Clinical Trial Results:
A multicenter, parallel-group, rater-blinded, randomized clinical study investigating the efficacy, safety, tolerability and pharmacokinetics of 2 dosing regimens of ND0612H, a solution of levodopa/carbidopa delivered via a pump system as a continuous subcutaneous infusion in subjects with advanced Parkinson's disease
|
Summary
|
|
EudraCT number |
2015-005078-39 |
Trial protocol |
DE AT IT |
Global end of trial date |
31 Jan 2017
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
16 Apr 2024
|
First version publication date |
16 Apr 2024
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
ND0612H-006
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT02577523 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
NeuroDerm Ltd.
|
||
Sponsor organisation address |
3 Pekeris Street, Rehovot, Israel, 7670212
|
||
Public contact |
Eti Lavi, NeuroDerm Ltd., 972 89462729, eti@neuroderm.com
|
||
Scientific contact |
Nelson Lopes, MD, NeuroDerm Ltd., 972 89462729, nelson@neuroderm.com
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
29 Nov 2017
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
31 Jan 2017
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
To assess the effect of continuous SC infusion of 2 dosing regimens of ND0612H on daily “OFF” time
|
||
Protection of trial subjects |
- Guidelines for Management of the Infusion Sites (i.e. location, rotation, cleaning, inspection).
- Named and trained study partner to help the trial subject with the study procedures.
- Health Care Professionals (a Home Nursing Service) to train and supervise both the subjects and study partners with study drug administration and handling of the infusion pump system throughout the outpatient period.
- Option to directly roll-over to an open-label, long-term, safety study ND0612H-012.
|
||
Background therapy |
- Stable anti-PD medications other than oral LD/DDI or entacapone to be continued without change throughout the study. - Adjunct oral IR LD/ CD as rescue or additional therapy was allowed as needed. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
29 Dec 2015
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Austria: 3
|
||
Country: Number of subjects enrolled |
Italy: 10
|
||
Country: Number of subjects enrolled |
Israel: 13
|
||
Country: Number of subjects enrolled |
United States: 12
|
||
Worldwide total number of subjects |
38
|
||
EEA total number of subjects |
13
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
19
|
||
From 65 to 84 years |
19
|
||
85 years and over |
0
|
||
|
||||||||||||||||||||||
|
Recruitment
|
||||||||||||||||||||||
Recruitment details |
Eleven (11) sites screened, randomized and treated subjects in 4 countries. The first subject was enrolled on 29 Dec 2015. | |||||||||||||||||||||
|
Pre-assignment
|
||||||||||||||||||||||
Screening details |
A total of 49 subjects were screened in this study, of whom 11 (22.4%) failed screening. Reasons for screening failures were: - Eligibility criteria not met (7 subjects, 14.3% of all screened subjects) - Subject withdrew consent (1 subject, 2.0% of all screened subjects) - Other (3 subjects, 6.1% of all screened subjects) | |||||||||||||||||||||
|
Period 1
|
||||||||||||||||||||||
Period 1 title |
Study treatment (overall period)
|
|||||||||||||||||||||
Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
|
|||||||||||||||||||||
Blinding used |
Single blind | |||||||||||||||||||||
Roles blinded |
Assessor [1] | |||||||||||||||||||||
Blinding implementation details |
The study was rater-blinded. The blinded rater responsible for assessing the motor state (“OFF”, “ON” without dyskinesia, “ON” with dyskinesia [mild, moderate, severe]) as well as time to full “ON” on Days 1, 2, 3, and 28, remained blinded to the subjects’ treatment. Subjects knew which treatment regimen they were assigned to, as did the unblinded staff responsible for administering the study treatments and for recording most assessment results.
|
|||||||||||||||||||||
|
Arms
|
||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||||||||||||||
|
Arm title
|
ND0612 (Levodopa/Carbidopa solution) Dosing Regimen 1 | |||||||||||||||||||||
Arm description |
Dosing Regimen 1 of ND0612 (Levodopa/Carbidopa solution) continuous SC infusion over 24 hours. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
ND0612 (Levodopa/Carbidopa solution)
|
|||||||||||||||||||||
Investigational medicinal product code |
||||||||||||||||||||||
Other name |
||||||||||||||||||||||
Pharmaceutical forms |
Solution for infusion
|
|||||||||||||||||||||
Routes of administration |
Subcutaneous use
|
|||||||||||||||||||||
Dosage and administration details |
The total daily dose of levodopa/carbidopa 720/90 mg. Device: CRONO TWIN pump system.
|
|||||||||||||||||||||
|
Arm title
|
ND0612 (Levodopa/Carbidopa solution) Dosing Regimen 2 | |||||||||||||||||||||
Arm description |
Dosing Regimen 2 of ND0612 (Levodopa/Carbidopa solution) continuous SC infusion over 14 hours. Infusion started at wake-up time supplemented with an oral IR LD/CD tablet. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
ND0612 (Levodopa/Carbidopa solution)
|
|||||||||||||||||||||
Investigational medicinal product code |
||||||||||||||||||||||
Other name |
||||||||||||||||||||||
Pharmaceutical forms |
Solution for infusion
|
|||||||||||||||||||||
Routes of administration |
Subcutaneous use
|
|||||||||||||||||||||
Dosage and administration details |
The total daily dose levodopa/carbidopa from ND0612 538/67 mg. Morning dose of oral IR-LD/CD 150/15 mg. Device: CRONO TWIN pump system.
|
|||||||||||||||||||||
| Notes [1] - The roles blinded appear inconsistent with a simple blinded trial. Justification: The study was rater-blinded (no such option to choose). The blinded rater responsible for assessing the motor state (“OFF”, “ON” without dyskinesia, “ON” with dyskinesia [mild, moderate, severe]) as well as time to full “ON” on Days 1, 2, 3, and 28, remained blinded to the subjects’ treatment. Subjects knew which treatment regimen they were assigned to, as did the unblinded staff responsible for administering the study treatments and for recording most assessment results. |
||||||||||||||||||||||
|
||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ND0612 (Levodopa/Carbidopa solution) Dosing Regimen 1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Dosing Regimen 1 of ND0612 (Levodopa/Carbidopa solution) continuous SC infusion over 24 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ND0612 (Levodopa/Carbidopa solution) Dosing Regimen 2
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Dosing Regimen 2 of ND0612 (Levodopa/Carbidopa solution) continuous SC infusion over 14 hours. Infusion started at wake-up time supplemented with an oral IR LD/CD tablet. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
ND0612 (Levodopa/Carbidopa solution) Dosing Regimen 1
|
||
Reporting group description |
Dosing Regimen 1 of ND0612 (Levodopa/Carbidopa solution) continuous SC infusion over 24 hours. | ||
Reporting group title |
ND0612 (Levodopa/Carbidopa solution) Dosing Regimen 2
|
||
Reporting group description |
Dosing Regimen 2 of ND0612 (Levodopa/Carbidopa solution) continuous SC infusion over 14 hours. Infusion started at wake-up time supplemented with an oral IR LD/CD tablet. | ||
|
|||||||||||||
End point title |
Change in Daily "OFF" Time [1] | ||||||||||||
End point description |
Based on Parkinson's disease symptom assessment, “ON” time is when there is good response to medication and few symptoms. "OFF" time is when no there is no response to medication and significant motor symptoms. An “ON/OFF” Log was completed by a blinded rater starting before the first dose of LD/DDI and following the first dose at 30 min intervals for 8 hrs. The changes in “OFF” time as hours (normalized to 16 hrs of awake time) during the 8 hrs of data collection were estimated. Negative change from baseline for "OFF" time indicates improvement.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Baseline to Day 28
|
||||||||||||
| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The purpose of this study was to explore efficacy and safety of the 2 treatment regimens; no formal hypothesis testing was to be performed (descriptive statistics only). |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||
End point title |
The Percentage of Subjects With Full "ON" at Approximately 08:00 and Approximately 09:00, as Determined by the Subject [2] | ||||||||||
End point description |
Based on Parkinson's disease symptom assessment, “ON” time is when there is good response to medication and few symptoms. "OFF" time is when no there is no response to medication and significant motor symptoms. Subjects were asked to indicate when exactly in their opinion they had turned to full “ON” (i.e. an “ON” response comparable to the “ON” response to standard oral LD/DDI treatment). Higher percentage of subjects with full “ON” on Day 28 indicates improvement.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
Baseline to Day 28
|
||||||||||
| Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis for Regimen 1 (24-hr infusion) only. Regimen 2 was not optimized for morning efficacy assessment (it required the arrival of a nurse in the morning to administer oral IR LD/CD and begin the infusion). |
|||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||||
End point title |
Change in Daily "Good ON" Time as Assessed by a Blinded Rater | ||||||||||||
End point description |
Based on Parkinson's disease symptom assessment, “ON” time is when there is good response to medication and few symptoms. "OFF" time is when no there is no response to medication and significant motor symptoms. “Good ON” time means “ON” time without troublesome dyskinesia (involuntary muscle movement), defined as the sum of "ON" time without dyskinesia and “ON” time with non-troublesome dyskinesia. An “ON/OFF” Log was completed by a blinded rater starting before the first dose of LD/DDI and following the first dose at 30 min intervals for 8 hrs. Daily total scores were normalized to 16 hours of awake time. Positive change from baseline for “ON” time without dyskinesia and for “Good ON” time, and a negative change in “ON” time with moderate or severe (troublesome) dyskinesia indicates
improvement.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to Day 28
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change in Morning UPDRS Part III (Motor) Scores | ||||||||||||
End point description |
The Unified Parkinson’s Disease Rating Scale (UPDRS) is an Investigator-used rating tool to follow the longitudinal course of Parkinson's disease. UPDRS part III (motor) score is calculated as the sum of the individual UPDRS items 18-31, each of which are measured on a 5-point scale (i.e., 0 is normal and 4 indicates a severe abnormality). UPDRS part III was done as a motor examination on Day 1 before the first dose of standard oral LD/DDI and at the same time on Day 28. The range of score values is from 0 to 132. Higher scores correlate with greater motor impairment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to Day 28
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change in UPDRS Part II (ADL) Scores | ||||||||||||
End point description |
The Unified Parkinson's disease rating scale (UPDRS) is an Investigator-used rating tool to follow the longitudinal course of Parkinson's disease. The UPDRS Part II (activity of daily living) score was calculated as the sum of the individual UPDRS items 5-17. The Part II score is the sum of the answers to the 13 questions that comprise Part II, each of which are measured on a 5-point scale (i.e., 0 is normal and 4 indicates a severe abnormality). The range of score values is from 0 to 52. Higher scores correlate with greater impairments for daily activities.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to Day 28
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
CGI-Improvement (CGI-I) Score as Assessed by Investigator | ||||||||||||||||||||||||||||||
End point description |
Global improvement was rated by the investigator or designee using Clinical Global Impression of Improvement (CGI-I). The CGI-I employs a 7-point scale with 1 being “very much improved” and 7 being “very much worse” for improvement rating.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Day 28
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||
End point title |
Change in PDQ-39 Summary Index and the 8-dimension Scores | ||||||||||||
End point description |
Subjects were requested to rate their quality of life using the Quality of Life in Parkinson’s Disease (PDQ)-39, a 39-item, self-administered questionnaire with 8 discrete dimensions (mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort). The PDQ-39 Summary Index is the sum of the dimension scores divided by the number of dimensions. The total score values range from 0 to 100%. Higher scores indicate a worse quality of life.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to Day 27
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change in PDSS-2 Total Score | ||||||||||||
End point description |
The quality of night sleep was rated by the subjects using the Parkinson’s Disease Sleep Scale (PDSS)-2, which includes questions addressing 15 commonly reported symptoms associated with sleep disturbance in PD. Each question is assessed from 0 (Always) to 10 (Never). The total score values range from 0 to 150. Higher scores indicate a lower quality of sleep, i.e., a reduction in the score indicates an improvement in sleep quality.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to Day 27
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||
End point title |
Percentage of Subjects Who Achieved at Least Certain Percent Reduction in Average Daily Normalized "OFF" Time [3] | ||||||||||
End point description |
Determination of percentage of subjects who had a complete and 50% reduction in daily “OFF” time from baseline to Day 28 during 8 hours observations.
|
||||||||||
End point type |
Post-hoc
|
||||||||||
End point timeframe |
Baseline to Day 28
|
||||||||||
| Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This was a post-hoc analysis for Regimen 1 (24-hr infusion) only. |
|||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From Baseline to the end of treatment plus 28 days
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Treatment emergent adverse events are defined as all AEs that start on or after the start of first study drug administration
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ND0612 Regimen 1 - 24-hr Infusion
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Dosing Regimen 1 of ND0612 (Levodopa/Carbidopa solution) continuous SC infusion over 24 hours. ND0612 (Levodopa/Carbidopa solution) The total daily dose of levodopa/carbidopa 720/90 mg. Device: CRONO TWIN pump system. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ND0612 Regimen 2 - 14-hr Infusion
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Dosing Regimen 2 of ND0612 (Levodopa/Carbidopa solution) continuous SC infusion over 14 hours. Infusion started at wake-up time supplemented with an oral IR LD/CD tablet. ND0612 (Levodopa/Carbidopa solution) + morning oral IR-LD/CD. The total daily dose levodopa/carbidopa from ND0612 538/67 mg. Morning dose of oral IR-LD/CD 150/15 mg. Device: CRONO TWIN pump system. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
06 Jan 2016 |
- Window for changing of infusion set, infusion initiation and duration added.
- ECG was added to the early termination visit.
- The injection sites instructions were revised.
- Cannabis was added to the list of prohibited medications.
- The prerequisites for an early termination visit were defined more clearly.
- Dosing Regimen Satisfaction Questionnaire was added on Day 28 or to the Early Termination Visit.
- Clarification on the conditions for administration of rescue/additional medication and for up/down titration of study treatment.
- Superfluous photographing was removed from assessment of injection sites. |
||
14 Apr 2016 |
- Clarifications regarding standard oral treatment, treatment regimen, named study partner, handling of the pump and study drug, Home Nursing Service.
- Malignancies and defined viral infections were included in list of exclusion criteria.
- Guidelines for the management of the infusion sites was added.
- Sample size information was updated to include the standard deviation for the estimated within group change in daily “OFF” time.
- The timing of urine pregnancy tests was updated.
- Visit windows were clarified for the Maintenance period.
- Storage conditions for study drug at the subjects’ home were updated.
- The investigator Adverse Event causality assessment was changed to a binary assessment of "Related" or "Unrelated".
Clarifications about SUSAR and SAE notification and publishing of the study results.
Additional guidance was included in the instructions on the assessment of local safety parameters. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
|||
| http://www.ncbi.nlm.nih.gov/pubmed/33164945 |
|||
