Clinical Trial Results:
The noradrenergic basis of Parkinson’s tremor: a systems-level fMRI approach
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Summary
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EudraCT number |
2016-004629-18 |
Trial protocol |
NL |
Global end of trial date |
06 Sep 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
16 Sep 2023
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First version publication date |
16 Sep 2023
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Other versions |
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Summary report(s) |
Main results summary |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
helmich-veni-2016
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Additional study identifiers
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ISRCTN number |
ISRCTN89589002 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Donders Institute
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Sponsor organisation address |
Kapittelweg 29, Nijmegen, Netherlands, PO Box 9101, 6500 HB
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Public contact |
Administration, Radboud University, Donders Institute for Brain, Cognition and Behaviour, 0031 243610750,
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Scientific contact |
Administration, Radboud University, Donders Institute for Brain, Cognition and Behaviour, 0031 243610750,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 Jul 2023
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
06 Sep 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Sep 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To investigate the role of the noradrenergic system in the pathophysiology of PD tremor, by testing how a behavioral induction of noradrenergic activity (cognitive coactivation task) and a pharmacological inhibition of noradrenergic activity (propranolol versus placebo) both influenced tremor power (accelerometry) and tremor-related brain activity (fMRI) in tremor-dominant PD patients.
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Protection of trial subjects |
First, we used extensive exclusion criteria and followed an extensive screening procedure including an interview over the telephone, a letter of the treating neurologist, and a repetition of all screening questions on both testing days. We performed an ECG either prior to propranolol intake, to rule out cardiac arrhythmias and bradycardia. In addition, we repeatedly measured heart rate before and after propranolol intake and performed constant monitoring of the subjects' heart rate and pupil during MRI scanning. Two researchers will be present at all times that will keep a close eye on the well-being of the participant, and to comfort the participant. If preferred, a partner could be present during all measurements performed.
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Background therapy |
N.A. | ||
Evidence for comparator |
N.A. | ||
Actual start date of recruitment |
01 Sep 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 64
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Worldwide total number of subjects |
64
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EEA total number of subjects |
64
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
35
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From 65 to 84 years |
29
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were recruited through two sources: 1) Neurologists at the Radboudumc preselected patients during consultation or multidisciplinary meetings and 2) the online patient platform ParkinsonNEXT was used, where patients registered via the project webpage, or were sent an open invitation to participate if they fulfilled inclusion criteria. | |||||||||||||||
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Pre-assignment
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Screening details |
Participants underwent an extensive phone screening prior to inclusion. Afterwards, medication use and PD diagnosis were checked check eligibility. At the start of the first visit, an ECG was recorded and checked by a medical doctor for any irregularities in rhythm and conductance that could indicate contraindications for propranolol. | |||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
64 | |||||||||||||||
Number of subjects completed |
57 | |||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Physician decision: 7 | |||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Carer | |||||||||||||||
Blinding implementation details |
Patients and assessing researchers did not know on which of the two testing days participants received propranolol and on which placebo. Dispersion of the propranolol tablet in water allows affordable blinding of the study subjects from treatment, as the inactive cellulose dispersed in water is indistinguishable from the dispersed tablet. Study medication was prepared by two qualified independent researchers before application. Deblinding happened after completion of all data collection.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Tremor-dominant group | |||||||||||||||
Arm description |
27 participants passed all screening and pre-assignment. This means that these 27 patients received propranolol and placebo, in a cross-over design, in a counterbalanced order (double blind). 24 participants completed all test procedures. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Propranolol
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Soluble tablet
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Routes of administration |
Oral use
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Dosage and administration details |
single dose of 40 mg, administered orally, dissolved in water.
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Investigational medicinal product name |
Cellulose
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
One teaspoon of cellulose is dispersed in water by two independent researchers
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Arm title
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Non-tremor control group | |||||||||||||||
Arm description |
This participant group was included to compare MRI measures, but did not receive any study medication. | |||||||||||||||
Arm type |
No intervention | |||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: All tremor-dominant participants have an ECG and blood pressure assessment at the start of the first testing day. At that time, they have been included in the trial, but if they do not meet all inclusion criteria they will not be allocated to the intervention (propranolol). For 7 patients, the ECG or blood pressure assessments showed irregularities and these patients thus were not allocated to receive study medication. |
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
This number is incorrect, but I cannot change it. It is 64: 30 in the non-tremor group and 34 in the tremor-dominant group. | ||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Clinical effects of propranolol on different PD tremor types
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
To explore the effect of cognitive load as well as propranolol on resting tremor outside of the MRI context, we performed a two-way repeated measures-analysis of variance (ANOVA) with the log-transformed tremor amplitude (averaged across two repetitions per condition) as dependent variable, and the two within-subject variables TRIAL (rest vs. coco trials) and DRUG (propranolol vs. placebo session). For the remaining two tremor conditions (postural tremor and kinetic tremor), we performed separate one-sided paired t-tests comparing the log-transformed tremor amplitudes between sessions (placebo vs. propranolol). We performed separate t-tests per tremor type because not all patients had all three types of tremor. We did the same analysis with tremor frequency as dependent variable. For one patient, tremor amplitude could not be compared due to technical issues, so for this patient only tremor frequency was compared between sessions.
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Subject analysis set title |
Effects of propranolol during the fMRI task
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Clinical effects during functional MRI: To assess whether the task indeed activated the noradrenergic system during coco blocks, we calculated the average time course across subjects for tremor amplitude (accelerometry), heart rate and pupil diameter. We then performed two-way repeated measures ANOVAs for these measures with two within-subject factors TRIAL (rest vs. coco) and DRUG (propranolol vs. placebo).
Cerebral effects: First-level contrasts were entered into our second-level analysis, which consisted of a two-way repeated measures ANOVAs for effects of factors TRIAL (rest vs. coco) and DRUG (propranolol vs. placebo) on both task-related and tremor-related brain activity. For analysis of task-related activity, we performed a whole brain search. Given our a-priori hypothesis on involvement of the cerebello-thalamo-cortical circuit in PD tremor, we focused our analysis on tremor-related activity on the regions within this circuit, using small volume correction.
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End points reporting groups
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Reporting group title |
Tremor-dominant group
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Reporting group description |
27 participants passed all screening and pre-assignment. This means that these 27 patients received propranolol and placebo, in a cross-over design, in a counterbalanced order (double blind). 24 participants completed all test procedures. | ||
Reporting group title |
Non-tremor control group
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Reporting group description |
This participant group was included to compare MRI measures, but did not receive any study medication. | ||
Subject analysis set title |
Clinical effects of propranolol on different PD tremor types
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
To explore the effect of cognitive load as well as propranolol on resting tremor outside of the MRI context, we performed a two-way repeated measures-analysis of variance (ANOVA) with the log-transformed tremor amplitude (averaged across two repetitions per condition) as dependent variable, and the two within-subject variables TRIAL (rest vs. coco trials) and DRUG (propranolol vs. placebo session). For the remaining two tremor conditions (postural tremor and kinetic tremor), we performed separate one-sided paired t-tests comparing the log-transformed tremor amplitudes between sessions (placebo vs. propranolol). We performed separate t-tests per tremor type because not all patients had all three types of tremor. We did the same analysis with tremor frequency as dependent variable. For one patient, tremor amplitude could not be compared due to technical issues, so for this patient only tremor frequency was compared between sessions.
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Subject analysis set title |
Effects of propranolol during the fMRI task
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Clinical effects during functional MRI: To assess whether the task indeed activated the noradrenergic system during coco blocks, we calculated the average time course across subjects for tremor amplitude (accelerometry), heart rate and pupil diameter. We then performed two-way repeated measures ANOVAs for these measures with two within-subject factors TRIAL (rest vs. coco) and DRUG (propranolol vs. placebo).
Cerebral effects: First-level contrasts were entered into our second-level analysis, which consisted of a two-way repeated measures ANOVAs for effects of factors TRIAL (rest vs. coco) and DRUG (propranolol vs. placebo) on both task-related and tremor-related brain activity. For analysis of task-related activity, we performed a whole brain search. Given our a-priori hypothesis on involvement of the cerebello-thalamo-cortical circuit in PD tremor, we focused our analysis on tremor-related activity on the regions within this circuit, using small volume correction.
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End point title |
Tremor [1] | ||||||||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Difference between propranolol and placebo session
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| Notes [1] - 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: That is because there are not two different groups receiving the drug and placebo: our study has a cross-over design. However, this system gives an error if less than two groups are selected so I had to select two groups that are practically the same people. All 27 tremor-dominant participants receive both propranolol and placebo on a different day. What I report is a comparison between tremor power between propranolol and placebo session. |
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Attachments |
Results tremor types Results tremor during fMRI |
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| Notes [2] - 27 participants received propranolol and placebo (on different days). |
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Statistical analysis title |
Effect propranolol on rest tremor | ||||||||||||||||||||||||
Statistical analysis description |
Cognitive coactivation increased tremor (main effect TRIAL: F(1,24)=10.5; p=.003), whereas propranolol reduced tremor (main effect DRUG: F(1,24)=10.6; p=.003), but there was no TRIAL*DRUG interaction (F(1,24)=0.0; p=.95).
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Comparison groups |
Tremor-dominant group v Clinical effects of propranolol on different PD tremor types
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Number of subjects included in analysis |
54
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
≤ 0.05 | ||||||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Effect propranolol on tremor during MRI | ||||||||||||||||||||||||
Statistical analysis description |
Similar to measurements outside the scanner, cognitive coactivation increased tremor amplitude (main effect TRIAL: F(1,19)=13.8; p=.001), while propranolol reduced tremor amplitude (main effect DRUG: F(1,19)=6.4; p=.02); no TRIAL*DRUG interaction (F(1,19)=0.7; p=.41).
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Comparison groups |
Tremor-dominant group v Effects of propranolol during the fMRI task
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Number of subjects included in analysis |
50
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
≤ 0.05 | ||||||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||||||
Confidence interval |
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End point title |
Tremor-related brain activity [3] | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Difference between propranolol and placebo session
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| 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: That is because there are not two different groups receiving the drug and placebo: our study has a cross-over design. However, this system gives an error if less than two groups are selected so I had to select two groups that are practically the same people. All 27 tremor-dominant participants receive both propranolol and placebo on a different day. What I report is a comparison between tremor-related activity between propranolol and placebo session. |
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| Notes [4] - 24 completed all test procedures, for N=1 there were technical issues so N=23 included in analysis |
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Statistical analysis title |
functional MRI analysis | ||||||||||||
Statistical analysis description |
There was no TRIAL*DRUG interaction and no main effect of TRIAL for tremor-related activity in either of the regions in the cerebello-thalamo-cortical circuit. Propranolol reduced tremor-related activity in the motor cortex across the two sessions (main effect DRUG: t(22)=2.2; p=.02). In the cerebellum, the effect of propranolol approached significance (main effect DRUG: t(22)=1.7; p=.06). There was no effect on tremor-related activity in the thalamus (VLpv; main effect DRUG: t(22)=0.15; p=.44).
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Comparison groups |
Tremor-dominant group v Effects of propranolol during the fMRI task
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Number of subjects included in analysis |
46
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
≤ 0.05 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events have been assessed during the whole period of data collection, namely between October 31, 2019 and September 6, 2021.
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Adverse event reporting additional description |
In case of suspected occurrence of an AE during the testing day, the investigator interviewed the participant to inquire any adverse symptoms. AEs were reported in data management system Castor. All AEs were followed until they were abated or stabilized. Depending on the event, follow up could include referral to the general physician.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||
Dictionary version |
1
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Reporting groups
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Reporting group title |
Propranolol 40 mg oral
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Reporting group description |
- | ||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
