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

Phase 1

Completed

Conditions: Parkinson's Disease

Interventions: Drug: TRIGEL
Drug: Duodopa

Registration Number: NCT02448914

Lead Sponsor: LobSor Pharmaceuticals AB

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 11

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
TRIGEL first, then Duodopa	TRIGEL	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.
Duodopa first, then TRIGEL	TRIGEL	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.
TRIGEL first, then Duodopa	Duodopa	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.
Duodopa first, then TRIGEL	Duodopa	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.

Primary Outcome Measures

Name	Time	Method
Dose Adjusted Area Under the Curve (AUC) (0-14h) for Levodopa	During 14 h infusion on 2 consecutive days

Secondary Outcome Measures

Name	Time	Method
Number of Adverse Events	Patients will be followed for the duration of the hospital stay, an expected average of 3 days
Intra-individual Coefficient of Variation (3-14h) for Levodopa	During 3-14h infusion on 2 consecutive days	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.
Dose Adjusted AUC (0-14h) for Carbidopa	During 14 h infusion on 2 consecutive days
Dose Adjusted AUC (0-14h) for 3-O-Methyldopa	During 14 h infusion on 2 consecutive days