Parkinson's Disease
Conditions
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.
Interventions
DRUGTRIGEL
All patients will receive TRIGEL. Treatment order is determined by randomization.
DRUGDuodopa
All patients will receive Duodopa. Treatment order is determined by randomization.
Sponsors
TFS Trial Form Support
LobSor Pharmaceuticals AB
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Dose Adjusted Area Under the Curve (AUC) (0-14h) for Levodopa | During 14 h infusion on 2 consecutive days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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 | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Treatment Response Scale (ON/OFF Effect) - Mean % of Time Patients Were in Functional ON State During 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. | 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. |
Countries
Sweden
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TRIGEL and Duodopa in Randomized Order TRIGEL, intestinal gel (20 mg/mL levodopa, 5 mg/mL carbidopa monohydrate, and 20 mg/mL entacapone). Duodopa, intestinal gel (20 mg/mL levodopa and 5 mg/mL carbidopa monohydrate).
All patients received TRIGEL and Duodopa treatment on two consecutive days in the study. Both TRIGEL and Duodopa were administered during 14 h in total. Each treatment consisted of three individually adjusted and pre-defined doses: a morning dose, a continuous administration, and extra doses (if required).
The TRIGEL doses corresponded to 80% of the pre-study individually optimized doses of Duodopa in the first cohort of 5 patients. After the first cohort, a pre-planned interim analysis was performed. It was decided that the morning dose would be adjusted from 80% to 90% of the corresponding Duodopa dose for the second cohort. No other changes to the dosage regimens were made. All Duodopa doses corresponded to 100% of the pre-study individually optimized doses of Duodopa. | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | TRIGEL and Duodopa in Randomized Order |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 69.5 years |
| Region of Enrollment Sweden | 11 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 11 | 2 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 |
Outcome results
Primary
Dose Adjusted Area Under the Curve (AUC) (0-14h) for Levodopa
Time frame: During 14 h infusion on 2 consecutive days
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TRIGEL | Dose Adjusted Area Under the Curve (AUC) (0-14h) for Levodopa | 40.6 h*ng/mL/mg |
| Duodopa | Dose Adjusted Area Under the Curve (AUC) (0-14h) for Levodopa | 29.4 h*ng/mL/mg |
Comparison: Levodopa AUC 0-14h/dose, was derived using the trapezoidal method and divided by the total administered dose of levodopa during the corresponding time interval.The primary endpoint was log transformed and analysed using an ANCOVA, adjusting for treatment, period and patient. The back-transformed ratio of TRIGEL over Duodopa was calculated together with 95% confidence intervals (CI) and the associated (2 sided) p value.p-value: <0.000195% CI: [1.264, 1.511]ANCOVA
Secondary
Dose Adjusted AUC (0-14h) for 3-O-Methyldopa
Time frame: During 14 h infusion on 2 consecutive days
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TRIGEL | Dose Adjusted AUC (0-14h) for 3-O-Methyldopa | 155 h*ng/mL/mg |
| Duodopa | Dose Adjusted AUC (0-14h) for 3-O-Methyldopa | 131 h*ng/mL/mg |
Secondary
Dose Adjusted AUC (0-14h) for Carbidopa
Time frame: During 14 h infusion on 2 consecutive days
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TRIGEL | Dose Adjusted AUC (0-14h) for Carbidopa | 22.1 h*ng/mL/mg |
| Duodopa | Dose Adjusted AUC (0-14h) for Carbidopa | 18.8 h*ng/mL/mg |
Secondary
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.
Time frame: During 3-14h infusion on 2 consecutive days
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TRIGEL | Intra-individual Coefficient of Variation (3-14h) for Levodopa | 13.8 percentage of variability |
| Duodopa | Intra-individual Coefficient of Variation (3-14h) for Levodopa | 10.6 percentage of variability |
Secondary
Number of Adverse Events
Time frame: Patients will be followed for the duration of the hospital stay, an expected average of 3 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TRIGEL | Number of Adverse Events | 10 adverse events |
| Duodopa | Number of Adverse Events | 6 adverse events |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| TRIGEL | Treatment Response Scale (ON/OFF Effect) - Mean % of Time Patients Were in Functional ON State During 3-14 h | 91.7 Mean % of time |
| Duodopa | Treatment Response Scale (ON/OFF Effect) - Mean % of Time Patients Were in Functional ON State During 3-14 h | 91.0 Mean % of time |