo and 274 mg ADS-5102, respectively, in the modified 
intent-to-treat (MITT) analysis set. In the present study, it is anticipated that the placebo response 
rate at Week 16 will be no greater than 20% and the response rate among subjects treated with 
274 mg or 137 mg ADS-5102 will be at least 33%. Using these estimates, 180 randomized 
subjects per active treatment group and placebo group will be needed for the test of differences 
in proportions (Farrington-Manning approach for the Miettimen-Nurminen [MN] test) to have 
80% power at the 2-sided 5% significance level to detect this 13% difference favoring 
ADS-5102. Assuming a 5% dropout rate during the 4-week Single-Blind Placebo Run-In Period, 
570 subjects will be enrolled in the study to randomize 540. 
For this sample size of 180 randomized subjects per group, power will be at least 80% to detect 
treatment differences (ADS-5102 versus placebo) of -2.7 seconds and 5.0 meters in the changes 
from baseline at Week 16 in the TUG test and 2MWT when the standard deviation of the 
changes from baseline is no greater than 6.0 sec and 14.9 meters, respectively, and the dropout 
rate is not greater than 20%.  
14.2. 
Analysis Sets 
The safety analysis set will include all randomized subjects who receive at least one dose of 
double-blind study drug and will be analyzed according to the treatment actually received. 
The intent-to-treat (ITT) analysis set will include all randomized subjects who receive at least 
one dose of study drug, and will be analyzed according to the randomized treatment assignment. 
This population will be used for the efficacy analyses including the analyses of primary and key 
secondary endpoints. 
The per-protocol (PP) analysis set will include all randomized and dosed subjects who provide 
Week 16 efficacy data and do not have any major protocol deviations that could confound this 
assessment. This population will also be used for efficacy analyses. 
14.3. 
Handling of Missing Data 
This will be described in the statistical analysis plan. 
14.4. 
Efficacy Analyses 
14.4.1. 
Primary Efficacy Analyses 
The primary efficacy endpoint is the proportion of responders in the 274 mg ADS-5102 
treatment group relative to the placebo group, where a responder is defined as a subject who has 
a ≥ 20% increase from Baseline to Week 16 in walking speed measured using the T25FW 
(average of two measurements 5 minutes apart). This analysis will be done using the ITT 
analyses set. Subjects who fail to have an increase of at least 20% at Week 16 in the T25FW 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
51 
(feet/seconds) will be considered non-responders. Subjects who do not have an observation at 
Week 16 for whatever reason will be considered to have an indeterminate outcome and will also 
be included in the denominators, effectively counting them as non-responders for the purpose of 
treatment comparisons. However, tabulations of each response category will be provided. For 
this endpoint, baseline will be defined as the average walking speed (feet/seconds) from the 
T25FW at Weeks 0 and 2 (prior to randomization).  
The objective of the primary efficacy analysis is to test for superiority of the 274 mg ADS-5102 
group compared to the placebo group in terms of the difference (active minus placebo) in the 
proportion of responders at Week 16 using the ITT analysis set. This test of proportions will be 
done using the MN test at the 2-sided 5% level. Both the 2-sided p-value and the 95% confidence 
interval (CI) for the difference will be obtained. Superiority will be concluded if the lower limit 
of the 95% CI is greater than zero (equivalently 2-sided p-value < 0.05).  
14.4.2. 
Key Secondary Efficacy Analyses 
Provided superiority of 274 mg ADS-5102 versus placebo is shown in the primary analysis, the 
key secondary objectives will be evaluated using a gatekeeping strategy to control the overall 
Type I error rate at 5%. Using this approach, the following research hypotheses will be evaluated 
sequentially in the order given using the ITT analyses set: (1) superiority of 274 mg ADS-5102 
compared to placebo in mean change from baseline at Week 16 in the T25FW (feet/second) test; 
(2) superiority of 274 mg ADS-5102 compared to placebo in mean change from baseline at 
Week 16 in the TUG (sec) test; (3) superiority of 274 mg ADS-5102 compared to placebo in 
mean change from baseline at Week 16 in the 2MWT (m); (4) superiority of 137 mg ADS-5102 
compared to placebo in terms of the proportion of T25FW responders at Week 16; (5) superiority 
of 137 mg ADS-5102 compared to placebo in mean change from baseline at Week 16 in the 
T25FW (feet/second) test; (6) superiority of 137 mg ADS-5102 compared to placebo in mean 
change from baseline at Week 16 in the TUG test; and (7) superiority of 137 mg ADS-5102 
compared to placebo in mean change from baseline at Week 16 in the 2MWT. For each 
hypothesis, if a non-significant result (p > 0.05) is obtained, no further inferential conclusions 
will be drawn and any statistically significant result will be declared supportive of efficacy only. 
The test of superiority of 137 mg ADS-5102 versus placebo in terms of the proportion of 
responders at Week 16 will be done using the same approach as for the primary analyses.  
The tests of superiority of 274 mg ADS-5102 and of 137 mg ADS-5102 versus placebo in terms 
of the mean change from baseline in the T25FW, TUG test, and the 2MWT will be done using 
t-tests derived from the corresponding linear mixed model with repeated measurement (MMRM) 
model with the change from baseline (i.e., T25FW, TUG, or 2MWT) as the dependent variable 
and fixed effects of treatment group, study week, and treatment by study week interaction. The 
baseline value will be included as a covariate and an unstructured variance-covariance matrix 
will be used for the within-subject residual variability. For the T25FW, TUG test, and the 
2MWT, baseline will be the average of Weeks 0 and 2 (prior to randomization).  
14.4.3. 
Secondary Supportive Analyses 
Each active dose will be compared to placebo in terms of the mean change from baseline at each 
study visit in the T25FW, TUG test, and the 2MWT. These analyses will be done using the 
MMRM model described earlier. The T25FW (sec) will be evaluated in a similar manner.  

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
52 
For the MSWS-12, the research hypothesis of superiority of 274 mg ADS-5102 compared to 
placebo in the mean changes from baseline at Week 16 will be evaluated using the pooled 
Phase 3 studies. Similar evaluations will be done for 137 mg ADS-5102. Details of these 
analyses will be provided in the SAP for the Integrated Summaries of Efficacy (ISE). 
14.5. 
Safety and Tolerability 
Adverse events will be recorded starting from the date/time of first dose during the Single-Blind 
Placebo Run-In Period through the EOS Visit. The time periods of AE recording will be divided 
into AEs with onset during the Single-Blind Placebo Run-In Period and AEs during the Double-
Blind Treatment Period (i.e., TEAEs). All AEs will be listed by subject and period. 
For AEs during double-blind treatment, standard incidence rates will be summarized by 
treatment group, system organ class (SOC) and preferred term (PT) within SOC in the safety 
analysis set. This includes all subjects who received at least one dose of double-blind study drug 
according to the treatment arm actually received. 
Incidence of TEAEs will be summarized for:  
• All TEAEs 
• Investigator-determined treatment-related TEAEs 
• TEAEs leading to drug discontinuation 
• TEAEs by severity 
• Serious TEAEs (SAEs) 
• Investigator- determined treatment-related SAEs 
• Discontinuation due to SAEs  
Clinical laboratory test parameters will be listed for individual subjects and values outside of the 
reference ranges will be flagged. Descriptive statistics for the mean and mean changes from 
baseline at each study week will be generated by treatment group. The incidence of potentially 
clinically significant changes in laboratory parameters will be tabulated by treatment group. Vital 
signs measurements at each timepoint will be listed by subject. The incidence of potentially 
clinically significant changes at each study visit will be summarized. 
Descriptive statistics for the mean and mean changes in the C-SSRS will be generated by 
treatment group and visit. Results will also be depicted graphically. 
14.6. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics (age at screening, gender, weight, height, BMI, race, 
ethnicity, medical history, physical examination) will be listed for individual subjects and will be 
summarized by treatment group. Demographic data and key baseline characteristics will be 
summarized for the safety population. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
53 
14.7. 
Prior and Concomitant Medications 
All prior and concomitant medications will be assigned a generic name and a drug class based on 
the World Health Organization (WHO) Dictionary. Prior and concomitant medications will be 
listed and summarized by treatment group. 
14.8. 
Completion of the Study and Withdrawals 
Withdrawals and the reason for withdrawal will be tabulated by treatment group. The number 
and percentage of subjects who complete the study will be summarized by treatment group. The 
number and percentage of subjects who withdraw from the study will be tabulated by original 
treatment group and last treatment taken at time of withdrawal. Study drug discontinuations will 
be summarized in a similar fashion. 
14.9. 
Protocol Deviations 
Significant protocol deviations will be listed and categorized (for example, deviations related to 
entry criteria, dosing, prohibited concomitant medications, other). 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
54 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Sponsor representatives and regulatory authority inspectors are responsible for contacting and 
visiting the investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the study (e.g., CRFs and other pertinent data), provided that subject 
confidentiality is respected. 
The study monitor is responsible for inspecting the CRFs at regular intervals throughout the 
study to verify the following: adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research. The monitor 
should have access to subject medical records and other study-related records needed to verify 
the entries on the CRFs. The investigator must agree to cooperate with the monitor to ensure that 
any problems detected in the course of these monitoring visits are resolved. 
15.2. 
Audits and Inspections 
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee, or an Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification. The purpose of the sponsor audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP) guidelines of the 
International Council on Harmonization (ICH), and any applicable regulatory requirements.  
In accordance with ICH GCP and the sponsor audit plans, this study may be selected for an 
audit. Inspection of All site facilities (e.g., pharmacy, drug storage areas, laboratories) and study-
related records contained within these facilities are subject to inspection during an audit.  
The investigator should contact the sponsor immediately if contacted by a regulatory agency 
about an inspection. 
15.3. 
Subject Confidentiality 
The investigator must ensure that each subject’s anonymity is maintained. Subjects will be 
identified by a unique Subject Identification Number. Study related documents should be kept in 
strict confidence by the investigator in compliance with applicable regulations and ICH GCP 
Guidelines. The investigator and Institution must permit authorized representatives of regulatory 
agencies, and the IRB/research ethics board (REB)/independent ethics committee (IEC) direct 
access to review the subject’s original medical records for verification of study-related 
procedures and data. Direct access includes examining, analyzing, verifying, and reproducing 
any records and reports that are needed for the evaluation of the study. The investigator is 
obligated to inform the subject in the ICF that the above-named representatives may review 
study-related records from subjects. 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
55 
15.4. 
Case Report Forms 
Electronic CRFs will be completed for each enrolled subject. The participants of the study will 
not be identified by name on any study documents to be collected by the sponsor or designee. 
The PI is required to review and sign-off on all eCRFs. The sign-off is done by an electronic 
signature within the EDC system. Also, a CD of all site specific subject data (including PI 
approval, audit history, and discrepancies) will be sent to each site that has subject data in the 
system for archival purposes. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
56 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. Please see Section 15.2 for more details regarding the audit 
process. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
57 
17. 
ETHICS 
17.1. 
Ethics Review 
The PI must obtain IRB/REB/IEC approval for the investigation. Initial IRB/REB/IEC approval, 
and all materials approved by the IRB/REB/IEC for this study including the ICF and recruitment 
materials must be maintained by the investigator and made available for inspection. 
This study will be conducted in accordance with the US Code of Federal Regulations (CFR) 
governing the protection of human subjects (21 CFR 50), IRB/REB/IEC (21 CFR 56), the 
obligations of clinical investigators (21 CFR 312), and ICH GCP guidelines. 
The sponsor expects the PI to comply with local IRB/REB/IEC requirements. The investigator 
will also comply with current standards of GCP, particularly in reference to the safety and rights 
of the subjects. Investigators are encouraged to discuss any ethical issues that arise prior to or 
during the conduct of the study with the sponsor. 
The PI at the site is responsible for obtaining IRB/REB/IEC approval for the final protocol, 
sponsor-approved ICF, and any advertisements to recruit subjects. Written approval of these 
documents must be obtained from the IRB/REB/IEC before any subject is enrolled at a site. 
The PI is also responsible for the following interactions with the IRB/REB/IEC: 
• Obtaining IRB approval for any protocol amendments and ICF revisions before 
implementing the changes; 
• Providing the IRB/REB/IEC with any required information before or during the 
study; 
• Submitting progress reports to the IRB/REB/IEC, as required, during the conduct of 
the study; requesting re-review and approval of the study, as needed; providing copies 
of all IRB/REB/IEC re-approvals and relevant communication to the sponsor; 
• Notifying the IRB/REB/IEC of all serious and unexpected adverse events related to 
the study drug reported by the sponsor, as required. 
17.2. 
Ethical Conduct of the Study 
This study will be conducted in compliance with GCP according to the ICH guidelines (Topic 
E6: Guideline for Good Clinical Practice), US Code of Federal Regulations (21 CFR), and local 
ethical and legal requirements that are consistent with the most current version of the Declaration 
of Helsinki. 
17.3. 
Written Informed Consent 
The sponsor must review the draft ICF prior to submission to the IRB/REB/IEC for approval. An 
IRB/REB/IEC -approved copy of the ICF will be forwarded to the sponsor or designee. 
Written informed consent will be obtained from all study subjects prior to any tests or 
evaluations. The contents and process of obtaining informed consent will be in accordance with 
all applicable regulatory requirements.  
The ICF documents the study-specific information the investigator provides to the subject and 
the subject’s agreement to participate. Among other things, the investigator or designee will fully 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
58 
explain in layman’s terms the nature of the study, along with the aims, methods, potential risks, 
and any discomfort that participation may entail, as well as insurance and other procedures for 
compensation in case of injury. It will be explained that the study is for research purposes only 
and may not provide any therapeutic benefit to the individual. The investigator must also explain 
to the volunteers that they are completely free to refuse to enter the study or to withdraw from it 
at any time without prejudice. Each subject will acknowledge receipt of this information by 
giving written informed consent for participation in the study. 
Each subject must sign and date the ICF before any study-related procedures are performed. 
When a protocol amendment (see Section 17.4) substantially alters the study design or the 
potential risks or burden to subjects, the ICF will be amended and approved by the 
IRB/REB/IEC, and all active subjects will again provide informed consent. The original and any 
amended signed and dated ICF(s) must be retained in the subject’s file at the study site and a 
copy must be given to the subject. 
The ICF must comply with all applicable US Code of Federal Regulations (21 CFR 50), and ICH 
GCP guidelines. It should also include any additional information required by local laws relating 
to institutional review. A statement that subject medical records must be available for 
investigations into SAEs must be included in the ICF. It should also include any additional 
information required by local laws relating to institutional review. 
17.4. 
Changes in the Conduct of the Study or Planned Analyses 
Only the sponsor may modify the protocol. Any change in study conduct considered necessary 
by the investigator will be made only after consultation with the sponsor, who will then issue a 
formal protocol amendment to implement the change. The only exception is when the 
investigator considers that a subject’s safety is compromised without immediate action. The 
investigator should inform the sponsor and the IRB/REB/IEC within one working day after the 
emergency occurred. With the exception of minor administrative or typographical changes, all 
amendments must be reviewed and approved by the IRB/REB/IEC in accordance with 
IRB/REB/IEC requirements. Amendments that have an impact on subject risk or the study 
objectives, or require revision of the ICF, must receive approval from the IRB/REB/IEC prior to 
their implementation. The investigator must send a copy of the approval letter for protocol 
amendments and changes to the ICF from the IRB/REB/IEC to the sponsor. 
17.5. 
Emergency Contact with Investigator 
Suitable arrangements will be made for subjects to make contact with the PI or a medically 
qualified sub-investigator in the event of an emergency during the study. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
59 
18. 
DATA HANDLING AND RECORDKEEPING 
The investigator must make study data accessible to the monitor, other authorized representatives 
of the sponsor, and Regulatory Agency inspectors upon request. A file for each subject must be 
maintained that includes the signed ICF and the investigator’s copies of all source documentation 
related to that subject. The investigator must ensure the reliability and availability of source 
documents from which the information on the CRF was derived. 
Investigators are required to maintain all study documentation, including copies of CRFs, ICFs, 
and adequate records for the receipt and disposition of all study drugs, for a period of 2 years 
following the FDA or other regulatory approval date of the drug, or until 2 years after the drug 
investigational program is discontinued, unless a longer period is required by applicable law or 
regulation. The investigator must not discard any records unless given authorization by the 
sponsor. 
Subject identity information will be maintained for 15 years unless applicable law or regulation 
requires a longer period. 
18.1. 
Inspection of Records 
Adamas will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
18.2. 
Retention of Records 
The PI must maintain all documentation relating to the study for a period of 2 years after the last 
marketing application approval (or for the duration specified by the IRB/REB/IEC or local 
Regulatory Authority, whichever is longer), or if not approved 2 years following the 
discontinuance of the test article for investigation (or for the duration specified by the 
IRB/REB/IEC or local Regulatory Authority, whichever is longer). If it becomes necessary for 
Adamas or the Regulatory Authority to review any documentation relating to the study, the 
investigator must permit access to such records. In the event that an investigator becomes unable 
to comply he/she must notify the Sponsor immediately, so that arrangements to store the records 
appropriately elsewhere can be made. 
19. 
INFORMATION DISCLOSURE AND INVENTIONS 
19.1. 
Ownership 
All information provided by Adamas Pharmaceuticals, Inc. and all data and information 
generated by the site as part of the study (other than a subject’s medical records) are the sole 
property of Adamas Pharmaceuticals, Inc. 
All rights, title and interests in any inventions, know-how or other intellectual or industrial 
property rights that are conceived or reduced to practice by site staff during the course of or as a 
result of the study are the sole property of Adamas Pharmaceuticals, Inc. and are hereby assigned 
to Adamas Pharmaceuticals, Inc. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
60 
If a written contract for the conduct of the study is executed between Adamas Pharmaceuticals, 
Inc. and a study site and includes ownership provisions that are inconsistent with this section of 
the protocol that contract’s ownership provisions shall apply rather than this statement. 
19.2. 
Confidentiality 
All information provided by Adamas Pharmaceuticals, Inc. and all data and information 
generated by the site as part of the study, other than a subject’s medical records, will be kept 
confidential by the investigator and other site staff. The investigator or other site personnel will 
not use this information and data for any purpose other than conducting the study. These 
restrictions do not apply to: 
• Information that becomes publicly available through no fault of the investigator or site 
staff 
• Information that it is necessary to disclose in confidence to an IRB solely for the 
evaluation of the study 
• Information that it is necessary to disclose to provide appropriate medical care to a study 
subject 
• Study results that may be published as described in Section 20 
If a written contract for the conduct of the study that includes confidentiality provisions 
inconsistent with this statement is executed, that contract’s confidentiality provisions shall apply 
rather than this statement. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
61 
20. 
PUBLICATION POLICY 
Adamas intends to work with its investigators to rapidly publish the results of this study. No 
publication of the results shall take place without Adamas Pharmaceuticals, Inc.’s express 
consent. Prior to submitting for any publication, presentation, use for instructional purposes, or 
otherwise disclosing the study results generated by the site (collectively, a “Publication”), the 
investigator shall provide Adamas Pharmaceuticals, Inc. with a copy of the proposed Publication 
and allow Adamas Pharmaceuticals, Inc. a period of at least thirty (30) days (or for abstracts, at 
least five [5] working days) to review the proposed Publication. Proposed publications shall not 
include Adamas Pharmaceuticals, Inc.’s confidential information. 
At Adamas Pharmaceuticals, Inc.’s request, the submission or other disclosure of a proposed 
Publication will be delayed a sufficient time to allow Adamas Pharmaceuticals, Inc. to seek 
patent or similar protection of any inventions, know how, or other intellectual or industrial 
property rights disclosed in the proposed Publication. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
62 
21. 
LIST OF REFERENCES 
Albuquerque E, Eldefrawi A, Eldefrawi M, Mansour N, Cheng-Ming T. Amantadine: 
neuromuscular blockade by suppression of ionic conductance of the acetylcholine receptor. 
Science. 1978; 199(4330): 788-790. 
Ampyra [package insert]. Ardsley, NY: Acorda Therapeutics, Inc.; 2017. 
Aoki F, Sitar D. Clinical pharmacokinetics of amantadine hydrochloride. ClinPharmacokinet. 
1988; 14(1): 35-51. 
Ashtari F, Fatehi F, Shaygannejad V, Chitsaz A. Does amantadine have favourable effects on 
fatigue in Persian patients suffering from multiple sclerosis? Neurol Neurochir Pol. 2009; 43(5): 
428-432. 
Berger JR. Functional improvement and symptom management in multiple sclerosis: clinical 
efficacy of current therapies. Am J Manag Care. 2011;17 Suppl 5 Improving: S146-S153.  
Bresink I, Danysz W, Parsons CG, Mutschler E. Different binding affinities of NMDA receptor 
channel blockers in various brain regions--indication of NMDA receptor heterogeneity. 
Neuropharmacology. 1995; 34(5): 533-540. 
Canadian MS Research Group. A randomized controlled trial of amantadine in fatigue associated 
with Multiple Sclerosis. Can J Neurol Sci. 1987;14(3): 273-278.  
Chiba S, Ito M, Matsumoto H. Amantadine treatment for refractory pain and fatigue in patients 
with multiple sclerosis. Can J Neurol Sci. 1992; 19(2): 309.  
Danysz W, Parsons C, Kornhuber J, Schmidt W, Quack G. Aminoadamantanes as NMDA 
receptor antagonists and antiparkinsonian agents- preclinical studies. Neurosci Biobehav Rev. 
1997; 21(4): 455-468. 
Dilokthornsakul P, Valuck RJ, Nair KV, Corboy JR, Allen RR, Campbell JD. Multiple sclerosis 
prevalence in the United States commercially insured population. Neurology. 2016; 86(11): 
1014-21. 
Goodman AD, Brown TR, Edwards KR, Krupp LB, Schapiro RT, Cohen R, Marinucci LN, 
Blight AR; MSF204 Investigators. A phase 3 trial of extended release oral dalfampridine in 
multiple sclerosis. Ann Neurol. 2010; 68(4): 494-502.  
Goodman AD, Brown TR, Krupp LB, Schapiro RT, Schwid SR, Cohen R, Marinucci LN, Blight 
AR, Fampridine MS-F203 Invstigators. Sustained-release oral fampridine in multiple sclerosis: a 
randomised, double-blind, controlled trial. Lancet. 2009; 373: 732-738. 
Hayden F, Gwaltney J, Van De Castle R, Adams K, Giordani B. Comparative toxicity of 
amantadine hydrochloride and rimantadine hydrochloride in healthy adults. Antimicrob Agents 
Chemother. 1981; 19(2): 226-233. 
Hobart J, Ziemssen T, Feys P, et al. Prolonged-release fampridine induces sustained clinically 
meaningful improvements in walking ability in people with multiple sclerosis: results from the 
ENHANCE trial (P6.364). Neurology. 2017; 88. 
Jackson G, Stanley E, Lee Muldoon R. Chemoprophylaxis of viral respiratory diseases. Bulletin 
Pan Am Health Org. 1967; 147: 595-603. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
63 
Kantarci O, Wingerchuk D. Epidemiology and natural history of multiple sclerosis: new insights. 
Curr Opin Neurol. 2006; 19(3): 248-254. 
Kornhuber J, Bormann J, Hubers M, Rusche K, Riederer P. Effects of the 1-amino-adamantanes 
at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem 
brain study. Eur J Pharmacol. 1991; 206: 297-300. 
Korsen M, Kunz R, Schminke U, Runge U, Kohlmann T, Dressel A. Dalfampridine effects on 
cognition, fatigue, and dexterity. Brain Behav. 2016; 7(1): e00559. 
Krupp LB, Coyle PK, Doscher C, Miller A, Cross AH, Jandorf L, Halper J, Johnson B, Morgante 
L, Grimson R. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, 
parallel trial of amantadine, pemoline, and placebo. Neurology. 1995; 45(11): 1956-1961. 
McEvoy JP, McCue M, Spring B, Mohs RC, Lavori PW, Farr RM. Effects of amantadine and 
trihexyphenidyl on memory in elderly normal volunteers. Am J Psychiatry. 1987 
May;144(5):573-7. 
Murray TJ. Amantadine therapy for fatigue in multiple sclerosis. Can J Neurol Sci. 1985 
Aug;12(3):251-4. PubMed PMID: 3902184. 
Northover BJ. Effect of pre-treating rat atria with potassium channel blocking drugs on the 
electrical and mechanical responses to phenylephrine. Biochem Pharmacol. 1994; 47(12): 
2163-2169. 
Ossola B, Schendzielorz N, Chen S, Bird G, Ruominen R, Mannisto P, Hong J. Amantadine 
protects dopanine neurons by a dual action: reducing activation of microglia and inducing 
expression of GNDF in astroglia. Neurology. 2011; 61: 574-582. 
Pahwa R, Tanner CM, Hauser RA, Isaacson SH, Nausieda PA, Truong DD, Agarwal P, Hull KL, 
Lyons KE, Johnson R, Stempien MJ. ADS-5102 (amantadine) extended-release capsules for 
levodopa-induced dyskinesia in Parkinson disease (EASE LID Study): a randomized clinical 
trial. JAMA Neurol. 2017; 74(8): 941-949.  
Pahwa R, Tanner CT, Hauser RA, Sethi K, Isaacson S, Truong D, Struck L, Ruby AE, McClure 
NL, Went GT, Stempien MJ. Amantadine extended release for levodopa-induced dyskinesia in 
Parkinson’s diease (EASED Study). Mov Disord. 2015; 30: 788-795. 
Parsons CG, Panchenko VA, Pinchenko VO, Tsyndrenko AY, Krishtal OA. Comparative 
patch-clamp studies with freshly dissociated rat hippocampal and striatal neurons on the NMDA 
receptor antagonistic effects of amantadine and memantine. Eur J Neurosci. 1995; 8: 446-454. 
Parsons CG, Quack G, Bresink I, Baran L, Przegalinski E, Kostowski W, Krzascik P, Hartmann 
S, Danysz W. Comparison of the potency, kinetics and voltage-dependency of a series of 
uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment 
activity in vivo. Neuropharmacology. 1996; 34(10): 1239-1258. 
Prugger M, Berger T. Assessing the long-term clinical benefit of prolonged-release fampridine 
tablets in a real-world setting: a review of 67 cases. Patient Relat Outcome Meas. 2013; 4: 75-85.  
Rosenberg GA, Appenzeller O. Amantadine, fatigue, and multiple sclerosis. Arch Neurol. 1988 
Oct;45(10):1104-6. 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
64 
Ruck T, Bittner S, Simon OJ, Göbel K, Wiendl H, Schilling M, Meuth SG. Long-term effects of 
dalfampridine in patients with multiple sclerosis. J Neurol Sci. 2014; 337(1-2): 18-24.  
Schumacher GA. Multiple sclerosis. J Am Med Assoc. 1950; 143(12): 1059-1065. 
Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, 
Filippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L, Lublin FD, Marrie 
RA, Miller AE, Miller DH, Montalban X, Mowry EM, Sorensen PS, Tintoré M, Traboulsee AL, 
Trojano M, Uitdehaag BMJ, Vukusic S, Waubant E, Weinshenker BG, Reingold SC, Cohen JA. 
Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2017 
Dec 21. pii: S1474-4422(17)30470-2 published online. 
Wallin MT. The prevalence of multiple sclerosis in the United States: a population-based 
healthcare database approach. 2017 ECTRIMS Abstract P344.  
Wang T, Huang X, Van K, Went T, Nguyen J, Lieth B. Amantadine improved cognitive 
outcome and increases neuronal survival after fluid percussion traumatic brain injury in rats. 
J Neurotrauma. 2014; 31(4): 370-377.  
Wesemann W, Dette-Wildenhahn G, Fellehner G. In vitro studies on the possible effects of 
1-aminoadamantanes on the serotonergic system in M. Parkinson. J Neural Transm. 1979; 44: 
263-285. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
65 
22. 
APPENDICES 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
66 
APPENDIX A. SCHEDULE OF EVENTS 
 
Screening 
Single-
Blind 
Placebo 
Run-In 
Period d 
Double Blind Treatment 
Perioda (±2 day) d 
 
Safety 
Follow-
Upb 
 (±2 day) 
Early 
Termination 
Baseline 
Maintenance  
Visit 
1 
2 
3  
4 
5 
6 
7 
8 
9 
 
Week 
 
0 
2 
4 
6 
8 
12 
16 
18 
 
Informed consent 
✓ 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
 
 
Demographics 
✓ 
 
 
 
 
 
 
 
 
 
Medical history  
✓ 
 
 
 
 
 
 
 
 
 
Medication history  
✓ 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Adverse events  
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Complete physical 
exam  
✓ 
 
 
 
 
 
 
✓ 
 
✓ 
Symptom-directed 
physical exam, as 
needed  
 
 
 
✓ 
 
✓ 
✓ 
 
✓ 
 
Height 
✓ 
 
 
 
 
 
 
 
 
 
Weight 
✓ 
 
 
 
 
 
 
✓ 
 
✓ 
Vital signs  
✓ 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Hematology  
✓ 
 
 
 
 
 
 
✓ 
 
✓ 
Serum chemistry  
✓ 
 
 
 
 
 
 
✓ 
 
✓ 
Urinalysis  
✓ 
 
 
 
 
 
 
✓ 
 
✓ 
ECG (12-lead) 
✓ 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
(if applicable) 
✓ 
 
 
 
 
 
 
✓ 
✓ 
✓ 
Urine pregnancy test (if 
applicable) 
 
✓ 
✓ 
✓ 
 
 
 
 
 
 
Expanded Disability 
Status Scale (EDSS) 
✓ 
 
 
 
 
 
 
 
 
 
Timed 25-Foot Walk 
(T25FW)c 
✓ 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Multiple Sclerosis 
Walking Scale-12 
(MSWS-12)c 
 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Timed Up and Go 
(TUG)c 
 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
2-Minute Walk Test 
(2MWT)c 
 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Columbia-Suicide 
Severity Rating Scale 
(C-SSRS) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Randomization 
 
 
 
✓ 
 
 
 
 
 
 
Collect returned study 
drug & assess 
compliance 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
✓ 
Dispense study drug  
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
Study drug dosing, 
once daily at bedtime  
 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
 
✓ 
 
 
a In addition, telephone visits will be conducted at Weeks 5 and 7 to review dosing instructions and assess and record 
AEs and any changes in concomitant medications. 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
67 
b For subjects who elect not to enter the open-label extension study 
c Efficacy assessments include Multiple Sclerosis Walking Scale-12 (MSWS-12), Timed 25-Foot Walk (T25FW), 
Timed Up and Go (TUG), and 2-Minute Walk Test (2MWT), to be performed in that order 
d  Study visits should occur on the day scheduled. There is a (+/-) 2 day of the visit window from Visit 3 through 
Visit 18. 
 
 
 

Protocol ADS-AMT-MS301 
Adamas Pharmaceuticals, Inc. 
28 February 2018 
            Confidential and Proprietary 
68 
APPENDIX B. STUDY DESIGN SCHEMATIC 
 

 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
Adamas Pharmaceuticals, Inc. 
 
ADS-AMT-MS301 
 
A 3-ARM, MULTICENTER, DOUBLE-BLIND, PLACEBO-
CONTROLLED, RANDOMIZED STUDY TO ASSESS THE EFFICACY 
AND SAFETY OF ADS-5102 AMANTADINE EXTENDED RELEASE 
CAPSULES IN MULTIPLE SCLEROSIS PATIENTS WITH WALKING 
IMPAIRMENT 
 
05Dec2019 
 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Prepared by: 
 
PPD On Behalf of 
Adamas Pharmaceuticals, Inc. 
1900 Powell Street, Suite 1000 
Emeryville, CA 94608 
 
 
 
 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
II 
 
 
 
 
 
 
 
 
 
Issued by: 
_____________________________           Date: __/__/____ 
 
Ian Robinson, MPH 
 
Lead Biostatistician, Biostatistics 
 
PPD 
 
 
 
Approved by: 
_____________________________ Date: __/__/____ 
 
Rajiv Patni, MD 
 
Chief Medical Officer 
 
Adamas Pharmaceuticals, Inc. 
 
 
 
Approved by: 
_____________________________ Date: __/__/____ 
 
Lily Llorens, PhD 
 
Biostatistician, consultant 
 
Adamas Pharmaceuticals, Inc. 
 
 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3
12/5/2019 | 3:53:37 PM PST
12/5/2019 | 3:53:37 PM PST

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
III 
 
 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... VI 
1. 
INTRODUCTION ............................................................................................................ 1 
2. 
OBJECTIVES ................................................................................................................... 1 
2.1. PRIMARY ............................................................................................................................ 1 
2.2. SECONDARY ....................................................................................................................... 1 
2.2.1. 
Key ........................................................................................................................... 1 
2.2.2. 
Supportive ................................................................................................................ 1 
2.2.3. 
Safety ....................................................................................................................... 1 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 2 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 2 
3.2. STUDY ENDPOINTS ............................................................................................................. 3 
3.2.1. 
PRIMARY ......................................................................................................................... 3 
3.2.2. 
SECONDARY .................................................................................................................... 3 
3.2.2.1. 
KEY ............................................................................................................................. 3 
3.2.2.2. 
SUPPORTIVE ................................................................................................................. 3 
3.2.2.3. 
SAFETY ........................................................................................................................ 4 
4. 
TREATMENTS ................................................................................................................ 4 
4.1. DOSE ADJUSTMENT/MODIFICATIONS ................................................................................. 4 
5. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 5 
5.1. RANDOMIZATION, STRATIFICATION, AND BLINDING .......................................................... 5 
5.2. SAMPLE SIZE ...................................................................................................................... 5 
5.3. ANALYSIS SET .................................................................................................................... 6 
5.3.1. 
All Enrolled.............................................................................................................. 6 
5.3.2. 
Intent-to-Treat (ITT) Set .......................................................................................... 6 
5.3.3. 
Per Protocol (PP) Set .............................................................................................. 6 
5.3.4. 
Safety Set.................................................................................................................. 6 
5.4. BASELINE ........................................................................................................................... 6 
5.5. STUDY COMPLETION .......................................................................................................... 7 
5.6. STUDY DAY ........................................................................................................................ 7 
5.7. STANDARD CONVERSIONS .................................................................................................. 7 
5.8. UNSCHEDULED VISITS ........................................................................................................ 7 
5.9. VISIT WINDOWING ............................................................................................................. 7 
5.10. 
SIGNIFICANCE LEVEL ...................................................................................................... 7 
5.11. 
DATA IMPUTATION .......................................................................................................... 8 
5.11.1. 
Missing/Partial Dates in Concomitant Medications ............................................... 8 
5.11.2. 
Missing/Partial Dates in Adverse Events ................................................................ 8 
5.11.3. 
Missing/Partial Dates for Multiple Sclerosis Symptom Onset and Diagnosis Date 9 
5.11.4. 
Multiple Sclerosis Walking Scale Imputations ........................................................ 9 
5.11.5. 
Laboratory Data Imputations .................................................................................. 9 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
IV 
 
 
 
5.12. 
SOFTWARE DETAILS ........................................................................................................ 9 
5.13. 
REPORTING CONVENTIONS .............................................................................................. 9 
6. 
SUBJECT DISPOSITION ............................................................................................. 10 
6.1. DISPOSITION ..................................................................................................................... 10 
6.2. PROTOCOL DEVIATIONS ................................................................................................... 11 
7. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 11 
7.1. DEMOGRAPHICS ................................................................................................................ 11 
7.2. MEDICAL HISTORY ........................................................................................................... 12 
7.2.1. 
General Medical History ....................................................................................... 12 
7.2.2. 
Multiple Sclerosis Disease History ........................................................................ 12 
7.3. INCLUSION AND EXCLUSION CRITERIA ............................................................................. 12 
8. 
TREATMENTS AND MEDICATIONS ....................................................................... 13 
8.1. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 13 
8.2. STUDY TREATMENTS ........................................................................................................ 13 
8.2.1. 
Extent of Exposure ................................................................................................. 14 
8.2.2. 
Drug Accountability and Treatment Compliance .................................................. 14 
9. 
EFFICACY ANALYSIS................................................................................................. 14 
9.1. PRIMARY EFFICACY ANALYSIS ......................................................................................... 14 
9.1.1. 
Sensitivity Analyses................................................................................................ 15 
9.1.2. 
Subgroup Analyses ................................................................................................ 15 
9.2. KEY SECONDARY EFFICACY ANALYSES ........................................................................... 16 
9.2.1. 
Sensitivity Analyses................................................................................................ 17 
9.3. SECONDARY SUPPORTIVE EFFICACY ANALYSES .............................................................. 18 
9.4. OTHER EFFICACY ANALYSES............................................................................................ 18 
9.4.1. 
Multiple Sclerosis Walking Scale -12 .................................................................... 18 
9.4.2. 
Change in Walking Speed using T25FW ............................................................... 18 
10. 
SAFETY ANALYSES .................................................................................................... 18 
10.1. 
ADVERSE EVENTS ......................................................................................................... 18 
10.2. 
CLINICAL LABORATORY EVALUATIONS ........................................................................ 20 
10.2.1. 
Hematology ............................................................................................................ 20 
10.2.2. 
Serum Chemistry.................................................................................................... 21 
10.3. 
VITAL SIGN MEASUREMENTS ........................................................................................ 23 
10.4. 
PHYSICAL EXAMINATION .............................................................................................. 23 
10.5. 
C-SSRS ........................................................................................................................ 23 
10.5.1. 
C-SSRS Outcomes, Endpoints, and Scoring .......................................................... 24 
11. 
CHANGES FROM THE PROTOCOL IN THE PLANNED ANALYSES............... 25 
12. 
CHANGES FROM THE INITIAL SAP VERSION ................................................... 26 
12.1. 
TIMED 25-FOOT WALK PERCENT CHANGE .................................................................... 26 
12.2. 
PRIOR AMANTADINE USE .............................................................................................. 26 
12.3. 
CONCOMITANT MULTIPLE SCLEROSIS THERAPIES ........................................................ 26 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
V 
 
 
 
13. 
REFERENCES ................................................................................................................ 27 
14. 
APPENDICES ................................................................................................................. 29 
14.1. 
SCHEDULE OF EVENTS ................................................................................................... 29 
14.2. 
STUDY DESIGN SCHEMATIC .......................................................................................... 32 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
VI 
 
 
 
List of Abbreviations 
Abbreviation  
Explanation 
2MWT 
2-Minute Walk Test 
2,4-DAP 
2,4-diaminopyridine 
4-AP 
4-aminopyridine 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase  
ATC 
Anatomical Therapeutic Chemical 
bpm 
Beats per Minute 
BUN 
Blood Urea Nitrogen 
CH 
Clinically High 
CI 
Confidence interval 
CL 
Clinically Low 
cm 
centimeters 
CRF 
Case report form (paper and/or electronic) 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CTMS 
Clinical Trial Management System 
DMT 
Disease Modifying Therapy 
ECG 
Electrocardiogram 
EDSS 
Expanded Disability Status Scale 
eGFR 
Estimated glomerular filtration rate 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
VII 
 
 
 
Abbreviation  
Explanation 
EOS 
End of study 
ER 
Extended Release 
ET 
Early termination 
HCl 
Hydrochloride 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
ICH 
International Conference on Harmonization 
ITT 
Intent-to-treat 
IV 
Intravenous 
IWRS 
Interactive web response system 
kg 
Kilograms 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal 
m 
Meters 
MAR 
Missing at Random 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mg/d 
Milligrams per day 
MI 
Multiple Imputation 
MITT 
Modified intent to treat 
mL/min 
Milliliters per minute 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
VIII 
 
 
 
Abbreviation  
Explanation 
mmHg 
Millimeters of Mercury 
MMRM 
Mixed model repeated measurement 
MN 
Miettinen-Nurminen 
MS 
Multiple sclerosis 
MSWS-12 
Multiple Sclerosis Walking Scale-12 
N/A 
Not Applicable 
NMAR 
Not Missing at Random 
OLE 
Open-label extension 
PCS 
Potentially clinically significant 
PP  
Per-protocol 
PT 
Preferred Term 
RBC 
Red Blood Cell 
s, sec 
Seconds 
SAP 
Statistical Analysis Plan 
SI 
International Standard 
SOC 
System organ class 
T25FW 
Timed 25-Foot Walk  
TEAE 
Treatment-emergent adverse event 
TUG 
Timed Up and Go 
ULN 
Upper Limit of Normal 
WBC 
White blood cell(s); leukocyte(s) 
WHO 
World Health Organization 
 
. 
 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
IX 
 
 
 
 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
1 
 
 
 
 
1. Introduction 
This statistical analysis plan (SAP) is based upon Section 14 (Statistics) of the Protocol dated 28 
February 2018 / Amendment 1.0 and is prepared in compliance with International Conference on 
Harmonization (ICH) E9. Furthermore, this SAP describes the analyses and data presentations 
for the final analysis of data collected for Study ADS-AMT-MS301. 
 
Adamas is developing ADS-5102, an extended-release (ER) capsule formulation of amantadine 
hydrochloride (HCl), as a treatment to improve walking in patients with multiple sclerosis (MS). 
2. 
Objectives 
2.1. 
Primary 
To evaluate the efficacy of 274 mg ADS-5102 in subjects with multiple sclerosis (MS) with 
walking impairment as measured by the Timed 25-foot Walk (T25FW, feet/second) at Week 16. 
2.2. 
Secondary 
2.2.1. 
Key 
• To evaluate the efficacy of 274 mg ADS-5102 in subjects with MS and walking 
impairment as measured by the Timed Up and Go (TUG) test (s), and the 2-Minute Walk 
Test (2MWT) (m) at Week 16. 
• To evaluate the efficacy of 137 mg ADS-5102 in subjects with MS and walking 
impairment as measured by the T25FW (feet/second), the TUG test (s), and the 2MWT 
(m) at Week 16. 
2.2.2. 
Supportive  
• To evaluate the efficacy of 274 mg ADS-5102 and 137 mg ADS-5102 in subjects with 
MS and walking impairment as measured by the T25FW (s), the TUG (s), and the 2MWT 
(m) across all study visits. 
• To evaluate the efficacy of 274 mg ADS-5102 and 137 mg ADS-5102 in subjects with 
MS and walking impairment as measured by the Multiple Sclerosis Walking Scale-12 
(MSWS-12) in subjects treated with 274 mg ADS-5102 and subjects treated with 137 mg 
ADS-5102. 
2.2.3. 
Safety 
• To evaluate the safety and tolerability of 274 mg and 137 mg of ADS-5102 in subjects 
with MS and walking impairment. 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
2 
 
 
 
3. 
Investigational Plan 
3.1. 
Overall Study Design and Plan 
This is a multicenter, 3-arm, randomized, placebo-controlled, double-blind, parallel-group study 
of ADS-5102 (amantadine ER capsules) in MS subjects with walking impairment, incorporating 
a Single-Blind Placebo Run-In Period prior to randomization, and forced up-titration for the 
high-dose group. 
 
All subjects will have received a stable regimen of MS medications, both disease modifying and 
symptomatic, for at least 30 days prior to screening, and will continue the same doses and 
regimens for the duration of their study participation, to the extent compatible with good 
neurological care. Subjects will not have used amantadine, dalfampridine, or any 4-AP or 2,4 
diaminopyridine (2,4-DAP) preparation within 30 days prior to screening. 
 
Consented subjects who complete the up to 3-week screening period will undergo a 4-week 
Single-Blind Placebo Run-In Period during which they will take their dose of 2 placebo capsules 
once daily at bedtime. 
 
 
Subjects who complete the Single-Blind Placebo Run-In Period and continue to meet study 
eligibility criteria will be randomized with equal probability to 1 of 3 treatment groups: placebo 
or ADS-5102 at a final dosage of either 137 or 274 mg/d (treatment groups are identified by their 
final dosage). Study drug will be administered as 2 capsules once daily at bedtime. 
 
Subjects who are randomized to placebo will receive placebo capsules throughout the 12-week 
Double-Blind Treatment Period, including the 2-week forced titration and 10-week maintenance 
phases. 
 
Subjects who are randomized to 274 mg of ADS-5102 will receive 137 mg for the first week 
(Week 1 of the forced titration phase of the Double-Blind Treatment Period), 205.5 mg for the 
second week (Week 2 of the forced titration phase of the Double-Blind Treatment Period), and 
274 mg for the remaining 10 weeks of the 12-week Double-Blind Treatment Period. 
 
Subjects will return to the clinic for safety and efficacy assessments at Week 0 and Week 2 prior 
to randomization and at Weeks 4 (randomization and baseline visit), 6 (only safety), 8, 12, and 
16 after randomization. In addition, telephone visits for safety assessments will be conducted at 
Weeks 5 and 7. Subjects who withdraw from the study before Week 16 will have an early 
termination visit that includes safety follow-up and efficacy assessments, as appropriate. 
 
Subjects who complete 12 weeks of double-blind treatment (16 weeks total treatment, including 
placebo run-in) without significant protocol deviations, as assessed by the investigator and the 
sponsor, will be eligible to enter an optional open-label extension (OLE) study, protocol ADS-
AMT-MS303. The Week 16 visit of Study ADS-AMT-MS301 will serve as the first study visit 
of Study ADS-AMT-MS303 for those subjects who consent to participate. 
 
Subjects who complete 12 weeks of double-blind treatment (16 weeks total treatment, including 
placebo run-in) but elect not to participate in the OLE study will return to the clinic for a final 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
3 
 
 
 
post-treatment safety and efficacy assessment 2 weeks after their Week 16 visit (Week 18), i.e., 
after being off treatment for approximately 2 weeks. 
 
The End of Study (EOS) is defined as when a subject completes the Week 16 visit (if electing to 
enter the OLE study) or the Safety Follow-Up Visit (Week 18) (if electing not to enter the OLE 
study). 
 
All study visits and efficacy assessments should be scheduled at approximately the same time of 
day for an individual subject. To the extent practicable, study visits and efficacy assessments 
should be scheduled to occur when a subject is not likely to be experiencing acute side effects 
from a concomitant medication (e.g., flu-like side effects following interferon-beta injection). 
Efficacy assessments should be conducted in the following sequence: MSWS-12; T25FW; TUG; 
2MWT. Subjects using an assistive device during the walking assessments at Screening should 
use the same assistive device for all subsequent walking tests. Each efficacy assessment for an 
individual should be performed by the same clinical rater, if possible. 
 
Adverse events and concomitant medications will be recorded beginning with the first dose of 
study drug and continuing through the last study visit. 
 
The schedule of assessments is provided in Appendix 14.1. 
3.2. 
Study Endpoints 
3.2.1. 
Primary 
The primary efficacy endpoint is the proportion of responders in each treatment group, where a 
responder is defined as a subject who has a ≥20% increase from Baseline to Week 16 in walking 
speed measured using the T25FW (average of two measurements 5 minutes apart), in the Intent-
to-Treat (ITT) analyses set. Subjects who do not have a Week 16 assessment will be classified as 
having an indeterminate outcome and will be included in the denominator (i.e., they will be 
treated as de-facto non-responders). If a subject has not completed two walking tests, then the 
result for the one T25FW will be used. 
3.2.2. 
Secondary 
3.2.2.1. 
Key 
The key secondary endpoints listed below will be used for comparisons between treatment 
groups for which inferential statistics, with appropriate control of the Type I error rate, will be 
used.  
  
• The mean change from baseline at Week 16 in the T25FW (feet/second)  
• The mean change from baseline at Week 16 in the TUG (s)  
• The mean change from baseline at Week 16 in the 2MWT (m)  
3.2.2.2. 
Supportive 
The following endpoints will be used for supportive comparisons among treatment groups.  
 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
4 
 
 
 
• Mean changes from baseline in the T25FW (feet/second) at Weeks 8 and 12 
• Mean changes from baseline in the T25FW (s) at Weeks 8, 12 and 16 
• Mean changes from baseline in the TUG (s) at Weeks 8 and 12 
• Mean changes from baseline in the 2MWT (m) at Weeks 8 and 12 
3.2.2.3. 
Safety 
Safety endpoints will include incidence of subjects with adverse events data, potentially 
clinically significant changes in laboratory data, and changes in the Columbia-Suicide Severity 
Rating Scale (C-SSRS) data.  
4. Treatments   
Study treatments consist of an oral formulation of extended release (ER) amantadine HCl (ADS-
5102) and a placebo control. The clinical supplies will include 137 mg and 68.5 mg ADS-5102 
capsules and matching placebo capsules. All capsules provided during the study are 
indistinguishable in size and appearance. 
 
The dosing regimens for the 2 active treatment arms are: 
• 137 mg/d (1 x 137 mg capsule + 1 placebo capsule) for 12 weeks for the 137 mg ADS-
5102 group 
• 137 mg/d for 1 week (1 x 137 mg capsule + 1 placebo capsule), followed by 205.5 mg/d 
(1 x 137 mg capsule + 1 x 68.5 mg capsule) for 1 week, followed by 274 mg/d (2 x 137 
mg capsules) for 10 weeks for the 274 mg ADS-5102 group 
 
Placebo capsules will be administered orally as 2 capsules once daily at bedtime for the 4-week 
Single-Blind Placebo Run-In Period for all subjects and for the 12-week Double-Blind Treatment 
Period for subjects randomized to the placebo arm. 
4.1. 
Dose Adjustment/Modifications 
Dose Adjustment for Renal Impairment 
 
Subjects whose estimated glomerular filtration rate (eGFR) falls below 60 mL/min/1.73 m2, 
confirmed by repeat testing, should discontinue study drug. These subjects should be encouraged 
to complete study visits per the protocol.  
 
Dose Adjustment for Adverse Events  
 
Study drug may only be withheld for the evaluation or treatment of an AE. If, in the judgement 
of the investigator, study drug should be withheld for the evaluation or treatment of an AE, the 
investigator may have the subject do so for up to 3 consecutive days, and is then to have the 
subject resume dosing at the same dose level. If, in the judgement of the investigator, study drug 
needs to be withheld for more than 3 consecutive days, the investigator must contact one of the 
study’s Medical Monitors to determine whether drug may be withheld for a longer period or the 
subject should be permanently discontinued from study drug. Study drug may not be down-
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
5 
 
 
 
titrated. This procedure applies to the withholding of study drug throughout the study with the 
exception of the titration phase of the Double-Blind Treatment Period. 
 
In the special case of study drug being withheld for the evaluation or treatment of an AE 
occurring during the titration phase of the Double-Blind Treatment Period (i.e., Week 4 to Week 
6), the investigator may have the subject do so for up to 3 consecutive days, and is then to have 
the subject resume dosing at the same dose level. The subject is to finish the remaining capsules 
in the blister card, i.e., including the 2-dose overage. The subject must return to the clinic to 
receive his or her next blister pack without missing any additional doses. If, in the judgement of 
the investigator, study drug needs to be withheld for more than 3 consecutive days, the subject is 
to be permanently discontinued from study drug. 
5. 
General Statistical Considerations 
5.1. 
Randomization, Stratification, and Blinding 
A subject is considered randomized at Baseline/Week 4, when the site confirms the 
randomization event via a centralized randomization system (interactive web response system 
[IWRS]).  
 
Following completion of the 4-week Single-Blind Placebo Run-in Period, consented subjects 
who continue to meet eligibility criteria will be randomly assigned in equal probability to 1 of 3 
treatment groups: placebo, 137 mg ADS-5102, or 274 mg ADS 5102. No stratifications are being 
utilized in the randomization design.  
 
The identity of the treatment assigned to individual subjects can be revealed in an emergency 
only. A subject’s treatment assignment should only be unblinded when knowledge of treatment 
is essential for the safety of the subject. Emergency unblinding will be considered a major 
protocol deviation.  
5.2. 
Sample Size 
Based on the results from the Phase 2 study, responder rates of 24% and 33% were observed at 
Week 4 for subjects treated with placebo and 274 mg ADS-5102, respectively, in the modified 
intent-to-treat (MITT) analysis set. In the present study, it is anticipated that the placebo response 
rate at Week 16 will be no greater than 20% and the response rate among subjects treated with 
274 mg or 137 mg ADS-5102 will be at least 33%. Using these estimates, 180 randomized 
subjects per active treatment group and placebo group will be needed for the test of differences 
in proportions (Farrington-Manning approach for the Miettinen-Nurminen [MN] test) to have 
80% power at the 2-sided 5% significance level to detect this 13% difference favoring ADS-
5102. Assuming a 5% dropout rate during the 4-week Single-Blind Placebo Run-In Period, 570 
subjects will be enrolled in the study to randomize 540. 
 
For this sample size of 180 randomized subjects per group, power will be at least 80% to detect 
treatment differences (ADS-5102 versus placebo) of -2.7 seconds and 5.0 meters in the changes 
from baseline at Week 16 in the TUG test and 2MWT when the standard deviations of the 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
6 
 
 
 
change from baseline are no greater than 6.0 sec and 14.9 meters, respectively, and the dropout 
rate is not greater than 20%. 
5.3. 
Analysis Set 
5.3.1. 
All Enrolled 
The all enrolled set will include all subjects who signed the study informed consent form and 
entered the placebo run-in period. 
5.3.2. 
Intent-to-Treat (ITT) Set 
The intent-to-treat (ITT) analysis set will include all randomized subjects who receive at least 
one dose of double-blind study drug, and will be analyzed according to the randomized treatment 
assignment. This population will be used for the efficacy analyses including the analyses of 
primary and key secondary endpoints. 
5.3.3. 
Per Protocol (PP) Set 
The per-protocol (PP) analysis set will include all randomized and dosed subjects who provide 
Week 16 T25FW data and do not have any major protocol deviations as outlined in Section 6.2 
that could confound this assessment. These deviations will be determined prior to unblinding and 
database lock. This population will also be used for select efficacy analyses. Subjects in the PP 
set will be analyzed according to the randomized treatment assignment. 
5.3.4. 
Safety Set 
The safety analysis set will include all randomized subjects who receive at least one dose of 
double-blind study drug, and will be analyzed according to the treatment actually received. If 
there are no treatment misallocations, this population will be identical to the ITT analysis set.  
5.4. 
 Baseline 
For endpoints based on the T25FW, Baseline will be defined as the average of up to two separate 
visit averages (each based on up to two measurements taken five minutes apart) collected at 
Weeks 2 and 4 (prior to randomization). If one of the two T25FW Baselines values is missing, 
then Baseline will be defined as the last non-missing measurement prior to or on the date of 
randomization. 
 
For endpoints based on the TUG, 2MWT, and MSWS-12, Baseline will be defined as the 
average of up to two separate measurements collected at Weeks 2 and 4 (prior to randomization). 
If one of the two TUG, 2MWT and/or MSWS-12 Baselines values is missing, Baseline will be 
defined as the last non-missing measurement prior to or on the date of randomization. 
 
For C-SSRS analyses, the questionnaire three-year history data obtained during the Screening 
visit will be considered Baseline.  
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
7 
 
 
 
 
For all other endpoints, Baseline is defined as the last non-missing measurement prior to or on 
the date of randomization. 
5.5. 
Study Completion 
Study completion is defined as study participation through the Week 16 Visit and rollover into 
OLE, or completion of a Safety Follow-Up Visit. 
5.6. 
Study Day 
Study Day 1 will correspond with the date of first dose of double-blind study drug. Study day 
will be calculated as follows: 
 
If the Date of Interest < First Dose Date of Double-Blind Study Drug then,   
𝑆𝑡𝑢𝑑𝑦 𝐷𝑎𝑦= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐼𝑛𝑡𝑒𝑟𝑒𝑠𝑡−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑅𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑎𝑡𝑖𝑜𝑛) 
 
If the Date of Interest ≥ First Dose Date of Double-Blind Study Drug then, 
𝑆𝑡𝑢𝑑𝑦 𝐷𝑎𝑦= 𝐷𝑎𝑡𝑒 𝑜𝑓 𝐼𝑛𝑡𝑒𝑟𝑒𝑠𝑡−𝐷𝑎𝑡𝑒 𝑜𝑓 𝑅𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑎𝑡𝑖𝑜𝑛+ 1 
 
For subjects that are never treated with double-blind study drug, study day will not be calculated.  
5.7. 
Standard Conversions 
The following conversions will be used: 
  
1 𝑌𝑒𝑎𝑟= 365.25 𝑑𝑎𝑦𝑠 
1 𝑀𝑜𝑛𝑡ℎ= 30 𝑑𝑎𝑦𝑠 
1 𝑊𝑒𝑒𝑘= 7 𝑑𝑎𝑦𝑠 
 
1 Meter = 39.37 inches 
5.8. 
Unscheduled Visits 
Data collected at unscheduled visits will be displayed in data listings and used to calculate 
maximum/minimum values, as applicable, but will not be displayed in summaries presented by 
study visit.  
5.9. 
Visit Windowing 
No programmatic visit windowing will be implemented.  
5.10. 
Significance Level 
Unless otherwise specified, all testing of statistical significance will be 2-sided, and a treatment 
difference resulting in a p-value less than or equal to 0.05 will be considered statistically 
significant. Similarly, all confidence intervals will be two-sided 95% confidence intervals. 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
8 
 
 
 
5.11. 
Data Imputation 
Unless otherwise specified, all available efficacy and safety data will be included in data listings 
and tabulations.  Prior to database lock, critical data that are potentially spurious or erroneous 
will be examined and queried according to standard data management operation procedures.  
 
For the efficacy analyses of responder rates, a subject with missing data will be defined as a non-
responder.  For all other endpoints, missing data will be treated as missing and no data 
imputations will be applied, unless otherwise specified. See Section 9.2.1 for sensitivity analyses 
concerning the missing data assumptions. 
5.11.1. 
Missing/Partial Dates in Concomitant Medications 
Concomitant medications with start dates that are completely or partially missing will be 
analyzed as follows: 
• If month and year are known, but day is missing, then impute day to first of the month 
• If year is known, but day and month are missing, then 1st of January of the year will be 
imputed 
• If the start date is completely missing, then impute date to first dose date of double-blind 
study drug 
• Should any of the previous concomitant medication start dates created come after the 
complete medication stop date provided, the medication stop date will be used instead 
Concomitant medications with stop dates that are completely or partially missing will be 
analyzed as follows: 
• If “ongoing” is checked, no imputation is necessary 
• If month and year are known but day is missing, the last day of the month will be 
imputed  
• If year is known, but day and month are missing, 
o If YYYY < year of last dose of double-blind study drug, then 31st of December 
will be imputed  
o If YYYY = year of last dose of double-blind study drug, then the last dose date of 
study drug will be imputed  
o If YYYY > year of last dose of double-blind study drug, then 1st of January will 
be imputed  
• If the stop date is completely missing, then impute date to last dose date of double-blind 
study drug 
• If subject dies, then use death date for concomitant medication stop date. After the 
imputation, all imputed stop dates will be checked against the corresponding start dates to 
ensure the stop date does not come before the start date. If the imputed stop date is prior 
to the start date, then the start date will be used. 
5.11.2. 
Missing/Partial Dates in Adverse Events 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
9 
 
 
 
Adverse events with start dates that are completely or partially missing will be imputed as 
follows: 
• If month and year are known but day is missing  
o If month and year are the same as month and year of first dose date of double-blind 
study drug, then impute to first dose date of double-blind study drug 
o If month and year are different than month and year of first dose date of double-blind 
study drug, then impute to first of the month 
• If year is known but day and month are missing  
o If year is same as year of first dose date of double-blind study drug, then first dose 
date of double-blind study drug will be used instead 
o If year is different than year of first dose date of double-blind study drug, then 1st of 
January of the year will be imputed 
• If the start date is completely missing, then it will be imputed with first dose date of double-
blind study drug 
5.11.3. 
Missing/Partial Dates for Multiple Sclerosis Symptom Onset and Diagnosis Date 
Multiple sclerosis symptom onset dates and diagnosis dates that are partially missing will be 
imputed as follows: 
• If year is present, but month and day are missing, impute to July 1 
• If year and month are present but day is missing, impute to 1st of month 
• If year and day are present but month is missing, impute to July 
• If year is missing, or date is completely missing – do not impute.  Leave as missing 
5.11.4. 
Multiple Sclerosis Walking Scale Imputations 
A maximum of three missing items in the twelve-item scale will be allowed. As necessary, any 
missing value will be imputed as the average of the non-missing items. If more than three of the 
twelve items have missing responses, no total score will be computed for the given timepoint.  
5.11.5. 
Laboratory Data Imputations 
If a lab value is reported using a non-numeric qualifier (e.g., less than [<] a certain value, or 
greater than [>] a certain value), the given numeric value will be used in the summary statistics, 
ignoring the non-numeric qualifier. For instance, a value reported as “<200” would be listed as 
such, but summarized as “200.” 
5.12. 
Software Details 
All statistical procedures will be performed using SAS® Version 9.3 or higher. 
5.13. 
Reporting Conventions 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
10 
 
 
 
All tables, listings, figures and any other supportive SAS output will include in the footer 
explanatory notes that will indicate, at a minimum, the programming source (i.e., name, file path 
of the SAS program that generates the output), data extraction date, and run date. 
 
Continuous data will be described using descriptive statistics as follows: number of observations 
(n), mean, median, standard deviation, minimum, and maximum, unless otherwise specified.  All 
minimum and maximum values will be displayed with the same number of decimal places 
relative to the raw data, the mean and median will be displayed with one additional decimal 
place, and the standard deviation will be displayed with two additional decimal places. 
 
Categorical data will be summarized by the number and percentage of subjects in each category. 
The denominator of all percentages will be number of subjects in the population of interest, 
unless otherwise stated. When count data are presented, the percent will be suppressed when the 
count is zero in order to draw attention to the non-zero counts. A row denoted “Missing” will be 
included in count tabulations where necessary to account for dropouts and missing values. Non-
zero percentages will be rounded to one decimal place, except 100% will be displayed without 
any decimal places.  
 
In summary tables for categorical data, all categories will be presented if they are specified on 
the Case Report Form (CRF), or if categories are ordered intervals (e.g., age groups), regardless 
of whether data were present in each category, unless otherwise specified. For other categorical 
data (e.g., AEs and medications), only categories with non-zero frequencies will be presented. 
 
P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be presented as 
‘<0.0001’ and p-values that round to 1.000 will be presented as ‘>0.9999’. Confidence intervals 
(CIs) will be presented as 2-sided 95% CIs unless specified differently in specific analysis. 
 
Data will be displayed in all listings sorted by treatment, study site, and subject number 
concatenated with site number. All summaries will be presented by treatment group, unless 
otherwise specified. 
 
When no data are available for a table or appendix, an empty page with the title will be produced 
with suitable text (e.g., “There are no observations for this table/appendix.”). 
6. 
Subject Disposition 
6.1. 
Disposition 
The all enrolled set will be utilized for a table summarizing the number of subjects included and 
excluded from each analysis set, along with reasons for exclusion. The summary will be 
provided by treatment group and overall and will also be provided in a data listing.  
 
The ITT set will be utilized for a table summarizing subjects discontinuing study drug early by 
treatment group and overall and will include the following information: 
• Whether the subject completed treatment through Week 16 (Yes, No) 
• As applicable, the reason for premature study drug discontinuation 
 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
11 
 
 
 
The ITT set will be utilized for a table summarizing subject study completion status by treatment 
group and overall and will include the following information: 
• Subject completion status (Yes, No) 
• Whether the subject consented to participate in the open label extension (Yes, No) 
• Reason for early termination  
 
All disposition information will also be provided in data listings.  
6.2. 
Protocol Deviations 
Protocol deviations will be recorded within the PPD Clinical Trial Management System (CTMS) 
and undergo cross-functional team review prior to database lock in order to finalize the PP set. 
The Deviation Guidance Document contains all potential protocol deviations classified by 
CTMS subtype. After review, deviations deemed to be of special interest will be classified as 
significant protocol deviations.  
 
Major protocol deviations are those deviations that may have an impact on the efficacy analysis 
or the safety of the subject. Major protocol deviations can be related to study inclusion/exclusion 
criteria, trial conduct, patient management, or patient assessments. Major protocol deviations 
will be determined by the sponsor and submitted to PPD prior to database lock. Major protocol 
deviations are a subset of significant deviations. 
 
The number and percentage of subjects with significant protocol deviations will be summarized 
by treatment group and overall using the ITT set. Subjects will be counted once within each 
deviation category regardless of how many deviations they have in that category. 
 
All significant protocol deviations will also be provided in a data listing.  
 
A blinded review of the data listings will be conducted prior to database lock to determine the 
extent to which subjects completed the study according to the protocol. In the event that the 
blinded data review reveals major protocol deviations that impact interpretation of efficacy 
assessments, the per-protocol (PP) analysis set may exclude additional subjects. Final decisions 
regarding subjects to be included in all analysis sets will be made prior to any unblinding of the 
treatment allocations and database lock. 
7. 
Demographics and Baseline Characteristics 
7.1. 
Demographics 
The following demographic information will be summarized for the Safety, ITT, and PP sets by 
treatment group and overall: 
• Age (years), calculated as (informed consent date – birth date + 1) / 365.25 
o No rounding will be performed and only the integer value will be retained 
• Categorical Age (<55, ≥55, <65, ≥65) 
• Gender (Female, Male) 
• Ethnicity (Hispanic or Latino, Not Hispanic and Not Latino) 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
12 
 
 
 
• Race (White, African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Other) 
• Height (cm) 
• Weight (kg) 
• BMI (kg/m2) 
• Categorical BMI (Underweight (<18.5), Normal (18.5 - <25), Overweight (25 - <30), 
Obese (≥30)) 
• Expanded Disability Status Scale (EDSS) score at Baseline 
• Baseline T25FW (<26.5 s, ≥26.5 s) 
Demographic information will also be provided via data listings.  
 
7.2. 
 Medical History 
7.2.1. 
General Medical History 
General medical history information will be summarized using the ITT set by system organ 
class.  
 
MedDRA dictionary Version 21.0 will be used for reporting and will be described in the relevant 
table and listing footnotes. 
 
General medical history information will also be provided via data listings.  
7.2.2. 
Multiple Sclerosis Disease History 
The following multiple sclerosis specific disease information will be summarized for the ITT set 
by treatment group and overall: 
• Type of Multiple Sclerosis (Relapsing Remitting, Secondary Progressive, Progressive 
with Relapse, Progressive Without Relapse) 
• Time Since Symptom Onset (years), calculated as (informed consent date – date + 1) / 
365.25 
• Time Since Diagnosis (years), calculated as (informed consent date – date + 1) / 365.25 
• Corticosteroids (IV or Oral) or ACTHAR Gel Use within 30 days prior to screening (Yes, 
No) 
• Prior Amantadine Use (Yes, No) 
• Prior Dalfampridine Use (Yes, No) and Form (Ampyra/Fampyra, 4-Aminopyrimidine, 2-
4-Diaminopyrimidine) and reason for stopping (Side Effects, Loss of Efficacy, No 
Efficacy, Other) 
Multiple sclerosis disease history will also be provided via data listings.  
7.3. 
Inclusion and Exclusion Criteria 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
13 
 
 
 
Inclusion and exclusion violations will be provided via data listings.  
8. 
Treatments and Medications 
8.1. 
Prior and Concomitant Medications 
Prior medications are defined as medications with a stop date occurring from 30 days prior to the 
screening visit up to the day prior to randomization.  Concomitant medications are defined as 
medications taken on or after the date of randomization through the date of last dose of study 
drug (inclusive) or listed as ongoing.  Medications with start and stop dates (or ongoing) which 
bracket the randomization date will be summarized as both prior and concomitant medications. 
 
All non-study drugs (including prescribed and over the counter medications) taken during the 
study will be collected on the CRF.  All medications will be coded according to the World 
Health Organization (WHO) Drug Dictionary and summarized using the Anatomical Therapeutic 
Chemical (ATC) class (Level 2) and preferred term (PT). The WHO Drug Dictionary dated 
March, 2018 will be used for study reporting and will be detailed in the relevant table and listing 
footnotes.  
 
Prior medications will be summarized for the Safety set. Medications taken prior to enrollment 
and prior to randomization will be summarized separately. At each level of summarization, a 
subject is counted once if he/she reported one or more medications at that level.  
 
Concomitant medications will be recorded beginning with the first dose of study drug and 
continuing through the last study visit. Concomitant medications will be summarized for the 
Safety set. At each level of summarization, a subject is counted once if he/she reported one or 
more medications at that level.  
 
Prior and concomitant medication information will also be provided via data listings.  
8.2. 
Study Treatments 
Study drug will be packaged in child-resistant blister wallets, each containing a total of 36 
capsules (two capsules per dose, allowing for a two-week supply plus two extra doses per week).  
 
Table 1: Expected Capsules Dispensed and Returned by Visit 
Visit 
Expected Capsules Dispensed at The 
Indicated Visit 
Expected Capsules Returned  
at The Next Visit 
Week 0 
72 
16* 
Week 2 
N/A 
N/A 
Week 4 
36 
8 
Week 6 
36 
8 
Week 8 
72 
16 
Week 12 
72 
16 
Week 16 
0 
N/A 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
14 
 
 
 
  * 2 blister wallets containing 36 capsules each are dispensed at Week 0. One is to be collected 
at Week 2, the other at Week 4 
8.2.1. 
 Extent of Exposure 
The extent of double-blind study drug exposure will be summarized for the active treatment arms 
with continuous measures (n, mean, median, standard deviation, minimum, and maximum) and 
categorical measures (1-7 days, 8-14 days, 15-28 days, 29-56 days, 57-84 days, and >84 days; 
>= 1 month, >=2 months, and >=3 months) using the Safety set. 
 
Extent of exposure will be calculated as follows: 
 
𝐸𝑥𝑡𝑒𝑛𝑡 𝑜𝑓 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 (𝑑𝑎𝑦𝑠)
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐿𝑎𝑠𝑡 𝐷𝑜𝑠𝑒 𝑜𝑓 𝐷𝑜𝑢𝑏𝑙𝑒 𝐵𝑙𝑖𝑛𝑑 𝑆𝑡𝑢𝑑𝑦 𝐷𝑟𝑢𝑔
−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 𝑜𝑓 𝐷𝑜𝑢𝑏𝑙𝑒 𝐵𝑙𝑖𝑛𝑑 𝑆𝑡𝑢𝑑𝑦 𝐷𝑟𝑢𝑔) + 1 
 
Study drug exposure details for both the Placebo Run-in and Double-Blind Treatment periods 
will also be provided via data listings.  
8.2.2. 
Drug Accountability and Treatment Compliance 
Treatment compliance in the Placebo Run-In and Double-Blind Treatment Periods will be 
summarized separately for the Safety set and calculated as follows: 
 
𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠, %) = (𝐴
𝑃) ∗100 
where 
 
𝑃= 𝑇ℎ𝑒 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑝𝑟𝑒𝑠𝑐𝑟𝑖𝑏𝑒𝑑= 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑎𝑦𝑠 𝑑𝑜𝑠𝑖𝑛𝑔 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑∗2 𝐶𝑎𝑝𝑠𝑢𝑙𝑒𝑠   
𝐴= 𝑇ℎ𝑒 𝑎𝑐𝑡𝑢𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑡𝑎𝑘𝑒𝑛 
 
Total number of capsules prescribed will be calculated based on the number of capsules 
prescribed from Day 1 to the last day of dosing. If the number of capsules returned at a given 
visit is missing, overall treatment compliance will be missing. Non-compliance is defined as less 
than 80% or more than 120% non-missing compliance with study drug. Subjects with missing 
compliance are classified as non-assessable.  
 
Drug accountability and treatment compliance data will also be provided via data listings.  
9. 
 Efficacy Analysis 
The ITT set will be used for the primary efficacy analysis, as well as for the primary analysis of 
each secondary endpoint.  
9.1. 
Primary Efficacy Analysis  
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
15 
 
 
 
The primary efficacy endpoint is the proportion of responders in each treatment group as defined 
in Section 3.2.1. 
 
The objective of the primary efficacy analysis is to compare the 274 mg ADS-5102 group versus 
the placebo group in terms of the difference (active minus placebo) in the proportion of 
responders at Week 16 using the ITT analysis set. The Farrrington-Manning test will be used to 
obtain a 2-sided p-value based on the resulting Z-score. The Miettinen-Nurminen (MN) approach 
will be used to obtain the 95% confidence interval (CI) for the difference. Superiority will be 
concluded if the 2-sided p-value is less than 0.05 and the lower limit of the 2-sided 95% CI is 
greater than 0.00. (Note that this test is effectively a one-sided test at the 0.025 level.)  
 
This test can be expressed mathematically as follows: 
 
H0: d = 0 
H1: d > 0 
 
Where d = p1 – p0 (i.e. risk difference between the proportion of responders in the 274 mg ADS-
5102 group and the proportion of responders in the placebo group). 
 
The primary efficacy analysis will be provided via a summary table.  
9.1.1. 
Sensitivity Analyses 
Subjects with missing data will be treated as non-responders for efficacy analyses of responder 
rates.  The following analyses will be performed to assess the impact of missing data: 
 
• The primary efficacy analysis specified in Section 9.1 will be repeated using: 
1. The Per-Protocol Set 
2. Study Completers. 
▪ Subjects who complete Week 16 treatment and have pertinent Week 16 
efficacy data.  
9.1.2. 
Subgroup Analyses 
Subgroup analyses for the primary efficacy analysis specified in Section 9.1 will be repeated 
using the following subgroups: 
• Categorical Age 
o <55 
o ≥55 
o <65 
o ≥65 
• Gender 
o Female 
o Male 
• Race 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
16 
 
 
 
o African American 
o White 
o Other (Asian, Native Hawaiian or Other Pacific Islander, American Indian or 
Alaska Native, Other) 
• Categorical BMI 
o Underweight (<18.5) 
o Normal (18.5 - <25) 
o Overweight (25 - <30) 
o Obese (≥30) 
• Type of MS 
o Relapsing remitting 
o Secondary progressive 
o Progressive with relapse 
o Progressive without relapse 
• Time Since MS diagnosis  
o < Median of enrolled trial population 
o ≥ Median of enrolled trial population 
• EDSS Score at Baseline 
o 0 to 3.5 (No to minimal walking limitation) 
o 4 to 5.5 (Walking limitation) 
o 6 to 6.5 (Need for assistive device) 
• Use of Assistive Devices During T25FW Test at Baseline 
o Yes / No 
• History of Dalfampridine Use 
o Yes / No 
• History of Amantadine Use 
o Yes / No 
• T2FW Category at Baseline 
o < 26.5 seconds 
o ≥26.5 seconds 
The results will be provided via summary tables and also presented graphically in a forest plot.  
9.2. Key Secondary Efficacy Analyses 
The key secondary endpoints are the mean changes from Baseline between treatment groups at 
Week 16 for the T25FW (feet/second), TUG (s), and 2MWT (m). These are described in Section 
3.2.2.1. 
 
Provided superiority of 274 mg ADS-5102 versus placebo is shown in the primary analysis, the 
key secondary objectives will be evaluated using a fixed-sequence gatekeeping strategy to 
control the overall Type I error rate at 5%. Using this approach, the following research 
hypotheses will be evaluated sequentially in the order given using the ITT analysis set: 
1. Superiority of 274mg ADS-5102 compared to placebo in mean change from baseline at 
Week 16 in the T25FW(feet/second) test 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
17 
 
 
 
2. Superiority of 274 mg ADS-5102 compared to placebo in mean change from baseline at 
Week 16 in the TUG (s) test 
3. Superiority of 274 mg ADS-5102 compared to placebo in mean change from baseline at 
Week 16 in the 2MWT (m) 
4. Superiority of 137 mg ADS-5102 compared to placebo in terms of the proportion of 
T25FW responders at Week 16 
5. Superiority of 137 mg ADS-5102 compared to placebo in mean change from baseline at 
Week 16 in the T25FW (feet/second) test 
6. Superiority of 137 mg ADS-5102 (s) compared to placebo in mean change from baseline 
at Week 16 in the TUG test 
7. Superiority of 137 mg ADS-5102 compared to placebo in mean change from baseline at 
Week 16 in the 2MWT(m) 
At each step, superiority will be concluded if the 2-sided p-value is less than 0.05 and the lower 
limit of the 2-sided 95% CI is greater than 0.00, for tests comparing responder rates or mean 
changes from baseline in 2MWT and T25FW, or the 2-sided 95% CI is less than 0.00, for tests 
comparing mean changes from baseline in the TUG. If a non-significant result (p-value ≥ 0.05) 
or a p-value <0.05 is noted but superiority is not shown, no further inferential conclusions will be 
drawn and any subsequent statistically significant result will be declared supportive of efficacy 
only. This strategy effectively controls the Type I error rate at the 2.5% level (one-sided) for 
testing superiority of ADS-5102 versus placebo. 
 
The statistical test of difference between 137 mg ADS-5102 versus placebo in terms of 
responders at Week 16 (Item 4 above) will be done using the same approach used for the primary 
analysis.  
 
The hypothesis tests of difference between 274 mg ADS-5102 and of 137 mg ADS-5102 versus 
placebo in terms of the mean change from baseline in the T25FW, TUG test, and the 2MWT, as 
described above, will be done using t-tests derived from the corresponding linear mixed model 
with repeated measurement (MMRM) model with the change from baseline (i.e., T25FW, TUG, 
or 2MWT) as the dependent variable and fixed effects of treatment group, study week, and 
treatment by study week interaction. The baseline value will be included as a covariate and an 
unstructured variance-covariance matrix will be used for the within-subject residual variability. 
Should the model fail to converge under this assumption, then a compound symmetry covariance 
structure will be assumed. The Kenward-Rogers method will be used to estimate the 
denominator degrees of freedom. 
 
All key secondary analyses will be repeated using the PP set.  
 
Least squared mean change from baseline values will be presented graphically by visit and 
treatment for the T25FW, TUG, and 2MWT. 
9.2.1. 
Sensitivity Analyses 
For the analyses of the key secondary variables, mean changes from baseline in T25FW, TUG 
and 2MWT, the MMRM model (Protocol Section 14.4.2) will be used based on available data 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
18 
 
 
 
and there will be no imputation of missing values. These analyses effectively assume that the 
missing observations are missing at random (MAR).  For each parameter, two sensitivity 
analyses will be conducted using a multiple imputation (MI) approach. The first sensitivity 
analysis will assume the data are MAR and will include additional covariates (Age, Duration of 
MS) in the imputation step that could be predictive of response and/or the probability of 
missingness. The second sensitivity analysis will assume the data are not missing at random 
(NMAR) and missing observations in the ADS-5102 treatment group will be imputed as if they 
had been obtained in the placebo treatment group. 
 
9.3. 
Secondary Supportive Efficacy Analyses 
The supportive secondary endpoints are the mean changes from Baseline between treatment 
groups at Weeks 8, 12, and 16 for the T25FW (s) and Weeks 8 and 12 for the T25FW 
(feet/second), TUG (s), and 2MWT (m). These are described in Section 3.2.2.2. 
 
Each active dose will be compared to placebo in terms of the mean change from baseline at each 
study visit in the T25FW (both feet/sec and sec), TUG test, and the 2MWT. These analyses will 
be done using the MMRM model described earlier. 
9.4. 
Other Efficacy Analyses 
9.4.1. 
Multiple Sclerosis Walking Scale -12 
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
provided for the MSWS-12 total score by study visit.  
 
For this scale, each of the twelve items can be answered with five options with 1 meaning no 
limitation and 5 meaning extreme limitation. The total score is generated and transformed to a 0 
to 100 scale by subtracting the minimum score possible (12) from the subject’s score, dividing 
by the maximum score possible minus the minimum possible (60 – 12 = 48), and multiplying the 
result by 100. Walking improvement on the MSWS-12 is indicated by negative change scores. 
9.4.2. 
Change in Walking Speed using T25FW 
The percent change in average walking speed from Baseline to Week 16 using the T25FW will 
be calculated by treatment group and presented in a summary table. The difference in the percent 
change in average walking speed between placebo and active drug (137 mg ADS-5102 and 274 
mg ADS-5102) will be analyzed. Point estimates, 95% confidence intervals, and p-values will be 
presented.  
10. 
Safety Analyses 
10.1. 
Adverse Events 
Adverse events (AE) will be recorded starting from the date/time of first dose during the Single-
Blind Placebo Run-In Period through the End of Study (EOS) Visit. The time periods of AE 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
19 
 
 
 
recording will be divided into AEs with onset during the Single-Blind Placebo Run-In Period and 
AEs with onset during the Double-Blind Treatment Period.  
 
A Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event that begins or 
worsens in severity on or after the date of randomization.  
 
Incidence of TEAEs during the Double-Blind Treatment Period (as well as number and 
percentage of subjects with TEAEs) will be tabulated according to Medical Dictionary for 
Regulatory Activities (MedDRA) by system organ class (SOC) and preferred term (PT) and will 
include the following categories: 
 
• All TEAEs 
• Most Commonly Reported TEAEs (≥5% in any treatment group) (by PT only) 
• TEAEs by Relatedness to Study Drug 
• TEAEs by Severity 
• TEAEs Leading to Study Drug Discontinuation 
• Serious TEAEs Leading to Study Drug Discontinuation by Relatedness to Study Drug 
• Serious TEAEs by Relatedness to Study Drug 
• Study Drug-Related Serious TEAEs 
• TEAEs of Special Interest 
 
MedDRA dictionary Version 21.0 will be used for reporting and will be described in the relevant 
table and listing footnotes. 
 
Subjects with the same AE more than once will have that event counted only once within each 
System organ class (SOC) and Preferred term (PT). Subjects with the same AE more than once 
will have the maximum intensity of that event counted within each SOC and once within each 
PT for summaries of severity. 
 
SOCs and PTs within SOC will be presented by descending frequency based on the ADS-5102 
274 mg and ADS-5102 137 mg groups combined. 
 
An overall summary AE table will include the numbers and percentages of subjects who had at 
least one of each of the following: TEAE, serious TEAE, study drug-related TEAE, TEAE 
leading to study drug discontinuation, serious TEAE leading to study drug discontinuation, study 
drug-related serious TEAE, AE of special interest, or on-study death. 
 
TEAEs that have missing severity will be classified in table summaries as severe. Similarly, 
TEAEs that have missing relationship to study drug will be classified in table summaries as 
related. 
 
All AEs will be listed by subject and period.  
 
The three AE categories listed below are considered adverse events of special interest (AESI): 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
20 
 
 
 
• Suicidality 
• Hallucinations 
• Events Potentially Related to Orthostatic Hypotension.  
For each of the AESIs listed above, an additional data listing will be provided to include 
additional information collected in the clinical database for each type of AESI.  Death 
Adverse events resulting in death will be provided in a separate data listing.  
10.2. 
Clinical Laboratory Evaluations 
The clinical laboratory assessments relating to safety to be performed include those for 
Hematology, and Serum Chemistry.  
 
Laboratory assessments for hematology and serum chemistry will be performed by a central 
laboratory. All summaries will be based on the International System (SI) units provided by the 
central lab. No unit conversions will be made. 
 
All clinical laboratory measures will be classified using the following alert flags: 
• LP - Low Panic 
• LT - Low Telephone 
• LN - Low Normal 
• N – Normal 
• HP - High Panic 
• HT - High Telephone 
• HN - High Normal 
• AB - Abnormal 
10.2.1. 
Hematology 
The number and percentage of subjects with any potentially clinically significant changes from 
baseline will be tabulated and summarized by treatment group. 
Table 2: Potential Clinical Significance (PCS) for Hematology Parameters 
Laboratory Parameter 
Flag 
Criteria* 
Observed 
Value 
Change from Baseline 
Hemoglobin 
High (CH) 
> 1.3 × ULN 
> 30% Increase from Baseline 
Low (CL) 
< 0.8 × LLN 
> 20% Decrease from Baseline 
Hematocrit 
High (CH) 
> 1.3 × ULN 
> 30% Increase from Baseline 
Low (CL) 
< 0.8 × LLN 
> 20% Decrease from Baseline 
Erythrocyte count (RBC) 
High (CH) 
> 1.3 × ULN 
> 30% Increase from Baseline 
Low (CL) 
< 0.8 × LLN 
> 20% Decrease from Baseline 
Mean corpuscular Volume (MCV) 
High (CH) 
> 1.15 × ULN 
> 15% Increase from Baseline 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
21 
 
 
 
Laboratory Parameter 
Flag 
Criteria* 
Observed 
Value 
Change from Baseline 
Low (CL) 
< 0.85 × LLN 
> 15% Decrease from Baseline 
Mean corpuscular hemoglobin 
(MCH) 
High (CH) 
> 1.15 × ULN 
> 15% Increase from Baseline 
Low (CL) 
< 0.85 × LLN 
> 15% Decrease from Baseline 
Mean corpuscular hemoglobin 
concentration (MCHC) 
High (CH) 
> 1.15 × ULN 
> 15% Increase from Baseline 
Low (CL) 
< 0.85 × LLN 
> 15% Decrease from Baseline 
Leukocyte count (WBC) 
High (CH) 
> 1.6 × ULN 
> 100% Increase from Baseline 
Low (CL) 
< 0.65 × LLN 
> 60% Decrease from Baseline 
Neutrophils 
High (CH) 
> 1.6 × ULN 
> 100% Increase from Baseline 
Low (CL) 
< 0.65 × LLN 
> 75% Decrease from Baseline 
Lymphocytes 
High (CH) 
> 1.5 × ULN 
> 100% Increase from Baseline 
Low (CL) 
< 0.25 × LLN 
> 75% Decrease from Baseline 
Eosinophils 
High (CH) 
> 4.0 × ULN 
> 300% Increase from Baseline 
Low (CL) 
N/A 
N/A 
Monocytes 
High (CH) 
> 4.0 × ULN 
> 300% Increase from Baseline 
Low (CL) 
N/A 
N/A 
Basophils 
High (CH) 
> 4.0 × ULN 
> 300% Increase from Baseline 
Low (CL) 
N/A 
N/A 
Platelets 
High (CH) 
> 1.5 × ULN 
> 100% Increase from Baseline 
Low (CL) 
< 0.65 × LLN 
> 50% Decrease from Baseline 
Notes:  PCS = potentially clinically significant 
            CH = high PCS based on criterion value and increase from predose. 
            CL = low PCS based on criterion value and decrease from predose. 
            *A postdose value is considered as a PCS value if it meets both criteria for observed value and 
              change from predose. 
 
Hematology data will also be provided via data listings.  
10.2.2. 
Serum Chemistry 
The number and percentage of subjects with any potentially clinically significant changes from 
baseline will be tabulated and summarized by treatment group. 
Table 3: Potential Clinical Significance (PCS) for Serum Chemistry Parameters 
Laboratory Parameter 
Flag 
Criteria* 
Observed 
Value 
Change from Baseline 
Bicarbonate 
High (CH) 
> 1.3 × ULN 
> 40% Increase from Baseline 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
22 
 
 
 
Laboratory Parameter 
Flag 
Criteria* 
Observed 
Value 
Change from Baseline 
Low (CL) 
< 0.7 × LLN 
> 40% Decrease from Baseline 
Sodium 
High (CH) 
> 1.1 × ULN 
> 10% Increase from Baseline 
Low (CL) 
< 0.85 × LLN 
> 10% Decrease from Baseline 
Potassium 
High (CH) 
> 1.2 × ULN 
> 20% Increase from Baseline 
Low (CL) 
< 0.8 × LLN 
> 20% Decrease from Baseline 
Phosphorus 
High (CH) 
> 3.0 × ULN 
> 200% Increase from Baseline 
Low (CL) 
< 0.5 × LLN 
> 50% Decrease from Baseline 
Chloride 
High (CH) 
> 1.2 × ULN 
> 20% Increase from Baseline 
Low (CL) 
< 0.8 × LLN 
> 20% Decrease from Baseline 
Calcium 
High (CH) 
> 1.3 × ULN 
> 30% Increase from Baseline 
Low (CL) 
< 0.7 × LLN 
> 30% Decrease from Baseline 
Alkaline phosphatase (ALP) 
High (CH) 
> 2.0 × ULN 
> 100% Increase from Baseline 
Low (CL) 
< 0.5 × LLN 
> 80% Decrease from Baseline 
Alanine Aminotransferase (ALT) 
High (CH) 
> 3.0 × ULN 
> 200% Increase from Baseline 
Low (CL) 
N/A 
N/A 
Aspartate Aminotransferase (AST) 
High (CH) 
> 3.0 × ULN 
> 200% Increase from Baseline 
Low (CL) 
N/A 
N/A 
Gamma-glutamyl transferase 
High (CH) 
> 3.0 × ULN 
> 200% Increase from Baseline 
Low (CL) 
N/A 
N/A 
Lactate Dehydrogenase (LDH) 
High (CH) 
> 4.0 × ULN 
> 300% Increase from Baseline 
Low (CL) 
< 0.4 × LLN 
> 60% Decrease from Baseline 
Bilirubin, Total 
High (CH) 
> 2.5 × ULN 
> 150% Increase from Baseline 
Low (CL) 
N/A 
N/A 
Glucose, non-fasting 
High (CH) 
> 3.0 × ULN 
> 200% Increase from Baseline 
Low (CL) 
< 0.6 × LLN 
> 40% Decrease from Baseline 
Protein, Total 
High (CH) 
> 1.5 × ULN 
> 50% Increase from Baseline 
Low (CL) 
< 0.5 × LLN 
> 50% Decrease from Baseline 
Albumin 
High (CH) 
> 1.5 × ULN 
> 50% Increase from Baseline 
Low (CL) 
< 0.5 × LLN 
> 50% Decrease from Baseline 
Serum creatinine 
High (CH) 
> 2.0 × ULN 
> 100% Increase from Baseline 
Low (CL) 
< 0.3 × LLN 
> 100% Decrease from Baseline 
Blood Urea Nitrogen (BUN) 
High (CH) 
> 3.0 × ULN 
> 200% Increase from Baseline 
Low (CL) 
< 0.2 × LLN 
> 100% Decrease from Baseline 
Notes:  PCS = potentially clinically significant 
            CH = high PCS based on criterion value and increase from predose. 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
23 
 
 
 
Laboratory Parameter 
Flag 
Criteria* 
Observed 
Value 
Change from Baseline 
            CL = low PCS based on criterion value and decrease from predose. 
            *A postdose value is considered as a PCS value if it meets both criteria for observed value and 
              change from predose. 
 
Serum chemistry data will also be provided via data listings.  
10.3. 
Vital Sign Measurements 
The number and percentage of subjects with any potentially clinically significant changes from 
baseline will be tabulated and summarized by treatment group for vital sign parameters including 
blood pressure and heart rate. 
Table 4: Potential Clinical Significance for Vital Signs Parameters 
Vital Sign Parameter 
Flag 
Criteria* 
Observed 
Value 
Change from Baseline 
Systolic Blood Pressure 
(mmHg) 
High (CH)  180 mmHg 
Increase of   20 mmHg 
Low (CL) 
   90 mmHg 
Decrease of  20 mmHg 
Diastolic Blood Pressure 
(mmHg) 
High (CH)  105 mmHg 
Increase of  15 mmHg 
Low (CL) 
   50 mmHg 
Decrease of  15 mmHg 
Heart Rate 
(bpm) 
High (CH)  120 bpm 
Increase of  15 bpm 
Low (CL) 
   50 bpm 
Decrease of  15 bpm 
Notes:   PCS = potentially clinically significant 
             CH = high PCS based on criterion value and increase from predose. 
             CL = low PCS based on criterion value and decrease from predose. 
              mmHg = Millimeter mercury.  bpm = Beat per minute. 
             *A postdose value is considered as a PCS value if it meets both criteria for observed value and 
              change from predose. 
 
Vital signs data will also be provided via data listings.  
10.4. 
 Physical Examination 
Complete physical examinations will be performed at Screening and Week 16 (or ET) and 
symptom-directed examinations will be performed as needed.  
 
Clinically significant abnormal findings will be summarized at Screening and Week 16 (or ET) 
by body system and overall for each treatment. 
 
All abnormal physical examination data will be provided via data listings.  
10.5. 
 C-SSRS 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
24 
 
 
 
C-SSRS data will be scored using the Columbia-Suicide Severity Rating Scale Score and Data 
Analysis Guide and the following summaries will be provided: 
• Number of subjects with suicidal ideation, suicidal behavior, and self-injurious behavior 
without suicidal intent during lifetime 
• Number of subjects with suicidal ideation, suicidal behavior, and self-injurious behavior 
without suicidal intent during past three years 
• Number of subjects with suicidal ideation, suicidal behavior, and self-injurious behavior 
without suicidal intent during double-blind treatment period 
• Shift-table to demonstrate changes in suicidal ideation scores from baseline during 
treatment 
CSSR-S data will also be provided via data listings.  
10.5.1. 
C-SSRS Outcomes, Endpoints, and Scoring 
The following outcomes are C-SSRS categories and have binary responses (yes/no): 
• Category 1: Wish to be Dead 
• Category 2: Non-specific Active Suicidal Thoughts 
• Category 3: Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
• Category 4: Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
• Category 5: Active Suicidal Ideation with Specific Plan and Intent 
• Category 6: Preparatory Acts or Behavior 
• Category 7: Aborted Attempt 
• Category 8: Interrupted Attempt 
• Category 9: Actual Attempt (non-fatal) 
• Category 10: Completed Suicide 
Self-injurious behavior without suicidal intent is also a C-SSRS outcome and has a binary 
response (yes/no). 
 
The following outcome is a numerical score derived from the C-SSRS categories. The score is 
created at each assessment for each patient and is used for determining treatment emergence. 
• Suicidal Ideation Score: The maximum suicidal ideation category (1-5 on the CSSRS) 
present at the assessment. Assign a score of 0 if no ideation is present. 
Composite endpoints using the categories described above are defined below. 
• Suicidal Ideation: A ”yes” answer at any time during treatment to any one of the five 
suicidal ideation questions (Categories 1-5) on the C-SSRS. 
• Suicidal Behavior: A ”yes” answer at any time during treatment to any one of the five 
suicidal behavior questions (Categories 6-10) on the C-SSRS. 
• Suicidal Ideation or Behavior: A ”yes” answer at any time during treatment to any one 
of the 10 suicidal ideation or behavior questions (Categories 1-10) on the C-SSRS. 
CSSR-S data will also be provided via data listings.  
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
25 
 
 
 
11. 
Changes from the Protocol in the Planned Analyses 
• Section 14.1 of the protocol version amendment 1 states that the primary efficacy 
endpoint is the proportion of responders in each treatment group, but in Section 14.4.1 
this same endpoint is said to be the proportion of responders in the 274 mg ADS-5102 
treatment group relative to the placebo group. The definition included in Section 14.4.1 is 
being used for this analysis.  
• Additional details on how the test for superiority will be performed for the primary 
efficacy analysis and the key secondary endpoints using the sequential gatekeeping 
strategy have been provided.  
• Emergency unblinding will be considered a major protocol deviation.  
• The Safety set will include all subjects who receive at least one dose of double-blind 
study drug.  
• Randomization date instead of first treatment with double-blind study drug will be used 
to determine adverse event treatment emergence. 
• Section 14.2 of protocol version amendment 1 states that any missing Week 16 efficacy 
data will remove a subject from the per-protocol population; the analysis will only use 
missing T25FW at Week 16 to exclude from that population.  
• During the finalization of the protocol, the numbering of the study weeks was revised as 
shown in the table below. 
 
Single Blind Placebo Run-in Period 
Double Blind 
Treatment Period 
Original 
numbering 
Week -4 
(prior to 
1rst pbo 
dose) 
Week -2 
Week 0 
(prior to 
randomization) 
Week 0 to Week 12 
Revised 
numbering 
Week 0 
(prior to 
1rst pbo 
dose) 
Week 2 
Week 4 
(prior to 
randomization) 
Week 4 to Week 16 
 
 
 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
26 
 
 
 
12. 
Changes from the Initial SAP version 
12.1.  Timed 25-foot Walk Percent Change 
The percent change in T25FW will be calculated and descriptive statistics (n, mean, median, 
standard deviation, minimum, and maximum) will be provided for the percent change by study 
visit. Additionally, the MMRM described in section 9.2 will be performed with the percent 
change from baseline as the dependent variable and fixed effects of treatment group, study week, 
and treatment by study week interaction. 
12.2. Prior Amantadine Use 
Prior Amantadine Use (Yes, No), form and reason for stopping (Side Effects, Loss of Efficacy, 
No Efficacy, Other), dose, and frequency of use will be summarized for the ITT set by treatment 
group and overall. 
12.3. Concomitant Multiple Sclerosis Therapies  
Concomitant multiple sclerosis therapies will be recorded beginning with the first dose of study 
drug and continuing through the last study visit. These medications will be summarized for the 
Safety set. At each level of summarization, a subject is counted once if he/she reported one or 
more medications at that level.  
 
 
 
 
 
 
 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
27 
 
 
 
13. References 
Dilokthornsakul P, Valuck RJ, Nair KV, Corboy JR, Allen RR, Campbell JD. Multiple sclerosis 
prevalence in the United States commercially insured population. Neurology. 2016; 86(11): 
1014-21. 
 
Goodman AD, Brown TR, Edwards KR, Krupp LB, Schapiro RT, Cohen R, Marinucci LN, 
Blight AR; MSF204 Investigators. A phase 3 trial of extended release oral dalfampridine in 
multiple sclerosis. Ann Neurol. 2010; 68(4): 494-502.  
 
Goodman AD, Brown TR, Krupp LB, Schapiro RT, Schwid SR, Cohen R, Marinucci LN, Blight 
AR, Fampridine MS-F203 Invstigators. Sustained-release oral fampridine in multiple sclerosis: a 
randomised, double-blind, controlled trial. Lancet. 2009; 373: 732-738. 
 
Hobart J, Ziemssen T, Feys P, et al. Prolonged-release fampridine induces sustained clinically 
meaningful improvements in walking ability in people with multiple sclerosis: results from the 
ENHANCE trial (P6.364). Neurology. 2017; 88. 
 
Kantarci O, Wingerchuk D. Epidemiology and natural history of multiple sclerosis: new insights. 
Curr Opin Neurol. 2006; 19(3): 248-254. 
 
Korsen M, Kunz R, Schminke U, Runge U, Kohlmann T, Dressel A. Dalfampridine effects on 
cognition, fatigue, and dexterity. Brain Behav. 2016; 7(1): e00559. 
 
Medical Dictionary for Regulatory Activities (MedDRA®). Version 21.0. IFPMA, International 
Committee on Harmonization. Geneva, Switzerland. 2018. 
 
Columbia-Suicide Severity Rating Scale (C-SSRS) Scoring and Data Analysis Guide. Version 
2.0. The Columbia Lighthouse Project. 2013 
 
Pahwa R, Tanner CM, Hauser RA, Isaacson SH, Nausieda PA, Truong DD, Agarwal P, Hull KL, 
Lyons KE, Johnson R, Stempien MJ. ADS-5102 (amantadine) extended-release capsules for 
levodopa-induced dyskinesia in Parkinson disease (EASE LID Study): a randomized clinical 
trial. JAMA Neurol. 2017; 74(8): 941-949.  
 
Pahwa R, Tanner CT, Hauser RA, Sethi K, Isaacson S, Truong D, Struck L, Ruby AE, McClure 
NL, Went GT, Stempien MJ. Amantadine extended release for levodopa-induced dyskinesia in 
Parkinson’s diease (EASED Study). Mov Disord. 2015; 30: 788-795. 
 
Prugger M, Berger T. Assessing the long-term clinical benefit of prolonged-release fampridine 
tablets in a real-world setting: a review of 67 cases. Patient Relat Outcome Meas. 2013; 4: 75-85.  
 
Ruck T, Bittner S, Simon OJ, Göbel K, Wiendl H, Schilling M, Meuth SG. Long-term effects of 
dalfampridine in patients with multiple sclerosis. J Neurol Sci. 2014; 337(1-2): 18-24.  
 
SAS Institute Inc. SAS Procedures Guide, Version 9.3. Cary, NC: SAS Institute Inc. 2010. 
 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
 
 
 
           Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
 
 
 
 
 
  Date Issued: 05Dec2019 
28 
 
 
 
Schumacher GA. Multiple sclerosis. J Am Med Assoc. 1950; 143(12): 1059-1065. 
 
WHO Drug Dictionary. WHODrug Global, Uppsala Monitoring Centre. Uppsala, Sweden, (Box 
1051, S-751). 2018. 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
                                                                                                    Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
                                                                                                                         Date Issued: 05Dec2019 
 
  
29 
 
 
 
14. 
Appendices 
14.1. 
Schedule of Events 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
                                                                                                    Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
                                                                                                                         Date Issued: 05Dec2019 
 
  
30 
 
 
 
Schedule of Study 
Procedures 
Screening 
Single-
Blind 
Placebo 
Run-In 
Period 
(±2 day)d 
Double Blind Treatment Perioda (±2 day) 
 
Safety 
Follow-Upb 
 (±2 day) 
Early 
Termination 
Baseline 
Maintenance  
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
 
Week 
 
0 
2 
4 
6 
8 
12 
16 
18 
 
Informed consent 
✓ 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
 
 
Demographics 
✓ 
 
 
 
 
 
 
 
 
 
Medical history  
✓ 
 
 
 
 
 
 
 
 
 
Medication history  
✓ 
 
 
 
 
 
 
 
 
 
Concomitant medications 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Adverse events  
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Complete physical exam  
✓ 
 
 
 
 
 
 
✓ 
 
✓ 
Symptom-directed physical 
exam, as needed  
 
 
 
✓ 
 
✓ 
✓ 
 
✓ 
 
Height 
✓ 
 
 
 
 
 
 
 
 
 
Weight 
✓ 
 
 
 
 
 
 
✓ 
 
✓ 
Vital signs  
✓ 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Hematology  
✓ 
 
 
 
 
 
 
✓ 
 
✓ 
Serum chemistry  
✓ 
 
 
 
 
 
 
✓ 
 
✓ 
Urinalysis  
✓ 
 
 
 
 
 
 
✓ 
 
✓ 
ECG (12-lead) 
✓ 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (if 
applicable) 
✓ 
 
 
 
 
 
 
✓ 
✓ 
✓ 
Urine pregnancy test (if 
applicable) 
 
✓ 
✓ 
✓ 
 
 
 
 
 
 
Expanded Disability Status 
Scale (EDSS) 
✓ 
 
 
 
 
 
 
 
 
 
Timed 25-Foot Walk (T25FW)c 
✓ 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Multiple Sclerosis Walking 
Scale-12 (MSWS-12)c 
 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Timed Up and Go (TUG)c 
 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
2-Minute Walk Test (2MWT)c 
 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
                                                                                                    Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
                                                                                                                         Date Issued: 05Dec2019 
 
  
31 
 
 
 
Schedule of Study 
Procedures 
Screening 
Single-
Blind 
Placebo 
Run-In 
Period 
(±2 day)d 
Double Blind Treatment Perioda (±2 day) 
 
Safety 
Follow-Upb 
 (±2 day) 
Early 
Termination 
Baseline 
Maintenance  
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
 
Week 
 
0 
2 
4 
6 
8 
12 
16 
18 
 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Randomization 
 
 
 
✓ 
 
 
 
 
 
 
Collect returned study drug & 
assess compliance 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
✓ 
Dispense study drug  
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
Study drug dosing, once daily 
at bedtime  
 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
 
✓ 
 
 
a In addition, telephone visits will be conducted at Weeks 5 and 7 to review dosing instructions and assess and record AEs and any changes in 
concomitant medications. 
b For subjects who elect not to enter the open-label extension study 
c Efficacy assessments include Multiple Sclerosis Walking Scale-12 (MSWS-12), Timed 25-Foot Walk (T25FW), Timed Up and Go (TUG), and 2-
Minute Walk Test (2MWT), to be performed in that order 
d Study visits should occur on the day scheduled. There is a (+/-) 2 day window for Visit 3 through Week 18. 
 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3

Adamas Pharmaceuticals, Inc 
 
                                                                                                    Statistical Analysis Plan, Version 2.0 
ADS-AMT-MS301 
 
 
                                                                                                                         Date Issued: 05Dec2019 
 
  
32 
 
 
 
14.2. 
Study Design Schematic 
 
 
DocuSign Envelope ID: 2C8CB54C-1B86-44D9-92CB-B7E1592EB2F3