- To evaluate efficacy of NBI-827104 in subjects with ET - To evaluate safety and tolerability of NBI-827104 in subjects with ET- To evaluate pharmacokinetics of NBI-827104 and metabolite (if quantified) for each treatment in subjects with ET
ID
Source
Brief title
Condition
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Change from baseline in amplitude at peak frequency (mg2/Hz) of postural
tremor (extended hand position) in the more severely affected hand1 measured
using laboratory tremography at the last day of each treatment period
* Incidence of:
o Adverse Events (AEs)
o Suicidality measured by Columbia Suicide Severity Rating Scale (C-SSRS)
* Absolute values and changes from baseline values in:
o clinical laboratory tests (haematology, chemistry)
o vital signs
o 12-lead ECGs
Secondary outcome
* Change from baseline by timepoint in the following:
* The Essential Tremor Rating Assessment Scale (TETRAS) Performance score
(independent blinded video rating)
* TETRAS ADL score
* Clinical Global Impression of Change (CGI-C).
* PK parameters for NBI-827104 and metabolites will be determined by standard
non-compartmental analysis of the plasma concentration-time data, including but
not limited to:
o AUCtau, CL/F, Cmax, Ctrough, lambdaz, t1/2, tmax
o Dose-normalized PK parameters: AUCtau, Cmax, Ctrough
Background summary
Essential tremor (ET) is one of the most common movement disorders, affecting
approximately 5% of adults aged 65 years or older. ET is considered a tremor
syndrome characterized by bilateral upper-limb action tremor, defined as tremor
occurring during muscle activity resulting in kinetic and/or postural tremor.
While tremor of the upper limbs is considered the cardinal symptom, additional
body parts can be affected by tremor, including the head, voice, and legs.
T-type calcium channels were identified as having a critical physiological and
pathological role in diseases or disorders such as ET, where abnormal
oscillatory activity occurs in the brain. They are expressed in several areas
of the network associated with tremor, particularly in neurons of the inferior
olive but also in Purkinje cells and neurons of the deep cerebellar nuclei. The
causal connection between T-type calcium channels and ET is based primarily on
studies using harmaline, a beta carboline derivate known to induce action
tremor of 8 to 12 Hz frequency in various species.
NBI-827104, a novel selective and orally available T-type calcium channel
blocker, is a potent inhibitor of the 3 T-type voltage-gated calcium channel
(Cav) subtypes Cav3.1, 3.2, and 3.3, and has demonstrated tremolytic activity
in 2 rodent models of action tremor, including the harmaline-induced rat model
of ET. NBI-827104 has been well tolerated in clinical studies in healthy adult
subjects at single doses up to 400 mg(7) and multiple doses up to 100 mg QD
following titration. Based on the mechanism of action, activity in nonclinical
models of action tremor, and clinical safety profile, NBI-827104 is being
evaluated for treatment of ET in adult subjects in this phase 2 clinical study.
Study objective
- To evaluate efficacy of NBI-827104 in subjects with ET
- To evaluate safety and tolerability of NBI-827104 in subjects with ET
- To evaluate pharmacokinetics of NBI-827104 and metabolite (if quantified)
for each treatment in subjects with ET
Study design
This is a phase 2, randomized, double-blind, placebo-controlled, 2 treatment
period crossover study with up-titrated dosing to evaluate the safety,
tolerability, PK and efficacy of oral NBI-827104 QD dosing in subjects with ET
Intervention
Placebo and NBI 827104 for 28 days (cross-over), with an up-titration regimen
for NBI 827104with weekly increases (10, 30, 60 and 100 mg)
Study burden and risks
The study population of male and female subjects 18 to 75 years of age is
appropriate based on the characteristic onset of ET during adult life and
nearly full penetrance of ET before the age of 65. Both male and female
subjects are included, as there is no evidence for predominance for ET in males
or females. In short, the risks to individuals enrolled to this trial have been
minimised by using an up-titration scheme. The decision to escalated to the
next dose level will be based upon individual safety assessments. We will also
be specifically monitoring target organs of toxicity based upon (pre)clinical
data * namely the eye lens, thyroid and central nervous system. The potential
benefits apply to patients with essential tremor, so they have the opportunity
to receive an investigational drug which more effectively relieves their tremor
with less side-effects than current standard treatment (e.g. propranolol and
primidone).
El Camino Real 12780
San Diego CA 92130
US
El Camino Real 12780
San Diego CA 92130
US
Listed location countries
Age
Inclusion criteria
1. Signed informed consent prior to any study-mandated procedure.
2. Male or female subjects, 18 to 75 years of age, inclusive at screening.
3. Body mass index (BMI) between 18 and 35 kg/m2, inclusive, at screening.
4. Diagnosis of Essential Tremor (inclusive of Essential Tremor plus) as
defined by the Movement Disorders Society Consensus Criteria for Tremor.
5. Confirmation of bilateral upper limb action tremor in the absence of overt
dystonia, ataxia, or parkinsonism by an independent rating based on the video
recorded at screening of the standardized exam following the TETRAS Performance
Subscale.
6. History of onset of tremor before 65 years of age.
7. Tremor Performance score of *2 on at least 2 of the 6 upper limb manoeuvres
(Item 4) on the TETRAS Performance Subscale and a total TETRAS Performance
score *15 at screening (investigator and independent video rating).
8. All women of childbearing potential and all males must practice effective
contraception (as defined in section 4.5.1 of the protocol) during the study
and be willing and able to continue contraception for at least 90 days after
their last dose of study drug.
9. Has the ability to communicate well with the Investigator in the Dutch or
English language and is willing to comply with the study procedures and
restrictions.
Exclusion criteria
1. Evidence of any acute (at screening or prior to first dose) or chronic
disease or condition that could interfere with, or for which the treatment
might interfere with, the conduct of the study, or that would pose an
unacceptable risk to the subject in the opinion of the investigator (following
a detailed medical history, physical examination, vital signs [systolic and
diastolic blood pressure, pulse rate, body temperature] and 12-lead ECG). For
example, neurological conditions other than ET [plus] like cognitive impairment
or myasthenia gravis, uncontrolled psychiatric disorders or malignancy. Minor
deviations from the normal range may be accepted, if judged by the Investigator
to have no clinical relevance.
2. Have direct or indirect trauma to the nervous system within 3 months
preceding the onset of tremor.
3. Have known history of other medical or neurological conditions that may
cause or explain subject's tremor, including, but not limited to: Parkinson's
disease, dystonia, cerebellar disease other than ET, traumatic brain injury,
alcohol abuse or withdrawal, mercury poisoning, hyperthyroidism,
pheochromocytoma, head trauma or cerebrovascular disease (within 3 months prior
to the onset of ET), multiple sclerosis, and family history of Fragile X
syndrome.
4. Have had prior magnetic resonance guided focused ultrasound or surgical
intervention (e.g., deep brain stimulation, ablative thalamotomy or gamma knife
thalamotomy).
5. Clinically significant impaired balance or at increased risk for falls,
including the inability to ambulate safely unaided.
11. Are currently taking any of the prohibitive medications listed in Appendix
2. Subjects who have received these medications in the past, must have been off
them for at least 30 days prior to first dose. Stable dosage of 1 other
anti-tremor medication, excluding primidone, is allowed from 30 days before
screening if anticipated to be stable from screening until end of study. If on
primidone, subjects are allowed to extend the screening period by 2 weeks (for
a total of 6 weeks) and discontinue primidone under the supervision of the
investigator.
22. Have a significant risk of suicidal or violent behaviour. Subjects will be
excluded if they have:
* Any lifetime history of suicidal behaviour or
* Any lifetime history of suicidal ideation of type 4 (active suicidal ideation
with some intent to act, without specific plan) or type 5 (active suicidal
ideation with specific plan and intent) based on the C-SSRS.
Design
Recruitment
Medical products/devices used
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 |
|---|---|
| EudraCT | EUCTR2020-006012-24-NL |
| CCMO | NL76780.056.21 |