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Response of Individuals With Ataxia-Telangiectasia to Metformin and Pioglitazone (RAMP)

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ClinicalTrials.gov Identifier: NCT02733679
Recruitment Status : Completed
First Posted : April 11, 2016
Last Update Posted : December 4, 2017
Sponsor:
Collaborator:
University of Dundee
Information provided by (Responsible Party):
Laura McCreight, NHS Tayside

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.


Condition or disease Intervention/treatment Phase
Ataxia-Telangiectasia Drug: Metformin Drug: Pioglitazone Phase 4

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Response of Individuals With Ataxia-Telangiectasia to Metformin and Pioglitazone
Actual Study Start Date : September 29, 2016
Actual Primary Completion Date : August 30, 2017
Actual Study Completion Date : August 30, 2017


Arm Intervention/treatment
Experimental: Ataxia Telangiectasia
Participants will receive two treatments - metformin and pioglitazone for eight weeks each, separated by a one week washout period.
Drug: Metformin
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.
Other Name: Glucophage

Drug: Pioglitazone
Pioglitazone will be given orally, regularly for eight weeks. Dose starts at 15mg once daily and after one week increases to 30mg once daily.
Other Name: Actos

Active Comparator: Healthy controls
Participants will receive two treatments - metformin and pioglitazone for eight weeks each, separated by a one week washout period.
Drug: Metformin
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.
Other Name: Glucophage

Drug: Pioglitazone
Pioglitazone will be given orally, regularly for eight weeks. Dose starts at 15mg once daily and after one week increases to 30mg once daily.
Other Name: Actos




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.



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Ages Eligible for Study:   18 Years to 30 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02733679


Locations
United Kingdom
Ninewells Hospital
Dundee, Angus, United Kingdom, DD19SY
Sponsors and Collaborators
NHS Tayside
University of Dundee
Investigators
Study Chair: Ewan Pearson, MD PhD University of Dundee

Publications:
GoDARTS 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.

Responsible Party: Laura McCreight, Clinical research Fellow, NHS Tayside
ClinicalTrials.gov Identifier: NCT02733679     History of Changes
Other Study ID Numbers: 2016GE03
First Posted: April 11, 2016    Key Record Dates
Last Update Posted: December 4, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Ataxia
Cerebellar Ataxia
Ataxia Telangiectasia
Spinocerebellar Ataxias
Telangiectasis
Dyskinesias
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Cerebellar Diseases
Brain Diseases
Central Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Neurocutaneous Syndromes
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Pioglitazone
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs