Intracerebroventricular anaerobic dopamine in Parkinson's disease with L-dopa-related complications: a phase 1/2 randomized-controlled trial

Abstract

Continuous compensation for cerebral dopamine deficiency represents an ideal treatment for Parkinson's disease. Dopamine does not cross the digestive and blood-brain barriers and is rapidly oxidized. The new concept is the intracerebroventricular administration of anaerobic dopamine (A-dopamine) using an abdominal pump connected to a subcutaneous catheter implanted in the third ventricle, near the striatum. An open-label phase 1 study showed no serious adverse reactions induced by A-dopamine in 12 patients. A randomized, controlled, open-label, crossover phase 2 study of 1 month of A-dopamine versus 1 month of optimized oral antiparkinsonian therapy was conducted in 9 patients. The primary endpoint, a blinded assessment of the percentage over target (that is, time with dyskinesia or bradykinesia), recorded by home actimetry using a wristwatch, was significantly reduced on A-dopamine compared with that on oral treatment alone (P = 0.027), with a median within-patient difference of -10.4 (Hedge g = -0.62 (95% confidence interval: -1.43, -0.08)). Home diaries were also significantly improved. These initial data on the feasibility, safety and effects of this new device-assisted therapy suggest validation by a large randomized double-blind trial. ClinicalTrials.gov registration: NCT04332276 .

Fig. 1. Therapeutic concept of brain infusion of A-dopamine.

a, The degeneration of dopaminergic neurons in the SNpc leads to dopamine depletion in the striatum (caudate nucleus and putamen), which is responsible for automaticity motor disorders (bradykinesia, akinesia, rigidity). To a lesser extent, other dopaminergic neurons of the mesocortical (cognition) and mesolimbic (behavior) pathways are also involved in PD. The dopamine deficit can be compensated for by direct continuous administration of dopamine through an abdominal pump and its catheter (middle). Ac, nucleus accumbens; Sep, septum pellucidum; Th, thalamus; SN, substantia nigra; Hyp, hypothalamus; Hip, hippocampus; p: pituitary; Am, amygdala. b, The preparation, storage and delivery of dopamine occurs under anaerobic conditions (A-dopamine; O₂ < 0.1%) to avoid rapid dopamine oxidation. c, Delivery takes place via a commercially available pump (Prometra Flowonix) for which the stability of A-dopamine and biocompatibility have been validated. Fine-tuning of the dose is determined by telemetry using the programmer. d, Neurosurgical targeting (red oval): right frontal horn of the lateral ventricle at the entrance of the interhemispheric foramen connecting the third ventricle and allowing the perfusion of A-dopamine right next to the striatum (C, caudate nucleus; P, putamen). e, Ergonomics: transcutaneous filling of the abdominal pump every 7–15 days under local anesthesia and then adjustment by telemetry of hourly and circadian doses (day and night).

Fig. 2. Primary and secondary efficacy outcomes.

a, Effect sizes in primary and secondary efficacy outcomes for A-dopamine versus oral l-dopa treatment. b, Diary outcomes expressed in hours according to treatment period. Effect sizes were Hedge’s g values (calculated using rank-transformed data), with non-central 95% CIs. The squares represent the effect sizes and the bars represent the 95% CIs. Effect sizes for actimetry and home diaries were calculated in the per-protocol primary efficacy analysis, which referred to outcome measures calculated after excluding weeks with deviations from the target oral l-dopa dose from the nine patients who performed phase 2. Diary outcome values are expressed in terms of the median hour estimated from the percentage of time in the condition and considering a 24 h period. The time to ‘on’ without dyskinesia, the time ‘on’ without dyskinesia or with mild dyskinesia or with mild bradykinesia (time to good autonomy).

Extended Data Fig. 1. Design of the clinical trial phase 1 and 2.

The deadlines are indicative and may vary depending on the state of health of the subject and the feedback acquired during the study D: day; vs: versus.

Extended Data Fig. 2. Flowchart.

Flowchart of patients selected, included and analyzed in the study.

Extended Data Fig. 3. Secondary efficacy analysis for actimetry and home diary outcomes considering all planned weeks.

Effect sizes in primary and secondary actimetry and home diary efficacy outcomes for A-dopamine vs. oral L-dopa treatment, in primary and secondary efficacy analyses. Effect sizes were Hedge’s g values (calculated using rank-transformed data), with non-central 95% Cis, from the 9 patients who performed the phase II. The squares represent the effect sizes and the bars represent the 95% confidence interval. Effect sizes calculated in perprotocol primary efficacy analysis (which referred to outcome measures calculated after excluding weeks with deviations from target L-dopa oral dose) are reported in black. Effect sizes calculated in secondary efficacy analysis (which referred to outcome measures calculated from all planned recording weeks) are reported in grey.