INfusion VErsus STimulation in Parkinson's Disease (INVEST)

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

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.

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.

Parkinson, Parkinson's Disease, Deep Brain Stimulation, levodopa-carbidopa, Duodopa, continuous intrajejunal infusion

Continuous delivery of levodopa-carbidopa intestinal gel through an intrajejunal percutaneous tube (Duodopa, CLI, CILI)

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.

Changes from Baseline on Parkinson's Disease Questionnaire-39 (PDQ-39; score 0-100, higher score is lower quality of life)

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)

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)

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

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)

Change from Baseline on clinical Dyskinesia Rating Scale (CDRS; score 0-28, high score is more dyskinesia)

Change from Baseline on Amsterdam Linear Disability Score (ALDS, 29 items; 0-100, high score is high level of functional status)

Change from Baseline on SCOPA-AUT (SCales for Outcomes in PArkinson's Autonomic symptoms; score 0-92, higher score is more symptoms)

Change from Baseline in Hoehn and Yahr stage (H&Y stage; 1-5: a higher score is more disease progression)

Change from Baseline on Parkinson's Disease Cognition Rating Scale (PD-CRS; 0-134, higher score is a result of better cognitive performance)

Change from Baseline in Mattis Dementia Rating score (score 0-144, higher score is better cognitive function)

Change from Baseline in WAIS IV (Wechsler Adult Intelligence Scale IV - subsection similarities; score 0-36, higher is better)

Change from Baseline in Rivermead Behavioral memory test (subsection stores; score 0-42, higher is better)

Change from Baseline in Trail making test (score 10-500, higher score is longer time, i.e. worse score)

Change from Baseline in Starkstein's Apathy Scale (SAS; score 0-42, high score is more signs of apathy)

Change in presence of Compulsive Disorder from Baseline assessed with Parkinson's Disease Impulsive-Compulsive Disorders Questionnaire (QUIP, utilizing established thresholds)

Changes from Baseline on Columbia Suicide Severity Rating Scale (range 0-25, higher score is worse outcome)

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;

van Poppelen D, Sisodia V, de Haan RJ, Dijkgraaf MGW, Schuurman PR, Geurtsen GJ, Berk AEM, de Bie RMA, Dijk JM. Protocol of a randomized open label multicentre trial comparing continuous intrajejunal levodopa infusion with deep brain stimulation in Parkinson's disease - the INfusion VErsus STimulation (INVEST) study. BMC Neurol. 2020 Jan 31;20(1):40. doi: 10.1186/s12883-020-1621-y.