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

Primary Purpose

Amyotrophic Lateral Sclerosis

Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
BLZ945
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis focused on measuring PET, ALS, Microglia, CSF

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Able to communicate well with the investigator, to understand and comply with the study visits and procedures of the study.
  2. Written informed consent must be obtained before any assessment is performed.
  3. 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.
  4. Able to swallow medication capsules, in the opinion of the investigator.
  5. Disease duration from symptoms onset no longer than 48 months at the screening visit.
  6. 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.
  7. Females of childbearing potential must have a negative pregnancy test at screening and baseline.
  8. 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.
  9. 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.
  10. 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.
  11. Upper Motor Neuron Burden (UMNB) scale of at least 25 at the screening visit
  12. BMI between 18-35 kg/m2 at the screening visit.

Exclusion Criteria:

  1. A history of clinically significant ECG abnormalities
  2. 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.
  3. 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.
  4. 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.
  5. History of hypersensitivity to any of the study treatments or excipients or to drugs of similar chemical classes.
  6. Presence of human immunodeficiency virus (HIV) infection based on screening lab results.
  7. Evidence of active or latent tuberculosis as assessed by Quantiferon testing at the screening visit.
  8. Positive serology for hepatitis B surface antigen, or hepatitis C antibodies confirmed by an appropriate licensed test at screening.
  9. 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.

  10. 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 or participants with a history of severe pulmonary hypertension. Participants with cardiac failure class 3 or 4 of the NYHA classification, or history of reduced LVEF or individuals with implanted cardiac pacemaker, or defibrillator.
  11. Significant hematological laboratory abnormalities.
  12. Clinical evidence of liver disease or liver injury or any of the following hepatic conditions at the screening visit:
  13. 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.
  14. Pregnant or nursing female participants
  15. 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.
  16. Any contraindications to MRI.
  17. Taking medications prohibited by the protocol
  18. Any contraindications to the arterial line sampling
  19. History or presence of impaired renal function at the screening visit.
  20. Active suicidal ideation.
  21. 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.
  22. 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.
  23. Active GI conditions such as Barrett's esophagus, achalasia, esophageal varices and active or history of esophageal cancer, pre-existing pancreatic disease at screening visit.
  24. History of active vasculitis or history of autoimmune disease autoimmune disease associated with vasculitis (eg., RA, SLE, Sjögrens disease, scleroderma).
  25. History or active cardiac valve disorder, such as clinically significant stenosis or regurgitation (CTCAE grade ≥2), congenital valve disease, or other clinical condition that might affect cardiac valve function
  26. Use of systemic anticoagulation that cannot be temporarily paused before study procedures

Sites / Locations

  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative Site
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm Type

Other

Other

Other

Other

Other

Other

Other

Other

Arm Label

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Cohort 5 Arm #1

Cohort 5 Arm #2

Cohort 5 Arm #1 extended treatment period

Cohort 5 Arm #2 extended treatment period

Arm Description

Dose 1 of BLZ945

Dose 2 of BLZ945

Dose 3 of BLZ945

Dose 4 of BLZ945

Dose 4, Regimen 1 of BLZ945

Dose 4, Regimen 2 of BLZ945

Dose 4, Regimen 1 of BLZ945

Dose 4, Regimen 2 of BLZ945

Outcomes

Primary Outcome Measures

Cohorts 1-4 and Cohort 5 (PET sub-study): Change from baseline in volume of distribution (Vt) in different brain regions for [11C]-PBR28 PET scan
Volume of distribution (Vt) in different brain regions for each [11C]-PBR28 PET scan, and change after BLZ945 treatment, compared to baseline.
Cohort 5: Change from baseline in esophageal wall thickness
Esophageal wall thickness measured in mm
Cohort 5: Change from baseline in cardiac valve thickness
Cardiac valve thickness on a three point ordinal scale
Cohort 5: Change from baseline in cardiac valve function
Cardiac valve thickness on a four point ordinal scale
Cohort 5: Change from baseline in Left Ventricular Ejection Fraction
Left Ventricular Ejection Fraction calculated as %
Cohort 5: Adverse events related to ECM accumulation
Number of patients with adverse events related to ECM accumulation

Secondary Outcome Measures

Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax
Measured by Cmax - The maximum plasma concentration of BLZ945
Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax
Measured by Tmax - Time to Reach the Maximum Concentration After Drug Administration of BLZ945
Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC
Measured by AUC - Area under the curve of BLZ945
Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - T1/2
Measured by T1/2 - The elimination half-life of BLZ945
Cohorts 1-4: Renal Clearance (CLR) of BLZ945
Urine renal clearance (CLR) of BLZ945
Cohorts 1-5: CYP2C8 genotyping
To assess the CYP2C8 genotyping
Cohorts 1-5: Number of patients with adverse events
Safety and tolerability

Full Information

First Posted
August 21, 2019
Last Updated
July 13, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT04066244
Brief Title
Study of Safety and of the Mechanism of BLZ945 in ALS Patients
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 30, 2019 (Actual)
Primary Completion Date
March 27, 2025 (Anticipated)
Study Completion Date
May 8, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. 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.
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, to evaluate the safety and tolerability of BLZ945 in participants with ALS at these doses and dosing regimens, and safety related effects on ECM accumulation. In Cohort 5, TSPO PET will be performed in a dedicated cohort (PET sub-study) while the remainder of Cohort 5 participants will undergo CSF-based biomarker analyses.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyotrophic Lateral Sclerosis
Keywords
PET, ALS, Microglia, CSF

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
This study is an exploratory, adaptive, open-label study of single or multiple cycles of BLZ945 in participants with ALS. Cohorts 1-4 are not randomized, while Cohort 5 is randomized in open label two treatment arms. Cohorts 1-4 have single group design and Cohort 5 has parallel design.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
56 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Other
Arm Description
Dose 1 of BLZ945
Arm Title
Cohort 2
Arm Type
Other
Arm Description
Dose 2 of BLZ945
Arm Title
Cohort 3
Arm Type
Other
Arm Description
Dose 3 of BLZ945
Arm Title
Cohort 4
Arm Type
Other
Arm Description
Dose 4 of BLZ945
Arm Title
Cohort 5 Arm #1
Arm Type
Other
Arm Description
Dose 4, Regimen 1 of BLZ945
Arm Title
Cohort 5 Arm #2
Arm Type
Other
Arm Description
Dose 4, Regimen 2 of BLZ945
Arm Title
Cohort 5 Arm #1 extended treatment period
Arm Type
Other
Arm Description
Dose 4, Regimen 1 of BLZ945
Arm Title
Cohort 5 Arm #2 extended treatment period
Arm Type
Other
Arm Description
Dose 4, Regimen 2 of BLZ945
Intervention Type
Drug
Intervention Name(s)
BLZ945
Intervention Description
Investigational drug
Primary Outcome Measure Information:
Title
Cohorts 1-4 and Cohort 5 (PET sub-study): Change from baseline in volume of distribution (Vt) in different brain regions for [11C]-PBR28 PET scan
Description
Volume of distribution (Vt) in different brain regions for each [11C]-PBR28 PET scan, and change after BLZ945 treatment, compared to baseline.
Time Frame
Baseline, up to Day 85
Title
Cohort 5: Change from baseline in esophageal wall thickness
Description
Esophageal wall thickness measured in mm
Time Frame
Up to Day 85
Title
Cohort 5: Change from baseline in cardiac valve thickness
Description
Cardiac valve thickness on a three point ordinal scale
Time Frame
Up to Day 85
Title
Cohort 5: Change from baseline in cardiac valve function
Description
Cardiac valve thickness on a four point ordinal scale
Time Frame
Up to Day 85
Title
Cohort 5: Change from baseline in Left Ventricular Ejection Fraction
Description
Left Ventricular Ejection Fraction calculated as %
Time Frame
Up to Day 85
Title
Cohort 5: Adverse events related to ECM accumulation
Description
Number of patients with adverse events related to ECM accumulation
Time Frame
Up to Day 85
Secondary Outcome Measure Information:
Title
Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax
Description
Measured by Cmax - The maximum plasma concentration of BLZ945
Time Frame
Day 1; up to Day 74
Title
Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax
Description
Measured by Tmax - Time to Reach the Maximum Concentration After Drug Administration of BLZ945
Time Frame
Day 1; up to Day 74
Title
Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC
Description
Measured by AUC - Area under the curve of BLZ945
Time Frame
Day 1; up to Day 74
Title
Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - T1/2
Description
Measured by T1/2 - The elimination half-life of BLZ945
Time Frame
Day 1; up to Day 74
Title
Cohorts 1-4: Renal Clearance (CLR) of BLZ945
Description
Urine renal clearance (CLR) of BLZ945
Time Frame
Day 1; up to Day 7
Title
Cohorts 1-5: CYP2C8 genotyping
Description
To assess the CYP2C8 genotyping
Time Frame
Day 1
Title
Cohorts 1-5: Number of patients with adverse events
Description
Safety and tolerability
Time Frame
Up to Day 281

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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. Disease duration from symptoms onset no longer than 48 months at the screening visit. Females of childbearing potential must have a negative pregnancy test at screening and/or baseline. Treatment with approved ALS therapies is allowed, but participants need to be on a stable dose and regimen for at least 30 days prior to baseline. Having completed the Core Treatment Period to be able to continue in the Extended Treatment Period. Exclusion Criteria: A history of clinically significant ECG abnormalities Active medical or neurologic diseases other than ALS, 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 or participants with a history of severe pulmonary hypertension. Participants with cardiac failure class 3 or 4 of the NYHA classification, or history of reduced LVEF or individuals with 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. 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. Active GI conditions such as Barrett's esophagus, achalasia, esophageal varices and active or history of esophageal cancer, pre-existing pancreatic disease at screening visit. History of active vasculitis or history of autoimmune disease autoimmune disease associated with vasculitis (eg., RA, SLE, Sjögrens disease, scleroderma). History or active cardiac valve disorder, congenital valve disease, or other clinical condition that might affect cardiac valve function Use of systemic anticoagulation that cannot be temporarily paused before study procedures Abnormal values on CT scan or echocardiography, signs of vasculitis, or evidence of a significant medical condition meeting treatment discontinuation criteria will be exclusionary for continuation in the extended treatment period. Participants who are planning to initiate treatment with an additional approved ALS therapy in the next 24 weeks are not allowed to continue in the extended treatment period.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Novartis Pharmaceuticals
Phone
1-888-669-6682
Email
novartis.email@novartis.com
First Name & Middle Initial & Last Name or Official Title & Degree
Novartis Pharmaceuticals
Phone
+41613241111
Facility Information:
Facility Name
Novartis Investigative Site
City
La Jolla
State/Province
California
ZIP/Postal Code
92037
Country
United States
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520-8048
Country
United States
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Individual Site Status
Withdrawn
Facility Name
Novartis Investigative Site
City
Turku
ZIP/Postal Code
20520
Country
Finland
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Stockholm
ZIP/Postal Code
14186
Country
Sweden
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
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

Learn more about this trial

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

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