Clinical trial NCT02804594
Conditions: Progressive Multiple Sclerosis Fatigue
Sponsor: University of California, San Francisco
Start date: 2016-10-01; Completion date: 2018-06-01
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 4-week randomized, placebo-controlled, parallel group, double-blind, single center trial on effect of N-acetyl cysteine versus placebo on fatigue in patients with progressive MS defined by McDonald criteria. Subjects who enter the treatment phase of study, will be randomly assigned to either N-acetyl cysteine (1250 mg three times a day) or placebo (three times a day) for 4 weeks. There will be 3 in-person study visits (screening, baseline, and week 4) and 2 visits over the phone (week 2, and week 6 which is 2 weeks after completing last study drug dose). Visits will all occur in the morning to maximize consistency of assessments and evaluate main outcomes within 2 hours of morning dose of study medication. Fatigue questionnaires, and research samples will be obtained before neurological examination, or magnetic resonance imaging. Research blood draws will be obtained just after fatigue questionnaire completion. Brain spectroscopy will be obtained less than 2 hours after morning dose of study drug to maximize detection of the biological effect of study medication.

Detailed description:
1Background 1.1 Multiple Sclerosis Multiple sclerosis is the most common cause of non-traumatic disability in young adults in the US. It is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system. Patients with MS often experience various types of disabling symptoms such as chronic fatigue or pain. Most patients with an initial relapsing-remitting course develop at some point insidious disability worsening, i.e. secondary progressive MS. In contrast, about 15% of multiple sclerosis patients experience an insidiously progressive course from onset. Primary and secondary progressive multiple sclerosis is thought to have similar physiopathology. As such, strategies for managing symptoms of relapsing patients may not necessarily apply to those with progressive disease; however, most symptomatic treatment trials have been done in relapsing-remitting or mixed populations of patients, neglecting a large fraction of patients with progressive forms of the disease. Investigator is planning to address an important clinical and pathophysiologic issue in this proposed study.

1.2 Fatigue in multiple sclerosis Fatigue as defined by a subjective lack of physical or mental energy perceived by the individual with usual activities is the most common and disabling symptom of multiple sclerosis. Fatigue severity is not correlated with depression or neurological disability. It can impact substantially physical and cognitive activities and thus, negatively affect the quality of life of many patients. There are no medications specifically approved for fatigue in multiple sclerosis. Many chronic inflammatory disorders are associated with fatigue and peripheral inflammation is postulated to be an important contributor to fatigue pathogenesis. A spectroscopy study has reported decreased N-acetylaspartate/creatine ratio in several brain regions, thus all pointing at axonal loss as a possible contributing factor . In a cross-sectional relapsing-remitting MS study, fatigued patients had more severe atrophy of the striatum, thalamus and frontal and parietal gyri as compared to non-fatigued patients.

As a direct consequence of the unknown pathophysiology, very little pharmacologic intervention is available for fatigue in multiple sclerosis. Glutamate, a critical neurotransmitter implicated in excitotoxicity and neurodegeneration, may also play a role in fatigue genesis. Two studies of a glutamate receptor antagonist (memantine) have reported worsening of fatigue in multiple sclerosis patients. In addition, Investigator have found that compared to placebo, riluzole (a medication with some anti-glutamate activity) worsened fatigue in patients with very early multiple sclerosis. This is in sharp contrast with the pathological evidence suggesting that excessive glutamate transmission may be a final effector in neuronal and axonal degeneration in multiple sclerosis animal models. Oxidative stress due to disequilibrium between oxidants and antioxidants in the central nervous system may also be a major contributor to neurodegeneration . It is unknown if oxidative stress plays a role in the pathogenesis of fatigue in multiple sclerosis.

1.3 Fatigue rating scales Most of the fatigue scales used in multiple sclerosis studies were primarily developed and validated for use in other medical conditions. The two widely used self-completed scales in multiple sclerosis research are the Fatigue Severity Scale, and the Modified Fatigue Impact Scale.

1.3a. Fatigue Severity Scale: This scale was originally designed to identify the common features of fatigue in multiple sclerosis, and lupus patients. It assesses the impact of fatigue on several outcomes, with an emphasis on physical fatigue. It is composed of 9 questions with responses provided on a 7-point Likert scale. Scale score is the mean of the item scores and higher scores indicate more severe fatigue.

1.3b.Modified Fatigue Impact Scale: This scale has been proposed by the Multiple Sclerosis Council for Clinical Practice Guidelines as the instrument of choice for assessing fatigue in multiple sclerosis. It is derived from the 40-item Fatigue Impact Scale. It has 21 items and assesses more dimensions of fatigue than the Fatigue Severity Scale: physical (9 items), cognitive (10 items) and psychosocial (2 items). The scale score is the sum of the 21 items and higher score indicates more severe fatigue. The scale has shown good reproducibility, ease of use and good correlation with fatigue severity scale scores. A cut-off value of 38 distinguishes fatigued from non-fatigued multiple sclerosis patients.

2.Rationale 2.1 Effect of N-acetyl cysteine in MS fatigue N-acetyl cysteine is an orally bioavailable precursor of the amino acid cysteine and is used to treat acetaminophen-induced hepatotoxicity. The medication half-life in adults is about 5.6 hours. As such it has been given twice or three times a day in various trials that have documented a biological effect. It protects the liver by restoring hepatic concentrations of cysteine and glutathione (GSH- a major intracellular antioxidant). Besides antioxidant properties, N-acetyl cysteine, by increasing the intracellular concentration of cysteine and activating the glutamate-cysteine antiporter eventually decreases glutamatergic transmission. Hypothetically, by decreasing excitotoxicity, it may protect neurons in different models of neuronal damage and neurodegeneration. Excellent safety profile and potential neuroprotective properties make N-acetyl cysteine an attractive target for examining its anti-fatigue properties in patients with progressive multiple sclerosis. Orally administered N-acetyl cysteine produces biologically relevant cerebrospinal fluid concentrations of N-acetyl cysteine at doses that are well tolerated. One study showed an effect of a single injection of N-acetyl cysteine on blood glutathione redox ratios followed by changes in glutathione concentration in the brain using 7T magnetic resonance spectroscopy in 3 patients with Parkinson's disease and 3 controls.

Clinical trials of oral N-acetyl cysteine for a wide variety of clinical conditions have used a range of different daily doses (from 600 mg to 6000 mg per day). The study investigator chose the daily dose of 3750 mg (1250 mg administered three times a day), based on its good tolerability, treatment compliance and minimum adverse effects reported in a recent clinical trial.

2.2 Reason for using a placebo group

There are no FDA-approved treatments for fatigue in multiple sclerosis. There are also no standard of care as various trials have reported inconsistent findings about the effect of amantadine in multiple sclerosis fatigue. Pursuant to the Helsinki Declaration, when standard treatment of a disease exists, placebo should generally not be used in clinical trials. However, Declaration of Helsinki supports the stance that placebo can be acceptable in the setting where no proven standard therapy exists:

The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention, except in the following circumstances:

* The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or
* Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm.

2.3 Gap in fatigue management Symptomatic treatment trials for fatigue have been small, underpowered and with methodological flaws. As such, drawing firm conclusions and making therapeutic recommendations has been difficult. Thus, fatigue in multiple sclerosis remains very difficult to manage despite its substantial impact on patients' life. An issue when studying fatigue in patients with relapsing-remitting multiple sclerosis has been the possibility of increased fatigue during disease relapses and with specific disease-modifying therapies such as interferon. There has been no study focusing on the effects of drug therapy in fatigue in patients with progressive disease. Furthermore, study investigator's knowledge regarding the underlying pathophysiology of fatigue in multiple sclerosis is scarce and future studies of intervention on fatigue should include biomarkers to further elucidate the potential mechanisms of observed effects.

The study investigator hypothesize that fatigue in progressive multiple sclerosis patients is associated with increased glutamate and decreased glutathione concentration on brain spectroscopy at baseline. The study investigator also hypothesize that fatigue is associated with changes of various oxidative pathway metabolites in peripheral blood.

4\. Study Design 4.1 Overview of study design: This is a 4-week randomized, placebo-controlled, parallel group, double-blind, single center trial on effect of N-acetyl cysteine versus placebo on fatigue in patients with progressive multiple sclerosis defined by McDonald criteria. Subjects, who enter the treatment phase of study, will be randomly assigned to either N-acetyl cysteine (1250mg 3 times a day or placebo ( three times a day)for 4 weeks.There will be 3 in-person study visits (screening, baseline, and week 4 and 2 visits over the phone (week 2, and week 6 which is 2 weeks after completing last study drug dose). Visits will all occur in the morning to maximize consistency of assessments and evaluate main outcomes within 2hours of morning dose of study medication. Questionnaires, and research samples will be obtained before neurological exam or magnetic resonance imaging. Research blood draws will be obtained just after questionnaire completion. Brain spectroscopy will be obtained less than 2hours after morning dose of study drug to maximize detection of the biological effect of study medication.

4.2 Enrollment sites Enrollment will start in August, 2016. Enrollment period will last 6 months. Patients will be enrolled in the trial at University of California San Francisco.

4.3 Study visits 4.3a Screening period: Total duration of screening period is 4 weeks. An additional 5 patients with progressive multiple sclerosis who volunteered for participation in the clinical trial, but had a screening modified fatigue impact scale score of \<38 or were recruited from site's clinic (who reported no fatigue and their fatigue scale score was \<38), will undergo brain imaging on 7Tesla magnetic resonance imaging machine, and research blood draws.

4.3b Treatment period: Total duration of the blinded treatment period is 4 weeks. After the screening visit, the inclusion/ exclusion criteria details of eligible patients will be reviewed by study investigator. The eligible study participants will be randomized in approximately a 2:1 ratio to one of the two arms of either N-acetyl cysteine or placebo. The treatment group assignment will be blinded for the duration of the study. A week-2 phone visit will be completed to determine the tolerance of study drug.

4.3c Follow up phone visit: Two weeks after taking the last dose of study medication, fatigue scale questionnaires are completed over phone by the study coordinator to collect the safety and efficacy measures of the study. Additional phone visit needs to be completed 2 weeks from randomization to assess the safety, tolerability, and compliance of study medication.

4.5 Study visit window: The screening period can be up to 4 weeks. The baseline visits needs to be completed within 28 days of screening visit. Week 2 phone visit in +/- 5 days of Day 14, and week 4visit in Day 28+/-7 days of baseline. Follow-up phone call is completed +/- 5 days of week 6 visit.

Arms: arm 1: 1250 mg of N-acetyl cysteine three times daily arm 2: placebo three times daily
Interventions: intervention 1: N-acetyl cysteine intervention 2: Placebo
Intervention descriptions: intervention 1: 1250 mg of N- acetyl cysteine taken three times daily intervention 2: placebo taken three times daily

Protocol documents:
Prot_SAP_000.pdf: 
Confidential – UCSF – NAC Pilot study (Version 4 dated 12 Oct 2016) 
Protocol title: A pilot study of oxidative pathways in MS fatigue 
Document Date: 10/12/2016 
Version: 4 
NCT: 02804594
PI: Emmanuelle Waubant, M.D., PhD 
Professor of Clinical Neurology and Pediatrics 
UCSF MS Center 
Neuroscience Building 
675 Nelson Rising Lane, suite 221 
San Francisco, CA94158 


Confidential – UCSF – NAC Pilot study (Version 4 dated 12 Oct 2016) 
 
 
 
 
 
 
 
 
Protocol title: A pilot study of oxidative pathways in MS fatigue 
 
PI: Emmanuelle Waubant, M.D., PhD 
Professor of Clinical Neurology and Pediatrics 
UCSF MS Center 
Neuroscience Building 
675 Nelson Rising Lane, suite 221 
San Francisco, CA94158 
 
8.Statistical consideration and analysis plan 
8.1 Statistical plan for specific aim 1- To test the tolerability and safety of NAC therapy (1250 
mg three times a day) compared to placebo for 4 weeks to treat progressive MS fatigue. 
 
Study Subjects: Target population- Adult patients with progressive MS and fatigue seen at UCSF. 
 
The safety outcome will be analyzed by including all subjects who have received at least one dose 
of study medication. Participants will be analyzed according to the actual treatment received. The 
assessment of safety will be based on the frequency of adverse events. 
The primary efficacy analysis will be done as an intent-to-treat analysis. Consequently, all 
randomized participants will participate in the analysis as allocated to NAC or placebo. 
8.2 Statistical plan for specific aim 2- To obtain preliminary data on changes in fatigue levels 
and oxidative pathway biomarkers on NAC therapy in subjects with progressive MS fatigue. 
In an intent-to-treat analysis, using Student t-test, the mean change in MFIS score from the 
baseline to week 4 will be compared between the NAC and placebo groups. The per-protocol 
secondary analysis will take into account treatment regimen. We will use similar models to 
compare the changes in brain GSH concentration and blood GSH/GSSG ratio, FSS, NeuroQOL 
fatigue item bank, 9-hole peg test, 25-foot timed ambulation, and Symbol Digit Modalities Test 
(SDMT) at the baseline and week fourth between the NAC and placebo groups. 


Confidential – UCSF – NAC Pilot study (Version 4 dated 12 Oct 2016) 
 
Because there is a possibility for imbalance in the baseline values of potential confounding 
factors (such as EDSS and depression), an a priori secondary analysis is planned. To assess 
the effectiveness of NAC vs. placebo, we will use a linear regression model, comparing the 
mean change in MFIS score from the baseline to week 4, adjusting the models for the 
baseline EDSS and HADS scores. 
We will use the same models to analyze the change in the severity of fatigue as measured 
by MFIS and FSS between week 4 (the end of study drug administration period) and week 
6 (2 weeks after patients have been off study drug). 
Because of the exploratory nature of these analyses, we will not correct our models for 
multiple comparison testing. Statistical analyses will be performed by a biostatistician from 
UCSF biostatistics department blinded to treatment assignment. 
Sample size calculation: There are no available data to base power calculation for this 
aim as such a study has never been performed prior. We will use the data generated for 
this aim to design future studies. 
Primary efficacy endpoint: The primary efficacy analysis will be done as an intent-to-treat 
analysis. Consequently, all randomized participants will participate in the analysis as 
allocated to NAC or placebo. Using Student t-test, the mean change in MFIS score from the 
baseline to week 4 will be compared between the NAC and placebo groups. The per-
protocol secondary analysis will take in account treatment regimen. 
MFIS consists of 21 items with a total score range of 0 to 84 (higher scores indicate worse 
fatigue). As the primary efficacy endpoint of the trial, we will compare the mean change in total 
MFIS score from baseline to week 4 visit between intervention and placebo groups. 
 
Secondary efficacy endpoints (differences between treatment groups): 
- 
Per protocol analysis for changes in MFIS from screening /baseline to week 4. 
- 
MFIS subscales changes between screen/baseline and week 4. 
- 
Change in FSS score from baseline to week 4. 
- 
Change in NeuroQOL fatigue item bank score from baseline to week 4. 
- 
Change in 9-HPT score from baseline to week 4. 
- 
Change in 25-FTW from baseline to week 4. 
- 
Change in SDMT score from baseline to week 4. 
- 
Changes in MFIS and FSS between week 4 and 6. 
 
8.3 Statistical plan for specific aim 3- To determine if fatigue severity is associated with 
baseline spectroscopy and oxidative pathway markers in patients with progressive MS. 
 
We will examine the correlation between biomarkers (spectroscopy and blood oxidation 
metabolites) and fatigue (MFIS) at baseline. We will use a linear regression model with MFIS 
score (or its change) as the outcome and the spectroscopy and metabolites as the predictors (in 


Confidential – UCSF – NAC Pilot study (Version 4 dated 12 Oct 2016) 
 
separate models). Using data obtained from the control subjects (patients with progressive MS 
and fatigue severity as measured by MFIS<38) we will also perform a case-control analysis (e.g. 
logistic regression with being fatigued or non-fatigued as the outcome and spectroscopy or blood 
metabolites as predictors. 
 
Study variables 
 
Demographic variables: Age, sex, self-reported race/ethnicity (based on the National Institute 
of Health classification), education (in years) and occupation will be recorded at the screening 
visit. Because the severity of fatigue may fluctuate during the day and based on the ambient 
temperature, the time of the visit and the outside temperature will also be recorded. 
 
Baseline MS-related information: Years since disease onset, type of MS (primary versus 
secondary progressive (per medical records), Expanded Disability Status Scale (EDSS) 
(obtained at screening visit by the examining physician), and 25-foot timed walk (25-FTW), 9-
hole peg test (9-HPT) and Single Digit Modalities test (SDMT) (obtained by a trained technician 
at screening, baseline and week 4). 
 
Fatigue: MFIS and FSS (questionnaires filled by patients after receiving appropriate instructions 
from study staff, see appendix) at screening, baseline, week 4 (last study drug dose), and week 
6 (2 weeks after stopping study drug). 
 
Depression: Hospital Anxiety and Depression Scale (HADS) depression subscale 
(questionnaires filled by patients after receiving appropriate instructions from a study staff, see 
appendix) at screening and baseline. 
 
Quality of life: NINDS NeuroQOL fatigue item bank (questionnaires filled by patients after 
receiving appropriate instructions from study staff, see appendix) at the screening, baseline and 
week 4. 
 
Safety laboratory assessment: At screening, CBC and differential, creatinine, AST, ALT, urine 
analysis and urine pregnancy test will be obtained. At week 4, only creatinine, urine pregnancy 
test, AST and ALT will be measured. 
 
Research laboratory assessment: Plasma level of reduced glutathione (GSH) and oxidized 
glutathione (GSSG) baseline and at 4 week visit for patients who enter treatment phase, and 
baseline research samples will be analyzed for patients who are controls in the study 
 
Conventional MRI sequences: The MR experiments will be performed on the GE 7T research 
scanner in the Surbeck Laboratory using a 32-channel phased array head coil. The 60-minute 
MR protocol will include standard imaging sequences with calibration scans (3-plane localizer, 
coil sensitivity maps), gradient recalled-echo, T1-weighted and T2-weighted images, and 
multiband DWI. Higher order shimming will be performed prior to the spectral data acquisitions. 
The volume of interest for 3D short TE MRSI will be prescribed to have full coverage of the 
thalamus that will enable to measure metabolite levels (such as Cho, Cr, NAA, Glutamate, 


Confidential – UCSF – NAC Pilot study (Version 4 dated 12 Oct 2016) 
 
Glutamine, mI, and GSH) in deep grey matter and surrounding normal appearing white matter. 
GSH-edited MRS will be acquired as well to provide unobstructed detection of 
GSH in the selected of regions of interest. 
 
Data collection: 
 
1) Blood samples from participating patients at the baseline and week 4 visits will be collected 
and analyzed for various metabolites on the oxidative pathway including GSH, GSSG, and 
response ratio for GSH, and GSSG. 
2) 7T MR spectroscopy at the baseline and 4 week visits will be obtained and analyzed for 
concentrations of N-acetyl-aspartate (NAA), glutamate (Glu), glutathione, myo-inositol 
(mI), creatine (Cr), and choline (Cho) over the region of interest (ROI) region and 
concentrations of NAA, Glu, glutathione, mI, Cr, and Cho from normal-appearing white-
matter areas within the ROI region. 
Power considerations: There are no available data to base power calculation for this exploratory 
aim as such a study has never been performed prior. We will use the data generated for this Aim 
to design future studies. 
9.Data collection, management and quality assurance 
 
We will use Redcap (http://project-redcap.org/), a secure web application for building online 
databases, as the trial data management software. The demographic and baseline information 
will be entered directly from the medical records by study coordinator into the study CRF. The 
study manger will review CRFs for completeness and enter into Redcap database. UCSF 
research 
fellow (Dr. Nourbakhsh) will double check the data entered into Redcap for accuracy.