Study of Safety and of the Mechanism of BLZ945 in ALS Patients

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04066244

Collaborator

(none)

Enrollment

Locations

Arms

52.4

Anticipated Duration (Months)

9.2

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

It is an open label study to evaluate safety, tolerability and brain microglia response in participants with ALS following multiple doses of BLZ945.

Condition or Disease	Intervention/Treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: BLZ945	Phase 2

Detailed Description

The purpose of the study is to identify a dose (or doses) of BLZ945, that measurably decrease(s) TSPO binding in the brain of participants with ALS, and to evaluate the safety and tolerability of BLZ945 in participants with ALS 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 participants with ALS will be assessed at different times post dosing.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

46 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Intervention Model Description:

This study is an exploratory, adaptive, open-label study of multiple oral doses of BLZ945 in participants with ALS.This study is an exploratory, adaptive, open-label study of multiple oral doses of BLZ945 in participants with ALS.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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 :

Dec 30, 2019

Anticipated Primary Completion Date :

Feb 2, 2024

Anticipated Study Completion Date :

May 13, 2024

Arms and Interventions

Arm	Intervention/Treatment
Other: Cohort 1 Dose 1 of BLZ945	Drug: BLZ945 Investigational drug
Other: Cohort 2 Dose 2 of BLZ945	Drug: BLZ945 Investigational drug
Other: Cohort 3 Dose 3 of BLZ945	Drug: BLZ945 Investigational drug
Other: Cohort 4 Dose 4 of BLZ945	Drug: BLZ945 Investigational drug
Other: Cohort 5 Dose 5 of BLZ945	Drug: BLZ945 Investigational drug

Outcome Measures

Primary Outcome Measures

Change from baseline in volume of distribution (Vt) in different brain regions for [11C]-PBR28 PET scan [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 participants by using PET imaging with [11C]-PBR28.

Secondary Outcome Measures

Plasma Pharmacokinetics (PK) of BLZ945 - Cmax [Day 1; up to Day 17]
Measured by Cmax - The maximum plasma concentration of BLZ945
Plasma Pharmacokinetics (PK) of BLZ945 - Tmax [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 [Day 1; up to Day 17]
Measured by AUC - Area under the curve of BLZ945
Plasma Pharmacokinetics (PK) of BLZ945 - T1/2 [Day 1; up to Day 17]
Measured by T1/2 - The elimination half-life of BLZ945
Renal Clearance (CLR) of BLZ945 [Day 1; up to Day 7]
Urine renal clearance (CLR) of BLZ945
CYP2C8 genotyping and BLZ945 plasma PK parameters [Day 1; up to Day 17]
To assess the CYP2C8 pharmacogenomic-pharmacokinetic relationship; CYP2C8 genotyping and BLZ945 plasma PK parameters

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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 participants who are 18 years old or older at screening, and 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 participants need to be on a stable dose and regimen for at least 3 months prior to baseline. For participants 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.

Exclusion Criteria:

A history of clinically significant ECG abnormalities
Active hematologic, hepatic, respiratory disorders that are clinically significant and may jeopardize the participant'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.

COVID-19 specifically: COVID-19 testing will be completed prior to first dosing. Positive results would exclude participants from being enrolled in the study.

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. Participants with cardiac failure class 3 or 4 of the NYHA classification, implanted cardiac pacemaker, or defibrillator.
Significant hematological laboratory abnormalities.
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 participants
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, participant would be at an increased risk for adverse events related to these procedures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	New Haven	Connecticut	United States	06520-8048
2	Novartis Investigative Site	Boston	Massachusetts	United States	02114
3	Novartis Investigative Site	New York	New York	United States	10032
4	Novartis Investigative Site	Turku		Finland	20520
5	Novartis Investigative Site	Stockholm		Sweden	14186