INfusion VErsus STimulation in Parkinson's Disease

Study Overview
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Brief Summary
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Both Continuous intrajejunal Levodopa Infusion (CLI) and Deep Brain Stimulation (DBS) are accepted therapies for the treatment of advanced Parkinson's disease (PD). To date, no comparative studies have been executed. The INVEST study is an open label randomised controlled trial with cost-effectiveness as primary outcome. The main clinical outcome is quality of life; secondary outcomes are motor symptoms and neurological impairments, among others.

Detailed Description
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Rationale: Both Continuous intrajejunal Levodopa Infusion (CLI) and Deep Brain Stimulation (DBS) are accepted therapies for the treatment of advanced Parkinson's disease (PD). As directly comparative studies are lacking, it is unknown whether one of the therapies is more effective. Besides, CLI seems to be more expensive. To determine the optimal treatment in advanced PD, a comparative study of CLI and DBS is warranted. Hypothesis: We hypothesize that CLI is a more expensive therapy in advanced PD than DBS and that the surplus in costs is not cost-effective with regard to benefits for the patient and caregivers in quality of life, PD symptoms and adverse events. Objective: To realize a cost-effective treatment strategy in advanced PD. Study design: Prospective, randomized, open label multicentre trial, with two additional patient preference treatment arms (patient preference randomized trial). Study population: Patients with PD who, despite optimal pharmacological treatment, have severe response fluctuations, dyskinesias, painful dystonia, or bradykinesia. A total of 66 patients will be randomized, at least 120 patients will be included in the patient preference arms. Intervention: Patients will be randomized to DBS or CLI. For DBS treatment, 2 electrodes will be implanted in the brain. The electrodes are connected to an implanted pulse generator, which will be placed subcutaneously in the subclavian area. For CLI treatment, a tube will be placed in the jejunum via a percutaneous endoscopic gastrostomy (PEG). This tube is connected to an external pump that delivers the levodopa-gel. Main study parameters: There are 8 specified assessment visits: at baseline, and 1 week, 3, 6, 9, 12, 24 and 36 months after start of the study treatment. The primary health economic outcomes are the costs per changed unit on the PDQ-39 (and the costs per changed QALY for the cost-effectiveness and cost-utility analyses, respectively. The EQ-5D will be applied as the utility measure. Change in quality of life (expressed in the between group difference in change from baseline to 12 months on the PDQ-39 summary index score) is the main clinical outcome. Among the secondary outcomes are functional health, complications and adverse effects, use of care and perceptions of patients and neurologists regarding both treatments.

Official Title
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Treatment in Advanced Parkinson's Disease: Continuous Intrajejunal Levodopa INfusion VErsus Deep Brain STimulation

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: Continuous intrajejunal infusion of levodopa-carbidopa
* Device: deep brain stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Idiopathic Parkinson's Disease with bradykinesia and at least two of the following signs; resting tremor, rigidity, and asymmetry; Despite optimal pharmacological treatment, at least one of the following symptoms: severe response fluctuations, dyskinesias, painful dystonia or bradykinesia; A life expectancy of at least two years. Exclusion Criteria: Age below 18 years Previous PD-neurosurgery (e.g., DBS, pallidotomy, thalamotomy); Previous CLI (through a PEG-tube or Nasal Jejuna| tube); Hoehn and Yahr stage 5 at the best moment during the day; Other severely disabling disease; Dementia or signs of severe cognitive impairment Psychosis; Current depression; Contraindications for DBS surgery, such as a physical disorder making surgery hazardous; Contraindications for PEG surgery such as interposed organs, ascites and oesophagogastric varices, or for Duodopa; Pregnancy, breastfeeding, and women of child bearing age not using a reliable method of contraception; No informed consent; Legally incompetent adults;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized Clinical Trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: continuous levodopa infusion<br>continuous intrajejunal infusion of levodopa-carbidopa | Drug: Continuous intrajejunal infusion of levodopa-carbidopa<br>* Continuous delivery of levodopa-carbidopa intestinal gel through an intrajejunal percutaneous tube (Duodopa, CLI, CILI)<br>* Other names: Intestinal levodopa-carbidopa infusion;|
| Active Comparator: deep brain stimulation<br>Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) | Device: deep brain stimulation<br>* Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN)<br>* Other names: DBS-STN;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cost effectiveness in costs per changed unit on PDQ-39 | The costs per changed unit on the PDQ-39. | 12 months | 
| Cost-utility in costs per changed Quality Adjusted Life Year (QALY, years) | The costs per QALY. The EuroQol 5D-3L (EQ-5D; 5 questions, each score 1-3, providing a health state, to be translated with provided Valuation set) will be applied as the utility measure. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life (on PDQ-39) | Changes from Baseline on Parkinson's Disease Questionnaire-39 (PDQ-39; score 0-100, higher score is lower quality of life) | 12, 24 and 36 months | 
| Quality of life (on EQ-5D) | Change from Baseline on EuroQol 5D-3L (EQ-5D; 5 questions, each score 1-3, providing a health state, to be translated with provided Valuation set) | 12, 24 and 36 months | 
| Motor symptoms | Score changes from Baseline in off and on state on Movement Disorder Society's Unified Parkinson Disease Rating Scale (MDS-UPDRS part 3; 0-132, high score is more motor symptoms) | 12 and 36 months | 
| Motor symptoms: time in off and on-state | Change from Baseline in time in off-state, on-state without dyskinesias, on-state without troublesome dyskinesias and on-state with troublesome dyskinesias measured with motor symptom diary | 12, 24 and 36 months | 
| Motor experiences of daily living | Changes from Baseline on MDS-UPDRS part 2 (Movement Disorder Society's Unified Parkinson Disease Rating Scale (MDS-UPDRS part 2; score 0-52, high score is more worse health) | 12, 24 and 36 months | 
| Dyskinesia | Change from Baseline on clinical Dyskinesia Rating Scale (CDRS; score 0-28, high score is more dyskinesia) | 12 and 36 months | 
| PD-medication (levodopa-equivalent dose) | Change from Baseline expressed in levodopa-equivalent dose | 12, 24 and 36 months | 
| Functional health status | Change from Baseline on Amsterdam Linear Disability Score (ALDS, 29 items; 0-100, high score is high level of functional status) | 12, 24 and 36 months | 
| Non-motor symptoms (Non Motor Symptom Checklist) | Changes from Baseline on Non Motor Symptom Checklist | 12, 24 and 36 months | 
| Non-motor symptoms (Rotterdam Symptom Checklist | Change from Baseline on Rotterdam Symptom Checklist | 12, 24 and 36 months | 
| Non-motor symptoms (SCOPA-AUT) | Change from Baseline on SCOPA-AUT (SCales for Outcomes in PArkinson's Autonomic symptoms; score 0-92, higher score is more symptoms) | 12, 24 and 36 months | 
| Disability | Change from Baseline in Hoehn and Yahr stage (H&Y stage; 1-5: a higher score is more disease progression) | 12, 24 and 36 months | 
| Cognitive functioning | Change from Baseline on Parkinson's Disease Cognition Rating Scale (PD-CRS; 0-134, higher score is a result of better cognitive performance) | 12 and 36 months | 
| Cognitive functioning Mattis | Change from Baseline in Mattis Dementia Rating score (score 0-144, higher score is better cognitive function) | 12 and 36 months | 
| Neuropsychologic functioning BNT | Change from Baseline in Boston Naming Test (range 0-30, higher is better) | 12 and 36 months | 
| Neuropsychologic functioning Letter Fluency | Change from Baseline in Letter Fluency (score 0-100, higher is better) | 12 and 36 months | 
| Neuropsychologic functioning WAIS IV | Change from Baseline in WAIS IV (Wechsler Adult Intelligence Scale IV - subsection similarities; score 0-36, higher is better) | 12 and 36 months | 
| Neuropsychologic functioning Reading | Change from Baseline in Dutch Reading Test (0-100, higher is better) | 12 and 36 months | 
| Neuropsychologic functioning Word Test | Change from Baseline in 15 word test (0-75, higher is better) | 12 and 36 months | 
| Neuropsychologic functioning Memory | Change from Baseline in Rivermead Behavioral memory test (subsection stores; score 0-42, higher is better) | 12 and 36 months | 
| Neuropsychologic functioning Trail making | Change from Baseline in Trail making test (score 10-500, higher score is longer time, i.e. worse score) | 12 and 36 months | 
| Neuropsychologic functioning Color Word | Change from Baseline in Stroop Color Word Test (score 10-1000, higher is better) | 12 and 36 months | 
| Neuropsychologic functioning Line Orientation | Change from Baseline in Judgement of line orientation (score 0-30, higher is better) | 12 and 36 months | 
| Neuropsychologic functioning Clock | Change from Baseline in Clock construction (score 0-14, higher is better) | 12 and 36 months | 
| Psychiatric disease | Change from Baseline in Mini International Neuropsychiatric Interview | 12 and 36 months | 
| Apathy | Change from Baseline in Starkstein's Apathy Scale (SAS; score 0-42, high score is more signs of apathy) | 12, 24 and 36 months | 
| Compulsive Disorders | Change in presence of Compulsive Disorder from Baseline assessed with Parkinson's Disease Impulsive-Compulsive Disorders Questionnaire (QUIP, utilizing established thresholds) | 12, 24 and 36 months | 
| Anxiety | Changes from Baseline on Hamilton Anxiety Scale (HAM-A; 0-56, high score is worse outcome) | 12 and 36 months | 
| Depression | Change from Baseline on Hamilton Depression Rating Scale (HDRS; 0-68, higher score is worse outcome) | 12 and 36 months | 
| Suicidality | Changes from Baseline on Columbia Suicide Severity Rating Scale (range 0-25, higher score is worse outcome) | 12 and 36 months | 
| Adverse effects | Number of participants with adverse effects and description of these | 12, 24 and 36 months | 
| Complications and description of complications | Number of participants with complications and description of these | 12, 24 and 36 months | 
| Stopping allocated treatment | Number of participants who stopped treatment | 12, 24 and 36 months | 
| Treatment failure | Number of participants with treatment failure | 12, 24 and 36 months | 
| Treatment cross-over | Number of participants with treatment cross-over | 12, 24 and 36 months | 
| Patient satisfaction | Descriptive questionnaire, no scale applied, descriptive statistics | 12, 24 and 36 months | 
| Patients attitude to treatment | Change from Baseline on Patient Reported Outcome Scale (range 0-128, high score is worse outcome) | 12, 24 and 36 months | 
| Medical costs | Calculation of the total costs in euro by means of iMCQ (iMTA Medical Consumption Questionnaire) | 12, 24 and 36 months | 
| Non-medical care costs | Calculation of the total costs in euro by means of iPCQ (iMTA Productivity Cost Questionnaire) | 12, 24 and 36 months | 
| Caregiver burden | Descriptive questionnaire, no scale applied, descriptive statistics | 12, 24 and 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson, Parkinson's Disease, Deep Brain Stimulation, levodopa-carbidopa, Duodopa, continuous intrajejunal infusion