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

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

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.

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease
• Intervention / Treatment: Drug: TRIGEL; Drug: Duodopa

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.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Uppsala, Sweden, SE-75185
    • Clinical Trial Consultants AB

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Willing and able to provide informed consent and judged by the Investigator to have decision-making capacity
2. Advanced levodopa-responsive idiopathic PD currently treated with Duodopa infusion since minimum 30 days
3. 30 years of age or older
4. BMI between 17.0 and 31.0 kg/m2, both inclusive
5. 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:

1. Hypersensitivity or allergy to the investigational medicinal product (IMP) or to chemically related products
2. Contraindications for the use of levodopa or carbidopa or entacapone
3. Needing a daily total dose of Duodopa during study participation exceeding 125 mL
4. Increased fluctuation in clinical PD symptoms within 7 days prior to Screening
5. 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
6. Use of any forbidden medication as specified in Section 9.6 of the protocol
7. Known hepatitis B, hepatitis C or HIV infection
8. Donation of blood or plasma or major blood loss (≥500 mL) within 3 months prior to Screening
9. Positive urine drug test (amphetamine, benzodiazepines, tetrahydrocannabinol, cocaine or opiates) at Screening
10. Known alcohol abuse
11. Unwilling to meet the requirements of the protocol
12. Other medical or social reasons for exclusion at the discretion of the Investigator

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TRIGEL first, then 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.	Drug: TRIGEL; All patients will receive TRIGEL. Treatment order is determined by randomization.; Other Names: Lecigon; Drug: Duodopa; All patients will receive Duodopa. Treatment order is determined by randomization.; Other Names: Duopa
Experimental: Duodopa first, then 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.	Drug: TRIGEL; All patients will receive TRIGEL. Treatment order is determined by randomization.; Other Names: Lecigon; Drug: Duodopa; All patients will receive Duodopa. Treatment order is determined by randomization.; Other Names: Duopa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Response Scale (ON/OFF Effect) - Mean % of Time Patients Were in Functional ON State During 3-14 h	Dyskinesia and parkinsonism symptoms were evaluated throughout the study period as an assessment of the clinical response. To assess the ON/OFF effect the Treatment Response Scale (TRS) was used. The TRS ranges from -3 (severe "OFF") to +3 ("ON" with severe dyskinesia). Results from the TRS recordings are presented as the mean percentage of time patients were in functional ON state (TRS: -1 to +1) during the time interval 3-14 h.	TRS assessments were made every 30 minutes from start of study drug administration until 3 h, every hour between 3 and 14 h and every 30 minutes between 14 and 17 h.

Collaborators and Investigators

• Sponsor: LobSor Pharmaceuticals AB
• Collaborators: TFS Trial Form Support
• Investigators: Principal Investigator: Dag Nyholm, Assoc. Prof., Department of Neuroscience, Neurology, Uppsala University Hospital, Sweden

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: May 12, 2015
• First Submitted That Met QC Criteria: May 15, 2015
• First Posted (Estimate): May 20, 2015

Study Record Updates

• Last Update Posted (Estimate): May 23, 2016
• Last Update Submitted That Met QC Criteria: April 19, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Immunologic Factors; Dopamine Agonists; Dopamine Agents; Adjuvants, Immunologic; Antiparkinson Agents; Anti-Dyskinesia Agents; Carbidopa, levodopa drug combination
• Other Study ID Numbers: LSM-003; 2014-004891-46 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided