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| ID | Type | Description | Link |
|---|---|---|---|
| 2014-004891-46 | EudraCT Number |
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| Name | Class |
|---|---|
| TFS Trial Form Support | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| TRIGEL first, then Duodopa | Experimental | 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. |
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| Duodopa first, then TRIGEL | Experimental | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TRIGEL | Drug | All patients will receive TRIGEL. Treatment order is determined by randomization. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Dose Adjusted Area Under the Curve (AUC) (0-14h) for Levodopa | During 14 h infusion on 2 consecutive days |
| 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 |
| 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. |
Inclusion Criteria:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Dag Nyholm, Assoc. Prof. | Department of Neuroscience, Neurology, Uppsala University Hospital, Sweden | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinical Trial Consultants AB | Uppsala | SE-75185 | Sweden |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 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. |
| FG001 | 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 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (1 Day) |
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| Second Intervention (1 Day) |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Dose Adjusted Area Under the Curve (AUC) (0-14h) for Levodopa | Posted | Least Squares Mean | Full Range | h*ng/mL/mg | During 14 h infusion on 2 consecutive days |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | TRIGEL | TRIGEL, intestinal gel (20 mg/mL levodopa, 5 mg/mL carbidopa monohydrate, and 20 mg/mL entacapone). 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Roger Bolsöy, CEO | LobSor Pharmaceutical AB | +46 (0) 72 222 44 08 | roger.bolsoy@lsmgroup.se |
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| ID | Term |
|---|---|
| D010300 | Parkinson Disease |
| ID | Term |
|---|---|
| D020734 | Parkinsonian Disorders |
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| C009265 | carbidopa, levodopa drug combination |
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| Duodopa | Drug | All patients will receive Duodopa. Treatment order is determined by randomization. |
|
|
| 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 |
| 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. |
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| Participants |
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| Age, Continuous | Mean | Full Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
|
| OG001 | Duodopa | 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). All Duodopa doses corresponded to 100% of the pre-study individually optimized doses of Duodopa. |
|
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| 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. | Posted | Least Squares Mean | Full Range | percentage of variability | During 3-14h infusion on 2 consecutive days |
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| Secondary | Dose Adjusted AUC (0-14h) for Carbidopa | Posted | Least Squares Mean | Full Range | h*ng/mL/mg | During 14 h infusion on 2 consecutive days |
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| Secondary | Number of Adverse Events | Posted | Number | adverse events | Patients will be followed for the duration of the hospital stay, an expected average of 3 days |
|
|
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| Secondary | Dose Adjusted AUC (0-14h) for 3-O-Methyldopa | Posted | Least Squares Mean | Full Range | h*ng/mL/mg | During 14 h infusion on 2 consecutive days |
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| 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. | Posted | Mean | Full Range | Mean % of time | 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. |
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|
| 0 |
| 11 |
| 6 |
| 11 |
| EG001 | Duodopa | 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). All Duodopa doses corresponded to 100% of the pre-study individually optimized doses of Duodopa. | 0 | 11 | 2 | 11 |
| Nausea | Gastrointestinal disorders |
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| Injection site haematoma | Injury, poisoning and procedural complications |
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| Laceration | Injury, poisoning and procedural complications |
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| Dizziness | Nervous system disorders |
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| Headache | Nervous system disorders |
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| Cold sweat | Skin and subcutaneous tissue disorders |
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| D009422 | Nervous System Diseases |
| D009069 | Movement Disorders |
| D000080874 | Synucleinopathies |
| D019636 | Neurodegenerative Diseases |