| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Parkinson's disease psychosis |
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| E.1.1.1 | Medical condition in easily understood language |
| Parkinson's disease psychosis |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Psychological processes [F02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10074835 |
| E.1.2 | Term | Parkinson's disease psychosis |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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| 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 |
Part I: To evaluate the safety and tolerability of CBD as a treatment in patients with Parkinson’s disease and psychosis (PDP) and identify the maximum tolerated dose (MTD).
PART II: To evaluate the safety and tolerability of the most appropriate dose level of CBD (as identified from Part I study) compared to matched placebo treatment in people with PDP.
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| E.2.2 | Secondary objectives of the trial |
PART I:
(i) To examine whether there is any evidence of drug-drug interaction with any of the safe and tolerated doses of CBD when given to people with PDP.
(ii) To identify safe and tolerated doses of CBD treatment for people with PDP that show any pharmacodynamic signal.
The most appropriate dose to be taken into Part II will be based on a full review of MTD, safety, tolerability and drug activity.
PART II:
(i)To obtain proof-of-concept evidence of activity of chosen dose of CBD as an antipsychotic for people with PDP.
(ii) To examine whether there is any evidence of drug-drug interaction with the chosen dose of CBD in people with PDP.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
NEUROIMAGING MECHANISTIC SUB-STUDY (included as an Addendum to main protocol, version 1.0)
Objective:
To investigate the neurophysiological mechanisms underlying the antipsychotic effects of CBD in PDP.
Mechanistic Efficacy Parameters/Outcome Measures:
-Within-subject change (pre-treatment minus 6-week post-treatment) in medial temporal, prefrontal, and striatal activation (as estimated from the blood oxygen level-dependent haemodynamic response signal measured using fMRI; BOLD signal) in the MRI scanner.
-Within-subject change (pre-treatment minus 6-week post-treatment) in functional connectivity between the medial temporal, prefrontal, striatal and visual cortical regions of interest (as estimated from the BOLD signal) and between these regions and the rest of the brain using both resting state and task-based fMRI data in the MRI scanner.
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| E.3 | Principal inclusion criteria |
1. Satisfy established diagnostic criteria (NINDS-NIMH criteria for the diagnosis of Parkinson’s disease psychosis) and UK Brian Bank criteria for idiopathic Parkinson’s disease.
2. Age 40 or older.
3. For psychotic symptoms, they should have developed after the PD diagnosis and should have been present for at least 1 month, occurring at least weekly over the month before screening and should have a combined score of at least 6 or an individual score of at least 4 on the neuropsychiatric inventory (NPI) A (delusions) and/or B (hallucinations) subscale in the month before screening.
4. Parkinson’s disease dementia would not be an exclusion criterion.
5. Participants with score greater than 18 on the Montreal Cognitive Assessment scale.
6. TAU will include patients on quetiapine and/ or cholinesterase inhibitors (rivastigmine/ donepezil) as well as standard antiparkinsonian treatments with dosage stable for at least 1 month.
7. At least 6 months post stereotaxic surgery (deep brain stimulation) and stimulator settings stable for at least 1 month prior to baseline and must remain stable during the trial.
8. Ability to participate in study evaluation and ingest oral medication.
9. Reliable informant/caregiver.
10. Written informed consent to participate.
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| E.4 | Principal exclusion criteria |
1. Insufficient understanding of trial.
2. History of significant psychotic disorders prior to or concomitantly with the diagnosis of Parkinson’s disease including, but not limited to, schizophrenia or bipolar disorder.
3. Psychotic symptoms secondary to other toxic or metabolic disorders.
4. Psychosis onset after ablative stereotaxic surgery.
5. Diagnosis of dementia made concurrent with or prior to a PD diagnosis.
6. Patients on clozapine due to the requirement of special safety monitoring required for clozapine, which will unblind the safety.
7. Patients taking part in another intervention trial concurrently. However, those withdrawn from another study or who have recently completed another intervention study will be eligible for inclusion if they satisfy study inclusion/ exclusion criteria. For pharmacological intervention, they will be eligible only after a sufficient period of washout (~ 5 times half-life of other study drug).
8. Participant no longer able to report symptoms as a result of cognitive impairment.
9. Presence of depressive symptoms would not be an exclusion criterion. However, we would exclude those participants who may have severe depression.
10. Participants who answer "yes" on the C-SSRS Suicidal Ideation Item 4 or Item 5 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan, or Active Suicidal Ideation with Specific Plan and Intent) and whose most recent episode meeting the criteria for C-SSRS Item 4 or Item 5 occurred within the last 6 months, OR Participants who answer "yes" on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behaviour) and whose most recent episode meeting the criteria for any of these 5 C-SSRS Suicidal Behavior items occurred within the last 2 years, OR Participants who, in the opinion of the investigator, present a serious risk of suicide.
11. Any medical or psychological condition or social circumstances which may impair their ability to participate reliably in the study, or who may increase the risk to themselves or others by participating in the study.
12. Significant ocular pathology.
13. Concomitant medication that has a clinically relevant interaction with the CYP2C19 or CYP3A classes of liver enzymes will not be permitted from two weeks before inclusion until the end of the study. Examples of co-medication that will be not allowed will include CYP3A4 inhibitors (such as itraconazole, ketoconazole, posaconazole, fluconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, telaprevir, boceprevir, imatinib, ticagrelor, voriconazole), CYP3A4 inducers (such as carbamazepine, efavirenz, nevirapin, etravirin) and CYP2C19 inhibitors (such as moclobemine, fluvoxamine, chloramphenicol, fluoxetine).
14. Female patients who are pregnant or lactating
15. Female patients of childbearing potential who are not willing to use a highly effective method of contraception for the duration of the trial to prevent pregnancy, or abstain from heterosexual activity.
*Females of child bearing potential are females who have experienced menarche and are not surgically sterilised (e.g. by hysterectomy, bilateral salpingectomy) or post-menopausal (defined as at least 1 year since last regular menstrual period).
** Highly effective methods of birth control are those with a failure rate of < 1% per year when employed consistently and correctly, e.g.
• combined (oestrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation:
o oral
o intravaginal
o transdermal
• progestogen-only hormonal contraception associated with inhibition of ovulation 1:
o oral
o injectable
o implantable 2
• intrauterine device (IUD)
• intrauterine hormone-releasing system ( IUS)
• vasectomised partner
Sexual abstinence is considered to be highly effective method only if defined as refraining from heterosexual activity from the date of consent until end of treatment and for 2 weeks after. The reliability of this method should be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.
16. Known hypersensitivity to CBD, gelatine or micro-crystalline cellulose.
17. Mechanistic sub-study only: Patients who have any contraindications to MRI, including: pacemakers, metallic foreign body in the eye, aneurysm clip in their brain, severe claustrophobia where patients would not be able to tolerate the scan etc
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I: We will report the maximum tolerated dose of CBD.
Phase II:
Safety/ Tolerability Outcomes: Change in safety and tolerability measures (listed below) (frequency or mean value, as appropriate) at the end of week 12 compared to baseline (pre-treatment) for each intervention arm.
Feasibility Outcomes:
(i) Percentage of patients recruited and followed up over the time-frame of the study
(ii) Percentage of patients compliant (*adherence) with treatment by the end of 12-weeks.
(iii) Retention rate (measured by drop-out) by the end of 12-week treatment.
*Adherence is defined as at least 50% of the dose taken, measured by pill count.
Tolerability measures: Review of Adverse Events (AE), Serious Adverse Events (SAEs), Serious Adverse Reactions (SARs) and Serious Unexpected Adverse Reactions (SUSARS) UKU side-effect rating scale for psychotropic drugs
Safety parameters: Clinical laboratory measures: Haematology (Haemoglobin, Red blood cell count, Platelet count, white blood cell count and differential count), Clinical chemistry (Sodium, Potassium, Creatinine, Urea); Glucose; Liver function test (Total bilirubin, Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline phosphatase); cholesterol (total, LDL, HDL); T3, T4 and thyroid stimulating hormone; Vital signs: Heart rate and Blood pressure; Physical examination; Electrocardiogram (ECG)- 12 lead ECG
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After the last visit of the final patient for each of the phases is complete |
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| E.5.2 | Secondary end point(s) |
Phase I:
At each CBD dose employed, we will describe-
(i) the frequency of dose-limiting toxicities per dose, over the 6-week period of treatment;
(ii) the change in safety and tolerability measures (frequency or mean value, as appropriate) at the end of week 6 compared to baseline (pre-treatment).
(iii) the change in CBD and quetiapine and its metabolite and/ or donepezil levels in blood at week 6 compared to baseline (pre-treatment).
(iv) the change in mean score at week 6 compared to baseline (pre-treatment) and 95% confidence intervals for measures of drug activity (pharmacodynamic signal)
(v) Percentage of patients compliant (*adherence) with treatment by the end of 6-weeks.
(vi) Retention rate (measure by drop-out) by the end of 6-week treatment and missing data.
*Adherence is defined as at least 50% of the dose taken, measured by pill count.
Phase II:
(i) Change in mean score on SAPS-PD at week 12 compared to baseline (pre-treatment)
(ii) Change in mean score on NPI-Q at week 12 compared to baseline (pre-treatment)
(iii) Change in mean score on SAPS-PD (delusion and hallucination subscales) at week 12 compared to baseline (pre-treatment)
(iv) Change in cannabidiol and quetiapine and its metabolite and/ or donepezil levels in blood at week 12 compared to baseline (pre-treatment).
(v) Change in score on United PD rating scale at week 12 compared to baseline (pre-treatment)
(vi) Change in score on Non-motor symptoms scale at week 12 compared to baseline (pre-treatment)
(vii) Change in score on Montreal Cognitive assessment scale at week 12 compared to baseline (pre-treatment)
(viii) Change in score on PDQ-39 scale at week 12 compared to baseline (pre-treatment)
(ix) Change in score on CGIC scale at week 12 compared to baseline (pre-treatment)
(x) Change in score on SCOPA-COG scale at week 12 compared to baseline (pre-treatment)
(xi) Change in score on SCOPA-SLEEP scale at week 12 compared to baseline (pre-treatment)
(xii) Change in score on Zarit Caregiver burden scale at week 12 compared to baseline (pre-treatment)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| at 6 weeks and 12 weeks for part 1 and part 2 respectively |
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| 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
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The end of the trial will be defined as database lock.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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