Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis

• Sponsor: MediciNova (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01982942
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute of Neurological Disorders and Stroke (NINDS) (NIH), National Multiple Sclerosis Society (Other)
• Enrollment: 255
• Locations: 28
• Arms: 2
• Duration (Months): 49
• Patients Per Site: 9.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the safety, tolerability and activity of ibudilast administered twice daily over a 96 week period in subjects with primary or secondary progressive multiple sclerosis who are currently untreated with long-term MS disease modifying therapy (DMT) or who are receiving either glatiramer acetate (GA) or interferon beta-1, any formulation (IFNβ-1A [Avonex, Rebif] or IFNβ-1B [Betaseron, Extavia]). Study drug or placebo will be administered to a total of 250 male and female subjects from 21 to 65 years old, inclusive, in two treatment groups. Randomization of subjects will be stratified by disease status (primary progressive multiple sclerosis or secondary progressive multiple sclerosis) and immunomodulating therapy status: current use of immunomodulating therapy or no current use of immunomodulating therapy.

The study will consist of a screening phase (up to 30 days) followed by a treatment phase (96 weeks) and a follow-up visit (1 month post Week 96 visit). Following the screening phase, subjects who continue to meet entry criteria will be randomly assigned to 1 of 2 treatment groups: doses up to ibudilast 100 mg/day or matching-placebo in a 1:1 ratio. Study drug will be administered twice daily (BID), e.g., ibudilast 50 mg or placebo taken in the morning and evening).

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis, Primary Progressive; Multiple Sclerosis, Secondary Progressive	Drug: ibudilast; Drug: Placebo oral capsule	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 255 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability and Activity of Ibudilast (MN-166) in Subjects With Progressive Multiple Sclerosis
• Study Start Date: Nov 1, 2013
• Actual Primary Completion Date: May 1, 2017
• Actual Study Completion Date: Dec 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ibudilast Subjects will receive up to 100 mg/d ibudilast for 96 weeks.	Drug: ibudilast; Subjects randomly assigned to the ibudilast (MN-166) cohort will receive up to 100 mg/day for 96 weeks.; Other Names: MN-166
Placebo Comparator: Placebo Oral Capsule Subjects will receive placebo for 96 weeks.	Drug: Placebo oral capsule; Subjects randomly assigned to the placebo cohort will receive placebo oral capsule for 96 weeks.

Outcome Measures

Primary Outcome Measures

1. Covariate-adjusted Mean Rate of Change in Brain Atrophy Over 96 Weeks as Measured by Brain Parenchymal Fraction (BPF). [96 weeks]

   To evaluate the activity of ibudilast (100 mg/day) versus placebo at 96 weeks as measured by quantitative magnetic resonance imaging (MRI) analysis for whole brain atrophy using brain parenchymal fraction (BPF), calculated as the ratio of brain parenchymal tissue volume to the total volume contained within the brain surface contour.

2. Percentage of Participants With Adverse Events. [96 weeks]

   Safety Measures: percentage of participants who experienced treatment-emergent adverse events, clinically significant abnormal laboratory and electrocardiogram results.

Secondary Outcome Measures

1. Diffusion Tensor Imaging (DTI) in Descending Pyramidal White Matter Tracts [48 weeks]

   Diffusion tensor imaging estimates the three-dimensional diffusion of water in brain tissue and has been explored as an outcome in MS.

2. Magnetization Transfer Ratio (MTR) Imaging in Normal-appearing Brain Tissue [96 weeks]

   A magnetization transfer MRI as a marker of brain myelin content including the cerebral cortex could be useful. MT imaging provides access to the restricted protons, which are located in biologically interesting tissue regions.Cortical and normal appearing grey matter MTR correlates strongly with measures of disability such as the multiple sclerosis functional composite score and can show treatment effects.

3. Retinal Nerve Fiber Layer as Measured by Optical Coherence Tomography (OCT). [96 weeks]

   Mean retinal nerve fiber layer thickness from baseline measured by Optical coherence tomography (OCT), a non-invasive imaging technique used to obtain high-resolution cross-sectional images of the retina. Increase in thickness is considered improvement.

Other Outcome Measures

1. New T1 Lesions Since Baseline [96 weeks]

   New T1 lesions since baseline as measured by least square mean (90% confidence interval).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent is obtained and willing and able to comply with the protocol in the opinion of the Investigator.

• Male or female subjects ages 21 to 65, inclusive

• Confirmed diagnosis of SPMS or primary progressive multiple sclerosis (PPMS) according to 2010 International Panel Criteria

• Typical MS lesions on MRI according to Swanton's MRI Criteria (at least one lesion in two or more of the following regions: periventricular, juxtacortical, infratentorial [brainstem/cerebellum], spinal cord)

• EDSS 3.0-6.5, inclusive

• Clinical evidence of disability progression in the preceding two years, as measured by any of the following (excluding progression during clinical relapses):

• worsening overall EDSS of at least 0.5 points (may be assessed retrospectively but cannot be during a clinical relapse) or

• 20% worsening in 25-foot walk (25-FW) or

• 20% worsening in 9-hole peg test (9-HPT) in either hand

• Existing multiple sclerosis pharmacotherapy status may include interferon-beta or glatiramer acetate or none (i.e. untreated).

• Females of child-bearing potential must have a negative serum ß-hCG at screening and must be willing to use appropriate contraception (as defined by the investigator) for the duration of study treatment and 30 days after the last dose of study treatment.

• Males should practice contraception as follows: condom use and contraception by female partner.

• Subject is in good physical health on the basis of medical history, physical examination, and laboratory screening, as defined by the investigator.

• Subject is willing and able to comply with the protocol assessments and visits, in the opinion of the study nurse/coordinator and the Investigator.

Exclusion Criteria:

• Progressive neurological disorder other than SPMS or PPMS

• Relapse and/or systemic corticosteroid steroid treatment for multiple sclerosis within 3 months of screening. Inhaled or topical steroids are allowed.

• Current use of intermittent systemic corticosteroids (i.e., monthly or bimonthly intravenous methylprednisolone)

• Use of oral immunosuppressants (e.g. azathioprine, methotrexate, cyclosporine, teriflunomide [Aubagio®]) within 6 months of screening

• Use of mitoxantrone, natalizumab, or IVIg within 6 months of screening

• Use of fingolimod or dimethyl fumarate [Tecfidera®] within 3 months of screening

• Use of rituximab or other B-cell therapy within 12 months of screening

• Current use of other MS disease-modifying therapies (DMTs) besides glatiramer acetate, IFNβ-1 (any formulation), and the above listed medications.

• Current use of cimetidine, cyclosporine, dronedarone, lopinavir, probenecid, quinidine (including Neudexta), ranolazine, rifampin, ritonavir, or tipranavir.

• Clinically significant cardiovascular disease, including myocardial infarct within last 6 months, unstable ischemic heart disease, congestive heart failure or angina

• Resting pulse < 50 bpm, sinoatrial (SA) or atrioventricular (AV) block, uncontrolled hypertension, or QTcF > 450 ms

• Clinically significant pulmonary conditions, including severe chronic obstructive pulmonary disease (COPD), fibrosis, or tuberculosis

• Evidence of acute hepatitis, clinically significant chronic hepatitis, or evidence of clinically significant impaired hepatic function through clinical and laboratory evaluation including ALP > 1.5x ULN; ALT or AST > 2x ULN; GGT > 3x ULN

• Immune system disease (other than multiple sclerosis and autoimmune thyroid disease)

• History of stomach or intestinal surgery or any other condition that could interfere with or is judged by the Investigator to interfere with absorption, distribution, metabolism, or excretion of study drug.

• Any significant laboratory abnormality which, in the opinion of the Investigator, may put the subject at risk and with the following laboratory abnormalities at screening:

• Creatinine: females > 0.95 mg/dL; males > 1.17 mg/dL

• WBCs < 3,000 mm3

• Lymphocytes < 800 mm3

• Platelets < 90,000 mm3

• History of malignancy < 5 years prior to signing the informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.

• History of HIV (human immunodeficiency virus), clinically significant chronic hepatitis, or other active infection.

• Subject currently has a clinically significant medical condition (other than MS) including the following: neurological, psychiatric, metabolic, hepatic, renal, hematological, pulmonary, cardiovascular (including uncontrolled hypertension), gastrointestinal, urological disorder, or central nervous system (CNS) infection that would pose a risk to the subject if they were to participate in the study or that might confound the results of the study.

Note: Active medical conditions that are minor or well-controlled are not exclusionary if, in the judgment of the Investigator, they do not affect risk to the subject or the study results. In cases in which the impact of the condition upon risk to the subject or study results is unclear, the Medical Safety Monitor should be consulted.

• Subjects with moderate to severe depression as determined by the Beck Depression Inventory-Fast Screen (BDI-FS).

• Subject has a history of alcohol or substance abuse (DSM-IV-TR criteria) within 3 months prior to screening or alcohol or substance dependence (DSM-IV-TR criteria) within 12 months prior to screening. The only exceptions include caffeine or nicotine abuse/dependence.

• Subject has poor peripheral venous access that will limit the ability to draw blood as judged by the Investigator.

• Subject is currently participating, or has participated in, a study with an investigational or marketed compound or device within 3 months prior to signing the informed consent.

• Subject is unable to cooperate with any study procedures, unlikely to adhere to the study procedures and keep appointments, in the opinion of the Investigator, or was planning to relocate during the study.

• Subject is unable to undergo MRI imaging because of having an artificial heart valve, metal plate, pin, or other metallic objects (including gun shots or shrapnel) in their body or is unable to complete all the five MRI scans required for this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	University of California Davis	Davis	California	United States	95817
3	University of California Los Angeles	Los Angeles	California	United States	90095
4	University of Colorado Denver	Denver	Colorado	United States	80045
5	University of Miami Miller School of Medicine	Miami	Florida	United States	33136
6	Emory University	Atlanta	Georgia	United States	30322
7	Northwestern University	Evanston	Illinois	United States	60208
8	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
9	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
10	Brigham and Women's Hospital	Boston	Massachusetts	United States	02445
11	Washington University School of Medicine in St Louis	Saint Louis	Missouri	United States	63110
12	Montefiore Medical Center	Bronx	New York	United States	10467
13	University at Buffalo, The State University of New York	Buffalo	New York	United States	14260
14	Cornell Medical College	New York	New York	United States	10021
15	Columbia University Medical Center	New York	New York	United States	10032
16	University of Rochester	Rochester	New York	United States	14627
17	University at Stony Brook, The State University of New York	Stony Brook	New York	United States	11794
18	University at Upstate, The State University of New York	Syracuse	New York	United States	13210
19	University of Cincinnati, Department of Neurology	Cincinnati	Ohio	United States	45267
20	Cleveland Clinic	Cleveland	Ohio	United States	44195
21	Ohio State University	Columbus	Ohio	United States	43210
22	Oregon Health and Science University	Portland	Oregon	United States	97239
23	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15261
24	Vanderbilt University	Nashville	Tennessee	United States	37235
25	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
26	University of Utah	Salt Lake City	Utah	United States	84112
27	University of Virginia Charlottesville	Charlottesville	Virginia	United States	22904
28	Swedish Medical Center - Seattle	Seattle	Washington	United States	98122

Sponsors and Collaborators

• MediciNova
• National Institutes of Health (NIH)
• National Institute of Neurological Disorders and Stroke (NINDS)
• National Multiple Sclerosis Society

Investigators

• Principal Investigator: Robert J Fox, MD, FAAN, The Cleveland Clinic

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Sep 5, 2017

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: MediciNova
• ClinicalTrials.gov Identifier: NCT01982942
• Other Study ID Numbers: NN102 SPRINT - MS; 1U01NS082329-01A1; RG 4778-A-6
• First Posted: Nov 13, 2013
• Last Update Posted: Jul 28, 2020
• Last Verified: Jul 1, 2020

• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Ibudilast

Study Results

Participant Flow

Arm/Group Title	Ibudilast	Placebo Oral Capsule
Arm/Group Description	Subjects will receive up to 100 mg/d ibudilast for 96 weeks. ibudilast: Subjects randomly assigned to the ibudilast (MN-166) cohort will receive up to 100 mg/day for 96 weeks.	Subjects will receive placebo for 96 weeks. Placebo oral capsule: Subjects randomly assigned to the placebo cohort will receive placebo oral capsule for 96 weeks.
Period Title: Overall Study
STARTED	129	126
COMPLETED	108	112
NOT COMPLETED	21	14

Baseline Characteristics

Arm/Group Title	Ibudilast	Placebo Oral Capsule	Total
Arm/Group Description	Subjects will receive up to 100 mg/d ibudilast for 96 weeks. ibudilast: Subjects randomly assigned to the ibudilast (MN-166) cohort will receive up to 100 mg/day for 96 weeks.	Subjects will receive placebo for 96 weeks. Placebo oral capsule: Subjects randomly assigned to the placebo cohort will receive placebo oral capsule for 96 weeks.	Total of all reporting groups
Overall Participants	129	126	255
Age, Customized (years) [Mean (Standard Deviation) ]
Age (years)	54.0 (7.8)	56.1 (6.6)	56.0 (7.3)
Sex: Female, Male (Count of Participants)
Female	67 51.9%	69 54.8%	136 53.3%
Male	62 48.1%	57 45.2%	119 46.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 3.1%	3 2.4%	7 2.7%
Not Hispanic or Latino	125 96.9%	121 96%	246 96.5%
Unknown or Not Reported	0 0%	2 1.6%	2 0.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.8%	0 0%	1 0.4%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	4 3.1%	7 5.6%	11 4.3%
White	122 94.6%	114 90.5%	236 92.5%
More than one race	2 1.6%	1 0.8%	3 1.2%
Unknown or Not Reported	0 0%	4 3.2%	4 1.6%
Region of Enrollment (participants) [Number]
United States	129 100%	126 100%	255 100%

Outcome Measures

1. Primary Outcome

Title	Covariate-adjusted Mean Rate of Change in Brain Atrophy Over 96 Weeks as Measured by Brain Parenchymal Fraction (BPF).
Description	To evaluate the activity of ibudilast (100 mg/day) versus placebo at 96 weeks as measured by quantitative magnetic resonance imaging (MRI) analysis for whole brain atrophy using brain parenchymal fraction (BPF), calculated as the ratio of brain parenchymal tissue volume to the total volume contained within the brain surface contour.
Time Frame	96 weeks

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat is the primary population for efficacy analysis, defined as all participants from the intent-to-treat population (all participants randomly assigned) who received at least one dose of study medication, have at least one efficacy assessment for at least one primary or secondary parameter in the double-blind treatment phase.

Arm/Group Title	Ibudilast	Placebo Oral Capsule
Arm/Group Description	Subjects will receive up to 100 mg/d ibudilast for 96 weeks. ibudilast: Subjects randomly assigned to the ibudilast (MN-166) cohort will receive up to 100 mg/day for 96 weeks.	Subjects will receive placebo for 96 weeks. Placebo oral capsule: Subjects randomly assigned to the placebo cohort will receive placebo oral capsule for 96 weeks.
Measure Participants	103	111
Mean (90% Confidence Interval) [ratio]	-0.00168	-0.00392

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ibudilast, Placebo Oral Capsule
	Comments	The null hypothesis states that the BPF rates of change in the treatment and placebo groups are equal, which can be evaluated based on as assessment of parameter estimates from a linear mixed model (LMM).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	Percentage of Participants With Adverse Events.
Description	Safety Measures: percentage of participants who experienced treatment-emergent adverse events, clinically significant abnormal laboratory and electrocardiogram results.
Time Frame	96 weeks

Outcome Measure Data

Analysis Population Description

Safety analysis population: comprises all subjects who received at least one dose of study medication. This is the population for all safety analyses, and subjects were analyzed based on the treatment they received.

Arm/Group Title	Ibudilast	Placebo Oral Capsule
Arm/Group Description	Subjects will receive up to 100 mg/d ibudilast for 96 weeks. ibudilast: Subjects randomly assigned to the ibudilast (MN-166) cohort will receive up to 100 mg/day for 96 weeks.	Subjects will receive placebo for 96 weeks. Placebo oral capsule: Subjects randomly assigned to the placebo cohort will receive placebo oral capsule for 96 weeks.
Measure Participants	129	126
Number (90% Confidence Interval) [percentage receiving study medication]	92.2	88.1

3. Secondary Outcome

Title	Diffusion Tensor Imaging (DTI) in Descending Pyramidal White Matter Tracts
Description	Diffusion tensor imaging estimates the three-dimensional diffusion of water in brain tissue and has been explored as an outcome in MS.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

modified intent-to-treat population

Arm/Group Title	Ibudilast	Placebo Oral Capsule
Arm/Group Description	Subjects will receive up to 100 mg/d ibudilast for 96 weeks. ibudilast: Subjects randomly assigned to the ibudilast (MN-166) cohort will receive up to 100 mg/day for 96 weeks.	Subjects will receive placebo for 96 weeks. Placebo oral capsule: Subjects randomly assigned to the placebo cohort will receive placebo oral capsule for 96 weeks.
Measure Participants	103	111
Left axial diffusivity mean	0.0001	-0.0006
Left radial diffusivity mean	-0.0077	0.0027
Right axial diffusivity mean	0.0014	-0.0017
Right radial diffusivity mean	-0.0029	0.0046

4. Secondary Outcome

Title	Magnetization Transfer Ratio (MTR) Imaging in Normal-appearing Brain Tissue
Description	A magnetization transfer MRI as a marker of brain myelin content including the cerebral cortex could be useful. MT imaging provides access to the restricted protons, which are located in biologically interesting tissue regions.Cortical and normal appearing grey matter MTR correlates strongly with measures of disability such as the multiple sclerosis functional composite score and can show treatment effects.
Time Frame	96 weeks

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat is the primary population for efficacy analysis, defined as all participants from the intent-to-treat population (all participants randomly assigned) who received at least one dose of study medication, have at least one efficacy assessment for at least one primary or secondary parameter in the double-blind treatment phase.

Arm/Group Title	Ibudilast	Placebo Oral Capsule
Arm/Group Description	Subjects will receive up to 100 mg/d ibudilast for 96 weeks. ibudilast: Subjects randomly assigned to the ibudilast (MN-166) cohort will receive up to 100 mg/day for 96 weeks.	Subjects will receive placebo for 96 weeks. Placebo oral capsule: Subjects randomly assigned to the placebo cohort will receive placebo oral capsule for 96 weeks.
Measure Participants	95	103
Least Squares Mean (90% Confidence Interval) [ratio]	0.325	0.247

5. Secondary Outcome

Title	Retinal Nerve Fiber Layer as Measured by Optical Coherence Tomography (OCT).
Description	Mean retinal nerve fiber layer thickness from baseline measured by Optical coherence tomography (OCT), a non-invasive imaging technique used to obtain high-resolution cross-sectional images of the retina. Increase in thickness is considered improvement.
Time Frame	96 weeks

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat is the primary population for efficacy analysis, defined as all participants from the intent-to-treat population (all participants randomly assigned) who received at least one dose of study medication, have at least one efficacy assessment for at least one primary or secondary parameter in the double-blind treatment phase.

Arm/Group Title	Ibudilast	Placebo Oral Capsule
Arm/Group Description	Subjects will receive up to 100 mg/d ibudilast for 96 weeks. ibudilast: Subjects randomly assigned to the ibudilast (MN-166) cohort will receive up to 100 mg/day for 96 weeks.	Subjects will receive placebo for 96 weeks. Placebo oral capsule: Subjects randomly assigned to the placebo cohort will receive placebo oral capsule for 96 weeks.
Measure Participants	94	103
Least Squares Mean (90% Confidence Interval) [micrometers]	83.0	79.5

6. Other Pre-specified Outcome

Title	New T1 Lesions Since Baseline
Description	New T1 lesions since baseline as measured by least square mean (90% confidence interval).
Time Frame	96 weeks

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat is the primary population for efficacy analysis, defined as all participants from the intent-to-treat population (all participants randomly assigned) who received at least one dose of study medication, have at least one efficacy assessment for at least one primary or secondary parameter in the double-blind treatment phase.

Arm/Group Title	Ibudilast	Placebo Oral Capsule
Arm/Group Description	Subjects will receive up to 100 mg/d ibudilast for 96 weeks. ibudilast: Subjects randomly assigned to the ibudilast (MN-166) cohort will receive up to 100 mg/day for 96 weeks.	Subjects will receive placebo for 96 weeks. Placebo oral capsule: Subjects randomly assigned to the placebo cohort will receive placebo oral capsule for 96 weeks.
Measure Participants	102	110
Least Squares Mean (90% Confidence Interval) [lesions]	0.355	0.317

Adverse Events

Time Frame	100 weeks
Arm/Group Title	Ibudilast		Placebo Oral Capsule
Arm/Group Description	Subjects will receive up to 100 mg/d ibudilast for 96 weeks. ibudilast: Subjects randomly assigned to the ibudilast (MN-166) cohort will receive up to 100 mg/day for 96 weeks.		Subjects will receive placebo for 96 weeks. Placebo oral capsule: Subjects randomly assigned to the placebo cohort will receive placebo oral capsule for 96 weeks.
All Cause Mortality
	Ibudilast		Placebo Oral Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/129 (0%)		0/126 (0%)
Serious Adverse Events
	Ibudilast		Placebo Oral Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/129 (15.5%)		24/126 (19%)
Blood and lymphatic system disorders
thrombocytopenia	0/129 (0%)	0	1/126 (0.8%)	1
Cardiac disorders
myocardial infarction	1/129 (0.8%)	1	0/126 (0%)	0
atrial fibrillation	0/129 (0%)	0	1/126 (0.8%)	1
Endocrine disorders
parotidectomy	0/129 (0%)	0	1/126 (0.8%)	1
Gastrointestinal disorders
colonic obstruction	0/129 (0%)	0	1/126 (0.8%)	1
intestinal obstraction	0/129 (0%)	0	1/126 (0.8%)	1
General disorders
Pain	2/129 (1.6%)	2	0/126 (0%)	0
Asthenia	1/129 (0.8%)	1	0/126 (0%)	0
Hepatobiliary disorders
febrile neutropenia	1/129 (0.8%)	1	0/126 (0%)	0
colelithiais	0/129 (0%)	0	1/126 (0.8%)	1
Infections and infestations
cystitis	0/129 (0%)	0	1/126 (0.8%)	1
urinary tract infection	2/129 (1.6%)	2	1/126 (0.8%)	1
sepsis	1/129 (0.8%)	1	1/126 (0.8%)	1
tooth infection	0/129 (0%)	0	1/126 (0.8%)	1
Metabolism and nutrition disorders
dehydration	1/129 (0.8%)	1	0/126 (0%)	0
hypercalcemia	1/129 (0.8%)	1	0/126 (0%)	0
hypokalemia	1/129 (0.8%)	1	0/126 (0%)	0
hyponatremia	0/129 (0%)	0	1/126 (0.8%)	1
Musculoskeletal and connective tissue disorders
rotator cuff syndrome	1/129 (0.8%)	1	0/126 (0%)	0
fracture	2/129 (1.6%)	2	1/126 (0.8%)	1
back pain	1/129 (0.8%)	1	1/126 (0.8%)	1
muscular weakness	0/129 (0%)	0	1/126 (0.8%)	1
cervical spinal stenosis	0/129 (0%)	0	1/126 (0.8%)	1
injury	0/129 (0%)	0	1/126 (0.8%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
cervix carcinoma stage 0	1/129 (0.8%)	1	0/126 (0%)	0
metastatic malignant melanoma	1/129 (0.8%)	1	0/126 (0%)	0
endometrial cancer	0/129 (0%)	0	1/126 (0.8%)	1
breast cancer	0/129 (0%)	0	1/126 (0.8%)	1
bladder transitional cell cancer	0/129 (0%)	0	1/126 (0.8%)	1
Nervous system disorders
ataxia	1/129 (0.8%)	1	0/126 (0%)	0
cerebral haemorrhage	1/129 (0.8%)	1	0/126 (0%)	0
spondylitic myelopathy	1/129 (0.8%)	1	0/126 (0%)	0
cerebrovascular accident	0/129 (0%)	0	1/126 (0.8%)	1
convulsion	0/129 (0%)	0	1/126 (0.8%)	1
Renal and urinary disorders
bladder prolapse	0/129 (0%)	0	1/126 (0.8%)	1
kideny infection	0/129 (0%)	0	1/126 (0.8%)	1
Respiratory, thoracic and mediastinal disorders
pulmonary embolism	0/129 (0%)	0	1/126 (0.8%)	1
Other (Not Including Serious) Adverse Events
	Ibudilast		Placebo Oral Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	119/129 (92.2%)		111/126 (88.1%)
Cardiac disorders
Bradycardia	3/129 (2.3%)	3	1/126 (0.8%)	1
Atrioventricular block first degree	1/129 (0.8%)	1	4/126 (3.2%)	7
Atrial fibrillation	0/129 (0%)	0	3/126 (2.4%)	3
Ear and labyrinth disorders
Vertigo	2/129 (1.6%)	3	3/126 (2.4%)	3
Eye disorders
Conjunctivitis	3/129 (2.3%)	3	2/126 (1.6%)	2
Gastrointestinal disorders
Nausea	35/129 (27.1%)	39	19/126 (15.1%)	21
Diarrhoea	19/129 (14.7%)	21	8/126 (6.3%)	9
Vomiting	9/129 (7%)	10	3/126 (2.4%)	3
Constipation	8/129 (6.2%)	10	7/126 (5.6%)	7
Abdominal pain	6/129 (4.7%)	7	0/126 (0%)	0
Dyspepsia	5/129 (3.9%)	5	3/126 (2.4%)	6
Abdominal pain upper	5/129 (3.9%)	5	0/126 (0%)	0
Abdominal distension	2/129 (1.6%)	2	1/126 (0.8%)	3
Gastro-oesophageal reflux disease	4/129 (3.1%)	4	2/126 (1.6%)	2
Flatulence	2/129 (1.6%)	2	6/126 (4.8%)	6
Dysphagia	2/129 (1.6%)	2	5/126 (4%)	5
General disorders
Fatigue	14/129 (10.9%)	14	10/126 (7.9%)	11
Oedema peripheral	5/129 (3.9%)	6	6/126 (4.8%)	6
Irritability	3/129 (2.3%)	3	0/126 (0%)	0
Chest pain	1/129 (0.8%)	1	3/126 (2.4%)	3
Influenza like illness	1/129 (0.8%)	1	3/126 (2.4%)	3
Infections and infestations
Urinary tract infection	35/129 (27.1%)	67	43/126 (34.1%)	88
Upper respiratory tract infection	13/129 (10.1%)	17	24/126 (19%)	26
Sinusitis	5/129 (3.9%)	7	6/126 (4.8%)	7
Bronchitis	5/129 (3.9%)	5	4/126 (3.2%)	5
Nasopharyngitis	5/129 (3.9%)	6	3/126 (2.4%)	4
Gastroenteritis	3/129 (2.3%)	3	3/126 (2.4%)	3
Tooth infection	3/129 (2.3%)	3	2/126 (1.6%)	2
Influenza	3/129 (2.3%)	3	0/126 (0%)	0
Influenza like illness	1/129 (0.8%)	1	3/126 (2.4%)	3
Injury, poisoning and procedural complications
Fall	29/129 (22.5%)	63	20/126 (15.9%)	35
Laceration	6/129 (4.7%)	7	7/126 (5.6%)	8
Contusion	6/129 (4.7%)	8	3/126 (2.4%)	3
Excoriation	5/129 (3.9%)	6	5/126 (4%)	5
Fracture	4/129 (3.1%)	4	1/126 (0.8%)	1
Humerus fracture	3/129 (2.3%)	3	2/126 (1.6%)	2
Rib fracture	1/129 (0.8%)	1	3/126 (2.4%)	3
Investigations
Urine analysis abnormal	4/129 (3.1%)	4	4/126 (3.2%)	4
Hepatic enzyme increased	4/129 (3.1%)	5	3/126 (2.4%)	4
Lymphocyte count decreased	4/129 (3.1%)	4	2/126 (1.6%)	2
White blood cell count decreased	4/129 (3.1%)	5	0/126 (0%)	0
Gamma-glutamyl transferase increased	4/129 (3.1%)	4	1/126 (0.8%)	1
Weight decreased	3/129 (2.3%)	3	1/126 (0.8%)	1
Blood alkaline phosphatase increased	3/129 (2.3%)	3	0/126 (0%)	0
Alanine aminotransferase increased	2/129 (1.6%)	3	4/126 (3.2%)	4
Metabolism and nutrition disorders
Decreased appetite	8/129 (6.2%)	9	4/126 (3.2%)	4
Hypokalaemia	4/129 (3.1%)	4	1/126 (0.8%)	1
Abnormal loss of weight	3/129 (2.3%)	3	2/126 (1.6%)	2
Musculoskeletal and connective tissue disorders
Muscular weakness	11/129 (8.5%)	13	12/126 (9.5%)	15
Back pain	10/129 (7.8%)	11	15/126 (11.9%)	16
Arthralgia	10/129 (7.8%)	11	10/126 (7.9%)	12
Pain in extremity	5/129 (3.9%)	6	13/126 (10.3%)	15
Musculoskeletal pain	4/129 (3.1%)	4	3/126 (2.4%)	3
Musculoskeletal chest pain	3/129 (2.3%)	3	2/126 (1.6%)	3
Myalgia	2/129 (1.6%)	2	3/126 (2.4%)	4
Neck pain	0/129 (0%)	0	4/126 (3.2%)	4
Nervous system disorders
Headache	23/129 (17.8%)	29	15/126 (11.9%)	19
Muscle spasticity	9/129 (7%)	9	12/126 (9.5%)	13
Paraesthesia	9/129 (7%)	11	8/126 (6.3%)	8
Dizziness	4/129 (3.1%)	4	0/126 (0%)	0
Tremor	4/129 (3.1%)	4	0/126 (0%)	0
Hypoaesthesia	1/129 (0.8%)	1	3/126 (2.4%)	4
Psychiatric disorders
Insomnia	14/129 (10.9%)	16	11/126 (8.7%)	11
Depression	12/129 (9.3%)	15	4/126 (3.2%)	4
Anxiety	3/129 (2.3%)	3	3/126 (2.4%)	3
Renal and urinary disorders
Nephrolithiasis	4/129 (3.1%)	5	7/126 (5.6%)	7
Respiratory, thoracic and mediastinal disorders
Cough	3/129 (2.3%)	3	4/126 (3.2%)	5
Nasal congestion	3/129 (2.3%)	3	3/126 (2.4%)	3
Dyspnoea	1/129 (0.8%)	1	3/126 (2.4%)	3
Skin and subcutaneous tissue disorders
Cellulitis	2/129 (1.6%)	2	3/126 (2.4%)	4
Skin infection	1/129 (0.8%)	1	9/126 (7.1%)	10
Herpes zoster	1/129 (0.8%)	1	3/126 (2.4%)	3
Folliculitis	0/129 (0%)	0	3/126 (2.4%)	3
Rash	8/129 (6.2%)	10	8/126 (6.3%)	8
Rash maculo-papular	6/129 (4.7%)	6	2/126 (1.6%)	2
Dermatitis acneiform	3/129 (2.3%)	3	2/126 (1.6%)	3
Pruritus	3/129 (2.3%)	3	1/126 (0.8%)	1
Skin ulcer	2/129 (1.6%)	2	3/126 (2.4%)	4
Vascular disorders
Hot flush	5/129 (3.9%)	5	2/126 (1.6%)	2
Hypertension	4/129 (3.1%)	4	7/126 (5.6%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.