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

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ClinicalTrials.gov Identifier: NCT04066244
Recruitment Status : Not yet recruiting
First Posted : August 26, 2019
Last Update Posted : August 26, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
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 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 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: This study is an exploratory, adaptive, open-label study of multiple oral doses of BLZ945 in ALS subjects
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
Estimated Study Start Date : October 23, 2019
Estimated Primary Completion Date : February 11, 2021
Estimated Study Completion Date : February 11, 2021


Arm Intervention/treatment
Cohort 1
Dose 1 of BLZ945
Drug: BLZ945
Investigational drug

Cohort 2
Dose 2 of BLZ945
Drug: BLZ945
Investigational drug

Cohort 3
Dose 3 of BLZ945
Drug: BLZ945
Investigational drug

Cohort 4
Dose 4 of BLZ945
Drug: BLZ945
Investigational drug

Cohort 5
Dose 5 of BLZ945
Drug: BLZ945
Investigational drug




Primary Outcome Measures :
  1. Change from Baseline Volume of distribution (Vt) in different brain regions for each [11C]-PBR28 PET scan [ Time Frame: Day -28, 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, at day 5 (or 8) following oral doses of BLZ945 in ALS subjects by using PET imaging with [11C]-PBR28.


Secondary Outcome Measures :
  1. Plasma Pharmacokinetics (PK) of BLZ945 - Cmax [ Time Frame: Day 1; up to Day 17 ]
    Measured by Cmax - The maximum plasma concentration of BLZ945

  2. 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

  3. Plasma Pharmacokinetics (PK) of BLZ945 - AUC [ Time Frame: Day 1; up to Day 17 ]
    Measured by AUC - Area under the curve of BLZ945

  4. 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

  5. Renal Clearance (CLR) of BLZ945 [ Time Frame: Day 1; up to Day 7 ]
    Urine renal clearance (CLR) of BLZ945

  6. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 subjects diagnosed with familial or sporadic ALS aged 18-75 years, weight > 50 kg, BMI between 18 - 35 kg/m2 at the screening visit.
  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 for gender, height, and age at the screening visit.
  7. Female subjects of childbearing potential must have a negative pregnancy test at screening and baseline.
  8. Subjects must be high-affinity binders (HAB) or mixed-affinity binders (MAB) to TSPO as evaluated by genotyping for the rs6971 polymorphism in the TSPO gene.
  9. Baseline PET scan of sufficient image quality to enable the measurement of [11C]-PBR28 volume of distribution (Vt) in the relevant CNS regions.
  10. Subjects being treated with riluzole and/or edaravone must 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.
  11. Subjects with at least level 25 on the MGH Upper Motor Neuron Burden (UMNB) scale at the screening visit

Exclusion Criteria:

  1. A history of clinically significant ECG abnormalities
  2. Subjects with 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.
  3. Subjects with 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 or clinically relevant abnormalities on the MRI scan indicating any other pathology than ALS.
  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 (ELISA and Western blot).
  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. Have had, in the judgement of the investigator, signs or symptoms of a clinically significant systemic viral, bacterial or fungal infection within 30 days prior to the screening visit.
  10. Subjects presenting at the screening visit with cardiac disorders. Subjects with recent cardiac history (within 6 months of screening) of acute coronary syndrome, acute heart failure, or significant ventricular arrhythmia. Patient with cardiac failure class 3 or 4 of the NYHA classification. Patients 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 subjects
  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. Subjects receiving treatment with medications that could interfere with BLZ945.
  17. Any contraindications to MRI.
  18. Taking medications prohibited by the protocol
  19. Any contraindications to the arterial line sampling
  20. History or presence of impaired renal function at the screening visit.
  21. Subjects with active suicidal ideation.
  22. 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.

Information from the National Library of Medicine

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): NCT04066244


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Sponsors and Collaborators
Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04066244     History of Changes
Other Study ID Numbers: CBLZ945C12201
First Posted: August 26, 2019    Key Record Dates
Last Update Posted: August 26, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
PET, ALS, Microglia
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases