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

• ClinicalTrials.gov Identifier: NCT04539041
• Recruitment Status: Recruiting
• First Posted: September 4, 2020
• Last Update Posted: February 14, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

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.

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 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.

Study Design

• 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 10, 2024
• Estimated Study Completion Date: October 10, 2024

Arms and Interventions

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; 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

Outcome Measures

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 or 9-month treatment plus 3-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 or 9-month treatment plus 3-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 or 9-month treatment plus 3-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)

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

Contact: Novartis Pharmaceuticals; 1-888-669-6682; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +41613241111

Locations

United States, California

Novartis Investigative Site; Recruiting

La Jolla, California, United States, 92037

United States, Florida

Novartis Investigative Site; Withdrawn

Boca Raton, Florida, United States, 33486

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

Bonn, North Rhine-Westphalia, Germany, 53127

Novartis Investigative Site; Recruiting

Duesseldorf, Germany, 40225

Novartis Investigative Site; Recruiting

Hannover, Germany, 30625

Novartis Investigative Site; Recruiting

Tübingen, Germany, 72076

Novartis Investigative Site; Recruiting

Ulm, Germany, 89081

United Kingdom

Novartis Investigative Site; Recruiting

Southampton, United Kingdom, SO16 6YD

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04539041
• Other Study ID Numbers: CNIO752A02101
• First Posted: September 4, 2020
• Last Update Posted: February 14, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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; adult

Additional relevant MeSH terms:

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