The primary goal of this phase 0 study is to assess the variability of mitochondrial function measurements in healthy volunteers and PD patients.
ID
Source
Brief title
Condition
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Characterize day-to-day, intra-individual and inter-individual variability of
mitochondrial function in the brain measured with 31-P MRS of early onset PD
patients, late onset PD patients, GBA mutation PD patients and healthy
volunteers.
Secondary outcome
Characterize day-to-day, intra-individual and inter-individual variability of
mitochondrial function measured in peripheral blood mononuclear cells or whole
blood of early onset Parkinson*s disease patients, late onset Parkinson*s
disease patients, GBA mutation Parkinson*s disease patients and healthy
volunteers.
Characterize day-to-day and inter-individual variability of circulating
biomarkers in plasma in idiopathic early onset Parkinson*s disease patients,
idiopathic late onset Parkinson*s disease patients, GBA mutation Parkinson*s
disease patients and healthy volunteers.
Characterize day-to-day, intra-individual and inter-individual variability of
mitochondrial function in the skin of early onset Parkinson*s disease patients,
late onset Parkinson*s disease patients, GBA mutation Parkinson*s disease
patients and healthy volunteers.
Background summary
Parkinson's disease (PD) is a progressive, neurodegenerative disorder of aging
that affects both motor and cognitive function. The core pathology of
Parkinson*s is degeneration of the dopaminergic neurons in the midbrain
(substantia nigra pars compacta) leading to a dopamine deficit in the striatum.
The dysregulation in this dopamine circuit leads to the development of motor
symptoms, as well as non-motor symptoms such as autonomic dysfunction, sleep
disturbance, depression, *****************************gastrointestinal
dysfunction, incontinence and cognitive impairment. In late-onset idiopathic PD
and dominantly inherited genetic variants, the degeneration of neurons occurs
in association with the formation of intraneuronal Lewy inclusion bodies.
Insight into the function and dysfunction of PD-associated gene products helped
to elucidate the underlying mechanisms leading to neuronal cell death.
Accumulating evidence indicated that PD-associated genes directly or indirectly
affect mitochondrial function *(Grünewald et al., 2019)*. Different aspects of
mitochondrial function seem to be affected, including membrane potential,
production of reactive oxygen species (ROS), import defects, dysfunction of
electron transport chain (ETC) complexes, adenosine triphosphate (ATP) levels
and imbalances in Ca+ homeostasis.
Therefore, improvement of mitochondrial function provides important targets for
new therapeutic agents for PD patients. In order to assess efficacy and target
engagement of these therapeutic agents, suitable biomarkers need to be
available. There are different ways to assess mitochondrial function,
31-phosphorus Magnetic Resonance Spectroscopy (31P-MRS) is a way to asses
mitochondrial function in vivo *(van Diemen et al., 2021)*. Inclusion of a
visual stimulus in 31P-MRS studies has shown specific differences between
patients with PD and healthy control subjects, particularly in the recovery
phase after stimulation *(Rango et al., 2006, 2020)*. Flow-mediated skin
fluorescence (FMSF) provides a non-invasive method to assess mitochondrial
function and has recently been used to demonstrated differences in patients
with primary mitochondrial disease *(van Kraaij et al., 2023)*. In addition,
mitochondrial dysfunction could be assessed via circulating biomarkers or by
assessing mitochondrial function in whole blood and peripheral blood
mononuclear cells (PBMCs****************************)
***************************(van Kraaij et al., 2023)*.
Study objective
The primary goal of this phase 0 study is to assess the variability of
mitochondrial function measurements in healthy volunteers and PD patients.
Study design
A non-interventional phase 0, method validation study to assess day-to-day,
inter-individual and intra-individual variability of biomarker measurements.
Participants will visit Centre for Human Drug Research (CHDR) on day 1 and 7
(up to day 28). On each day mitochondrial function measurements will be
performed.
Study burden and risks
This is a non-interventional biomarker study. No investigational drug will be
administered. Biomarkers will be assessed using 31P-MRS or via blood sampling.
All blood collections will be performed at the clinical research unit and will
be medically supervised by qualified medical staff. 31P-MRS will be performed
in the university medical center by qualified staff. The blood sampling, flow
mediated skin fluorescence and the 31P-MRS are considered low-risk procedures
and the burden for the participants related to the study procedures will be
kept to a minimum.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
Healthy volunteers:
1. Adult male or female subjects 50 years of age or older, inclusive.
2. Healthy status as defined by absence of evidence of any significant active
acute or chronic disease or illness following a detailed medical and surgical
history, a complete physical examination including vital signs, 12-lead ECG,
haematology, blood chemistry and urinalysis, as judged by the investigator,
3. Body mass index (BMI) between 18-32 kg/m2, inclusive.
4. Evidence of a personally signed and witnessed informed consent document
indicating that the subject has been informed of all pertinent aspects of the
study.
5. Women of childbearing potential must use an effective form of contraception
(e.g., oral contraceptive, condom use, intrauterine device (IUD), abstinence of
heterosexual intercourse) during the study.
Parkinsons disease patients:
6. Adult male or female subjects 50 years of age or older, inclusive, with a
confirmed diagnosis of Parkinson*s disease (Hoehn and Yahr grade 1-3).
7. Healthy status as defined by absence of evidence of any significant active
acute or chronic disease or illness following (apart from Parkinson*s disease)
a detailed medical and surgical history, a complete physical examination
including vital signs, 12-lead ECG, haematology, blood chemistry and
urinalysis, as judged by the investigator.
8. BMI between 18-32 kg/m2, inclusive.
9. Evidence of a personally signed and witnessed informed consent document
indicating that the subject has been informed of all pertinent aspects of the
study.
10. Women of childbearing potential must use an effective form of contraception
(e.g., oral contraceptive, condom use, IUD, abstinence of heterosexual
intercourse) during the study.
Exclusion criteria
Healthy subjects
1. Legal incapacity or inability to understand or comply with the requirements
of the study
2. Clinically significant findings as determined by medical history taking,
physical examination, ECG, laboratory findings and vital signs
3. Female participant is pregnant or planning to become pregnant during the
study.
4. Have a urine drug screen detecting illicit drug(s) of abuse (morphine,
benzodiazepines, cocaine, amphetamine, THC) or positive alcohol breath test at
screening. A positive urine drug screen for prescribed medication is allowed at
the discretion of the investigator.
5. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab),
or human immunodeficiency virus antibody (HIV Ab) at screening
6. Consume, on average, >8 units/day of (methyl)xanthines (e.g., coffee, tea,
cola, chocolate) and not able to refrain from use during each stay at the CHDR
clinic
7. History or clinical evidence of drug abuse
8. History (within 3 months of screening) of alcohol consumption exceeding 2
standard drinks per day on average. Unwillingness or inability to refrain from
alcohol consumption at least 24 hours before screening and before each
scheduled visit.
9. Smoking of >5 cigarettes/day or equivalent and unwillingness or inability to
refrain from tobacco usage within 12 hours before each visit until the end of
that visit.
10. Loss of blood >= 500 ml within 3 months before screening
11. Presence of any contraindication to have magnetic resonance imaging (MRI)
scans with checkerboard stimulus performed (e.g. claustrophobia, pacemaker,
intracranial clips, deep brain stimulation, photosensitive epilepsy etc.).
12. Participation in a clinical trial including an investigational medicinal
product within 90 days of screening or more than 4 times within a year.
13. A visual acuity below -10 or above +10
14. Not being able to lay still and flat on back for 30-60 minutes.
Parkinsons disease patients
15. Legal incapacity or inability to understand or comply with the requirements
of the study
16. Any known PD-related gene mutations, except for GBA mutation.
17. Reside in a nursing home or assisted care facility
18. Clinically significant findings as determined by medical history taking,
physical examination, ECG, laboratory findings and vital signs, other than
Parkinson*s disease
19. Any current, clinically significant, known medical condition other than
Parkinson*s disease. Patients with a diagnosis of neurological diseases, other
than Parkinson*s disease, including Alzheimer*s disease, Huntington*s disease,
vascular dementia, progressive supranuclear gaze palsy, multiple system
atrophy, drug-induced parkinsonism, essential tremor, primary dystonia,
epilepsy, etc., that are considered clinically relevant by the investigator
20. Female participant is pregnant or planning to become pregnant during the
study.
21. Have a urine drug screen detecting illicit drug(s) of abuse (morphine,
benzodiazepines, cocaine, amphetamine, THC) or positive alcohol breath test at
screening. A positive urine drug screen for prescribed medication is allowed at
the discretion of the investigator.
22. Positive HBsAg, HCV Ab, or HIV Ab at screening
23. Consume, on average, >8 units/day of (methyl)xanthines (e.g., coffee, tea,
cola, chocolate) and not able to refrain from use during each stay at the CHDR
clinic
24. History or clinical evidence of drug abuse
25. History (within 3 months of screening) of alcohol consumption exceeding 2
standard drinks per day on average. Unwillingness or inability to refrain from
alcohol consumption at least 24 hours before screening and before each
scheduled visit.
26. Smoking of >5 cigarettes/day or equivalent and unwillingness or inability
to refrain from tobacco usage within 12 hours before each visit until the end
of that visit.
27. Loss of blood >= 500 ml within 3 months before screening, including plasma
donation.
28. Presence of any contraindication to have MRI scans with checkerboard
stimulus performed (e.g. claustrophobia, pacemaker, intracranial clips, deep
brain stimulation, photosensitive epilepsy etc.).
29. Participation in a clinical trial including an investigational medicinal
product within 90 days of screening or more than 4 times within a year.
30. A visual acuity below -10 or above +10
31. Not being able to lay still and flat on back for 30-60 minutes.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL86774.056.24 |