A Pharmacokinetics and Safety Study of BIIB132 in Adults With Spinocerebellar Ataxia 3

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety and tolerability of multiple ascending doses of BIIB132 administered via intrathecal (IT) injection to participants with spinocerebellar ataxia type 3 (SCA3). The secondary objective of this study is to characterize the multiple-dose pharmacokinetics (PK) of BIIB132 administered via IT injection to participants with SCA3.

Detailed Description
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BIIB132 is an investigational anti-sense oligonucleotide developed to target ataxin-3 (ATXN3) pre-messenger ribonucleic acid (pre-mRNA). Preclinical studies have shown that lowering of ATXN3 protein is associated with decreased progression of SCA3-like disease. This trial consists of a blinded 12 week study period with a 26 week follow up period to evaluate the safety and tolerability of intrathecal BIIB132 and to assess the effect on treatment response biomarkers in symptomatic SCA3 participants.

Official Title
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A Phase 1, Blinded, Randomized, Placebo-controlled Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Multiple Ascending Doses of BIIB132 Administered Intrathecally to Adults With Spinocerebellar Ataxia 3

Conditions
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Spinocerebellar Ataxia Type 3

Intervention / Treatment
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* Drug: BIIB132
* Drug: BIIB132-Matching Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of SCA3 with CAG repeats ≥60 in ATXN3 gene. Symptomatic ataxia with a screening Scale for Assessment and Rating of Ataxia (SARA) score 3 to 15 (still ambulatory) and a minimum SARA gait subscore of 1. Able to ambulate 8 m independently without any assistive device. Treatment naïve or on a stable dose of symptomatic therapy for a minimum of 4 weeks prior to screening. Key Exclusion Criteria: Unstable psychiatric illness or untreated major depression within 90 days before screening. History or screening magnetic resonance imaging (MRI) results show evidence of structural abnormalities that could contribute to the participant's clinical state other than findings typical of SCA3 or any finding that might pose a risk to the participant. MRI brain findings of prior cerebellar stroke or clinical stroke within 12 months before screening. History of brain surgery regardless of purpose. Any contraindications to undergoing brain MRI. History of, or ongoing, malignant disease, (with the exception of basal cell carcinomas and squamous cell carcinomas that have been completely excised and considered cured at least 12 months prior to screening). Participants with cancers in remission for longer than 5 years may be included. History of epilepsy or the occurrence of seizures within 3 years prior to screening. Evidence of untreated/unstable thyroid disease. Poorly controlled diabetes mellitus. History of alcohol or substance abuse within the past year prior to screening. Use of off-label drugs for ataxia within 4 weeks prior to screening. Prior enrollment in any interventional clinical study in which an investigational treatment or approved therapy for investigational use is administered within 5 half-lives or 3 months, whichever is longer, prior to the screening visit. Any antiplatelet [except for aspirin up to 100 milligrams per day (mg/day)] or anticoagulant medication that cannot be safely interrupted for an lumbar puncture (LP) procedure. Any contraindications to LP procedures. Participants who are pregnant or currently breastfeeding and those intending to become pregnant during the study. Prior enrollment in any interventional clinical study in which an investigational treatment or approved therapy for investigational use is administered within 3 months prior to screening visit. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: BIIB132 Dose 1 or Matching Placebo<br>Participants will be randomized to receive BIIB132 Dose 1 or matching placebo, intrathecally (IT), every 4 weeks (Q4W), up to Day 85. | Drug: BIIB132<br>* Administered as specified in the treatment arm<br>Drug: BIIB132-Matching Placebo<br>* Administered as specified in the treatment arm<br>|
| Experimental: Cohort 2: BIIB132 Dose 2 or Matching Placebo<br>Participants will be randomized to receive BIIB132 Dose 2 or matching placebo, IT, Q4W, up to Day 85. | Drug: BIIB132<br>* Administered as specified in the treatment arm<br>Drug: BIIB132-Matching Placebo<br>* Administered as specified in the treatment arm<br>|
| Experimental: Cohort 3: BIIB132 Dose 3 or Matching Placebo<br>Participants will be randomized to receive BIIB132 Dose 3 or matching placebo, IT, Q4W, up to Day 85. | Drug: BIIB132<br>* Administered as specified in the treatment arm<br>Drug: BIIB132-Matching Placebo<br>* Administered as specified in the treatment arm<br>|
| Experimental: Cohort 4: BIIB132 Dose 4 or Matching Placebo<br>Participants will be randomized to receive BIIB132 Dose 4 or matching placebo, IT, Q4W, up to Day 85. | Drug: BIIB132<br>* Administered as specified in the treatment arm<br>Drug: BIIB132-Matching Placebo<br>* Administered as specified in the treatment arm<br>|
| Experimental: Cohort 5: BIIB132 Dose 5 or Matching Placebo<br>Participants will be randomized to receive BIIB132 Dose 5 or matching placebo, IT, either Q4W or every 12 weeks (Q12W), up to Day 85 or every 8 weeks (Q8W) up to Day 57. | Drug: BIIB132<br>* Administered as specified in the treatment arm<br>Drug: BIIB132-Matching Placebo<br>* Administered as specified in the treatment arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events (AEs) | An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. | Day 1 to Day 267 | 
| Number of Participants with Serious Adverse Events (SAEs) | A serious adverse event (SAE) is any untoward medical occurrence that at any dose results in death, in the view of the investigator, places the participant at immediate risk of death (a-life threatening event), requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect or is a medically important event. | Screening to Day 267 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-Time Curve (AUC) of BIIB132 |  | Pre-dose and at multiple timepoints post-dose on Day 1 up to Day 85 | 
| Area Under the Concentration Versus Time Curve, from Time of Dosing (Time = 0) to Infinity (AUCinf) of BIIB132 |  | Pre-dose and at multiple timepoints post-dose on Day 1 up to Day 85 | 
| Area Under the Concentration Versus Time Curve, from Time of Dosing (Time = 0) to Time of the Last Measurable Effect (AUClast) of BIIB132 |  | Pre-dose and at multiple timepoints post-dose on Day 1 up to Day 85 | 
| Maximum Observed Concentration (Cmax) of BIIB132 |  | Pre-dose and at multiple timepoints post-dose on Day 1 up to Day 85 | 
| Time to Reach Maximum Observed Concentration (Tmax) of BIIB132 |  | Pre-dose and at multiple timepoints post-dose on Day 1 up to Day 85 | 
| Elimination Half-Life (t½) of BIIB132 |  | Pre-dose and at multiple timepoints post-dose on Day 1 up to Day 85 |