A Trial of Tocilizumab in ALS Subjects (TCZALS-001)

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ClinicalTrials.gov Identifier: NCT02469896

Recruitment Status : Completed

First Posted : June 12, 2015

Results First Posted : December 18, 2019

Last Update Posted : December 18, 2019

Sponsor:

Collaborators:

ALS Association

Barrow Neurological Foundation

Massachusetts General Hospital

Genentech, Inc.

Information provided by (Responsible Party):

Shafeeq Ladha, MD, Barrow Neurological Institute

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Conditions	ALS Amyotrophic Lateral Sclerosis Lou Gehrig's Disease Motor Neuron Disease
Interventions	Drug: Tocilizumab Other: Placebo
Enrollment	22

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Placebo	Active Drug
Arm/Group Description	8 subjects will receive matching IV...	16 subjects will receive 8mg/kg of ...
Arm/Group Description	8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Period Title: Overall Study
Started	8	14
Completed	6	14
Not Completed	2	0
Reason Not Completed
Withdrawal by Subject	2	0

Baseline Characteristics

Arm/Group Title		Placebo	Active Drug	Total
Arm/Group Description		8 subjects will receive matching IV...	16 subjects will receive 8mg/kg of ...	Total of all reporting groups
Arm/Group Description		8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion	Total of all reporting groups
Overall Number of Baseline Participants		8	14	22
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	8 participants	14 participants	22 participants
		59.2 (8.6)	61.9 (8.7)	60.9 (8.6)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	8 participants	14 participants	22 participants
	Female	3 37.5%	3 21.4%	6 27.3%
	Male	5 62.5%	11 78.6%	16 72.7%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	8 participants	14 participants	22 participants
	Hispanic or Latino	1 12.5%	0 0.0%	1 4.5%
	Not Hispanic or Latino	7 87.5%	14 100.0%	21 95.5%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	8 participants	14 participants	22 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 12.5%	0 0.0%	1 4.5%
	White	7 87.5%	14 100.0%	21 95.5%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment Measure Type: Count of Participants Unit of measure: Participants
United States	Number Analyzed	8 participants	14 participants	22 participants
United States		8 100.0%	14 100.0%	22 100.0%

Outcome Measures

1.Primary Outcome


Title	Number of Patients Tolerant to Study Drug
Description	Tolerability will be assessed by on the proportion of participants rem...
Description	Tolerability will be assessed by on the proportion of participants remaining on study drug through all 3 doses and remaining on study and free from possibly drug-related and dose-limiting SAEs to the end of follow-up. Safety will be assessed by the occurrence of severe adverse events (SAEs), overall rates of adverse events (AEs), clinically significant abnormal laboratory tests, and changes in vital signs.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Placebo Tolerability	Active Drug Tolerability
Arm/Group Description:	8 subjects will receive matching IV...	14 subjects will receive 8mg/kg of ...
Arm/Group Description:	8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	14 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Overall Number of Participants Analyzed	8	14
Measure Type: Count of Participants Unit of Measure: Participants
	6 75.0%	12 85.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Tolerability, Active Drug Tolerability
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.602
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.875
	Confidence Interval	(2-Sided) 95% 0.556 to 1.377
	Estimation Comments	[Not Specified]

2.Primary Outcome


Title	Rates of All-cause Mortality
Description	Safety will be assessed by the occurrence of all-cause mortality.
Description	Safety will be assessed by the occurrence of all-cause mortality.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Placebo	Active Drug
Arm/Group Description:	8 subjects will receive matching IV...	14 subjects will receive 8mg/kg of ...
Arm/Group Description:	8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	14 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Overall Number of Participants Analyzed	8	14
Measure Type: Count of Participants Unit of Measure: Participants
Died	0 0.0%	0 0.0%
Alive	8 100.0%	14 100.0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Other Statistical Analysis		No statistical data was obtain because no patients died during the trial.

3.Secondary Outcome


Title	Rate of Decline in Slow Vital Capacity (SVC)
Description	Efficacy will be assessed by the change in the rate of change of SVC a...
Description	Efficacy will be assessed by the change in the rate of change of SVC as measured by change in percent predicted per month. The SVC is a measure of lung capacity that is reported as the percent of the predicted value expected based on gender and height. In ALS patients, this measure declines over time as a result of progressive respiratory muscle weakness.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.


Arm/Group Title	Placebo	Active Drug
Arm/Group Description:	8 subjects will receive matching IV...	16 subjects will receive 8mg/kg of ...
Arm/Group Description:	8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Overall Number of Participants Analyzed	8	14
Least Squares Mean (Standard Error) Unit of Measure: Percentage points change per month
	-0.765 (0.829)	-0.666 (0.560)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.922
	Comments	Unadjusted
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.099
	Confidence Interval	(2-Sided) 95% -1.902 to 2.099
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Rate of Decline ALS Functional Rating Scale Revised (ALSFRS-R)
Description	Efficacy will be assessed by the mean change in ALSFRS-R total score.T...
Description	Efficacy will be assessed by the mean change in ALSFRS-R total score.The ALSFRS-R scale measures the functional capabilities of an ALS patient in multiple domains such as swallowing, speech, fine motor, and breathing functions. It ranges from a maximum score of 48 for normal functioning to 0 for death or dependance on mechanical ventilation and declines by approximately 1 point per month on average for an ALS patient.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.


Arm/Group Title	Placebo	Active Drug
Arm/Group Description:	8 subjects will receive matching IV...	16 subjects will receive 8mg/kg of ...
Arm/Group Description:	8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Overall Number of Participants Analyzed	8	14
Least Squares Mean (Standard Error) Unit of Measure: units on a scale
	-0.583 (0.313)	-0.591 (0.211)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.983
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference of slopes
	Estimated Value	-0.008
	Confidence Interval	(2-Sided) 95% -0.761 to 0.745
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Rate of Decline Handheld Dynamometry (HHD)
Description	Efficacy will be assessed by the change in the rate of change of HHD u...
Description	Efficacy will be assessed by the change in the rate of change of HHD upper and lower extremity mega-scores. HHD utilizes an electronic pressure sensor to measure strength of individual muscles in kilograms. To calculate megascores, the mean and standard deviation of each muscle or muscle group, without regard to laterality, will be calculated from the baseline assessment of all participants. Strength estimates of each bilateral muscle or muscle group will be converted to Z scores by subtracting the relevant mean and dividing by the relevant standard deviation. Z scores for all upper extremity measurements (shoulder flexion, elbow flexion, elbow extension, wrist extension, and first dorsal interosseous contraction) and all lower extremity measurements (hip flexion, knee flexion, knee extension, and ankle dorsiflexion) will be averaged to yield upper and lower extremity megascores. Larger values indicate greater strength.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.


Arm/Group Title		Placebo	Active Drug
Arm/Group Description:		8 subjects will receive matching IV...	16 subjects will receive 8mg/kg of ...
Arm/Group Description:		8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Overall Number of Participants Analyzed		8	14
Mean (Standard Error) Unit of Measure: Z-score
HHD Upper extremity mega-score	Number Analyzed	8 participants	14 participants
HHD Upper extremity mega-score		-0.028 (0.035)	-0.070 (0.024)
HHD Lower extremity mega-score	Number Analyzed	7 participants	14 participants
HHD Lower extremity mega-score		-0.018 (0.039)	-0.032 (0.026)

6.Secondary Outcome


Title	Change in Peripheral Blood Mononuclear Cell (PBMC) Gene Expression
Description	Target engagement will be assessed by comparing the PBMC fold change i...
Description	Target engagement will be assessed by comparing the PBMC fold change in cytokine gene expression from baseline to week 4-16 average of ALS patients receiving drug versus placebo.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.


Arm/Group Title		Placebo	Active Drug
Arm/Group Description:		8 subjects will receive matching IV...	16 subjects will receive 8mg/kg of ...
Arm/Group Description:		8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Overall Number of Participants Analyzed		8	14
Geometric Mean (95% Confidence Interval) Unit of Measure: Fold change in gene expression
PBMC IL-6 fold-change	Number Analyzed	8 participants	14 participants
PBMC IL-6 fold-change		1.21 (0.60 to 2.54)	1.39 (0.52 to 5.00)
PBMC IL-8 fold-change	Number Analyzed	8 participants	14 participants
PBMC IL-8 fold-change		1.33 (0.08 to 39.4)	1.79 (0.38 to 14.8)
PBMC Matrix Metalloproteinase 1 (MMP1)fold-change	Number Analyzed	8 participants	13 participants
PBMC Matrix Metalloproteinase 1 (MMP1)fold-change		1.01 (0.37 to 2.13)	1.21 (0.42 to 3.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	PBMC IL-6 fold-change
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.684
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	1.150
	Confidence Interval	(2-Sided) 95% 0.566 to 2.337
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.663
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	1.344
	Confidence Interval	(2-Sided) 95% 0.331 to 2.080
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.500
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	1.198
	Confidence Interval	(2-Sided) 95% 0.691 to 2.080
	Estimation Comments	[Not Specified]

7.Secondary Outcome


Title	Changes in Cytokine Levels in the Plasma
Description	Target engagement will be assessed by mean change in plasma cytokine c...
Description	Target engagement will be assessed by mean change in plasma cytokine concentration between weeks 4 and 16 in ALS subjects receiving placebo or active drug.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.


Arm/Group Title		Placebo	Active Drug
Arm/Group Description:		8 subjects will receive matching IV...	16 subjects will receive 8mg/kg of ...
Arm/Group Description:		8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Overall Number of Participants Analyzed		8	14
Least Squares Mean (95% Confidence Interval) Unit of Measure: Fold change in concentration
CRP (ug/mL)	Number Analyzed	8 participants	13 participants
CRP (ug/mL)		1.051 (0.279 to 3.952)	0.049 (0.019 to 0.126)
IL-1beta (pg/mL)	Number Analyzed	8 participants	14 participants
IL-1beta (pg/mL)		0.969 (0.608 to 1.545)	1.266 (0.871 to 1.840)
IL-6 (pg/mL)	Number Analyzed	8 participants	14 participants
IL-6 (pg/mL)		0.897 (0.532 to 1.515)	17.974 (12.900 to 25.043)
IL-8 (pg/mL)	Number Analyzed	8 participants	14 participants
IL-8 (pg/mL)		1.241 (0.862 to 1.787)	1.569 (1.169 to 2.105)
IL-17 (pg/mL)	Number Analyzed	6 participants	14 participants
IL-17 (pg/mL)		0.962 (0.470 to 1.967)	1.342 (0.809 to 2.226)
Tumor necrosis factor (TNF)-alpha (pg/mL)	Number Analyzed	8 participants	14 participants
Tumor necrosis factor (TNF)-alpha (pg/mL)		1.180 (0.981 to 1.419)	1.054 (0.923 to 1.204)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of fold change
	Estimated Value	0.047
	Confidence Interval	(2-Sided) 95% 0.010 to 0.217
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.247
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of fold change
	Estimated Value	1.306
	Confidence Interval	(2-Sided) 95% 0.828 to 2.059
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of fold change
	Estimated Value	19.591
	Confidence Interval	(2-Sided) 95% 11.143 to 34.446
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.185
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of fold change
	Estimated Value	1.264
	Confidence Interval	(2-Sided) 95% 0.892 to 1.791
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.427
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of fold change
	Estimated Value	1.396
	Confidence Interval	(2-Sided) 95% 0.608 to 3.206
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.285
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of fold change
	Estimated Value	0.893
	Confidence Interval	(2-Sided) 95% 0.725 to 1.100
	Estimation Comments	[Not Specified]

8.Secondary Outcome


Title	Change in Mean Concentration Cytokines in the Cerebrospinal Fluid (CSF)
Description	Target engagement will be assessed by the mean change in CSF cytokine ...
Description	Target engagement will be assessed by the mean change in CSF cytokine concentration between baseline and week 8 in ALS subjects receiving placebo or active drug.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Placebo	Active Drug
Arm/Group Description:	8 subjects will receive matching IV...	14subjects will receive 8mg/kg of I...
Arm/Group Description:	8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	14subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Overall Number of Participants Analyzed	8	14
Least Squares Mean (95% Confidence Interval) Unit of Measure: Fold change in concentration
CRP (ng/mL)	0.641 (0.216 to 1.903)	0.107 (0.044 to 0.260)
IL-1beta (pg/mL)	1.498 (0.542 to 4.138)	1.110 (0.459 to 2.679)
IL-6 (pg/mL)	1.242 (0.781 to 1.974)	4.115 (2.813 to 6.018)
IL-8 (pg/mL)	0.946 (0.758 to 1.181)	1.020 (0.854 to 1.218)
TNF-alpha (pg/mL)	0.989 (0.727 to 1.346)	1.066 (0.833 to 1.365)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.011
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of fold change
	Estimated Value	0.167
	Confidence Interval	(2-Sided) 95% 0.043 to 0.643
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.604
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of fold change
	Estimated Value	0.741
	Confidence Interval	(2-Sided) 95% 0.228 to 2.405
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of fold change
	Estimated Value	2.940
	Confidence Interval	(2-Sided) 95% 1.823 to 4.740
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.587
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of fold change
	Estimated Value	1.078
	Confidence Interval	(2-Sided) 95% 0.813 to 1.431
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.697
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of fold change
	Estimated Value	1.078
	Confidence Interval	(2-Sided) 95% 0.728 to 1.595
	Estimation Comments	[Not Specified]

9.Secondary Outcome


Title	Change in CSF Soluble Interleukin-6 (sIL-6) Receptor Concentrations
Description	Target engagement will be assessed by comparing the mean change in CSF...
Description	Target engagement will be assessed by comparing the mean change in CSF sIL-6 receptor concentrations (ng/mL) between baseline and week 8 of the placebo and active drug groups.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.


Arm/Group Title	Placebo	Active Drug
Arm/Group Description:	8 subjects will receive matching IV...	16 subjects will receive 8mg/kg of ...
Arm/Group Description:	8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Overall Number of Participants Analyzed	8	14
Least Squares Mean (95% Confidence Interval) Unit of Measure: ng/mL
	1.029 (0.886 to 1.195)	1.836 (1.621 to 2.080)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Active Drug
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Ratio of fold change
	Estimated Value	1.785
	Confidence Interval	(2-Sided) 95% 1.502 to 2.121
	Estimation Comments	[Not Specified]

10.Secondary Outcome


Title	Peripheral Benzodiazepine Receptor 28 (PBR28) Positron Emission Tomography (PET)
Description	Measure the effects of tocilizumab on reducing glial activation measur...
Description	Measure the effects of tocilizumab on reducing glial activation measured by PBR28 PET in a subset of trial participants.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Only 2 patients met inclusion criteria for the PET portion of the study and thus, the data could not be statistically analyzed.


Arm/Group Title	Placebo	Active Drug
Arm/Group Description:	8 subjects will receive matching IV...	16 subjects will receive 8mg/kg of ...
Arm/Group Description:	8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Overall Number of Participants Analyzed	1	1
Measure Type: Number Unit of Measure: Standardized Uptake Variable Ratio(SUVR)
Baseline	1.225282	1.059685
Week 8	1.361542	1.056888

Adverse Events

Time Frame	Adverse events were collected over the study lasting up to 16 weeks in each subject.
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Placebo		Active Drug
Arm/Group Description	8 subjects will receive matching IV...		16 subjects will receive 8mg/kg of ...
Arm/Group Description	8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion		16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
All-Cause Mortality
	Placebo		Active Drug
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/8 (0.00%)		0/14 (0.00%)
Serious Adverse Events Serious Adverse Events
	Placebo		Active Drug
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/8 (12.50%)		0/14 (0.00%)
Respiratory, thoracic and mediastinal disorders
Pneumonia Aspiration ^† 1	1/8 (12.50%)	1	0/14 (0.00%)	0
1 Term from vocabulary, MedDRA (17.1) † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo		Active Drug
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/8 (75.00%)		11/14 (78.57%)
Blood and lymphatic system disorders
Neutropenia ^† 1	0/8 (0.00%)	0	1/14 (7.14%)	1
Ear and labyrinth disorders
Ear Pruritus ^† 1	1/8 (12.50%)	1	0/14 (0.00%)	0
Gastrointestinal disorders
Abdominal Distension ^† 1	0/8 (0.00%)	0	1/14 (7.14%)	1
Abdominal Pain ^† 1	0/8 (0.00%)	0	1/14 (7.14%)	1
Aphthous Stomatitis ^† 1	1/8 (12.50%)	1	0/14 (0.00%)	0
Constipation ^† 1	0/8 (0.00%)	0	1/14 (7.14%)	1
Faecal Incontinence ^† 1	0/8 (0.00%)	0	1/14 (7.14%)	1
Nausea ^† 1	2/8 (25.00%)	4	1/14 (7.14%)	1
Salivary Hypersecretion ^† 1	0/8 (0.00%)	0	2/14 (14.29%)	2
General disorders
Catheter Site Related Reaction ^† 1	1/8 (12.50%)	1	0/14 (0.00%)	0
Fatigue ^† 1	1/8 (12.50%)	2	2/14 (14.29%)	2
Infusion Site Pruritus ^† 1	1/8 (12.50%)	1	0/14 (0.00%)	0
Injection Site Pain ^† 1	0/8 (0.00%)	0	1/14 (7.14%)	1
Puncture Site Pain ^† 1	4/8 (50.00%)	4	2/14 (14.29%)	2
Infections and infestations
Catheter Site Infection ^† 1	1/8 (12.50%)	1	0/14 (0.00%)	0
Clostridium Difficile Colitis ^† 1	0/8 (0.00%)	0	1/14 (7.14%)	1
Gingival Abscess ^† 1	1/8 (12.50%)	1	0/14 (0.00%)	0
Nasopharyngitis ^† 1	0/8 (0.00%)	0	2/14 (14.29%)	2
Pneumonia ^† 1	0/8 (0.00%)	0	1/14 (7.14%)	1
Upper Respiratory Tract Infection ^† 1	1/8 (12.50%)	1	1/14 (7.14%)	1
Urinary Tract Infection ^† 1	1/8 (12.50%)	1	0/14 (0.00%)	0
Injury, poisoning and procedural complications
Contusion ^† 1	0/8 (0.00%)	0	1/14 (7.14%)	1
Fall ^† 1	2/8 (25.00%)	3	3/14 (21.43%)	4
Foot Fracture ^† 1	0/8 (0.00%)	0	1/14 (7.14%)	1
Post Lumbar Puncture Syndrome ^† 1	0/8 (0.00%)	0	2/14 (14.29%)	2
Procedural Pain ^† 1	1/8 (12.50%)	2	3/14 (21.43%)	4
Investigations
Alanine Aminotransferase Increased ^† 1	0/8 (0.00%)	0	1/14 (7.14%)	1
Aspartate Aminotransferase Increased ^† 1	0/8 (0.00%)	0	1/14 (7.14%)	1
Blood Pressure Increased ^† 1	0/8 (0.00%)	0	2/14 (14.29%)	2
Platelet Count Increased ^† 1	1/8 (12.50%)	1	0/14 (0.00%)	0
White Blood Cell Count Increased ^† 1	1/8 (12.50%)	1	0/14 (0.00%)	0
Musculoskeletal and connective tissue disorders
Muscular Weakness ^† 1	1/8 (12.50%)	1	3/14 (21.43%)	4
Musculoskeletal Pain ^† 1	0/8 (0.00%)	0	1/14 (7.14%)	1
Nervous system disorders
Dizziness ^† 1	2/8 (25.00%)	3	1/14 (7.14%)	1
Headache ^† 1	0/8 (0.00%)	0	2/14 (14.29%)	3
Presyncope ^† 1	0/8 (0.00%)	0	1/14 (7.14%)	1
Renal and urinary disorders
Urinary Tract Pain ^† 1	1/8 (12.50%)	1	0/14 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	2/8 (25.00%)	2	0/14 (0.00%)	0
Dysphonia ^† 1	0/8 (0.00%)	0	2/14 (14.29%)	2
Dyspnoea ^† 1	1/8 (12.50%)	1	3/14 (21.43%)	3
Oropharyngeal Pain ^† 1	1/8 (12.50%)	1	1/14 (7.14%)	1
Skin and subcutaneous tissue disorders
Pruritus ^† 1	1/8 (12.50%)	1	1/14 (7.14%)	3
1 Term from vocabulary, MedDRA 17.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

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Name/Title:	Shafeeq Ladha, MD
Organization:	Barrow Neurological Institute
Phone:	602-406-8989
EMail:	Shafeeq.Ladha@Barrowneuro.org

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Milligan C, Atassi N, Babu S, Barohn RJ, Caress JB, Cudkowicz ME, Evora A, Hawkins GA, Wosiski-Kuhn M, Macklin EA, Shefner JM, Simmons Z, Bowser RP, Ladha SS. Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients. Muscle Nerve. 2021 Sep;64(3):309-320. doi: 10.1002/mus.27339. Epub 2021 Jun 24.

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Responsible Party:	Shafeeq Ladha, MD, Barrow Neurological Institute
ClinicalTrials.gov Identifier:	NCT02469896
Other Study ID Numbers:	2015TCZALS-001
First Submitted:	June 3, 2015
First Posted:	June 12, 2015
Results First Submitted:	August 6, 2019
Results First Posted:	December 18, 2019
Last Update Posted:	December 18, 2019

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