- ICH GCP
- Amerikanska kliniska prövningsregistret
- Klinisk prövning NCT02984644
Paradoxical Stimulation of Hepatic Glucose Production With Dapagliflozin (AZ11040)
2 december 2019 uppdaterad av: The University of Texas Health Science Center at San Antonio
Paradoxical Stimulation of Hepatic Glucose Production With Dapagliflozin (P2)
To determine the role of plasma glucagon and insulin in the rise of endogenous glucose production (EGP) following the SGLT2 inhibition.
Studieöversikt
Status
Avslutad
Betingelser
Intervention / Behandling
Detaljerad beskrivning
The increase in plasma glucagon conc and/or decrease in plasma insulin conc in response to glucosuria is (are) important signal(s) responsible, at least in part, for the increase in EGP, which the investigators anticipate will be derived primarily from the liver.
Insulin and glucagon are powerful regulators of HGP.
Therefore, the investigators anticipate that, at least in part, an increase in HGP secondary to the rise in plasma glucagon concentration and decrease in plasma insulin concentration in response to dapagliflozin-induced glucosuria will account for the majority of increase in EGP in both NGT and T2DM subjects.
This study will define whether the increase in plasma glucagon and/or the decrease in plasma insulin are the trigger to stimulate EGP.
Eligible subjects will receive three 5-hour measurements of endogenous glucose production (EGP), which is the biosynthesis of new glucose, with administration of study drug after a 3-hour tracer equilibration period.
Hepatic glucose production (HGP), which is the net release of glucose from the liver, will be measured for 5 hours after drug administration to allow sufficient time for a significant increase in HGP above baseline after dapagliflozin administration (10).
In study 1, HGP will be measured for 5 hours after dapagliflozin (10 mg) or placebo administration.
This is the control study.
The investigators expect to observe the "paradoxical" rise in EGP following dapagliflozin.
Study 2 will be performed under glucose clamp conditions (i.e.
maintaining the plasma glucose concentration stable at each subject's fasting level).
This study will define whether the decline in plasma glucose concentration is the trigger to stimulate EGP.
Study 3 will be performed under pancreatic clamp conditions (maintaining the plasma glucagon and insulin concentrations constant at the basal level).
This study will define whether the increase in plasma glucagon and/or the decrease in plasma insulin are the trigger to stimulate EGP.
Subjects will be randomized in a 2:1 ratio; 32 subjects will receive dapagliflozin and 16 subjects will receive placebo.
Each study will be performed on a separate day, after a 10-12 hour overnight fast within 1-2 week period.
Following studies 1-3, subjects will return for a renal (kidney) MRI-measurement to record kidney size.
Studietyp
Interventionell
Inskrivning (Faktisk)
30
Fas
- Fas 3
Kontakter och platser
Det här avsnittet innehåller kontaktuppgifter för dem som genomför studien och information om var denna studie genomförs.
Studieorter
-
-
Texas
-
San Antonio, Texas, Förenta staterna, 78229
- University of Texas Health Science Center
-
-
Deltagandekriterier
Forskare letar efter personer som passar en viss beskrivning, så kallade behörighetskriterier. Några exempel på dessa kriterier är en persons allmänna hälsotillstånd eller tidigare behandlingar.
Urvalskriterier
Åldrar som är berättigade till studier
18 år till 70 år (Vuxen, Äldre vuxen)
Tar emot friska volontärer
Nej
Kön som är behöriga för studier
Allt
Beskrivning
Inclusion Criteria:
- T2DM according to ADA criteria-HbA1C < 8.0%
- BMI = 25-35 kg/m2
- Subjects must be in good general health as determined by physical exam, medical history, blood chemistries, CBC, TSH, T4, EKG and urinanalysis
- Body weight has been stable (± 3 lbs) over the preceding three months
- Do not participate in an excessively heavy exercise program
- Taking stable dose (more than 3 months) of monotherapy or combination therapy with metformin and/or a sulfonylurea
Exclusion Criteria:
- Subjects taking drugs known to affect glucose metabolism (other than metformin and sulfonylurea) will be excluded
- Individuals with evidence of proliferative diabetic retinopathy, plasma creatinine >1.4 females or >1.5 males, or 24-hour urine albumin excretion > 300 mg will be excluded
Studieplan
Det här avsnittet ger detaljer om studieplanen, inklusive hur studien är utformad och vad studien mäter.
Hur är studien utformad?
Designdetaljer
- Primärt syfte: Behandling
- Tilldelning: Randomiserad
- Interventionsmodell: Parallellt uppdrag
- Maskning: Enda
Vapen och interventioner
Deltagargrupp / Arm |
Intervention / Behandling |
---|---|
Aktiv komparator: Dapagliflozin
32 subjects will receive dapagliflozin 10mg
|
Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days.
Andra namn:
|
Placebo-jämförare: Placebo
16 subjects will receive placebo
|
Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.
Andra namn:
|
Vad mäter studien?
Primära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
---|---|---|
Measurement of the Change in Plasma Glucose (mg/dL): Study 1
Tidsram: Baseline to 240-300 minutes
|
Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose concentration
|
Baseline to 240-300 minutes
|
Change in Plasma Glucose Measurement Using a Glucose Clamp: Study 2
Tidsram: Baseline to 240-300 minutes
|
Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose for study 2: EGP plus glucose clamp.
The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose.
This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism.
Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism.
The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP.
After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)
|
Baseline to 240-300 minutes
|
Change in Plasma Glucose Using a Pancreatic Clamp: Study 3
Tidsram: Baseline to 240-300 minutes
|
Change from Baseline to the last hour of the study (240-300 minutes) in plasma glucose using a pancreatic clamp.
In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique.
Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration.
Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
|
Baseline to 240-300 minutes
|
Change in EGP: Study 1
Tidsram: Baseline to 240-300 minutes
|
Change from baseline to the last hour of the study (240-300 minutes) in EGP
|
Baseline to 240-300 minutes
|
Change in EGP With Glucose Clamp: Study 2
Tidsram: Baseline to 240-300 minutes
|
Change from baseline to the last hour of the study (240-300 minutes) in EGP using a glucose clamp.
The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose.
This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism.
Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism.
The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP.
After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)
|
Baseline to 240-300 minutes
|
Change in EGP With Pancreatic Clamp: Study 3
Tidsram: Baseline to 240-300 minutes
|
Change from baseline to the last hour of the study (240-300 minutes) of EGP with a pancreatic clamp.
In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique.
Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration.
Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.VIn this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique.
Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration.
Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
|
Baseline to 240-300 minutes
|
Sekundära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
---|---|---|
Change in Plasma Insulin Concentrations: Study 1
Tidsram: Baseline to 240-300 minutes
|
Plasma insulin concentrations during measurement of EGP
|
Baseline to 240-300 minutes
|
Plasma Insulin Concentrations During Measurement of EGP Plus Glucose Clamp: Study 2
Tidsram: Baseline to 240-300 minutes
|
Plasma insulin concentration is measured from baseline to the last hour of the study while using a glucose clamp.
The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose.
This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism.
Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism.
The 3-3H-glucose infusion will be started at 6 AM to measure the basal rate of EGP.
After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM)
|
Baseline to 240-300 minutes
|
Change in Plasma Insulin While Using Pancreatic Clamp: Study 3
Tidsram: Baseline to last hour of the study
|
Plasma insulin concentration during measurement of EGP while using pancreatic clamp.
In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique.
Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration.
Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
|
Baseline to last hour of the study
|
Change in Glucagon: Study 1
Tidsram: Baseline to 240-300 minutes
|
Change in glucagon concentrations during measurement of EGP
|
Baseline to 240-300 minutes
|
Change in Glucagon Using Glucose Clamp: Study 2
Tidsram: Baseline to 240-300 minutes
|
Plasma glucagon concentration during measurement of EGP using a glucose clamp.
The glucose clamp technique is achieved by increase plasma glucose concentration to 125 mg/dl above basal levels by a continuous infusion of glucose.
This hyperglycemic plateau is maintained by adjustment of a variable glucose infusion, based on the rate of insulin secretion and glucose metabolism.
Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of insulin secretion and glucose metabolism.
|
Baseline to 240-300 minutes
|
Change in Glucagon Using Pancreatic Clamp: Study 3
Tidsram: Baseline to 240-300 minutes
|
Measurement of change in plasma glucagon from baseline to one hour prior to end of study while using a pancreatic clamp.
In this study, EGP will be measured as described in Study 1 and plasma insulin and glucagon concentrations will be clamped at the basal level using the pancreatic clamp technique.
Plasma glucose concentration will be allowed to decrease spontaneously after dapagliflozin or placebo administration.
Somastatin will be infused with glucagon and insulin to replace basal plasma glucagon and insulin until study end.
|
Baseline to 240-300 minutes
|
Samarbetspartners och utredare
Det är här du hittar personer och organisationer som är involverade i denna studie.
Studieavstämningsdatum
Dessa datum spårar framstegen för inlämningar av studieposter och sammanfattande resultat till ClinicalTrials.gov. Studieposter och rapporterade resultat granskas av National Library of Medicine (NLM) för att säkerställa att de uppfyller specifika kvalitetskontrollstandarder innan de publiceras på den offentliga webbplatsen.
Studera stora datum
Studiestart (Faktisk)
6 september 2017
Primärt slutförande (Faktisk)
16 november 2018
Avslutad studie (Faktisk)
16 november 2019
Studieregistreringsdatum
Först inskickad
30 november 2016
Först inskickad som uppfyllde QC-kriterierna
2 december 2016
Första postat (Uppskatta)
7 december 2016
Uppdateringar av studier
Senaste uppdatering publicerad (Faktisk)
18 december 2019
Senaste inskickade uppdateringen som uppfyllde QC-kriterierna
2 december 2019
Senast verifierad
1 november 2019
Mer information
Termer relaterade till denna studie
Ytterligare relevanta MeSH-villkor
Andra studie-ID-nummer
- HSC20160586H
Läkemedels- och apparatinformation, studiedokument
Studerar en amerikansk FDA-reglerad läkemedelsprodukt
Ja
Studerar en amerikansk FDA-reglerad produktprodukt
Nej
Denna information hämtades direkt från webbplatsen clinicaltrials.gov utan några ändringar. Om du har några önskemål om att ändra, ta bort eller uppdatera dina studieuppgifter, vänligen kontakta register@clinicaltrials.gov. Så snart en ändring har implementerats på clinicaltrials.gov, kommer denna att uppdateras automatiskt även på vår webbplats .
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