Clinical Trials Register

Summary
EudraCT Number:	2022-001685-35
Sponsor's Protocol Code Number:	ADT-2022-003
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2023-01-30
Trial 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

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2022-001685-35

A.3

Full title of the trial

Clinical trial of (+)-α-dihydrotetrabenazine in patients with moderate to severe tardive dyskinesia with open-label Part I and randomized, double-blind, placebo-controlled Part II.

Klinické skúšanie s (+)-α-dihydrotetrabenazínom u pacientov so stredne ťažkou až ťažkou tardívnou dyskinézou s otvorenou Časťou I a randomizovanou, dvojito zaslepenou, placebom kontrolovanou Časťou II.

A.3.1

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

A trial to evaluate the efficacy, safety and tolerability of (+)-α-dihydrotetrabenazine for treatment of Tardive Dyskinesia

A.4.1

Sponsor's protocol code number

ADT-2022-003

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	Adeptio Pharmaceuticals Limited
B.1.3.4	Country	United Kingdom
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	Adeptio Pharmaceuticals Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Adeptio Pharmaceuticals Limited
B.5.2	Functional name of contact point	Andrew Duffield
B.5.3	Address:
B.5.3.1	Street Address	Suite 1, 7th Floor, 50 Broadway
B.5.3.2	Town/ city	London
B.5.3.3	Post code	SW1H 0BL
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44020 8654 2251
B.5.6	E-mail	andrew.duffield@adeptioltd.com

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	ADE513
D.3.4	Pharmaceutical form	Oral solution
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	(+)-α-dihydrotetrabenazine
D.3.9.1	CAS number	85081-18-1
D.3.9.2	Current sponsor code	(+)-Alpha-DHTBZ, ADE 513
D.3.9.3	Other descriptive name	(2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-ol
D.3.9.4	EV Substance Code	SUB283931
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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	Oral solution
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

Tardive dyskinesia

E.1.1.1

Medical condition in easily understood language

Involuntary movements

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	10043118
E.1.2	Term	Tardive dyskinesia
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 ADE513 in reducing abnormal involuntary movements of tardive dyskinesia.

E.2.2

Secondary objectives of the trial

To evaluate safety and tolerability of ADE513 in titration and maintenance therapy in subjects with tardive dyskinesia in both Parts, and to confirm pharmacokinetic parameters in target population in Part I.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject aged between 18 and 75 years, inclusive.
2. Subject with a clinical diagnosis of tardive dyskinesia.
3. Subject with symptoms of TD which are bothersome and/or cause functional impairment.
4. Subject with total motor AIMS score of ≥6, and with abnormal movements judged as moderate or severe by the Investigator (based on Item 8 of the AIMS).
5. Subject with body weight of not less than 45kg for females and 55kg for males.
6. Subject in a psychiatrically stable condition with no change in psychoactive medications (eg. neuroleptics, benzodiazepines, anticonvulsants, mood stabilizers etc.) within the last 30 days before Screening, and with no anticipated changes to the subject’s treatment regimen in the next 3 months.
7. Subject living in a stable environment as judged by the Investigator, with adequate supervision when necessary.
8. Subject having a caregiver who is in regular personal contact with the subject (no less than 5 days a week); if locally required.
9. Subject compliant with prescribed treatment regimen as judged by the Investigator.
10. Subject in good general health with expectation to attend all study visits and complete all study assessments as judged by the Investigator.
11. Subject able to read, comprehend and provide the written informed consent.
12. Subject able to complete subject-facing rating scales.
13. Female subject of childbearing potential who agrees to use a highly effective form of contraception (as defined by the Protocol) throughout the Study.

E.4

Principal exclusion criteria

1. Subject who received any of the following medications within 30 days of Screening or Baseline:
o Tetrabenazine, deutetrabenazine, valbenazine, reserpine, α-methyl-p-tyrosine (AMPT),
o Trihexyphenidyl, orphenadrine, procyclidine, biperiden or other strong anticholinergics
o Metoclopramide, promethazine, and prochlorperazine
o Methylphenidate, amphetamine/dextroamphetamine, or other stimulants,
o Monoamine oxidase inhibitors (MAOIs)
o Levodopa or dopamine agonists
o Botulinum toxin (within 3 months of Screening)
Note: Existing medication for the subject’s TD symptoms must not be discontinued solely for the purpose of inclusion in this clinical trial.
2. Subject with a neurological condition that may interfere with the assessment of dyskinesia severity.
3. Subject with presence of parkinsonism, pheochromocytoma and prolactin dependent tumours, e.g. pituitary or breast cancer.
4. Subject with a serious psychiatric condition that is untreated or undertreated at Screening and/or Baseline.
5. Subject with active suicidal ideation at Screening or Baseline.
6. Subject with history of either previous intent to act on a suicidal ideation with a specific plan, or previous preparatory acts to commit suicide or suicidal behaviour, or a previous actual, interrupted or aborted suicide attempt.
7. Subject with an abnormal score on the depression subscale of the Hospital Anxiety and Depression Scale (HADS) at Screening or Baseline. Abnormal score is defined as score ≥11.
8. Subject with an unstable or serious medical condition at Screening or Baseline.
9. Subject with developmental disability or evidence of dementia confirmed by Mini-Mental State Exam (MMSE score ≤24).
10. Subject showing violent behaviour, or subject with a history thereof within 3 months of start of study participation.
11. Subject with clinically significant cardiac abnormality or QTcF >450 ms (males) or >470 ms (females) on 12-lead ECG at Screening.
12. Subject with any of the following abnormal values in laboratory test results at Screening:
o aspartate transaminase (AST) or alanine aminotransferase (ALT) >2.5 times the upper limit of normal (ULN)
o alkaline phosphatase (ALP) or total bilirubin >2 times the ULN,
o serum creatinine >1.5 times the ULN
o any other results outside of laboratory reference ranges judged as clinically significant by the Investigator
o positive hepatitis B surface antigen (HbSAg, indicating ongoing hepatitis B infection), or
positive human immunodeficiency virus antibody (HIV-Ab), , or positive hepatitis C antibodies (HCV) test result.
13. Subject with a known allergy or hypersensitivity to any component of ADE513, or to a VMAT2 inhibitor e.g. tetrabenazine, deutetrabenazine, valbenazine.
14. Subject who has received any investigational drug product within 30 days (or 5 drug half-lives, if longer than 30 days) of Screening.
15. Subject acknowledging present alcohol or substance abuse at Screening, or subject with a history thereof within 12 months of Screening, or subject expected to be unable to refrain from substance abuse during the study.
16. Subject with a positive urine drug screen at Screening.
17. Pregnant or breastfeeding subject.

E.5 End points

E.5.1

Primary end point(s)

Change in AIMS score (items 1 through 7) from Baseline (Day 0) to Week 12, as assessed by central rating.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 12

E.5.2

Secondary end point(s)

Part I Secondary Endpoints:
- Change in AIMS score (items 1 through 7) from Baseline (Day 0) to Week 12) in Part I, as assessed by the on-site Investigator.
- Change in AIMS score (items 1 through 7 from Baseline (Day 0) to Week 9 in Part I, as assessed by the on-site Investigator.
- Change in AIMS score (items 1 through 7) from Week 6 to Week 12 in Part I, as assessed by the on-site Investigator.

Part II Secondary Endpoints:

- Dose level associated with adequate control of dyskinesia (defined as dose level used in Maintenance period) in Part II.
- Proportion of subjects with the value of Much or Very Much Improved on the Clinical Global Impression of Change (CGIC) at Week 12 in Part II.
- Proportion of subjects with the value of Much or Very Much Improved on the Patient Global Impression of Change (PGIC) at Week 12 in Part II.

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 9 and 12

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

Yes

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

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Open label (active treatment only) in Part I

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

Yes

E.8.2.3.1

Comparator description

no control in Part I, placebo in Part II

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

E.8.9.2

In all countries concerned by the trial years

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.4.2

For a multinational trial

F.4.2.1

In the EEA

102

F.4.2.2

In the whole clinical trial

102

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)

Planned rollover safety study

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

2023-05-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-02-21

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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