A comparison of Glycosade® and Uncooked Cornstarch (UCCS) for the dietary management of hepatic glycogen storage diseases (GSD)

The hepatic glycogen storage diseases (GSDs) comprise a group of rare inherited
disorders of glycogen metabolism which arise due to one of a number of enzyme
deficiencies. Hepatic GSDs comprise GSD I, GSD III, GSD VI & GSD IX. Patients
are usually diagnosed in infancy and childhood and depending upon the type of
GSD may present with:
* hypoglycaemia,
* hyperlipidaemia,
* hyperuricaemia,
* hyperlactataemia,
* hyperketosis,
* hepatomegaly
* lethargy,
* seizures
* faltering growth
(Chen 2001, Dagli, 2010).

The major metabolic consequence of hepatic GSD is hypoglycaemia provoked by
relatively short fasts, and maintaining normal blood glucose has been shown to
improve the secondary biochemical features;
* hyperlipidaemia,
* hyperuricaemia,
* hyperlactataemia,
* hyperketosis,
depending upon the individual enzyme deficiency, as well as some of the
clinical parameters (Rake et al 2002a; Rake et al 2002b, Kishnani et al 2010).
Thus the primary aim of dietary management of patients with GSD is achieving
and maintaining normal blood glucose levels which have been shown to improve
the secondary biochemical disturbances and promote normal growth.

The introduction of continuous overnight nasogastric glucose polymer feeds
demonstrated this clearly (Greene et al. 1976). The subsequent introduction of
uncooked corn starch (UCCS) into the daily dietary management of these patients
at least matched this improvement (Chen et al. 1993; Chen, Cornblath, & Sidbury
1984). Whilst the introduction of UCCS has dramatically improved the quality of
life for patients with GSD, its use does have problems. For some, the duration
of normal blood glucose levels can be very short with some studies suggesting
that corn starch therapy only prevents hypoglycaemia for a median time of 4.25
hours in children (Weinstein & Wolfdorf 2002). Thus patients may need to be
given another intake of UCCS through the night which has a considerable impact
on the quality of life for the patient and families (Correia et al 2008). In
addition many find UCCS neither palatable nor convenient, and for others there
can be symptoms of bloating, flatulence and diarrhoea with large intakes (Lee,
Dixon, & Leonard 1996). Whilst some of these gastrointestinal symptoms may be a
feature of GSD itself they may be exacerbated by the use of UCCS (Sanderson et
al 1991; Visser et al 2002). There is also some evidence that UCCS is only
partially digested and can be associated with malabsorption (Bodamer et al.
2002).

The features of an ideal starch for the dietary management of patients with the
hepatic GSDs include sustained normal blood glucose levels of approximately 8
hours without an excessive insulin rise and normalisation of other secondary
biochemical abnormalities, palatability, convenience, well tolerated and
maintenance of normal appetite (without excessive weight gain) (Correia et al
2008; Rake et al. 2002; Wolfsdorf et al 1990; Smit et al. 1984).

Recently, short and medium term studies conducted in patients with GSD I and
III have found improved blood glucose control and improved nutritional outcomes
with a physically modified corn starch, Glycosade® (manufactured by Vitaflo
International Ltd, UK) (Bhattacharya et al. 2007; Correia et al. 2008). One
study of GSD I patients showed that Glycosade® resulted in the improved
maintenance of plasma glucose levels compared to UCCS (Correia 2008). Another
study indicated a longer duration of normal blood glucose levels, a slower
decrease in plasma glucose and a more rapid suppression of lactate with
Glycosade® compared to UCCS (Bhattacharya et al. 2007). However, on an
individual patient basis, not all patients have an increased duration of normal
blood glucose levels with Glycosade® and some still appear to respond better to
standard UCCS (personal communications from the investigators; Hubert A, 2013;
Corrado M, 2013). The reasons for these potential differences in response
remain unclear.

In light of the variability in response in patients with hepatic GSD, this
study aims to establish if Glycosade® improves the dietary management of GSD.
The trial is a randomised double blind cross over study comparing the short
term changes in blood glucose, insulin and ketone levels of patients with
hepatic GSD (Types I, III, VI and IX) following equivalent intakes of
carbohydrate provided by UCCS and Glycosade® supplied by Vitaflo International
Ltd, with the aim of identifying a starch which provides the greatest duration
of normal blood glucose levels for each patient.

In light of the variability in response between UCCS and Glycosade® in patients
with hepatic GSD (personal communication from authors and published data
(Bhattacharya et al. 2007; Correia et al. 2008; Corrado M et al, 2013; Hubert A
et al, 2013)); this study aims to establish whether Glycosade improves dietary
management for patients with hepatic GSD (types I, III, VI & IX) compared to
UCCS therapy by comparing the duration of normal blood sugars, lactate and
ketone levels.

Participants will be randomised to receive either UCCS or Glycosade® for the
initial intervention period crossing over to the other product for the second
intervention period (part 1). Participants will continue in an open label part
of the study for up to 24 months on the product considered most appropriate by
the clinician and patient.

At the end of the two intervention periods (i.e. the starch loads), the
clinician will become unblinded to the dietary management and test starch the
participant received in each period. The investigator/clinician will discuss
which starch (Glycosade® or UCCS) and intake level is the most appropriate for
the participant to continue for the open follow-up period of the study.

Participation in the trial puts patients at no greater risk than they would be
exposed to outside of the trial, except for the additional DEXA forearm scan
required at visit 5. However, this specific risk does not exist for patients at
the UMCG, because -as discussed with the sponsor- MRI and DEXA scans will not
be part of the trial protocol at the UMCG. These studies will only be performed
after discussion with the patients, when they are indicated based on guidelines
and clinical pathways. However the risks associated with this level of exposure
are defined as Trivial (IPEM, 2002. Medical and Dental Guidance Notes. A Good
Practice Guide on all Aspects of Ionising Radiation Protection in the Clinical
Environment. Journal of Radiological Protection, 22(3), p.334. Available at:
http://stacks.iop.org/0952-4746/22/i=3/a=705.). A greater dose increase would
occur if someone, normally resident in York, took a holiday to Cornwall for 2
weeks.

During the open label phase of the study, participants will be regularly
checking their blood sugar levels to assess glycaemic status as is routine
practice for this group of patients.

In respect of the starch load tests these will be carried out in a hospital
setting and under the supervision of appropriately qualified study personnel.

In the UMCG the application of DEXCOM G4 subcutaneous continuous glucose sensor
monitoring is standard of care. The system measures glucose each 5 minutes and
is capable to alarm at low and/or quickly decreasing levels. The system will be
provided during the entire trial when needed, for example during starch loading
tests to improve safety.