ADepT-PD: Antidepressants Trial in Parkinson's Disease

Sponsor

University College, London (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT03652870

Collaborator

London North West Healthcare NHS Trust (Other), King's College London (Other), University Hospital Plymouth NHS Trust (Other), NHS Lothian (Other)

408

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This is a randomised trial in a NHS setting, comparing the clinical effectiveness and cost-effectiveness of the selective serotonin reuptake inhibitor, escitalopram, and of the tricyclic antidepressant, nortriptyline, to placebo, undertaken in a real-life setting in addition to standard psychological care for the treatment of patients with depression in Parkinson's disease. Participants will be randomly allocated 1:1:1 to receive escitalopram or nortriptyline or placebo.

Condition or Disease	Intervention/Treatment	Phase
Depression Parkinson Disease	Drug: Nortriptyline Drug: Escitalopram Drug: Placebo	Phase 3

Detailed Description

Parkinson's disease is a progressive neurological disorder that leads to increasing disability and functional decline. Currently no medications have been shown to halt or delay disease progression and one of the most common complications in patients with this diagnosis is depression . Depressive disorders which affects approximately 40% of patients with Parkinson's disease. They are linked to functional impairment, cognitive decline and faster disease progression and are the main determinant of poor quality of life in Parkinson's disease. Psychological therapies are used via standard access to appropriate psychological services in the NHS, but often antidepressant medications are required. Despite the high incidence of depression in this population, However, no conclusive evidence on appropriate choice of antidepressants in Parkinson's disease exists in the NHS, and the risk of worsening of Parkinsonism and aggravation of non-motor features of Parkinson's disease by antidepressants pose particular challenges in this population.

Based on the previous evidence from small trials, the hypothesis is that both selective serotonin reuptake inhibitors and tricyclic antidepressants are effective compared to placebo and the difference in efficacy between tricyclic antidepressants and selective serotonin reuptake inhibitors is likely to be small, but that the tolerability of selective serotonin reuptake inhibitors is higher in this population than that of tricyclic antidepressants due to the rate of adverse effects. The trial is designed to have statistical power to identify effects that are clinically important and slightly smaller than the pooled effects identified in the existing trials of selective serotonin reuptake inhibitors.

Escitalopram is an selective serotonin reuptake inhibitor similar to citalopram, the most widely used selective serotonin reuptake inhibitor in the UK. Both citalopram and escitalopram, the S-enantiomer, are now off-patent with comparable costs and similar trial results. Until recently, escitalopram has been used less commonly in the NHS as because it was more expensive. However comparative trial data in major depression (including non-industry funded research) suggest that escitalopram is more effective than citalopram with similar or lower rates of side effects, and that it is associated with increased probability of response in trials of older patients with dementia and agitation. In addition, it has been reported that escitalopram has the highest probability of remission and is the most effective and cost-effective pharmacological treatment in a primary care setting.

Amitriptyline is the most widely used tricyclic antidepressants in the UK, but is used predominantly at low doses for pain and insomnia in Parkinson's disease. The side effect profile of amitriptyline makes it poorly tolerated in patients with Parkinson's disease at higher, antidepressant doses. Nortriptyline is a metabolite of amitriptyline. However, unlike amitriptyline it has mainly noradrenergic effects, and weakly blocks dopaminergic reuptake. It also has fewer sedative, α1-blocking and anticholinergic effects than amitriptyline (by a factor of 8). It has been evaluated in multiple trials over several decades and its efficacy and adverse event profile in depressive disorders has been well studied. The trial evidence on tricyclic antidepressants in depression in Parkinson's disease mainly reports on nortriptyline and desipramine (which is not available in the NHS). Whilst nortriptyline has a slightly higher cost than amitriptyline in the NHS, nortriptyline is a more appropriate medication for treatment of depression in this population. In addition, there is accumulating evidence from pre-clinical studies that nortriptyline may delay disease progression in Parkinson's disease.

Patients who meet eligibility criteria at the screening visit will be randomly assigned to receive 52 weeks of double-blind treatment with either escitalopram, or nortriptyline or placebo in a 1-1-1 ratio.

For the first two weeks of double-blind treatment, participants aged 65 years and under will be instructed to take one tablet per day of study drug, containing either 5 mg escitalopram or 25mg nortriptyline or placebo. Thereafter, the daily study medication dosage will be increased by one tablet per day, at two-weekly intervals, to a maximum of four tablets per day unless a subject is experiencing troubling side effects. In those aged over 65 years and in those with hepatic impairment the dose will be increased to two tablets after 2 weeks only, from 5 mg escitalopram to 10mg escitalopram or from 25 nortriptyline to 50mg nortriptyline.

After the primary endpoint at 8 weeks, all participants will continue on the same dose until the study visit at 52 weeks with an intermediate assessment at 26 weeks. Following the study assessment after 52 weeks on medication, the trial drug will be tapered off over 4 weeks in dose reductions of 25 mg for nortriptyline and 5mg for escitalopram every week (4 weeks for participants 65 years or under and 2 weeks for participants aged over 65 years or those with hepatic impairment).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

408 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Double blind

Primary Purpose:

Treatment

Official Title:

A Randomised Placebo-Controlled Trial of Escitalopram and Nortriptyline With Standard Psychological Care for Depression in Parkinson's Disease

Anticipated Study Start Date :

Nov 1, 2019

Anticipated Primary Completion Date :

Feb 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Nortriptyline 25mg tablet to be escalated from one tablet per day to a maximum of 4 tablets per day	Drug: Nortriptyline A medication used to treat conditions such as depression Other Names: Nortriptyline 25mg
Active Comparator: Escitalopram 5mg tablet to be escalated from one tablet per day to a maximum of 4 tablets per day	Drug: Escitalopram A medication used to treat conditions such as depression Other Names: Escitalopram 5mg
Placebo Comparator: Placebo The placebo tablet consists of lactose and magnesium stearate. One tablet to be escalated from one tablet per day to a maximum of 4 tablets per day	Drug: Placebo Lactose and magnesium stearate tablet to be used as a placebo. Other Names: Placebo oral tablet

Arm

Intervention/Treatment

Active Comparator: Nortriptyline

25mg tablet to be escalated from one tablet per day to a maximum of 4 tablets per day

Drug: Nortriptyline

A medication used to treat conditions such as depression

Other Names:

Nortriptyline 25mg

Active Comparator: Escitalopram

5mg tablet to be escalated from one tablet per day to a maximum of 4 tablets per day

Drug: Escitalopram

A medication used to treat conditions such as depression

Other Names:

Escitalopram 5mg

Placebo Comparator: Placebo

The placebo tablet consists of lactose and magnesium stearate. One tablet to be escalated from one tablet per day to a maximum of 4 tablets per day

Drug: Placebo

Lactose and magnesium stearate tablet to be used as a placebo.

Other Names:

Placebo oral tablet

Outcome Measures

Primary Outcome Measures

Depressive symptoms [8 weeks]
Measured using the Beck Depression Inventory II to assess the severity of depression

Secondary Outcome Measures

Level of depression [26 and 52 Weeks]
Measured using Beck Depression Inventory II to assess the severity of depression
Severity of depression [8, 26 and 52 Weeks]
Measured using Patient Health Questionnaire 9 to monitor the severity of depression and response to treatment
Number of patients suffering side effects [8, 26 and 52 Weeks]
Measured using the Toronto side effects scale which records symptoms specific to depression.
Number of participants suffering side effects [8, 26 and 52 Weeks]
Measured using reporting of other adverse events not reported on the Toronto side effects scale.
Overall clinical effectiveness [8, 26 and 52 Weeks]
Measured using the Global Clinical Impression scale - change in health question to rate the severity of the patient's illness.
Anxiety symptoms [8, 26 and 52 Weeks]
Measured using the Parkinson's Anxiety Scale (PAS) to measure anxiety in patients with Parkinson's disease
Capability [8, 26 and 52 Weeks]
Measured using ICECAP to measure the patient's capability
Self-rated health score [8, 26 and 52 Weeks]
Measured using EQ-5D-5L to measure the patients' health score on the day of assessment
Health and social care resource [8, 26 and 52 Weeks]
Measured using modified Client Service Receipt Inventory (CSRI) to collect information on the whole range of services and supports patients may use
Changes in concomitant medication [8, 26 and 52 Weeks]
Measured using concomitant medication logs
Motor and non-motor experiences [8, 26 and 52 Weeks]
Measured using the Movement Disorder Society - Unified Parkinson's Disease Rating Scale to assess both motor and non-motor symptoms associated with Parkinson's disease
Cognitive function [8, 26 and 52 Weeks]
Measured using Montreal Cognitive Assessment (MoCA) to assess for mild cognitive dysfunction
Levodopa equivalence dose [8, 26 and 52 Weeks]
Measured using concomitant medication logs to calculate the contribution made by each of the patient's Parkinson's drugs, using, as a common denominator, an estimate of the levodopa equivalent dose
Number of drop outs [8, 26 and 52 Weeks]
Measured using recruitment logs to determine the number of patients who did not complete the study to the end of study treatment
Carer's self-rated health score [8, 26 and 52 Weeks]
Measured using EQ-5D-5L to measure the carer' health score on the day of assessment
Carer reported quality of life [8, 26 and 52 Weeks]
Measured using Carers Quality of Life Questionnaire for Parkinsonism to assess the quality of life of carers of patients with Parkinson's disease

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with a diagnosis of idiopathic Parkinson's Disease, based on a history and neurological exam performed by the enrolling investigator with presence of at least two of the three cardinal signs of Parkinson's Disease: rigidity, bradykinesia, and rest tremor with no evidence of diagnostic alternatives. Patients who have been treated with levodopa must have demonstrated a clear response.
Aged 18 to 85 years
Fulfilling diagnostic (DSM-V) criteria for a depressive disorder (i.e., major depressive disorder or persistent depressive disorder) or operationally defined subsyndromal depression (presence of two or more depressive symptoms at threshold or subthreshold levels, at least one of which has to include depressed mood or anhedonia
Beck Depression Inventory-II (BDI-II) score ≥14
Written informed consent provided

Exclusion Criteria:

Women who are pregnant, breastfeeding or of childbearing potential without effective contraception (hormonal or barrier method of birth control; or abstinence)
Patients not able to communicate answers to the self-rating questionnaires
Patients with Montreal Cognitive Assessment (MoCA) score <16 or without capacity to consent
Treatment with an antidepressant within 4 weeks of enrolment (except for a small dose of amitriptyline up to 50 mg for indications other than depression)
Absolute contraindications to escitalopram or nortriptyline
Medications contraindicated on nortriptyline or escitalopram. These include:
Non-selective and selective irreversible monoamine oxidase inhibitors (MAOIs) within 14 days. However, the antiparkinsonian selective reversible MAO-B inhibitors rasagiline, selegiline and safinamide are not contraindicated
Concomitant QT prolonging drugs, including domperidone, apomorphine at high doses (single dose or hourly rate of >6mg), certain neuroleptics (not quetiapine or clozapine), quinine, class IA and III antiarrhythmics (amiodarone, dronedarone and disopryamide), the antihistamines astemizole, mizolastine, the antimicrobial agents sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, anti-malarian treatment),and some antiretrovirals
Patients indicating active suicidal ideation or intent on the BDI-II item 9 and who, after clinical review of risk using the standardised Suicide Risk Management Protocol, need to be referred for immediate treatment
Treatment with antiparkinsonian medication should be optimized and stable within 4 weeks of screening and with no plans to change up to primary endpoint (8 weeks)
Participation in another clinical trial of an investigational medicinal product or device within the last 30 days