Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT04062890 |
| Other study ID # |
ADHS18-201472b |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
December 15, 2019 |
| Est. completion date |
December 30, 2022 |
Study information
| Verified date |
August 2019 |
| Source |
University of Arizona |
| Contact |
Benjamin J Renquist, PhD |
| Phone |
520-349-0277 |
| Email |
bjrenquist[@]email.arizona.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
50% of Arizonans are diabetic or pre-diabetic resulting in $6.4 billion in health care and
productivity costs. The severity and incidence of Type 2 Diabetes Mellitus (T2DM) is directly
related to the hepatic lipid concentration. The degree of hepatic lipid accumulation is
communicated by the hepatic vagal afferent nerve (HVAN) to regulate pancreatic insulin
secretion and whole body insulin sensitivity. We have shown that obesity enhances expression
of GABA-Transaminase (GABA-T) decreasing hepatic release of the excitatory neurotransmitter,
aspartate, and increasing release of the inhibitor neurotransmitter, GABA. This enhanced
inhibitory tone decreases hepatic vagal afferent nerve activity, increasing pancreatic
insulin release and decreasing skeletal muscle glucose clearance/insulin sensitivity.
Pharmacological inhibition of GABA-T robustly improves glucose homeostasis in diet induced
obese mice. We propose 2 clinical objectives that will test the effect of GABA-T inhibition
on glucose tolerance and insulin sensitivity in obese, hyperglycemic, hyperinsulinemic
patients.
Description:
Experimental Design: Hyperglycemic, hyperinsulinemic and mildly hypertensive (taking
medication for hypertension or with systolic blood pressure of ≥135 mmHG) adult patients
(18-60 y) with BMI ≥ 25 on insulin or metformin only and will be recruited using existing
relationships between community partners and the University of Arizona Division of
Endocrinology. Patients will be stratified into 2 treatments (Vigabatrin or Placebo) based on
age, sex, and HbA1c (day -24).
For each treatment, Vigabatrin and placebo participants will be stratified as such: Each
group will have equal distribution of male and female participants and each group will have
similar HbA1c. This is a double-blind study and only the research pharmacist and Dr. Renquist
will know which participants receive Vigabatrin or Placebo treatments. Dr. Renquist will be
the one to place subjects into each treatment group using the guideline mentioned above.
Study Visit 1: (day -24; relative to treatment initiation) Dr. Herbst will be present to
discontinue metformin and initiate a monitoring plan. Participants on long acting insulin
will stop taking insulin 3 days prior to visits 2,3,4 and 5 and those on short acting insulin
with stop taking insulin 12 hours prior to visits 2,3,4 and 5. On day (-24), patients will
enter the CaTS (Clinical and Translational Science) Center after an overnight fast without
having taken the blood pressure medication (if on any) that morning for a baseline assessment
of body weight, height and blood pressure along with temperature, heart rate, O2 and
respiration. A fasting blood sample will be collected into EDTA tubes to allow for
measurement of plasma insulin, c-peptide, glucose, glucagon, and GABA. Following
centrifugation (15 min, 3000xg) plasma will be aliquoted into 10 individual samples that will
be immediately frozen at -80C for analyses in the Renquist laboratory. A peripheral vision
field test will be performed on all participants and urine pregnancy test will be performed
on female participants. A medical history will be taken from the subjects (self disclosure)
and physical examination will be done. At this time, participants will be given a ledger in
which to note daily blood glucose taken after an overnight fast for those on metformin.
Participants taking insulin will note daily blood glucose taken after an overnight fast and
immediately prior to lunch and dinner for the entire study (3 times daily). If fasting blood
glucose rises more than 30 mg/dL after discontinuing metformin treatment (occurs in less than
5% of patients), patients will be advised to resume metformin treatment and visit their
primary care physician. They will also be withdrawn from the study at this time. If it is
after hours and they have concerns related to glucose levels, and are unable to reach
clinical staff, they will be informed to go to the nearest Emergency Department, if they
consider it to be an emergency. Participants will also be asked to not donate blood, change
their physical activity habits or start a weight loss program while part of the study. This
visit will take approximately 2 hours.
Study Visit 2: (Day -3 relative to treatment initiation) Three weeks after the initial visit
(day -3 ), study participants will arrive at the CaTS Center after an overnight fast without
having taken the blood pressure medication (if on any) that morning . They will have been
reminded to stop taking insulin 3 days or 12 hours prior depending if they are on long acting
insulin or short acting insulin, respectively. Time, temperature, heart rate, O2, respiration
along with body weight, blood pressure, and a fasting blood sample will be collected (15 min
after Peripheral IV insertion). Urine pregnancy test will also be done on female
participants. The ledger will be examined to ensure that the participants are recording
information appropriately and completely. We will subsequently perform the 2h, 7 sample
glucose tolerance test (OGTT). Patients will be given a solution containing 75 g glucose to
consume within 3 minutes. Blood samples will be collected at 0, 10, 20, 30, 60, 90, and 120
minutes for measurement of plasma glucose, insulin, and c-peptide. Once the glucose is back
to 300mg/dl or lower, participants will be allowed to leave for the day. This visit will take
approximately 3 hrs.
Study Visit 3: (day 0, relative to treatment initiation) 3 days post OGTT (day 0),
participants will again arrive at the CaTS Center after an overnight fast without having
taken the blood pressure medication (if on any) that morning. They will have been reminded to
stop taking insulin 3 days or 12 hours prior depending if they are on long acting insulin or
short acting insulin, respectively. Urine pregnancy test will also be done for female
participants. Clinical lab personnel will take time, temperature, heart rate, O2, respiration
along with body weight, blood pressure and collect fasting blood for measure of plasma
insulin, glucose, glucagon, c-peptide and HbA1c (15 min after Peripheral IV insertion.)
Participants' arm with IV will be place inside a heated box the entire study to promote blood
flow. Subsequent to baseline measures, CaTS staff will perform hyperinsulinemic euglycemic
clamps. Glucose tracer infusion will start and will be given continuously. 2 hours after the
tracer infusion, Insulin will be intravenously infused at 80 mU/m2/min (dose per body surface
area per minute). This infusion rate will result in a hyperinsulinemic state, simultaneously
increasing glucose disposal into skeletal muscle and adipose tissue and depressing hepatic
glucose production. Blood glucose is monitored every 5 minutes and 20% D-Glucose with a
6,6-2H2 Glucose tracer will be infused at a variable rate to maintain euglycemia. After at
least 1 hour of constant insulin infusion, steady state conditions for plasma insulin, blood
glucose and the glucose infusion rate will be achieved. Steady state will be defined as a
glucose infusion rate that varies less than 5% for at least 30 minutes. Insulin and glucose
infusion will be done for 2 hours once insulin infusion starts. At least 4 samples will be
taken at 10 minute intervals during the steady state conditions for analysis of 2H-labeled
glucose. Dilution of the 6,6-2H2 glucose relative to total glucose in the blood will indicate
the rate of hepatic glucose production. The hepatic glucose production rate + glucose
infusion rate sum to equal whole-body glucose clearance. Participants will be given lunch
after study is finished. Subsequently, patients will be given either placebo or vigabatrin to
be taken over the following weeks. Participants will be asked to come in at the end of each
week to refill their medication and conduct a brief visit with nursing staff at CaTS.
Patients will be instructed to take1 pill 2X/day for the first 7 days (days 0-6; 1000mg/day),
2 pills 2X/day for days 7-13 (2000mg/day), and three pills 2X/day for days 14-23
(3000mg/day). This visit will take approximately take 5 hours.
Brief visit 1, 2: (days 7 and 14, relative to treatment initiation) Medication will be
refilled and dosage will be increased each week. Participants will speak to the nurses (Alma
D-Leon, RN and Guadalupe E-Ortega, MSN, ACNP-BC) about general health and compliance with
medication regiment.
Study Visit 4: (day 21, relative to treatment initiation) Participants will again arrive at
the CaTS Center after an overnight fast without having taken the blood pressure medication
(if on any) that morning. Time, temperature, heart rate, O2, respiration along with body
weight, blood pressure, and a fasting blood sample will be collected. They will have stopped
taking insulin 3 days or 12 hours prior depending if they are on long acting insulin or short
acting insulin, respectively. A urine pregnancy test will also be done for female
participants. The ledger will be examined to ensure that the participants are recording
information appropriately and completely. The OGTT and all performed on day -3 (Study Visit
2) will be repeated on day 21. This visit will take approximately 3 hours.
Study Visit 5: (Day 24, relative to treatment initiation). Participants will again arrive at
the CaTS Center after an overnight fast without having taken the blood pressure medication
(if on any) that morning. They will have been reminded to stop taking insulin 3 days or 12
hours prior depending if they are on long acting insulin or short acting insulin,
respectively. Their ledger will be reviewed. A peripheral vision field test will be performed
on all participants. Temperature, heart rate, O2, respiration along with body weight, blood
pressure, and a fasting blood sample will be collected (15 min after Peripheral IV
insertion). The hyperinsulinemic-euglycemic clamp performed on day 0 (Study Visit 3) will be
repeated on day 24. Beginning on day 24, participants on the vigabatrin and placebo treatment
will initiate the step-down as recommended by the manufacturer, moving to the 2 pill 2X/day
dose for days 24-30, and 1 pill 2X/day dose for days 31-37 before discontinuing treatment.
Participants will be asked to come in at the end of each week to refill their medication and
a brief visit with nursing staff at CaTS. Throughout the study, participants and lab
personnel will be blinded to treatments. This visit will take approximately 5 hours.
Brief visit 3: (Day 31, relative to treatment initiation) Medication will be refilled and
dosage will be decreased each week. Participants will speak to the nurses (Alma D-Leon, RN
and Guadalupe E-Ortega, MSN, ACNP-BC) about general health and compliance with medication
regiment.
Study Visit 6: (Day 45, relative to treatment initiation) On day 45, 1 week after the last
dose of vigabatrin or placebo, patients on the vigabatrin and placebo treatment will be seen
for an exit evaluation. Participants will again arrive at the CaTS Center after an overnight
fast without having taken the blood pressure medication (if on any) that morning. Clinical
lab personnel will take temperature, heart rate, O2, respiration, body weight and blood
pressure and collect fasting blood for measure of plasma insulin, glucose, glucagon,
c-peptide and HbA1c. A peripheral field vision test will be performed on all participants.
The ledger of blood glucose measures will be collected for study analysis. Participants will
be scheduled to follow up for vision exam within 6 months of study completion. This visit
will take approximately 2 hours.
Timeline of proposed study, including Oral glucose tolerance tests (OGTT) and
hyperinsulinemic euglycemic clamps (HEC). Weeks and days are numbered relative to treatment
initiation.
Blood Samples Collected
Baseline samples:
Blood samples (< 10 mL) will be collected on days -24, -3, 0, 21, 24, and 45.
During oral glucose tolerance test:
Blood samples (< 10 mL) will be collected at 0, 10, 20, 30, 60, 90, and 120 minutes. Total
blood < 100mLs.
During Hyperinsulinemic euglycemic clamps:
Blood samples (<10 mL) will be collected at times -120, -30, -20, -10, 0 and +90, +100, +110
and +120.
Risks
During the Informed Consent process, study personnel will address potential discomfort and
risks associated with the study protocol. These will be included in the Informed Consent
form.
