The Duodopa concept is to provide patients with advanced Parkinson’s disease suffering from motor (“on-off” and dyskinesia) and other symptom fluctuations a new formulation of a well-known and basic drug combination, levodopa/carbidopa, in a device suitable for long-term ambulatory care. Several groups of investigators have reported that stabilization of the plasma levodopa concentrations at a constant level is accompanied by less incapacitating motor fluctuations (Table 1). However, due to the low water solubility of levodopa, continuous intravenous or intraduodenal infusion of large volumes of aqueous solutions of levodopa/carbidopa is not practical. The new formulation of levodopa/carbidopa, with ten times higher concentration of the drug, seems to have solved the practical problems in permitting continuous infusion via a permanent surgically (PEG) inserted intraduodenal tube over at least 16 hours per day in the home environment. The objectives of the clinical development program for Duodopa are:
To confirm previous results with dilute water solutions of levodopa/carbidopa regarding less variability of plasma levodopa concentrations and less motor fluctuations.
To provide evidence that Duodopa can be used long-term for treatment of patients with Parkinson’s disease.
Patients included in the Duodopa clinical studies were usually above 50 years of age (age range: 47–76 years). Their duration of illness ranged from 4 to 31 years, they had been on levodopa treatment for 4–21 years or more, and they had suffered from motor fluctuations for 3–17 years in spite of many permutations of treatment with levodopa/carbidopa in combination with other antiparkinson drugs (COMT inhibitors, dopamine agonists, anticholinergics). Their stage of disease according to Hoehn and Yahr “at worst” was 3–5 (on a 5-point scale). On test days, plasma levodopa concentrations have been measured at 15–30 minute intervals for 8–9 hours or more on oral treatment or during intraduodenal infusion with Duodopa in order to determine its variability. Motor fluctuations have been measured by the PLM test, an automated system for determination of the speed of certain movements that are difficult to perform for patients with Parkinson’s disease. A decrease in movement time is a sign of improvement. The PLM test has also been administered at 20–30 minute intervals over 8–9 hours in order to determine the variability in movement time. Motor fluctuations have also been assessed with a rating scale usually running from -3 (severe “off”) t o 0 (“on”) to +3 (“on” with severe dyskinesia) from video recordings taken every 30–60 minutes for 8–9 hours. Details of the procedures are described in the enclosed Study Reports and publications.
Long-term follow-up studies have been done by reviewing hospital case records for patients who have been treated with Duodopa long-term. In some patients, the above test-day procedures have been repeated after several months or years of Duodopa treatment in order to objectively determine maintenance of improvement.
In the study by Bredberg et al. (1993), the first concept test, 5 patients were tested on their optimised oral treatment and 6 weeks later during nasoduodenal infusion with a suspension of milled Sinemet (levodopa/carbidopa) tablets in methylcellulose corresponding to 20 mg/ml of levodopa and 5 mg/ml of carbidopa. The results showed that there was less variability in plasma levodopa concentrations and less variability in the PLM test with intraduodenal levodopa/carbidopa in combination with the same concomitant antiparkinson drugs as compared to oral levodopa/carbidopa with concomitant drugs. The video scoring showed less “off”-time and less dyskinesia and more “on”-time (near normality).
The PLM test and the video scoring results were replicated in Study Report No. NPP-001-92, an open?label study where 7 patients were included and tested according to a similar procedure, comparing nasoduodenal infusion of Duodopa and oral levodopa/carbidopa, both with the same concomitant antiparkinson medication. Comparison of the variability in plasma levodopa concentrations could not be done because of differences in blood sampling intervals between the treatments. After completion of the testing with nasoduodenal infusion of Duodopa, permanent intraduodenal tubes were surgically implanted (via PEG) and the patients were continued on Duodopa treatment for 6 months with test days on Duodopa after 1, 3, and 6 months. Also, at 6 months on Duodopa, the patients spent more time “on” and less time “off” and less time “on” with hyperkinesia (dyskinesia) as compared with oral treatment 6 months earlier. Ratings with UPDRS (Fahn et al., 1987) showed that 5/7 patients were improved and 6/7 patients had less motor complications. There was no change of stage of illness according to Hoehn and Yahr. There were no complications or adverse events that could be attributed to Duodopa. The data from Study Report No. NPP-001-92 have been published by Nilsson et al., 1998, together with data on 2 additional patients on Duodopa for up to 31 months. Pharmacokinetic data from these 2 patients showed significantly less variability in plasma levodopa concentrations on duodenal infusion of Duodopa as compared with oral levodopa treatment. Video scoring data showed less “off”-time and more time “on”, thus confirming the study by Bredberg et al., 1993.
Study Report No. NPP-001-99 was an open label, crossover study of oral levodopa/carbidopa versus Duodopa, both without concomitant antiparkinson medication. Twelve (12) patients with advanced Parkinson’s disease and with motor fluctuations not responding to various oral drug combinations were included. The patients were first optimised on oral Sinemet Depot (CR) for 1 week and tested on 3 occasions during the next 2 weeks. The patients were then optimised on nasoduodenal infusion of Duodopa for 1 week and tested 3 times during the next 2 weeks on Duodopa. The variability in plasma levodopa concentrations was significantly lower on Duodopa as compared with the oral treatment. Similarly, the video scoring data showed a statistically significant difference between the 2 treatments in favor of Duodopa. The PLM tests, however, showed no difference between the 2 treatment periods due to skewed distribution of data. Except for 1 serious adverse event (heart arrhythmia), there were no unexpected adverse events considering the severity and complications of the disease itself.
Study Report No. NPP-002-00 concerns a follow-up of 31 out of 34 consecutive patients treated long-term with Duodopa via a permanent intraduodenal tube. A review of hospital medical records was made from the time of surgery (PEG) until the census date. The median treatment time with Duodopa was 3 years and 8 months (range: 15 days up to 8 years and 7 months). Reasons for unexpected interruptions of treatment were dislocations of the tip of the tube from the duodenum into the stomach (n=8), occlusion of tube (n=7), changing of tube (n=4), pump dysfunction (n=2), and problems with distribution of the product (2 occasions). Nine (9) of the 31 patients had discontinued Duodopa treatment permanently due to mental disorders (n=3), repeated tube dislocation (n=3), Parkinson-plus development (n=1), gastric pain (n=1), and general health impairment (n=1). No serious or severe adverse events due to treatment with Duodopa were reported.
The publication by Nilsson et al. (2001), deals with the results of PLM tests and video scoring in 5 patients tested previously on oral levodopa/carbidopa and now having been treated with Duodopa for 4–7 years, and with general aspects of long-term treatment with Duodopa in 28 patients (87 patient-years of experience; median time on Duodopa = 44 months). The PLM tests showed improvement over previous oral treatment in 2/5, deterioration in 2/5, and was unchanged in 1/5 patients. The results from video scoring showed maintained improvement over previous oral treatment in 4/5 patients. With regard to long-term utility of the treatment with Duodopa, most of the 28 patients had improved relative to the previous oral treatment. Only 6/28 patients had returned to oral therapy for various reasons (lack of improvement, symptoms of multiple-system atrophy, difficulties handling the system due to dementia) in spite of the inconvenience in carrying the pump and technical complications in some cases. The authors conclude that “continuous intraduodenal levodopa infusion seems to be one of the best alternatives for treatment of very advanced Parkinson’s disease patients with disabling motor fluctuations.”
In summary, it can be concluded that intraduodenal infusion with Duodopa has a favorable effect on the variability in plasma levodopa concentrations as compared with oral tablet administration. The studies with Duodopa hitherto performed confirm the improvement of motor fluctuations associated with intraduodenal infusion and stabilization of levodopa levels in plasma shown previously for intravenous and intraduodenal infusion of levodopa solutions by several independent groups of investigators (cf. Table 1). The favorable effects on motor fluctuations have been demonstrated to persist over at least 6 months and, in some patients, for several years. There are no concerns regarding the safety and tolerability of treatment with Duodopa. The fact that most patients, once they have tried it, have decided to continue with the Duodopa treatment for an average of almost 4 years, and the low rate of treatment discontinuations testifies to patients’ acceptance of the treatment long-term.
