VTS270 in Subjects with Niemann-Pick Type C1 Disease.
Research type
Research Study
Full title
A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham-Controlled Trial of VTS270 (2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann-Pick Type C1 (NPC1) Disease.
IRAS ID
187661
Contact name
Allan Darling
Contact email
Sponsor organisation
Vtesse Inc
Eudract number
2015-002548-15
Clinicaltrials.gov Identifier
113273, IND Number
Duration of Study in the UK
2 years, 6 months, 1 days
Research summary
Research Summary
Niemann-Pick Type C1 (NPC1) disease is a rare, fatal, disorder that can be passed down through families with conditions that primarily affect the neurons in the brain. The disorder is caused by mutations in the NPC1 gene. The disease is characterized by the inability to properly process waxy fats in the body and naturally occurring molecules within the cell, causing waxy fats to accumulate in the brain, liver and spleen. Although symptoms can appear well into adulthood, the typical onset of symptoms is in early childhood, and with earlier onset, there is more rapid progression of disease and death often before age 20. Owing to different clinical presentations and course of disease, NPC1 disease is typically categorized as early-infantile onset (< 2 years), late-infantile onset (2 to < 6 years), juvenile onset (6 to < 15 years) and adolescent/adult onset (> 15 years).
51 subjects enrolled in this pivotal study will be randomly assigned in a 3:1 ratio (in Study Part A for 8 weeks for dose selection for part B) or a 2:1 ratio (in Study Part B) to receive either intrathecally administered drug or a sham control procedure for a total of 12 months. The sham procedure control group provides the most unbiased assessment of the efficacy and safety of drug in the intended population of children with Niemann-Pick Type C1 disease in this Phase 2b/Phase 3 pivotal study. This blinded control group is critical to the interpretation of the study data.
The randomization rates favour receiving the drug: overall a total of 16 patients will be randomized to sham and 35 patients will receive study drug.Summary of Results
Short Study Title: VTS270 in Subjects with Niemann-Pick Type C1 Disease Full Study Title: A Phase 2b/3 Prospective, Randomized, Double Blind, Sham Controlled Trial of VTS-270 (2-hydroxypropyl-β-cyclodextrin) in Subjects with Neurologic Manifestations of Niemann-Pick Type C1 (NPC1) Disease.
IRAS ID: 187661
REC Reference: 15/YH/0435
EudraCT Number: 201500254815
ClinicalTrials.gov Number: NCT04958642Who sponsored the study and how can I contact them?
The Sponsor of this study was Vtesse LLC, a Mallinckrodt Pharmaceuticals Company who would like to thank everyone who took part.General Information about the research:
The overall goal of this study was to test whether adrabetadex is safe and effective for the treatment of patients with Niemann-Pick Type C1 (NPC1) disease.
The study consisted of 3 parts. The primary goal of Part A was to choose the dose of adrabetadex to be used in Part B and C. The primary goal of Part B was to test whether adrabetadex is safe and well-tolerated, and whether it can improve the neurological signs and symptoms of Niemann-Pick Type C1 (NPC1) disease. The primary goal of Part C is to test whether adrabetadex is safe and well-tolerated long-term.
The study took place from 24-September 2015 to 11-April 2022 in 29 locations worldwide, primarily in the United States and Europe, including 2 locations in the United Kingdom. A total of 58 patients participated in Parts A and B of the study, and 66 patients participated in Part C. Patients were eligible to be in the study if they were 4 to 21 years of age, with symptoms of NPC1 disease before the age of 15, and diagnosed by the doctors with NPC1 disease.
In the study, adrabetadex was given every 2 weeks via lumbar puncture (spinal tap), in which the drug was injected into the fluid around the spinal cord in the back. In Parts A and B of the study, some patients received a sham lumbar puncture in which a needle stick was performed in the back without injection of any drug. All patients received adrabetadex in Part C of the study. Patients were treated for 52 weeks in Parts A and B of the study and up to 260 weeks in Part C of the study, until the study was ended by the sponsor.
On 20 January 2021, the sponsor of the study announced, after an extensive and comprehensive review of all available information on adrabetadex, that there was no clear evidence that treatment with adrabetadex was beneficial to patients with NPC1 disease and that the risk of the treatment was higher than the chance of receiving benefit from the treatment. The sponsor decided to terminate the study and patients and parents were asked to discuss and decide with the treating physicians whether they should continue treatment until the end of the study.What Treatments did the participants receive?
In Part A, 9 subjects received 3 different dose levels of adrabetadex, and 3 subjects did not receive the study drug. The adrabetadex dose groups were divided into 900 mg, 1200 mg, and 1800 mg with 3 subjects each. The drug was injected intrathecally through a lumbar puncture which is an injection into the spinal canal through the lower back every 2 weeks for 4 doses. For the subjects who did not receive adrabetadex, they received 1 to 2 needle pricks in the lower back where the drug would be injected. The subjects were put into their 4 groups by chance (randomized) to reduce differences between the groups and to make sure the treatment groups were chosen fairly. The trial was also “double-blinded” so none of the participants, doctors, or study site staff knew what treatment was given until the study had finished. This was done to make sure that the study results were not influenced in any way.In Part B, the dose of 900 mg was chosen to be used after Part A. A total of 56 patients took part, 38 were given 900 mg of adrabetadex intrathecally through a lumbar puncture (or highest tolerated if a dose reduction was needed) and 18 were given an identical injection with no medication every 2 weeks for up to 52 weeks. Part B included the 12 patients from Part A. Part B was also randomized and double-blinded.
In Part C, 66 subjects received 900mg of adrabetadex intrathecally through a lumbar puncture every 2 weeks for up to 260 weeks, or until the development program was discontinued. In Part C, 18 patients had never received treatment, 13 were from a previous study (Study 13-CH-0001), and 35 were from Part A/B. Part C was open-label meaning the study doctors and participants knew what treatments were given since all patients were given adrabetadex.
What medical problems (side effects) did the participants have?
Side effects (adverse events) are unwanted medical events (such as a headache) that happen during the study and are reported regardless of whether the study doctor (investigator) believes the side effects were related to the treatments in the trial. Not all the patients in this trial had side effects.Serious side effects are reactions that are life threatening or require the individual to have to go to hospital. In Part A and B of the study, more patients treated with adrabetadex had serious side effects (52.6%) than those treated with the sham treatment (22.2%). These serious side effects were similar to complications that happen in patients with NPC1 disease, such as hearing loss (4 out of 38 adrabetadex-treated patients and 1 out of 18 sham-treatment patients), pneumonia (infection in the lung, 4 out of 38 adrabetadex-treated patients and 1 out of 18 sham-treatment patients), seizure (3 out of 38 adrabetadex-treated patients and 1 out of 18 sham-treatment patients), and difficulty swallowing (3 out of 38 adrabetadex-treated patients and 1 out of 18 sham-treatment patients). No patients died in Part A and B of the study.
Side effects in Parts A and B of the study that happened in at least 30% more patients treated with adrabetadex than sham-treatment patients were vomiting (55.3% compared to 11.1%), those related to hearing loss (71.1% compared to 44.4%), back pain (50.0% compared to 16.7%) and tiredness (47.4% compared to 16.7%). The proportion of patients with worsening hearing loss as assessed by hearing test after 52 weeks of treatment was also higher in the adrabetadex treated group, 21.1% compared to 5.6% in the sham treatment group.
During Part C of the study, a detailed safety evaluation was done. It was found that hearing loss, balance problems (including unsteady walking) and tiredness were associated with treatment with adrabetadex, although it is not known whether these problems may also be related to worsening NPC1 disease.
What were the results of the study?
In Part A, the primary goal of was to choose the dose of adrabetadex to be studied in Parts B and C of the study. The dose of 900 mg every 2 weeks was chosen to be used in Parts B and C, based on the opinion of a panel of experts.The effectiveness of adrabetadex in treating the symptoms of NPC1 disease was studied in Parts A and B of the study using the the Niemann Pick Type C Severity Scale (NPC-SS) and the Clinician Global Impression Change (CGIC).
The NPC-SS Scale assessed four parts: ambulation (ability to move about), cognition (thinking), fine motor (fine movement)), and swallowing, on a scale of 0 (better) to 5 (worse) for a total score of 0 (best) to 20 (worst). The CGIC scale was used by the study doctor for their impression on the change in the patient’s condition from 1 (marked improvement) to 7 (marked worsening).
In Part A/B, adrabetadex was found to be no better than the group who did not receive the medication (sham treatment) in treating the symptoms of NPC1 disease based on the NPC-SS and CGIC scores, after 52 weeks of treatment. The reason why there was no difference is not known.
The primary goal of Part C was to evaluate the longer-term safety and tolerability of adrabetadex. The most common side effects related to treatment with adrabetadex are hearing loss, balance problem and tiredness, shown in all parts of the study and are described in the previous section.
How has this study helped patients and researchers?
The results of this study show that the most common side effects of adrabetadex are hearing loss, problems with balance and tiredness that were generally not serious. However, treatment with adrabetadex did not improve the symptoms and signs of NPC1 disease overall. As the patients who participated in the study is a broad group of patients who ranged from 4 to 21 in age at the time that they entered the study and had moderate to severe symptoms of the disease, it is not known if patients within a more specific age group or severity of symptoms may have a better response to treatment.Researchers look at the results of many studies to understand which drugs work and how they work. It takes lots of people in many studies all around the world to advance medical science. This summary only shows the results from this one study. Other studies may find different results.
You should not change your treatment based on the results of this study without first talking to your doctor/healthcare professional providing your care about what these results might mean for you.
Are further studies planned?
There are no further studies planned.Where can I learn more about this study?
Not applicableREC name
Yorkshire & The Humber - Sheffield Research Ethics Committee
REC reference
15/YH/0435
Date of REC Opinion
9 Nov 2015
REC opinion
Further Information Favourable Opinion