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
This research study is being done to find out if tocilizumab, also known as Actemra™, can help with Amyotrophic Lateral Sclerosis (ALS). The investigators also want to find out if tocilizumab is safe to take without causing too many side effects.
Currently ALS has no cure and 2 modestly effective treatment to slow the progression of the disease. Although not the initial cause of ALS, the immune system plays a role in the death of motor neurons. The immune cells that participate in this process are stimulated by a substance called interleukin-6 (IL-6) whose effect is blocked by tocilizumab and thus, may slow the death of motor neurons and slow the disease.
|Condition or disease||Intervention/treatment||Phase|
|ALS Amyotrophic Lateral Sclerosis Lou Gehrig's Disease Motor Neuron Disease||Drug: Tocilizumab Other: Placebo||Phase 2|
This is a multicenter, randomized, double-blind, placebo-controlled 16-week study evaluating the safety and tolerability of tocilizumab in subjects with ALS.
The primary objective of the study is to determine the safety and tolerability of intravenous administration of 8 mg/kg of tocilizumab every 4 weeks vs. matched intravenous placebo administered every 4 weeks over an 8 week period.
The secondary objectives of the study are to describe the expression of pro-inflammatory genes in Peripheral Blood Mononuclear Cells (PBMCs) of sporadic ALS patients, to assess the ability of tocilizumab to reduce the expression of pro-inflammatory genes in PBMCs and pro-inflammatory cytokines in the cerebrospinal fluid (CSF) of patients with sporadic ALS and to assess the CSF penetration of tocilizumab. Mean peripheral benzodiazepine receptor 28 (PBR28) uptake will be measured in the motor cortices as regions of interest (ROIs), and will be compared between pre- and post-dose, for Massachusetts General Hospital (MGH) subjects.
Approximately 5 Northeast ALS Consortium (NEALS) Centers in the US will participate in the study. Twenty-four subjects will be randomized in the study.
This study will be conducted in subjects who meet the El Escorial criteria of possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS. At screening, eligible subjects must be at least 18 years old, must have a slow vital capacity (SVC) ≥ 40% of predicted capacity for age, height and gender (and in the opinion of the investigator is able to comply with and complete the trial), and must provide written informed consent prior to screening. Subjects on a stable dose of riluzole and those not taking riluzole, and women of child-bearing age at screening are eligible for inclusion as long as they meet specific protocol requirements. Detailed criteria are described in the body of the protocol.
Subjects participating in the magnetic resonance imaging - positron emission tomography (MRI-PET) portion of the study (MGH only) must meet the following additional criteria.High or mixed affinity to bind translocator protein (TSPO) (Ala/Ala or Ala/Thr,) Upper Motor Neuron Burden (UMNB) Scale Score ≥25 (out of 45) at the Screening Visit.
and have the ability to safely undergo MRI-PET scans based on the opinion of the site investigator.
Subjects will be randomly assigned in a 2:1 ratio to intravenous tocilizumab 8 mg/kg or matching placebo every 4 weeks over an 8 week period.
This research study protocol allows the subject to receive up to 3 infusions of Tocilizumab. Even if the treatment is shown to be of benefit, additional infusions of Tocilizumab beyond that allowed in the protocol cannot be given to the subject while she/he is participating in this study.
Subjects will remain on randomized, placebo-controlled, double-blind treatment until the Week 8 visit. Each randomized subject will also have a Week 12 Follow-up visit and Week 16 End-of-Study visit to assess for adverse events (AEs), changes in concomitant medications, to administer the ALS Functional Rating Scale (ALSFRS-R) and selected study procedures.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||22 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||A Phase 2 Randomized, Placebo Controlled Trial of Tocilizumab in ALS Subjects|
|Study Start Date :||November 2015|
|Actual Primary Completion Date :||July 11, 2018|
|Actual Study Completion Date :||July 11, 2018|
Placebo Comparator: Placebo
8 subjects will receive matching IV placebo every 4 weeks for 3 months.
Other Name: Saline
Active Comparator: Active drug
14 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months.
Other Name: Actemra
- Number of Patients Tolerant to Study Drug [ Time Frame: 16 weeks ]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.
- Rates of All-cause Mortality [ Time Frame: 16 weeks ]Safety will be assessed by the occurrence of all-cause mortality.
- Rate of Decline in Slow Vital Capacity (SVC) [ Time Frame: 16 weeks ]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.
- Rate of Decline ALS Functional Rating Scale Revised (ALSFRS-R) [ Time Frame: 16 weeks ]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.
- Rate of Decline Handheld Dynamometry (HHD) [ Time Frame: 16 weeks ]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.
- Change in Peripheral Blood Mononuclear Cell (PBMC) Gene Expression [ Time Frame: 16 weeks ]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.
- Changes in Cytokine Levels in the Plasma [ Time Frame: 16 weeks ]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.
- Change in Mean Concentration Cytokines in the Cerebrospinal Fluid (CSF) [ Time Frame: 8 weeks ]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.
- Change in CSF Soluble Interleukin-6 (sIL-6) Receptor Concentrations [ Time Frame: 8 weeks ]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.
- Peripheral Benzodiazepine Receptor 28 (PBR28) Positron Emission Tomography (PET) [ Time Frame: 8 weeks ]Measure the effects of tocilizumab on reducing glial activation measured by PBR28 PET in a subset of trial participants.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02469896
|United States, Arizona|
|Barrow Neurological Institute|
|Phoenix, Arizona, United States, 85013|
|United States, Kansas|
|University of Kansas Medical Center|
|Kansas City, Kansas, United States, 66160|
|United States, Massachusetts|
|Massachusetts General Hospital|
|Boston, Massachusetts, United States, 02114|
|United States, North Carolina|
|Wake Forest University School of Medicine|
|Winston-Salem, North Carolina, United States, 27157|
|United States, Pennsylvania|
|Penn State College of Medicine Milton S. Hershey Medical Center|
|Hershey, Pennsylvania, United States, 17033|
|Principal Investigator:||Shafeeq Ladha, MD||Barrow Neurological Institute|