- ICH GCP
- 미국 임상 시험 레지스트리
- 임상시험 NCT01813929
Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes (MeT1)
연구 개요
연구 유형
등록 (실제)
단계
- 4단계
연락처 및 위치
연구 장소
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Colorado
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Aurora, Colorado, 미국, 80045
- University of Colorado Denver
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참여기준
자격 기준
공부할 수 있는 나이
건강한 자원 봉사자를 받아들입니다
연구 대상 성별
설명
Inclusion Criteria:
- Age 20-59 years of age,
- Type 1 diabetes based on antibody-positivity, rapid persistent conversion to insulin requirement after diagnosis, absent C-peptide, or DKA at diagnosis, or a clinical course consistent with T1D,
- HbA1c 6.0 - 9.5, and
- Willing and able to commit to two 6 week-long periods of blinded medication followed by hyperinsulinemic euglycemic clamp, vascular testing, and muscle biopsies.
Exclusion Criteria:
Any comorbid condition associated with:
- inflammation,
- insulin Resistance, or
dyslipidemia including:
- cancer,
- heart failure,
- active or end stage liver disease,
- kidney disease, or
- rheumatological disease;
- Tobacco use;
- Pregnancy or women who are breastfeeding;
- Steroid use;
- Scheduled strenuous physical activity >3 days a week;
- Angina, known CAD, or any other cardiovascular or pulmonary disease;
- A history of COPD or asthma;
- Presence of systolic blood pressure >190 at rest or >250 with exercise, or diastolic pressure >95 at rest or >105 with exercise;
- Untreated thyroid disease;
- Proteinuria (urine protein >200 mg/dl) or a creatinine > 1.5 mg/dl (males) or 1.4 mg/dL (females), suggestive of severe renal disease;
- Severe Proliferative retinopathy;
- Niacin treatment;
- Administration of experimental agent for T1D within 30 days prior to screening;
- Recent (prior 6 months) or current metformin or thiazolidenedione use;
- Hypoglycemia unawareness or recurrent severe hypoglycemia (no symptoms of hypoglycemia with FSBS<40 and episodes of this severity >1 per week);
- Weight instability (weight change >5% in last 6 months);
- History of any organ transplant, including islet cell transplant;
- Current or prior infection with HIV, hepatitis B or hepatitis C or hepatic -insufficiency (AST or ALT > 2x the upper limits of normal);
- Any condition, medical or otherwise that would, in the opinion of the investigator, prevent complete participation in the study, or that would pose a significant hazard to the subject;
- History of substance abuse within the 12 months prior to screening.
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 치료
- 할당: 무작위
- 중재 모델: 크로스오버 할당
- 마스킹: 더블
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
---|---|
위약 비교기: 위약
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Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
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실험적: 메트포르민
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Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention.
If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.
다른 이름들:
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연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
---|---|---|
Insulin Sensitivity by Hyperinsulinemic Euglycemic Clamp
기간: End of each 6 week intervention period
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Determine the effect of metformin on insulin sensitivity in T1D.
Reported measure is glucose infusion rate during hyperinsulinemic euglycemic clamp normalized to total body weight.
For this measure, insulin was infused at 40 mU/m2 surface area.
Blood sugar wass checked every 5 minutes and glucose infusion adjusted to maintain glucose level at 90 mg/dL for 2 hours.
The glucose infusion rate for the final 30 minutes is reported as GIR (aka M-value or glucose disposal rate) in mg glucose/kg*min.
A higher value corresponds to greater sensitivity to insulin.
There is no strictly defined normal range.
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End of each 6 week intervention period
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Flow-mediated Brachial Artery Dilation
기간: End of each 6 week intervention period
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Measure of endothelial function by brachial ultrasound of the percent dilation after 5 minutes of occlusion.
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End of each 6 week intervention period
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2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
---|---|---|
Arterial Stiffness by PWV
기간: End of each 6 week intervention period
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Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec.
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End of each 6 week intervention period
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Arterial Stiffness by AI@75
기간: End of each 6 week intervention period
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Augmentation index by Sphygmacor is a measure of aortic arterial stiffness.
AI@75 is the ratio of augmented pressure/pulse pressure adjusted to a heart rate of 75.
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End of each 6 week intervention period
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Mitochondrial Measures: Oxygen Consumption
기간: End of each 6 week intervention period
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Oxygen consumption rate with various substrates and max uncoupled O2 consumption. Measure is performed on permeabilized muscle fibers from biopsy tissue from the vastus lateralis using the Oroboros OxygraphO2k high resolution respirometer. State 3 is full coupled oxygen flux using PMG or PMGS (pyruvate, malate, glutamate, +/- succinate) or OCMS (octanyl carnitine, malate, +/- succinate) as substrates. state 4 is after addition of oligomycin to inhibit the ATP synthase and thus corresponds to the maximum leak state where O2 consumption is limited by the buildup of the proton gradient and can only proceed as fast as the protons can leak back across the membrane. FCCP is added as an uncoupler, allowing free leakage of protons across the inner membrane, and thus measures maximum possible O2 flux. There are no defined normal ranges, but higher state 3 and uncoupled flux indicate better mitochondrial function, while state 4 is needed to correct state 3 to the fully coupled flux. |
End of each 6 week intervention period
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Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes
기간: End of each 6 week intervention period
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Mito content by Western Blotting of electron transport chain complexes I, II, III, and V. complex 1 utilizes NADH from pyruvate/malate/glutamate while complex II utilizes FADH from succinate.
complex III is the cytochrome c reductase while complex V is the ATP synthase.
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End of each 6 week intervention period
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Inflammatory Marker: hsCRP
기간: End of each 6 week intervention period
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hsCRP (mg/L) by Beckman Coulter assay
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End of each 6 week intervention period
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Heart Rate Variability
기간: End of each 6 week intervention period
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measure of autonomic function: ratio of fastest to slowest heart rate during valsalva maneuver
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End of each 6 week intervention period
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Continuous Glucose Monitor Measures of Mean Glucose
기간: Last Week of each 6 Week Intervention Period (over 7 days)
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Mean Glucose & Glucose Standard Deviation (Glycemic Variability) by Dexcom CGM
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Last Week of each 6 Week Intervention Period (over 7 days)
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Continuous Glucose Monitor Measures of Hypoglycemia
기간: Last Week of each 6 Week Intervention Period (over 7 days)
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Percent of time less than 70 mg/dL during the final week of each phase by Dexcom CGM.
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Last Week of each 6 Week Intervention Period (over 7 days)
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Metabolic Markers: Glucagon
기간: End of each 6 week intervention period
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Glucagon (pg/ml); baseline on AM of each phase final study visit.
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End of each 6 week intervention period
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Metabolic Markers: Glucose, Triglycerides, Cholesterol
기간: End of each 6 week intervention period
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Glucose (mg/dL), triglycerides (mg/dL), cholesterol (mg/dL) at baseline after each phase
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End of each 6 week intervention period
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Metabolic Markers: Fatty Acids
기간: End of each 6 week intervention period
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fatty acids (microeq/L) at baseline after each phase in the AM of the final visit
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End of each 6 week intervention period
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Metabolic Markers: Glycerol
기간: End of each 6 week intervention period
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glycerol (micromol/L) at baseline after each phase in the AM of the final phase visit
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End of each 6 week intervention period
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Metabolic Markers: Insulin
기간: End of each 6 week intervention period
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insulin (microIU/ml) at baseline after each phase in the AM of the final phase visit
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End of each 6 week intervention period
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Metabolic Markers: Lactate
기간: End of each 6 week intervention period
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lactate (mmol/L) at baseline after each phase in the AM of the final phase visit
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End of each 6 week intervention period
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Metabolic Markers: Adiponection
기간: End of each 6 week intervention period
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adiponection (microg/ml) at baseline after each phase in the AM of the final phase visit
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End of each 6 week intervention period
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Vascular Markers: Endothelin-1 (pg/ml)
기간: End of each 6 week intervention period
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endothelin-1 at baseline after each phase in the AM of the final phase visit by peninsula labs radioimmunoassay
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End of each 6 week intervention period
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In Vivo Mitochondrial Function: Ratio of the Amount of ATP Generated Per Unit of Oxygen Consumed
기간: End of each 6 week intervention period
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Measured by 31P-mass spec.
This ratio measures mitochondrial efficiency.
The higher the ratio, the more efficiently the individual converts metabolic substrates into ATP, with the ATP then available for energy-demanding cellular processes such as protein synthesis and biomass production
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End of each 6 week intervention period
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In Vivo Mitochondrial Function: Time Constants
기간: End of each 6 week intervention period
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Measured by 31P-mass spec.
ADP time constant and phosphocreatine time constant.
ADP time constant is a measure of the time required to convert ADP → ATP and is a measure of muscle mitochondrial health (energy metabolism).
A faster recovery is a better outcome; a slower recovery is a worse outcome.
Similarly for phosphocreatine.
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End of each 6 week intervention period
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In Vivo Mitochondrial Function: QMax, VPCr
기간: End of each 6 week intervention period
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Measured by 31P-mass spec. For each measure, a higher value indicates better mitochondrial function. All re calculated from multiple measures from the MRS spectra. These are relatively new research measures and normal values are not known or generally accepted.
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End of each 6 week intervention period
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In Vivo Mitochondrial Function: Oxidative Phosphorylation
기간: End of each 6 week intervention period
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Measured by 31P-mass spec.
A higher value indicates better mitochondrial function.
All re calculated from multiple measures from the MRS spectra.
These are relatively new research measures and normal values are not known or generally accepted.
Oxidative Phosphorylation measures the rate at which electron transport activity generates phosphorylated energy sources (ATP and PCr)
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End of each 6 week intervention period
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In Vivo Mitochondrial Function:AnGly
기간: End of each 6 week intervention period
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Measured by 31P-mass spec.
Anaerobic glycolysis measures the amount of anaerobic ATP generation for energy.
It is generally felt that a higher value here reflects impaired mitochondrial function necessitating greater reliance on anaerobic metabolism.
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End of each 6 week intervention period
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Cardiac Function
기간: End of each 6 week intervention period
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Cardiac output
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End of each 6 week intervention period
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기타 결과 측정
결과 측정 |
측정값 설명 |
기간 |
---|---|---|
Vascular Markers: PAI-1
기간: End of each 6 week intervention period
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PAI-1 exploratory thromobotic marker.
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End of each 6 week intervention period
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Vascular Markers: Exploratory
기간: End of each 6 week intervention period
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ICAM
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End of each 6 week intervention period
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Oxidative Stress Markers
기간: End of each 6 week intervention period
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TBARs, GSSG:GSH ratio
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End of each 6 week intervention period
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Mitochondrial Measures: Oxidant Generation
기간: End of each 6 week intervention period
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oxidant generation
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End of each 6 week intervention period
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Inflammatory Markers: Exploratory
기간: End of each 6 week intervention period
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IL6, TNF alpha
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End of each 6 week intervention period
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Mitochondrial Oxidant Generation
기간: after each 6 week intervention
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exploratory measure looking at H2O2 production.
not performed due to equipment not available.
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after each 6 week intervention
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공동 작업자 및 조사자
수사관
- 수석 연구원: Irene Schauer, MD, PhD, University of Colorado, Denver
연구 기록 날짜
연구 주요 날짜
연구 시작
기본 완료 (실제)
연구 완료 (실제)
연구 등록 날짜
최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (추정)
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
추가 정보
이 정보는 변경 없이 clinicaltrials.gov 웹사이트에서 직접 가져온 것입니다. 귀하의 연구 세부 정보를 변경, 제거 또는 업데이트하도록 요청하는 경우 register@clinicaltrials.gov. 문의하십시오. 변경 사항이 clinicaltrials.gov에 구현되는 즉시 저희 웹사이트에도 자동으로 업데이트됩니다. .
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