Primary Objectives* To investigate the intra-variability (day-to-day) of glucocerebrosidase pathway biomarkers in HV, PD-GBA+ and PD-GBA-Secondary Objectives* To investigate the intra-variability (within-day) of glucocerebrosidase pathway biomarkers…
ID
Source
Brief title
Condition
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Day-to-day variability (%CV) of:
* Glucocerebrosidase and galactocerebrosidase activity (in Dried blood spots)
* Acid ceramidase activity (in PBMCs)
* Glucosylsphingosine concentration (in granulocytes)
* Ceramide and dihydroceramide concentrations (in lymphocytes)
Secondary outcome
Within-a-day variability (%CV) of:
* Glucocerebrosidase and galactocerebrosidase activity (in Dried blood spots)
* Acid ceramidase activity (in PBMCs)
* Glucosylsphingosine concentration (in granulocytes)
* Ceramide and dihydroceramide concentrations (in lymphocytes)
Between subject variability (%CV) of:
* Glucocerebrosidase and galactocerebrosidase activity (in Dried blood spots)
* GCase activity (in PBMCs)
* Acid ceramidase activity (in PBMCs)
* Glucosylsphingosine concentration (in granulocytes)
* Ceramide and dihydroceramide concentrations (in lymphocytes)
* Glucosylsphingosine, ceramide and dihydroceramide concentrations (in plasma)
* Glucosylceramide and lactosylceramide concentrations (in lymphocytes)
* Metabolic profile (in plasma)
* Metabolic flux through ceramide, dihydroceramide, glucosylceramide,
lactosylceramide, and sphingomyelin (in lymphocytes)
Background summary
*-Glucocerebrosidase (GCase) is lysosomal enzyme that is encoded by the
glucosylceramidase beta gene (GBA1). GCase metabolizes the sphingolipid
glucosylceramide (GluCer) to ceramide (Cer) and glucose. Several studies have
shown that heterozygous or homozygous GBA1 mutations that reduce enzymatic
activity are associated with approximately a 20-fold increased risk of PD.
Though the exact underlying mechanisms of the are not known, an increased
deposition of alpha-synuclein is a hallmark of PD pathology. There is a
bi-directional association between GCase and alpha-synuclein (aSyn), where a
reduced activity of GCase increases deposition of aSyn, which then further
reduces GCase activity. PD patients with GBA1 mutations are clinically
indistinguishable from patients with idiopathic PD. However, in patients with
GBA1 mutations the onset of symptoms is generally at an earlier age and
cognitive impairment is more frequently seen than in idiopathic PD.
There is low variation in plasma GluCer for healthy volunteers, but the effect
of disease state and GBA mutation status is not known. Variation of leukocyte
sphingolipids has not been described in the literature. Plasma GluCer is
elevated in PD with or without GBA mutation. In whole blood, GCase activity in
PD with GBA mutation is lower than control. GCase activity in monocytes is
lower in PD, with or without GBA mutation. Though baseline sphingolipid levels
have been studied, the effect of disease state and GBA mutation status on flux
through the sphingolipid pathway has not been examined.
This cross sectional, 3 arms phase 0 study is designed to assess the
day-to-day, within-day and inter-individual variability of sphingolipid pathway
biomarkers, including lysosomal enzyme activity, baseline sphingolipid levels,
and flux through the sphingolipid pathway, in healthy volunteers (HV) and
Parkinson*s disease patients with a mutation in the GBA1 mutations gene
(PD-GBA+) and without a mutation in the GBA1 gene (PD-GBA*) in preparation for
future clinical studies with a GCase-activator or other lysosomal enzyme
modulators.
Study objective
Primary Objectives
* To investigate the intra-variability (day-to-day) of glucocerebrosidase
pathway biomarkers in HV, PD-GBA+ and PD-GBA-
Secondary Objectives
* To investigate the intra-variability (within-day) of glucocerebrosidase
pathway biomarkers in HV, PD-GBA+ and PD-GBA-
* To investigate the inter-individual-variability (between subjects) of
glucocerebrosidase pathway biomarkers in HV, PD-GBA+ and PD-GBA-
* To investigate the inter-individual variability (between subjects from cohort
B only) of flux through spingolipid pathway biomarkers in HV, PD
Study design
This is a non-interventional, ex-vivo, phase 0 biomarker study, consisting of 2
cohorts: Cohort A will be used to evaluate intra-individual variability at
multiple days and multiple timepoints throughout a single day. Cohort A will
have 3 groups of 8 subjects each: healthy adults (HV) and patients with
Parkinson*s disease (PD) with (PD-GBA+) and without (PD-GBA-) heterozygous GBA1
mutations. Cohort B will participate for a single inter-individual variability
measurement for flux through the sphingolipid pathway. The 3 groups of cohort B
will consist of 8 healthy adults (HV), 8 patients with Parkinson*s disease (PD)
without GBA1 mutation and a up to a maximum of 8 subjects with Parkinson*s
disease with GBA1 mutation (PD-GBA+) depending on recruitment.
Study burden and risks
This non-interventional biomarker study requires the collection of blood
samples. All collections will be performed in a state of the art clinical
research unit and medically supervised by qualified medical staff. This is
considered a very low risk procedure and the burden for the volunteers related
to the study procedures will be kept to a minimum. Only existing genotyping
data is used and genotyping will not be performed for this study
À Avenida da Siderurgia Nacional .
Coronado (S. Romão e S. Mamede) 4745 457
PT
À Avenida da Siderurgia Nacional .
Coronado (S. Romão e S. Mamede) 4745 457
PT
Listed location countries
Age
Inclusion criteria
Cohort A
Group 1 (healthy volunteers)
1. Male or female 18 * 55 years of age at screening (inclusive)
2. BMI in the range of 18 * 32 kg/m2.
Cohort B
Group 1 (healthy volunteers)
1. Male or female 18 * 65 years of age at screening (inclusive)
2. BMI in the range of 18 * 32 kg/m2.
Cohort A and B
Group 2 and 3 (PD-GBA+ and PD-GBA-)
3. Confirmed clinical diagnosis of Parkinson disease by a qualified neurologist.
4. Hoehn and Yahr stage I-IV, inclusive
5. Male or female of 30-85 years of age at screening (inclusive)
6. BMI in the range of 18 * 32 kg/m2.
7. PD-GBA+ group (2): confirmed presence of GBA1 mutation via (historic)
genotyping
8. PD-GBA- group (3): confirmed absence of GBA1 mutation via (historic)
genotyping
Groups 1, 2 and 3
9. Able to speak, read, and understand study procedures in Dutch sufficiently
to allow completion of all study assessments.
10. Must understand and provide written informed consent prior to the
initiation of any protocol-specific procedures.
11. Willing and able to maintain stable doses and regimens for all medications,
herbal treatments, medical marijuana, dietary supplements and caffeine intake
from the screening visit through the last study visit.
12. Willing and able to abstain from alcohol 24 hours prior to all study
procedures at study visits 1, 2 and 3.
13. Women of childbearing potential must use a form of birth control (e.g. oral
contraceptive, condom use, IUD, abstinence of hetero-sexual intercourse)
Exclusion criteria
Group 1 and 2 and 3
1. Significant haematological abnormalities during screening such as anaemia,
leukopenia, (haemoglobin level <7.0 mmol/L (males) or <6.0 mmol/L (females)),
or any other significant abnormalities in clinical laboratory test values.
2. Recent participation (<90 days / 5x T1/2) in an interventional study for
Parkinson disease
3. Any other clinically significant neuro-degenerative disorder
4. Recent blood loss or blood donation (>500mL whole blood) in the past 30 days.
5. Recent infection with hospital admission (<1 month)
6. Alcohol or drugs abuse in the past 12 months
7. Have no clinical or electrocardiographic signs of ischemic heart disease as
determined by the Investigator with normal cardiac intervals appropriate for
their gender. The Screening 12 lead ECG conduction intervals must be within
gender specific normal range (e.g., QTcf female *470 msec QTcF males *450 msec,
PR interval *220 msec).
8. Vital sign measurements must be within the following ranges during
screening:
a. body temperature, >35C to *38C
b. systolic blood pressure, >90 to *160 mm Hg
c. diastolic blood pressure, >40 to *95 mm Hg
d. pulse rate, >40 to *100 bpm
9. Positive serology for human immunodeficiency virus (HIV), hepatitis B virus
(HBV) (positive hepatitis B core antibody [anti-HBc] with negative hepatitis B
DNA is acceptable), or hepatitis C virus (HCV) (treated/resolved hepatitis C
with negative polymerase chain reaction [PCR] RNA is allowed)
10. Any other issue that, in the opinion of the investigator, would make the
participant ineligible for study participation
Group 1
11. Clinical evidence or history of Parkinson disease, parkinsonism or Gaucher
disease
12. First order relative with Parkinson disease or Gaucher disease
13. Any historyof unstable or poorly controlled psychiatric, endocrine,
pulmonary, cardiovascular, gastrointestinal, hepatic, pancreatic, renal,
metabolic, hematologic, immunologic, or allergic disease, or other major
disorders. Well-controlled conditions are permitted if investigator and Sponsor
agree.
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 | NL79102.100.21 |