| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language | |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main 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.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.4 | Principal 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.5.1 | Primary 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.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary 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.5.2.1 | Timepoint(s) of evaluation of this end point | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial 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.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
