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

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ClinicalTrials.gov Identifier: NCT02448914
Recruitment Status : Completed
First Posted : May 20, 2015
Results First Posted : May 23, 2016
Last Update Posted : May 23, 2016
Sponsor:
Collaborator:
TFS Trial Form Support
Information provided by (Responsible Party):
LobSor Pharmaceuticals AB

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Parkinson's Disease
Interventions Drug: TRIGEL
Drug: Duodopa
Enrollment 11
Recruitment Details  
Pre-assignment Details  
Arm/Group Title TRIGEL First, Then Duodopa Duodopa First, Then TRIGEL
Hide Arm/Group Description

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.

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.

Period Title: First Intervention (1 Day)
Started 6 5
Completed 6 5
Not Completed 0 0
Period Title: Second Intervention (1 Day)
Started 6 5
Completed 6 5
Not Completed 0 0
Arm/Group Title TRIGEL and Duodopa in Randomized Order
Hide Arm/Group Description

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.

Overall Number of Baseline Participants 11
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 11 participants
<=18 years
0
   0.0%
Between 18 and 65 years
1
   9.1%
>=65 years
10
  90.9%
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 11 participants
69.5
(63 to 76)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 11 participants
Female
4
  36.4%
Male
7
  63.6%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Sweden Number Analyzed 11 participants
11
1.Primary Outcome
Title Dose Adjusted Area Under the Curve (AUC) (0-14h) for Levodopa
Hide Description [Not Specified]
Time Frame During 14 h infusion on 2 consecutive days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title TRIGEL Duodopa
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 11 11
Least Squares Mean (Full Range)
Unit of Measure: h*ng/mL/mg
40.6
(22.3 to 69.4)
29.4
(21.7 to 52.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TRIGEL, Duodopa
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Analysis was first to attempt to show non-inferiority. To show non-inferiority of TRIGEL over Duodopa, the lower limit of the two-sided CI for the treatment ratio had to be above the chosen non-inferiority margin of 0.9. If non-inferiority was shown, analysis continued with test of superiority. To show superiority of TRIGEL versus Duodopa, the lower confidence limit had to be above 1 (corresponding to a p-value less than 0.05).
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter back-transformed ratio
Estimated Value 1.382
Confidence Interval (2-Sided) 95%
1.264 to 1.511
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Intra-individual Coefficient of Variation (3-14h) for Levodopa
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title TRIGEL Duodopa
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 11 11
Least Squares Mean (Full Range)
Unit of Measure: percentage of variability
13.8
(6.5 to 36.7)
10.6
(6.1 to 19.2)
3.Secondary Outcome
Title Dose Adjusted AUC (0-14h) for Carbidopa
Hide Description [Not Specified]
Time Frame During 14 h infusion on 2 consecutive days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title TRIGEL Duodopa
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 11 11
Least Squares Mean (Full Range)
Unit of Measure: h*ng/mL/mg
22.1
(13.6 to 52.5)
18.8
(11.5 to 37.9)
4.Secondary Outcome
Title Number of Adverse Events
Hide Description [Not Specified]
Time Frame Patients will be followed for the duration of the hospital stay, an expected average of 3 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title TRIGEL Duodopa
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 11 11
Measure Type: Number
Unit of Measure: adverse events
10 6
5.Secondary Outcome
Title Dose Adjusted AUC (0-14h) for 3-O-Methyldopa
Hide Description [Not Specified]
Time Frame During 14 h infusion on 2 consecutive days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title TRIGEL Duodopa
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 11 11
Least Squares Mean (Full Range)
Unit of Measure: h*ng/mL/mg
155
(83.9 to 258.3)
131
(72.1 to 182.2)
6.Other Pre-specified Outcome
Title Treatment Response Scale (ON/OFF Effect) - Mean % of Time Patients Were in Functional ON State During 3-14 h
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title TRIGEL Duodopa
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 11 11
Mean (Full Range)
Unit of Measure: Mean % of time
91.7
(18.3 to 100.0)
91.0
(0.758 to 100.0)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title TRIGEL Duodopa
Hide Arm/Group Description

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.

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.

All-Cause Mortality
TRIGEL Duodopa
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
TRIGEL Duodopa
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/11 (0.00%)      0/11 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
TRIGEL Duodopa
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/11 (54.55%)      2/11 (18.18%)    
Gastrointestinal disorders     
Diarrhoea  0/11 (0.00%)  0 1/11 (9.09%)  1
Nausea  1/11 (9.09%)  1 1/11 (9.09%)  2
Injury, poisoning and procedural complications     
Injection site haematoma  1/11 (9.09%)  3 1/11 (9.09%)  1
Laceration  1/11 (9.09%)  1 0/11 (0.00%)  0
Nervous system disorders     
Dizziness  2/11 (18.18%)  2 0/11 (0.00%)  0
Headache  3/11 (27.27%)  3 1/11 (9.09%)  1
Skin and subcutaneous tissue disorders     
Cold sweat  0/11 (0.00%)  0 1/11 (9.09%)  1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
 
Results Point of Contact
Name/Title: Roger Bolsöy, CEO
Organization: LobSor Pharmaceutical AB
Phone: +46 (0) 72 222 44 08
Responsible Party: LobSor Pharmaceuticals AB
ClinicalTrials.gov Identifier: NCT02448914     History of Changes
Other Study ID Numbers: LSM-003
2014-004891-46 ( EudraCT Number )
First Submitted: May 12, 2015
First Posted: May 20, 2015
Results First Submitted: February 19, 2016
Results First Posted: May 23, 2016
Last Update Posted: May 23, 2016