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.

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.

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/exclusion criteria may apply

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com