Clinical Trial Page

EudraCT Number:2022-000271-39
Sponsor's Protocol Code Number:2022-01
National Competent Authority:Croatia - MIZ
Clinical Trial Type:EEA CTA
Trial Status:Ongoing
Date on which this record was first entered in the EudraCT database:2022-09-27
Trial results
A. Protocol Information
A.1Member State ConcernedCroatia - MIZ
A.2EudraCT number2022-000271-39
A.3Full title of the trial
Single-arm, open-label dose titration phase 2 clinical trial of (+)-α-DHTBZ for the treatment of tardive dyskinesia (TD)
Otvoreno kliničko ispitivanje faze 2 titriranja doze lijeka (+)-α-DHTBZ za liječenje tardivne diskinezije (TD) u jednoj skupini ispitanika

A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
Evaluate the Efficacy, Safety and Tolerability of (+)-α-dihydrotetrabenazine for Treatment of Tardive Dyskinesia
A.4.1Sponsor's protocol code number2022-01
A.7Trial is part of a Paediatric Investigation Plan No
A.8EMA Decision number of Paediatric Investigation Plan
B. Sponsor Information
B.Sponsor: 1
B.1.1Name of SponsorAdeptio Pharmaceuticals Ltd
B.1.3.4CountryUnited Kingdom
B.3.1 and B.3.2Status of the sponsorCommercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1Name of organisation providing supportAdeptio Pharmaceuticals Ltd
B.4.2CountryUnited Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1Name of organisationAdeptio Pharmaceuticals Limited
B.5.2Functional name of contact pointAndrew Duffield
B.5.3 Address:
B.5.3.1Street AddressSuite 1, 3rd Floor, 11-12 St. James's Square
B.5.3.2Town/ cityLondon
B.5.3.3Post codeSW1Y 4LB
B.5.3.4CountryUnited Kingdom
B.5.6E-mail[email protected]
D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3IMP RoleTest
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation No
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product name(+)-α-dihydrotetrabenazine
D.3.4Pharmaceutical form Oral solution in bottle
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPOral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INN(+)-α-dihydrotetrabenazine
D.3.9.1CAS number 85081-18-1
D.3.9.2Current sponsor code(+)-Alpha-DHTBZ, ADE 513
D.3.9.3Other 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.3.9.4EV Substance CodeSUB283931
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number2
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin Yes
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D. cell therapy medicinal product No
D. therapy medical product No
D. Engineered Product No
D. ATIMP (i.e. one involving a medical device) No
D. on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product No
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.8 Information on Placebo
E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1Medical condition(s) being investigated
Tardive dyskinesia
E.1.1.1Medical condition in easily understood language
Tardive dyskinesia
E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
MedDRA Classification
E.1.2 Medical condition or disease under investigation
E.1.2Version 21.1
E.1.2Level PT
E.1.2Classification code 10043118
E.1.2Term Tardive dyskinesia
E.1.2System Organ Class 10029205 - Nervous system disorders
E.1.3Condition being studied is a rare disease No
E.2 Objective of the trial
E.2.1Main objective of the trial
The objectives of this study are to evaluate the efficacy, safety, and tolerability of different ascending doses (10 to 25 mg) of (+)-α-DHTBZ administered twice daily (bid) and once daily (od) for the treatment of tardive dyskinesia in subjects with schizophrenia, schizoaffective disorder, mood disorder, gastrointestinal disorder or neuroleptic-induced TD.
E.2.2Secondary objectives of the trial
Not applicable
E.2.3Trial contains a sub-study No
E.3Principal inclusion criteria
• Male or female aged 18 to 85 years (inclusive).
• Dated and signed informed consent.
• Meet clinical diagnoses of schizophrenia, schizoaffective disorder, mood disorder, gastrointestinal disorder (e.g., gastroparesis, gastroesophageal reflux disease), and have a clinical diagnosis of neuroleptic-induced TD as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V) for at least 3 months prior to screening with TD assessed as moderate or severe by AIMS Item 8 (≥3)
• Maintenance medication(s) for schizophrenia or schizoaffective disorder, mood disorders, or gastrointestinal disorders (except metoclopramide) must be at a stable dose for ≥30 days before screening.
• Subjects who are not using an antipsychotic medication must have a stable psychiatric status as clinically determined by the investigator. Subjects with a diagnosis of bipolar disorder must be on stable dose of mood stabilizer(s) (e.g., lithium, valproate, olanzapine) for a minimum of 30 days before screening
• Have the doses of concurrent medications and the conditions being treated be stable for a minimum of 30 days before study start and be expected to remain stable during the study.
• Subjects of childbearing potential must agree to use a highly effective contraception method during the study.
• Be in good general health and expected to complete the clinical study as designed.
• Have a body mass index (BMI) of 18 to 38 kg/m2.
• Have adequate hearing, vision, and language skills to perform the procedures specified in the protocol.
• Have a negative urine drug screen at screening and study start (negative for amphetamines, barbiturates, benzodiazepine, phencyclidine, cocaine, opiates, or cannabinoids), except for any subject receiving a stable dose of benzodiazepine or opiates. Subjects with positive cannabinoid results may be allowed to participate in the study provided that the subject is given thorough counselling and agrees to refrain from using cannabinoids for the duration of his/her study participation. Subjects must also have a negative alcohol breath test at screening and study start.
E.4Principal exclusion criteria
• Have an active, clinically significant unstable medical condition within 1 month (30 days) prior to screening.
• Have a history of substance dependence or substance (drug) or alcohol abuse within the 3 months before study start (nicotine and caffeine dependence are not exclusionary).
• Have a significant risk of suicidal or violent behavior. Subjects with any suicidal behavior or 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 in the 3 months prior to screening, will be excluded.
• Have a known history of neuroleptic malignant syndrome.
• Have a known history of long QT syndrome or cardiac tachyarrhythmia.
• Have a screening or Day -1 average triplicate ECG QT interval corrected for heart rate using QTcF of >450 ms (males) or >470 ms (females) or the presence of any clinically significant cardiac abnormality.
• Subjects with clinical diagnoses of schizophrenia or schizoaffective disorder must not have a CDSS total score ≥10 at screening or Day -1 or PANSS total score ≥70 at Day -1.
• Female pregnant women.
• Receiving any excluded concomitant medication such as reserpine, metoclopramide, carbamazepine, stimulants, or tetrabenazine, or any other specified in the protocol.
• Receiving medication for the treatment of tardive dyskinesia.
• Have a positive human immunodeficiency virus antibody, (HIV-Ab), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody result at screening or have a history of positive result.
• Have received an investigational drug within 30 days before screening or plan to use an investigational drug (other than (+)-α-DHTBZ) during the study
• Have an allergy, hypersensitivity, or intolerance to tetrabenazine.
• Have had previous exposure with (+)-α-DHTBZ.
E.5 End points
E.5.1Primary end point(s)
• AIMS Dyskinesia Total Score at week 8 (End of Treatment visit) compared to baseline.
Severity of TD symptoms assessed by AIMS dyskinesia total score (sum of items 1 through 7), as assessed by on-site investigators. The AIMS Total Dyskinesia Score rates a total of 7 items, rating involuntary movement from 0 (no dyskinesia) to 4 (severe dyskinesia). Items 1 through 7 include facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). The AIMS dyskinesia total score for Items 1-7 ranges from 0 to 28; a higher score reflects increased severity. Additionally, an exploratory central blinded AIMS video rating will also be performed in 50% of patients per site at baseline and week 8, on basis of patients’ voluntary agreement, to assess the degree of concordance of measurements and feasibility for future clinical development.
• Safety: Number of Participants with Adverse Events following dosing with (+)-α-DHTBZ. Outcome assessment includes monitoring of:
o Nature and frequency of clinical adverse events
o Clinical laboratory tests
o Vital signs
o Physical examinations
o 12-lead ECG
o Changes from baseline in tests of psychiatric symptoms and cognitive function.
E.5.1.1Timepoint(s) of evaluation of this end point
8 weeks
E.5.2Secondary end point(s)
• AIMS Dyskinesia Total Score at weeks specified in the SoA compared to baseline.
• Clinical Global Impression of Tardive Dyskinesia (CGI-TD) at weeks specified in the SoA compared to baseline. Clinician's perspective of the participant's overall improvement of TD symptoms over time. The CGI-TD is based on a 7-point scale (range: 1=very much improved to 7=very much worse).
• Calgary Depression Scale for Schizophrenia (CDSS) at weeks specified in the SoA compared to baseline. The Calgary Depression Scale for Schizophrenia (CDSS) is a nine-item structured interview scale that was designed in 1990 specifically to assess depression independently of symptoms of psychosis in schizophrenia.
• Columbia Suicide Severity Rating Scale (C-SSRS) at weeks specified in the SoA compared to baseline. It rates an individual's degree of suicidal ideation on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent and behaviors." The scale identifies specific behaviors which may be indicative of an individual's intent to complete suicide. An individual exhibiting even a single behavior identified by the scale was 8 to 10 times more likely to complete suicide. The C-SSRS is recommended by the United States Food and Drug Administration for clinical trials.
• Positive and Negative Syndrome Scale (PANSS) at weeks specified in the SoA compared to baseline. It is a scale used for measuring symptom severity of patients with schizophrenia.
• The University of California, San Diego Brief Assessment of Capacity to Consent (UBACC) at weeks specified in the SoA compared to baseline. A test for assessing decisional capacity for clinical research..
• Pharmacokinetics. Plasma samples will be collected at the end of weeks 2, 4, 6, 8 and 2 weeks after the last dose of the study drug (or early termination) for determination of plasma concentrations of (+)-α-DHTBZ, to assess treatment compliance.
E.5.2.1Timepoint(s) of evaluation of this end point
10 weeks
E.6 and E.7 Scope of the trial
E.6Scope of the trial
E.6.1Diagnosis No
E.6.2Prophylaxis No
E.6.3Therapy Yes
E.6.4Safety Yes
E.6.5Efficacy Yes
E.6.6Pharmacokinetic Yes
E.6.7Pharmacodynamic No
E.6.8Bioequivalence No
E.6.9Dose response Yes
E.6.10Pharmacogenetic No
E.6.11Pharmacogenomic No
E.6.12Pharmacoeconomic No
E.6.13Others No
E.7Trial type and phase
E.7.1Human pharmacology (Phase I) No
E.7.1.1First administration to humans No
E.7.1.2Bioequivalence study No
E.7.1.3Other No
E. trial type description
E.7.2Therapeutic exploratory (Phase II) Yes
E.7.3Therapeutic confirmatory (Phase III) No
E.7.4Therapeutic use (Phase IV) No
E.8 Design of the trial
E.8.1Controlled No
E.8.1.1Randomised No
E.8.1.2Open Yes
E.8.1.3Single blind No
E.8.1.4Double blind No
E.8.1.5Parallel group No
E.8.1.6Cross over No
E.8.1.7Other No
E.8.2 Comparator of controlled trial
E.8.2.1Other medicinal product(s) No
E.8.2.2Placebo No
E.8.2.3Other No
E.8.3 The trial involves single site in the Member State concerned No
E.8.4 The trial involves multiple sites in the Member State concerned Yes
E.8.4.1Number of sites anticipated in Member State concerned3
E.8.5The trial involves multiple Member States No
E.8.6 Trial involving sites outside the EEA
E.8.6.1Trial being conducted both within and outside the EEA No
E.8.6.2Trial being conducted completely outside of the EEA No
E.8.7Trial has a data monitoring committee No
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
E.8.9 Initial estimate of the duration of the trial
E.8.9.1In the Member State concerned years
E.8.9.1In the Member State concerned months3
E.8.9.1In the Member State concerned days
F. Population of Trial Subjects
F.1 Age Range
F.1.1Trial has subjects under 18 No
F.1.1.1In Utero No
F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
F.1.1.3Newborns (0-27 days) No
F.1.1.4Infants and toddlers (28 days-23 months) No
F.1.1.5Children (2-11years) No
F.1.1.6Adolescents (12-17 years) No
F.1.2Adults (18-64 years) Yes
F.1.2.1Number of subjects for this age range: 12
F.1.3Elderly (>=65 years) Yes
F.1.3.1Number of subjects for this age range: 6
F.2 Gender
F.2.1Female Yes
F.2.2Male Yes
F.3 Group of trial subjects
F.3.1Healthy volunteers No
F.3.2Patients Yes
F.3.3Specific vulnerable populations Yes
F.3.3.1Women of childbearing potential not using contraception No
F.3.3.2Women of child-bearing potential using contraception Yes
F.3.3.3Pregnant women No
F.3.3.4Nursing women No
F.3.3.5Emergency situation No
F.3.3.6Subjects incapable of giving consent personally No
F.3.3.7Others No
F.4 Planned number of subjects to be included
F.4.1In the member state18
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)
G. Investigator Networks to be involved in the Trial
N. Review by the Competent Authority or Ethics Committee in the country concerned
N.Competent Authority Decision Authorised
N.Date of Competent Authority Decision2022-09-02
N.Ethics Committee Opinion of the trial applicationFavourable
N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
N.Date of Ethics Committee Opinion2022-03-10
P. End of Trial
P.End of Trial StatusOngoing