Dopaminergic restauratIon by intraVEntriculaire Administration

Study Overview
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Brief Summary
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Prospective monocentric randomized controlled open-label proof-of-concept study in cross-over of two 1-month periods and a long-term follow-up period not to exceed September 30, 2023, with 2 groups: Intracerebroventricular A-dopamine versus optimized oral medical treatment in parkinsonian patients at the stage of severe motor complications (fluctuations and dyskinesias) related to oral L-dopa. In this study it will be expected to: 1) a higher benefit on motor symptoms 2) without tachyphylaxis, 3) a good ergonomic of the intra-abdominal pump refilled with A-dopamine every two weeks as compared with the numerous daily L-dopa doses and 4) a good safety profile of this classical neurosurgical procedure.

Detailed Description
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Parkinson's disease (PD) is the second most frequent neurodegenerative disorder worldwide. The loss of dopamine through denervation in the striatum as a result of progressive neuronal degeneration in the substantia nigra pars compacta (SNpc), is the primary neurotransmitter marker of the disease. Since dopamine does not cross the digestive mucosa or the blood brain barrier, its lipophilic precursor L-dopa has been employed and remains the pivotal oral medication. However, after persistent use over several years, many pharmacokinetic drawbacks contribute to the occurrence of motor fluctuations and dyskinesia. Indeed L-dopa has a short half-life, limited and variable reabsorption through the digestive and blood brain barriers and potentially harmful peripheral distribution. Moreover, L-dopa requires the aromatic L-amino acid decarboxylase for the synthesis of dopamine, which declines in the striatum with disease progression. Intermittent oral doses of L-dopa induce discontinuous stimulation of striatal dopamine receptors that in turn contribute to dysfunctional dopaminergic pathways. Thus, continuous dopamine administration is considered more physiologically appropriate by preventing oscillations in neurotransmitter concentration. It has been previously demonstrated that intracerebroventricular (i.c.v.) administered dopamine with an anti-oxidant adjuvant (sodium metabisulfite; SMBS) transiently improved motor handicap and increased dopamine in rat brains with unilateral neurotoxin 6-hydroxydopamine (6-OHDA)-induced damage as well as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated monkeys. The clinical feasibility of this administrative route has been supported by two PD patient case reports of dopamine infusion to the frontal ventricle, whereby a reduction in motor handicap was observed. Indeed, human case reports described a good tolerance to dopamine infusion over 1 year with a smooth control of motor symptoms. However, both preclinical and clinical reports also highlight two overriding problems that prevented further development; occurrence of tachyphylaxis and oxidation of dopamine causing enhanced dopamine metabolism and oxidative stress. These prior challenges had been overcome by demonstrating that dopamine oxidation can be avoided by preparing, storing and administering dopamine in very low oxygen conditions (<0.01% of O2 = anaerobia = A-dopamine). In vitro, a positive effect of dopamine was observed on non-oncogenic dopaminergic neurons (LHUMES) survival. In vivo, A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal dopaminergic neurons in mice after 7 days of MPTP intoxication that was not evident with either dopamine prepared aerobically (O-dopamine) or in the presence of a conservator (sodium metabisulfite, SMBS) or L-dopa. In the 6-OHDA rat model, continuous circadian i.c.v injection of A-dopamine over 30 days also improved motor activity without occurrence of tachyphylaxis. This safety profile was highly favorable, as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral L-dopa treatment. In MPTP monkeys, A-dopamine improved the doparesponsive motor symptoms without inducing any dyskinesia or tachyphylaxis during 2 months. Indicative of a new therapeutic strategy for patients suffering from L-dopa related complications with dyskinesia, continuous i.c.v of A-dopamine had greater efficacy in mediating motor impairment over a large therapeutic index without inducing dyskinesia and tachyphylaxis. In addition, greater advances in programmable pumps now minimize tachyphylaxis by allowing administration of a lower effective dopamine dose in accordance with the circadian cycle. Of note, PD patients from previous studies received O-dopamine and at the same dose throughout a 24 hours cycle. Prior experience obtained from the use of an apomorphine pump and duodopa® has identified the need to differentiate between diurnal and nocturnal minimum efficient dose in order to avoid worsening motor fluctuations. Thus, continuous circadian i.c.v. administration of dopamine close to the striatum is feasible, efficient and safe in models of PD, supporting clinical development of this strategy to be revisited in PD patients with L-dopa related complications with dyskinesia.

Official Title
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A New Concept of Continuous Dopaminergic Stimulation by Cerebroventricular Administration of A-dopamine (Dopamine Stored in Anaerobia) for Severe Motor Fluctuations in Parkinson's Disease?

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: A-dopamine
* Drug: optimized oral treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Parkinson's disease in the stage of severe motor and non-motor complications related to L dopa Parkinson's disease according to MDS criteria Severe motor fluctuations with at least 2 hours of Off period and/or 1 hour of dyskinesia despite an optimized oral dopaminergic treatment with at least 5 daily doses of oral L-dopa and a dopaminergic agonist (daily taken or at least tried: oral, subcutaneous patch, apomorphine pump) Patient who met criteria for a second-line invasive treatment such as deep brain stimulation (subthalamic or internal pallidum) or intrajunal administration of levodopa gel (Duodopa®) Patient with a contraindication or who preferred the DIVE strategy as compared with the two other invasive treatments (subthalamic nucleus stimulation Duodopa®) because of the following advantages: lower neurosurgical risk than bilateral deep brain implantation of electrodes and a better ergonomic than Duodopa® but knowing that the benefits of DIVE are not yet demonstrated. Affiliate or beneficiary of a social security scheme Subject having signed informed consent Patient willing to comply with all procedures of the study and its duration No planned changes in lifestyle (nutritional and physical, social interactions) during the life of the protocol Exclusion Criteria: Patients aged over 75 years Patients with severe other chronic neurological or mental pathology Patients without at least 5 doses of L-dopa per day and/or with less than 2 hours of Off period and/or 1 hour of dyskinesia Patients with no try of apomorphine pump Subjects with a previous psychiatric history (based on the semi-structured psychiatric interview with the MINI of DSM V) : severe depression, severe generalized anxiety, suicidal tendencies, psychotic symptoms, severe mood disorders, mania, schizophrenia. Dysthymia and an isolated history of depression or moderate anxiety do not constitute an exclusion criterion. Patients with dementia according to the MDS criteria and MOCA score ≤ 22. Patients with severe other pathology that could impact the survival at short- or medium-term, malnourished patients, cachexia Patients with contra indication to general anesthesia Taking treatments containing guanethidine or its relatives, or non-selective and selective monoamine oxidase A inhibitors (iproniazid, moclobemide, toloxatone) Patients with contra indication to neurosurgery (severe cerebral atrophy, brain tumor, severe infractus, ventricular pathology or other brain pathology) that can interfere with ventricular access. Contraindication to the abdominal placement of a pump and a subcutaneous catheter altering the healing and the transcutaneous filling (ex: major obesity, skin pathology,...) Contraindication to the realization of an MRI (pace maker, claustrophobia...). In case of allergy or intolerance to gadolinium, the latter will not be injected during the preoperative MRI Contraindication to DaTscan and/or F-dopa PET (for the first 5 patients included) Patients with active infectious disease Patient with hemostasis disorders Patient with uncontrolled cardiac diseases and uncontrolled arterial hypertension Patients with congenital or acquired immune deficiency that could favor infection Subject during breastfeeding or pregnancy Patient under guardianship or curatorship Patient already participating in another therapeutic trial with the use of an investigational drug or in a period of exclusion period

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cerebroventricular administration of A- dopamine<br>Cerebroventricular administration of dopamine prepared and stored in anaerobia | Drug: A-dopamine<br>* During the phase 1 (titration), it is planned to increase dopamine by maximum 0.25 mg per hour over the daytime period, which corresponds to a maximum increase of 4.5 mg per day (based on the 18 hours of the daytime period, since nocturnal needs are much less important). Then, depending on tolerance and efficacy, conservative titration will be continued for a target dose of 30-87 mg per day. During the phase 2 (efficacy), the treatment will be maintained at the minimum effective dose, planned between 30 and 87 mg per day, for 30 days.<br>|
| Active Comparator: Optimized oral dopaminergic treatment<br>Optimized oral dopaminergic treatment with L-dopa (at least 5 doses a day) with dopaminergic agonist, monoamine B inhibitor and catechol-o-methyl inhibitor (if tolerated) (A-dopamine replaced by saline un the pump during optimized oral dopaminergic treatment) | Drug: optimized oral treatment<br>* The patient will received his usual dopaminergic treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Time Over Target | This is the amount of time that the BKS was over target and is a representation of OFF time in the period from 09:00-18:00 and is the proportion of time that a subject's BKS is greater than the target used in this study (BKS=26). The PTO does not include periods of immobility. | Month 1 through Month 2 | 
| The number of hours with either perfect control or with a slight slowdown on the 7-day schedule | Primary endpoint of the long-term follow-up phase . This will be compared to that obtained in phase 2 to demonstrate the maintenance of long-term efficacy control. | follow up visits every 6 months until the deadline of September 30, 2023 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| bradykinesia score | BKS calculated every two minutes throughout the period of wearing the logger. The median value of these BKS over the period from 09:00-18:00 for the full recording period is known as the median BKS and this correlates with the UPDRS III assessed at the time of doing the Kinetigraph Connected Actimeter (PKG®, Globalkinetics) | At baseline and during the last day of each month of assessment ( an average 4 months) | 
| dyskinesia score | DKS is calculated every two minutes throughout the period of that the logger is worn. The median value of these DKS over the period from 09:00-18:00 for the full recording period is known as the median DKS and this correlates with the modified Abnormal Involuntary Movement Score assessed at the time of donning the Kinetigraph Connected Actimeter (PKG®, Globalkinetics) | At baseline and during the last day of each month of assessment ( an average 4 months) | 
| The Percent Time Immobile | PTI over the period from 09:00-18:00. Immobility means that the logger, while being worn by the subject was entirely still for a two-minute period. This has been shown to correlate with the polysomnographic recordings of sleep. | At baseline and during the last day of each month of assessment ( an average 4 months) | 
| The Fluctuation Dyskinesia Score | FDS estimates the amount of variability in bradykinesia and dyskinesia as measured by the PKG over the course of the 6 days of recording. It provides a measure of the extent of fluctuations in bradykinesia and dyskinesia. | At baseline and during the last day of each month of assessment ( an average 4 months) | 
| The Percent Time Tremor | PTT is the proportion of time in the period from 09:00-18:00 that a subject spends with tremor. Tremor is likely to be present if PTT score >1%. | At baseline and during the last day of each month of assessment ( an average 4 months) | 
| Unified Parkinson's Disease Rating Scale part III | The Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III. MDS-UPDRS Part III measures motor examination. Part III consists of 33 scores based on 18 items, and each question is anchored with five response scale from 0(normal) to 4(severe). | At baseline and during the last day of each month of assessment ( an average 4 months); and follow up visits every 6 months until the deadline of September 30, 2023 | 
| Abnormal Involuntary Movement Score | The AIMS rates 10 items of involuntary movement, each item ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Items assess facial, oral, extremity, and trunk movements, as well as self-awareness of abnormal movements. | At baseline and during the last day of each month of assessment ( an average 4 months); and follow up visits every 6 months until the deadline of September 30, 2023 | 
| Unified Dyskinesia Rating Scale | The scale provides measurements for 'on-dyskinesias' and 'off-dyskinesias' and contains recommendations for descriptions of each type of involuntary movement | At baseline and during the last day of each month of assessment ( an average 4 months); and follow up visits every 6 months until the deadline of September 30, 2023 | 
| Montreal Cognitive Assessment | Cognitive function was assessed by using MoCA score. Cognitive impairment was considered present when MoCA scores were <26 . | At baseline and during the last day of each month of assessment ( an average 4 months); and follow up visits every 6 months until the deadline of September 30, 2023 | 
| Neuropsychiatric Inventory | otal NPI score is defined as the sum of the individual category scores. Higher scores on NPI indicate a more frequent and/or severe presence of neuropsychiatric behavioral changes. The following domains will be included in the subscore: Depression/Dysphoria, Anxiety, Apathy/Indifference, Irritability/Lability, Agitation/Aggression, and Disinhibition. | At baseline and during the last day of each month of assessment ( an average 4 months); and follow up visits every 6 months until the deadline of September 30, 2023 | 
| parkinson anxiety scale | This scale is a 12-item observer or patient-rated scale with three subscales, for persistent and episodic anxiety, and avoidance behavior. | At baseline and during the last day of each month of assessment ( an average 4 months); and follow up visits every 6 months until the deadline of September 30, 2023 | 
| Lille apathy rating scale | The Lille apathy rating scale is a measure of apathy through nine domains (each corresponding to a clinical manifestation of apathy: everyday productivity, interests, taking the initiative, novelty seeking, motivation - Voluntary actions, emotional responses, concern, social life & self-awareness) and 33 queries. The interview is structured, with a precise scoring mode for each reply (-2 to 2); when an item does not apply to the patient or the reply cannot be classified, it is scored 0 (for non-applicable and/or non-classifiable) The scale's overall score ranges from -36 to +36, with highest scores reflecting apathy severity. 4 factorial sub-scores (intellectual curiosity, emotion, action initiation and self-awareness) are calculated from sub-scale scores. | At baseline and during the last day of each month of assessment ( an average 4 months); and follow up visits every 6 months until the deadline of September 30, 2023 | 
| Parkinson's Disease Behavioral Assessment | It rates 21 items that have 0 to 4 options : 0 = absent 1 = mild 2 = moderate 3 = marked 4 = severe | At baseline and during the last day of each month of assessment ( an average 4 months); and follow up visits every 6 months until the deadline of September 30, 2023 | 
| Global Impression of change | The clinician Global Impression of change provides a brief, stand-alone assessment of the clinician's view of the patient's global functioning prior to and after initiating a study medication. It ranges from severely impaired to dramatically improved. | At baseline and during the last day of each month of assessment ( an average 4 months); and follow up visits every 6 months until the deadline of September 30, 2023 | 
| the Schwab and England scale | The Schwab & England activities of daily living evaluates patients' autonomy through a percentage ranging from 0% (=Vegetative functions such as swallowing, bladder and bowel functions are not functioning. Bedridden.) to 100% ( = Completely independent. Able to do all chores without slowness, difficulty or impairment. Essentially normal). | At baseline and during the last day of each month of assessment ( an average 4 months); and follow up visits every 6 months until the deadline of September 30, 2023 | 
| Epworth Sleepiness Scale Questionnaire | Epworth Sleepiness Scale Questionnaire. Outcome measure is between 0 and 24 with a score between 0-8 indicating normal Daytime sleepiness, a score between 9-14 indicating mild sleep deficiency and a score above 15 an excessive daytime sleepiness. | At baseline and during the last day of each month of assessment ( an average 4 months); and follow up visits every 6 months until the deadline of September 30, 2023 | 
| Parkinson's Disease Sleep Scale | his scale allows to self-rate and quantify the level of sleep disruption being experienced. It rates 15 items that have 0 to 4 options, 4 is the worth option. | At baseline and during the last day of each month of assessment ( an average 4 months); and follow up visits every 6 months until the deadline of September 30, 2023 | 
| Parkinson's Disease Quality of Life Questionnaire (PDQ39) | Parkinson's Disease Quality of Life Questionnaire (PDQ-39): the 39-Item Parkinson's Disease Questionnaire (PDQ-39) is a commonly used measure of self-appraisal in PD. It is a measure of health status and quality of life, by assessing difficulties in 8 dimensions of daily living: mobility (10 items), activities of daily living (6 items), emotional well-being (6 items), stigma (4 items), social support (3 items), cognition (4 items), communication (3 items) and bodily discomfort (3 items). The frequency of each event is determined by selecting one of 5 options: never (scored 0) / occasionally (scored 1) / sometimes (2) / often (3) / always (4). Each dimension total score range from 0 to 100, with lower scores reflecting better quality of life. | At baseline and during the last day of each month of assessment ( an average 4 months); and follow up visits every 6 months until the deadline of September 30, 2023 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's disease, dopamine, L-dopa related motor complications, dyskinesia, symptomatic treatment, disease modifying effect