Response of Individuals With Ataxia-Telangiectasia to Metformin and Pioglitazone
RAMP
1 other identifier
interventional
27
1 country
1
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_4
Started Sep 2016
Shorter than P25 for phase_4
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
March 31, 2016
CompletedFirst Posted
Study publicly available on registry
April 11, 2016
CompletedStudy Start
First participant enrolled
September 29, 2016
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 30, 2017
CompletedStudy Completion
Last participant's last visit for all outcomes
August 30, 2017
CompletedDecember 4, 2017
November 1, 2017
11 months
March 31, 2016
November 30, 2017
Conditions
Outcome Measures
Primary Outcomes (1)
Change in insulin sensitivity after taking metformin in A-T compared to controls
Difference between groups (A-T and control) in the change in EGP from baseline to post-metformin.
After eight weeks of metformin treatment
Secondary Outcomes (3)
Difference in insulin sensitivity at baseline between groups.
Baseline visit
Change in insulin sensitivity after taking pioglitazone in A-T compared to controls
After eight weeks of pioglitazone treatment (end of study)
Difference in fat distribution between groups
Baseline
Study Arms (2)
Ataxia Telangiectasia
EXPERIMENTALParticipants will receive two treatments - metformin and pioglitazone for eight weeks each, separated by a one week washout period.
Healthy controls
ACTIVE COMPARATORParticipants will receive two treatments - metformin and pioglitazone for eight weeks each, separated by a one week washout period.
Interventions
Metformin will be given orally, regularly for eight weeks. Dose starts at 500mg once daily for one week, increasing by 500mg per week, to final dose of 1000mg twice daily.
Pioglitazone will be given orally, regularly for eight weeks. Dose starts at 15mg once daily and after one week increases to 30mg once daily.
Eligibility Criteria
You may qualify if:
- Age 18 - 30
- White European descent
- Non-diabetic
- No history of malignancy
- Normal renal function (eGFR \> 60 ml/min/1.73m2)
- CASES - Diagnosis of 'classic' Ataxia Telangiectasia (as opposed to 'mild-variant', or related conditions e.g. AOA1)
- CONTROLS - Sex matched to cases
- CONTROLS - BMI 20-25
You may not qualify if:
- HbA1c ≥ 48mmol/mol.
- Age out-with 18 - 30
- CASES - Unconfirmed diagnosis of A-T, or non-'classic' form of A-T
- History of diabetes
- History of renal dysfunction
- History of malignancy
- History of heart failure
- Long-term steroid treatment
- Chronic lung infections / bronchiectasis
- Recent (\<30 days since completion) or current participation in another clinical trial or interventional study
- Pregnancy
- Athletes (as muscles mass has a direct effect on insulin sensitivity)
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- NHS Taysidelead
- University of Dundeecollaborator
Study Sites (1)
Ninewells Hospital
Dundee, Angus, DD19SY, United Kingdom
Related Publications (5)
Miles PD, Treuner K, Latronica M, Olefsky JM, Barlow C. Impaired insulin secretion in a mouse model of ataxia telangiectasia. Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E70-4. doi: 10.1152/ajpendo.00259.2006. Epub 2007 Mar 13.
PMID: 17356010BACKGROUNDTakagi M, Uno H, Nishi R, Sugimoto M, Hasegawa S, Piao J, Ihara N, Kanai S, Kakei S, Tamura Y, Suganami T, Kamei Y, Shimizu T, Yasuda A, Ogawa Y, Mizutani S. ATM Regulates Adipocyte Differentiation and Contributes to Glucose Homeostasis. Cell Rep. 2015 Feb 17;10(6):957-967. doi: 10.1016/j.celrep.2015.01.027. Epub 2015 Feb 12.
PMID: 25683718BACKGROUNDConnelly PJ, Smith N, Chadwick R, Exley AR, Shneerson JM, Pearson ER. Recessive mutations in the cancer gene Ataxia Telangiectasia Mutated (ATM), at a locus previously associated with metformin response, cause dysglycaemia and insulin resistance. Diabet Med. 2016 Mar;33(3):371-5. doi: 10.1111/dme.13037. Epub 2015 Dec 24.
PMID: 26606753BACKGROUNDGoDARTS and UKPDS Diabetes Pharmacogenetics Study Group; Wellcome Trust Case Control Consortium 2; Zhou K, Bellenguez C, Spencer CC, Bennett AJ, Coleman RL, Tavendale R, Hawley SA, Donnelly LA, Schofield C, Groves CJ, Burch L, Carr F, Strange A, Freeman C, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Craddock N, Deloukas P, Dronov S, Duncanson A, Edkins S, Gray E, Hunt S, Jankowski J, Langford C, Markus HS, Mathew CG, Plomin R, Rautanen A, Sawcer SJ, Samani NJ, Trembath R, Viswanathan AC, Wood NW; MAGIC investigators; Harries LW, Hattersley AT, Doney AS, Colhoun H, Morris AD, Sutherland C, Hardie DG, Peltonen L, McCarthy MI, Holman RR, Palmer CN, Donnelly P, Pearson ER. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet. 2011 Feb;43(2):117-20. doi: 10.1038/ng.735. Epub 2010 Dec 26.
PMID: 21186350BACKGROUNDvan Leeuwen N, Nijpels G, Becker ML, Deshmukh H, Zhou K, Stricker BH, Uitterlinden AG, Hofman A, van 't Riet E, Palmer CN, Guigas B, Slagboom PE, Durrington P, Calle RA, Neil A, Hitman G, Livingstone SJ, Colhoun H, Holman RR, McCarthy MI, Dekker JM, 't Hart LM, Pearson ER. A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts. Diabetologia. 2012 Jul;55(7):1971-7. doi: 10.1007/s00125-012-2537-x. Epub 2012 Mar 28.
PMID: 22453232BACKGROUND
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- STUDY CHAIR
Ewan Pearson, MD PhD
University of Dundee
Study Design
- Study Type
- interventional
- Phase
- phase 4
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- CROSSOVER
- Sponsor Type
- OTHER GOV
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Clinical research Fellow
Study Record Dates
First Submitted
March 31, 2016
First Posted
April 11, 2016
Study Start
September 29, 2016
Primary Completion
August 30, 2017
Study Completion
August 30, 2017
Last Updated
December 4, 2017
Record last verified: 2017-11
Data Sharing
- IPD Sharing
- Will not share