Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02869945 |
| Other study ID # |
P130939 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 2016 |
| Est. completion date |
July 1, 2021 |
Study information
| Verified date |
February 2022 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Parkinson's disease onset is clinically defined as the appearance of motor symptoms including
akinesia, tremor and hypertonia. Several studies have shown that motor symptoms occur when at
least 50 % of dopaminergic neurons are lost. However, there are evidence suggesting that the
level of dopaminergic denervation is not homogenous at the time of diagnosis.
Some patients have a higher level of dopaminergic loss at disease onset indicating the
existence of compensation mechanisms. The aim of this study is to decipher how the metabolism
of dopamine is involved in this compensation with a focus on the polymorphism of the COMT
gene. This gene is expressed according to two variant: (i) COMT H that encodes a form of the
enzyme with a high level of activity and (ii) COMT L that encode a form of the enzyme with a
low level of activity. Thus, there are 3 possible genotypes in the population: (i) COMT HH
associated with an increased degradation of dopamine, (ii) COMT LL associated with a
decreased degradation of dopamine and (iii) COMT HH (intermediary between COMT HH and COMT
LL).
The hypothesis is that this polymorphism of the COMT gene may participate to compensation
mechanisms in early PD. Patients with COMT HH genotype may have an earlier motor symptoms
onset than patients with COMT LL genotype.
To test this hypothesis, we will recruit 51 patients with de novo PD will be recruited (17
patients for each genotype). Given the distribution of COMT polymorphism in the population, a
maximum sample of 76 patients will be screened to recruit 17 patients for each genotype.
Clinical evaluation will include MDS-UPDRS, Non Motor Symptoms Scale, segmental symptoms
scale, Montreal Cognitive assessment, MMSE, Frontal assessment battery and Parkinson's
disease behavioral assessment scale (ECMP). All the patients will have a monophotonic
emission tomography with I-123-Ioflupane in order to assess the level of dopaminergic
denervation and an MRI scan with resting state study. Cerebrospinal fluid sampling will be
optional and will allow direct measurements of dopamine metabolites.
The main outcome measure will be the level of dopaminergic denervation on I-123-Ioflupane
scans according to COMT genotype, age, gender and severity of motor symptoms on the MDS-UPDRS
part 3.
If this hypothesis is confirmed, this will allow to test the efficacy of COMT inhibitors in
order to delay dopaminergic drugs initiation for PD patients.
Description:
Parkinson's disease onset is clinically defined as the appearance of motor symptoms including
akinesia, tremor and hypertonia. Several studies have shown that motor symptoms occur when at
least 50 % of dopaminergic neurons are lost. However, there are evidence suggesting that the
level of dopaminergic denervation is not homogenous at the time of diagnosis. Some patients
have a higher level of dopaminergic loss at disease onset indicating the existence of
compensation mechanisms.
The aim of this study is to decipher how the metabolism of dopamine is involved in this
compensation with a focus on the polymorphism of the COMT gene. This gene is expressed
according to two variants: (i) COMT H that encodes a form of the enzyme with a high level of
aactivity and (ii) COMT L that encode a form of the enzyme with a low level of activity.
Thus, there are 3 possible genotypes in the population: (i) COMT HH associated with an
increased degradation of dopamine, (ii) COMT LL associated with a decreased degradation of
dopamine and (iii) COMT HH (intermediary between COMT HH and COMT LL).
The hypothesis is that this polymorphism of the COMT gene may participate to compensation
mechanisms in early PD. Patients with COMT HH genotype may have an earlier motor symptoms
onset than patients with COMT LL genotype.
To test this hypothesis, 51 patients with de novo PD will be included (17 patients for each
genotype). Given the distribution of COMT polymorphism in the population, a maximum sample of
76 patients will be screened for inclusion of 17 patients for each genotype.
Only untreated patients will be included in the study in order to have a reliable assessment
of motor severity without interference of dopaminergic drugs.
The study will be scheduled as follow:
- At the first visit (V1), inclusion criteria will be checked and patients will sign the
informed consent. COMT genotype of selected patients will be analyzed.
- Result of COMT genotype will be obtained within 4 weeks. Only the 17 first patients with
each genotype will continue the study
- For these patients, an evaluation visit with clinical assessment including MDS-UPDRS,
Non Motor Symptoms Scale, segmental symptoms scale, Montreal Cognitive assessment, MMSE,
Frontal assessment battery and Parkinson's disease behavioral assessment scale (ECMP)
will be performed..
All the patients will have a monophotonic emission tomography with I-123-Ioflupane in order
to assess the level of dopaminergic denervation. An MRI scan with resting state study will
also be performed to assess the compensation mechanisms at the networks level. Cerebrospinal
fluid sampling will be optional and will allow direct measurements of dopamine metabolites.
The main outcome measure will be the level of dopaminergic denervation on I-123-Ioflupane
scans according to COMT genotype with and without adjustment for age, gender and severity of
motor symptoms on the MDS-UPDRS part 3.
Secondary outcome measures will include:
- level of dopaminergic denervation compared across the 3 genotypes (COMT HH, COMT HL and
COMT HH) with and without adjustment for age, gender and motor scores
- determination of functional compensation at the networks scale assessed on fMRI resting
state scan according to dopaminergic denervation
- determination of CSF dopamine metabolite profile at the time of diagnosis (CSF sampling
will be optional).
If this hypothesis is confirmed, this will allow to test the efficacy of COMT inhibitors in
order to delay dopaminergic drugs initiation for PD patients.
