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

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ClinicalTrials.gov Identifier: NCT04539041
Recruitment Status : Recruiting
First Posted : September 4, 2020
Last Update Posted : August 11, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
Progressive Supranuclear Palsy (PSP) Drug: antisense oligonucleotide Drug: placebo Phase 1

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 64 PSP participants in 6 cohorts will be randomized to receive NIO752 or placebo in a ratio of 3:1. Intrathecal ( IT ) injections of NIO752 or placebo will be given 4 times over 3 months. All participants will remain in this study for an additional 9 month follow-up period with 6 scheduled visits.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : February 16, 2021
Estimated Primary Completion Date : October 17, 2023
Estimated Study Completion Date : January 16, 2025


Arm Intervention/treatment
Experimental: Cohort A NIO752
4 injections of NIO752 at dose A
Drug: antisense oligonucleotide
solution of antisense oligonucleotide injected intrathecally (spine tap) at multiple dose levels
Other Name: NIO752

Experimental: Cohort B NIO752
4 injections of NIO752 at dose B
Drug: antisense oligonucleotide
solution of antisense oligonucleotide injected intrathecally (spine tap) at multiple dose levels
Other Name: NIO752

Placebo Comparator: Placebo
4 injections of placebo
Drug: placebo
matching placebo for each dose level

Experimental: Cohort C NIO752
4 injections of NIO752 at dose C
Drug: antisense oligonucleotide
solution of antisense oligonucleotide injected intrathecally (spine tap) at multiple dose levels
Other Name: NIO752

Experimental: Cohort D NIO752
4 injections of NIO752 at dose D
Drug: antisense oligonucleotide
solution of antisense oligonucleotide injected intrathecally (spine tap) at multiple dose levels
Other Name: NIO752

Experimental: Cohort E NIO752
4 injections of NIO752 at dose E
Drug: antisense oligonucleotide
solution of antisense oligonucleotide injected intrathecally (spine tap) at multiple dose levels
Other Name: NIO752

Experimental: Cohort F NIO752
4 injections of NIO752 at dose F
Drug: antisense oligonucleotide
solution of antisense oligonucleotide injected intrathecally (spine tap) at multiple dose levels
Other Name: NIO752




Primary Outcome Measures :
  1. Number of adverse events and serious adverse events [ Time Frame: Baseline up to approximately one year (3 month treatment plus 9 month follow-up) ]
    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

  2. Change in severity scores for Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline up to approximately 1 year (3 month treatment plus 9 month follow-up) ]
    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.

  3. Levels of infection indicators in Cerebrospinal fluid (CSF) [ Time Frame: Baseline up to approximately 1 year (3 month treatment plus 9 month follow-up) ]
    CSF safety labs measure levels of proteins, glucose, lactate and white blood cell counts with differential indicating infections.


Secondary Outcome Measures :
  1. Concentrations of NIO752 in blood 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 ]
    concentrations of NIO752 in plasma

  2. 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 ]
    concentrations of NIO752 in CSF

  3. Cmax, Ctrough in blood 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 ]
    Maximum and trough level concentrations of NIO752 in plasma

  4. Tmax in blood 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 ]
    Time of Cmax in plasma post first injection

  5. AUClast in blood plasma [ Time Frame: 0 to 24 hours after first injection ]
    Area under curve (AUC) from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1)

  6. AUCinf in blood plasma [ Time Frame: 0 to 24 hours after first injection ]
    The AUC from time zero to infinity (mass x time x volume-1)



Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


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): NCT04539041


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

Locations
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United States, Minnesota
Novartis Investigative Site Recruiting
Rochester, Minnesota, United States, 55905
United States, Tennessee
Novartis Investigative Site Recruiting
Nashville, Tennessee, United States, 37221
Canada, Quebec
Novartis Investigative Site Recruiting
Montreal, Quebec, Canada, H2X0A9
Novartis Investigative Site Recruiting
Montreal, Quebec, Canada, H3A 2B4
Germany
Novartis Investigative Site Recruiting
Duesseldorf, Germany, 40225
Novartis Investigative Site Recruiting
Hannover, Germany, 30625
Novartis Investigative Site Recruiting
Ulm, Germany, 89081
United Kingdom
Novartis Investigative Site Recruiting
Southampton, United Kingdom, SO16 6YD
Sponsors and Collaborators
Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04539041    
Other Study ID Numbers: CNIO752A02101
First Posted: September 4, 2020    Key Record Dates
Last Update Posted: August 11, 2021
Last Verified: August 2021

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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 ):
progressive supranuclear palsy
PSP
antisense oligonucleotide
ASO
tau
NIO752
Additional relevant MeSH terms:
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Paralysis
Supranuclear Palsy, Progressive
Neurologic Manifestations
Nervous System Diseases
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Movement Disorders
Ophthalmoplegia
Ocular Motility Disorders
Cranial Nerve Diseases
Tauopathies
Neurodegenerative Diseases
Eye Diseases