A Study to Compare Plasma Levels of Levodopa, Carbidopa and Entacapone After TRIGEL or Duodopa Infusion in PD Patients

Study Overview
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Brief Summary
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This study evaluates the continuous addition of entacapone to infused levodopa and carbidopa on the pharmacokinetic (PK) profile in patients with advanced Parkinson's disease (PD). All patients will receive both study drugs, i.e. TRIGEL (levodopa, carbidopa, and entacapone) and Duodopa (levodopa and carbidopa), in randomized order.

Detailed Description
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Intestinal infusion of Duodopa (levodopa and carbidopa) provides faster absorption, comparable levodopa bioavailability and significantly reduced intra-patient variability in levodopa concentrations relative to oral administration. TRIGEL also contains a third ingredient, entacapone. In tablet form, entacapone is shown to improve the bioavailability of levodopa and might extend the half-life of levodopa, avoiding deep troughs in levodopa plasma levels, and providing more continuous delivery of levodopa to the brain. The intention with the study is to confirm that TRIGEL administration increases the area under the curve (AUC) for levodopa by combining levodopa, carbidopa, and entacapone and thereby lower the daily levodopa dose needed. It is expected that TRIGEL administration will result in a similar intra-patient variability in plasma levodopa concentrations as Duodopa during continuous administration.

Official Title
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A Single Centre, Two-period, Open Label, Randomised, Cross-over Study to Assess Plasma Levodopa, Carbidopa and Entacapone Concentrations After Continuous Infusion of TRIGEL or Duodopa in Patients With Advanced Parkinson´s Disease

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: TRIGEL
* Drug: Duodopa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide informed consent and judged by the Investigator to have decision-making capacity Advanced levodopa-responsive idiopathic PD currently treated with Duodopa infusion since minimum 30 days 30 years of age or older BMI between 17.0 and 31.0 kg/m2, both inclusive Agreed to use adequate contraceptive measures: Female patients who have been post-menopausal for more than one year or female patients of childbearing potential using a highly efficient method of contraception during the study (i.e. a method with less than 1% failure rate [e.g. sterilisation, hormone implants, hormone injections, some intrauterine devices, or vasectomised partner]). Oral contraceptives in combination with other contraceptives are accepted. Male patients being vasectomised or agreeing to use condoms during the study and having a partner who is using a highly efficient method of contraception as described above. Exclusion Criteria: Hypersensitivity or allergy to the investigational medicinal product (IMP) or to chemically related products Contraindications for the use of levodopa or carbidopa or entacapone Needing a daily total dose of Duodopa during study participation exceeding 125 mL Increased fluctuation in clinical PD symptoms within 7 days prior to Screening Administration of an investigational drug within 3 months prior to Screening and/or current participation in another clinical study involving a pharmaceutical or a medical device class III Use of any forbidden medication as specified in Section 9.6 of the protocol Known hepatitis B, hepatitis C or HIV infection Donation of blood or plasma or major blood loss (≥500 mL) within 3 months prior to Screening Positive urine drug test (amphetamine, benzodiazepines, tetrahydrocannabinol, cocaine or opiates) at Screening Known alcohol abuse Unwilling to meet the requirements of the protocol Other medical or social reasons for exclusion at the discretion of the Investigator

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TRIGEL first, then Duodopa<br>First Intervention (Day 1): TRIGEL, intestinal gel (20 mg/mL levodopa, 5 mg/mL carbidopa monohydrate, and 20 mg/mL entacapone). Second Intervention (Day 2): Duodopa, intestinal gel (20 mg/mL levodopa and 5 mg/mL carbidopa monohydrate). Both TRIGEL and Duodopa treatment consists of 3 individually adjusted and pre-defined doses: a morning dose, a continuous 14 h infusion, and extra bolus doses (if required). All TRIGEL doses correspond to 80% of the pre-study individually optimised doses of Duodopa. All Duodopa doses correspond to 100% of the pre-study individually optimized doses of Duodopa. Administration is done through duodenal or upper jejunal infusion via the patient's permanently inserted gastrojejunostomy tube by means of an ambulatory infusion pump. | Drug: TRIGEL<br>* All patients will receive TRIGEL. Treatment order is determined by randomization.<br>* Other names: Lecigon;Drug: Duodopa<br>* All patients will receive Duodopa. Treatment order is determined by randomization.<br>* Other names: Duopa;|
| Experimental: Duodopa first, then TRIGEL<br>First Intervention (Day 1): Duodopa, intestinal gel (20 mg/mL levodopa and 5 mg/mL carbidopa monohydrate). Second Intervention (Day 2): TRIGEL, intestinal gel (20 mg/mL levodopa, 5 mg/mL carbidopa monohydrate, and 20 mg/mL entacapone). Both TRIGEL and Duodopa treatment consists of 3 individually adjusted and pre-defined doses: a morning dose, a continuous 14 h infusion, and extra bolus doses (if required). All TRIGEL doses correspond to 80% of the pre-study individually optimised doses of Duodopa. All Duodopa doses correspond to 100% of the pre-study individually optimized doses of Duodopa. Administration is done through duodenal or upper jejunal infusion via the patient's permanently inserted gastrojejunostomy tube by means of an ambulatory infusion pump. | Drug: TRIGEL<br>* All patients will receive TRIGEL. Treatment order is determined by randomization.<br>* Other names: Lecigon;Drug: Duodopa<br>* All patients will receive Duodopa. Treatment order is determined by randomization.<br>* Other names: Duopa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Adjusted Area Under the Curve (AUC) (0-14h) for Levodopa |  | During 14 h infusion on 2 consecutive days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intra-individual Coefficient of Variation (3-14h) for Levodopa | The individual patient's coefficient of variation (CV) of levodopa plasma concentration during administration of TRIGEL and Duodopa respectively between 3 and 14 h after start of study drug. CV=100*sqrt (exp (SDlog*SDlog)-1) were SDlog denotes the standard deviation computed on logged plasma concentrations. | During 3-14h infusion on 2 consecutive days | 
| Dose Adjusted AUC (0-14h) for Carbidopa |  | During 14 h infusion on 2 consecutive days | 
| Number of Adverse Events |  | Patients will be followed for the duration of the hospital stay, an expected average of 3 days | 
| Dose Adjusted AUC (0-14h) for 3-O-Methyldopa |  | During 14 h infusion on 2 consecutive days |