This study has been transitioned to CTIS with ID 2023-510278-14-00 check the CTIS register for the current data. Primary Objective:In all jurisdictions except the United States (US), the primary objective is to evaluate the efficacy of N-Acetyl-L-…
ID
Source
Brief title
Condition
- Inborn errors of metabolism
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
In Europe and Australia, the primary endpoint is the Scale for the Assessment
and Rating of Ataxia (SARA). SARA is an eight-item clinical rating scale (range
0-40, where 0 is the best neurological status and 40 the worst). It is a
reliable and valid clinical scale with a high internal consistency that
measures the severity of ataxia and increases with ataxia disease stage.
In the United States (US), the primary endpoint is the modified Scale for the
Assessment and Rating of Ataxia (mSARA). The mSARA is a six-item clinical
rating scale (range 0-30, where 0 is the best neurological status and 30 the
worst).
The primary endpoint is defined as the total SARA / mSARA value at the end of
Period I (Visit 4) versus the end of Period II (Visit 6).
Secondary outcome
Secondary Endpoints:
The following secondary assessments will be evaluated:
• Spinocerebellar Ataxia Functional Index (SCAFI)
• SARA (key secondary endpoint - US only)
• Quality of Life EQ-5D-5L for patients aged >=18; EQ-5D-Y for children aged <18
years
• Modified Disability Rating Scale (mDRS)
• Treating Physician*s, Caregiver*s (if applicable) and Patient*s (if able)
Clinical Global Impression of Improvement (CGI-I)
Exploratory Endpoints:
• Sparse PK sampling will be collected to characterize the PK of
N-Acetyl-L-Leucine in patients with NPC
• Modified SARA (Europe/ Australia only)
• Niemann-Pick disease type C Clinical Severity Scale (NPC-CSS)
• 5-domain NPC-CSS
• Treating Physician*s, Caregiver*s (if applicable), and Patient*s (if able)
Clinical Global Impression of Severity (CGI-S
Background summary
The goal of this study is to demonstrate that N-Acetyl-L-Leucine is efficacious
in improving symptoms, functioning, and quality of life against the defined
endpoints in patients with Niemann-Pick Type C disease (NPC) for the purpose of
establishing the benefit/risk balance of investigational medicinal product in
the proposed clinical setting.
NPC is a rare, devastating, neurovisceral autosomal-recessive inherited
metabolic, lysosomal storage disorder (LSD) that predominantly affects
pediatric patients [Vanier, 2010; Utz et al, 2017]. In general, patients with
neurological onset early in life have more severe symptoms, deteriorate faster,
and die sooner [Wraith et al, 2009]. NPC is estimated to affect 1:100,000 live
births [Vanier, 2010].
There are limited and no curative treatments approved for NPC worldwide, and no
approved treatments in the United States. Therefore, there is a strong need for
the development of novel and more effective therapies to treat these
intractable diseases.
N-Acetyl-L-Leucine is the L-enantiomer of N-Acetyl-DL-Leucine, a modified amino
acid that has been available in France since 1957 under the trade name
Tanganil® (Pierre Fabre Laboratories) as a treatment for acute vertigo and is
available as a solution for injection and as a tablet. N-Acetyl-L-Leucine is
not currently authorized anywhere in the world for the treatment of any
condition. The safety profiles of both N-Acetyl-DL-Leucine and
N-Acetyl-L-Leucine have been characterized in both preclinical and clinical
studies, including observational/ clinical trials in patients with NPC.
The Sponsor*s (IntraBio Ltd.) development of Acetyl-Leucine for NPC began with
the commercially available racemic mixture, N-acetyl-DL-leucine (*racemate*) In
2015, IntraBio*s collaborators first reported in a case series on 12 patients
with NPC that N-acetyl-DL-leucine (3 g/day for one week followed by 5 g per day
for three weeks) significantly improved the symptoms of NPC.
N-acetyl-DL-leucine was very well tolerated, and no side effects except
intermittent dizziness were reported [Bremova et al, 2015]. Later case series
demonstrated the neuroprotective, disease modifying effect of long-term
treatment with N-Acetyl-DL-Leucine in 10 patients with NPC treated for a median
length of 7.7 months (maximum 21.2, minimum 2.7 months) [Cortina-Borja et al,
2018] and 13 patients with NPC treated for a minimum of one-year [Kaya et al,
2021].Primary pharmacology studies in cell and animal models of NPC have
directly linked N-Acetyl-L-Leucine*s novel, multi-modal mechanism of action
with its symptomatic and neuroprotective, disease-modifying effect. These
studies have also demonstrated that the L-enantiomer is the active ingredient
of the racemate responsible for the neuroprotective, disease modifying effects,
and indicate superior clinical effects when used independently. IntraBio is
therefore focusing on the development of N-Acetyl-L-Leucine without the
presence of D-enantiomer.
Based on this comprehensive body of non-clinical and observational clinical
evidence, IntraBio conducted a multinational, open-label, rater-blinded Phase
II clinical trial with IB1001 for NPC (IB1001-201). The trial met its primary
and key secondary endpoints, demonstrating a statistically significant and
clinical meaningfully improvement in pediatric and adult patients with NPC
[Bremova et al, 2021]. The major findings of the IB1001-201 trial were: first,
N-Acetyl-L-Leucine improved symptoms, including gait and stance, upper
extremity function, and fine motor skills, which worsened during the
post-treatment washout. Second, consistent with its pharmacological action,
N-Acetyl-L-Leucine improved cerebellar signs and functioning after 6 weeks.
Third, improvement of neurological status was observed across all demographics
of patients (age, gender, age of onset, disease severity, etc.) establishing
the rationale for IB1001 to be used as a treatment for all NPC patients.
Fourth, the low frequency (7 related AEs in 4 patients of 32 participants) and
the transient, mild nature of these AEs inform a favorable benefit-risk
profile.
Based on these findings, IntraBio is conducting this Phase III randomized,
placebo-controlled, crossover trial investigating the efficacy and safety of
N-Acetyl-L-Leucine (IB1001) for the treatment of NPC.
Study objective
This study has been transitioned to CTIS with ID 2023-510278-14-00 check the CTIS register for the current data.
Primary Objective:
In all jurisdictions except the United States (US), the primary objective is to
evaluate the efficacy of N-Acetyl-L-Leucine (IB1001) based on the Scale for the
Assessment and Rating of Ataxia (SARA) for the chronic treatment of NPC.
In the US, the primary objective is to evaluate the efficacy of
N-Acetyl-L-Leucine (IB1001) based on the modified Scale for the Assessment and
Rating of Ataxia (mSARA) for the chronic treatment of NPC.
Note: the mSARA is not administered separately to the original SARA scale but
rather comprises a subset of domains of the original SARA scale. Therefore, the
original SARA will be administered at each visit in all countries
Secondary Objectives:
o To assess the clinical efficacy of N-Acetyl-L-Leucine on symptoms,
functioning, and quality of life for patients with NPC;
o To evaluate the safety and tolerability of N-Acetyl-L-Leucine at 4 g/day in
NPC patients aged >=13 years, and weight-tiered doses in NPC patients 4 to 12
years of age
Exploratory Objective:
• To characterize the pharmacokinetics (PK) of N-Acetyl-L-Leucine in patients
with NPC
Study design
This is a multinational, randomized, placebo-controlled, double-blinded,
cross-over Phase III study.
Patients will be assessed during three study periods: a baseline period, the
first intervention period (*Period I*), and the second intervention period
(*Period II*).
Patients will be assessed twice during each intervention period. Section 7 of
the protocol contains more detailed information on which study assessments and
procedures will be conducted for each study period and visit.
Intervention
The study drug is N-Acetyl-L-Leucine (internal development name: IB1001)
formulated as 1000 mg granules for oral suspension in sachet.
Chemical name: 2(S)-(acetylamino)-4-methylpentanoic acid
Generic name: N-Acetyl-L-Leucine
Trade name: to be determined
Dosage form: N-Acetyl-L-Leucine, 1000 mg Granules for oral suspension in Sachet
Description: The granules for oral suspension contain the following
excipients:
- Isomalt
- Hypromellose
- Strawberry Flavour
Strawberry flavour contains natural flavouring substances, flavouring
preparations, and carrier additives.
- carboxymethylcellulose sodium
- xanthan gum
- carrageenan
- calcium sulfate
- trisodium phosphate
- citric acid and sodium phosphate as buffers
- dimethicone antifoam emulsion
- preserved with methylparaben and potassium sorbate
The placebo is formulated as granules for oral suspension in a sachet.
The granules for oral suspension contain the following excipients:
- Lactose
- Microcrystalline Cellulose
- Isomalt
- Hypromellose
- Strawberry Flavour
- Citric Acid
- Denatonium Benzoate
Study burden and risks
N-Acetyl-L-Leucine is being developed for the treatment of adults and children
with NPC, a rare and ultimately fatal disorder that predominantly affects
pediatric patients [Vanier, 2010; Utz et al, 2017]. To ensure the feasibility
of this trial, NPC clinical experts [Dr Marc Patterson, MD, Mayo Clinic,
Professor Pediatric Neurology] and the heads of multinational NPC patient
organizations [Dr William Evans, Chairman Nieman-Pick UK; Joslyn Crowe,
Executive Director, National Niemann-Pick Disease Foundation, Inc.] were
consulted and involved in its design.
The degree of burden to participants in the study is defined by the description
of assessments in Section 7.
The behavioral tests for evidence of efficacy are routinely used in the
evaluation of NPC and are relatively fast to perform, with the individual
subtests of the SCAFI rarely taking more than 2 minutes for patients with NPC
to complete [Bremova et al, 2015]. With regard to the secondary endpoint
assessments, the Scale for Assessment and Rating of Ataxia (SARA) takes about
15 minutes and the Niemann-Pick type C Clinical Severity Scale (NPC-CSS) takes
about 45 minutes to complete [Dr Marc Patterson, MD, Mayo Clinic, Professor
Pediatric Neurology]. The use of these tests was determined together with
representatives of the patient community and parents of patients with NPC as
being clinically meaningful for the patients and families and reflective of the
ability to perform acts of everyday life safety and securely, while at the same
time not being exhausting [Dr William Evans, Chairman Nieman-Pick UK, Personal
Communication; Joslyn Crowe, Executive Director, National Niemann-Pick Disease
Foundation, Inc].
To minimize blood draws sparse PK sampling will be carried out at the same
times that blood is drawn for the safety blood laboratory tests in the Parent
Study. Topical anesthesia may be applied before blood sampling. The total
amount of blood taken per subject during Parent Study will be approximately 78
mL (42 mL for safety analysis, and 24 mL for the PK analysis, 12 mL for
research purposes). Patients will be >=15 kg and the total blood volume taken in
accordance with the maximum allowable research-related blood sample volumes
provided in the incoming EU ethical considerations for clinical trials on
medicinal products conducted with minors [EudraLex Volume 10, 2017].
The impact of the interventions will be assessed by patient-reported outcomes
(measurement of global impression, see Section 6.1.5, where feasible, and
quality of life assessments (EQ-5D-5L and EQ-5D-Y, see Section 6.1.3.
The investigator will monitor the degree of stress to patients and the risk
threshold throughout the trial. Patients will be instructed to report any AEs
that they experience to the Investigator and the Investigator will ask about
the occurrence of AEs at each visit. As described in Section 11.6, if the
Investigator (or the Sponsor or Medical Monitor) becomes aware of conditions or
events that suggest a possible hazard to patients if the study continues, the
clinical study may be terminated after appropriate consultation between the
involved parties.
In addition, as described in Section 11.5, the Data Safety Monitoring Board
(DSMB), in conjunction with the study Medical Monitor and/or Sponsor, will
monitor the level of risk on a regular basis throughout the study. The DSMB is
a multidisciplinary group consisting of clinicians with pediatric experience
and a biostatistician. The DSMB has been set up to safeguard the interests of
study participants by providing an independent review of patient safety data to
monitor that no undue harm is occurring to patients due to their participation.
The DSMB may recommend changes in the conduct of the studies to IntraBio, if
needed, to ensure the safety of patients in the study and the proper conduct of
the studies. The DSMB may also recommend suspending recruitment or terminate
the study early because of undue safety risks to patients or any issues
concerning the rights of patients. For this purpose, the DSMB will receive
regular updates of safety and review all safety data on a regular basis.
Based upon the nature of the drug, the available non-clinical and clinical data
for N-Acetyl-L-Leucine and N-Acetyl-DL-Leucine, the current lack of effective
treatments NPC, and in the context of a marketed racemate, this clinical trial
is concluded to pose acceptable levels of risk and burden on participants.
Berkeley Street 17-Flat 1
Londen W1J 8EA
GB
Berkeley Street 17-Flat 1
Londen W1J 8EA
GB
Listed location countries
Age
Inclusion criteria
Individuals who meet all of the following criteria are eligible to participate
in the study: 1. Written informed consent signed by the patient and/or their
legal representative/ parent/ impartial witness 2. Male or female aged >=4 years
with a confirmed diagnosis of NPC at the time of signing informed consent.
Confirmed diagnosis includes on of the following [Patterson et al, 2017]: a)
Clinical features and positive biomarker screen and/or filipin test without
genetic tests results (has not been performed) b) Clinical features and
positive genetic test c) Clinical features and positive biomarker screen and/or
filipin test but only one NPC mutation identified on genetic test d) Clinical
features with positive biomarker screen and/or filipin test and positive
genetic test 3. Females of childbearing potential, defined as a premenopausal
female capable of becoming pregnant, will be included if they are either
sexually inactive (sexually abstinent for 14 days prior to the first dose and
confirm to continue through 28 days after the last dose) or using one of the
following highly effective contraceptives (i.e. results in <1% failure rate
when used consistently and correctly) 14 days prior to the first dose
continuing through 28 days after the last dose: a) intrauterine device (IUD);
b) surgical sterilization of the partner (vasectomy for 6 months minimum); c)
combined (estrogen or progestogen containing) hormonal contraception associated
with the inhibition of ovulation (either oral, intravaginal, or transdermal);
d) progestogen only hormonal contraception associated with the inhibition of
ovulation (either oral, injectable, or implantable); e) intrauterine hormone
releasing system (IUS); f) bilateral tubal occlusion. 4. Females of
non-childbearing potential who have undergone one of the following
sterilization procedures at least 6 months prior to the first dose: a)
hysteroscopic sterilization; b) bilateral salpingectomy; c) hysterectomy; d)
bilateral oophorectomy; OR be postmenopausal with amenorrhea for at least 1
year prior to the first dose and follicle stimulating hormone (FSH) serum
levels consistent with postmenopausal status. FSH analysis for postmenopausal
women will be done at screening. FSH levels should be in the postmenopausal
range as determined by the central laboratory. 5. Non-vasectomized male patient
agrees to use a condom with spermicide during the study until 90 days beyond
the last dose of study medication and the female partner agrees to comply with
inclusion criteria 3 or 4. For a vasectomized male who has had his vasectomy 6
months or more prior to study start, it is required that they use a condom
during sexual intercourse. A male who has been vasectomized less than 6 months
prior to study start must follow the same restrictions as a non-vasectomized
male. 6. If male, patient agrees not to donate sperm from the first dose until
90 days after their last dose. 7. Patients must fall within: a) A SARA score of
7 <= X <= 34 points (out of 40) AND b) Either: i. Within the 2-7 range (0-8
range) of the Gait subtest of the SARA scale OR ii. Be able to perform the
9-Hole Peg Test with Dominant Hand (9HPT-D) (SCAFI subtest) in 20 <= X <=150
seconds. 8. Weight >=15 kg at screening. 9. Patients are willing to disclose
their existing medications/therapies for (the symptoms) of NPC, including those
on the prohibited medication list. Non-prohibited medications/therapies
(authorized medicines for NPC [e.g. miglustat], speech therapy, and
physiotherapy) are permitted provided: a) The Investigator does not believe the
medication/therapy will interfere with the study protocol/results b) Patients
have been on a stable dose/duration and type of therapy for at least 42 days
before Visit 1 (Baseline 1) c) Patients are willing to maintain a stable
dose/do not change their therapy throughout the duration of the study. 10. An
understanding of the implications of study participation, provided in the
written patient information and informed consent by patients or their legal
representative/parent, and demonstrates a willingness to comply with
instructions and attend required study visits (for children this criterion will
also be assessed in parents or appointed guardians).
Exclusion criteria
Individuals who meet any of the following criteria are not eligible to
participate in the study:
1. Patients who have any known hypersensitivity or history of hypersensitivity
to:
a. Acetyl-Leucine (DL-, L-, D-) or derivatives.
b. Excipients the IB1001 sachet (namely isomalt, Hypromellose, and Strawberry
Flavour).
c. Excipients the placebo sachet (namely isomalt, Hypromellose, Strawberry
Flavour, Citric acide, microcrystalline cellulose, lactose, denatonium
benzoate).
2. Simultaneous participation in another clinical study or participation in any
clinical study involving administration of an investigational medicinal product
(IMP; *study drug*) for at least 42 days prior to Visit 1. At the discretion of
the investigator, Medical Monitor, and Sponsor, the washout period for specific
IMPs may be longer based on the pharmacological activity and pharmacokinetics
of the drug.
3. Patients with a physical or psychiatric condition which, at the
investigator*s discretion and in consultation with the Medical Monitor and
Sponsor (as applicable), may put the patient at risk, may confound the study
results, or may interfere with the patient*s participation in the clinical
study, i.e. reliably perform study assessments.
4. Known or persistent use, misuse, or dependency of medication, drugs, or
alcohol.
5. Current or planned pregnancy or women who are breastfeeding.
6. Patients with severe vision or hearing impairment (that is not corrected by
glasses or hearing aids) that, at the investigator*s discretion, interferes
with their ability to perform study assessments.
7. Patients who have been diagnosed with arthritis or other musculoskeletal
disorders affecting joints, muscles, ligaments, and/or nerves that by
themselves affects patient*s mobility and, at the investigator*s discretion,
interferes with their ability to perform study assessments.
8. Patients unwilling and/or not able to undergo a 42-day washout period from
any of the following prohibited medication prior to Visit 1 (Baseline 1) and
remain without prohibited medication through Visit 6.
a) N-Acetyl-DL-Leucine (e.g. Tanganil®);
b) N-Acetyl-L-Leucine (prohibited if not provided as IMP in the IB1001-301
trial);
c) Sulfasalazine;
d) Rosuvastatin.
Design
Recruitment
Medical products/devices used
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-510278-14-00 |
| EudraCT | EUCTR2021-005356-10-NL |
| ClinicalTrials.gov | NCT05163288 |
| CCMO | NL79787.018.21 |