Progressive Supranuclear Palsy Richardson Syndrome (PSP-RS)
Conditions
Keywords
Progressive Supranuclear Palsy (PSP), NIO752, Anti-Sense Oligonucleotide (ASO), Microtubule Associated Protein Tau (MAPT)
Brief summary
This Phase III study is intended to evaluate the efficacy and safety of NIO752 in participants with Progressive Supranuclear Palsy (PSP). Eligible participants will be randomized to receive either NIO752 or placebo followed by an open-label extension.
Detailed description
This is a randomized, double-blind, placebo-controlled, parallel group, study to evaluate the efficacy of NIO752 in participants with Progressive Supranuclear Palsy followed by an open-label extension (OLE). The participants with or without symptomatic therapy will be randomly allocated to either NIO752 or placebo treatment in a 2:1 randomization ratio. Upon completion of the core double-blind treatment period, participants will be offered to continue with NIO752 treatment in the OLE.
Interventions
OTHERNIO752
Solution of antisense oligonucleotide.
DRUGPlacebo
Placebo solution
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
41 Years to 81 Years
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent must be obtained prior to participation in the study. 2. Male or female participants, age between 41-81 yrs inclusive. 3. Diagnosis of mild-moderate, probable/possible PSP Richardson syndrome as per MDS-PSP 2017 criteria with symptoms onset \< 5 years. 4. PSPRS total score less than 40 at Baseline. 5. Reliable study partner such as spouse, sibling, close friend, or caregiver able and willing to provide accurate information (including clinical symptoms and medical history) about the participant and to participate in study visits and informant-based assessments for the duration of the study. A reliable study partner is expected to spend enough time (at least 5 hours per week) with the study participant. 6. Participant is able to ambulate defined as the ability to take at least 10 steps independently or with minimal assistance (stabilization of one arm to minimize fall risk). 7. Mini Mental State Examination (MMSE) score ≥ 20 at Screening.
Exclusion criteria
1. Diagnosis of other significant neurological or psychiatric disorders including (but not limited to) Parkinsons' Disease (which has not subsequently been revised to a diagnosis of PSP); Alzheimer's disease (AD), dementia with Lewy bodies; prion disease; any psychotic disorders; severe Major depressive disorder; seizure; brain tumor or other space-occupying lesion; history of clinically significant stroke (e.g., stroke with permanent neurological deficit); history of head injury with loss of consciousness for at least 15 minutes within the past 20 years. 2. Diagnosis of amyotrophic lateral sclerosis or other motor neuron diseases. 3. Diagnosis of cerebellar ataxia, choreoathetosis, and early symptomatic autonomic dysfunction. 4. History of or screening brain MRI scan indicative of significant abnormality, including, but not limited to, prior hemorrhage or infarct \>1 cm3, \>3 lacunar infarcts, cerebral contusion, aneurysm, vascular malformation \>1 cm3, subdural hematoma, hydrocephalus, and space-occupying lesion (e.g., abscess or brain tumor). 5. Contraindications to undergo MRI procedure, including metal (ferromagnetic) implants and/or a cardiac pacemaker that is not compatible with MRI. 6. Medical conditions that would, as per Investigator's judgement, prevent the participant from undergoing lumbar puncture, including but not limited to: 1. Known allergy to local anesthetic 2. History of back surgery (with the exception of microdiscectomy or laminectomy over 1 level) 3. Spinal deformities 4. Current dermatological infection at the lumbar puncture spot and/or significant skin alterations at the planned puncture place 5. Risk of increased or uncontrolled bleeding and/or risk of bleeding that if not managed optimally, could place a participant at an increased risk for procedural bleeding. These could include, but are not limited, to anatomical factors at or near the LP site (e.g., vascular abnormalities, neoplasms) and underlying disorders of coagulation, platelet function or platelet count (e.g. abnormal coagulation parameters, hemophilia, Von Willebrand's disease, liver disease). 7. History of deep brain stimulator surgery other than sham surgery for participation in a deep brain stimulation clinical trial. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in the mPSPRS-10 score | Baseline, Week 72 | The 10-item Progressive Supranuclear Palsy Rating Scale (mPSPRS-10) is a modified version of the original 28 item PSPRS developed to improve clinical meaningfulness and statistical performance. The 10 items measure three key motor domains: gait, limb function, and bulbar. The mPSPRS-10 ranges between 0 and 30, with higher scores indicating greater disability. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in the PSPRS-28 items score | Baseline, Week 72 | 28-item Progressive Supranuclear Palsy Rating Scale (PSPRS-28) , scale ranges between 0 and 100 with higher scores indicating greater disability. |
| Changes from baseline in activities of daily living on the Cortical Basal ganglia Functional Scale (CBFS) | From baseline up to week 72 | The CBFS is a patient/study partner reported rating scale designed to evaluate the functional impact of 4 repeat tauopathies (4RTs), including PSP. The level of disability assessed by the CBFS correlates with motor, cognitive and psychiatric impairments. The CBFS consists of 14 questions on Motor experiences in daily living (EDL's) and 17 questions on non-Motor EDL's, each rated on a Likert 5-point scale that goes from 0 (Normal/No problems) to 4 (Severe problems). |
| Change from baseline on the PSP-ShoQoL | From baseline up to week 72 | The Progressive Supranuclear Palsy - Short version Quality of Life (PSP-ShoQoL) is a patient reported outcome that comprises 12 items, covering phyisical (7 items) and mental health (5 items) states. Items are scored from 0 (no problem) to 4 (extreme problems), total score ranges from 0 to 48 with higher scores indicating greater impact of the disease on the quality of life. |
| Change from baseline in Category (or Semantic) Fluency test over time | From baseline up to week 72 | The Category Fluency test is a measure of semantic retrieval and executive functions. It requires the study participant to name as many objects as possible belonging to a given category within one minute. The total score is given by the number of correct words generated within the time limit. |
| Change from baseline in Letter (or Phonemic) Fluency test over time | From baseline up to week 72 | The Letter Fluency test is a measure of language and executive functions. It requires the study participant to name as many words as possible starting with a certain letter within one minute. The total score is given by the number of correct words generated within the time limit. |
| Change from baseline in Symbol Digit Modality Test (SDMT) over time | From baseline up to week 72 | The SDMT is a measure of attention and processing speed. It requires the study participant to orally pair specific numbers with symbols as quickly and as accurately as possible using a reference key. |
| Change from baseline in Letter-Number Sequencing task (LNS) over time | From baseline up to week 72 | The LNS is a sub-test of the Weschler Adult Intelligence Scale - Fourth Edition (WAIS-IV) and it is a measure of working memory and executive function. The study participant is read a sequence of numbers and letters and is required to recall the numbers in ascending order followed by the letters in alphabetical order. |
| Ratio to baseline of NfL (CSF) | From baseline up to week 72 | Neurofilament light chain (NfL) is a specific marker of neuroaxonal damage. NfL in CSF will be used to assess the effect of NIO752 on neurodegeneration. |
| Ratio to baseline of CSF phospho-Tau-181 and CSF Total-Tau | From baseline up to week 72 | Ratio to baseline in Total -Tau and Phospho-Tau-181 will be used as measures of target engagement |
| Changes from baseline in volumes of brain structures as measured by MRI | From baseline up to week 72 | MRI measured volumes will be collected for ventricles, whole brain, midbrain, pons, superior cerebellar peduncle, third ventricle and frontal lobe |
| Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first treatment administration up to 72 weeks | Incidence and severity of AEs and SAEs by treatment group, including clinical laboratory evaluations, vital signs, ECG, C-SSRS qualifying and reported as AEs. |
Countries
Australia, China, France, Germany, Italy, Japan, Netherlands, South Korea, Spain, United States
Contacts
CONTACTNovartis Pharmaceuticals
Outcome results
None listed