Clinical Trials Register

Summary
EudraCT Number:	2020-006012-24
Sponsor's Protocol Code Number:	NBI-827104-ET2016
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-03-10
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2020-006012-24

A.3

Full title of the trial

A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of NBI-827104 in Subjects with Essential Tremor

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Safety and efficacy of an investigational drug for essential tremor

A.4.1

Sponsor's protocol code number

NBI-827104-ET2016

A.5.4

Other Identifiers

Name:	CHDR internal number	Number:	CHDR2028
Name:	Toetsingonline number	Number:	NL76780.056.21

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Neurocrine Biosciences
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Neurocrine Biosciences
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Centre for Human Drug Research
B.5.2	Functional name of contact point	NA
B.5.3	Address:
B.5.3.1	Street Address	Zernikedreef 08
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 CL
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31715246400
B.5.5	Fax number	+31715246499
B.5.6	E-mail	clintrials@chdr.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	NBI-827104
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NBI-827104
D.3.9.2	Current sponsor code	NBI-827104
D.3.9.3	Other descriptive name	NBI-827104
D.3.9.4	EV Substance Code	SUB218208
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	NBI-827104
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NBI-827104
D.3.9.2	Current sponsor code	NBI-827104
D.3.9.3	Other descriptive name	NBI-827104
D.3.9.4	EV Substance Code	SUB218208
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Essential tremor

E.1.1.1

Medical condition in easily understood language

Tremor

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10015496
E.1.2	Term	Essential tremor
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

- To evaluate efficacy of NBI-827104 in subjects with Essential Tremor (ET)
- To evaluate safety and tolerability of NBI-827104 in subjects with ET

E.2.2

Secondary objectives of the trial

-To evaluate pharmacokinetics of NBI-827104 and metabolite (if quantified) for each treatment in subjects with ET

E.2.3

Trial contains a sub-study

E.3

Principal 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 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.

E.4

Principal 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 the protocol 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.

E.5 End points

E.5.1

Primary end point(s)

1.
• Change from baseline in amplitude at peak frequency (mg2/Hz) of postural tremor (extended hand position) in the more severely affected hand measured using laboratory tremography at the last day of each treatment period

2.
• 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

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Baseline till last day of each treatment period
2. Baseline to follow up

E.5.2

Secondary end point(s)

1.
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).

2.
• Plasma NBI-872104 and metabolite concentrations at each sampling timepoint
• 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

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Baseline till end of treatment.
2. 0h (dosing) till 24h post dose (for each treatment period)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-03-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-04-06

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-06-13

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