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Safety, Tolerability and Pharmacokinetics of Multiple Ascending Doses of NIO752 in Progressive Supranuclear Palsy

Primary Purpose

Progressive Supranuclear Palsy (PSP)

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
antisense oligonucleotide
placebo
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Progressive Supranuclear Palsy (PSP) focused on measuring progressive supranuclear palsy, PSP, antisense oligonucleotide, ASO, tau, NIO752, adult

Eligibility Criteria

40 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Signed informed consent
  2. Between 40 to 75 years old (inclusive)
  3. Have PSP diagnosed for less than 5 years with a current classification of probable PSP Richardson syndrome, a progressive supranuclear palsy rating scale (PSPRS) score < 40 and MOCA score >17 at screening
  4. Be able to ambulate independently or able to take at least 5 steps with minimal assistance
  5. At least a 12-month history of postural instability or falls within 3 years from disease onset as per medical history
  6. Vertical supranuclear gaze palsy, or reduced velocity of vertical saccade
  7. Able and willing to meet all study requirements including:

    Have a study partner who is reliable, competent, and at least 18 years of age, and will be able to accompany the participant to study visits, be knowledgeable of the participant's ongoing condition during the study to provide study related information to study site when required both in person and via a phone Reside in a proximity to the study site to allow a timely unscheduled visit if necessary (ideally less than 2 hours) Able to undergo lumbar puncture (LP), CSF draws and blood draws

  8. If the participant is receiving levodopa/carbidopa, levodopa/benserazide, a dopamine agonist, catechol-o-methyltransferase (COMT) inhibitor, rasagiline, CoQ10 or other Parkinson's medications, acetylcholinesterase inhibitors, antipsychotics, memantine, or other non-tau modifying Alzheimer's medication the dose must have been stable for at least 30 days prior to the screening visit and must remain stable for the duration of the study. No such medication can be initiated during the study.

Exclusion Criteria:

  1. Live in a skilled nursing facility or dementia care facility
  2. Evidence of motor neuron disease, or any other neurological disease that could explain symptoms
  3. Clinically significant laboratory abnormality
  4. Attempted suicide, suicidal ideation with a plan that required hospital admission within 12 months prior to Screening. In addition, patients deemed by the Investigator to be at significant risk of suicide, major depressive episode, psychosis, confusion state, or violent behavior should be excluded.
  5. A clear and robust benefit from levodopa by history
  6. Use of lithium, methylene blue or other putative disease modifying drugs for PSP within 30 days of screening
  7. Any previous use of experimental therapy within 30 days or 5 half-lives prior to Day 1, whichever is greater
  8. Any condition that increases risk of meningitis unless participant is receiving appropriate prophylactic treatment
  9. History of post-lumbar-puncture headache of moderate or severe intensity and/or blood patch

11. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study 12. Unable to undergo magnetic resonance imaging (MRI) due to for example claustrophobia, or presents absolute contraindications to MRI (e.g., metallic implants, metallic foreign bodies, pacemaker, defibrillator) 13. Patients with other significant brain MRI abnormalities by history or at screening.

Sites / Locations

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Placebo Comparator

Experimental

Experimental

Experimental

Arm Label

Cohort A NIO752

Cohort B NIO752

Placebo

Cohort C NIO752

Cohort D NIO752

Cohort E NIO752

Arm Description

4 injections of NIO752 at dose A

4 injections of NIO752 at dose B

4 injections of placebo

4 injections of NIO752 at dose C

4 injections of NIO752 at dose D

4 injections of NIO752 at dose E

Outcomes

Primary Outcome Measures

Number of adverse events and serious adverse events
Adverse events will be collected at clinical visits and other contacts. All abnormalities from safety assessments (physical exams and neurological exams and clinical safety labs) considered clinically significant will be recorded as adverse events
Change in severity scores for Columbia-Suicide Severity Rating Scale (C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively assesses Suicidal Ideation and Suicidal Behavior. The C-SSRS must be administered at visits. If, at any time after "screening and/or baseline" version, the score is "yes" on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS or "yes" on any item of the Suicidal Behavior section, the participant must be referred to a mental health care professional for further assessment and/or treatment.
Levels of infection indicators in Cerebrospinal fluid (CSF)
CSF safety labs measure levels of proteins, glucose, lactate and white blood cell counts with differential indicating infections.

Secondary Outcome Measures

Concentrations of NIO752 in blood plasma
concentrations of NIO752 in plasma
Concentrations of NIO752 in CSF
concentrations of NIO752 in CSF
Cmax, Ctrough in blood plasma
Maximum and trough level concentrations of NIO752 in plasma
Tmax in blood plasma
Time of Cmax in plasma post first injection
AUClast in blood plasma
Area under curve (AUC) from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1)
AUCinf in blood plasma
The AUC from time zero to infinity (mass x time x volume-1)

Full Information

First Posted
August 25, 2020
Last Updated
October 11, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT04539041
Brief Title
Safety, Tolerability and Pharmacokinetics of Multiple Ascending Doses of NIO752 in Progressive Supranuclear Palsy
Official Title
A Randomized, Participant, Investigator and Sponsor Blinded, Placebo-Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Multiple Ascending Doses of Intrathecally Administered NIO752 in Participants With Progressive Supranuclear Palsy
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 16, 2021 (Actual)
Primary Completion Date
November 12, 2024 (Anticipated)
Study Completion Date
November 12, 2024 (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
Yes

5. Study Description

Brief Summary
This is a phase 1, multi-center, double-blind, placebo-controlled, multiple dose escalation study with NIO752 in progressive supranuclear palsy (PSP) participants.
Detailed Description
This is a phase 1, multi-center, double-blind, placebo-controlled, multiple dose escalation study with NIO752 in progressive supranuclear palsy (PSP) participants. Approximately 58 PSP participants in 5 cohorts will be randomized to receive NIO752 or placebo in a ratio of 3:1. Intrathecal (IT) injections will be given multiple times over 3 months and participants will remain in study for an additional 9-month follow-up period; or will be given multiple times over 9 months and participants will remain in study for an additional 3-month follow-up period. Cohorts will be enrolled sequentially. Safety assessments will include physical and neurological examinations, ECGs, vital signs, standard clinical laboratory evaluations (hematology, blood chemistry, and urinalysis), CSF laboratory test, adverse event, and serious adverse event monitoring.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Progressive Supranuclear Palsy (PSP)
Keywords
progressive supranuclear palsy, PSP, antisense oligonucleotide, ASO, tau, NIO752, adult

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
66 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort A NIO752
Arm Type
Experimental
Arm Description
4 injections of NIO752 at dose A
Arm Title
Cohort B NIO752
Arm Type
Experimental
Arm Description
4 injections of NIO752 at dose B
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
4 injections of placebo
Arm Title
Cohort C NIO752
Arm Type
Experimental
Arm Description
4 injections of NIO752 at dose C
Arm Title
Cohort D NIO752
Arm Type
Experimental
Arm Description
4 injections of NIO752 at dose D
Arm Title
Cohort E NIO752
Arm Type
Experimental
Arm Description
4 injections of NIO752 at dose E
Intervention Type
Drug
Intervention Name(s)
antisense oligonucleotide
Other Intervention Name(s)
NIO752
Intervention Description
solution of antisense oligonucleotide injected intrathecally (spine tap) at multiple dose levels
Intervention Type
Drug
Intervention Name(s)
placebo
Intervention Description
placebo for each dose level
Primary Outcome Measure Information:
Title
Number of adverse events and serious adverse events
Description
Adverse events will be collected at clinical visits and other contacts. All abnormalities from safety assessments (physical exams and neurological exams and clinical safety labs) considered clinically significant will be recorded as adverse events
Time Frame
Baseline up to approximately one year (3-month treatment plus 9-month follow-up or 9-month treatment plus 3-month follow-up)
Title
Change in severity scores for Columbia-Suicide Severity Rating Scale (C-SSRS)
Description
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively assesses Suicidal Ideation and Suicidal Behavior. The C-SSRS must be administered at visits. If, at any time after "screening and/or baseline" version, the score is "yes" on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS or "yes" on any item of the Suicidal Behavior section, the participant must be referred to a mental health care professional for further assessment and/or treatment.
Time Frame
Baseline up to approximately 1 year (3-month treatment plus 9-month follow-up or 9-month treatment plus 3-month follow-up)
Title
Levels of infection indicators in Cerebrospinal fluid (CSF)
Description
CSF safety labs measure levels of proteins, glucose, lactate and white blood cell counts with differential indicating infections.
Time Frame
Baseline up to approximately 1 year (3-month treatment plus 9-month follow-up or 9-month treatment plus 3-month follow-up)
Secondary Outcome Measure Information:
Title
Concentrations of NIO752 in blood plasma
Description
concentrations of NIO752 in plasma
Time Frame
From the 1st dose administration (day 1), through study completion, where the longest duration would be approximately 1 year for those who receive 4 treatment doses
Title
Concentrations of NIO752 in CSF
Description
concentrations of NIO752 in CSF
Time Frame
From the 1st dose administration (day 1), through study completion, where the longest duration would be approximately 1 year for those who receive 4 treatment doses
Title
Cmax, Ctrough in blood plasma
Description
Maximum and trough level concentrations of NIO752 in plasma
Time Frame
From the 1st dose administration (day 1), through study completion, where the longest duration would be approximately 1 year for those who receive 4 treatment doses
Title
Tmax in blood plasma
Description
Time of Cmax in plasma post first injection
Time Frame
From the 1st dose administration (day 1), through study completion, where the longest duration would be approximately 1 year for those who receive 4 treatment doses
Title
AUClast in blood plasma
Description
Area under curve (AUC) from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1)
Time Frame
0 to 24 hours after first injection
Title
AUCinf in blood plasma
Description
The AUC from time zero to infinity (mass x time x volume-1)
Time Frame
0 to 24 hours after first injection

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Signed informed consent Between 40 to 75 years old (inclusive) Have PSP diagnosed for less than 5 years with a current classification of probable PSP Richardson syndrome, a progressive supranuclear palsy rating scale (PSPRS) score < 40 and MOCA score >17 at screening Be able to ambulate independently or able to take at least 5 steps with minimal assistance At least a 12-month history of postural instability or falls within 3 years from disease onset as per medical history Vertical supranuclear gaze palsy, or reduced velocity of vertical saccade Able and willing to meet all study requirements including: Have a study partner who is reliable, competent, and at least 18 years of age, and will be able to accompany the participant to study visits, be knowledgeable of the participant's ongoing condition during the study to provide study related information to study site when required both in person and via a phone Reside in a proximity to the study site to allow a timely unscheduled visit if necessary (ideally less than 2 hours) Able to undergo lumbar puncture (LP), CSF draws and blood draws If the participant is receiving levodopa/carbidopa, levodopa/benserazide, a dopamine agonist, catechol-o-methyltransferase (COMT) inhibitor, rasagiline, CoQ10 or other Parkinson's medications, acetylcholinesterase inhibitors, antipsychotics, memantine, or other non-tau modifying Alzheimer's medication the dose must have been stable for at least 30 days prior to the screening visit and must remain stable for the duration of the study. No such medication can be initiated during the study. Exclusion Criteria: Live in a skilled nursing facility or dementia care facility Evidence of motor neuron disease, or any other neurological disease that could explain symptoms Clinically significant laboratory abnormality Attempted suicide, suicidal ideation with a plan that required hospital admission within 12 months prior to Screening. In addition, patients deemed by the Investigator to be at significant risk of suicide, major depressive episode, psychosis, confusion state, or violent behavior should be excluded. A clear and robust benefit from levodopa by history Use of lithium, methylene blue or other putative disease modifying drugs for PSP within 30 days of screening Any previous use of experimental therapy within 30 days or 5 half-lives prior to Day 1, whichever is greater Any condition that increases risk of meningitis unless participant is receiving appropriate prophylactic treatment History of post-lumbar-puncture headache of moderate or severe intensity and/or blood patch 11. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study 12. Unable to undergo magnetic resonance imaging (MRI) due to for example claustrophobia, or presents absolute contraindications to MRI (e.g., metallic implants, metallic foreign bodies, pacemaker, defibrillator) 13. Patients with other significant brain MRI abnormalities by history or at screening.
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
Boca Raton
State/Province
Florida
ZIP/Postal Code
33486
Country
United States
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37221
Country
United States
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H2X0A9
Country
Canada
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3A 2B4
Country
Canada
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Bonn
State/Province
North Rhine-Westphalia
ZIP/Postal Code
53127
Country
Germany
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Duesseldorf
ZIP/Postal Code
40225
Country
Germany
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Muenchen
ZIP/Postal Code
81377
Country
Germany
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Tuebingen
ZIP/Postal Code
72076
Country
Germany
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Southampton
ZIP/Postal Code
SO16 6YD
Country
United Kingdom
Individual Site Status
Completed

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Safety, Tolerability and Pharmacokinetics of Multiple Ascending Doses of NIO752 in Progressive Supranuclear Palsy

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