Clinical Trial: Response of Individuals With Ataxia-Telangiectasia to Metformin and Pioglitazone

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Response of Individuals With Ataxia-Telangiectasia to Metformin and Pioglitazone

Brief Summary:

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.


Detailed Summary:

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. At
Sponsor: NHS Tayside

Current Primary Outcome: Change in insulin sensitivity after taking metformin in A-T compared to controls [ Time Frame: After eight weeks of metformin treatment ]

Difference between groups (A-T and control) in the change in EGP from baseline to post-metformin.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Difference in insulin sensitivity at baseline between groups. [ Time Frame: Baseline visit ]
    Insulin sensitivity - calculated from rate of appearance of glucose (Ra) and rate of disappearance of glucose (Rd) - at baseline in A-T compared to control.
  • Change in insulin sensitivity after taking pioglitazone in A-T compared to controls [ Time Frame: After eight weeks of pioglitazone treatment (end of study) ]
    Insulin sensitivity, measured as change in change in Ra, Rd and EGP, while taking pioglitazone compared to baseline and metformin.
  • Difference in fat distribution between groups [ Time Frame: Baseline ]
    Fat distribution on MRI - intra-abdominal (visceral) vs subcutaneous, in A-T compared to "healthy" individuals.


Original Secondary Outcome: Same as current

Information By: NHS Tayside

Dates:
Date Received: March 31, 2016
Date Started: September 2016
Date Completion:
Last Updated: October 26, 2016
Last Verified: October 2016