Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02389127 |
| Other study ID # |
203867 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
February 26, 2015 |
| Last updated |
November 6, 2017 |
| Start date |
July 2015 |
| Est. completion date |
June 1, 2017 |
Study information
| Verified date |
November 2017 |
| Source |
University of Arkansas |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Cirrhosis and advanced liver disease have been associated with an increased risk for
hyperglycemia and type 2 diabetes mellitus (T2DM). The diagnostic yield of common tests used
to define diabetes and insulin resistance in the general population differs significantly
from the one observed in patients with liver disease. Glycosylated hemoglobin A1c (HbA1c), a
reliable test to assess chronic glycemia and recommended both for the diagnosis and
monitoring of T2DM, is neither accurate nor reliable in patients with cirrhosis. A validation
study has not been performed to define its true usefulness in the setting of cirrhosis. The
study aims to determine the level of HbA1c that better corresponds to the diagnosis of T2DM -
as determined by an oral glucose tolerance test (OGTT) - and to correlate the levels of HbA1c
with the average glucose over a 12-week period in patients with cirrhosis and known T2DM, in
cirrhotic patients with different degrees of liver impairment as compared to patients with
T2DM and no liver disease.
Description:
Glycosylated hemoglobin A1c (HbA1c), a reliable test to assess chronic glycemia and
recommended both for the diagnosis and monitoring of T2DM, is neither accurate nor reliable
in patients with cirrhosis. A validation study has not been performed to define its true
usefulness in the setting of cirrhosis. The study aims to determine the level of HbA1c that
better corresponds to the diagnosis of T2DM - as determined by an oral glucose tolerance test
(OGTT) - and to correlate the levels of HbA1c with the average glucose over a 12-week period
in patients with cirrhosis and known T2DM, in cirrhotic patients with different degrees of
liver impairment. This study is designed as a pilot, observational, cross-sectional (Group A
- cirrhotics with no T2DM) and longitudinal study (Group B - cirrhotics with known diabetes).
For our first aim (Group A) the diagnostic yield of HbA1c for T2DM will be compared to that
of an OGTT. Regarding the second aim (Group B) HbA1c will be compared to glucose reading from
a continuous glucose monitor. In both groups, the following study labs will be performed:
fructosamine, Complete Blood Count (CBC), liver function tests, chemistry, International
Normalized Ratio (INR), and pre albumin. A total of 26 patients per group will be included.
STUDY AIMS
The study will look into three primary aims:
1. To determine the level of HbA1c that better corresponds to the diagnosis of T2DM - as
determined by an OGTT - in cirrhotic patients with different degrees of liver
impairment.
- Will test the hypothesis of lower levels of HbA1c being found in T2DM in patients with
decompensated cirrhosis when compared to those with compensated disease.
2. To correlate the levels of HbA1c with the average glucose (AG) over a 12-week period in
patients with cirrhosis and known T2DM, according to different degrees of liver
impairment.
- Will test the hypothesis of progressively lower levels of HbA1c being associated with
hyperglycemia in diabetic patients with decompensated cirrhosis when compared to those
with compensated disease.
3. To compare the performance of continuous glucose monitoring, particularly the level of
agreement between the AG over a 12-week period and HbA1c, in patients with cirrhosis and
known T2DM with that of controls with T2DM but no known chronic liver disease (including
cirrhosis).
As secondary aims will:
1. Determine the prevalence of T2DM in cirrhotics with different degrees of liver disease
according to use of fasting glucose, HbA1c, or OGTT.
2. Determine the level of HbA1c that better defines well-controlled diabetes in patients
with cirrhosis and known T2DM, according to different degrees of liver impairment.
3. Glucose variability in patients with cirrhosis and T2DM with that of patients with T2DM
but no chronic liver disease (including cirrhosis).
Study Procedures
All patients will be identified and recruited from any of the Liver or GI clinics in the
Outpatient Center, UAMS. To test the first aim (Group A) - the cross-sectional part of the
study - patients with cirrhosis and varying degrees of liver dysfunction but no prior
diagnosis of T2DM will have an OGTT performed after overnight fasting (8-12 hours). The OGTT
consists of taking a baseline glucose determination, followed by a second one 2 hours after
swallowing a 75-g glucose load. HbA1c will be obtained before OGTT (with baseline glucose)
along with the following tests: HbA1c, fructosamine, insulin, CBC, HFP, GGT, OP Chem 7, INR,
and prealbumin. Anthropometrics (height, weight, and waist circumference) will be obtained as
well (Research Visit 1, see calendar).
All patients will be identified and recruited from any of the Liver or GI clinics in the
Outpatient Center, UAMS. For the second aim (Group B) - the longitudinal part of the study -
patients with known diabetes and cirrhosis with varying degrees of liver dysfunction will
wear a continuous glucose monitor (Dexcom, San Diego, CA) for ≥3 continuous days during week
days and week ends, every 4 weeks for 12 consecutive weeks, according to the manufacturer's
recommendations. The continuous glucose monitor will record patient's glucose from the odd to
the even research visit (i.e. from 1 to 2, 3 to 4, 5 to 6, and 7 to 8). On the last day the
continuous glucose monitor is retrieved by the investigators, patients will have the
following blood tests performed after overnight fasting (8-12 hours): HbA1c, fructosamine,
CBC, HFP, GGT, BMP, INR, and prealbumin. Anthropometrics (height, weight, and waist
circumference) will be obtained as well (Research Visit 8, see calendar). In order not to
affect glucose control during the study period glucose reads from the continuous glucose
monitor will not be disclosed to the patient until the end of the study.
All controls will be identified from the Endocrinology or Internal Medicine clinics in the
Outpatient Center, UAMS. Controls will wear a continuous glucose monitor (Dexcom, San Diego,
CA) for ≥3 continuous days during week days and week ends, every 4 weeks for 12 consecutive
weeks, according to the manufacturer's recommendations. The continuous glucose monitor will
record patient's glucose from the odd to the even research visit (i.e. from 1 to 2, 3 to 4, 5
to 6, and 7 to 8). On the last day the continuous glucose monitor is retrieved by the
investigators, patients will have the following blood tests performed after overnight fasting
(8-12 hours): HbA1c, CBC, and a metabolic profile; as per standard of care recommendations.
Anthropometrics (height, weight, and waist circumference) will be obtained as well (Research
Visit 8, see calendar - this research visit will occur on the same day of a diabetes follow
up outpatient visit). In order not to affect glucose control during the study period glucose
reads from the continuous glucose monitor will not be disclosed to the patient until the end
of the study.
Given that the study only attempts to investigate the accuracy of HbA1c by comparing it to
glucose and other biomarkers, no specific therapeutic interventions or recommendations
concerning treatment of diabetes will be required during the study.
Sample Size
Since there is no precedent in the literature showing preliminary data to allow for sample
calculation, will include 30 patients for each of the CTP stages A, B, and C, for both
groups. This number should allow more than the minimum needed to perform correlation analyses
(between and within groups) with confidence.
Sample Size
Since there is no precedent in the literature showing preliminary data to allow for sample
calculation, will aim to have complete data on 26 patients per group (10 CTP A, 8 CTP B, and
8 CTP C in each group). However, given that the estimated attrition rate in Group B is 30%,
will aim to recruit up to 34 patients for this group. We are planning on recruiting one
control for each subject in control B, so that the number of controls would not exceed 34.
Thus, the total number of subjects in study will be no more than 94. This number should allow
more than the minimum needed to perform correlation analyses (between and within groups) with
confidence.
Data Analysis
All glucose determinations from the continuous glucose monitoring will be summarized as an
arithmetic mean. Shapiro-Wilk will be used to determine normal distribution of data. Receiver
operation characteristic (ROC) curves will be constructed to determine the best cut-off to
diagnose T2DM, using OGTT results as the gold standard. Spearman's or Pearson's correlation
coefficient will be used to compare HbA1c to average glucose (eAG). Bland-Altman will be used
to determine agreement. The estimated average glucose from HbA1c will be derived from a
linear regression model, as previously described. Linear regression models will be performed
to identify factors affecting HbA1c for both Groups A and B, such as hemoglobin, CTP, MELD,
total protein, and prealbumin. CTP will be transformed to dummy variables for this analysis.
Data collection and handling Apart from the data generated by the study, demographics and
clinical information to properly classify the hepatic functional and diabetes of each
participant will be retrieved from the electronic medical record (EMR). Such information will
include results from standard of care laboratories, imaging, and other special studies (EGD),
to calculate Child-Turcotte-Pugh (CTP) and MELD scores.
A database will be created to accumulate all of the clinical information generated during
this study. No identifiers, apart from name and Date of Birth(DOB), will be collected. All
data will be stored in databases kept in a study folder created at PI's computer
(password-protected). Main database will include identification (ID) assigned, and once an
analytic table is created, all PHI will be removed from the table (after approval by the PI).
Only this de-identified dataset with unique study ID's will be used for statistical analyses.
Therefore, the risk to the privacy of the individuals will be minimized.
The access to the research folder and its contents will be restricted to the research staffs
listed in this submission form. The PHI will be kept in the main database for no more than 10
years. The main database containing PHI will be kept in the study folder and will be never
transferred out without de-identification of the data. No hard copy research data will be
generated in this project.
Risks and Benefits
The risks associated with venipuncture and repeated blood collection from a vein are minor
bleeding, bruising, infection (a small risk any time the skin is broken), or needing more
than one attempt to locate veins.
There are no risks to the OGTT, although subjects may not like the taste of the highly
concentrated glucose beverage. Occasionally someone may have low blood sugar or high blood
sugar after the test. Blood glucose will be monitored before and during the test.
Some risks associated with the Dexcom G4 System Device have been reported: placing the
devices in your skin may cause some anxiety, pain, irritation, redness, and swelling. There
is also the risk of infection, excessive bleeding, or hematoma (swelling filled with blood
caused by a broken blood vessel) - these risks are rare. Removing the sensor may also cause
some discomfort or irritation because of the tape used. This reaction usually goes away
within a few hours, but may last up to a week. There may be some itching in the area, which
is a normal healing response.
In rare cases, the sensor may break while inserted. If this happens, the study team and will
examine the area. Sometimes the study team may decide to leave the sensor fragment in place.
If there is redness, pain, or infection, the study team will decide how to treat it. You
should not try to remove the sensor yourself if it is broken unless the study team tells you
to.
the University of Arkansas (UAMS) firewall and only used for specific research purposes in
this project. Aggregated data will be analyzed and published, but specific data elements will
not be made available. Further, subjects will not forfeit any rights by participating - their
health care and eligibility for health benefits will not be affected in any way. Although a
breach in confidentiality is always a risk when collecting personal information from
patients, we believe this is small given the system that has been developed to obtain and
handle data.
Ethics This study will be conducted according to US and international standards of Good
Clinical Practice (FDA regulations) for all studies. Applicable government regulations,
University of Arkansas for Medical Sciences research policies and procedures will also be
followed. This protocol and any amendments will be submitted and approved by the University
of Arkansas for Medical Sciences Institutional Review Board (IRB) to conduct the study. All
subjects for this study will be provided a consent form describing this study and providing
sufficient information in language suitable for subjects to make an informed decision about
their participation in this study. The formal consent of a subject, using the IRB-approved
consent form, will be obtained before that subject is submitted to any study procedure. This
consent form must be signed by the subject or legally acceptable surrogate, and the
investigator-designated research professional obtaining the consent.
