Niemann-Pick Type C Disease
Conditions
Keywords
Nizubaglustat
Brief summary
An 18-month double-blind, randomized, placebo-controlled, multicenter, Phase 3 study to evaluate the safety and efficacy of oral nizubaglustat (AZ-3102) in late-infantile and juvenile forms of Niemann-Pick type C disease
Detailed description
Please see NCT #07054515 for information on the AZA-001-301 Master Protocol PRIMARY OBJECTIVE The primary objective of this study is to demonstrate superior efficacy on ataxic manifestations with oral nizubaglustat dosing compared with placebo when administered over 18 months in participants with late-infantile and juvenile forms of NPC disease SECONDARY OBJECTIVES I. To assess additional efficacy in ataxic and non-ataxic manifestations comparing nizubaglustat dosing with placebo when administered over 18 months in participants with late-infantile and juvenile forms of NPC disease II. To assess the pharmacokinetic (PK) properties of nizubaglustat after administration of the first dose (Visit 1) and at steady state after multiple once daily doses III. To assess the pharmacodynamic (PD) effects of nizubaglustat IV. To assess the safety and tolerability of daily oral nizubaglustat dosing compared with placebo, when administered over 18 months in participants with late-infantile and juvenile forms of NPC disease
Interventions
DRUGNizubaglustat
AZ-3102
DRUGPlacebo
Matching placebo
Sponsors
Azafaros B.V.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent * Confirmed diagnosis of NPC disease * Patient is unable or unwilling to take miglustat, or is, in the opinion of the investigator, unsatisfactorily treated with miglustat * Male and female participants aged 4 years and older at the time of informed consent * Onset of neurological symptoms from 2 to 15 years * Disability level at Baseline: Ataxic disturbances with a total SARA score of ≥3 and ≤30 at Baseline * Female of childbearing potential who are sexually active willing to follow the contraceptive guidance * Male participants with a female partner of childbearing potential willing to follow the contraceptive guidance
Exclusion criteria
* A history of medical conditions other than NPC disease that, in the opinion of the Principal Investigator, would confound scientific rigor or the interpretation of results * Body weight of \<10 kg * The presence of another neurologic disease * The presence of moderate or severe hepatic impairment * The presence of moderate or severe renal impairment * Platelet count of \<100x10\^9/L * The dose of any anti-epileptic treatment(s) was not stable (required a change in dose within the previous 3 months) and/or a new anti-epileptic treatment (drug or procedure) was prescribed in the month before Baseline * Prior use of an investigational drug within the 3 months before Screening; or prior participation in a clinical study involving gene therapy or stem cell transplantation within 2 years prior to Screening * A positive serum pregnancy test (for women of childbearing potential) * Current treatment with miglustat, provided the patient has been using the recommended dose for most of the past 12 months AND is, in the opinion of the investigator, satisfactorily treated with miglustat. Any participants receiving miglustat are required to undergo a 1-month washout period before starting study medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in total Scale for the Assessment and Rating of Ataxia (SARA) score | Baseline to month 18 | Total SARA comprises eight categories with a cumulative score ranging from 0 (no ataxia) to 40 (most severe ataxia) |
| Change from baseline in functional SARA score | Baseline to month 18 | Functional SARA uses an abbreviated scale that scores 0 to 16, with higher scores indicating more severe impairment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in SARA score for gait/posture | Baseline to months 6, 12, and 18 | Assessed on a 9-point scale with higher scores indicating inability to complete the task |
| Change from baseline in SARA score for speech | Baseline to months 6, 12, and 18 | Assessed on a 7-point scale with higher scores indicating unintelligible speech/anarthria |
| Change from baseline in SARA score for kinetics | Baseline to months 6, 12, and 18 | Assessed on a 5-point scale with higher scores indicating more severe impairment |
| Change from baseline in Vineland Adaptive Behavior Scale (VABS) | Baseline to months 6, 12, and 18 | Assesses four domains of function: communication, daily living skills, socialization, and motor skills |
| Change from baseline in Penetration-Aspiration Scale (PAS) | Baseline to months 6, 12, and 18 | Assessed on an 8-point ordinal scale, with 1 representing the lowest and 8 the highest/most severe score |
| Change from baseline in 9-Hole Peg Test (9-HPT-D) | Baseline to months 6, 12, and 18 | Assessed by the number of pegs per second placed in a 50-second, 9-HPT using the dominant hand |
| Change from baseline in NPC-Clinical Severity Scale (NPC-CSS) | Baseline to months 6, 12, and 18 | Scores can range from 0 to 61, with a higher score indicating more severe clinical impairment |
| Change from baseline in Goal Attainment scale (GAS) | Baseline to months 6, 12, and 18 | Assesses individual goals achieved during the study |
| Change from baseline in Clinician Global Impression of Change (CGI-C) | Baseline to months 6, 12, and 18 | Assessed on a 7-point scale with higher scores indicating lower improvement |
| Change from baseline in Participant/Caregiver Global Impression of Change (PGI-C) | Baseline to months 6, 12, and 18 | Assessed on a 7-point scale with higher scores indicating lower improvement |
| Change from baseline in Seizure frequency and duration, as per the seizure diary | Baseline to months 6, 12, and 18 | — |
| Time-to-event comparison between nizubaglustat and placebo over the study duration for pre-defined detrimental events of an increase in total SARA score of ≥2 points | Baseline to month 18 | — |
| Time-to-event comparison between nizubaglustat and placebo over the study duration for pre-defined detrimental events of an increase in functional SARA of ≥1.5 points | Baseline to month 18 | — |
| Time-to-event comparison between nizubaglustat and placebo over the study duration for pre-defined detrimental events of a decrease in PAS of ≥1 point | Baseline to month 18 | — |
| Time-to-event comparison between nizubaglustat and placebo over the study duration for pre-defined detrimental events of participants leaving the study due to participant/caregiver perception of disease progression/lack of efficacy | Baseline to month 18 | — |
| Maximum observed plasma concentration (Cmax) | Baseline and months 1,18, and 21 | — |
| Time to Cmax (Tmax) | Baseline and months 1,18, and 21 | — |
| Plasma trough concentration (Ctrough) | Baseline and month 1 | — |
| Area under the plasma concentration-time curve from time of dosing (zero) to 24 hours post-dose (AUC0-24) at baseline | Baseline (Day 1) | — |
| Accumulation ratio for Cmax | Baseline and months 1,18, and 21 | — |
| Change from baseline in plasma concentration of glucosylceramide (GlcCer) C16:0; C18:0 | Baseline and months 1, 6, 12, and 18 | — |
Countries
Argentina, Australia, Brazil, Canada, Germany, India, Italy, Mexico, Pakistan, Portugal, Spain, Switzerland, Turkey (Türkiye), United Kingdom, United States
Contacts
CONTACTPatient Advocacy Representative
CONTACTContact for Healthcare Professionals
Outcome results
None listed