The clinical problem the panel sought to address is one of the most familiar and frustrating in neurology. Levodopa remains the foundational treatment for the motor symptoms of Parkinson’s disease, but it is almost always given in combination with an inhibitor of dopa decarboxylase, such as carbidopa or benserazide, to prevent its breakdown outside the brain. Immediate-release formulations of this combination have a short half-life and are absorbed inconsistently, producing plasma levodopa concentrations that rise and fall with each dose. These fluctuations can emerge within two years of starting therapy and are a major, though not exclusive, driver of motor complications: delayed ON periods, unpredictable ON-OFF swings, end-of-dose wearing OFF and peak-dose dyskinesias, along with non-motor symptoms that erode quality of life. Patients often respond by taking doses ever more frequently, adding adjunctive drugs, and eventually facing the question of device-aided therapies such as deep brain stimulation or infusion pumps.

IPX203 was engineered specifically to flatten those pharmacokinetic peaks and troughs. Each capsule contains a mixture of immediate-release granules and extended-release pellets: the immediate-release component delivers the full carbidopa dose and 25 percent of the levodopa dose for rapid onset, while the remaining 75 percent of the levodopa is released gradually from pellets coated with sustained-release, mucoadhesive and enteric layers that promote absorption in the proximal small intestine. The design goal is to provide both a fast start and sustained plasma levodopa concentrations, reducing peak-to-trough variability and allowing less frequent dosing. In clinical studies, including the pivotal randomised phase 3 RISE-PD trial against immediate-release levodopa/carbidopa, the formulation increased Good ON time, defined as ON time without dyskinesia plus ON time with non-troublesome dyskinesia, significantly reduced OFF time and improved motor symptom control.

The consensus process itself was deliberately structured. The sponsor, Zambon Biotech SA, drafted eight initial statements grounded in current literature and unmet patient needs, which the board reviewed, voted on using a three-point scale, and then debated in a moderated roundtable. One statement was judged to fall outside the scope of the initiative because it did not centre on IPX203 and was dropped. The remaining statements were refined and re-voted, with final agreement levels ranging from 88.9 percent to 100 percent across seven topics covering the definition of motor symptom control, patient selection, positioning within the treatment pathway, switching strategies, and monitoring and follow-up.

On definitions, the panel reached unanimous agreement that motor complications in Parkinson’s disease should be understood as the combination of the number of motor fluctuations, the duration and severity of OFF time, and the presence and severity of dyskinesia as rated by the patient on the MDS-UPDRS part IV scale throughout the day. The experts stressed that motor fluctuations and dyskinesia are distinct phenomena that should not be conflated, and they flagged the exclusion of non-motor fluctuations, such as anxiety, pain and cognitive swings, as a gap, since these track closely with patients’ overall experience. They also debated the reliance on the patient-completed Hauser diary alone, calling instead for objective functional assessment and standardised severity ratings that blend patient and clinician perspectives. A second unanimous statement defined optimal motor control primarily as maximising Good ON time, though participants noted that the RISE-PD endpoint’s exclusion of freezing of gait, which affects roughly 38 to 65 percent of patients depending on disease duration, may yield an incomplete picture of treatment efficacy.

Perhaps the most consequential recommendation concerns who should receive the drug and when. The panel agreed unanimously that IPX203 should be considered for patients experiencing motor fluctuations who remain inadequately controlled even on an optimised levodopa/carbidopa regimen, and it pushed back against the idea that the formulation is a late-stage rescue therapy. Instead, the experts argued it should be viewed as a viable and earlier option in the optimisation process, potentially a first-line choice for managing motor fluctuations once initial levodopa dosing has been refined. They acknowledged, however, that RISE-PD enrolled patients with advanced disease, so broader use in earlier stages will require real-world evidence or further studies. Although the product label does not include an OFF-time threshold, the panel noted that the trial’s inclusion criterion of at least 2.5 hours of daily OFF time, along with the so-called 5-2-1 rule, levodopa taken five or more times per day, at least two hours of OFF time daily, and at least one hour of troublesome dyskinesia, offers practical benchmarks for identifying candidates.

The panel also addressed the drug’s relationship with device-aided therapies, though with the lowest agreement of any statement at 88.9 percent. IPX203 should be positioned as an oral optimisation strategy that can be used before deep brain stimulation, magnetic resonance-guided focused ultrasound or pump-based therapies, potentially serving as a bridge for patients not yet ready or indicated for invasive procedures, or as an alternative for those unwilling or unsuitable to undergo them. The experts were careful to say that the current evidence base is not mature enough to conclude that IPX203 can meaningfully delay the need for such interventions: the nine-month open-label extension of RISE-PD provides encouraging signals, but longer-term prospective and real-world data are required. They emphasised that the drug should be one option within a therapeutic sequence rather than a mandatory step, preserving patient choice and shared decision-making, and they preferred the phrase person with Parkinson’s disease with motor complications over the ambiguous label advanced PD.

Practical switching questions received detailed attention, particularly the combination of IPX203 with catechol-O-methyltransferase inhibitors. COMT inhibitors were excluded from RISE-PD because, by blocking the conversion of levodopa into the inactive metabolite 3-O-methyldopa, they alter levodopa metabolism and would have confounded the trial’s pharmacokinetic analysis. The panel unanimously agreed that this exclusion does not mean the combination cannot be used in practice, but it warned that no safety or efficacy data on the pairing currently exist. Because COMT inhibitors increase levodopa bioavailability and prolong its half-life, combining them with IPX203’s sustained-release profile could raise peak plasma levodopa concentrations in some cases, for example with opicapone, increasing the risk and severity of dyskinesia. Differences in dosing frequency add further complexity, and the experts called for phase 4 trials or real-world evidence to guide dose adjustments.

On monitoring, the group unanimously recommended that initial follow-up after conversion be based on patient response and tolerability, with subsequent visits guided by clinical need rather than a fixed schedule. They judged pre-scheduled visits within the first few days of switching unfeasible in busy practices and instead favoured patient-initiated contact, supported by comprehensive education covering expected adverse events, recognition of problems requiring clinic contact, management of overdosing and increased fluctuations, and instructions for tapering or re-titration during the first one to two weeks. Structured support through nurse-led assistance, phone or digital communication channels and trained staff was seen as essential to keep minor issues from falling back on physicians.

The panel closed with a wide-ranging research agenda and a communication strategy aimed at both patients and general neurologists, who manage a large share of people with Parkinson’s across Europe. Open questions include whether IPX203 can prevent motor fluctuations by acting at the synaptic level, its long-term effects on dyskinesia, non-motor symptoms, night-time akinesia, early morning ON status, orthostatic hypotension and freezing of gait, and how to distinguish good from poor levodopa absorbers. The experts also urged clinicians to confront levodopa phobia, the misplaced fear that levodopa is neurotoxic or loses effectiveness over time, and to explain that IPX203’s higher nominal levodopa dose is designed to sustain exposure rather than raise peak concentrations. Patients should be told the onset may be slightly slower than immediate-release levodopa, that high-fat meals may delay absorption, and that capsule contents can be sprinkled on applesauce for those with swallowing difficulties. With clear education, practical conversion tools and collaboration with neurological societies, the panel concluded, the formulation could meaningfully increase mobility and reduce treatment burden for patients living with motor fluctuations.

Subject of Research: Consensus recommendations for integrating the modified-release levodopa/carbidopa formulation IPX203 into the management of motor fluctuations in Parkinson's disease

Article Title: Consensus-based perspectives on integrating IPX203 into Parkinson’s disease management

Article References: Höglinger, G., Buhmann, C., Ebersbach, G., Fabbri, M., Kägi, G., Pagonabarraga, J., Santos García, D., Tessitore, A., & Tinazzi, M. (2026). Consensus-based perspectives on integrating IPX203 into Parkinson’s disease management. Journal of Neurology, 273(11), Article 656. https://doi.org/10.1007/s00415-026-14186-1

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14186-1

Keywords: Parkinson's disease, IPX203, levodopa, carbidopa, motor fluctuations, dyskinesia, modified-release formulation, RISE-PD trial, device-aided therapies, deep brain stimulation, COMT inhibitors, clinical consensus

The introductory paper, published on 17 September 2026, is the work of Fiammetta Piersigilli of Louvain University’s Saint Luc neonatal intensive care unit in Brussels, together with Kevin Hugill, Robin van der Lee, Matheus F. P. T. van Rens, Giovanni Barone, Tobias Werther, Bernhard Schwaberger and Suzy Van Eenoo, writing on behalf of the Pediatric and Neonatal Vascular Access Special Interest Group of the European Society for Paediatric Research (ESPR) and the vascular access network NEVAT. The group spans institutions across Belgium, the Netherlands, Italy, Austria, Portugal, Bulgaria, France, Spain, the United Kingdom and the United States, reflecting a deliberate effort to build recommendations that transcend local custom and national tradition. The authors state plainly that vascular access is a pervasive facet of contemporary neonatal practice that lacks standardization, and that some long-standing practices have never been supported by solid evidence.

The technical challenge at the heart of neonatal vascular access is scale. A peripheral vein in a premature infant weighing 500 grams may be less than a millimeter in diameter, with a wall thinner than a human hair. Inserting a cannula into such a vessel demands extraordinary precision, and even a successful placement can fail within hours if the device is not secured and managed correctly. Peripheral intravenous cannulation, the most common procedure in neonatal care, carries substantial complication rates. A multicenter observational study cited by the authors reported significant rates of infiltration, phlebitis and inadvertent dislodgement in neonates, and subsequent research has identified both unmodifiable factors, such as gestational age and vein characteristics, and potentially modifiable factors, such as securement technique and dressing choice, that shape how long a device survives and how often it fails.

Beyond the mechanical risks, the series highlights a dimension of neonatal care that has gained increasing scientific attention in recent years: the developmental and neurobiological cost of repeated painful procedures. Neonates undergoing intensive care may experience dozens of invasive procedures during their stay, and systematic reviews have linked early procedural pain exposure to adverse developmental outcomes in children born preterm. Researchers have also framed the cumulative stress of intensive care as a form of toxic stress that can alter infant outcomes, making every avoided cannulation attempt and every extended device dwell time a meaningful gain for the developing brain. In this light, vascular access is not merely a technical task but a determinant of long-term neurodevelopment, which is precisely why the authors argue that objective, evidence-based standardization matters so much.

The ten recommendations that structure the special series cover the full lifecycle of a vascular access device, from the moment a clinician decides that one is needed to the moment it is removed. A central theme is that the decision to place a device should be made deliberately rather than reflexively. The authors point to the Abba Project, whose name stands for Assess Better before Access, a retrospective cohort study of neonatal intravascular device outcomes that encouraged teams to evaluate whether a device was truly necessary and which type was most appropriate before any needle touched the skin. Decision-support tools such as the neonatal DAV-Expert algorithm, developed through an Italian consensus process, guide clinicians toward the most suitable venous access for a given newborn, balancing expected duration of therapy, osmolarity and pH of infusates, and the condition of available vessels.

Assessment of the infant’s veins before insertion is another pillar of the recommendations. The Rapid Superficial Vein Assessment protocol, known as RASUVA, provides a structured pre-procedural evaluation of superficial veins to optimize catheterization, reducing the number of failed attempts. Once a device is in place, the series draws on insertion bundles that have demonstrated measurable reductions in complications. These include the SIUVEC protocol for safe insertion of umbilical venous catheters, the SIECC insertion bundle for epicutaneo-caval catheters, the so-called GAVECELT bundle applied to central venous catheterization in neonates and children in a prospective study of more than 700 cases, and the Neo-Echotip protocol, which uses ultrasound for tip navigation and tip location during placement of central venous access devices. Intracavitary electrocardiography, in which the catheter itself is used as an electrode to confirm tip position, offers an alternative to chest radiography for verifying that a catheter tip sits in the correct position, reducing radiation exposure and delays.

Securement and infection prevention receive equally rigorous treatment. Central line-associated bloodstream infections remain among the most feared complications of neonatal intensive care, and quality improvement work has shown that adopting evidence-based care bundles can drive infection rates toward zero. The recommendations also embrace a material innovation that has rapidly entered neonatal practice: cyanoacrylate glue, the same class of medical adhesive used in tissue bonding. Randomized and observational studies have evaluated octyl-butyl-cyanoacrylate glue for sutureless securement of epicutaneo-caval catheters, umbilical venous catheters and peripheral intravenous catheters in neonates, with results suggesting reduced dislodgement and fewer complications compared with traditional adhesive dressings and sutures. Because glue eliminates puncture sites from sutures and creates a microbial seal at the insertion point, it represents a technically elegant solution to one of the most persistent problems in the field.

Standardization also extends to language. The series incorporates the Navigate Project, a position statement from European vascular access societies establishing a common nomenclature for vascular access devices. The authors argue that inconsistent terminology, in which the same device may be called different things in different countries or even different wards of the same hospital, undermines research, benchmarking and safe communication between teams. A shared vocabulary allows complication rates to be compared meaningfully across units and allows evidence generated in one setting to be translated reliably into another. This effort aligns with broader international frameworks, including the Infusion Therapy Standards of Practice, whose ninth edition provides an overarching reference for infusion-related care, and the ERPIUP consensus on the proper indication and use of peripheral venous access devices in adults, whose methodology the neonatal group adapted to its own population.

What makes the series notable is its candor about the limits of the evidence. The authors emphasize that the recommendations consolidate existing knowledge and consensus rather than presenting definitive trial data, and they explicitly frame the series as a means of highlighting priorities for further research to address gaps in knowledge. Many practices in neonatal vascular access have evolved through apprenticeship and habit rather than randomized evidence, and the ten recommendations are as much a research agenda as a clinical guideline. By naming where the evidence is thin, the group hopes to direct future studies toward the questions that matter most for outcomes, from optimal dwell times to the long-term developmental impact of procedural pain.

For clinicians, the practical message is that objective standardization of neonatal vascular access is achievable now, with tools that already exist. For the smallest patients, whose veins are fragile and whose developing brains are exquisitely sensitive to stress, the stakes of getting this right could hardly be higher. If the series succeeds in bridging practice gaps and supporting evidence-based standardization across neonatal units worldwide, it may quietly transform one of the most routine yet consequential procedures in medicine, turning an area long governed by individual habit into one governed by shared, scrutinized and continually improved evidence.

Subject of Research: Standardization of neonatal vascular access through international expert consensus recommendations

Article Title: Introduction to the special article series to guide neonatal vascular access

Article References: Piersigilli, F., Hugill, K., van der Lee, R., van Rens, M. F. P. T., Barone, G., Werther, T., Schwaberger, B., Van Eenoo, S., on behalf of the Pediatric and Neonatal Vascular Access SIG of the ESPR and NEVAT, Van Der Lee, R., van Rens, M., van Eenoo, S., van den Hoogen, A., Rodriguez-Perez, C., Breschan, C., Pittiruti, M., Oulego-Erroz, I., Ouwehand, T., Debuf, M.-J., … Tuna, M. L. (2026). Introduction to the special article series to guide neonatal vascular access. Pediatric Research. https://doi.org/10.1038/s41390-026-05468-5

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05468-5

Keywords: neonatal vascular access, Pediatric Research, clinical consensus, central venous catheters, peripheral intravenous cannulation, cyanoacrylate glue, ultrasound guidance, catheter-related bloodstream infection, neonatal pain, ESPR, NEVAT, patient safety