Conditions: Multiple Sclerosis
Keywords: multiple sclerosis magnetic resonance imaging gait neuroprotective agents thioctic acid alpha-lipoic acid mobility chronic progressive multiple sclerosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 115
Healthy volunteers: no

Brief summary:
The purpose of the study is to determine if lipoic acid can preserve mobility and protect the brain in progressive forms of multiple sclerosis.

Detailed description:
This two-year study will determine if daily oral intake of lipoic acid will prove superior to placebo in reducing injury to the brain and maintaining mobility in progressive MS. Mobility will be assessed with the timed 25-foot walk test and 2-minute timed walk test as well as fall counts. Neuroprotection will be measured by the extent of brain volume loss seen on MRI.

Arms:
arm 1: 59 subjects receive oral lipoic acid 1200mg daily arm 2: 59 subjects receive placebo daily

Interventions: intervention 1: Lipoic acid intervention 2: Placebo
Intervention descriptions: intervention 1: 1200 mg taken by mouth daily for two years starting on day one of the study and ending on the last day of study participation. intervention 2: The placebo comparator will be taken by mouth daily for two years starting on day one of the study and ending on the last day of study participation

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
#1740 Lipoic Acid for Treatment of Progressive Multiple Sclerosis 
Funding Agencies: Rehabilitation Research & Development, National Multiple Sclerosis 
Society, MS Society of Canada 
Principal Investigator/Study Chair: Rebecca Spain 
Version 8.0: 18 February 2021 
Approved 30 March 2021 
NCT# 03161028 
 
 
 
 
 
 
 


 
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INVESTIGATOR AGREEMENT 
 
Protocol Version 8.0 
Lipoic Acid for Treatment of Progressive Multiple Sclerosis 
 
By signing, the Investigator agrees to have read the foregoing protocol and agrees to 
conduct the study as described herein. 
 
The Investigator agrees to keep all study documents stored appropriately to ensure their 
confidentiality. The Investigator should not disclose study information to others without 
authorization, except to the extent necessary to conduct the study. 
 
 
 
 
 
_____________________________________  
Investigator Name (Print)  
 
 
______________________________________  
_______________________  
Investigator Signature  
 
 
 
 
Date 
 
 
 
 


 
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Synopsis 
Study Investigator/Sponsor: Rebecca Spain, MD, MSPH 
Funding Sources: VA Merit review (RX002682-01, RR&D) National MS Society (R-
1705-27628), MS Society of Canada 
Investigational product: Lipoic acid (previous names alpha lipoic acid, thiotic acid). 
Investigational drug provided by Pure Encapsulations® 
IND#: 110132 
Title: Lipoic acid for treatment of progressive multiple sclerosis. 
Study Centers: VA and non-VA MS Centers (United States), Ottawa, Ontario (Canada) 
Study Sites: VA Portland Health Care System (VAPORHCS), VA Puget Sound Health 
Care System, Washington DC VA Medical Center, VA Salt Lake City Health Care 
System, Dallas VA Medical Center, Ottawa Hospital Research Institute, Swedish 
Medical Center, University of Alabama at Birmingham, University of Utah, University of 
Vermont, and University of Colorado. 
Duration of Study: Approximately 2 years 
Phase of Development: Phase 2 
Study Objectives: 
Primary objective: 
• Determine if lipoic acid (LA) is superior to placebo at 2 years in maintaining a 
clinically meaningful outcome, mobility, as measured by the primary outcome of 
change in completion time of the Timed 25 Foot Walk (T25FW). Two Minute 
Timed Walk (2MTW) and fall count will be evaluated to confirm the primary 
outcome results. 
 
Secondary objectives: 
• Determine if LA is superior to placebo at 2 years in slowing whole brain atrophy 
with an estimated 40-50%% effect size. Additional secondary outcome measures 
will include neurological disability, cognition, mood, and quality of life.  
• Monitor safety and tolerability of LA via laboratory testing and adverse event 
reporting. 
Study Design: Participants with primary progressive and secondary progressive 
multiple sclerosis (MS) will be randomized on a 1:1 basis to LA or placebo. Subjects will 


 
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complete 7 study visits over 2 years. Walking tests and secondary outcome measures 
will be performed at every visit. MRIs will be completed at baseline and study end. 
Safety laboratory measures will be collected at every study visit. The sample size of 59 
per arm will allow for a 25% drop-out rate. 
List of Abbreviations 
ACR, albumin to creatinine ratio 
AE, Adverse Event 
AIRC, Advanced Imaging Research Center 
ALP, alkaline phosphatase 
ALT, alanine aminotransferase 
AST, aspartate aminotransferase 
BBB, blood brain barrier  
BDP, Biostatistics & Design Program 
BND, Biorepository for Neurological Diseases 
CCC, Clinical Coordinating Center 
CDA, Career Development Award 
CFR, Code of Federal Regulations 
CNS, central nervous system 
DCC, Data Coordinating Center 
DMT, disease-modifying therapies 
DSMB, Data Safety and Monitoring Board 
EAE, experimental autoimmune encephalomyelitis 
EDSS, Expanded Disability Status Scale 
eGFR, estimated glomerular filtration rate using MDRD calculation 
FESI, Falls Efficacy Scale-International 
FDA, Food & Drug Administration 
GGT, gamma-glutamyl transferase 
GI, gastrointestinal 
GLTEQ, Godin Leisure-Time Exercise Questionnaire, modified 
ICF, informed consent form 
IND, Investigational New Drug 
IRB, Institutional Review Board 
LA, lipoic acid 
LSI, local site investigator 
M, month 
MDRD, Modification of Diet in Renal Disease  
MedDRA, Medical Dictionary for Regulatory Activities 
MPRAGE, Magnetization Prepared Rapid Acquisition Gradient Echo 
MS, multiple sclerosis 


 
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NMSS, National Multiple Sclerosis Society 
OCTRI, Oregon Clinical & Translational Research Institute 
OHSU, Oregon Health & Science University 
PCBV, percent change brain volume 
PCP, Primary Care Provider 
PD, Protocol Deviation 
PHI, protected health information 
PMS, progressive multiple sclerosis 
QC, quality control 
RCT, randomized controlled trial  
RIC, Recruitment Innovation Center 
RRMS, relapsing-remitting multiple sclerosis 
SAE, serious adverse events 
SBQ-R, Suicide Behaviors Questionnaire-Revised 
SC, Subcutaneous  
SCC, Statistical Coordinating Center 
SDMT, Symbol Digit Modalities Test 
SIENA, Structural Image Evaluation using Normalization of Atrophy 
SPMS, secondary progressive multiple sclerosis 
T, Tesla 
T25FW, Timed 25 Foot Walk 
UP, Unanticipated Problem 


 
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 Table of Contents 
 
Synopsis ............................................................................................................................... 3 
List of Abbreviations .......................................................................................................... 4 
Table of Contents ................................................................................................................ 6 
Protocol Title ........................................................................................................................ 9 
1.0 Key Study Personnel/Study Centers ...................................................................... 9 
2.0 Introduction .............................................................................................................. 10 
3.0 Objectives ................................................................................................................. 12 
4.0 Resources and Personnel ...................................................................................... 13 
5.0 Study Procedures .................................................................................................... 15 
5.1 Study Design ....................................................................................................... 15 
5.1a Design and specific aims ........................................................................... 15 
5.1b Study population ........................................................................................ 15 
5.1c Study timeline and visit scheduling ........................................................... 15 
5.1d Unscheduled visits for relapse evaluation and adverse events .............. 16 
5.1e Source of investigational drug ................................................................... 17 
5.1f Investigational new drug ............................................................................. 18 
5.1g Labeling ...................................................................................................... 18 
5.1h Blinding ....................................................................................................... 18 
5.1i Duration of treatment .................................................................................. 18 
5.1j Randomization............................................................................................. 18 
5.1k Compliance and medication reconciliation ............................................... 18 
5.1l Risks............................................................................................................. 18 
5.1m Protection from risks ................................................................................. 19 
5.1n Data banking .............................................................................................. 22 
5.1o. Optional biorepository participation……………………………………….22 
5.2 Recruitment Methods .......................................................................................... 23 
5.2a Recruitment goal ........................................................................................ 23 
5.2b Subject identification/recruitment .............................................................. 23 
5.2c Recruitment of specific subpopulations .................................................... 24 
5.2d Recruitment of Veterans ............................................................................ 24 
5.2e Sources of materials .................................................................................. 24 
5.2f Benefits ........................................................................................................ 24 
5.2g Cost to subjects.......................................................................................... 24 
5.2h Subject compensation ............................................................................... 25 
5.3 Informed Consent Procedures ........................................................................... 25 
5.4 Inclusion/Exclusion Criteria ................................................................................ 25 
5.5 Study Evaluations ............................................................................................... 27 
5.5a Study flowsheet .......................................................................................... 27 


 
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5.5b Consent, medical history, general medical exam .................................... 29 
5.5c Vital signs ................................................................................................... 29 
5.5d Concomitant medication review ................................................................ 29 
5.5e Safety laboratory analyses ........................................................................ 29 
5.5f Inclusion/Exclusion review ......................................................................... 29 
5.5g Walking tests .............................................................................................. 30 
5.5h EDSS .......................................................................................................... 30 
5.5i 9HPT ............................................................................................................ 30 
5.5j Cognitive tests ............................................................................................. 30 
5.5k Patient-reported outcome measures ........................................................ 31 
5.5l Fall count ..................................................................................................... 31 
5.5m MRI procedures......................................................................................... 31 
5.5n Suicidality monitoring ................................................................................. 32 
5.5o Adverse event monitoring .......................................................................... 32 
5.5p Investigational drug dispensing................................................................. 33 
5.5q Subject/provider blinding questionnaire ................................................... 33 
5.5r Subject disposition form ............................................................................. 33 
5.6 Data Analysis....................................................................................................... 33 
5.6a Sample size ................................................................................................ 33 
5.6b Data analysis plan...................................................................................... 33 
5.7 Withdrawal of Subjects ....................................................................................... 35 
6.0 Reporting .................................................................................................................. 35 
6.1 Adverse event reporting...................................................................................... 36 
6.2 Limited collection of non-serious AE .................................................................. 36 
6.3 Limited reporting of AE ....................................................................................... 36 
6.3a Limited reporting of AE, UP, and PD to the DCC .................................... 36 
6.4 Adverse event definition ..................................................................................... 37 
6.5 Serious adverse event definition ........................................................................ 37 
6.6 Unanticipated problem definition ........................................................................ 37 
6.7 Protocol deviation ................................................................................................ 37 
6.7a Mild PD ....................................................................................................... 37 
6.7b Moderate PD .............................................................................................. 38 
6.7c Severe PD .................................................................................................. 38 
6.8 Data and Safety Monitoring Plan ....................................................................... 39 
7.0 Privacy and Confidentiality .................................................................................... 39 
7.1 Protected health information .............................................................................. 39 
7.2 Privacy and confidentiality .................................................................................. 40 
7.3 Information and specimen management ........................................................... 40 
8.0 Communication Plan............................................................................................... 42 
8.1 Multi-site study coordination plan ....................................................................... 42 


 
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8.2 Ongoing communication ..................................................................................... 42 
8.3 Study monitoring ................................................................................................. 43 
9.0 References……………………………………………………………………………..44 


 
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Protocol Title:  Lipoic Acid for Treatment of Progressive Multiple Sclerosis 
1.0 
Key Study Personnel/Study Centers 
A current personnel list is provided with the manual of operations 
Principal Investigator/Study Chair: 
Rebecca Spain, MD, MSPH 
VA Portland Health Care System 
L226, 3181 SW Sam Jackson Park Road 
Portland, OR, 97239 
Ph: (503) 346-0768 
Fax: (503) 346-6921 
spainr@ohsu.edu (preferred); Rebecca.Spain@va.gov 
Project Manager: 
Carin Waslo, MPH 
VA Portland Health Care System 
waslo@ohsu.edu (preferred); Carin.Waslo@va.gov 
Clinical Coordinating Center (Rebecca Spain) 
VA Portland Health Care System 
 
Data Coordinating Center 
Oregon Clinical & Translational Research Institute (OCTRI) 
Oregon Health & Sciences University (OHSU) 
Portland, OR 
 
Statistical Coordinating Center 
OHSU Biostatistics & Design Program (BDP) 
Portland, OR  
 
Central MRI Reading Site 
OHSU Advanced Imaging Research Center  
Portland, OR   
 
 


 
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2.0 
Introduction 
Scientific Rationale and Significance  
Multiple sclerosis (MS) is a chronic progressive autoimmune disease of the central 
nervous system (CNS), and the most common neurologic disease of young adults 
including Veterans. More than 2.5 million people worldwide and around 500,000 people 
in the U.S live with MS. At any time, nearly half have a progressive MS (PMS) 
phenotype characterized by clinical worsening in the absence of exacerbations 
associated with CNS inflammation (1). Mobility deficits are a hallmark of MS with 
approximately half of all patients requiring a walking aid by 15 years after diagnosis. MS 
is divided into subtypes according to its course. About 85% people present with a 
relapsing-remitting MS (RRMS) subtype, then transition into a secondary progressive 
subtype (SPMS) after 10-20 years. The remaining 10-15% present with unremitting 
progression from onset called primary progressive MS (PPMS) (2). Taken together, 
PPMS and SPMS are termed progressive MS (PMS). Patients with PMS, including 
veterans, use a disproportionate quantity of social and medical services, and report a 
lower quality of life than RRMS (3). 
MS is traditionally considered an inflammatory disorder characterized by episodic CNS 
demyelination but current understanding is that neurodegeneration accompanies 
progression from disease onset. Neurodegeneration causes generalized atrophy 
throughout the CNS including the brain, spinal cord, and optic nerves (4-6). Atrophy of 
both the brain and spinal cord can be observed on MRI using now standard post-
processing techniques (7). Targeting specific mechanisms of neurodegeneration is a 
rational strategy for development and validation of therapeutic interventions for PMS. 
Lipoic acid (LA) is an endogenously-produced eight carbon sulfur-containing fatty acid 
that is synthesized de novo in plants and animals. Endogenous LA is bound to proteins 
and is involved in acyl transfer reactions (8). It can also be absorbed from natural food 
sources and nutritional supplements. LA and its reduced form dihydrolipoic acid (DHLA) 
form a redox couple serves as a cofactor for at least five enzymes. LA in addition has 
antioxidant functions including free-radical scavenging, metallic ion chelation, 
regeneration of intracellular glutathione, and repair of oxidative damage to 
macromolecules (9). In mitochondria, the LA/DHLA redox couple serves as a key co-
factor for the pyruvate dehydrogenase complex of oxidative respiration, and aids 
synthesis of nucleic acids (10). LA is involved in modulation of signal transduction 
including the PKB/Akt signaling pathway important for vascular endothelial integrity, 
redox-sensitive transcription factors including Nrf2, and acts as an insulin mimetic to 
reduce insulin resistance (11, 12). LA is available as an inexpensive dietary 


 
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supplement, and the most common synthetic formulation of LA is the racemic mixture of 
its R and S enantiomers.  
Our center and others have shown that LA reduces impairment in a dose-dependent 
fashion in the murine model of MS, experimental autoimmune encephalomyelitis (EAE) 
(13, 14). Our center has also shown that LA is safe and tolerated in people with MS, 
and conducted dose-finding pharmacokinetic (PK) studies. Oral administration of LA at 
1200 mg/day produces easily detectable blood levels in people with MS and achieves 
levels comparable to therapeutic blood levels in mice with EAE (15). The same dose of 
LA has been used in trials for diabetic polyneuropathy and shown to be well-tolerated in 
two year trials for this indication (16). The most common adverse reactions in LA trials 
are gastrointestinal intolerance, headache, malodourous urine, and rash (16, 17). One 
participant in our Center’s prior clinical trial of LA in secondary progressive MS and one 
in the currently ongoing study developed biopsy-proven membranous 
glomerulonephritis (18). Both participants developed urine protein and limb edema 
leading to the diagnosis. At 6 months follow-up from study exit, the participant no longer 
had abnormal labs, edema, or required nephrologist care. This participant is under 
ongoing care monitoring.  
We discovered that LA significantly reduced brain atrophy in people with SPMS 
compared to placebo in our pilot randomized controlled trial (RCT, see Preliminary 
studies) (18). The natural antioxidant, LA, produced a significant reduction in brain 
atrophy assessed by MRI in people with secondary progressive MS (SPMS). 
Additionally, the LA cohort had a trend toward improvement in walking tests and a 
reduction in falls. Importantly, LA was safe, well tolerated, and had very high 
compliance.  
Significance: The impressive results of the pilot LA in SPMS trial make LA an attractive, 
safe, natural, and tolerated DMT candidate for people who suffer from PMS. The goal of 
this larger, multi-site, Phase 2 RCT of LA in a broader PMS population is to confirm the 
effects on brain atrophy rate reduction and 
to establish the clinical benefits of LA. 
Preliminary Studies 
LA suppresses EAE, the animal model of 
MS, in a dose-dependent fashion. In a 
study of EAE mice treated with LA before 
disease onset, LA in doses of 100 
mg/kg/day, 50 mg/kg/day, and 20 
mg/kg/day were all effective in 
Fig. 1. Dose-response curve of EAE 
suppression in LA-treated mice. 


 
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Figure 4. LA reduces brain atrophy in 
SPMS participants using intention-to-
treat analysis. 
suppressing EAE (19). An LA dose of 20 mg/kg/day suppressed EAE development by 
almost 50% (according to Cumulative Disease Scores scores), a dose of 50 mg/kg/day 
suppressed EAE by ~80%, and a dose of 100 mg/kg/day suppressed EAE by 100% 
over 10 days (Fig.1).  
PK studies in EAE and humans have determined the human equivalent dose to the 
therapeutically effective dose in EAE. Two PK studies of LA in people with MS were 
conducted at OHSU and determined that doses of 1200mg taken with food were easily 
detectable LA levels in the serum and had reasonable gastrointestinal tolerability (15, 
17). A formulation from the PK studies was used in the pilot LA in SPMS trial and will be 
used again in the current trial of LA in PMS. 
Spain et al conducted a single-center, 2-year 
randomized, double-blind, placebo-controlled 
phase 2 trial (n=51) of daily oral LA in SPMS 
(18). The LA cohort demonstrated a 68% 
reduction in the annualized rate of whole 
brain atrophy (0.21% vs -0.65%, p = 0.002, 
Fig 4). Although not powered to detect 
clinical outcomes, the LA cohort had a trend 
toward improvement in walking speed in the 
T25FW (-0.54 SD 0.36 vs 0.14 SD 0.25, p = 
0.06). Overall LA was safe and well tolerated 
with high compliance and at the time, no 
unexpected deleterious adverse events (AE) 
were attributed to LA. A later review of AE’s 
in light of safety data emerging from the 
present study indicate that the serious 
adverse event of biopsy-proven glomerulonephritis and a second case of proteinuria in  
subjects in the LA cohort was related to lipoic acid (see above). To date, all three cases 
resolved within a 3-12 month period. Gastrointestinal (GI) upset was significantly 
greater in the LA cohort compared to placebo (17% v 3% p = 0.004). Unexpectedly, the 
LA cohort had a significantly lower number of falls than the placebo cohort (15% v 38%, 
p = 0.03). The results of this study formed the basis of the current research trial.  
3.0 
Objectives 
Hypothesis:  The purpose of this study is to determine if the oral antioxidant LA provides 
clinical benefits and reduces brain atrophy in PMS. The hypothesis is that daily LA will 
both maintain mobility and reduce whole brain atrophy, thus paving the way for 


 
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consideration of LA as a disease-modifying therapy for PMS. The specific aims of this 
multi-center RCT of 1200mg oral daily LA versus placebo in PMS are: 
Specific Aim 1. Determine if LA is superior to placebo in maintaining mobility as 
measured by the primary outcome of change in completion time of the Timed 25 Foot 
Walk (T25FW). Secondary outcomes are changes in the 2 Minute Timed Walk (2MTW) 
and fall count for consistency of the effects of LA on mobility.  
 
Specific Aim 2. Determine if LA is superior to placebo in slowing whole brain atrophy 
with an estimated 40-50%% effect size. Additional secondary outcome measures are 
changes in neurological disability, cognition, mood, and quality of life.  
 
Specific Aim 3. Monitor safety and tolerability via laboratory testing and adverse event 
reporting. 
4.0 
Resources and Personnel 
The research study will be conducted at both VA and non-VA study sites.  VA Portland 
Health Care System (VAPORHCS) is the lead study site and serves as the Clinical 
Coordinating Center (CCC). The Oregon Clinical & Translational Research Institute 
(OCTRI) within Oregon Health & Science University (OHSU, Portland, OR) will serve as 
the Data Coordinating Center (DCC). The Statistical Coordinating Center (SCC) is 
housed in the OHSU Biostatistics & Design Program (BDP). The OHSU Advanced 
Imaging Research Center will act as the Central MRI Reading Site. 
Rebecca Spain is the Grant PI and the Sponsor-Investigator for this IND study. Dr. 
Spain is responsible for the overall conduct of the study. She has access to PHI from all 
study subjects. She is permitted to be the LSI and treating neurologist at VAPORHCS. 
Local Site Investigators (LSI): Each study site has a LSI that is responsible for the 
overall conduct of the study at their site including regulatory oversight. The LSI has 
access to PHI for subjects from their site only.  
Site treating neurologist: The treating neurologist is responsible for reviewing the 
inclusion/exclusion criteria, conducting the screening medical history and exam, 
reviewing safety laboratory results, adverse event recording and reporting, and 
conducting unscheduled visits as needed for adverse event evaluation. The site treating 
neurologist has access to PHI for subjects from their site only. The treating neurologist 
may also hold the role of LSI. 


 
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Project Manager (PM): This person at principal study site (Portland) will assist the study PI 
in all aspects of study management and coordination. The PM will not collect primary data 
from subjects. The PM will work closely with all study team members to attain initial IRB 
approval, ensure the accurate and timely collection and recording of study data, monitor 
recruitment, assist with site IRB submissions and revisions, improve study logistics, 
conduct conference calls, tabulate data for the DSMB, and assist in any other aspects of 
study required for successful completion. The PM will serve as the study monitor. The PM 
has access to PHI for all study subjects. 
Site blinded EDSS examiners: EDSS examiners must have training in the neurological 
exam and experience conducting EDSS exams. The blinded EDSS examiner should not 
be the usual treating neurologist of the subject in order to maintain the blind. The blinded 
EDSS examiners may have access to PHI for subjects from their site only. 
Central Research Pharmacy: Portland VA Research Pharmacy will act as the Central 
Research Pharmacy for the entire study. They will receive bulk study drug from the 
product donor and redistribute it to US study site Research Pharmacies who then prepare 
study drug for individual subjects. The Central Research Pharmacy works with the SCC to 
maintain the randomization lists for each study site. The Central Research Pharmacy has 
access to PHI for all study subjects.  
Site research pharmacies: The US site research pharmacies will receive study drug from 
the Central Research Pharmacy and package it for individual subjects according to the 
randomization schedule. They will also provide medication reconciliation reports. The 
Canadian site research pharmacy will receive study drug directly from the product donor 
and then perform the same functions as the US site pharmacies. The site research 
pharmacies have access to PHI for subjects from their site only. 
Clinical Coordinating Center (CCC): VAPORHCS will serve as the CCC. The CCC will 
serve as the primary communication hub between study sites, study centers, and 
monitoring bodies.  
Data Coordinating Center (DCC): The DCC and the PM will work closely to set up and 
maintain the study database, create policies and procedures for the study, monitor data 
quality and accuracy, and help create DSMB reports. The DCC will receive reports from all 
study sites regarding adverse events (AE), serious adverse events (SAE), unexpected 
problems (UP), and protocol deviations (PD) and ensure proper reporting to IRBs per 
reporting requirements. 


 
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Statistical Coordinating Center (SCC): The SCC will conduct all data analyses, assist in 
DSMB reports, and create all final reports, figures, and statistical analysis sections of 
manuscripts that result from this study. The SCC will have access to PHI from all subjects.  
Central MRI Reading Site: The Central MRI Reading Site will receive MRI images from all 
study sites, perform QC monitoring of images and facilities, provide feedback on image 
quality issues, conduct all study related image analyses, and enter the analysis results into 
the study database. The Central MRI Reading Site will have access to PHI from all study 
subjects. 
Data Safety and Monitoring Board (DSMB): The DSMB will develop the DSMB charter and 
will meet at least yearly to review aggregate safety data and study progress. The DSMB 
will provide a report to the PI with recommendations regarding ongoing conduct of the 
study. As a member of the DSMB, Dr. Mary Samuels will be the Medical Monitor for this 
study. Dr. Rupali Avasare, a nephrologist at OHSU, will monitor any abnormal kidney 
function at the time of entry of during the course of treatment. The DSMB will have access 
to PHI from all study subjects. 
5.0 
Study Procedures 
5.1 Study Design 
5.1a. Design and specific aims: This is a phase 2, double-blind, multi-center RCT to 
compare the daily administration of 1200 mg oral LA to a placebo, as a disease-
modifying treatment in PMS. A total of 118 subjects with PMS will be randomized 1:1 to 
LA or placebo. None of the study procedures involve usual care. All study procedures 
will be covered by study funding. 
5.1b. Study population: A convenience sample of adults with PMS will be recruited 
from the study sites. The multi-site design of the trial is intended to promote 
generalizability of the study results.  
5.1c. Study timeline and visit scheduling. The anticipated study recruitment period is for 
the first 18 months once the study is approved at the first study site or until enrolment is 
completed, whichever occurs first. The study will end when the last participant exits the 
study. There should be no more than 60 days inclusive between the screen and 
baseline visits. Subsequent study visits will occur at 3 months, 6 months, and every 6 
months thereafter, each visit within +/- 2 weeks from the ideal visit based on the 
baseline/month zero (M0) visit. The MRI can take place up to 2 weeks prior to the 
baseline and final visits. Should the final MRI be postponed for any reason until after the 


 
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final visit, the subjects should continue taking study drug until the MRI has been done. 
Reasons for conducting visits outside the scheduling window are recorded. 
 
Performance on clinical measures may be subject to variation due to the day-to-day 
fluctuations characteristic of PMS. Effects of fluctuations on study outcomes will be 
minimized by encouraging subjects to maintain their usual sleep, eating, and medication 
intake patterns on study days. Study visits will be scheduled at the same time-period 
each visit (morning versus afternoon). Study visits may be postponed for concurrent 
non-MS related illness affecting neurological performance on the discretion of the 
treating neurologist. 
 
5.1d. Unscheduled visits for relapse evaluation and adverse events (AE): Unscheduled 
visits will occur in the event of MS clinical relapses or investigations of AE of at least 
moderate severity considered directly related to the study drug or study procedures. 
The unscheduled visit for AE is for the purpose of evaluation by the treating neurologist, 
documentation, and reporting according to IRB guidelines. If sufficient medical 
documentation by other health providers for the symptoms of the AE exist, or if the 
symptoms had resolved by the time of reporting, the treating neurologist may use the 
medical documentation or telephone interview in lieu of an unscheduled visit. 
Asymptomatic elevations or depression in laboratory values considered related to the 
investigational drug do not require an unscheduled visit but instead follow the 
monitoring procedure (5.1m. Protection from risks).  If AEs warranting an unscheduled 
visit are noted during a scheduled study visit, procedures for both the unscheduled visit 
for AE and the scheduled study visit are completed. An unscheduled visit for AE 
evaluation includes collection of case report forms for:  
 
AE evaluation documentation including event history 
 
General medical exam 
 
Vital signs 
 
Concomitant medications 
 
Safety laboratory measures (per treating neurologist discretion) 
 
Adverse events monitoring  
 
SBQ-R 
A protocol-defined MS clinical relapse is defined as new or recurrent neurological 
symptoms, not associated with fever or infection, lasting for at least 24 hours, which is 


 
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followed by a period of stability or improvement. In addition, a protocol-defined relapse 
requires an increase in the EDSS Functional System corresponding to the symptom(s) 
of the relapse, or an increase in the overall EDSS secondary to a functional change 
related to symptoms(s) of the relapse. A relapse is not considered an adverse event. 
MS clinical relapses can occur in PMS and may be treated by the usual treating 
neurologist with standard courses of intravenous methylprednisolone or oral steroids of 
less than 2 weeks duration.  
An unscheduled visit should be conducted within 1 week of a reported MS clinical 
relapse. The unscheduled visit for MS clinical relapse evaluation includes: 
 
MS clinical relapse evaluation documentation including 
 
General medical exam 
 
Vital signs 
 
Concomitant medications  
 
EDSS examination (blinded) 
 
Safety laboratory measures (per treating neurologist discretion) 
 
 
Adverse events monitoring 
 
SBQ-R 
Subjects who have discontinued the investigational drug for adverse events including 
laboratory monitoring (see section 5.1m.) do not require unscheduled visits for 
subsequent MS clinical relapses.  
Scheduled study visits involving MRIs will be delayed for at least 30 days following high 
dose oral or intravenous corticosteroid treatment given for any indication.  MS clinical 
relapses not treated with corticosteroids do not affect study visit scheduling. Ongoing 
MS clinical relapses noted during a scheduled study visit have procedures for both the 
unscheduled visit for MS clinical relapse and the scheduled study visit completed. 
Subjects who withdraw early from the study follow the procedures outlined in 
Withdrawal of Subjects (sec 5.7). 
 5.1e. Source of investigational drug. Pure Encapsulations®, which follows Good 
Manufacturing Procedures in their production of LA, will provide gelatin capsules 


 
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containing 600 mg of LA and the encapsulated placebo rendered to appear similar to LA 
(Letter of support, Appendix A).  
5.1f.  Investigational New Drug (IND). Dr. Spain holds an IND for testing LA in PMS 
(#110132). The current proposed study has been added as an amendment to the 
current IND. Reporting requirements to the FDA will be followed. 
5.1g. Labeling: The investigational product will have a label that will be visible on the 
pertinent storage containers. The label or labeling of an investigational new drug shall 
not bear any statement that is false or misleading in any particular and shall not 
represent that the investigational new drug is safe or effective for the purposes for which 
it is being investigated.  
5.1h. Blinding. Blinding of the investigational drug will be implemented by the site 
research pharmacies using identical containers, and instructions. The Central Research 
Pharmacy will maintain a master record of subject assignment. Subjects and all 
personnel involved in conducting the trial will remain blinded to treatment assignment 
and undergo a blinding questionnaire at study end. 
 
5.1i.  Duration of treatment: Treatment with study drug will be for 2 years. Treatment 
will extend beyond 2 years if the final study visit is postponed. See section 5.7 for 
reasons for early termination of treatment. 
 
5.1j.  Randomization. The assignment of subjects to the treatment arms will be based 
on permuted block randomization defined by study site. The Central Research 
Pharmacy and SCC will oversee the randomization schedule. The Central Research 
Pharmacy will also maintain a master list of all study subjects in order to ship 
appropriate amounts of bulk study drug to the US site pharmacies for individual subject 
packaging and shipping.  
5.1k. Compliance and medication reconciliation: Compliance with taking the 
investigational drug will be encouraged at each visit and between visits by telephone 
calls. Unused pills will be collected at each study visit and if necessary, by mail between 
visits. The study site research pharmacies will conduct medication reconciliation with 
returned pills and provide feedback to research staff to monitor if compliance is less 
than 75% or more than 125% of prescribed doses to encourage proper compliance. 
5.1l. 
Risks: Risks of the investigational drug, study procedures, and potential loss of 
confidentiality are reviewed with potential subjects during the informed consent process. 
Risks, reporting, responses to risks, and methods to minimize risks are further outlined 
in section 6.0, Reporting and 7.0, Privacy and Confidentiality. Briefly, risks of the 


 
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investigational drug are minimized by adverse event reporting safety and safety 
laboratory studies. Risks of study procedures are minimized by careful screening 
procedures and trained study personnel. Risks of loss of confidentiality are minimized 
by limiting collection of PHI, limiting access of PHI to the minimum necessary study 
staff, and use of secure data transfer methods. 
Risks of LA: Oral LA can cause physical side effects including gastrointestinal (GI) 
intolerance, nausea and vomiting and rash. LA may cause liver, renal and urinary 
disorders. There is a possibility of developing proteinuria and/or membranous 
glomerulonephritis due to study drug. It is not known how LA could affect a fetus. LA 
may increase the risk of hypoglycemia in diabetics. The risks of LA taken with DMTs or 
with alcohol are unknown.  
Risks of study procedures and loss of confidentiality: There is a risk of falls and injury 
during gait testing. The MRI magnet can cause metal in the body to move, heat, and 
cause injury. The MRI space is small, so those with claustrophobia are at risk of 
discomfort during the study. There is a risk of psychological harm from incidental 
findings unrelated to the study found on MRI such as brain tumors, stroke, other. The 
risks of blood draws include discomfort, vasovagal syncope, bleeding, bruising, and 
infection. The risks of clinical testing and patient-reported outcome measures include 
psychological discomfort from discovering or reporting deficits due to MS. There is a risk 
of loss of confidentiality of the study data. 
5.1m. Protection from risks: The informed consent process will inform potential subjects 
of the risks of participation. The study will be conducted with IRB oversight. Procedures 
in this study were specifically designed to minimize risks to the subjects. The 
investigators will adhere to the Data and Safety Monitoring Plan (sec. 6.2). Trained 
study personnel will perform all data collection, and information will be coded with a 
subject identifier to protect subject confidentiality. Findings that could affect the subjects’ 
health or welfare will be reported to the appropriate authorities (e.g. IRB) and 
communicated to the subjects and appropriate medical service(s) which could include 
the primary care physician. 
Risks to subjects from LA will be minimized by excluding unsuitable patients from 
enrollment, reviewing medical histories and medications at each study visit for potential 
interactions with the investigational drug, reviewing AEs for relation to investigational 
drug, and requiring unscheduled visits for AE evaluation and management.  
To minimize the possible GI side effects of oral LA, we recommend subjects take the 
investigational drug with food, or if necessary, to divide the daily dose, or the dose 


 
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reduced by 50% at the discretion of the treating neurologist. Serum renal panels and 
urinalyses will monitor for kidney damage at every visit.  
Trained phlebotomists will perform blood draws to minimize the associated risks of 
blood draws. Safety monitoring laboratory panels will monitor for liver, kidney, and 
hematological problems, pregnancy for women of childbearing potential and changes in 
HbA1c.  
a. Proteinuria monitoring: Subjects must have urine protein monitored every 3 
months for the duration of the study.  Subjects must pause study drug if they 
skip or miss a visit until draw can occur.   
Subjects with baseline (screening) negative or trace proteinuria may participate 
in the study. Subjects with baseline 1+ or higher proteinuria are further tested for 
albumin to creatinine ratio (ACR): 1) ACR ≤ 300mg/g may participate, 2) ACR 
>300mg/g are excluded and receive referral to PCP. No repeat screening for 
proteinuria in subjects who have ACR >300mg/g will be done. 
Subjects who experience 1+ or higher proteinuria during the study are further 
tested for ACR: 1) ACR ≤ 300mg/g may continue participation, 2) ACR >300mg/g 
permanently stop study drug and receive referral to PCP or nephrologist along 
with notification of the Medical Monitor. A referral to Nephrology is recommended 
if ACR>1000mg/g. A kidney biopsy is recommended if proteinuria >300 does not 
resolve within 6 weeks of drug cessation. 
b. Renal function monitoring: Subjects with baseline eGFR ≥ 60 may participate in 
the study. Subjects with baseline eGFR<50 are excluded. Subjects with baseline 
eGFR 50-59.9 are retested: 1) eGFR ≥ 60 may participate in the study, 2) 
eGFR<60 are excluded.   
Subjects who experience eGFR 50-59.9 during the study are retested within 1 
month: 1) eGFR ≥ 60 may continue participation in the study, 2) eGFR<60 
permanently stop study drug and are referred to PCP. Subjects who experience 
eGFR<50 during the study permanently stop study drug and referred to PCP. 
Regardless of the eGFR, if the eGFR decreases by 25% or more compared to 
the baseline eGFR, the Medical Monitor should be notified and should review the 
information to determine the next course of action.   
c. Liver function monitoring: Abnormal liver laboratory results are graded according 
to the Common Terminology Criteria for Adverse Events v5.0 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm). 


 
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Subjects who have stable and asymptomatic baseline Grade 1 abnormal 
laboratory liver values may, at the discretion of the site treating neurologists, 
participate in the study. Subjects who experience laboratory abnormalities of 
Grade 1 during the study will be permitted to continue at the full dose of study 
drug unless advised otherwise by the DSMB or other monitoring entities.  
Abnormal laboratory tests may be repeated immediately if laboratory testing error 
is suspected. Laboratory tests should be repeated within 1 month for any liver 
values reaching a Grade 2 or greater.  
If laboratory liver value(s) are still Grade 2 or greater by 1 month, the 
investigational drug will be reduced by 50% and levels checked again within 1 
month. The rationale is that liver-related abnormalities are often dose-dependent. 
If laboratory liver value(s) improve to Grade 1 or less, the study drug dose is then 
increased to the full dose. If the same subsequent laboratory value(s) worsen 
again at the full dose, the subject may continue for the study duration at the 50% 
dose as long as subsequent laboratory values do not meet Grade 2 or greater 
levels. If subjects on a 50% dose demonstrate continued Grade 2 value(s) at a 
maximum of 1 month, subjects should stop the investigational drug. Those 
subjects for whom laboratory values do not improve to Grade 1 or better levels 
after 2 months off study drug permanently stop study drug. Only two 
investigational drug cessations are allowed for each subject. Any subject who 
experiences a third Grade 2 or higher laboratory test must permanently 
discontinue the investigational drug. If in question, permanent study drug 
discontinuations can be discussed with the Medical Monitor to establish the 
relationship of the laboratory result to the investigational drug. Subjects continue 
study procedures following the study flowsheet until study end during any 
investigational drug dose reductions and temporary cessations (see 5.1d for 
special handling of MS clinical relapse evaluations).  
Safety laboratory results will be reviewed by site treating neurologists within 3 business 
days to determine if dose adjustments or safety reporting is required along with 
documentation and reporting as required (section 6.0 Reporting). 
Sexually active female subjects capable of becoming pregnant and female partners of 
sexually active male subjects will be asked to use effective birth control during the 
study. If a female participant or partner of a male participant becomes pregnant during 
the research study, study personnel must be notified immediately. Subjects will be 
advised not to breastfeed while taking this investigational drug. Screening for pregnancy 
in female subjects of child-bearing potential will be conducted via pregnancy tests at 
study visits.  


 
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Because LA may increase the risk of hypoglycemia in diabetics, otherwise eligible 
subjects who are diabetics must have their diabetes controlled on non-insulin 
medications. Safety monitoring labs at every visit for all subjects includes non-fasting 
blood glucose levels, and HbA1c levels.  
Because the risks of LA taken with DMTs are unknown, safety laboratory monitoring will 
screen for interactions affecting target organs. Subjects will be advised not to drink 
alcohol while taking the investigational drug and to store it out of reach of children.  
The risk of falls during gait testing will be minimized by having trained research staff 
present at all times during gait testing, and a gait belt will be utilized as needed. Gait 
testing will be aborted if there is concern for safety or falls by either the participant or 
research staff. 
Risks of MRI will be minimized by careful attention to MRI exclusion criteria at the 
screening visit including those who require non-oral sedatives during the scan. Any 
incidental findings unrelated to the study found on MRI such as brain tumors, stroke, 
etc., will be reviewed by the site treating neurologist who will consider referral to the 
appropriate medical service, determine ongoing safety for the subject’s continued 
participation in the study, and to fulfil any reporting requirements necessary. Site 
treating neurologists will counsel subjects with unexpected findings on MRI to minimize 
any psychological trauma incurred by the discovery.  
Overall, the risks of LA are considered minimal and are outweighed by the potential 
benefits to be gained by the study. 
5.1n. Data banking: MRI and images and analyses results along with subject 
demographics and medical histories will be banked in the VAPORHCS Biorepository for 
Neurological Diseases (BND #2916). The only PHI included in the data repository is the 
date of study visit. These dates are necessary for the proper identification of images 
and data in subjects with multiple data entry points. The banking of the images is 
described in the Informed Consent Form (ICF). 
5.1o. Optional biorepository participation: All subjects who have consented to the 
LAPMS study will be asked if they would like to contribute their blood to the 
Biorepository for Neurological Diseases (BND) #2916 (Rebecca Spain, director, 
Portland, OR). If the subject consents to the blood donation, approximately 10ml (2 
teaspoons) of the blood collected at each study visit requiring a routine lab draw will be 
saved for storage in the BND indefinitely for future research. A coded data set including 
study ID, date of specimen collection, study visit, sex, age at time of blood draw, 
education, diagnosis, disease duration, study arm, and comorbid health conditions is 


 
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also stored indefinitely with the donated blood. Subjects are allowed to start or stop 
participation in the biorepository at any time, however, per the consent for the BND, 
blood samples already provided to recipient IRB-approved studies cannot be extracted 
after donation.  
 
Subjects who consented to the LAPMS trial, prior to the addition of blood donation to 
the BND, will be asked to sign an updated consent indicating if they do or do not 
consent to adding their blood to the BND. Only subjects who sign an updated ICF 
indicating agreement will have their blood included in the biorepository.  
5.2 Recruitment Methods 
5.2a. Recruitment goal: A total of 118 subjects will be recruited for the study which 
includes an expected 25% will-drop rate out after enrolment. More potential subjects will 
be screened than enrolled as it is expected that some will not meet eligibility 
requirements despite screening methods. The PM and DCC will monitor recruitment 
across study sites and provide feedback on when enrolment is complete in order to stop 
recruitment (see Communication Plan 8.0). Recruitment data and reasons for failing to 
enroll in the study will be collected periodically from all study sites for the purpose of 
encouraging enrolment and identifying barriers to participation. 
5.2b. Subject Identification/Recruitment: Potential subjects for the study will be recruited 
by the site study staff from MS clinics and from the general public by methods approved 
by the study site’s local Institutional Review Board (IRB) and/or a Central IRB. Sample 
advertisements recruitment flyers (Appendix B), recruitment letters to local MS 
practitioners (Appendix C), and telephone scripts for interested Veterans and non-
veterans (Appendix D) are provided to each site. Email blasts to potential subjects will 
be sent from the National MS Society using the approved language contained in the 
recruitment flyers and letters (Appendix E). The NMSS promotes the study by hosting a 
webpage including a study summary, site locations, and study coordinator contact 
information. A short URL (Appendix X), linking to the NMSS webpage, may be 
distributed during media interviews, and added to promotion materials (Appendix Y) 
during MS related events, such as but not limited to, MS Walks, MS races, and MS 
support groups. ResearchMatch.org will be used as one of the recruitment tools for this 
research study/protocol. ResearchMatch Volunteers will be contacted through 
ResearchMatch.org using the approved language contained in the recruitment message 
(Appendix W). A release of information will be obtained as needed to request medical 
records for eligibility review prior to scheduling screening visits. Participants enrolled in 
the North American Research Committee on Multiple Sclerosis (NARCOMS) registry for 
Multiple Sclerosis will receive an approved study flyer in the mail. As with other 
recruitment tools, a release of information will be obtained as needed to request medical 


 
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records for eligibility review prior to scheduling screening visits. We will make use of the 
contact information in Dr. Rebecca Spain’s MS Research Repository (IRB#18541). This 
repository contains names and contact information of people interested in research 
participation. All subjects included in the repository have consented to being contacted 
for opportunities for participation in research. Initial contact with potential participants 
will be made by the research coordinator. The CCC will also work with the Recruitment 
Innovation Center (RIC) at Vanderbilt University to implement a 4-week, multicity, social 
media ad campaign in partnership with a marketing agency, Red Deluxe. Red Deluxe, a 
recruitment tool, will have 3rd party administrative access to a study Facebook page, 
managed by the CCC, in order to monitor and push Facebook ads to a targeted 
audience based on eligibility criteria and interest in MS. Examples and text of the 
components within the social media ad campaign include the Facebook page (Appendix 
Z), the Facebook Ads (Appendix AA), and the study webpage (Appendix BB) and 
content (Appendix CC), adhering to the VA Graphic Standards Guide. 
5.2c. Recruitment of specific subpopulations. MS has a predilection for affecting 
women in a 3-4:1 ratio. Therefore we expect women to be adequately represented in 
this current study using a convenience sample. Minorities will not be preferentially 
recruited as there is no data to suggest a differential effect of LA on specific minority 
populations and/or with particular genetic characteristics. MS is rare in children, and 
progressive forms of MS rare within this small population. Therefore no children will be 
enrolled. 
5.2d. 
Recruitment of Veterans: The pilot trial of LA recruited 21 Veterans from the 
total 51 subjects. The current proposed study has more restrictive inclusion criteria than 
the pilot study, requiring that subjects are ambulatory. Recruitment of non-Veterans and 
use of VA and non-VA study sites is necessary to fulfil the enrolment timeline. 
5.2e. Sources of materials: Sources from human subjects will include blood and urine 
samples and data in the form of clinical tests (e.g. gait, neurologic exam), patient-
reported outcomes, and radiographic information (MRI). Medical records will be 
reviewed prior to the screening visit to assess for eligibility and confirm MS diagnosis. 
Data will be collected solely for research purposes.  
5.2f. 
Benefits:  Subjects may or may not benefit directly from the study. The benefits to 
society may be the discovery of a safe and low-cost oral therapy to treat PMS. 
5.2g. Costs to subjects: There will be no cost to subjects to participate in this study. 
The study drug and investigations will be covered by the study budget.  


 
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5.2h. Subject compensation: Subjects will receive $50 per visit including unscheduled 
visits and $25 for extra laboratory visits if needed and cannot be performed locally. In 
addition, subjects are compensated for travel with $0.50/mile over 30 miles up to a 
maximum of $100 per visit. The payments will be in the form approved by each local 
study site, and will cover the costs of transportation and meals during the study visits. 
The compensation is included in the ICF. Subjects will be provided compensation after 
each visit regardless if all procedures are completed. 
5.3 Informed Consent Procedures 
Subjects will be required to sign IRB- approved ICFs in accordance with FDA Code of 
Federal Regulations (21 CFR 50). The ICF will be presented to all potential subjects at 
the screening visit by study personnel who are trained in human subjects protection as 
required by the site IRBs. Briefly, the ICF describes the purpose of the study, 
procedures and participant involvement, potential risks, protection against risks, 
alternatives to participation, costs and compensation, confidentiality, right to withdraw, 
potential benefits, relevant contact personnel, and new information regarding the Health 
Insurance Portability and Accountability Act of 1996. Potential subjects will have ample 
time to read and ask questions, and, when satisfied, will document their consent to 
participate by signing the ICF. A copy of the ICF is given to the participant and the other 
retained for study records. All subjects must be able to provide informed consent in 
English. Potential subjects with impaired decision making ability will not be included in 
the study as they may not be able to adhere to study procedures per the eligibility 
requirements.  
5.4 Inclusion/Exclusion Criteria 
Inclusion criteria: 
i. Age > 18 years. 
ii. Previous diagnosis of RRMS or PPMS by 2010 revised McDonald criteria.(20) 
iii. Current SPMS or PPMS. 
iv. Progression of MS in the previous 2 years defined by medical record or reliable 
historical interview as: 
a. Non relapse-related MS decline resulting in a 0.5 step change in EDSS, 
decline in T25FW, or other clinically documented decline (can be assigned 
retrospectively) if not on a DMT, OR 
b. If currently on a DMT, non-relapse-related MS decline resulting in a 0.5 
step change in EDSS, decline in T25FW, or other clinically documented 
decline (can be assigned retrospectively) while on the current DMT taken 
continuously for at least 1 year prior to enrolment. 


 
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v. Able to give informed consent and to adhere to study procedures. 
vi. EDSS 3.0 to 6.5. 
 
Exclusion criteria:  
i. 
A self-reported medical or neurological problem other than MS that is a cause of 
progressive or fluctuating gait dysfunction (e.g. worsening neuropathy, 
uncontrolled lower extremity arthritis, uncontrolled cardiopulmonary disease). 
Fixed and/or stable conditions of greater than 1 year that affect their gait are 
permitted (e.g. joint replacement, stable lumbar stenosis, remote alcoholism, 
remote stroke, etc.). 
ii. 
MRI constraints (metal implants including pacemaker, devices with electrodes, or 
shrapnel, excessive weight per site MRI requirements, need for sedation with 
non-oral agents due to claustrophobia or muscle spasticity). 
iii. 
MS clinical relapse in the 1 year prior to enrolment. 
iv. 
Unable to follow directions in English as standardized scales are not all validated 
in other languages.  
v. 
Current major disease or disorder other than MS (e.g., cancer, renal disease, 
end-stage cardiopulmonary disease, post-traumatic stress disorder, etc.) that 
may interfere with study procedures. Stable abnormal laboratory values of no 
more than Grade 1 determined to not be of clinical significance to the primary 
treating physician for that condition may be permitted per LSI discretion and 
comply with specific renal and liver testing requirements described in section 
5.1m. 
vi. 
Pregnant or breast-feeding. 
vii. 
Insulin-dependent diabetes or diabetes not controlled on oral diabetes 
medications. 
viii. 
Scheduled (every 3 months or more frequently) IV or oral steroids in the year 
prior to enrolment. 
ix. 
IV or oral steroids in the 60 days prior to enrolment. 
x. 
Use of LA in the prior 2 years exceeding the equivalent of 1200mg daily for 3 
months.  
xi. 
Participation in the pilot LA in SPMS trial. 
 
 
 
 


 
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5.5 Study Evaluations 
5.5a. Study flowsheet 
Procedure 
Screen 
Baseline 
M 0 
M 3 
M 6 
M 12 
M 18 
M 24 
Consent 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
General medical exam 
X 
 
 
 
 
Inclusion/Exclusion review 
X 
X 
 
 
 
Safety labsab 
X 
Xc 
X 
Xh 
X 
Randomization 
 
Xg 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
T25FW 
X 
X 
 
X 
X 
9 HPT 
X 
X 
 
X 
X 
2MTW 
X 
X 
 
X 
X 
EDSS 
X 
X 
 
X 
X 
Cognitive 
tests 
SDMT 
 
X 
 
M12 only 
X 
CVLT-2ed 
 
X 
 
M12 only 
X 
BVMT-R 
 
X 
 
M12 only 
X 
Patient 
reported 
outcome 
measures 
PROMIS – pain intensity 
 
X 
 
X 
X 
PROMIS – pain 
interference 
 
X 
 
X 
X 
PROMIS- participation in 
social roles 
 
X 
 
X 
X 
PHQ-9 
 
X 
 
X 
X 


 
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SS-MOS 
 
X 
 
X 
X 
MFIS 
 
X 
 
X 
X 
FESI 
 
X 
 
M12 only 
X 
GLTEQ 
 
X 
 
X 
X 
Fall count 
 
 
X 
 
X 
MRI 
 
Xe 
 
 
Xe 
SBQ-R 
X 
X 
X 
X 
X 
Adverse event monitoring & compliance 
reviewd 
 
X 
X 
X 
X 
Investigational drug dispensing 
 
X 
X 
X 
 
Subject/provider blinding questionnaire  
 
 
 
 
X 
Subject compensation 
X 
X 
X 
X 
X 
Subject dispositionf 
 
 
 
 
X 
Length of visit (hours) 
3 
4 
1 
3 
4 
BVMT-R, Brief Visuospatial Memory Test- Revised; CVLT-2ed, California Verbal 
Learning Test- Second Edition; EDSS, Expanded Disability Status Scale; FESI, Fall 
Efficacy Scale-International; GLTEQ, Godin Leisure-Time Exercise Questionnaire, 
modified; MRI, magnetic resonance imaging; MFIS, Modified Fatigue impact Scale; 9 
HPT, 9 Hole Peg Test; PHQ-9, Patient Health Questionnaire-9; PROMIS, Patient 
Reported Outcome Measures Information Systems; SBQ-R, Suicide Behaviors 
Questionnaire-Revised; SDMT, Symbol Digit Modalities Test; SS-MOS, Sleep Scale 
from the Medical Outcomes Study; T25FW, Timed 25 Foot Walk; 2MTW, 2 Minute 
Timed Walk 
aIncludes pregnancy test for female subjects of childbearing potential only 
b Optional Biorepository #2916 participation 
cOnly pregnancy test for female subjects of childbearing potential. 
dOccurs at study visits and approximately halfway between each visit after baseline by 
telephone calls 
eMRIs scheduled up to 14 days prior to M0 and up to 14 days prior to M24 visits. MRIs 
can be same day as M0 and M24 visits. 


 
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fOccurs at visit M24, at final visit for early termination, and when a subject is determined 
lost to follow-up. 
gMay occur prior to M0 visit day, when appropriate for logistical purposes, to avoid 
excessive M0 study visit times. 
hUrine protein additionally tested M9, M15, M21. 
5.5b. Consent, medical history, general medical exam: The ICF will be presented by 
the PI, LSI, or designated study staff. After consent has been obtained, the rest of the 
study procedures can occur. The medical history and general medical exam is 
conducted by the treating neurologist for the purpose of eligibility.  
5.5c. Vital signs: Resting blood pressure, pulse, and weight are collected by trained 
study staff at every study visit for the purpose of initial eligibility and ongoing health 
monitoring. Consistent methods of obtaining data (e.g. same resting period prior to 
blood pressure and pulse assessments, etc.) is encouraged across study visits. Height 
is assessed at the screening visit only. 
5.5d. Concomitant medication review: Current use of prescribed scheduled and as 
needed medications as well as over the counter medications and supplements is 
recorded by the study staff and reviewed at the screen visit by the treating neurologist 
for study eligibility. Concomitant medications are reviewed at each subsequent visit by 
study staff and changes reviewed by the treating neurologist. Any start, stop, or change 
to MS disease-modifying therapies will be noted and dated for data analysis purposes. 
Supplements will be reviewed by research staff in case they contain lipoic acid or other 
potential confounders to the study results. 
5.5e. Safety laboratory analyses: Laboratory studies will be collected from all subjects 
at the screening visit if not available within the prior 3 months for establishing eligibility. 
Additional laboratory analyses occur at visits M3, M6, M12, M18 and M24 to monitor 
blood cell count, renal function, liver function, urine protein, non-fasting blood glucose 
levels, HbA1c, and (for women of child-bearing potential) pregnancy testing. Subjects 
must have urine protein monitored every 3 months for the duration of the study.  
Pregnancy testing is additionally conducted at the baseline visit for women of child-
bearing potential. This involves taking approximately 15-25 mL (3 to 5 teaspoons) of 
blood at each draw for a total of 90-150mL (2/3 cup) over the course of the study. 
Laboratory draws will be performed by trained phlebotomists using universal 
precautions. 
5.5f. Inclusion/Exclusion review: Eligibility criteria are reviewed by the treating 
neurologist during the screening visit. Once all criteria are met and confirmed at the 
baseline visit, the study staff will use REDCap to assign a randomization code and then 


 
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request study drug using the blinded randomization code.  For logistical purposes, this 
may occur prior to M0 visit day to avoid excessive M0 study visit times. Each site 
pharmacy will then dispense the drug according to the assigned treatment on the 
randomization schedule, which will be located at each site pharmacy. Subject screens 
who do not meet inclusion/exclusion requirements will be accounted for in the 
recruitment monitoring process (See 5.2 Recruitment Methods). 
5.5g. Walking tests. The T25FW and 2MTW will be collected at the screening and 
baseline visits, and every 6 months during the study (21, 22). For the T25FW, subjects 
are instructed to walk 25 feet marked on the ground “quickly but safely” (Appendix F). 
The measure is immediately repeated and the two results averaged. Assistive walking 
devices including canes and walkers are permitted. The 2MTW determines the distance 
a participant walks in 2 minutes. Dalfampridine is an FDA-approved symptomatic 
treatment for improving walking speed in MS. Subjects will be asked to maintain their 
usual dose of dalfampridine at all study visits. Subjects will be strongly encouraged to 
use the same assistive devices (insoles, orthotics, canes, walkers, etc.) if used at the 
study start throughout the remainder of the study as safely possible. Subjects who 
become unable to complete the mobility testing during the course of the study due to 
worsening MS will continue the study and be analyzed as having worsening mobility 
according to the data analysis plan. Subjects who are unable to complete mobility 
testing for non-MS related reasons will not have data recorded for that study visit. 
Because gait testing is the primary outcome measure, subjects should be tested as 
early as possible during each study visit. Testing conditions should be as uniform as 
possible from visit to visit (see 5.1 Study Design, Study timeline and visit scheduling).  
5.5h. EDSS: The EDSS is an eight functional system scale to assess overall MS 
disability including motor, sensory, cerebellar, brain stem, visual, mental, sphincteric, 
and other systems (24). Each functional system is graded from 0 (no disability) to 5 or 6 
(maximal disability). An integrated score between 0 (normal examination) and 10 (death 
from MS) is formed based on the score in each functional system. The EDSS exam will 
be performed by a blinded and trained EDSS examiner who is not the subject’s usual 
treating neurologist (Appendix G). 
5.5i.  9HPT: The 9 Hole Peg Test (9HPT) is a timed test of upper extremity arm and 
hand function. Subjects place pegs into a platform with hole and then take them out 
again (Appendix F). The 9HPT and T25FW will be administered in accordance with the 
instructions for the Multiple Sclerosis Functional Composite (21). 
5.5j.  Cognitive tests: Cognitive testing will utilize the Brief International Cognitive 
Assessment for MS (BICAMS (25) which includes the Symbol Digit Modalities Test (26) 
(Appendix H), the California Verbal Learning Test- Second Edition (27) (Appendix I), 


 
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and the Brief Visuospatial Memory Test- Revised (28) (Appendix J). These measures 
will be assessed at baseline, M12 and M24. 
5.5k. Patient-reported outcome measures: The Patient Reported Outcome Measures 
Information Systems (PROMIS) will pain intensity (Appendix K), pain interference 
(Appendix L), and ability to participate in social roles (Appendix M) (29). Additional 
measures of depression (Patient Health Questionnaire-9, Appendix N), sleep the 
previous 4 weeks (Sleep Scale from the Medical Outcomes Study, Appendix O), 
exercise (Godin Leisure-Time Exercise Questionnaire, modified, Appendix V), and the 
Modified Fatigue impact Scale (Appendix P) will be administered at baseline and every 
6 months thereafter (30, 31).  The Fall Efficacy Scale-International (FESI) (Appendix T) 
is administered annually. 
5.5l.  Fall count: Fall count will be kept by a daily Fall Count Diary (Appendix Q). Each 
calendar page will cover 1 month and will include space to count falls and fall-related 
injuries each day. Each page will include the definition of a fall as “any unexpected 
event that results in you ending up on the ground, floor, or any lower surface” (23). At 
the baseline visit, subjects will be given calendars to cover the first 3 months. Subjects 
will be called once at the between visit telephone call to encourage falls calendar 
reporting and have the opportunity to answer any fall counting related questions. A final 
3 month supply of falls calendars will be mailed before the end of the study with a target 
start date on the calendar corresponding to 3 months prior to the final study visit. 
Subjects will again be called once to encourage compliance and answer any related 
questions. 
5.5m. MRI procedures.  
a. MRI acquisition protocol: A 3T MRI will be utilized to acquire the following series 
of the brain. 1. A high resolution Magnetization Prepared Rapid Acquisition 
Gradient Echo (MPRAGE) for high resolution structural (T1-weighted) 
information, as the basis for brain atrophy measures. Partitions will be 1.0 mm; 
voxels 1 mm3. 2. Conventional brain imaging with T2-weighted, and FLAIR 
series; 2mm (non-gapped) slice acquisition, with in plane resolution 1mm2. 
Intravascular MR contrast will not be administered. 3. The American College of 
Radiology phantom scan will be utilized as necessary for quality control. The 
imaging procedure will require 60 minutes with approximately 30 minutes 
participant scan acquisition time, 10 minute phantom scan acquisition time (when 
needed), and the remaining 20 minutes for positioning and questions. Careful 
screening of subjects prior to MRI will be done to reduce the chance of injury due 
to MRI-contraindicated conditions. 
b. MRI clinical readings. MRIs will receive a clinical read from site clinical radiology 
staff and results reviewed by site treating neurologists for concerning findings 


 
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(tumor, stroke, etc.) which, if found, will be communicated to the appropriate 
clinical service for optimal management including treatment of MS exacerbations. 
c. MRI volumetric analyses: MRI analyses used for study outcomes will be 
analyzed by the Central MRI Reading Site at OHSU. MRI images are sent to the 
Reading Site via secure methods. Prior to analyses, AIRC staff will ensure that 
only the study ID and PHI element of date of study visit are visible to the analysts 
to reduce any bias. Brain volume measures will be based on SIENAX software 
and brain atrophy measures on SIENNA tools in the FSL software library 
produced by the Oxford Centre for Functional MRI of the Brain (32). Total brain 
T2-hyperintense lesions will be determined using in-house software. In-house 
and FSL software will be used to explore differential gray versus white matter 
atrophy as an exploratory MRI outcome measure. Study MRIs will be reviewed 
for quality within 2 weeks of receipt in order to rescan a subject (1 rescan per 
subject per MRI visit permitted) if needed within an acceptable time-frame.  
d. MRI quality control (QC): In order to ensure high quality and comparable images 
across study sites, the Central MRI Reading Site will coordinate QC by having 
each site perform test scans prior to study start and after every scanner upgrade 
during the study to review for image quality. In addition, each site will conduct 
standard phantom scan according to protocols set by the American College of 
Radiology. Feedback from the Central MRI Reading Site staff to the study sites 
regarding test, phantom QC, and study MRIs will occur in a timely manner so that 
errors can be fixed promptly.  
5.5n. Suicidality monitoring: Monitoring suicidality is a requirement by the Food and 
Drug Administration for all neurology studies involving an IND. Monitoring using the with 
the Suicide Behaviors Questionnaire-Revised (SBQ-R) occurs at the screen to establish 
a baseline and every subsequent study visit to evaluate for the development of new 
suicidality (Appendix R). 
5.5o. Adverse event (AE) monitoring: This occurs at baseline, every subsequent visit, 
at between visit telephone calls, and ad hoc. Unscheduled visits will occur to evaluate 
AE per the protocol guidelines (sec. 5.1d). AE are coded by the DCC according to 
MedDRA and reported per the reporting guidelines (sec. 6.0). 
Subjects will be encouraged to remain in the study through study completion if they 
start, stop, or switch a DMT, if their disability progresses due to MS to an EDSS of more 
than 6.5, or if they have an MS relapse. Subjects who develop MRI contraindications 
may continue through the study end without further MRIs. Study staff will review 
eligibility at study visits and during regularly scheduled meetings. 


 
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5.5p. Investigational drug dispensing: Drug dispensing occurs at baseline and every 
study visit according to dispensing schedules by the site research pharmacies. 
5.5q. Subject/provider blinding questionnaire: All blinded study staff and subjects take 
a blinding questionnaire at M24 to evaluate the blind (Appendix S). 
5.5r. Subject disposition form: Final disposition of each subject is recorded on this form 
at the M24, early termination visit, or when determined that the subject is unable to 
attend an early termination visit. 
5.6 Data Analysis 
5.6a. Sample size: The sample size and power analysis were based on the pilot LA in 
SPMS trial in which LA had improved time to complete the T25FW (-0.54 seconds SD 
0.36 vs 0.14 SD 0.25, p = 0.06). A sample size of 44 per group will have 80% power to 
detect a difference between the LA group with a coefficient, β1 regression slope of -0.50 
seconds and the placebo group coefficient, β2 slope of -1.00, assuming that the 
standard deviation of the difference between the groups is 2.20 and the standard 
deviation of the residuals (repeated measures within each participant) is 1.80 with a 
0.05 two-sided significance level and the correlation of 0.85 between the measurements 
over time, which if lower increases the power. The delta of improvement is a reduction 
in the rate of walking slowing of 0.5 seconds per unit of time. This translates into 2 
seconds on the average timed walk over 2 years. A sample size of 59 per arm will allow 
for a 25% drop-out rate. The pilot study had a 10% drop out rate however 25% is more 
realistic for a multi-site trial in an era with more therapeutic options for MS. Screen visit 
failures are likely to be minimal (<10% of all screen visits) as most eligibility 
requirements can be made prior to the screening visit using the methods described in 
5.2 Recruitment Methods. 
As a check on these calculations we compared the estimates, Altmann et al.’s estimates 
of sample size when using SIENA as the method of determining whole brain atrophy 
rate, the current sample of 44 per group will achieve 80% power at significance level 
0.05 assuming a 40-50% effect size (33).  
5.6b. Data analysis plan: Data is analyzed by the SCC at study completion or at 
any point requested by the DSMB. Only subjects that complete the baseline 
evaluation and take at least one dose of study drug will be included in the data 
analysis. 
The SCC will use the mixed model approach to compare, between the treatment 
groups, mean rates of change from baseline in the times to complete the T25FW. The 
SCC will use the transformation 25/T25FW, which is the walking speed in feet per 


 
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second. In constructing these models for the T25FW walking speed outcome, baseline 
disability will be incorporated as a predictor. The primary outcomes is whether there is a 
difference between the treatment groups in the T25FW rate changes. Given evidence of 
interaction, comparisons of both 12 and 24 month change between the treatment 
groups will be made, using a Bonferroni multiple comparison adjustment for two time 
points of interest. Additional models will include as covariates, baseline measures of 
disease duration and use of MS medications if significantly related to the response 
when added to the original model or result in a 10% change or greater in the estimated 
overall treatment effect. Secondarily, the SCC will compare with a t-test or 
nonparametric tests the proportion of participants who demonstrate clinically significant 
worsening in gait defined by a 20% improvement in the T25FW and/or 2MTW and/or 
requires greater assistance to walk (e.g. newly require a cane, transition from cane to 
walker, etc.). A sensitivity analyses will be performed using an intention to treat analysis 
with the cross-over with and without participants who have a change in their disease-
modifying therapy during the course of the study. Compliance information will be added 
as determined by pill-counts to the mixed model.  
The impact of LA on falls frequency will be assessed by comparing changes in fall 
frequency from the first to the last 3 months. A principal intention-to-treat analysis using 
linear Poisson mixed models to evaluate the association between time period, fall 
frequency, and group allocation will test the hypothesis that fall frequency is reduced 
more by LA than placebo. Mixed models will be used to correct for autocorrelation of 
within-subject repeated measures and allow for missing data, and include covariates 
associated with falling such as age, level of disability, and use of a walking aid. As 
exploratory secondary outcome measure, the SCC will investigate the disconjugate 
composite endpoint based on sustained change in EDSS, clinically significant 
worsening in gait as defined above, or 20% increase in 9HPT. 
The mixed model approach will compare the mean rates of change from baseline in 
brain as measured by SIENA. Age, sex, and disease duration will be used as covariates 
along with disability.   
Adverse and serious adverse events will be tabulated and compare the differences in 
the occurrence and the frequencies between the two groups. The frequency of side 
effects will be compared using χ2 tests or Fisher’s exact test as appropriate depending 
on the number of adverse events seen. For evaluation of patient safety, laboratory test 
results at baseline and changes from baseline will be summarized and compared using 
t-tests for continuous measures and Fisher’s exact test for proportions.  
 
 


 
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5.7 Withdrawal of Subjects 
Subjects can withdraw from the study at any time. Reason for withdrawal will be recorded. 
Subjects may also be withdrawn from the study by LSIs and in agreement with the study 
PI for any of the following reasons: 1. New or worsening medical conditions (e.g., cancer, 
renal disease, end-stage cardiopulmonary disease, post-traumatic stress disorder, 
uncontrolled diabetes, etc.) that may interfere with study procedures or otherwise pose 
concern for subject health or safety, 2. New pregnancy, 3. Inability of subjects to comply 
with study procedures, 4. Other reasons deemed important to subject safety or data 
quality raised by the DSMB, IRB, FDA, or any other regulatory body that has the authority 
to do so. If subjects are deemed no longer safe to take the investigational drug but 
otherwise are able to participate in the study outcomes for the remainder of the study, they 
are encouraged to do so. 
Female study subjects of childbearing potential will be encouraged to use effective birth 
control methods during the study. Pregnancy testing in female subjects of childbearing 
potential will be conducted as part of safety laboratory studies at each study visit according 
to the study flowsheet. Should pregnancies occur during the study, those female subjects 
will be withdrawn from the study. Information will be collected as to the pregnancy course, 
outcome and health of the newborn infant. Because LA is available as an over the counter 
supplement, male subjects whose female partners become pregnant will continue in the 
study, however pregnancy and birth outcomes of the female partners will be recorded and 
presented to the DSMB.  
If a subject wants to withdraw from the study, the subject will contact the site study staff 
using the contact information and procedures on the ICF and request withdrawal. If a 
subject withdraws or is removed from the study for any reason and is unable or 
unsuitable to continue the study procedures off investigational drug, the reason and 
date of discontinuation of the investigational drug is recorded. At the time of study 
discontinuation, every effort will be made to schedule the subject for an early 
termination visit following the procedures for M24 without the MRI or Fall Count Diary if 
termination is within 6 months of the baseline visit, and M24 procedures with MRI but 
without fall count if termination is greater than 6 months of the baseline visit. Subjects 
withdrawn due to reportable adverse events and subjects with adverse events thought 
related to the study that are ongoing at the final study visit are followed for 30 days or 
until resolved, whichever is first, or longer per request of the Medical Monitor. 
 
6.0 
Reporting: All SAE, UAP, and PD are reported to the IRB within defined 
timelines. 
 


 
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6.1 Adverse event reporting 
Adverse event (AE) information will be monitored in detail throughout the course of the 
study. AEs are defined as and will be graded as to their expectedness and attribution 
(unrelated, possibly, probably, or definitely related to the protocol). Dr. Mary Samuels 
will act as the medical monitor to determine relationship of AEs to the study intervention 
if uncertain. AEs will be reviewed by site treating neurologists, graded, and reported to 
the DCC. The DCC will code the events using MedDRA and will assist the CCC with 
IRB reporting per reporting guidelines.  
6.2 Limited collection of non-serious AE 
Some AEs are expected, so a limited set of AEs will be collected for this trial. Upper 
respiratory and urinary tract infections will not be tracked or reported, unless they reach 
an intensity of severe. Gastrointestinal distress is a known side effect of LA. Therefore 
only GI distress related and probably related to study of any intensity is tracked and 
reported. All other AEs are collected and stored at the study sites. 
 
6.3 Limited reporting of AE 
Not all AE captured at sites are reported to the DCC. The limited set of AE reported to 
the DCC via the REDCap database is according to guidelines in 6.3a below. Serious AE 
(SAE) and select UP and PD are reported under expedited guidelines according to IRB 
and other monitoring entity requirements. 
 
6.3a Limited reporting of AE, UP, and PD to the DCC. Bold items require expedited 
reporting to the DCC via REDCap. 
AE Intensity* 
AE related to 
study 
AE probably 
related to 
study 
AE possibly 
related to 
study 
AE unrelated 
to study 
Mild 
REDCap 
AE Log only 
AE log only 
AE log only 
Moderate 
REDCap 
REDCap 
AE log only 
AE log only 
Severe 
REDCap 
REDCap 
REDCap 
REDCap 
SAE  
REDCap 
REDCap 
REDCap 
REDCap 
UP with risk to 
subjects or 
others 
REDCap 
REDCap 
AE log only 
AE log only 
Severe PD: REDCap 
Moderate PD: REDCap.  
Mild PD: AE log only 
* Increases after Screen in CTCAEv5 grades (ALT, AST), new ACR >300mg/g, and new 
eGFR<60 are always reported in REDCap regardless of intensity or relationship to study. GI 
distress related and probably related to study of any intensity is reported in REDCap. 
 
ALT, Alanine Aminotransferase; AST, Aspartate Aminotransferase; ACR, Albumin to creatinine ratio 


 
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6.4 Adverse event (AE) definition: Any untoward or undesirable, although not 
           necessarily unexpected, event experienced by a human subject that may be a  
           result of: 
• The interventions and interactions used in the research. 
• The collection of identifiable private information in the research. 
• An underlying disease, disorder, or condition of the subject. 
• Other circumstances unrelated to the research or any underlying disease, 
disorder, or condition of the subject. 
6.5 Serious Adverse Event (SAE) definition: Any AE that: 
• Is fatal. 
• Is life-threatening. 
• Is persistent or significantly disabling or incapacitating. 
• Results in inpatient hospitalization or prolongation of hospitalization. 
• Results in psychological or emotional harm requiring treatment. 
• Creates a persistent or significant disability. 
• Causes a congenital anomaly or birth defect. 
• Results in a significant medical incident (considered to be a serious study  
  related event because, based upon appropriate medical judgment, it may  
  jeopardize the subject and may require medical or surgical intervention to     
  prevent one of the outcomes listed in this definition). 
6.6 Unanticipated problem (UP) definition: 
• Any event that is not expected given within the context of the study. 
• Any event that places subjects or others at a greater risk of harm or 
discomfort relative to what was previously known. 
• No harm to a subject needs to occur for an event to be an unanticipated  
problem. 
 
6.7 Protocol Deviation (PD): The term “protocol deviation” is not defined by 
either the HHS human subjects regulations (45 CFR 46) or the FDA human 
subjects regulations (21 CFR 50). All PD are graded by the treating neurologist 
and entered into REDCap. Severe PD have expedited reporting to the DCC via 
REDCap. Moderate PD are entered into REDCap according to the usual 
timelines. Mild PD are recorded on the site AE log only. 
 
6.7a. Mild PD:  
• 
The deviation resulted in no harm or risk of harm to research participants; or 
• 
The deviation did not result in or require any substantive action to be taken or 
result in a substantive change to the subject’s condition or status (i.e., did not 


 
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affect the subject’s participation in a substantive way, did not result in a change 
to the subject’s emotional or clinical condition, did not cause an adverse 
experience or require a change to the clinical care of the subject, etc.)  
• 
The deviation had no substantive effect on the value of the data collected (i.e., 
the deviation does not confound the scientific analysis of the results);  
• 
The deviation did not result from willful or knowing misconduct on the part of the 
investigator(s);  
• 
The deviation is easily corrected (e.g., consenting a subject with an old version of 
an ICF, recording data on an expired/incorrect form, forgetting to record data that 
may be acceptably recorded at the next visit, etc.)  
 
6.7b. Moderate PD: 
• 
The deviation resulted in a harm or risk of harm that is not significant; or  
• 
The deviation resulted in the need for minimal risk interventions, such as those 
defined in 45CFR46.110 and 21CFR56.110;  
• 
The deviation resulted in the loss or improper collection or recording of some 
data for one or more subjects, but did not invalidate the entire data set for the 
study;  
• 
The deviation resulted in a regulatory violation that can be acceptably resolved;   
• 
Repeated minor protocol deviations from the same laboratory, site or research 
team; or  
• 
There has been a failure to follow action ordered to correct minor or moderate 
protocol deviations. 
 
6.7c. Severe PD: 
• 
The deviation resulted in or required a substantive action to be taken or resulted 
in a change to the subject’s condition or status;  
• 
The deviation has significantly harmed or posed a risk of significant harm to 
research participants; 
• 
The deviation has substantially damaged the scientific integrity of the data 
collected for the entire study;  
• 
The deviation is evidence of willful or knowing misconduct on the part of the 
investigator(s);  
• 
The deviation involves serious or continuing noncompliance with federal, state, or 
local research regulations;  
• 
There have been repeated minor and/or moderate protocol deviations from the 
same laboratory, site or research team;  
• 
There has been a failure to follow action ordered to correct minor and/or 
moderate protocol deviations;   


 
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• 
There has been a failure to follow action ordered in accordance with the 
emergency action provision of this policy.  
6.8 Data and Safety Monitoring Plan  
Data and safety monitoring will involve AE reporting by site study staff, and review of 
AE, SAE, UP, protocol deviations (PD), dropouts, complaints, or breaches of 
confidentiality by the DCC. Subjects will be encouraged to report any study-related 
and/or health problems at any time to the study site staff. AEs reported to the DCC and 
other data and safety issues found during site visit audits will be subject to additional 
reporting (IRB, FDA) per reporting policies.  
 
A Data Safety Monitoring Board (DSMB) will be assembled for subject safety. This 
board will consist of members who have expertise in any of the following: neurology, 
multiple sclerosis, clinical trials, and medical safety. The board members will document 
their lack of conflict of interest and approve a DSMB Charter prior to study start. All 
members of the DSMB will review and approve study protocol and informed consent 
forms for all study sites prior to enrollment. 
 
The DSMB Chair or DSMB member designee reviews SAE in real time according to 
reporting timetables (6.0). The DSMB receives quarterly reports, developed by the DCC 
and SCC, which includes aggregate reports of AE, SAE, UP, and PD, including the 
safety lab data according to Limited Reporting of AE (6.3) presented grouped by study 
arm and study site (as necessary). The board will meet every six months, as necessary, 
to review quarterly reports, enrollment/screening progress, data collection problems, 
and missing data. No non-safety related study outcome analyses will be performed until 
study completion, unless the committee determines there is a compelling reason to do 
so related to patient safety concerns. The DSMB also meets when the last subject 
completes participation. The DSMB will provide a written summary of each meeting to 
the PI with a statement about appropriateness of continuation of the study. DSMB 
reports are communicated at least annually to the Central IRB and non-VA IRBs.  
 
7.0 
Privacy and Confidentiality 
7.1. Protected health information (PHI) 
Study subjects will be given a unique study ID that will be linked to the name and 
contact information by a key. The key will be held by the LSIs for their site subjects, and 
for all subjects by the PI. Local sites may collect PHI elements including name, address, 
email address, telephone numbers, dates of birth, social security numbers, and medical 
record numbers for the purpose of recruitment, screening potential subjects, scheduling, 


 
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and creating site medical charts. These identifiers are necessary to avoid duplication of 
recruitment and screening efforts and to ensure that the correct study procedures such 
as laboratory assessments and MRIs are performed at the local sites. Dates of study 
visit will be the only PHI element recorded in the REDCap study database, the only PHI 
viewed by the SCC, and the only PHI retained in the data repository (BND #2916). PHI 
will be transmitted on MRIs to the Central MRI Reading Site in order to properly identify 
the scans. The PHI elements may include dates of study visits, names, dates of birth, 
social security numbers, and medical record numbers. Prior to analyses and to ensure 
blinding, staff at the Central MRI Reading Site will ensure that only the subject ID along 
with the PHI element of date of study visit are visible to the MRI analysts. This is 
outlined on the ICF. All other PHI including names, addresses, contact information and 
medical records will be managed according to the procedures below. 
7.2 Privacy and Confidentiality 
Privacy of subjects will be maintained by obtaining and storing the minimum necessary 
PHI for the purposes of screening, enrolling, and maintaining subject participation. 
Study data will be seen only by study staff authorized to do so. 
7.3 Information and specimen management 
Subject data, initially identifiable when obtained, will be coded and dated according to the 
date of study visit. The key to the code will be maintained by each LSI and available to the 
study PI. Hard copies of study data will be stored in on-site locked cabinets, and electronic 
data stored on secure servers according to the privacy regulations of each study site.  
Trained and designated study staff will enter study data, from each site and the Central 
MRI Reading Site, into a web-based REDCap database. OCTRI's REDCap software is a 
highly secure and robust web-based research data collection and management system, 
which is physically housed on servers located in the OHSU’s Advanced Computing 
Center. The servers are housed behind both the OHSU firewall and a second ACC 
firewall. All web-based data transmissions are encrypted with industry-standard SSL 
methods.   
REDCap is a robust multi-level security system that will enable the PM and study PI to 
easily implement "minimum necessary" data access for their research staff, including 
specification of data fields that are identifiers. The only PHI entered into REDCap will be 
the dates of study visits. Study sites will maintain up-to-date study staff personnel lists so 
that REDCap access is limited to approved study staff. User activities are logged to 
enable auditing of all data access. REDCap is jointly managed in accordance with 
OHSU Information Security Directives by ACC staff and members of OCTRI's 


 
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Biomedical Informatics Program, ensuring fidelity of database configuration and back-
ups.   
Hard copies of study data containing PHI will be sent, when necessary, through secure 
methods. For VA to VA transmission, this can include email using PKI or RMS encryption. 
Otherwise, transmission is via secure fax or secure mail such as FedEx/UPS with tracking. 
MRI images will be sent to the Central MRI Reading Site by secure electronic methods as 
allowed by OHSU and the sending institution such as an sftp account, or on compact disks 
by secure mail such as FedEx/UPS with tracking.  
Study data management is under the oversight of the DCC. Members of the DCC will have 
REDCap access to view, enter and edit data, and update the REDCap database 
throughout the study for the purposes of quality control. The DCC will work with the PM 
and site study staff to resolve data discrepancies in an ongoing fashion throughout the 
study.  
Blood samples for subjects participating in the optional BND are shipped to the VA 
Portland Health Care System via secure mail, such as FedEx/UPS with tracking. The only 
PHI on the specimen label is the date of specimen collection. An electronic copy of 
coded data that does not contain protected health information, except for the date of 
specimen collection, will be transferred to the BND for storage via methods allowed by 
the VA and the sending institution, such as an sftp account, or on compact disks by secure 
mail. 
The BND is located at the VA Portland Health Care System in Portland, Oregon, in VA 
Building 101, Room 434 which is secured by card access only. An electronic copy of 
coded data is stored on secure VA networks located behind VA firewalls. Dr. Rebecca 
Spain, director of the biorepository, makes the decisions regarding how the blood 
samples and data are used in the future under IRB-approved protocols. Samples from 
the biorepository released to other investigators may include the date of specimen 
collection. 
The ICF and HIPAA authorization provide information about how specimens will be 
transferred, how long they will be kept, and who will view/use the specimens. Subjects 
who consented to the LAPMS study prior to the addition of the option of donating blood 
to the biorepository will re-consent with the version that includes the blood donation to 
the BND either at the next study visit, or if necessary, via an approved phone script. 
The ICF will describe that the HIPAA identifier, date of study visit, will be included on all 
stored study data including in the REDCap database on MRI images sent to the Central 
MRI Reading Site, and on specimens within the BND.. The ICF also describes that 


 
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additional PHI including name, date of birth, social security number and medical record 
number may be sent to the Central MRI Reading Site if those elements are unable to be 
removed by the local sites prior to sending. Only study staff at each site, the Central MRI 
Reading Site study staff, the DCC, and members of the DSMB will have access to the 
study data that includes PHI. Once the study has concluded, study records will be 
maintained at each site for the duration of time required by each site regulations.   
8.0 
Communication Plan 
8.1 Multi-site study coordination plan 
The Principal Study site will be responsible for initial submission and ongoing reporting 
to the VA Central IRB. The PI and PM will provide notification to study site Directors 
when VA Central IRB approval has been obtained. The Principal Study site will provide 
support to both VA and non-VA study sites for obtaining local IRB approval. The 
Principal Study site will be responsible for reconciling protocol-changing differences 
between IRBs. In addition, the Principal Study site will provide Standard Operating 
Procedures, a Manual of Operations & Procedures, and data collection forms to each 
site. An Investigator Meeting will familiarize the LSIs with the study prior to study start. 
As necessary, the study monitor (PM) will hold 1 training visit with study staff at each 
site to review the protocol, study documents, review data collection techniques, review 
communication plans, demonstrate and certify use of the REDCap database, inspect 
facilities and study materials, and verify site readiness to participate in the study prior to 
enrolment of subjects at the site. Investigators are required to store all source 
documents per study site requirements.  
8.2 Ongoing communication 
Local site investigators will participate in regular LSI Research Teleconferences led by 
Dr. Spain and the PM to discuss study-related matters including but not limited to IRB 
issues, training, study preparation, subject recruitment, data collection, REDCap 
database entry, adverse events, budgets, and publications. The PM with conduct 
regular (e.g. monthly) teleconferences with site study staff for data collection and related 
issues. LSIs are expected to hold regular meetings with their site research staff in order 
to review study progress, review adverse events, and other study matters. Email will 
also be utilized as a primary method of communicating information about changes to the 
protocol, informed consent, and HIPAA authorization. Communication about AEs, 
SAEs, unanticipated problems, or DSMB reports will also be conducted by email, 
phone, or the LSI teleconferences as appropriate to the level of urgency of information 


 
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transmitted. This information will be relayed to the appropriate IRBs under the direction 
of the DCC according to the DSMP (sec. 6.8). 
Initial and ongoing IRB approval documents will be provided by each study site to the PI 
to ensure that no study activities occur without IRB approval. Acknowledgment of these 
notifications will be maintained as documentation of understanding from each study site. 
Study sites will be notified when enrolment targets are reached, when sites have 
completed their final study visits, and when the entire study has completed. 
Acknowledgment of these notifications will be maintained as documentation of 
understanding from each study site. Study LSIs will have the opportunity to participate 
in manuscript preparation with authorship order related to recruitment achieved and/or 
level of participation in manuscript editing. 
8.3 Study monitoring 
Yearly on-site study monitoring visits and study closing visits by the PM will be 
performed to assess critical study procedures including study data endpoints, subject 
safety, protocol compliance, and regulatory compliance. The monitoring may include the 
following: Audit data listings to source documentation, ensure subject eligibility, verify 
reporting of adverse events, assess compliance with protocol, audit regulatory files, and 
ensure adequate site personnel training. The Central Research Pharmacy may request 
site pharmacy investigational drug accountability review during these visits. Centralized 
monitoring processes at the DCC occur at regular intervals and will include data quality 
checks, site performance checks, and safety reporting monitoring. Regular feedback 
and data queries will be issued to each site by the DCC, and resolution of queries 
managed by the PM and DCC. 
 
 
 
 
 
 
 


 
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9.0 
References 
1. 
Scalfari A, Neuhaus A, Daumer M, Muraro PA, Ebers GC. Onset of secondary 
progressive phase and long-term evolution of multiple sclerosis. J Neurol 
Neurosurg Psychiatry. 2014;85(1):67-75. 
2. 
Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of 
an international survey. National Multiple Sclerosis Society (USA) Advisory 
Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 
1996;46(4):907-11. 
3. 
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Appendix – Supporting Documents List 
 
 
 
 
 
A.   Letter of Support, Pure Encaps 
B. Recruitment Flyer 
C. Recruitment Letter to MS Practitioners 
D. Recruitment Telephone Script 
E. Recruitment Email Blast 
F. Timed 25 Foot Walk & 9 Hole Peg Test 
G. Expanded Disability Status Scale 
H. Symbol Digit Modalities Test 
I. California Verbal Learning Test- 2nd edition 
J. Brief Visuospatial Memory Test – Revised 
K. PROMIS - Pain Intensity 
L. PROMIS - Pain Interference 
M. PROMIS - Ability Partic in Soc Roles and Activities 
N. Patient Health Questionnaire-9 
O. Sleep Scale from the Medical Outcomes Study  
P. Modified Fatigue Impact Scale 
Q. Fall Count Diary 
R. Suicide Behaviors Questionnaire-Revised 
S. Subject Blinding Questionnaire 
T. Falls Efficacy Scale-International 
U. Study Drug Instructions 
V. Godin Leisure-Time Exercise Questionnaire, modified 
W. ResearchMatch Message 
X. Short URL 
Y. LAPMS sticker 
Z. LAPMS Facebook page 
AA. LAPMS Facebook ad 
BB. LAPMS webpage 
CC. LAPMS Webpage Content