Clinical trial NCT04539041: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Progressive Supranuclear Palsy (PSP)
Keywords: progressive supranuclear palsy
PSP
antisense oligonucleotide
ASO
tau
NIO752
adult
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-09-04
Enrollment: 59
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Number of adverse events and serious adverse events
timeFrame: Baseline up to approximately one year (3-month treatment plus 9-month follow-up or 9-month treatment plus 3-month follow-up)
measure: Change in severity scores for Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: Baseline up to approximately 1 year (3-month treatment plus 9-month follow-up or 9-month treatment plus 3-month follow-up)
measure: Levels of infection indicators in Cerebrospinal fluid (CSF)
timeFrame: Baseline up to approximately 1 year (3-month treatment plus 9-month follow-up or 9-month treatment plus 3-month follow-up)
Secondary outcomes:
measure: Concentrations of NIO752 in blood plasma
timeFrame: 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
measure: Concentrations of NIO752 in CSF
timeFrame: 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
measure: Cmax, Ctrough in blood plasma
timeFrame: 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
measure: Tmax in blood plasma
timeFrame: 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
measure: AUClast in blood plasma
timeFrame: 0 to 24 hours after first injection
measure: AUCinf in blood plasma
timeFrame: 0 to 24 hours after first injection
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Nashville
country: United States
facility: Vanderbilt University Medical CenterX
state: Tennessee
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Bonn
country: Germany
facility: Novartis Investigative Site
state: North Rhine-Westphalia
city: Duesseldorf
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Tuebingen
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Southampton
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
References: