Duodopa - Scientific Information
|Condition:||Parkinson's Disease, Periodic Limb Movement Disorder, Restless Legs Syndrome|
|Class:||Dopaminergic antiparkinsonism agents|
|Form:||Cream, gel, liniment or balm, lotion, ointment, etc|
|Ingredients:||levodopa, carbidopa, carmellose sodium, purified water|
|Chemical name:||(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid|
|Molecular formula and molecular mass:||C9H11NO4 197.2|
|Physicochemical properties:||Levodopa, an aromatic amino acid, is a white or slightly cream-coloured, crystalline compound that is slightly soluble in water and practically insoluble in alcohol and ether. It is freely soluble in 1M HCl and sparingly soluble in 0.1 M HCl.
Levodopa is light and oxygen sensitive.
|Proper name:||Carbidopa monohydrate|
|Chemical name:||(2S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoic acid, monohydrate|
|Molecular formula and molecular mass:||C10H14N2O4·H2O 244.3|
|Physicochemical properties:||Carbidopa monohydrate, an inhibitor or aromatic amino acid decarboxylation, is a white or yellowish-white, crystalline compound that is slightly soluble in water and very slightly soluble in alcohol. It is practically insoluble in methylene chloride and dissolves in dilute solutions of mineral acids.
Carbidopa monohydrate is light and oxygen sensitive.
An Early Stage Clinical Development Program for DUODOPA (levodopa/carbidopa intestinal gel) provided preliminary efficacy and safety data, for the initial conditional marketing authorization of this product. The DUODOPA Phase III Clinical Development Program was conducted subsequent to conditional marketing authorization, to confirm the preliminary findings from the Early Stage Clinical Development Program.
Study Demographics and Trial Design
|Study #||Trial Design||Dosage, Route of Administration and Duration||Study
|I||Early stage, open label, cross-over, single centre, PK study comparing DUODOPA nasoduodenal infusion versus oral levodopa/carbidopatablets||3 weeks DUODOPA by nasoduodenal infusiona:
Individually adjusted infusion rates; mean total daily doses of 945 to 2694 mg levodopa
3 weeks oral levodopa/carbidopa tabletsa:
Individually adjusted doses with; daily doses of 850 to 2933 mg levodopa
|12||39 to76 years||10/2|
|II||Early stage, open label, cross-over study comparing DUODOPA nasoduodenal infusion versus conventional anti-PD medicationb||3 weeks DUODOPA by nasoduodenal infusiona: Individually adjusted infusion rates; mean total daily doses of 456 to 3556 mg levodopa
3 weeks conventional anti-PD medication:
Individually adjusted doses; mean daily doses of 275 to 2400 mg levodopa.
|24||50 to 79 years||18/6|
|III||Phase III, randomized, double-blind, double- dummy, active- controlled, parallel group, multicenter study||12 weeks DUODOPA via PEG-J + placebo oral capsules
12 weeks Placebo gel via PEG-J + levodopa/carbidopa oral capsules (100/25 mg levodopa/carbidopa immediate-release tablets, encapsulated)
Dose of DUODOPA and active control individually optimized by titration
|71||39 to 83 years
(64.4 ± 8.3)
|a Co-administration of other antiparkinsonian medications was not permitted during this treatment period. Extra doses of levodopa were permitted as required.
b Conventional anti-PD medications included levodopa/dopa-decarboxylase inhibitor often used in combination with other dopamine enhancing treatments.
Definitions: PEG-J: percutaneous endoscopic gastrostomy with jejunal extension.
Early Stage Clinical Development Program
There were 46 patients included in the early stage clinical development program. All studies were open-label.
Study I was a 6-week open-label, cross-over, single-centre, study comparing the pharmacokinetics of levodopa administered as DUODOPA nasoduodenal infusion versus oral levodopa/carbidopa in 12 patients with advanced, idiopathic levodopa-responsive Parkinson’s disease with diurnal motor fluctuations despite optimized levodopa treatment. Patients ranged in age from 39 to 76 years, with disease duration ranging from 7 to 29 years and duration of levodopa treatment ranging from 4 to 26 years. The primary efficacy endpoint was plasma levodopa variance. Intraindividual plasma levodopa variance was reduced during DUODOPA treatment compared to optimized oral levodopa treatment. In addition, mean intraindividual coefficient of variation (standard deviation/mean) was also significantly lower (p < 0.01) during DUODOPA treatment (0.15 and 0.15 for each group) than during oral treatment (0.30 and 0.39).
Study II was a 6-week, open-label, cross-over study comparing the efficacy and safety of DUODOPA nasoduodenal infusion versus conventional anti-Parkinson medication in 24 patients with advanced idiopathic levodopa-responsive Parkinson’s disease with severe fluctuating response despite frequent administrations of oral levodopa. Patients ranged in age from 50 to 79 years, with disease duration ranging from 6 to 23 years and duration of levodopa treatment ranging from 5 to 21 years. The primary efficacy endpoint was the duration and/or intensity of “On”, “Off” and “hyperkinetic” periods as assessed by rater-blinded assessments of video scoring. During DUODOPA treatment, an increase in mean percentage “On” time was accompanied by a significant decrease in the mean percentage “Off” time (or “On” time with Parkinsonism). The percentage of “On” time with moderate to severe dyskinesia was not different for the 2 treatments.
Phase III Clinical Development Program
The efficacy of DUODOPA in controlling motor fluctuations in patients with advanced Parkinson’s disease was confirmed in a Phase III, 12-week, randomized, double-blind, double- dummy, active-controlled, parallel group, multicenter study evaluating the efficacy, safety, and tolerability of the DUODOPA System. The study was conducted with patients with advanced Parkinson’s disease who were levodopa-responsive, had persistent motor fluctuations, and experienced at least 3 hours of “Off” time per day, despite optimized treatment with oral levodopa/carbidopa and other available anti-Parkinson’s disease medications. The study data were from 2 identically designed studies that were combined prior to breaking the blind and conducting the analysis (Table 1, Study III).
Seventy-one (71) patients were randomized to treatment with levodopa/carbidopa intestinal gel + placebo capsules (DUODOPA n=37) or placebo intestinal gel + levodopa/carbidopa capsules (LC-oral n=34). A total of 66 patients completed the treatment (DUODOPA n=35; LC-oral n=31).
Mean age was similar in both treatment groups (overall mean age was 64.4 years), but the DUODOPA group had a greater proportion of patients < 65 years old (21/37 versus 15/34). The overall disease duration was 10.9 years, but mean disease duration was slightly less in the DUODOPA group than in the LC-oral group (10 years versus 11.9 years).
DUODOPA or placebo gel was infused for 16 hours daily through a PEG-J tube via the CADD Legacy ambulatory infusion pump. Patients in both treatment arms had a PEG-J device placement; therefore the primary difference between the treatment groups was the route of administration of levodopa/carbidopa (intestinal versus oral).
Study medication doses were optimized during the first 4 weeks of treatment after PEG-J tube placement, and from Weeks 5 to 12 patients were to remain on a fixed dose of study medication. Rescue medication (oral immediate-release levodopa/carbidopa tablets) was permitted throughout the 12 week treatment period, to manage serious medical needs such as rapid deterioration of motor symptoms. The proportions of patients using rescue medication at least once during Weeks 5 to 12 were similar in both treatment groups (21/37 in the DUODOPA group versus 21/34 in the LC-oral group), but throughout the study the average dose of levodopa/carbidopa rescue medication was higher in the oral levodopa/carbidopa group than in the DUODOPA group. Rescue medication use on valid efficacy assessment days (mean 22.1 mg/day for DUODOPA and 35.7 mg/day for LC-oral) was incorporated as a covariate in the analysis of the primary efficacy endpoint. The mean total daily levodopa dose (from all sources) was 1117.3 mg/day levodopa for the DUODOPA group and 1350.6 mg/day levodopa for the LC-oral group. Most patients in both treatment groups continued to receive other permitted antiparkinson medications concomitantly throughout the study, if the doses of these medications were stable for at least 4 weeks prior to baseline.
The primary efficacy endpoint was the difference between treatments in the change from baseline to endpoint (Week 12) in the mean total daily “Off” time based on Parkinson’s Disease Diary© data collected for 3 days before the Week 12 study visit, with “Off” time normalized to a 16-hour awake/infusion period. The key secondary efficacy variable was the change from baseline to endpoint (Week 12) in “On” time without troublesome dyskinesia ("On" time without dyskinesia and "On" time with non-troublesome dyskinesia). The baseline values were collected 3 days prior to randomization and after 28 days of oral therapy standardization.
There was a clinically and statistically significant reduction in the average daily normalized “Off” time (baseline to endpoint) of -1.91 hours (p=0.0015) in the DUODOPA group compared to the oral levodopa/carbidopa group (LS mean change: -4.04 hours versus -2.14 hours (Table 2).
The change in “Off” time was associated with a clinically and statistically significant increase in the average daily normalized “On” time without troublesome dyskinesia (baseline to endpoint) of 1.86 hours (p = 0.0059), in the DUODOPA group compared to the oral levodopa/carbidopa group (LS mean change: 4.11 hours versus 2.24 hours) (Table 2).
|Treatment Group||N||Baseline Mean (SD) (hours)||Endpoint (SD) (hours)||LS Mean (SE) of Change (hours)||LS Mean (SE) of Difference (hours)||P Value|
|"Off" Time (Primary Endpoint)|
|LC-orala||31||6.90 (2.06)||4.95 (2.04)||-2.14 (0.66)|
|DUODOPA||35||6.32 (1.72)||3.05 (2.52)||-4.04 (0.65)||-1.91 (1.57)||0.0015b|
|"On" Time Without Troublesome Dyskinesiac (Key Secondary Endpoint)|
|LC-oral||31||8.04 (2.09)||9.92 (2.62)||2.24 (0.76)|
|DUODOPA||35||8.70 (2.01)||11.95 (2.67)||4.11 (0.75)||1.86 (0.65)||0.0059d|
|a. LC-oral: levodopa/carbidopa (100/25 mg) immediate-release encapsulated tablets.
b. Two sided p value from ANCOVA model including effects for treatment and country, and covariates of corresponding Baseline and the natural logarithm of the mean daily dose of rescue medication on valid Parkinson's Disease Diary Data.
c. "On" time without troublesome dyskinesia is the sum of "On" time without dyskinesia and "On" time with non-troublesome dyskinesia.
d. Treatment comparisons are based on an ANCOVA model including effects for treatment and country, and with the corresponding Baseline as a covariate.
Definitions: ANCOVA = analysis of covariance; LS = least squares; SD = standard deviation; SE = standard error
Outcomes based on the Parkinson’s Disease Diary data were supported by outcomes from other secondary endpoints including PDQ-39 Summary Index, Clinical Global Impression (CGI-I) score, and UPDRS Part II score (Activities of Daily Living).
12-Month Open Label Study
An open-label, single-arm, multicenter study was conducted to assess the long-term safety and tolerability of DUODOPA over 12 months. The study included 354 levodopa-responsive patients with advanced Parkinson’s disease who experienced motor fluctuations and at least 3 hours of “Off” time per day, despite optimized treatment with available Parkinson’s disease medications. Patients included in this study were not previously treated with DUODOPA in Study III. DUODOPA was administered as monotherapy in this study, but oral immediate release levodopa/carbidopa tablets were permitted as rescue medication in case of acute deterioration. The mean total daily dose of levodopa at the study endpoint was 1620.9 ± 589.8 mg/day. The overall magnitude of the reduction in "Off" time and increase in “On” time without troublesome dyskinesia from baseline to Week 54 was consistent with what was observed in the DUODOPA group in the 12-week active controlled study.
Levodopa is a hydrophilic compound (log D < -2; octanol/water buffer partitioning at pH 5.5 to 7.4) with an expected low passive membrane diffusion. Accordingly, the high small intestinal permeability of levodopa is a consequence of an efficient transepithelial transport by the amino acid carrier for large neutral amino acids (LNAA). The longer levodopa remains in the stomach or small intestine, the more extensively it is metabolised and made unavailable for absorption. Gastric emptying has also been shown to be an important factor contributing to the large intraindividual variability seen in the plasma concentration profile of patients on oral levodopa.
The principle behind constant levodopa infusion is to achieve continuous dopaminergic stimulation with an optimised dose that can be kept stable within the therapeutic window. Gastric emptying must be bypassed to achieve this. Intravenous infusions and intraduodenal or intrajejunal infusions of levodopa or levodopa/carbidopa have been shown to reduce fluctuations in plasma levodopa concentrations and to improve mobility compared to standard oral therapy.
DUODOPA contains hydrazine, a degradation product of carbidopa that can be genotoxic and possibly carcinogenic. In animal studies, hydrazine showed notable systemic toxicity, particularly by inhalation exposure. These studies reported that hydrazine is hepatotoxic, has CNS toxicities (although not described after oral treatment), and is genotoxic as well as carcinogenic.
At dosage ratios of 1:1, 1:2, 1:3, 1:4, 1:5 and 1:10 carbidopa to L-dopa, oral LD50 values in mice were 1930, 2280, 3270, 3090, 2940 and 3360 mg/kg, respectively. Clinical signs of toxicity were central stimulation appearing within 30 minutes of dosing and persisting 1to 2 days. Deaths were mainly in the first 24 hours.
Ratios of 25:250, 50:250 and 100:250 carbidopa/levodopa, with a fixed dose of 250 mg/kg/day of levodopa, given by gavage, were investigated in groups of 10 male and 10 female Sprague- Dawley rats for 26 days. The study was controlled with 10 male and 10 female rats receiving 0.5% methylcellulose. Apart from salivation, increased micturition and hyperactivity, no other findings were made.
Ratios of 25:500, 50:500 and 100:500 carbidopa/levodopa, with a fixed dose of 500 mg/kg/day of levodopa, given by gavage, were investigated in groups of 10 male and 10 female Sprague- Dawley rats for 33 days. The study was controlled with 10 male and 10 female rats receiving 0.5% methylcellulose. Mortality was recorded in all treatment groups and the high dose group was sacrificed after 19 days. Marked depression in body weight gain was recorded in the high and the intermediate groups. Meningeal hemorrhage was found in 2 high dose females and 1 intermediate group female.
Ratios of 2:1, 5:1 and 10:1 levodopa/carbidopa, with a fixed dose of 10 mg/kg/day of carbidopa, given by gavage, were investigated in groups of 70 male and 70 female Sprague-Dawley rats for 106 weeks. The study was controlled with 70 male and 70 female rats receiving 0.5% methylcellulose. Interim sacrifices of 10 male and 10 female animals were made at 26 and 52 weeks. Ptyalism was seen in the high dose animals until week 35 and these animals were slightly sedated until week 15. There were no differences in mortality between groups. Body weight gain was decreased in the high dose animals and the intermediate dose males. Slight increases in kidney weights were found in the high dose animals at 26 weeks and high and intermediate dose animals at 52 weeks. Slight increases in liver weights were found in high and intermediate dose females at 52 weeks. No significant pathologies were found at any time points.
Ratios of 2:1, 5:1 and 10:1 levodopa/carbidopa, with a fixed dose of 10 mg/kg/day of carbidopa, given by gavage, were investigated in groups of 6 male and 6 female rhesus monkeys for 54 weeks. The study was controlled with 6 male and 6 female monkeys receiving 0.5% methylcellulose. An interim sacrifice of 3 males and 3 females was made at 26 weeks. Hyperactivity was noted over weeks 1to 14 in the medium dose group and 1to 26 weeks for the high dose group. Three deaths occurred: 1 low dose animal in week 6, 1 medium dose animal in week 15 and 1 control animal in week 47; these deaths were not treatment related. There were no effects on body weight and hematological and biochemical parameters were within the normal range. Dose related melanuria was found in all treated monkeys. Axonal degeneration of peripheral nerves was recorded in all treatment groups. Basophilic lamellar bodies occurred in the brain of two high dose animals.
Studies on dyskinesias in monkeys
It has been shown that squirrel monkeys treated twice daily with levodopa and carbidopa (15 mg/kg and 3.75 mg/kg, respectively, by oral gavage) for 2 weeks developed dyskinesias. A study in cynomolgus monkeys showed that at the dose of 80 mg/kg/day levodopa and 20 mg/kg/day carbidopa for 13 weeks developed dyskinesias, which progressively intensified over the course of the study.
Mutagenicity and Carcinogenicity
Ratios of 2:1, 5:1 and 10:1 levodopa/carbidopa, with a fixed dose of 10 mg/kg/day of carbidopa, given by gavage, were investigated in groups of 70 male and 70 female Sprague-Dawley rats for 106 weeks. The study was controlled with 70 male and 70 female rats receiving 0.5% methylcellulose. Interim sacrifices of 10 male and 10 female animals were made at 26 and 52 weeks. Sufficient animals survived the treatment period to allow for proper interpretation of the data. There was no alteration to the tumour profile associated with the administration of this combination product.
Reproduction and Teratology
Fertility and early embryonic development
Groups of 12 male Sprague-Dawley rats were given ratios of 2:1, 5:1 and 10:1 levodopa/carbidopa, with a fixed dose of 10 mg/kg/day of carbidopa, by oral gavage, for 70 days and each male mated to 3 untreated females. The control group was of 20 male animals. The females were sacrificed on day 14 of gestation. No effects were seen on the number of pregnancies, implantations, resorptions or foetuses per female when compared to the controls.
Groups of 24 female Sprague-Dawley rats were given ratios of 2:1, 5:1 and 10:1 levodopa/carbidopa, with a fixed dose of 10 mg/kg/day of carbidopa, by oral gavage, for 14 days and mated to untreated males. The control group was of 42 female animals. Half the animals were sacrificed on day 14 and the other half allowed to litter. No effects were seen on the number of pregnancies, implantations, resorptions or foetuses per female when compared to the respective controls.
Ratios of 250:25, 250:50, 250:125 and 500:100 mg/kg/day levodopa/carbidopa were administered, by oral gavage, to groups of 23 pregnant CF1 mice from day 6 to 15 of gestation. The study was controlled with a group of 46 pregnant animals. In animals receiving the 250:125 and 500:100 mg/kg/day of levodopa/carbidopa significant decreases of foetal weights were found and the number of stunted foetuses was higher than the controls. There was no increase in foetal mortality and malformations in comparison to the controls.
Ratios of 2.5:25, 12.5:125 and 25:250 mg/kg/day levodopa/carbidopa were administered by oral gavage to groups of 32 pregnant CF1 mice from day 6 to15 of gestation. The study was controlled with a group of 32 pregnant animals. On day 19, 18 females from each group were sacrificed and the foetuses examined. One-third of the foetuses were examined for visceral malformations and ⅔ for skeletal abnormalities. Fourteen females from each group were permitted to litter normally and the pups observed for 4 weeks. Of the 32 females on each dose, 18, 19, 21 and 13 were pregnant from the control, low, intermediate and high dose, respectively. There were no effects on maternal or pup weight gains. No abnormalities above control values were found. At week 4 the number live pups was marginally lower in animals dosed at the high combination dosage.
Ratios of 125:62.5, 187:37.5 and 250:25 mg/kg/day levodopa/carbidopa were administered by oral gavage to groups of 10 pregnant New Zealand White rabbits from day 7 to 15 of gestation. The study was controlled with a group of 25 pregnant rabbits. There was decreased weight of the live foetuses in all test groups. The number of resorptions was increased. Visceral abnormalities of the lung, heart and greater vessels, together with skeletal deformities were found at all dose levels. These effects are attributable to levodopa.
The ratio of 125:12.5 mg/kg/day of levodopa/carbidopa was administered by gavage to 21 pregnant Sprague-Dawley rats from day 7 to 15 of gestation. The study was controlled with a group of 31 pregnant animals. Eleven females from each group were sacrificed at day 21 and the other 10 animals allowed to litter. No differences were observed in numbers of resorptions, implants, pregnant females, live pups per litter or foetal abnormalities. In females allowed to litter, the average number of live pups were 14.7 for the control group and 10.7 for the treated group.