| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Neurologic Manifestations of Niemann-Pick Type C1 (NPC1) Disease |
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| E.1.1.1 | Medical condition in easily understood language |
| Niemann-Pick Type C1 (NPC1) Disease |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part A:
The primary study objective in Part A was to select the dose of VTS-270
to be used in Part B and Part C. Dose selection criteria included safety
and tolerability including a thorough audiologic evaluation. Preliminary
efficacy data was provided to the Dose Selection Committee (DSC) to
assist, if necessary, in dose selection.
Part B:
The primary study objective in Part B is to evaluate, in a double-blind
sham-controlled design, the progression of the neurologic
manifestations of NPC1 disease following 52 weeks of treatment for
subjects treated with VTS-270 compared to sham control, using the
following assessments:
•The NPC-SS composite which consists of the sum of 4 components of
the Neimann Pick Type C Severity Scale (NPC-SS): ambulation, fine
motor, cognition, and swallowing.
•The blinded Clinician-Global Impression of Change (CGIC)
Part C:
The primary study objective in Part C is to evaluate the long-term safety,
tolerability, and efficacy of VTS 270.
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| E.2.2 | Secondary objectives of the trial |
Part A:
There are no secondary objectives for Part A.
Part B
The secondary objectives for Part B are divided into 2 categories: Key
Secondary Objectives and Other Secondary Objectives.
The key secondary objective for Part B is to evaluate the progression of
the neurologic manifestations of NPC1 disease using the total NPC-SS
score, excluding the hearing domain and auditory brainstem response
(ABR) modifier results, following 52 weeks of treatment for subjects
treated with VTS-270 compared to sham controls and the Caregiver
CGIC.
Part C:
The secondary study objectives in Part C are to:
1. Assess the safety and tolerability of the B. Braun Celsite Spinal Access
Port utilized to administer VTS-270 (device safety and tolerability
substudy).
2. Assess the plasma and CSF PK of VTS-270 and trough HP-β-CD
concentration in subjects receiving the 900 mg dose of VTS-270 via the
B. Braun Celsite Spinal Access Port (device PK substudy).
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
(1) Part C European Site-Specific Device Safety and Tolerability Substudy
and (2) European Site-Specific Device PK Substudy.
The both sub-studies are included into the main Protocol v11.0 dated 24-
Aug-2018.
Objectives for substudy (1):
Assess the safety and tolerability of the B. Braun Celsite Spinal Access
Port utilized to administer VTS-270 in approximately 6 subjects who are
currently enrolled in VTS301 Part C.
Objectives for substudy (2):
Assess the plasma and CSF PK of VTS-270 and trough HP-β-CD
concentration in subjects receiving the 900 mg dose of VTS-270 via the
B. Braun Celsite Spinal Access Port.
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| E.3 | Principal inclusion criteria |
1. Male or female subjects, 4 to 21 years of age at time of screening with onset of neurological symptoms prior to 15 years of age.
2. Diagnosis of NPC1 determined by one of the following:
a. Two NPC1 mutations;
b. Positive filipin staining or oxysterol testing and at least one NPC1 mutation;
c. Vertical supranuclear gaze palsy (VSNGP) in combination with either:
i. One NPC1 mutation, or
ii. Positive filipin staining or oxysterol levels consistent with NPC1 disease and no NPC2 mutations.
3. Subject or parent/guardian must provide written informed consent to participate in the study. In addition to parental consent, assent to participate must also be sought from minor children.
4. Ability to undergo a LP and IT drug administration under monitored anesthesia care (conscious sedation) or if medically necessary, general anesthesia.
5. An NPC SS score of 0 through 4, inclusive, on the cognition component, and 1 through 4 in two or more of the following components: ambulation, fine motor skills, or swallowing.
6. Total NPC SS score of 10 or greater.
7. Subjects with adequately controlled seizures may qualify for enrollment. Subjects with a history of seizures should have a stable pattern of seizure activity and be on a stable dose and regimen of antiepileptic medication during the 3 months prior to screening without change in dose or regimen up to and including Study Day 0.
8. If taking miglustat, must have been on a stable dose for the past 6 to 8 weeks and be willing to remain on a stable dose for the duration of participation in Parts A and B of the study. Alternatively, subjects may elect to discontinue miglustat use and be eligible for trial entry after undergoing a minimum 6 week washout period prior to Study Day 0.
9. Agree to discontinue all nonprescription supplements such as coenzyme Q10, curcumin, cinnamon, fish oil supplements, high dose vitamin D (>500 mIU/day), N-acetylcystine, acetylleucine, or gingko biloba at least 1 month prior to first dose (Study Day 0). Note: Daily administration of an age-appropriate multivitamin is allowed.
10. Agree to discontinue any other investigational treatments for NPC including, for example, vorinostat or arimoclomol, acetylleucine, or curcumin at least 3 months prior to first dose (Study Day 0).
11. Females of childbearing potential (not surgically sterile) must use a medically acceptable method of contraception and must agree to continue use of this method for the duration of the study and for 30 days after participation in the study. Acceptable methods of contraception include barrier method with spermicide, intrauterine device, steroidal contraceptive in conjunction with a barrier method, or abstinence.
12. Subject or caregiver must possess the ability, per the Investigator, to understand and comply with protocol requirements including clinical outcome measurements and instructions for the entire duration of the study.
13. Caregiver, parent, guardian or responsible adult must be able and willing to accompany the subject to study visits.
Part C
1. Subject has completed Part B, meets the criteria for dose reduction for a second time, or meets the criteria for the rescue option
OR
2. Subject is a current participant in the NIH phase 1/2a open-label study and
a. Subject agrees to convert from the dose of VTS-270 currently receiving as a subject in the NIH phase 1/2a protocol to the dose chosen for Parts B and C of this study 900 mg;
b. Subject agrees to convert from the monthly dosing regimen used in the NIH phase 1/2a protocol to an every 2 week dosing regimen.
c. In instances where NIH phase 1/2a subjects eligible to enroll into Part C are unable to convert from their current NIH phase 1/2a dose or monthly regimen, the investigator must receive prior written authorization from the sponsor for the subject to enter Part C of the study on an amended dose and/or regimen.
OR
3. Subject has received prior written authorization from Vtesse to enroll directly into Part C.
4. Females of childbearing potential (not surgically sterile) must use a medically acceptable method of contraception and must agree to continue use of this method for the duration of the study and for 30 days after participation in the study. Acceptable methods of contraception include barrier method with spermicide, intrauterine device, steroidal contraceptive in conjunction with a barrier method, abstinence, or same-sex partner.
5. Subject or parent/guardian must provide written informed consent to participate in the study. In addition to parental consent, assent to participate must also be sought from minor children.
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| E.4 | Principal exclusion criteria |
1. Exclusion criteria as assessed by NPC SS:
a. Unable to walk, wheelchair dependent (ambulation score=5)
b. Needs a nasogastric tube or gastric tube for all feedings (swallowing=5). Note: Nasogastric or gastric tube use
for supplemental feeding or medication administration is permitted and will not exclude a subject from this trial.
c. Severe dysmetria (fine motor score=5)
d. Minimal cognitive function (cognition score=5)
2. Body weight < 15 kg.
3. Prior treatment with IV HP-β-CD for NPC1 disease, unless the subject has undergone a minimum 3-month washout period prior to Study Day 0. Note: Any prior IT administration of HP-β-CD for the treatment of NPC1 disease will exclude a subject from enrollment.
Treatment of other medical conditions with drug preparations containing HP-β-CD as an excipient (inactive ingredient) is acceptable and will not exclude a subject from immediate entry into this trial (no washout period required).
4. Status epilepticus occurring within 3 months of screening and/or seizure frequency that cannot be quantified.
5. Subjects on typical or atypical antipsychotics for treatment of psychosis. Note: Use of antipsychotic medication for treatment of other disorders (e.g., attention deficit hyperactivity disorder) will not exclude a subject from this trial.
6. History of hypersensitivity reactions to any product containing HP-β-CD.
7. Prior treatment with any other investigational product within 3 months prior to first dose (Study Day 0).
8. Female subjects who are pregnant or nursing.
9. Subjects with suspected infection of the central nervous system (CNS) or any systemic infection.
10. Spinal deformity that could impact the ability to perform a LP.
11. Skin infection in the lumbar region within 2 months of study entry.
12. Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1.5 x 109/L.
13. Thrombocytopenia (platelet count less than 75 x 109/L).
14. Activated partial thromboplastin time (aPTT) or prothrombin time (PT) prolonged by greater than 1.5 times the upper limit of normal (ULN) or known history of a bleeding disorder.
15. Evidence of obstructive hydrocephalus or normal pressure hydrocephalus.
16. Recent use of anticoagulants (in past 2 weeks prior to first dose [Study Day 0].
17. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 4 times the ULN.
18. Anemia: Hemoglobin more than 2 standard deviations below normal for age and gender.
19. Estimated glomerular filtration rate (eGFR) < 60 mL/minute/1.73m2 calculated using the modified Schwartz formula (2009) for subjects aged
4 through 17 years old or using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for subjects aged 18 years or older.
20. Active pulmonary disease, oxygen requirement, or clinically significant history of decreased blood oxygen saturation, pulmonary therapy, or requiring active suction.
21. Subjects who, in the opinion of the investigator, are unable to comply with the protocol or have medical conditions that would potentially increase the risk of participation.
22. Life expectancy less than one year.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A
After all subjects in Part A have received 4 IT infusions at the randomized dose levels or sham LP, including 2 weeks of observation following the 4th dosing, all safety and efficacy data were provided to the DSC. The DSC included 2 neurologists with expertise in NPC1
disease who were also allowed to participate, in an unblinded role, in the conduct of the study. The DSC also included a physician who was not allowed to be otherwise involved in the conduct of the study.
The single dose selected for Parts B and C of the study was based on identification of the highest dose with acceptable safety and tolerability, including results of audiologic testing, as determined by the DSC. All data available through the 8- week time point was evaluated by the DSC in an unblinded fashion. These data included information on all AEs and SAEs through 8 weeks. Results of efficacy assessments were also provided to the committee.
On the basis of these data, the DSC recommended a dose of 900 mg to be administered every 2 weeks for the remainder of the trial for subjects randomized to receive the active treatment. This dose was selected for its appropriate balance of safety, tolerability, and potential for efficacy. If at any time following the second dose of study drug during Part A of the study, a subject was reported to have clinically significant hearing loss [CTCAE grade 3 or higher], this was reviewed in an unblinded manner by the DSC, which could have made recommendations in light of other available ototoxicity data from the study. Such individuals were to have repeat pure tone audiometry (PTA) and distortion product otoacoustic emission DPOAE) testing as part of the hearing loss AE evaluation. Such recommendations could have included, for example, continuing on the current dose scheme, decreasing that subject's dose by 300 to 600 mg, decreasing all subjects in a specific dose cohort by 300 to 600 mg, discontinuing that subject from the study, or discontinuing that dose cohort.
Primary Efficacy Endpoint for Part B:
The co-primary efficacy analysis will be based on:
• Change from baseline in NPC-SS composite score at Week 52 in the
group treated with VTS-270 vs. the sham control group.
• Blinded Clinician CGIC at Week 52 in the group treated with VTS-270
vs the sham control group.
Primary Endpoints in Part C:
• The change from baseline to each assessment in a composite outcome
that is the sum of the ambulation, cognition, fine motor, and swallowing
components of the NPC-SS
• The change from baseline to each assessment in total NPC-SS with the
hearing domain and ABR modifiers removed
• Proportion of responders (defined as no change or improvement on
NPC-SS total score with hearing domain and ABR modifiers removed) at
each assessment
• Proportion of Blinded Clinician-CGIC (defined as a score of no change,
minimally improved, moderately improved, or markedly improved) at
each assessment compared to baseline
• Summary of AEs, concomitant medications, physical examinations,
audiologic examination, and clinical laboratories
• Change from baseline in the EQ-5D-3L questionnaire at each
assessment
• Change from baseline to each assessment in each of the 9 clinical
domains of the NPC-SS
• Change from baseline to each assessment in the total NPC-SS with
hearing domain and ABR modifier included
• Time to one point increase (worsening) in NPC-SS composite score
• The composite NPC-SS mean annualized rate of change (slope) from
baseline to each assessment
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: 26 weeks
Part B: 52 weeks
Part C: until the investigator considers VTS-270 to no longer be beneficial, VTS-270 receives marketing authorization, or the development program is discontinued.
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| E.5.2 | Secondary end point(s) |
Part B:
The secondary outcomes for Part B are divided into 2 categories: Key
secondary outcome and other secondary outcomes.
The key secondary endpoints are:
• Change from baseline at Week 52 in the total NPC–SS score with the
hearing domain and ABR modifiers removed in the group treated with
VTS-270 vs. the sham control group.
• Proportion of Caregiver CGIC responders (defined as a score of no
change, minimally improved, moderately improved or markedly
improved) at Week 52 in the group treated with VTS-270 vs. the sham
control group
Other (non-key) secondary endpoints:
• Summary of AEs, concomitant medications, physical examinations,
audiologic examination, and clinical laboratories
• Change from baseline in the EQ-5D-3L questionnaire at Week 52
• Proportion of subjects in each group, treated for at least 6 months who
qualified for the rescue option.
• Change from baseline to Week 52 in each of the 9 clinical domains of
the NPC-SS
• Change from baseline to Week 52 in the total NPC-SS with hearing
domain and ABR modifier included
• Time to one point increase (worsening) in NPC-SS composite score
• The composite NPC-SS mean annualized rate of change (slope) from
baseline to Week 52
• Change from baseline in the TUG test at Week 52
• Change from baseline in the 9-hole peg test at Week 52
Secondary endpoints for Part C will be evaluated for the device safety
and tolerability substudy for the first nine port infusions:
• Summary of wound check, examination of port site and catheter track
at access port infusion visits
• Intracranial pressure via LP
• Summary of plasma and CSF pharmacokinetic parameters following a
single dose of VTS-270 as well as trough HP-β-CD. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A: 26 weeks
Part B: 52 weeks
Part C: until the investigator considers VTS-270 to no longer be beneficial, VTS-270 receives marketing authorization, or the development program is discontinued.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Part C (Substudy): Safety and tolerability of the B. Braun Celsite Access Port System and Pharmacokinetics-Substudy |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Parts A and B of the trial are sham-controlled. Part C is open labelled. |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| France |
| Germany |
| Italy |
| Spain |
| Switzerland |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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