Study of Safety and of the Mechanism of BLZ945 in ALS Patients
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It is an open label study to evaluate safety, tolerability and brain microglia response in ALS patients following multiple doses of BLZ945.
Condition or disease
Amyotrophic Lateral Sclerosis
The purpose of the study is to identify a dose (or doses) of BLZ945, that measurably decrease(s) TSPO binding in the brain of ALS subjects, and to evaluate the safety and tolerability of BLZ945 in ALS subjects at these doses and dosing regimen. PET imaging with a ligand selective for TSPO is widely used as a marker for microglial activation. Following microglia reduction, the repopulation of microglia in ALS subjects will be assessed at different times post dosing.
This study is an exploratory, adaptive, open-label study of multiple oral doses of BLZ945 in ALS subjects
None (Open Label)
An Open-label, Adaptive Design Study in Patients With Amyotrophic Lateral Sclerosis (ALS) to Characterize Safety, Tolerability and Brain Microglia Response, as Measured by TSPO Binding, Following Multiple Doses of BLZ945 Using Positron Emission Tomography (PET) With the Radioligand [11C]-PBR28
Actual Study Start Date :
December 30, 2019
Estimated Primary Completion Date :
February 11, 2021
Estimated Study Completion Date :
October 14, 2021
Resource links provided by the National Library of Medicine
Change from baseline in volume of distribution (Vt) in different brain regions for [11C]-PBR28 PET scan [ Time Frame: Day -42, up to Day 22 ]
Volume of distribution (Vt) in different brain regions for each [11C]-PBR28 PET scan, and change after BLZ945 treatment, compared to baseline. Evaluate brain microglial reduction, as measured by reduction in TSPO binding following oral doses of BLZ945 in ALS subjects by using PET imaging with [11C]-PBR28.
Secondary Outcome Measures :
Plasma Pharmacokinetics (PK) of BLZ945 - Cmax [ Time Frame: Day 1; up to Day 17 ]
Measured by Cmax - The maximum plasma concentration of BLZ945
Plasma Pharmacokinetics (PK) of BLZ945 - Tmax [ Time Frame: Day 1; up to Day 17 ]
Measured by Tmax - Time to Reach the Maximum Concentration After Drug Administration of BLZ945
Plasma Pharmacokinetics (PK) of BLZ945 - AUC [ Time Frame: Day 1; up to Day 17 ]
Measured by AUC - Area under the curve of BLZ945
Plasma Pharmacokinetics (PK) of BLZ945 - T1/2 [ Time Frame: Day 1; up to Day 17 ]
Measured by T1/2 - The elimination half-life of BLZ945
Renal Clearance (CLR) of BLZ945 [ Time Frame: Day 1; up to Day 7 ]
Urine renal clearance (CLR) of BLZ945
CYP2C8 genotyping and BLZ945 plasma PK parameters [ Time Frame: Day 1; up to Day 17 ]
To assess the CYP2C8 pharmacogenomic-pharmacokinetic relationship; CYP2C8 genotyping and BLZ945 plasma PK parameters
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Ages Eligible for Study:
18 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study:
Accepts Healthy Volunteers:
Able to communicate well with the investigator, to understand and comply with the study visits and procedures of the study.
Written informed consent must be obtained before any assessment is performed.
Male and female subjects aged 18-75, inclusive, who are diagnosed with familial or sporadic ALS according to the World Federation of Neurology Revised El Escorial criteria of either bulbar or limb onset.
Able to swallow medication capsules, in the opinion of the investigator.
Disease duration from symptoms onset no longer than 48 months at the screening visit.
Having a SVC (slow vital capacity) equal to or more than 60% predicted normal value per local standards for gender, height, and age at the screening visit.
Females of childbearing potential must have a negative pregnancy test at screening and baseline.
High-affinity binders (HAB) or mixed-affinity binders (MAB) to TSPO as evaluated by genotyping for the rs6971 polymorphism in the TSPO gene at the screening visit.
Baseline PET scan of sufficient image quality, as determined locally by the PET experts, to enable the measurement of [11C]-PBR28 volume of distribution (Vt) in the relevant CNS regions.
Treatment with riluzole and/or edaravone are allowed, but subjects need to be on a stable dose and regimen for at least 3 months prior to screening. For subjects taking edaravone, BLZ945 dosing must be scheduled during the 20 days off-drug period of the edavarone treatment regimen.
Upper Motor Neuron Burden (UMNB) scale of at least 25 at the screening visit
BMI between 18-35 kg/m2 at the screening visit.
A history of clinically significant ECG abnormalities
Active hematologic, hepatic, respiratory disorders that are clinically significant and may jeopardize the patient's safety if participating in the study or limit his/her participation in the study, including ability to tolerate the imaging studies.
Active dementia, neurologic diseases other than ALS, or psychiatric illness that in the opinion of the investigator would limit their participation in the current study.
Use of other investigational drugs within 5 half-lives of screening, or until the expected PD effect has returned to baseline , whichever is longer; or longer if required by local regulations.
History of hypersensitivity to any of the study treatments or excipients or to drugs of similar chemical classes.
Presence of human immunodeficiency virus (HIV) infection based on screening lab results.
Evidence of active or latent tuberculosis as assessed by Quantiferon testing at the screening visit.
Positive serology for hepatitis B surface antigen, or hepatitis C antibodies confirmed by an appropriate licensed test at screening.
Signs or symptoms, in the judgement of the investigator, of a clinically significant systemic viral, bacterial or fungal infection within 30 days prior to the screening visit.
Cardiac disorders, such as recent cardiac history (within 6 months of screening) of acute coronary syndrome, acute heart failure, or significant ventricular arrhythmia at the screening visit. Patient with cardiac failure class 3 or 4 of the NYHA classification. Patients with implanted cardiac pacemaker, or defibrillator.
Clinical evidence of liver disease or liver injury or any of the following hepatic conditions at the screening visit:
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 14 days after last dose of BLZ945.
Pregnant or nursing female subjects
Sexually active males unless they use a condom during intercourse while taking the drug during treatment, for 14 days after stopping BLZ945 and should not father a child in this period.
Any contraindications to MRI.
Taking medications prohibited by the protocol
Any contraindications to the arterial line sampling
History or presence of impaired renal function at the screening visit.
Active suicidal ideation.
History of drug abuse or harmful alcohol use within the 12 months prior to dosing within the judgement of the investigator, or evidence of such abuse as indicated by the laboratory assays conducted during screening.
Inability or unwillingness to undergo repeated venipuncture or arterial cannulation, or in the opinion of the investigator, patient would be at an increased risk for adverse events related to these procedures.
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:
Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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Studies a U.S. FDA-regulated Drug Product:
Studies a U.S. FDA-regulated Device Product:
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Nervous System Diseases
Spinal Cord Diseases
Central Nervous System Diseases