Ataxia-Telangiectasia Clinical Trial
Official title:
Response of Individuals With Ataxia-Telangiectasia to Metformin and Pioglitazone
This study aims to investigate the link between the Ataxia Telangiectasia Mutated (ATM) gene
and metformin response. This link has been identified from large studies of the human genome,
and this study aims to confirm this link in a clinical study. The ATM gene is involved in DNA
repair - if a person inherits a "faulty" copy of this gene from both their parents, they have
a genetic condition called Ataxia-telangiectasia (A-T).
A-T is associated with, among other things, a resistance to insulin, which causes fatty liver
and diabetes. This study will recruit people who have A-T, but have not developed diabetes,
and compare this group to "healthy" controls, i.e. people who do not have A-T or diabetes.
The study will compare how the groups respond to two drugs used to treat diabetes (metformin
and pioglitazone), with the intention that this will guide the management of diabetes in A-T.
This is an, open label unblinded study recruiting 15 people with A-T and 15 age and gender
matched controls. Each participant will have three study visits to the Clinical Research
Centre at Ninewells hospital in Dundee - one at baseline, a second after 8 weeks of metformin
and the final visit after eight weeks of pioglitazone. During each visit we will carry out a
number of investigations to study the insulin resistance of A-T and how it responds to
metformin and pioglitazone.
Metformin is a commonly-prescribed drug, used as first-line medical management of type 2
diabetes mellitus (T2DM), but also off-license in non-diabetics for Polycystic Ovary Syndrome
(PCOS). Over 120 million people worldwide are prescribed metformin. Despite this, its
mechanism of action is not fully understood. Both tolerance of and response to metformin
varies greatly from patient to patient, and highlights the need for further research into the
pharmacokinetics and dynamics of the drug.
As a team of diabetes researchers, our group have been interested in the genetics of drug
response in diabetes. A Genome Wide Association Study carried out by members of our group
highlighted the locus carrying the ATM gene as a potential link to metformin response. We
have designed this study to investigate this link clinically. In doing so we hope to guide
the management of diabetes in a condition called Ataxia Telangiectasia.
ATM (Ataxia Telangiectasia Mutated) is a gene involved in DNA repair - homozygous recessive
mutations in this gene cause Ataxia Telangiectasia (A-T), which is associated with cerebellar
ataxia, ocular telangiectasia and lymphoproliferative cancers. The incidence of A-T is
between 1 in 40,000 to 1 in 100,000 live births, though this increases dramatically with
consanguineous parents. Interestingly, A-T has also been associated with insulin resistance.
Both "fatty liver" and diabetes have been documented in this patient group, but there is
little research into the link between A-T and these conditions. Approximately 1 in 100 people
are carriers of a loss of function mutation in the ATM gene, which is associated with an
increased risk of ischaemic heart disease and certain cancers.
Several studies of ATM deficiency in a mouse model have been carried out. Atm −/− mice
display an early defect in glucose-stimulated insulin release and later develop
hyperglycaemia, and insulin resistance[1]. Unpublished data from the McCrimmon Group at
University of Dundee suggest that mice heterozygous for ATM deficiency have impaired fasting
glucose, but demonstrated a marked improvement in fasting glucose with metformin. A Cell
Reports paper, detailing a mouse model of ATM deficiency, demonstrates insulin resistance in
ATM deficient mice, with a lipodystrophic phenotype[2]. This phenotype (paucity of
subcutaneous fat, and increased visceral fat) was attenuated by metformin and
thiazolidinedione (TZD) use.
A small study published by the Pearson group from University of Dundee, which compared data
from oral glucose tolerance tests (OGTTs) in A-T patients versus healthy individuals,
confirmed increased insulin resistance in A-T patients[3]. As mentioned above, a genome wide
association study, also by the Pearson group, highlights the ATM locus as a potential genetic
link to metformin response[4, 5]. With the mouse models and information from genetic studies,
this study now aims to assess insulin resistance in this A-T patient group, and to understand
how they respond to drugs commonly used to treat insulin resistance / diabetes.
The potential genetic link between ATM and metformin response will be investigated. Thus far
it is unclear from the genetic studies how ATM deficiency affects an individual's metformin
response - is their response greater or less than that of the general population? Similarly,
magnitude of this response has not been quantified. There are anecdotal reports of patients
with A-T who have had a marked improvement in glycaemic control with metformin use. Mouse
model studies have indicated an increased response to metformin in heterozygous ATM deficient
mice.
The study will also investigate the response of individuals with A-T to TZDs. Studies of the
mouse model of A-T has demonstrated response to the TZD pioglitazone,. Of note, pioglitazone
is now used off-licence in non-diabetics for the treatment of Non-Alcoholic Fatty Liver
Disease (NAFLD) [6, 7], therefore we know it is safe for use in a non-diabetic cohort.
This study will assess the effect of ATM deficiency on metformin and pioglitazone response in
humans, by studying people with A-T, and comparing their response to that of a matched
control group.
This study will recruit non-diabetic individuals - 15 cases (people with A-T) vs 15 age and
gender matched controls - in a crossover design. Participants will be 18 - 30 years of age.
This age group is most realistic for recruiting patients with "classic", as opposed to "mild
variant" A-T, as people with classic A-T rarely survive to their 30s. Exclusion of
individuals with other milder forms of A-T will provide a more detectable difference between
the two cohorts. Participants will be of white European descent, as this will narrow the
genetic differences between individuals. Ethnic origin also has an effect on an individual's
insulin resistance, therefore all the participants should be of the same ethnicity.
The study is made up of two treatment periods each lasting eight weeks, and separated by a
one week washout period. Initial treatment shall be with metformin, titrated to 1000mg twice
daily. The second treatment will be pioglitazone titrated to 30mg once daily.
The study will last a total of approximately 17 weeks, and involves three visits to the
Clinical Research Centre at Ninewells hospital in Dundee. The first visit will be the
longest, lasting 1.5 days, and the other two visits last one full day with a short
preparatory visit for 30 minutes the day before.
Multiple methods will be used to investigate the relationship between ATM, diabetes and drug
response:
- Dual tracer mixed meal tests with indirect calorimetry (see Tracer Studies SOP)
- MRI (see MRI SOP)
- Blood and urine sampling (see Sample Collection SOP)
- Fat biopsy (see Fat Biopsy SOP)
In summary, each individual will have three tracer studies: an initial study at baseline; a
second after eight weeks of metformin; and a final tracer study after eight weeks of the TZD,
pioglitazone. Tracer studies involve a standardised meal the night before the study, and
fasting from midnight in preparation. No alcohol should be consumed for 24 hours before the
study. On the day of the tracer study two cannulae will be inserted, one in each forearm. One
cannula will be used to infuse a stable glucose tracer [6,6-2H2] for the duration of the
eight hour study. After two hours of this infusion, the participant will be fed a mixed meal
containing [U-13C] glucose (stable). The participant is observed for a further six hours,
while the [6,6-2H2] glucose infusion continues. Throughout the tracer study, blood will be
taken from the second cannula at multiple time-points, to allow for measurement of glucose
(including the tracers), insulin, C-peptide, glucagon, glucagon-like peptide 1 (GLP-1) and
nonesterified fatty acids (NEFAs). A total of 150ml of blood will be taken during the tracer
study. Urine is collected in two phases (before and after the meal) during the tracer study,
for the measurement of glucose excretion. Indirect calorimetry will be used for twenty minute
episodes at several time-points to measure substrate utilisation during the study. This
involves the participant wearing a "hood" which is lightweight, and has a see-through visor.
All of these measurements will enable us to model glucose fluxes in the participant and
calculate indices of insulin sensitivity. Repetition of the tracer studies on two
anti-hyperglycaemic agents will provide comparison of these indices on and off treatment.
At the baseline visit an MRI, blood sampling and fat biopsy will take place during the half
day visit before the tracer study. This will allow us to assess fat distribution using MRI
and obtain adipose tissue to carry out lab-based studies to assess the adipocyte function and
response to metformin and pioglitazone. Blood samples are taken for "safety bloods" (i.e. to
ensure normal renal function and HbA1c <48mmol/mol) but also for future DNA analysis, to
confirm the diagnosis in the A-T group, and to check for carrier status of the controls.
Visits two and three involve a full day at the clinical research centre (CRC) for a tracer
study. On the day before the tracer, a short half-hour visit to obtain "safety bloods" (in
this case, to check renal function) and provide the standardised meal is necessary to prepare
for the tracer study the following day.
If this study can clinically confirm the hypothesis that individuals with ATM-deficiency
respond well to either metformin or pioglitazone, and individuals show marked improvement in
insulin resistance while taking either study drug, this study could direct clinical
decision-making in the care of patients with A-T and fatty liver / insulin resistance.
In conjunction with the clinical studies cell experiment studies will be carried out on
induced pluripotent stem cell (IPSC) derived hepatocytes from individuals with A-T, to assess
drug response at a cellular level. This will be a collaboration with the Sanger Institute in
Cambridge, where they have already developed IPSC-derived hepatocytes from the blood of A-T
patients. These cells will be used to create a drug response model at a cellular level. These
cell lines are not from our recruited patients directly, but serve as a cellular model of
A-T. However, we will offer the A-T group the chance to donate blood to the INSIGNIA study,
run by the Sanger Institute, which is a study focused on the investigation of patterns of
mutations (signatures) in inherited and other progressive genetic diseases (please see
INSIGNIA PIS and consent forms). This is optional and taking part in RAMP does not commit
those with A-T to contributing to INSIGNIA.
;
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
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