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Trial record 4 of 8 for:    KCNJ11

Study of Sulphonylurea Synergy With Incretins (LOGIC)

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ClinicalTrials.gov Identifier: NCT03705195
Recruitment Status : Active, not recruiting
First Posted : October 15, 2018
Last Update Posted : November 4, 2019
Sponsor:
Collaborator:
NHS Tayside
Information provided by (Responsible Party):
University of Dundee

Brief Summary:

The Study of Sulphonylurea Synergy with Incretins (LOGIC) is a Proof-of-Concept Physiological study in the form of two matched isoglycaemic clamps. A matched clamp consists of an of oral glucose tolerance test followed by an isoglycaemic intravenous glucose infusion (IGII). The study will investigate whether there is synergy between a physiological sulphonylurea (SU) stimulus and the incretin effect, causing augmentation of insulin secretion in patients with type 2 diabetes mellitus (T2DM). The study will take place at The Clinical Research Centre at Ninewells Hospital in Dundee over five visits. It will evaluate 20 patients with T2DM on no diabetes therapy, or metformin monotherapy.

All participants will undergo two matched clamps. The first matched clamp will be with no intervention. The second intervention matched clamp, low-dose liquid gliclazide will be administered 1-hour prior to each test. The sulphonylurea, Gliclazide, in this this instance will be used as a physiological stimulus and will only be given on two occasions as part of the second matched clamp. The first eight participants will participate in the dose-ranging phase. They will receive either 10mg or 20mg gliclazide as a stimulus to augment the incretin effect. A further twelve participants will then be recruited to complete the study utilising the dose which caused the greatest increment in insulin secretion. LOGIC will also evaluate the cohort for effect of KCNJ11 genotype on physiological response.


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Drug: Gliclazide Not Applicable

Detailed Description:

The Study of Sulphonylurea Synergy with Incretins (LOGIC) is a Proof-of-Concept Physiological study in the form of two matched isoglycaemic clamps. A matched clamp consists of an of oral glucose bolus test followed by an isoglycaemic intravenous glucose infusion (IGII) the next day. The study will investigate whether there is synergy between a physiological sulphonylurea (SU) stimulus and the incretin effect, causing augmentation of insulin secretion in patients with type 2 diabetes mellitus (T2DM).

The study will take place at The Clinical Research Centre at Ninewells Hospital in Dundee over five visits. It will evaluate 20 patients with T2DM on no diabetes therapy, or metformin monotherapy.

The first visit is a screening visit to ensure the participant meets inclusion and exclusion criteria, and, if so, to obtain written informed consent for study. Visits 2-5 will all occur following an overnight 10-hour fast at home. The second and third visits will make up the first matched clamp. In visit 2, the participant will undergo a 75-gram oral glucose bolus with frequent blood sampling to assess the glucose variance, insulin secretion and incretin hormone response from an oral glucose stimulus. Blood glucose level (BGL) will be sampled every 5 minutes along with hormone biochemical analysis at regular defined time points. The third visit consists of an IGII to replicate the glucose curve from the OGTT to allow measurement of incretin effect. BGL will again be sampled every 5 minutes with regular biochemical analysis of hormones.

The investigators aim to establish whether a low-dose of sulphonylurea will have a synergistic role on insulin secretion with endogenously secreted GLP-1 and GIP, therefore visits four and five will complete the same matched clamp, however, low-dose liquid gliclazide will be administered 1-hour prior to each test. The sulphonylurea, Gliclazide, in this this instance will be used as a physiological stimulus and will only be given on two occasions as part of the second matched clamp. The first eight participants will receive either 10mg or 20mg gliclazide as a stimulus to augment the incretin effect. A further twelve patients will then be recruited to complete the study utilising the dose which caused the greatest increment in insulin secretion.

The comparison of these tests will investigate the hypothesis that there is a synergistic effect between low-dose sulphonylurea and augmentation of the incretin effect on the beta cell. LOGIC will also evaluate the cohort for effect of KCNJ11 genotype on physiological response. Participants will be consented for genotyping as part of this study.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Proof-of-Concept Physiological Study
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Study of Sulphonylurea Synergy With Incretins
Actual Study Start Date : August 3, 2018
Actual Primary Completion Date : June 26, 2019
Estimated Study Completion Date : December 20, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
No Intervention: No Intervention
All participants in study will complete two matched clamp studies (OGTT + IGII). The first matched clamp without any intervention the second matched clamp with low dose gliclazide
Experimental: Low Dose Gliclazide

The first 8 participants will complete the dose-ranging phase of LOGIC study. Low dose gliclazide is being used a physiological stimulus. In the dose-ranging phase, 4 participants will receive 10mg gliclazide, the remaining 4 will receive 20mg gliclazide. The allocation to 10mg or 20mg will be randomised and unblinded. The study will analyse after the first 8 participants to assess which dose produces the greatest augmentation of insulin secretion when acting synergistically with the incretin effect.

The further 12 participants will complete the study with the identified best dose.

Drug: Gliclazide
Low dose liquid gliclazide will be used with the second matched clamp (OGTT/IGII) in visits 4 & 5.
Other Names:
  • Diamicron
  • Zicron




Primary Outcome Measures :
  1. Difference in insulin secretion and incretin effect between two matched clamps (presence and absence of low dose gliclazide) [ Time Frame: Through four study visits completed over 4 weeks ]
    Comparison of two matched clamps (oral glucose tolerance test + isoglycaemic intravenous glucose infusion). Matched clamp 1 - control. Matched clamp 2 - low dose gliclazide. Levels of insulin/c-peptide, incretin hormones and plasma glucose will be compared in the presence and absence of low dose gliclazide


Secondary Outcome Measures :
  1. Insulin secretory response analysed by KCNJ11 Genotype (E23K, E23E, K23K) [ Time Frame: Through four study visits completed over 4 weeks ]
    Difference in insulin secretory response to low dose gliclazide calculated by insulin/cpeptide levels in matched clamp(gliclazide). Differences will then be compared by participants genotype e.g. insulin secretory response for E23K, E23E, K23K variants.



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Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 40 - 80,
  • Age of Diabetes Diagnoses ≥ 35
  • T2DM on no treatment or metformin monotherapy
  • White British
  • HbA1c ≤ 8% (64mmol/mol)
  • eGFR ≥ 50ml/min-1
  • ALT ≤ 2.5 x ULN
  • Able to consent

Exclusion Criteria:

  • Type 1 Diabetes Mellitus
  • HbA1c > 8.0% (> 64mmol/mol)
  • eGFR <50ml/min-1
  • ALT >2.5 x ULN
  • Anaemia (Haemoglobin <12.0 g/dL for women, <13.0 g/dL for men)
  • Pregnancy, lactation or a female planning to conceive within the study period
  • Established pancreatic disease
  • Participating in clinical phase of another interventional trial/study or have done so within the last 30 days
  • Any other significant medical reason for exclusion as determined by the investigator

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): NCT03705195


Locations
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United Kingdom
Ninewells Hospital and Medical School
Dundee, United Kingdom, DD1 9SY
Sponsors and Collaborators
University of Dundee
NHS Tayside
Investigators
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Study Chair: Ewan R Pearson University of Dundee

Publications:

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Responsible Party: University of Dundee
ClinicalTrials.gov Identifier: NCT03705195     History of Changes
Other Study ID Numbers: 2018DM01
First Posted: October 15, 2018    Key Record Dates
Last Update Posted: November 4, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Gliclazide
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Hypoglycemic Agents