Prediction
**Amended Eligibility Criteria (version 40)**
**Key Inclusion Criteria: Parts A and B:**
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.
Confirmed 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 lumbar puncture (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-acetylcysteine, 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 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.
**Key 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 score = 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 intravenous 2-hydroxypropyl-β-cyclodextrin (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 will exclude a subject from enrollment.
4.
Subjects on 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.
5.
History of hypersensitivity reactions to any product containing 2-hydroxypropyl-β-cyclodextrin (HP-β-CD).
6.
Spinal deformity that could impact the ability to perform a lumbar puncture.
7.
Skin infection in the lumbar region within 2 months of study entry.
8.
Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1.5 X 10^9/L.
9.
Thrombocytopenia (platelet count of less than 75 X 10^9/L).
10.
Activated partial thromboplastin time (aPTT) or prothrombin time (PT) prolonged by > 1.5 times the upper limit of normal (ULN) or known history of a bleeding disorder.
11.
Status epilepticus occurring within 3 months of screening and/or seizure frequency that cannot be quantified.
12.
Evidence of obstructive hydrocephalus or normal pressure hydrocephalus.
13.
Recent use of anticoagulants [in past 2 weeks prior to first dose (Study Day 0); re: lumbar puncture safety].
14.
Subjects unable to comply with the study procedures or with a clinical disease or laboratory abnormality that in the opinion of the investigator would potentially increase the risk of participation.