Niemann-Pick Disease, Type C
Conditions
Keywords
Niemann-Pick Type C1 (NPC1) Disease, neurologic disease, gross motor dysfunction, fine motor dysfunction, dysphagia, swallowing problems, cognitive dysfunction, gait abnormalities, pediatrics
Brief summary
Due to different study designs, the sponsor separated Part C into a separate registration (NCT04958642), leaving Parts A/B here in NCT02534844. This study is to find out how safe and effective VTS-270 is for patients with Niemann-Pick Type C1 (NPC1) disease who have neurologic symptoms (listed under Keywords). In Parts A/B, two out of every three patients will receive the study drug. The third patient will receive 1 to 2 small needle pricks at the location where the LP and IT injection is normally made (sham control). In Part C, all participants will receive study drug, as described in the Part C registration record. Start date for this record is the first day a participant was enrolled in Parts A/B. The trial is actually continuing until the last primary outcome measure of safety data are collected from Part C participants. The last primary outcome measure of safety, along with final adverse events results will be posted in the separate Part C registration record.
Detailed description
Non-clinical studies and a Phase 1 clinical trial suggest that intrathecal administration of VTS-270 in patients with neurologic manifestations of Niemann-Pick Type C1 (NPC1) disease has the potential to slow the rate of progression of their neurologic disease. Niemann-Pick Type C1 (NPC1) disease is a rare, neurodegenerative, inherited, autosomal recessive lysosomal lipid storage disorder primarily in children and teenagers. The disease is characterized by the inability to properly metabolize cholesterol and other lipids within the cell due to mutations in the NPC1 gene, causing unesterified cholesterol to accumulate in the brain, liver and spleen. This study plans to enroll about 51 participants with NPC1 disease. It will be conducted in three parts: Parts A, B, and C. * Part A will evaluate 3 different dose levels of VTS-270 in 12 participants to determine the dose level for Parts B and C. * In Part B, 39 more participants will join the original 12 to evaluate the safety and effectiveness of the dose selected from Part A compared to sham control. * Part C will be an open-label extension phase of the study for Part B participants who either complete Part B or have met rescue therapy criteria, as well as participants entering Part C from other trials. Participants in Part C will receive treatment with VTS-270 until the product is licensed or the program is terminated (anticipated within 5 years). Final results will be posted in the Part C registration record (NCT04958642).
Interventions
DRUGParts A/B: Adrabetadex
900 - 1800 milligram (mg) of adrabetadex administered every 2 weeks via lumbar intrathecal infusion
OTHERParts A/B: Sham Control
No experimental drug is administered to participants - intrathecal administrations are simulated by skin prick
Sponsors
Mandos LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Caregiver, Investigator)
Masking description
While it is a double-blind trial, the participant and outcomes assessor will be blinded, as well as the Care Provider and Investigator.
Intervention model description
In Parts A/B (see other registration for Part C description)
Eligibility
Sex/Gender
ALL
Age
4 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: Parts A/B: 1. Had onset of neurological symptoms prior to 15 years of age 2. Has confirmed diagnosis of NPC1 determined by either: 1. two NPC1 mutations 2. positive filipin staining and at least one NPC1 mutation 3. vertical supranuclear gaze palsy (VSNGP) in combination with either: one NPC1 mutation, OR positive filipin staining or oxysterol levels consistent with NPC disease and no Niemann-Pick Type C2 (NPC2) Disease mutations 3. Adult participant or parent/guardian has provided written informed consent, with assent collected from minors of appropriate age 4. Is able to undergo a lumbar puncture (LP) and IT drug administration under conscious sedation or general anesthesia 5. Has an NPC Clinical Severity Scale Score of 1 through 4, inclusive, in two or more of the following components: ambulation, fine motor skills, or swallowing; and has a score of 0 through 4 on the cognition component 6. Has a total NPC Clinical Severity Scale Score of 10 or greater 7. If taking miglustat, must have been on a stable dose for past 6-8 weeks and be willing to remain on a stable dose 8. If participant has seizures, they have been adequately controlled for 3 months without changing dose or regimen 9. Has agreed to discontinue all non-prescription supplements at least 1 month prior to first dose (Study Day 0) 10. Has agreed to discontinue any other investigational treatments for NPC including vorinostat or arimoclomol at least 3 months prior to first dose (Study Day 0) 11. If of child-bearing potential (not surgically sterile), agrees to use a medically acceptable method continuously, until at least 30 days after participation in the study Key
Exclusion criteria
1. Has
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Parts A/B: Change From Baseline to Week 52 in 4-Item Composite Score of Niemann Pick Type C Severity Scale (NPC-SS) Score | Baseline, Week 52 | The NPC-SS composite score is the sum of the ambulation, cognition, fine motor, and swallowing domains of the NPC-SS. Each of the four NPC-SS components (ambulation, cognition, fine motor, and swallowing) are rated on a scale from 0 (better) to 5 (worse). The total score was the sum of individual components scores which ranges from 0 (best) to 20 (worst), with higher scores indicating more severe clinical impairment. |
| Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Week 52 | The Clinician CGIC is a 7-point Likert scale. The scale requires assessment of change from a baseline level of disease activity, with anchors ranging from markedly improved, moderately improved, and minimally improved to no change and corresponding worsening (minimally, moderately, markedly). The Investigator rates his/her impression of the change in each participant's condition at week 52 on a scale from marked improvement (1) to marked worsening (7). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parts A/B: Number of Participants Classified as Responders on NPC-SS Total Score (Excluding Hearing and ABR) at Week 52 | Week 52 | The NPC-SS total score is based on 9 domains including ambulation, fine motor skills, cognition, swallowing, memory, speech, eye movement, hearing (sensorineural) and seizures. The hearing domain and ABR modifiers are removed from the total NPC-SS total score for this measure. A Likert-like scale is used to assign the remaining 8 major domain scores of 0 to 5 (better to worse). The total score was the sum of individual components scores which ranges from 0 (best) to 40 (worst), with higher scores indicating more severe clinical impairment. Responders on NPC-SS Total Score are defined as participants with no change or improvement on NPC-SS total score from baseline to Week 52. |
| Parts A/B: EQ-5D-3L Questionnaire Visual Analog Scale (VAS) Score (for Health Status) at Baseline and at Week 52 | Baseline, Week 52 | The EQ-5D-3L assessment is a self-reported, simple, descriptive system measuring 5 dimensions including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. A vertical VAS allows the participants to indicate their health state that day, and ranges from 0 (worst imaginable) to 100 (best imaginable), with higher scores indicating better health state. |
| Parts A/B: Number of Participants Treated for at Least 6 Months Who Qualified for the Rescue Option | Baseline up to Week 26 | Participants who manifested significant disease progression according to predefined clinical criteria after treatment of 26 weeks or more had the option to rescue. Number of participants who qualified for the rescue option following a minimum of 26 weeks of treatment were analyzed. |
| Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Baseline, Week 52 | The NPC-SS total score is based on 9 domains including ambulation, fine motor skills, cognition, swallowing, memory, speech, eye movement, hearing (sensorineural) and seizures. A Likert-like scale is used to assign to each domain score of 0 to 5 (better to worse) with higher scores indicating more severe clinical impairment. |
| Parts A/B: Change From Baseline to Week 52 in the Total NPC-SS (With Hearing Domain and ABR Modifier Included) | Baseline, Week 52 | The NPC-SS total score is based on 9 domains including ambulation, fine motor skills, cognition, swallowing, memory, speech, eye movement, hearing (sensorineural) and seizures. A Likert-like scale is used to assign to each domain score of 0 to 5 (better to worse). The total score was the sum of individual components scores which ranges from 0 (best) to 45 (worst), with higher scores indicating more severe clinical impairment. |
| Parts A/B: Change From Baseline to Week 52 in NPC-SS Total Score (Excluding Hearing and Auditory Brainstem Response [ABR]) | Baseline, Week 52 | The NPC-SS total score is based on 9 domains including ambulation, fine motor skills, cognition, swallowing, memory, speech, eye movement, hearing (sensorineural) and seizures. The hearing domain and auditory brainstem response modifiers are removed from the total NPC-SS total score for this measure. A Likert-like scale is used to assign the remaining 8 major domain scores of 0 to 5 (better to worse). The total score was the sum of individual component scores which ranges from 0 (best) to 40 (worst), with higher scores indicating more severe clinical impairment. |
| Parts A/B: Change From Baseline in the Timed Up and Go (TUG) Test at Week 52 | Baseline, Week 52 | The TUG is a test of balance and risk for falls. This test measures the time taken by a participant to walk 3 meters starting from a sitting position and it ends when the participant is seated again. |
| Parts A/B: Change From Baseline in the 9-Hole Peg Test at Week 52 | Baseline, Week 52 | The 9-Hole Peg Test is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. |
| Parts A/B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Baseline up to Week 52 | A TEAE is defined as an adverse event (AE) with onset on or after start of study Drug. An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
| Parts A/B: Change From Baseline to Week 52 in Mean Annualized Rate of Change (Slope) of NPC-SS Composite Score | Baseline, Week 52 | The NPC-SS composite score is the sum of the ambulation, cognition, fine motor, and swallowing domains of the NPC-SS. Each of the four NPC-SS components (ambulation, cognition, fine motor, and swallowing) are rated on a scale from 0 (better) to 5 (worse). The total score was the sum of individual components scores which ranges from 0 (best) to 20 (worst), with higher scores indicating more severe clinical impairment. The Annualized rate of change (Slope) is calculated as 365.25 \*(\[measurement at post-baseline visit - measurement at baseline\]/\[date of post-baseline visit - date of baseline visit + 1\]). |
| Parts A/B: Time to One Point Increase (Worsening) in NPC-SS Composite Score | Baseline up to Week 52 | The NPC-SS composite score is the sum of the ambulation, cognition, fine motor, and swallowing domains of the NPC-SS. Each of the four NPC-SS components (ambulation, cognition, fine motor, and swallowing) are rated on a scale from 0 (better) to 5 (worse). The total score was the sum of individual components scores which ranges from 0 (best) to 20 (worst), with higher scores indicating more severe clinical impairment. The product-limit survival analysis method is used to estimate the time to one point increase (worsening) in NPC-SS composite score. Time to worsening in NPC-SS Composite Score defined as the interval from study drug administration to a one point increase in the NPC-SS composite score. If a subject discontinued from the study prior to Week 52, then the subject was censored at time of discontinuation. If a subject completed the Week 52 visit, then the subject was censored at the time of last study visit. |
| Parts A/ B: Number of Participants Classified as CGIC Responders at Week 52 | Week 52 | The Clinician CGIC is a 7-point Likert scale. The scale requires assessment of change from a baseline level of disease activity, with anchors ranging from markedly improved, moderately improved, and minimally improved to no change and corresponding worsening (minimally, moderately, markedly). The Investigator rates his/her impression of the change in each participant's condition at week 52 on a scale from marked improvement (1) to marked worsening (7). CGIC Responders are defined as participants who received the caregiver's rating of no change, minimally improved, moderately improved, or markedly improved from baseline to Week 52. |
Countries
Australia, France, Germany, New Zealand, Singapore, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sham Control Participants received sham control procedures once every 2 weeks for a total of 52 weeks. | 18 |
| Adrabetadex Participants received lumbar IT infusions of adrabetadex once every 2 weeks for a total of 52 weeks. | 38 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part B | Withdrawal by Subject | 0 | 0 | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Adrabetadex | Total | Sham Control |
|---|---|---|---|
| Age, Continuous | 12.7 years STANDARD_DEVIATION 5.64 | 12.4 years STANDARD_DEVIATION 5.45 | 11.7 years STANDARD_DEVIATION 5.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 46 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 31 Participants | 47 Participants | 16 Participants |
| Sex: Female, Male Female | 16 Participants | 26 Participants | 10 Participants |
| Sex: Female, Male Male | 22 Participants | 30 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 1 / 3 | 0 / 3 | 0 / 29 | 1 / 15 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 28 / 29 | 14 / 15 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 | 2 / 3 | 0 / 3 | 16 / 29 | 3 / 15 |
Outcome results
Primary
Parts A/B: Change From Baseline to Week 52 in 4-Item Composite Score of Niemann Pick Type C Severity Scale (NPC-SS) Score
The NPC-SS composite score is the sum of the ambulation, cognition, fine motor, and swallowing domains of the NPC-SS. Each of the four NPC-SS components (ambulation, cognition, fine motor, and swallowing) are rated on a scale from 0 (better) to 5 (worse). The total score was the sum of individual components scores which ranges from 0 (best) to 20 (worst), with higher scores indicating more severe clinical impairment.
Time frame: Baseline, Week 52
Population: Modified intent-to-treat (mITT) population included all randomized participants who received at least one treatment (sham or adrabetadex). As per planned analysis, efficacy data were collected and presented by overall randomized treatment assignment (either sham or adrabetadex). These two treatment arms (either sham or adrabetadex) combine data from Parts A and B of the study. Here, number analyzed = participants evaluable at specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Control | Parts A/B: Change From Baseline to Week 52 in 4-Item Composite Score of Niemann Pick Type C Severity Scale (NPC-SS) Score | Baseline | 8.1 score on a scale | Standard Deviation 4.27 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in 4-Item Composite Score of Niemann Pick Type C Severity Scale (NPC-SS) Score | Change from Baseline at Week 52 | -0.1 score on a scale | Standard Deviation 1.55 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in 4-Item Composite Score of Niemann Pick Type C Severity Scale (NPC-SS) Score | Baseline | 8.8 score on a scale | Standard Deviation 3.12 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in 4-Item Composite Score of Niemann Pick Type C Severity Scale (NPC-SS) Score | Change from Baseline at Week 52 | 0.0 score on a scale | Standard Deviation 2.45 |
Primary
Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52
The Clinician CGIC is a 7-point Likert scale. The scale requires assessment of change from a baseline level of disease activity, with anchors ranging from markedly improved, moderately improved, and minimally improved to no change and corresponding worsening (minimally, moderately, markedly). The Investigator rates his/her impression of the change in each participant's condition at week 52 on a scale from marked improvement (1) to marked worsening (7).
Time frame: Week 52
Population: mITT population included all randomized participants who received at least one treatment (sham or adrabetadex). As per planned analysis, efficacy data were collected and presented by overall randomized treatment assignment (either sham or adrabetadex). These two treatment arms (either sham or adrabetadex) combine data from Parts A and B of the study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sham Control | Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Markedly worse (7) | 0 Participants |
| Sham Control | Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Markedly improved (1) | 0 Participants |
| Sham Control | Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Moderately improved (2) | 1 Participants |
| Sham Control | Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Minimally improved (3) | 4 Participants |
| Sham Control | Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Unchanged (4) | 9 Participants |
| Sham Control | Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Minimally worse (5) | 2 Participants |
| Sham Control | Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Moderately worse (6) | 2 Participants |
| Adrabetadex | Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Moderately improved (2) | 5 Participants |
| Adrabetadex | Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Markedly worse (7) | 1 Participants |
| Adrabetadex | Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Unchanged (4) | 16 Participants |
| Adrabetadex | Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Markedly improved (1) | 0 Participants |
| Adrabetadex | Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Moderately worse (6) | 1 Participants |
| Adrabetadex | Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Minimally worse (5) | 6 Participants |
| Adrabetadex | Parts A/B: Number of Participants Classified With Each Score on the Clinician Global Impression of Change (CGIC) at Week 52 | Minimally improved (3) | 9 Participants |
Secondary
Parts A/B: Change From Baseline in the 9-Hole Peg Test at Week 52
The 9-Hole Peg Test is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded.
Time frame: Baseline, Week 52
Population: mITT population included all randomized participants who received at least one treatment (sham or adrabetadex). As per planned analysis, efficacy data were collected and presented by overall randomized treatment assignment (either sham or adrabetadex). These two treatment arms (either sham or adrabetadex) combine data from Parts A and B of the study. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sham Control | Parts A/B: Change From Baseline in the 9-Hole Peg Test at Week 52 | -1.49 seconds | Standard Deviation 15.958 |
| Adrabetadex | Parts A/B: Change From Baseline in the 9-Hole Peg Test at Week 52 | -1.79 seconds | Standard Deviation 34.76 |
Secondary
Parts A/B: Change From Baseline in the Timed Up and Go (TUG) Test at Week 52
The TUG is a test of balance and risk for falls. This test measures the time taken by a participant to walk 3 meters starting from a sitting position and it ends when the participant is seated again.
Time frame: Baseline, Week 52
Population: mITT population included all randomized participants who received at least one treatment. As per planned analysis, efficacy data were collected and presented by overall randomized treatment assignment (either sham or adrabetadex). These two treatment arms (either sham or adrabetadex) combine data from Parts A and B of the study. Here, overall number of participants analyzed = participants evaluable for this outcome measure, and number analyzed = participants evaluable at specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Control | Parts A/B: Change From Baseline in the Timed Up and Go (TUG) Test at Week 52 | Baseline | 18.04 seconds | Standard Deviation 19 |
| Sham Control | Parts A/B: Change From Baseline in the Timed Up and Go (TUG) Test at Week 52 | Change from Baseline at Week 52 | 0.86 seconds | Standard Deviation 19.232 |
| Adrabetadex | Parts A/B: Change From Baseline in the Timed Up and Go (TUG) Test at Week 52 | Baseline | 16.40 seconds | Standard Deviation 13.218 |
| Adrabetadex | Parts A/B: Change From Baseline in the Timed Up and Go (TUG) Test at Week 52 | Change from Baseline at Week 52 | 2.70 seconds | Standard Deviation 9.633 |
Secondary
Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS
The NPC-SS total score is based on 9 domains including ambulation, fine motor skills, cognition, swallowing, memory, speech, eye movement, hearing (sensorineural) and seizures. A Likert-like scale is used to assign to each domain score of 0 to 5 (better to worse) with higher scores indicating more severe clinical impairment.
Time frame: Baseline, Week 52
Population: mITT population included all randomized participants who received at least one treatment (sham or adrabetadex). As per planned analysis, efficacy data were collected and presented by overall randomized treatment assignment (either sham or adrabetadex). These two treatment arms (either sham or adrabetadex) combine data from Parts A and B of the study. Here, Number analyzed = participants evaluable at specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Fine Motor (Baseline) | 2.06 score on a scale | Standard Deviation 1.349 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Fine Motor (Change from Baseline at Week 52) | 0.07 score on a scale | Standard Deviation 0.917 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Cognition (Baseline) | 2.56 score on a scale | Standard Deviation 1.199 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Cognition (Change from Baseline at Week 52) | -0.14 score on a scale | Standard Deviation 0.663 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Swallowing (Baseline) | 1.67 score on a scale | Standard Deviation 1.495 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Swallowing (Change from Baseline at Week 52) | 0.00 score on a scale | Standard Deviation 1.109 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Memory (Baseline) | 1.56 score on a scale | Standard Deviation 1.294 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Memory (Change from Baseline at Week 52) | 0.00 score on a scale | Standard Deviation 0.784 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Hearing (Baseline) | 0.94 score on a scale | Standard Deviation 0.998 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Hearing (Change from Baseline at Week 52) | -0.22 score on a scale | Standard Deviation 1.302 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Seizures (Baseline) | 1.00 score on a scale | Standard Deviation 1.572 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Seizures (Change from Baseline at Week 52) | -0.50 score on a scale | Standard Deviation 1.286 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Ambulation (Baseline) | 1.83 score on a scale | Standard Deviation 1.15 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Ambulation (Change from Baseline at Week 52) | 0.00 score on a scale | Standard Deviation 0.679 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Speech (Baseline) | 1.17 score on a scale | Standard Deviation 0.707 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Speech (Change from Baseline at Week 52) | 0.14 score on a scale | Standard Deviation 0.663 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Eye Movement (Baseline) | 2.11 score on a scale | Standard Deviation 0.471 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Eye Movement (Change from Baseline at Week 52) | 0.00 score on a scale | Standard Deviation 0.679 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Memory (Baseline) | 1.63 score on a scale | Standard Deviation 1.051 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Fine Motor (Baseline) | 2.16 score on a scale | Standard Deviation 1.128 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Hearing (Change from Baseline at Week 52) | 1.14 score on a scale | Standard Deviation 1.236 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Fine Motor (Change from Baseline at Week 52) | 0.24 score on a scale | Standard Deviation 1.103 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Seizures (Baseline) | 1.13 score on a scale | Standard Deviation 1.63 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Cognition (Baseline) | 2.58 score on a scale | Standard Deviation 1.222 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Speech (Baseline) | 1.42 score on a scale | Standard Deviation 0.722 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Cognition (Change from Baseline at Week 52) | 0.06 score on a scale | Standard Deviation 0.919 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Seizures (Change from Baseline at Week 52) | -0.06 score on a scale | Standard Deviation 0.952 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Swallowing (Baseline) | 1.79 score on a scale | Standard Deviation 1.398 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Eye Movement (Baseline) | 1.92 score on a scale | Standard Deviation 0.428 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Swallowing (Change from Baseline at Week 52) | -0.29 score on a scale | Standard Deviation 1.36 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Ambulation (Baseline) | 2.21 score on a scale | Standard Deviation 1.298 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Speech (Change from Baseline at Week 52) | -0.18 score on a scale | Standard Deviation 0.673 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Memory (Change from Baseline at Week 52) | 0.18 score on a scale | Standard Deviation 1.218 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Eye Movement (Change from Baseline at Week 52) | -0.06 score on a scale | Standard Deviation 0.547 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Ambulation (Change from Baseline at Week 52) | 0.06 score on a scale | Standard Deviation 1.434 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Each of the 9 Clinical Domains of the NPC-SS | Hearing (Baseline) | 0.94 score on a scale | Standard Deviation 1.145 |
Secondary
Parts A/B: Change From Baseline to Week 52 in Mean Annualized Rate of Change (Slope) of NPC-SS Composite Score
The NPC-SS composite score is the sum of the ambulation, cognition, fine motor, and swallowing domains of the NPC-SS. Each of the four NPC-SS components (ambulation, cognition, fine motor, and swallowing) are rated on a scale from 0 (better) to 5 (worse). The total score was the sum of individual components scores which ranges from 0 (best) to 20 (worst), with higher scores indicating more severe clinical impairment. The Annualized rate of change (Slope) is calculated as 365.25 \*(\[measurement at post-baseline visit - measurement at baseline\]/\[date of post-baseline visit - date of baseline visit + 1\]).
Time frame: Baseline, Week 52
Population: mITT population included all randomized participants who received at least one treatment (sham or adrabetadex). As per planned analysis, efficacy data were collected and presented by overall randomized treatment assignment (either sham or adrabetadex). These two treatment arms (either sham or adrabetadex) combine data from Parts A and B of the study. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sham Control | Parts A/B: Change From Baseline to Week 52 in Mean Annualized Rate of Change (Slope) of NPC-SS Composite Score | -0.05 score on NPC-SS scale/year | Standard Deviation 1.64 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in Mean Annualized Rate of Change (Slope) of NPC-SS Composite Score | 0.08 score on NPC-SS scale/year | Standard Deviation 2.441 |
Secondary
Parts A/B: Change From Baseline to Week 52 in NPC-SS Total Score (Excluding Hearing and Auditory Brainstem Response [ABR])
The NPC-SS total score is based on 9 domains including ambulation, fine motor skills, cognition, swallowing, memory, speech, eye movement, hearing (sensorineural) and seizures. The hearing domain and auditory brainstem response modifiers are removed from the total NPC-SS total score for this measure. A Likert-like scale is used to assign the remaining 8 major domain scores of 0 to 5 (better to worse). The total score was the sum of individual component scores which ranges from 0 (best) to 40 (worst), with higher scores indicating more severe clinical impairment.
Time frame: Baseline, Week 52
Population: mITT population included all randomized participants who received at least one treatment. As per planned analysis, efficacy data were collected and presented by overall randomized treatment assignment (either sham or adrabetadex). These two treatment arms (either sham or adrabetadex) combine data from Parts A and B of the study. Here, overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable at specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Control | Parts A/B: Change From Baseline to Week 52 in NPC-SS Total Score (Excluding Hearing and Auditory Brainstem Response [ABR]) | Baseline | 16.94 score on a scale | Standard Deviation 8.164 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in NPC-SS Total Score (Excluding Hearing and Auditory Brainstem Response [ABR]) | Change from Baseline at Week 52 | -0.74 score on a scale | Standard Deviation 2.357 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in NPC-SS Total Score (Excluding Hearing and Auditory Brainstem Response [ABR]) | Baseline | 17.81 score on a scale | Standard Deviation 6.476 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in NPC-SS Total Score (Excluding Hearing and Auditory Brainstem Response [ABR]) | Change from Baseline at Week 52 | -0.34 score on a scale | Standard Deviation 4.226 |
Secondary
Parts A/B: Change From Baseline to Week 52 in the Total NPC-SS (With Hearing Domain and ABR Modifier Included)
The NPC-SS total score is based on 9 domains including ambulation, fine motor skills, cognition, swallowing, memory, speech, eye movement, hearing (sensorineural) and seizures. A Likert-like scale is used to assign to each domain score of 0 to 5 (better to worse). The total score was the sum of individual components scores which ranges from 0 (best) to 45 (worst), with higher scores indicating more severe clinical impairment.
Time frame: Baseline, Week 52
Population: mITT population included all randomized participants who received at least one treatment). As per planned analysis, efficacy data were collected and presented by overall randomized treatment assignment (either sham or adrabetadex). These two treatment arms (either sham or adrabetadex) combine data from Parts A and B of the study. Here, overall number of participants analyzed = participants evaluable for this outcome measure, and number analyzed = participants evaluable at specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Control | Parts A/B: Change From Baseline to Week 52 in the Total NPC-SS (With Hearing Domain and ABR Modifier Included) | Baseline | 15.64 score on a scale | Standard Deviation 7.531 |
| Sham Control | Parts A/B: Change From Baseline to Week 52 in the Total NPC-SS (With Hearing Domain and ABR Modifier Included) | Change from Baseline at Week 52 | 0.000 score on a scale | Standard Deviation 1 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in the Total NPC-SS (With Hearing Domain and ABR Modifier Included) | Baseline | 17.76 score on a scale | Standard Deviation 5.349 |
| Adrabetadex | Parts A/B: Change From Baseline to Week 52 in the Total NPC-SS (With Hearing Domain and ABR Modifier Included) | Change from Baseline at Week 52 | 0.75 score on a scale | Standard Deviation 4.5 |
Secondary
Parts A/B: EQ-5D-3L Questionnaire Visual Analog Scale (VAS) Score (for Health Status) at Baseline and at Week 52
The EQ-5D-3L assessment is a self-reported, simple, descriptive system measuring 5 dimensions including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. A vertical VAS allows the participants to indicate their health state that day, and ranges from 0 (worst imaginable) to 100 (best imaginable), with higher scores indicating better health state.
Time frame: Baseline, Week 52
Population: mITT population included all randomized participants who received at least one treatment. As per planned analysis, efficacy data were collected and presented by overall randomized treatment assignment (either sham or adrabetadex). These two treatment arms (either sham or adrabetadex) combine data from Parts A and B of the study. Here, overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable at specified time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Control | Parts A/B: EQ-5D-3L Questionnaire Visual Analog Scale (VAS) Score (for Health Status) at Baseline and at Week 52 | Baseline | 71.9 score on a scale | Standard Deviation 16.28 |
| Sham Control | Parts A/B: EQ-5D-3L Questionnaire Visual Analog Scale (VAS) Score (for Health Status) at Baseline and at Week 52 | Week 52 | 73.2 score on a scale | Standard Deviation 13.04 |
| Adrabetadex | Parts A/B: EQ-5D-3L Questionnaire Visual Analog Scale (VAS) Score (for Health Status) at Baseline and at Week 52 | Baseline | 68.3 score on a scale | Standard Deviation 19.97 |
| Adrabetadex | Parts A/B: EQ-5D-3L Questionnaire Visual Analog Scale (VAS) Score (for Health Status) at Baseline and at Week 52 | Week 52 | 75.7 score on a scale | Standard Deviation 19 |
Secondary
Parts A/ B: Number of Participants Classified as CGIC Responders at Week 52
The Clinician CGIC is a 7-point Likert scale. The scale requires assessment of change from a baseline level of disease activity, with anchors ranging from markedly improved, moderately improved, and minimally improved to no change and corresponding worsening (minimally, moderately, markedly). The Investigator rates his/her impression of the change in each participant's condition at week 52 on a scale from marked improvement (1) to marked worsening (7). CGIC Responders are defined as participants who received the caregiver's rating of no change, minimally improved, moderately improved, or markedly improved from baseline to Week 52.
Time frame: Week 52
Population: mITT population included all randomized participants who received at least one treatment (sham or adrabetadex). As per planned analysis, efficacy data were collected and presented by overall randomized treatment assignment (either sham or adrabetadex). These two treatment arms (either sham or adrabetadex) combine data from Parts A and B of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sham Control | Parts A/ B: Number of Participants Classified as CGIC Responders at Week 52 | 7 Participants |
| Adrabetadex | Parts A/ B: Number of Participants Classified as CGIC Responders at Week 52 | 23 Participants |
Secondary
Parts A/B: Number of Participants Classified as Responders on NPC-SS Total Score (Excluding Hearing and ABR) at Week 52
The NPC-SS total score is based on 9 domains including ambulation, fine motor skills, cognition, swallowing, memory, speech, eye movement, hearing (sensorineural) and seizures. The hearing domain and ABR modifiers are removed from the total NPC-SS total score for this measure. A Likert-like scale is used to assign the remaining 8 major domain scores of 0 to 5 (better to worse). The total score was the sum of individual components scores which ranges from 0 (best) to 40 (worst), with higher scores indicating more severe clinical impairment. Responders on NPC-SS Total Score are defined as participants with no change or improvement on NPC-SS total score from baseline to Week 52.
Time frame: Week 52
Population: mITT population included all randomized participants who received at least one treatment (sham or adrabetadex). As per planned analysis, efficacy data were collected and presented by overall randomized treatment assignment (either sham or adrabetadex). These two treatment arms (either sham or adrabetadex) combine data from Parts A and B of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sham Control | Parts A/B: Number of Participants Classified as Responders on NPC-SS Total Score (Excluding Hearing and ABR) at Week 52 | 13 Participants |
| Adrabetadex | Parts A/B: Number of Participants Classified as Responders on NPC-SS Total Score (Excluding Hearing and ABR) at Week 52 | 22 Participants |
Secondary
Parts A/B: Number of Participants Treated for at Least 6 Months Who Qualified for the Rescue Option
Participants who manifested significant disease progression according to predefined clinical criteria after treatment of 26 weeks or more had the option to rescue. Number of participants who qualified for the rescue option following a minimum of 26 weeks of treatment were analyzed.
Time frame: Baseline up to Week 26
Population: mITT population included all randomized participants who received at least one treatment (sham or adrabetadex). As per planned analysis, efficacy data were collected and presented by overall randomized treatment assignment (either sham or adrabetadex). These two treatment arms (either sham or adrabetadex) combine data from Parts A and B of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sham Control | Parts A/B: Number of Participants Treated for at Least 6 Months Who Qualified for the Rescue Option | 2 Participants |
| Adrabetadex | Parts A/B: Number of Participants Treated for at Least 6 Months Who Qualified for the Rescue Option | 2 Participants |
Secondary
Parts A/B: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
A TEAE is defined as an adverse event (AE) with onset on or after start of study Drug. An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time frame: Baseline up to Week 52
Population: Safety population was defined as all randomized participants who received at least 1 procedure (adrabetadex infusion via LP or sham).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sham Control | Parts A/B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Adrabetadex | Parts A/B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Part A: Adrabetadex 1800 mg | Parts A/B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Part A: Sham Control | Parts A/B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Part B: Adrabetadex 900 mg | Parts A/B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 28 Participants |
| Part B: Sham Control | Parts A/B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 14 Participants |
Secondary
Parts A/B: Time to One Point Increase (Worsening) in NPC-SS Composite Score
The NPC-SS composite score is the sum of the ambulation, cognition, fine motor, and swallowing domains of the NPC-SS. Each of the four NPC-SS components (ambulation, cognition, fine motor, and swallowing) are rated on a scale from 0 (better) to 5 (worse). The total score was the sum of individual components scores which ranges from 0 (best) to 20 (worst), with higher scores indicating more severe clinical impairment. The product-limit survival analysis method is used to estimate the time to one point increase (worsening) in NPC-SS composite score. Time to worsening in NPC-SS Composite Score defined as the interval from study drug administration to a one point increase in the NPC-SS composite score. If a subject discontinued from the study prior to Week 52, then the subject was censored at time of discontinuation. If a subject completed the Week 52 visit, then the subject was censored at the time of last study visit.
Time frame: Baseline up to Week 52
Population: mITT population included all randomized participants who received at least one treatment (sham or adrabetadex). As per planned analysis, efficacy data were collected and presented by overall randomized treatment assignment (either sham or adrabetadex). These two treatment arms (either sham or adrabetadex) combine data from Parts A and B of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sham Control | Parts A/B: Time to One Point Increase (Worsening) in NPC-SS Composite Score | 118 Days |
| Adrabetadex | Parts A/B: Time to One Point Increase (Worsening) in NPC-SS Composite Score | 169 Days |