XML Template (2009) [7.9.2009–9:27am] [1–14]
{TANDF_FPP}CMO/CMO_A_370737(NEW).3d (CMO) [First Proof]
Current Medical Research and Opinion
C213
Volume 25, Number 3 2008
single-blind, placebo run-in period. All patients with ade-
Safety endpoints
quate compliance (C2175% as assessed by tablet counts)
during the placebo run-in period had baseline assessments
Data were collected on clinical and laboratory adverse
and were randomized to one of six oral treatments for
experiences, physical examinations, vital signs, and elec-
24 weeks using a computer-generated allocation schedule:
trocardiograms (ECGs) throughout the study. All clinical
placebo (n¼176), sitagliptin 100mg q.d. (n¼179), met-
adverse experiences were rated by investigators for inten-
formin 500mg b.i.d. (n¼182), metformin 1000mg b.i.d.
sity and relationship to study drug. Laboratory evaluations
(n¼182), sitagliptin 50mg b.i.d. þ metformin 500mg
included complete blood chemistry, hematology, and uri-
nalysis. Clinical adverse experiences of interest included
b.i.d. (low dose; n¼190), and sitagliptin 50mg b.i.d. þ
hypoglycemia and prespecified, select, gastrointestinal
metformin 1000mg b.i.d. (high dose; n¼182). All
adverse experiences (abdominal pain, nausea, vomiting,
patients received the same number of active or placebo-
and diarrhea).
matched tablets throughout the study. At week 24,
Patients were counseled regarding the symptoms of
patients initially randomized to placebo were switched,
hypoglycemia (e.g., weakness, dizziness, shakiness,
in a double-blind manner, to metformin 1000mg b.i.d.
increased sweating, palpitations, or confusion) and
for 30 weeks, with gradual up-titration of 500mg/week
received instruction on blood glucose monitoring and
over the initial 4 weeks. All other patients continued on
treating symptoms of hypoglycemia. If any symptoms
their prior study medication for an additional 30 weeks.
occurred that may have been related to hypoglycemia,
Compliance was assessed by tablets counts throughout the
patients were requested to immediately perform a finger-
study.
stick glucose measurement, but to avoid delay in treating
Patients not meeting progressively stricter glycemic
these symptoms. To assist the investigator in assessing the
goalswere providedopen-label rescue therapywithglybur-
severity of an event, patients were provided with, and
ide (glibenclamide) as previously described
15
. Throughout
instructed in the use of, a hypoglycemia assessment log
the 30-week continuation phase, the criterion for initia-
to document potential hypoglycemia episodes and collect
tion of glycemic rescue therapy was an HbA
1c
value of
information on the severity of the events (such as the
48.0%.
requirement for the assistance of another person or medi-
cal treatment). Symptomatic events assessed by the inves-
tigator as hypoglycemia were reported as clinical adverse
Efficacy endpoints
experiences of hypoglycemia; documentation of a glucose
determination at the time the patient had symptoms was
Theendpointsincluded changefrombaseline(i.e.,change
not required. Events of hypoglycemia were analyzed as
from randomization) at week 54 for HbA
1c
, fasting plasma
follows: those not requiring assistance; those requiring
glucose (FPG), 2-hour postprandial glucose (PPG), fasting
the(non-medical)assistanceofothers;andthoserequiring
serum insulin, fasting serum proinsulin, proinsulin/insulin
medical intervention or exhibiting markedly depressed
ratio, homeostasis model assessment C12-cell function
level of consciousness, including loss of consciousness, or
(HOMA-C12), and HOMA-insulin resistance (HOMA-
seizure.
IR), fasting lipids (total cholesterol [TC], high-density
Laboratory measurements and ECGs were analyzed at
lipoprotein cholesterol [HDL-C], low-density lipoprotein central laboratories (PPD Global Central Labs, LLC,
cholesterol [LDL-C], non-HDL-C, and triglycerides), and Highland Heights, KY, and Zaventem, Belgium; and
body weight. The proportion of continuing patients with Covance Central Diagnostics, Inc., Reno, NV, respec-
an HbA
1c
57% at week 54 was calculated, as was the tively) by technicians blinded to treatment group as pre-
proportion patients who had an HbA
1c
57% at both viously described
10
.
week 24 and week 54.
A standard meal-tolerance test was administered at
baseline (prior to first dose of study medication) and at
Statistical analyses
week 54. Patients took study medication 30 minutes prior
The primary efficacy analysis was based on the continua-
to the standard meal, which was ingested within 15 min-
tion all-patients-treated population (CAPT), which con-
utes and consisted of one nutrition bar and one nutrition
sisted of all randomized patients who had a baseline
drink (C24460kcal; 75g carbohydrate, 9g fat, 18g protein).
measurement, did not receive glycemic rescue therapy in
Blood was collected at 0, 60, and 120 minutes from the
phase A, received at least one dose of study medication in
meal start. Plasma glucose, serum insulin, and serum the continuation phase, and had at least one efficacy mea-
C-peptide were measured and used to determine 2-hour surement during the continuation phase. Results for
PPG, area under the glucose concentration–time curve patients randomized to receive active therapy throughout
(AUC), insulin AUC, C-peptide AUC, and the insulin this 54-week study are the focus of this article. To avoid
AUC/glucose AUC ratio. the confounding influence of glycemic rescue therapy on
!
2009 Informa UK Ltd
www.cmrojournal.com 54-week efficacy and safety of sitagliptin/metformin Williams-Herman et al.
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