The primary objective is to test the feasibility of EGP quantification in adult GSDIa patients by stable isotopes after a single oral D-[6,6-2H2]glucose dose. Secondary objectives are to compare EGP assessed by a single oral D-[6,6-2H2]glucose dose…
ID
Source
Brief title
Condition
- Inborn errors of metabolism
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameter is the EGP quantification assessed by measurement of
blood D-[6,6-2H2]glucose enrichment.
Secondary outcome
Secondary study parameters are glucose area under the curve, glucose clearance
rate, glucose bioavailability, glucose apparent volume of distribution and CGM
data.
Background summary
Glycogen storage disease type I (GSDI) is characterised by severe fasting
intolerance, associated with hypoketotic hypoglycaemia, accumulation of
glycogen and fat in the liver and kidneys, causing hepatomegaly and renomegaly.
Two major subtypes are recognized: GSDIa, due to glucose 6-phosphatase defect
(G6PC gene variants) and GSDIb due to defect of glucose 6-phosphate transporter
(SLC37A4 gene variants). Large phenotypic variability is observed within GSDIa
patients with respect to clinical picture, biochemical parameters and dietary
response.
Notably, GSDIa patients retain a limited capacity for endogenous glucose
production (EGP). Despite several mechanisms for residual EGP have been
proposed, the origin of residual EGP in GSDIa patients is unknown. Data from
G6PC-deficient hepatocytes suggest that either increased glycogen debranching
or lysosomal glycogen breakdown accounts for residual EGP in GSDIa.
Medically prescribed diets are the cornerstone of management, but novel,
innovative treatments are promising, such as AAV8-mediated gene therapy and
mRNA therapy. Therefore, longitudinal monitoring of outcomes after therapeutic
interventions in GSDIa patients becomes warranted, for which nowadays (1)
assessment of microsomal glucose-6-phosphatase activities ex vivo
(necessitating invasive liver biopsies) and (2) execution of (invasive,
clinical) fasting challenges in vivo are available.
Theoretically, less-invasive monitoring may include the application of (3)
stable isotope methods to quantify EGP, and (4) advanced continuous glucose
monitoring (CGM) in the home situation, but proper studies are lacking.
Study objective
The primary objective is to test the feasibility of EGP quantification in adult
GSDIa patients by stable isotopes after a single oral D-[6,6-2H2]glucose dose.
Secondary objectives are to compare EGP assessed by a single oral
D-[6,6-2H2]glucose dose (a) in GSDIa patients versus matched healthy
participants, (b) in severe versus attenuated GSDIa patients, (c) in the
pre-prandial state versus the fed state in GSDIa patients, (d) in the
pre-prandial state versus the fed state in healthy participants, (e) in the
controlled hospital setting versus the at home setting in GSDIa patients, (f)
in the controlled hospital setting versus the at home setting in healthy
participants.
In addition, we will compare the CGM data from GSDIa patients versus matched
healthy participants.
Study design
An investigator-initiated human pilot-study.
Study burden and risks
The trial is considered to be a low-risk study.
For the healthy participants there is no benefit in this study. By careful
history taking we aim to reduce the risk of including patients with diabetes or
fasting intolerance.
The sites* clinical research team at the UMCG has previously performed stable
isotopes oral loads in healthy volunteers and has a longstanding tradition in
supervised controlled clinical dynamic tests in patients with inborn errors of
metabolism, and GSD in particular. To minimize the impact on quality of life
and discomfort due to hospitalization and sample collections, two experiments
will be conducted under controlled circumstances during a short hospital stay
(<24 hours) and one experiment will take place at home.
The stable isotope that will be used is safe, normally metabolised and without
any expected adverse effects; the dose of the stable isotope is relatively low
and does not affect metabolism either.
The blood tests will be conducted on capillary blood obtained by fingerstick
(or fingerprick) and collected on filter paper as dried blood spots (DBS),
before analysis. CGM will be performed throughout the study, which will
increase safety for GSDIa patients.
For GSDIa patients, the results of this study may develop into methods to
quantify glucose metabolism in a relative non-invasive mode, to assess outcomes
after novel, innovative treatments, such as AAV8-mediated gene therapy and mRNA
therapy.
Hanzeplein 1
Groningen 9700 RB
NL
Hanzeplein 1
Groningen 9700 RB
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, The GSDIa patients must
meet all of the following criteria:
• The diagnosis should be confirmed by G6PC mutation analysis
• Age above 16 years
• Stable medical condition before the start of the test procedures
Exclusion criteria
A potential GSD Ia patient who meets any of the following criteria will be
excluded from participation in this study:
• Age < 16 years
• Recent (< 1 month) history of hospitalization due to hypoglycaemia
• Intercurrent illness, defined as (a combination of) decreased dietary intake,
vomiting, diarrhoea and fever (>38.5*C) in the week prior to the visit
• Pregnancy
A potential age and gender-matched healthy participant who meets any of the
following criteria will be excluded from participation in this study:
• Confirmed diagnosis or history suggestive of diabetes mellitus
• First grade family member with a confirmed diagnosis associated with fasting
intolerance
• History suggestive of fasting intolerance
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 |
|---|---|
| ClinicalTrials.gov | NCT04311307 |
| CCMO | NL73191.042.20 |