Clinical trial NCT03498131
Conditions: Relapsing Remitting Multiple Sclerosis
Keywords: Multiple Sclerosis MS Melatonin Supplement
Sponsor: Providence Health & Services
Start date: 2018-05-09; Completion date: 2023-12-11
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To date, there are no published data on the role of melatonin supplementation or the appropriate dose for patients with multiple sclerosis. Because of the potential benefits of melatonin, this pilot study will be an exploratory investigation to evaluate the effect of supplementing melatonin in subjects with multiple sclerosis who are taking an oral disease modifying therapy (DMT) for 6 months or longer. It is our intent that the results of this study will support the rationale and be a prelude to a larger trial which can focus on clinical efficacy of melatonin therapy outcomes.

Detailed description:
The primary objective of this study is to evaluate the change in 24 hour urinary 6-sulfatoxymelatonin (6SMT) collected for 24 hours in two twelve hour sessions. The secondary objectives are to evaluate the change in serum morning melatonin level. In addition, quality of life (QOL) measures will be assessed including the Modified Fatigue Impact Scale (MFIS), Multiple Sclerosis Impact Scale (MSIS-29), and the Pittsburgh Sleep Quality Index (PSQI). Clinical objectives include the number of relapses during the trial and a change in the Patient Determined Disease Steps (PDDS) \& Performance Scales (PS).

The pilot study is a one-year randomized, rater- and dose-blinded trial evaluating the potential role of melatonin in subjects with relapsing multiple sclerosis who have been taking a stable dose of an oral disease modifying therapy (DMT) for at least 6 months. The oral DMTs include dimethyl fumarate, fingolimod, teriflunomide, diroximel fumarate, siponimod, and ozanimod. Thirty subjects with relapsing forms of multiple sclerosis who meet all of the eligibility criteria will be enrolled at Providence Neurological Specialties in Portland, Oregon.

Arms: arm 1: Subjects will receive 3 mg melatonin once a day. arm 2: Subjects will receive 5 mg melatonin once a day.
Interventions: intervention 1: 3 mg Melatonin intervention 2: 5 mg Melatonin
Intervention descriptions: intervention 1: 3 mg melatonin once each day intervention 2: 5 mg Melatonin once each day

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 19 
STUDY TITLE: 
Evaluating the Potential Role of Melatonin in Subjects with Relapsing 
Multiple Sclerosis (MS) 
PRINCIPAL INVESTIGATOR: 
Kyle Smoot, MD 
Providence Neurological Specialties West 
Providence Health and Services 
SUB-INVESTIGATORS: 
Stanley Cohan, MD, PhD 
Elisabeth Lucassen, MD 
Justine Brink, MD 
Leah Gaedeke, MSN, FNP-BC 
INSTITUTION: 
Providence Brain and Spine Institute 
Providence Health & Services 
PROTOCOL VERSION & DATE: 
Version 3.0 09JUN2020 
NCT#: NCT03498131 


 
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A. Background/specific aims:  
Multiple sclerosis is an immune mediated disorder with no clear cause determined. Likely, the 
combination of genetics and environmental factors trigger this disorder
1. The disease is driven 
possibly by pro-inflammatory cells, Th17 and Th1 cells. There is also a decrease in number and 
function of regulatory T cells (RegT) and B cells (RegB). This inflammation is responsible for 
clinical relapses and radiographic changes. However, if the disease is left untreated, the majority 
of patients transition to the progressive phase. The exact cause for this transition is unclear; 
however, mitochondrial injury and loss of axonal homeostasis due to demyelination may 
contribute to this degeneration
2. This mitochondrial injury may be secondary to oxidative stress 
driven by chronic inflammation
3. 
Melatonin is primarily produced in the pineal gland, helps regulate the sleep-wake cycle, and a 
reduction in melatonin contributes to insomnia
4, 5. However, melatonin also can be produced by 
mitochondria which can help optimize cell function
6. In addition, melatonin can modulate the 
immune system by acting as both an anti-oxidant and an anti-inflammatory agent by scavenging 
toxic free radicals, reducing the up-regulation of pro-inflammatory cytokines, and reducing 
transendothelial migration
7. 
Melatonin levels are higher in fall and winter as production is stimulated by darkness. 
Interestingly, MS disease activity is higher in spring and summer when melatonin production is 
lower
8, 9. In a study of 139 relapsing MS patients, there was a 32% reduction in the number of 
relapses in the fall and winter
10. In the same study, Farez and colleagues were able to 
demonstrate a reduction in clinical symptoms in the Experimental Autoimmune Encephalitis 
(EAE) model when mice were give melatonin. Also, in this study, they detected a decrease in 
pro-inflammatory cells, Th17, and an increase in IL-10 which has anti-inflammatory properties. 
Fatigue is one of the most disabling symptoms in patients with multiple sclerosis, affecting 
approximately 90% of patients with MS
11. There are multiple reasons for this fatigue, but poor 
sleep is a contributing factor. Treatment naïve MS patients have demonstrated a reduction in 24 
hour urinary 6-sulfatoxymelatonin (6-SMT) 
12. In the same study, the levels increased when 
interferon-β treatment was added with a trend in improving fatigue. 
B. Research Strategy: 
To date, there are no published data on the role of melatonin supplementation or the 
appropriate dose for patients with multiple sclerosis. Because of the potential benefits of 
melatonin, this pilot study will be an exploratory investigation to evaluate the effect of 
supplementing melatonin in subjects with multiple sclerosis who are taking an oral disease 
modifying therapy (DMT) for 6 months or longer.  It is our intent that the results of this study 
will support the rationale and be a prelude to a larger trial which can focus on clinical efficacy of 
melatonin therapy outcomes. 
        C. Research Objectives 
1. The primary objective of this study is to evaluate the change in 24 hour urinary 6-SMT 
collected for 24 hours in two twelve hour sessions. 
2. The secondary objectives are to evaluate the change in serum morning melatonin level.  In 
addition, quality of life (QOL) measures will be assessed including the Modified Fatigue Impact 


 
Page 3 of 19 
Scale (MFIS)13, Multiple Sclerosis Impact Scale (MSIS-29)14, and the Pittsburgh Sleep Quality 
Index (PSQI)15.  Clinical objectives include the number of relapses during the trial and a change in 
the Patient Determined Disease Steps & Performance Scales (PDDS-PS).16-19 
          D. Study Design 
The proposed pilot study is a one-year randomized, rater- and dose-blinded trial evaluating the 
potential role of melatonin in subjects with relapsing multiple sclerosis who have been taking a 
stable dose of an oral DMT for at least 6 months. The oral DMTs include dimethyl fumarate, 
fingolimod, teriflunomide, diroximel fumarate, siponimod, and ozanimod. Thirty subjects with 
relapsing forms of multiple sclerosis who meet all of the eligibility criteria will be enrolled at 
Providence Neurological Specialties in Portland, Oregon.  The subjects will be consented by the 
investigator or delegated research personnel before undergoing any study procedures. Subjects 
will be randomized to melatonin 3 mg, or melatonin 5 mg.  There will be 15 subjects in each 
group. As this is a pilot study, we do not include a sample size calculation. 
Urinary and serum melatonin testing will be conducted at baseline, month 3, month 6, month 
12, and any early termination or unscheduled visits.  Subject reported measures for the 
assessment of fatigue, QoL, sleep, and MS severity (MFIS, MSIS-29, PSQI, and PDDS-PS) will be 
administered at baseline, month 3, month 6, month 12, and any early termination or 
unscheduled visits. Relapses during the study will be documented and recorded. If the subject 
does have a relapse, they will be treated per our clinical protocol which consists of Solu-Medrol 
1 gram IV once a day for 3 to 5 days depending on the severity of symptoms. 
If discontinuation of oral DMT and/or melatonin occurs, the subject may continue in the trial for 
observational purposes. An unscheduled (UNS) visit will be completed within 7 days after the 
last dose of oral DMT and/or melatonin (date of whichever is stopped first, if both 
discontinued). They will complete all applicable visits items moving forward (urinary 6-SMT 
reminder, urinary 6-SMT collection, dispense 24- hour urine collection materials, serum 
melatonin collection, dispense subject dosing diary, dispense study drug, study medication 
compliance/accountability, and potentially oral DMT compliance assessment will no longer be 
relevant/required). If oral DMT and/or melatonin is discontinued and the subject is 
unwilling to stay on the study for observational purposes, an early termination visit must 
be performed within 7 days after the last dose date of whichever is stopped first. 
Melatonin will be provided by the study.  However, oral DMT will be provided by the subject’s 
specialty pharmacy and paid by the subject or the subject’s insurance. 
           E. Outcome Measures 
1. Primary Outcome 
i. Change in urinary 6-SMT in 24 hours urine 
 
2. Secondary Outcomes: 
 
 
i. Change in Serum morning Melatonin level  
ii. Change in MFIS 


 
Page 4 of 19 
iii. Change in MSIS-29 
iv. Change in PSQI 
v. Number of Relapses during enrollment 
vi. Change in PDDS-PS 
            F. Methods 
 
1. Subject Selection 
a. Inclusion Criteria 
i. Male and female subjects with relapsing forms of MS who have been on a stable dose 
of dimethyl fumarate, fingolimod, teriflunomide, diroximel fumarate, siponimod, or 
ozanimod for 6 months or longer  
ii. Confirmed diagnosis of Relapsing MS 
iii. Ages 18 to 65 who are able to provide informed consent 
iv. Women of childbearing potential must employ proven methods to prevent 
pregnancy during the course of the trial; the acceptable method will be left to the 
judgment of the investigator 
v. Not pregnant or lactating 
vi. No evidence of significant cognitive or psychiatric disorder 
vii. Able to understand the purpose and risks of the study 
viii. Must be willing to sign an informed consent and follow the protocol requirements 
b. Exclusion Criteria 
i. Use of melatonin within 30 days of enrollment 
ii. The addition of any sleep aide or change in dose within 30 days of enrollment or 
during the trial  
iii. The addition or change in dose of Vitamin D within 30 days of enrollment or during 
the trial 
iv. Change in DMT during the trial 
v. Steroid therapy within 30 days of enrollment 
vi. Use of anticoagulation at the time of enrollment and during the trial 
vii. The addition of an antidepressant is not allowed during the study period; if on an 
antidepressant at screening, the dose must be stable 30 days prior to enrollment and 
dose changes are prohibited during the study 


 
Page 5 of 19 
 
viii. The addition or change in dose of any stimulants, including but not limited to, 
amantadine, armodafinil, methylphenidate, or modafinil within 30 days of enrollment 
or during the trial 
 
2. Discontinuation of Subjects from the Study 
i. Subjects may voluntarily withdraw consent and discontinue their participation in the 
study at any time 
ii. If a subject has a relapse during the study, the study doctor may discontinue 
melatonin and/or oral DMT 
a. A relapse is defined as a new symptom, or worsening of pre-existing 
neurologic symptoms, of at least 24 hours duration, in subjects who had 
been clinically stable for the prior 30 days, in the absence of fever, sleep 
deprivation or severe emotional stress. 
iii. Subject has an adverse event that presents unacceptable risk, per investigator 
discretion 
iv. Subject has inadequate adherence to the protocol, per investigator discretion 
v. Subject is lost to follow-up 
vi. Subject becomes pregnant 
 
3. Method of Treatment Assignment 
The randomization sequence will be generated using R statistical software and will be stratified 
by age group and gender with a 1:1 allocation using a fixed block size of four. The following four 
strata will be used: 1) younger females, 2) older females, 3) younger males, and 4) older males.  
As subjects enter the study, they will be designated to a stratum and will be assigned either a 3 
mg or 5 mg melatonin dose based on the pre-generated randomization scheme within that 
stratum. A master list containing drug kit numbers and drug assignment will be kept in a 
password-protected computer file in the research pharmacy.  The investigator, study 
coordinator and subjects will remain blinded until study completion.  The blind will only be 
violated if, in the judgment of the treating investigator, unblinding is necessary for subject 
safety. 
 
4. Study Treatment 
i. All subjects will continue their oral DMT and start the study drug on Day 1 (Baseline 
Visit).  
ii. Oral DMT will be taken per standard of care dosing and paid for by the 
subject/subject insurance. 
iii. Subjects randomized to melatonin will take either 3mg once a day or 5mg once a day. 
Melatonin will be supplied by Thorne Pharmaceuticals.  The study drug will be taken 
at 21:00 each day ±2 hours. 


 
Page 6 of 19 
 
5. Concomitant and Excluded Therapy 
The addition of a sleep aide is not allowed during the study period.  If subjects were on a sleep 
aide prior to the trial, no change in this medication is allowed and the dose must be stable 30 
days prior to enrollment. 
No change in Vitamin D supplementation will be allowed during the study and the dose must be 
stable 30 days prior to enrollment. 
The addition of an antidepressant is not allowed during the study period. If on an antidepressant 
at screening, the dose must be stable 30 days prior to enrollment and dose changes are 
prohibited during the study. 
Stimulants, amantadine, armodafinil, methylphenidate or modafinil cannot be added during the 
study period. If subjects were on any of these listed medications prior to the trial, no change in 
this medication is allowed and the dose must be stable 30 days prior to enrollment. 
The enrolling investigator is to review prior and concomitant medications at screening to ensure 
concomitant and excluded therapy requirements are met. 
 
6. Study Assessments 
The investigator or designated research staff will obtain informed consent from each subject 
after explaining the purpose of the study and the potential risks and benefits known or can be 
reasonable expected. The IRB approved informed consent will be signed by the subject before 
any screening assessments or procedures are performed. 
The serum melatonin level will be drawn in the morning (09:00±2 hours). 
i. 
Assessments During Treatment 
a. Visit 1 or Screening Visit (1-30 days prior to baseline) 
i. Informed consent 
ii. Inclusion/exclusion criteria review 
iii. Demographic Information 
iv. Vital signs (including height and weight at screening)  
v. Review of concomitant medications  
vi. Review of all prior medications taken within last 30 days 
vii. Medical history 
viii. MS history 
ix. Childbearing potential review 
x. Physical exam [If a subject had a physical exam during the screening window 
(1-30 days prior to baseline) with a trial investigator but it was completed 


 
Page 7 of 19 
prior to consent as part of standard of care, the data from this exam may be 
used for the screening visit physical exam requirement. This is allowed only 
if all elements of the required exam were completed.] 
xi. Neurological exam [If a subject had a neurological exam during the 
screening window (1-30 days prior to baseline) with a trial investigator but it 
was completed prior to consent as part of standard of care, the data from 
this exam may be used for the screening visit neurological exam 
requirement. This is allowed only if all elements of the required exam were 
completed.] 
xii. Oral DMT compliance assessment 
xiii. Vitamin D laboratory level (the most recent vitamin D laboratory level that 
was collected as part of standard of care, not to be ordered specifically for 
trial) 
xiv. Dispense lab collection materials/instructions for Urinary 6-
sulfatoxymelatonin collection (24-hr urine collection), specimen to be 
collected within -3 days of visit 2 and returned to clinic at visit 2 
xv. Adverse event assessment (starting after informed consent obtained) 
xvi. Telephone contact-remind subject to complete 24 hour collection within -3 
days of visit 2 (to be completed within -5 days of visit 2, not 
applicable/required if screening and baseline are 1 day apart) 
b. Visit 2 or Baseline Visit (Day 1) 
i. Urine collection (within -3 days of visit 2) 
1. Urinary 6-SMT collection will begin and continue for 24 hours  
ii. Vital signs 
iii. Serum melatonin level collection (09:00±2 hours) 
iv. Review of concomitant medications 
v. Dispense Subject Dosing Diary 
vi. Adverse event assessment  
vii. Relapse assessment 
viii. MFIS 
ix. MSIS-29 
x. PSQI 
xi. PDDS-PS 


 
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xii. Oral DMT compliance assessment 
xiii. Vitamin D laboratory level (if collected since the last trial visit as part of 
standard of care, not to be ordered specifically for trial)Inclusion/exclusion 
criteria review 
xiv. Randomization 
xv. Dispense study drug-first dose at 21:00 ±2 hours on Day 1 
xvi. Dispense lab collection materials/instructions for Urinary 6-
sulfatoxymelatonin collection (24-hr urine collection), specimen to be 
collected within -3 days of visit 3 and returned to clinic at visit 3 
xvii. Telephone contact-study medication compliance, verify study drug first 
dose date/time (within +3 days of visit 2) 
xviii. Telephone contact-remind subject to complete 24 hour collection within -3 
days of visit 3 (to be completed within -5 days of visit 3) 
c. Visit 3 (3 months +/- 14 days from baseline) 
i. Urine collection (within -3 days of visit 3) 
1. Urinary 6-SMT collection will begin and continue for 24 hours  
ii. Vital signs 
iii. Serum melatonin level collection (09:00±2 hours) 
iv. Review of concomitant medications 
v. Adverse event assessment 
vi. Relapse assessment 
vii. MFIS 
viii. MSIS-29 
ix. PSQI 
x.  PDDS-PS 
xi. Physical exam 
xii. Neurological exam 
xiii. Study medication compliance and accountability assessment 
xiv. Collect study medication and dispense new study medication 
xv. Oral DMT compliance assessment 


 
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xvi. Vitamin D laboratory level (if collected since the last trial visit as part of 
standard of care, not to be ordered specifically for trial)Collect and 
dispense new Subject Dosing Diary 
xvii. Dispense lab collection materials/instructions for Urinary 6-
sulfatoxymelatonin collection (24-hr urine collection), specimen to be 
collected within -3 days of visit 4 and returned to clinic at visit 4 
xviii. Telephone contact-remind subject to complete 24 hour collection within -3 
days of visit 4 (to be completed within -5 days of visit 4) 
d. Visit 4 (6 months +/- 14 days from baseline) 
i. Urine collection (within -3 days of visit 4) 
1. Urinary 6-SMT collection will begin and continue for 24 hours  
ii. Vital signs 
iii. Serum melatonin level collection (09:00±2 hours) 
iv. Review of concomitant medications 
v. Adverse event assessment 
vi. Relapse assessment 
vii. MFIS 
viii. MSIS-29 
ix. PSQI 
x.  PDDS-PS 
xi. Physical exam 
xii. Neurological exam 
xiii. Study medication compliance and accountability assessment 
xiv. Collect study medication and dispense new study medication 
xv. Oral DMT compliance assessment 
xvi. Vitamin D laboratory level (if collected since the last trial visit as part of 
standard of care, not to be ordered specifically for trial)Collect and dispense 
new Subject Dosing Diary 
xvii. Dispense lab collection materials/instructions for Urinary 6-
sulfatoxymelatonin collection (24-hr urine collection), specimen to be 
collected within -3 days of visit 5 and returned to clinic at visit 5 


 
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xviii. Telephone contact-remind subject to complete 24 hour collection within -3 
days of visit 5 (to be completed within -5 days of visit 5) 
e. Visit 5 (12 months +/- 14 days from baseline) 
i. Urine collection (within -3 days of visit 5) 
1. Urinary 6-SMT collection will begin and continue for 24 hours  
ii. Vital signs  
iii. Serum melatonin level collection (09:00±2 hours) 
iv. Review of concomitant medications 
v. Adverse event assessment  
vi. Relapse assessment 
vii. MFIS 
viii. MSIS-29 
ix. PSQI 
x.  PDDS-PS 
xi. Physical exam 
xii. Neurological exam 
xiii. Study medication compliance and accountability assessment 
xiv. Collect study medication  
xv. Oral DMT compliance assessment 
xvi. Vitamin D laboratory level (if collected since the last trial visit as part of 
standard of care, not to be ordered specifically for trial)Collect Subject 
Dosing Diary 
 
f. Early Termination Visit (ET) 
If discontinuation of oral DMT and/or melatonin occurs and the subject is 
unwilling to continue in the trial for observation, an ET visit must be performed 
within 7 days after the last dose of oral DMT and/or melatonin (date of 
whichever is stopped first, if both discontinued). 
i. Urine collection (±3 days of visit ET) 
1. Urinary 6-SMT collection will begin and continue for 24 hours  


 
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ii. Vital signs 
iii. Serum melatonin level collection (09:00±2 hours) 
iv. Review of concomitant medications 
v. Adverse event assessment  
vi. Relapse assessment 
vii. MFIS 
viii. MSIS-20 
ix. PSQI 
x.  PDDS-PS 
xi. Physical exam (only required if subject was last examined more than 6 
months ago or per treating physician’s discretion)  
xii. Neurological exam (only required if patient was last examined more than 6 
months ago or per treating physician’s discretion) 
xiii. Study medication compliance and accountability assessment 
xiv. Collect study medication  
xv. Oral DMT compliance assessment 
xvi. Vitamin D laboratory level (if collected since the last trial visit as part of 
standard of care, not to be ordered specifically for trial)Collect Subject 
Dosing Diary 
g. Unscheduled Visits(UNS) 
Subjects will be instructed to contact their treating investigator in the event of a 
relapse and may be asked to return for an UNS visit.  Additionally, an UNS visit 
will be completed within 7 days after the last dose of oral DMT and/or melatonin 
(date of whichever is stopped first, if both discontinued) if stopped between 
visits and the subject is willing to continue in the trial for observation. 
i. Urine collection (±3 days of visit UNS) 
1. Urinary 6-SMT collection will begin and continue for 24 hours  
ii. Vital signs 
iii. Serum melatonin level collection (09:00±2 hours) 
iv. Review of concomitant medications 
v. Adverse event assessment 


 
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vi. Relapse assessment 
vii. MFIS 
viii. MSIS-29 
ix. PSQI 
x.  PDDS-PS 
xi. Physical exam (only required if a relapse is suspected or per treating 
physician’s discretion) 
xii. Neurological exam (only required if a relapse is suspected or per treating 
physician’s discretion) 
xiii. Study medication compliance and accountability assessment 
xiv. Oral DMT compliance assessment 
xv. Vitamin D laboratory level (if collected since the last trial visit as part of 
standard of care) 
xvi. Collect and dispense new Subject Dosing Diary 
h. Discontinuation of study drug 
i. If the subject becomes pregnant 
ii. At the discretion of the investigator for medical or ethical reasons 
iii. If the subject withdrawals consent 
iv. If the subject is unwilling or unable to comply with the protocol, per 
investigator discretion 
G. Statistical Methods 
Subject characteristics for each arm will be reported for continuous variables (mean, standard 
deviation, median, and range) and categorical variables (counts and percentages). All analyses will 
use two-sided tests at the 0.05 significance level. This study is based on an intention to treat model, 
in which all subjects receiving at least one dose of melatonin will be included. 
a. Primary Analysis 
Longitudinal analyses using a linear mixed models for repeated measures will be used to 
compare changes in 24-hour urinary 6-sulfatoxymelatonin and serum morning Melatonin over 
time between arms. Each outcome will be treated as continuous and identify link functions will 
be used.  Overall trajectories as well as the mean change from baseline to 3, 6, and 12 months 
for each arm will be reported and compared. 
b. Secondary Analysis 


 
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Changes in the MFIS, MSIS-29, PSQI, & PDDS-PS from baseline to 3, 6, and 12 months will be 
reported and tested using a paired t or Wilcoxon signed-rank test for related samples. Two-
sample t or Mann-Whitney tests will be used to compare change between arms at each time 
point. The mean number of relapses during enrollment for each arm will be reported and 
compared using a Poisson analysis. Kaplan-Meier survival analysis methodology will be used to 
estimate the proportion of subjects relapse-free at months 3, 6, and 12 and log rank tests will be 
used to compare arms. 
 
To examine agreement between 24-hour urinary 6-sulfatoxymelatonin and serum morning 
melatonin level, the measurements will be plotted and compared using prediction intervals 
from regression analysis as outlined in 2003 paper by J. M. Bland and D. G. Altman
20. 
 
H. Regulatory 
a. Regulatory Requirements 
The study will be performed in accordance with ICH GCP Guidelines and the Code of Federal 
Regulations for clinical research.  Any amendments to the study protocol must be approved by 
Providence Health and Services Institutional Review Board before implementation.  AEs and 
protocol violations or deviations must be reported according to the guidelines of Providence 
Health and Services Institutional Review Board.  
b. Safety Assessments 
Full physical and neurological exams will be performed at months 3, 6 and 12 visits.  Any 
worsening or new abnormality that is clinically significant is to be recorded as AE and will be 
analyzed as such.  MS relapse symptoms are not to be reported as AE unless, in the opinion of 
the investigator, the symptoms are unusually serious and relevant. 
An adverse event (AE) is any unfavorable or unintended sign, symptom, or disease that is 
experienced by a subject who has received an investigational drug, whether or not there is a 
causal relationship with the investigational drug. At the signing of the informed consent form, 
each subject will be given the names and telephone numbers of investigational site personnel 
for reporting adverse events and medical emergencies. The investigator must conduct thorough 
assessment to determine the severity of the AE and the relationship to the study drug. Any 
clinically significant AE of severity moderate or higher, requires follow up until resolution or 
stabilization. 
 
I. Reporting Adverse Events 
a.  Per International Conference of Harmonization (ICH) guidelines, an AE for this trial will be any 
untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment and AE can therefore be any unfavorable and unintended sign, including an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a product, 
whether or not considered related to the medicinal product. Pre-existing conditions which 
worsened during his stay are to be reported as adverse events. All adverse events fitting this 
description will be captured and recorded on the case report forms. 
 


 
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b.  In the event that the subject is withdrawn from the study because of an adverse event, it must 
be recorded on the case report form as such. 
c.  Serious Adverse Events 
 i. Death 
ii. Life-threatening experience which places his subject at immediate risk of death 
from the event as it occurred. 
iii. Full inpatient hospitalization or prolongation of hospitalization 
iv. Persistent or significant disability/incapacity 
v. Congenital anomaly or birth defect 
d.  All adverse events (including pre-dosing and treatment-emergent) should be recorded in the 
subject’s Adverse Event CRF regardless of severity or relationship to study drug.  This includes 
abnormal, clinically significant laboratories being drawn as standard of care for routine 
monitoring with oral DMT. The investigator must review the laboratory findings and sign and 
date the laboratory report either electronically in the EMR, or as a paper source copy for 
significance review.  All SAEs must be reported by the investigator to the regulatory associate 
and study manager by email to suzanne.balleisen@providence.org and tiffany.gervasi-
follmar@providence.rog or fax to 503-215-6547 and 503-216-1039 within 24 hours of the 
investigator’s knowledge of the event. All SAEs must be recorded on the Medwatch 3500A form 
and be reported, whether or not the event is considered by the investigator to be related to 
study drug. 
e.  Severity 
 
The intensity of severity of an AE will be graded as follows: 
Mild 
Symptoms(s) barely noticeable to subject or does not make subject uncomfortable; 
does not influence performance or functioning; prescription drug not ordinarily 
needed for relief of symptoms(s) but may be given because of personality of 
subject 
Moderate  
Symptom(s) of a sufficient severity to make subject uncomfortable; performance of 
daily activity is influenced; subject is able to continue in study; treatment for 
symptom(s) may be needed. 
Severe 
Symptom(s) cause severe discomfort; symptoms cause incapacitation or significant 
impact on subject’s daily life; severity may cause cessation of treatment with 
investigational drug; treatment for symptom(s) may be given and/or subject 
hospitalized. 
f.  Relationship to Study Drug 
The relationship or association of the AE to a study drug will be characterized as follows: 
Not related Any event that does not follow a reasonable temporal sequence from 
administration of investigational drug AND that is likely to have been produced by 
the subject’s clinical state or other modes of therapy administered to the subject. 


 
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Unlikely 
Any event that does not follow a reasonable temporal sequence from 
administration of investigational drug OR that is likely to have been produced by 
the subject’s clinical state or other modes of therapy administered to the subject. 
Possibly 
Any reaction that follows a reasonable temporal sequence from administration of 
investigational drug OR that follows a known response pattern to the suspected 
drug AND that could not be reasonably explained by the known characteristics of 
the subject’s clinical state or other modes of therapy administered to the subject. 
Related 
Any reaction that follows a reasonable temporal sequence from administration of 
investigational drug AND that follows a known response pattern to the suspected 
drug AND that recurs with re-challenge, AND/OR is improved by stopping the drug 
or reducing the dose. 
Investigator Reporting Responsibilities for Safety and Monitoring 
• 
Monitor and record all adverse events 
• 
Determine the seriousness, causality, and severity of each adverse event 
• 
Form a Data Safety Monitoring Board (DSMB) and conduct regular meetings to review 
safety findings 
• 
Report all serious adverse events to the FDA according to the code of federal regulations 
• 
Actively and persistently pursue follow-up of serious adverse events 
• 
Submit annual reports to study sponsor 
 
J. Estimated Duration of the Study and Critical Timeline Elements 
a. IRB Approval – April 26th, 2018 
b. Study Start Date– May 9th, 2018 
c. Enrollment Completion Date, Estimated – November 9th, 2020 
d. Study Completion Date, Estimated – November 9th, 2021 


 
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Table 1: Schedule of Events 
Visit Number 
Visit 1 
TC 
Visit 2A 
TC 
TC 
Visit 3 
TC 
Visit 4 
TC 
Visit 5 
Visit ET 
Visit UNS 
Visit Schedule 
Screening  
1-30 Days prior 
to Baseline 
Within -5 
days of 
Visit 2 
Baseline 
Day 1 
Within +3 
days of 
Visit 2 
Within -5 
days of 
Visit 3 
Month 3 K    
±14 days 
Within -5 
days of 
Visit 4 
Month 6 K    
±14 days 
Within -5 
days of 
Visit 5 
Month 12 K    
±14 days 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Review 
X 
 
X 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
Vitals B 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior Medication Review 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication Review 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Adverse Event Assessment 
X M 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
MS History  
X 
 
 
 
 
 
 
 
 
 
 
 
Childbearing Potential Review C 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
XQ 
 
 
 
 
X 
 
X 
 
X 
XN 
XO 
Neurological Exam 
XR 
 
 
 
 
X 
 
X 
 
X 
XN 
XO 
Urinary 6-SMT reminder 
 
X L 
 
 
X 
 
X 
 
X 
 
 
 
Urinary 6-SMT Collection D 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Dispense 24hr Urine Collection Materials 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
Serum Melatonin Collection E 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Standard of Care Vitamin D LevelP 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Collect/Dispense Subject Dosing Diary J 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Relapse Assessment 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
MFIS  
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
MSIS-29  
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
PSQI  
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
PDDS-PS 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
Collect/Dispense Study Drug 
 
 
X G 
 
 
X 
 
X 
 
X H 
X H 
X F 
Study Medication Compliance 
 
 
 
X I 
 
X 
 
X 
 
X 
X 
X 
Study Medication Accountability 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Oral DMT Compliance Assessment 
X 
 
X  
 
 
X 
 
X 
 
X 
X 
X 
A: Screening and baseline may occur one day apart if all screening procedures are completed/reviewed at time of baseline. Urine and serum melatonin labs must be collected prior to dosing on Day 1. These visits cannot be 
completed on the same day due to the required 24 hour urinary 6-sulfatoxymelatonin collection to be initiated after consent. 
B: Vitals to include blood pressure, respiration rate, pulse, and oral temperature after being seated at rest for 5 minutes. 
C: Adequate contraception method for female subjects of childbearing potential will be left to the discretion of the treating investigator. 
D: Urinary 6-sulfatoxymelatonin collection for 24 hours in two twelve hour sessions. See local laboratory manual for reference ranges and collection specifications. To be collected within -3 days of indicated visit date, with the 
exception of ET and UNS visits-to be collected within ±3 days of visit.  
E: Serum melatonin be collected at 0900 ±2 hours. See local laboratory manual for reference ranges and collection specifications.  
F: Collect study drug only if reason for UNS visit is stopping DMT and/or study medication. None to be dispensed in this case 
G: Dispense study drug only, none to be collected.  
H: Collect study drug only, none to be dispensed.  
I: Phone contact to be completed within +3 days of baseline visit to verify study drug first dose date and time.  


 
Page 17 of 19 
J: Dispense Subject Dosing Diary at baseline. Collect and dispense new diary at each subsequent visit. Collect diary at visit 5 or ET and do not dispense new diary.  
K: One month is equal to 30 days. 
L: Not applicable/required if screening and baseline are 1 day apart.  
M: Adverse events to be reviewed during screening period after informed consent is obtained (i.e., at end of screening visit). 
N: only if requested by the treating physician or if subject was examined more than 6 months ago 
O: only if requested by the treating physician or if a relapse is suspected   
P: At screening, the most recent vitamin D level collected as part of standard of care for the subject will be reported in the trial. At all additional visits, if a vitamin D level was collected since the last trial visit as part of standard 
of care, it will be reported in the trial. Not to be ordered specifically for the trial.  
Q: If a subject had a physical exam during the screening window (1-30 days prior to baseline) with a trial investigator but it was completed prior to consent as part of standard of care, the data from this exam may be used for 
the screening visit physical exam requirement. This is allowed only if all elements of the required exam were completed. 
R: If a subject had a neurological exam during the screening window (1-30 days prior to baseline) with a trial investigator but it was completed prior to consent as part of standard of care, the data from this exam may be used 
for the screening visit neurological exam requirement. This is allowed only if all elements of the required exam were completed. 


 
Page 18 of 19 
 
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29): a new patient-based outcome measure. Brain : a journal of neurology 2001;124:962-973. 
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A new instrument for psychiatric research and practice. Psychiatry Research 28:193-213, 1989. 
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