Dopaminergic RestauratIon by IntraVEntriculaire Administration

NCT ID: NCT04332276

Last Updated: 2024-09-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-18
• Study Completion Date: 2024-05-06

Brief Summary

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

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.

Conditions

Parkinson Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Cerebroventricular administration of A- dopamine

Cerebroventricular administration of dopamine prepared and stored in anaerobia

Group Type: EXPERIMENTAL

A-dopamine

Intervention Type: DRUG

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.

Optimized oral dopaminergic treatment

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)

Group Type: ACTIVE_COMPARATOR

optimized oral treatment

Intervention Type: DRUG

The patient will received his usual dopaminergic treatment.

Interventions

A-dopamine

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.

Intervention Type: DRUG

optimized oral treatment

The patient will received his usual dopaminergic treatment.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Parkinson&#39;s disease at the stage of L-dopa-induced severe motor and non-motor complications
• Men or women over 18 years old
• Parkinson&#39;s disease according to MDS criteria
• Severe motor complications including motor fluctuations with at least 2 hours of Off and 1 hour of dyskinesias uncontrolled by optimized oral drug therapy, i.e. with at least 5 doses of L-dopa and the addition or trial of a dopaminergic agonist (if tolerated) per os or by apomorphine pump
• The patient meets the criteria for a second-line invasive treatment such as deep brain stimulation (subthalamic or medial pallidum) or intrajejunal administration of levodopa gel (Duodopa®).
• Patients with a contraindication or who prefer this invasive therapeutic alternative to the other two existing and validated therapies (subthalamic stimulation or Duodopa®) because of its advantages: lower theoretical risk of intracerebroventricular delivery compared to subthalamic stimulation and better ergonomics than Duodopa®, but with the disadvantage of an as yet unproven benefit.
• Social security
• Able to provide free and informed consent to participate in research
• Patient willing to comply with all study procedures and duration
• Patient not planning to change lifestyle (nutritionally, physically or socially) during study participation

Exclusion Criteria

• Over 75 years of age
• Subjects not receiving at least 5 doses per day of oral dopaminergic therapy
• Subject without a prior trial of an apomorphine pump (of lower risk); apomorphine pump treatment being a failure or a contraindication or refused by the patient
• Patient with parkinsonian dementia (DSM IV and MDS criteria and MOCA score &lt; or equal to 22)
• Isolated patient, defined as the absence of a caregiver present at least 3 hours/day in the patient&#39;s home.
• History of a fall in the last 6 months and/or a score &gt;1 on items 2.12 (Walking and balance) and/or 3.12 (Postural stability) of the MDS-UPDRS scale
• Presence of another serious pathology threatening short- or medium-term vital prognosis, malnourished or cachectic patient.
• Hemostasis disorders
• Cardiac rhythm disorders and/or heart failure not controlled by treatment
• Uncontrolled blood pressure release
• Breastfeeding and pregnancy
• Women of childbearing age without effective contraception
• Contraindication to general anaesthesia
• Taking treatments containing guanethidine or related compounds or non-selective and selective monoamine oxidase A inhibitors (iproniazid, moclobemide, toloxatone)
• Neurosurgical contraindication (severe cerebral atrophy, brain tumor, infarction or other cerebral pathology, CSF flow disorder)
• Contraindication to abdominal placement of a subcutaneous pump and catheter that impairs healing and transcutaneous filling (e.g. major obesity, skin pathology, etc.).
• Contraindication to MRI (pacemaker, claustrophobia, etc.) and/or intolerance to gadolinium
• Active infectious pathology (including Covid-19)
• Immunologically deficient pathology likely to promote superinfection of equipment
• Patients under guardianship or trusteeship
• Patient already participating in another therapeutic trial using an investigational drug or in an exclusion period

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

InBrain Pharma

UNKNOWN

Sponsor Role: collaborator

University Hospital, Lille

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Caroline Moreau, MD,PhD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Lille

David DEVOS, MD, PhD

Role: STUDY_CHAIR

University Hospital, Lille

Locations

Hopital Roger Salengro, CHU Lille

Lille, , France

Countries

France

References

Moreau C, Odou P, Labreuche J, Demailly A, Touzet G, Reyns N, Gouges B, Duhamel A, Barthelemy C, Lannoy D, Carta N, Palas B, Vasseur M, Marchand F, Ollivier T, Leclercq C, Potey C, Ouk T, Baigne S, Dujardin K, Carton L, Rolland AS, Devedjian JC, Foutel V, Deplanque D, Fisichella M, Devos D. Intracerebroventricular anaerobic dopamine in Parkinson's disease with L-dopa-related complications: a phase 1/2 randomized-controlled trial. Nat Med. 2025 Mar;31(3):819-828. doi: 10.1038/s41591-024-03428-2. Epub 2025 Jan 7.

Reference Type: DERIVED

PMID: 39775041 (View on PubMed)

Other Identifiers

2020-000155-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2018_49

Identifier Type: -

Identifier Source: org_study_id