140 subjects will be enrolled into the clinical study and randomized into the Control Group
or the Experimental Group by block randomization. The subjects must meet all inclusion and
none of the exclusion criteria. Each subject will have 7 clinic visits and 3 phone visits.
The Baseline Visit will consist of a complete history, vitals, a physical examination and
completion of the consent and screening process. All clinic visits, except for the Baseline
Visit will include meter/PDA download. In addition, meter education will be provided to all
subjects, and PDA education will be provided to the Experimental group at the Baseline Visit
and 2-Week Visit as needed to ensure subject understanding. The phone visits will consist
of a history including any changes in insulin dose, and any hypoglycemic events,
hyperglycemic events, or other adverse events that have occurred since the last clinic
The primary endpoint in this study was to show a reduction in A1c of at least 0.4% or higher
in the insulin guidance software group at 6 months and/or 1 year.
Research Design and Methods A total of 123 adult subjects with type 1 diabetes with a
baseline A1c of 7.5-11% were enrolled in the study at the Barbara Davis Center for Childhood
Diabetes at the University of Colorado at Denver Health Sciences Center. Two patients
screen failed (entry criteria not met) before randomization, leaving 60 subjects randomized
to the control group and 61 subjects randomized to the experimental group (Advisor).
Subjects were randomized based on lottery system using sealed envelopes. All patients had
baseline blood work which included a complete blood count (CBC), complete metabolic panel
(CMP), creatnine kinase (CK) and an A1c. The mean A1c at baseline was 8.54 ±0.11 in the
control group and 8.42 ±0.11 in the experimental group (p=0.4265).
Subjects were randomized on a 1:1 basis to either the experimental or control group. All
subjects in the experimental group received the same training for insulin guidance software
program for personal data assistant (PDA). All subjects were given a glucose meter and an
unlimited supply of test strips for self monitoring of blood glucose (SMBG). Women who were
pregnant or planning to become pregnant were excluded from participation in the study as
were patients on insulin pumps, those taking glucocorticoid therapy, and those diagnosed
with cancer, liver disease, anemia or hepatitis. Patients who exercised more than five days
a week, or often traveled internationally were also excluded.
The protocol was approved by the Colorado Multiple Institutional Review Board (COMIRB). All
subjects signed an informed consent form before being enrolled in the study.
Visits All subjects were asked to attend 7 in clinic visits (baseline, 2 week, 6 week, 3
month, 6 month, 9 month and 12 month) and participate in 3 telephone visits (4.5month,
7.5month, 9.5 month) throughout the course of the study. Data for blood glucose values,
testing frequency, hyperglycemic excursions, hypoglycemic events (all, nocturnal, and
severe), insulin dose, weight and BMI, hospitalizations, emergency room visits and illnesses
were recorded at each in clinic visit. All subjects completed a patient satisfaction
questionnaire and the experimental group also completed an Advisor questionnaire.
As part of their routine clinical care, any additional phone visits were equally encouraged
in both groups.
Advisor Insulin Guidance Software (Figure 1a) Subjects randomized to the experimental group
received a PDA loaded with the insulin guidance software. At baseline (visit 1), a
healthcare provider and/or certified diabetes educator (CDE) reviewed the features of the
software on the PDA and loaded a subject specific insulin dosing algorithm into the software
based on the physician's recommendations. The software program allowed the healthcare
provider to enter demographic data such as age, height and weight which could potentially
affect the insulin sensitivity factor already programmed into the device. The program
advised basal, bolus and correction insulin dosages based on individual patients'
prescriptions in addition to being alerted for SMBG testing. Subjects in the experimental
group were also asked to input their blood glucose values into the PDA via the touch screen.
Subjects then received a recommended insulin dose based on their prescription which was
programmed by the healthcare provider. The patients were asked to either agree with the
recommended insulin dose or disagree, and manually enter the insulin dose they took for a
given event. All the data from the glucose meters and the PDAs were downloaded at every
Glucose Target Ranges Glucose values were captured in one of the following categories to
assess target glycemia and pie charts were created. Within Target Range (WTR) glucose
values were those between 70-150mg/dL (3.89 to 8.33 mmol/L) (20). Below Target Range (BTR)
glucose values were defined as ≤ 69mg/dL (3.83 mmol/L) and Above Target Range (ATR) glucose
values were those values above 150mg/dL (8.33 mmol/L). These glucose levels were chosen
based on our previous research on SMBG downloads (20).
Hypoglycemia Hypoglycemia was defined as glucose values ≤ 59mg/dL (3.27mmol/L). Severe
hypoglycemia was defined as subjects needing assistance as previously described by DCCT
Research Group (1).
A1c and Other Lab Measurement
The A1c values were measured by the DCA 2000® Analyzer, distributed by Bayer Corporation
(Elkhart, IN). The DCA 2000® A1c assay gives accurate and precise results over a range of
total hemoglobin from 7 to 24 g/dL. All subjects had hemoglobin concentrations well within
these values. Normal A1c values are 3.4 to 6.2 % (18). The CBC (Beckman Coulter LH750,
Beckman Coulter, Hialeah, FL), CMP (AU-5200 Olympus Japan Co Ltd, Tokyo) and CK (Olympus
AU-800; Olympus, Tokyo, Japan) were performed by Quest Diagnostics, Denver, Colorado.
Statistical Analysis Wilcoxon Rank Sum and Chi Square tests of independence were used to
compare continuous and categorical variables, respectively, at baseline. Chi Square test of
independence was used to compare the number of discontinued subjects between the two groups.
Mixed model repeated measures analysis with an unstructured covariance structure and
pre-planned contrasts were used to compare the experimental and control groups on A1c,
percent of glucose readings within, above, and below target, percent of total hypoglycemic
events, basal insulin dose, weight, and BMI. Paired t-tests were used to test the within
group change in weight from baseline to 12 months among those who completed all 12 months.
Fisher's Exact test was used to compare the number of patients achieving target values
between groups at each time point. Poisson regression was used to compare the frequency of
severe hypoglycemic events between the two groups. Data are presented as least squares mean
± SE unless otherwise noted. All analyses were performed using SAS 9.1. Results were
considered significant at p < 0.05 using a two-sided alpha.
- Adult male or female, 18 to 60 years of age
- Diagnosed with Type 1 diabetes mellitus at least six months
- HbA1c 7.5% and 11.0% at screening
- Insulin dose 0.5 - 2.0 units/kg
- Hematocrit between 25% and 65%
- Weight 100-300 pounds
- On a dual insulin therapy supported by Accu-Chek Insulin Advisor software
- On a "day shift" schedule (typical day begins before noon)
- Willing to perform a minimum of three blood glucose tests per day - before breakfast,
before lunch, and before dinner (standard of care)
- Willing to complete at least 7 clinic visits in 12 months (Baseline, 2-Week, 6-Week,
3-Month, 6-Month, 9-Month, and 12-Month)
- Willing to complete 3 study phone calls conducted by study coordinator (4.5-month,
7.5-Month and 10.5-Month)
- Able and willing to provide written informed consent to participate
- Willing to comply with the study protocol
- Willing to be randomized into either the Control Group or the Experimental Group
- On insulin pump therapy
- On oral, inhaled or pre-mixed insulin
- Engaged in a minimum of 30 minutes of cardiovascular (aerobic) exercise 5 days out of
a 7-day week
- Conditions that can cause significant increase of the insulin sensitivity factor,
such as a steroid therapy, diabetic ketosis, insulin-resistant syndrome
- Creatinine above 2.5mg/dl, renal transplantation or currently undergoing kidney
- Pregnant or intends to become pregnant during the course of the study
- Undergoing therapy for a malignancy, other than basal cell or squamous cell skin
- Plan to travel to a different time zone more than three times per month
- Clinical signs or symptoms of liver disease such as jaundice
- Diagnosis of acute or chronic hepatitis
- Diagnosis of hemoglobinopathy or chronic anemia
- Severe unexplained hypoglycemia in the past 3 months that required ED admission
- Participation in another clinical trial in the past 1 month
- Weight under 100 pounds or over 300 pounds