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PHAR 9942 / PSCI 6602 JOURNAL CLUB ACTIVITY GRADING EVALUATION
Presenter:_______________________________________________
Date:_____________
Reviewer:_______________________________________________
STYLE / PRESENTATION
2 points
Presentation
Exhibited professional appearance and
demeanor, and spoke clearly throughout
the presentation
Mannerisms
Eye Contact
Slides
Handout
TOTAL
Comments
Adapted from Am J Pharm Educ. 2007;71(4):Article 63.
1 point
SOMEWHAT exhibited professional
appearance and demeanor, was difficult
to hear or understand SOME things
spoken
Few (or no) distracting mannerisms
(e.g., um)
Maintained eye contact throughout the
presentation
Slides were organized, easy to read, and
aesthetically pleasing
Handout was organized, easy to read,
and aesthetically pleasing
0 points
Did NOT exhibit professional
appearance and demeanor, was difficult
to hear or understand MOST things
spoken
Score
/2
Had distracting mannerisms
/1
Did NOT maintain eye contact
/1
Slides were NOT organized and difficult
to read
Handout was NOT organized and
difficult to read
/1
/1
/6
PHAR 9942 / PSCI 6602 JOURNAL CLUB ACTIVITY GRADING EVALUATION
CONTENT / CRITICAL EVALUATION
Study Overview
Introduction
– Authors’ affiliations/study support
– Study objective(s) & rationale
Methods – Design
– Case-control, cohort, controlled experiment, etc.
– Type of design (cross-over, parallel, etc.)
– Type of assignment used
– Blinding
Methods – Patients/Subjects
– How enrolled/from where?
– Inclusion/exclusion criteria
– # enrolled per group
Methods – Treatment Regimen
– Treatments used
– Dosages/administration
– Therapy duration
Methods – Outcome Measures
– Primary measures
– Secondary measures
Methods – Data Handling
– Intention to treat, per protocol, etc.
– # lost to follow-up
– Reasons for dropouts
Methods – Statistics
– Tests used
– Power of study
Results
– Results for each outcome measure
– Confidence intervals
– P-values
– Compliance
– Adverse effects
Conclusion – Authors’ conclusion
Adapted from Am J Pharm Educ. 2007;71(4):Article 63.
2 points
1 point
0 points
Score
Accurately and completely
reported ALL relevant
introduction, study design,
and patients/subject
components
Accurately and completely
reported MOST of the
relevant introduction, study
design, and patients/subject
components
Did NOT accurately and
completely report most of
the relevant introduction,
study design, and
patients/subject
components
/2
Accurately and completely
reported ALL relevant
treatment regimens,
outcome measures, and
data handling components
Accurately and completely
reported MOST of the
relevant treatment
regimens, outcome
measures, and data
handling components
Did NOT accurately and
completely most of the
relevant treatment
regimens, outcome
measures, and data
handling components
/2
Accurately and completely
reported ALL relevant
statistics, results, and
authors’ conclusion
components
Accurately and completely
reported MOST of the
relevant statistics, results,
and authors’ conclusion
components
Did NOT accurately and
completely most of the
relevant statistics, results,
and authors’ conclusion
components
/2
PHAR 9942 / PSCI 6602 JOURNAL CLUB ACTIVITY GRADING EVALUATION
STUDY OVERVIEW TOTAL
/6
Comments
Analysis
Analyzed
all parts of
study
4 points
ALL parts
appropriately
critiqued with ALL
relevant questions
accurately addressed
with strengths,
weaknesses and their
impact described
3 points
Missed only ONE or
TWO considerations
or relevant questions
in critique, with the
rest appropriately
addressed with
strengths,
weaknesses, and their
impact described
TOTAL
Comments
Adapted from Am J Pharm Educ. 2007;71(4):Article 63.
2 points
1 point
0 points
MOST parts
appropriately
critiqued, some
relevant questions
with strengths,
weaknesses, and their
impact overlooked or
inaccurate
Only SOME parts
appropriately
critiqued, most
relevant questions
with strengths,
weaknesses, and their
impact overlooked or
inaccurate
Failed to
appropriately critique
any part, all relevant
questions with
strengths,
weaknesses, and their
impact overlooked or
inaccurate
Score
/4
PHAR 9942 / PSCI 6602 JOURNAL CLUB ACTIVITY GRADING EVALUATION
Conclusion
Clear, concise
conclusion stated
1 point
Summarized accurately & completely: key points to
be taken from study (which reflected limitations),
drug’s role in therapy or clinical practice implications,
and need for any further research in area
0 points
Did NOT summarize accurately & completely a
conclusion OR conclusion completely inaccurate
TOTAL
Comments
Preparedness
Response to
questions
TOTAL
Comments
Score
/1
/1
1 point
Correctly answered questions in a confident manner
STYLE / PRESENTATION TOTAL POINTS:
Score
/1
/1
______/6
CONTENT / CRITICAL EVALUATION TOTAL POINTS: ______/12
Adapted from Am J Pharm Educ. 2007;71(4):Article 63.
0 points
Did NOT correctly answer questions OR handled
questions unprofessionally
DIABETICMedicine
DOI: 10.1111/dme.13003
Research: Treatment
Open-label randomized non-inferiority trial of a
fixed-dose combination of glimepiride and atorvastatin
for the treatment of people whose Type 2 diabetes is
uncontrolled on metformin
P. Ambery1, A. Stylianou2, G. Atkinson3, C. Dott3, L. Baylor Curtis3, N. Haque3, K. LaCroix4
and K. W. Min5 on behalf of the Glimepiride/Atorvastatin Investigational Team
1
Department of Medicine, Addenbrooke’s Hospital, Cambridge, 2Clinical Statistics, GlaxoSmithKline, Stevenage, 3Alternative Discovery and Development,
GlaxoSmithKline, Brentford, UK, 4Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Research Triangle Park, NC, USA and 5Diabetes Centre, Eulji
Hospital, Eulji University School of Medicine, Seoul, Republic of Korea
Accepted 15 October 2015
Abstract
Aims To evaluate, in a randomized, open-label study, the non-inferiority of a bioequivalent fixed-dose combination of
glimepiride and atorvastatin vs. separately co-administered tablets in people with Type 2 diabetes mellitus.
Methods Participants with HbA1c ≥ 53 to < 80 mmol/mol (≥ 7.0 to < 9.5%), average fasting blood glucose > 7.0 mmol/l, who were on metformin for ≥ 3 months, were randomized to combination (n = 215) or co-administered
glimepiride and atorvastatin (n = 212) once daily for 20 weeks. Up-titration of glimepiride (1–4 mg) and atorvastatin
(10–20 mg) were based on average fasting blood glucose and LDL cholesterol, respectively. Co-primary endpoints were
change from baseline to week 20 in HbA1c and LDL cholesterol.
Non-inferiority was demonstrated for both co-primary endpoints: the upper limits of 95% CIs for differences
(combination-reference) were less than the prespecified margins of 3.3 mmol/mol (0.3%) for change from baseline in
HbA1c [difference 0.1 mmol/mol (95% CI 1.6, 1.9); 0.01% (95% CI 0.15, 0.17)] and 6% for percentage change
from baseline in LDL cholesterol [difference 0.87% (95% CI 2.47, 4.21)]. Similar proportions of participants on
combination and reference had treatment-emergent adverse events (64 vs. 61%). More participants on combination had
hypoglycaemia (21 vs. 13%); most events were considered by the treating physician to be unrelated to study drug.
Results
Conclusions The combination was non-inferior to separately co-administered tablets and the safety profile was
consistent with the known profiles of glimepiride and atorvastatin. The observed increase in hypoglycaemia on the
combination cannot be explained, but may be attributable to non-systematic collectiof glucose readings and may have
been influenced by reporting bias in this open-label trial.
Diabet. Med. 33, 1084–1093 (2016)
Introduction
Type 2 diabetes mellitus is a chronic illness that requires
continuing medical care, self-management and support. A
stepwise approach to management is recommended, starting
with advice concerning diet, exercise and weight reduction
[1]. If glucose targets are not met by lifestyle interventions,
treatment with metformin is recommended [1]. Other
glucose-lowering therapies, such as a sulphonylurea, may
then be added if glycaemic control is not achieved [1]. As
Correspondence to: Anastasia Stylianou.
E-mail: [email protected]
1084
people with Type 2 diabetes have an increased risk of
cardiovascular disease [2], predominantly driven by risk
factors such as dyslipidaemia and hypertension [3], multifactorial risk reduction strategies beyond glycaemic control
are required; therefore, consensus treatment guidelines now
recommend antihypertensives and lipid-lowering therapy for
most people with Type 2 diabetes [1,4,5].
Persistence and adherence to therapy are critical in improving outcomes in Type 2 diabetes, but many people do not meet
their personalized targets; for example, almost half of the
surveyed adults with diagnosed diabetes participating in a
national surveillance programme in the USA did not meet the
ª 2015 Diabetes UK
Research article
What’s new?
• We evaluated a bioequivalent fixed-dose combination
of glimepiride plus atorvastatin versus separately coadministered tablets in people with Type 2 diabetes
mellitus on metformin.
• The combination was non-inferior to separately coadministered tablets with respect to reductions in
HbA1c and LDL cholesterol after 20 weeks.
• The safety profile of the combination was consistent
with the known profiles of glimepiride and atorvastatin.
• More participants on the combination reported hypoglycaemia. This cannot be explained but may be
attributable to non-systematic collection of glucose
readings and may have been influenced by reporting
bias in this open-label trial.
recommended goals for glycaemic control, blood pressure and
lipids [6]. Simplification of dosage regimens, by combining
medications in a single dosage form, is likely to improve
compliance [7–9], thereby improving clinical outcomes.
The aim of the present study was to demonstrate the noninferiority of a fixed-dose combination of glimepiride plus
atorvastatin, compared with both agents taken concomitantly as separate tablets, in improving glucose control and
lipid profiles in Type 2 diabetes. Glimepiride and atorvastatin are well-established medicines, with substantial clinical
trials and post-marketing experience [10–12]. In a previous
trial in healthy people, the glimepiride-atorvastatin formulation was shown to be bioequivalent to separately administered glimepiride and atorvastatin tablets, in terms of rate
and extent of exposure (data on file).
Participants and methods
Study design and ethics
This was an open-label, randomized, two-arm, parallel group
study conducted at 33 centres in six countries (Malaysia,
Mexico, Philippines, Russia, South Korea and Thailand)
between December 2011 and September 2013. The study
protocol (ATG115317) was approved by the relevant independent ethics committee for each centre and written
informed consent was obtained from each participant. The
procedures followed were in accordance with guidelines for
good clinical practice and the Declaration of Helsinki. The
trial was registered with ClinicalTrials.gov (NCT01495013).
Participants
Men and women aged ≥ 18 years with Type 2 diabetes on a
stable dose of metformin for ≥ 3 months, with HbA1c ≥ 53
ª 2015 Diabetes UK
DIABETICMedicine
to < 80 mmol/mol (≥ 7.0 to < 9.5%) and average fasting blood glucose > 7.0 mmol/l, taken on 4 days in the week
before enrolment, were eligible. Participants had to be statinna€ıve or have no statin use for 2 months before screening and
be eligible for statin therapy (history of cardiovascular
disease; ≥ 40 years with a cardiovascular risk factor;
< 40 years with LDL cholesterol > 100 mg/dl).
Exclusions were: other lipid-lowering or antidiabetic
agents; Type 1 diabetes or current need for insulin therapy;
concurrent myalgia; symptomatic hyperglycaemia requiring
therapy; hypertriglyceridaemia; clinically significant cardiovascular disease; end-stage renal disease; cancer in the past
3 years; a clinically significant abnormality on physical
examination or laboratory tests; receiving drug therapy to
treat liver disease; antiviral or immunosuppressive therapy;
haemoglobinopathy that could interfere with the assessment
of HbA1c; and hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption.
Interventions
Participants were randomly assigned (1:1) using an interactive web response system to receive glimepiride-atorvastatin
fixed-dose combination or co-administration of glimepiride
and atorvastatin (reference) once daily for 20 weeks. Block
randomization was used and the randomization list was
computer-generated using statistical software.
The combination tablets (1/10, 2/10, 3/10, 4/10, 1/20, 2/20,
3/20 and 4/20 mg of glimepiride/atorvastatin, respectively)
were manufactured by Dr Reddy’s Laboratories (Hyderabad,
India). Glimepiride (1, 2, 3 and 4 mg) and atorvastatin (10 and
20 mg) tablets were sourced from commercial supplies
(Amaryl ; Sanofi Aventis, Anagni, Italy; Lipitor ; Pfizer,
Berlin, Germany).
All participants started on 10 mg atorvastatin and 1 mg
glimepiride, either as combination or separate tablets.
Participants were advised to take study drug(s) shortly
before or during a substantial breakfast or the first main
meal. Glimepiride was up-titrated at weeks 2, 4, 6 and 10 if
average fasting blood glucose was > 7 mmol/l in the preceding week and no individual value was < 4.5 mmol/l. Atorvastatin was up-titrated at weeks 6 or 12 if LDL cholesterol at the preceding visit was > 2.6 mmol/l. The study was
designed to achieve rapid titration to enable participants to
have exposure at the higher doses; thus, participants who
required down-titration were to be withdrawn.
Assessments
The co-primary efficacy endpoints were change from baseline
to week 20 in HbA1c and percent change from baseline to
week 20 in LDL cholesterol. Secondary efficacy endpoints
were change from baseline to week 12 in HbA1c and percent
change from baseline to weeks 4 and 10 in LDL cholesterol.
1085
DIABETICMedicine
Fixed-dose combination of glimepiride and atorvastatin for type 2 diabetes P. Ambery et al.
Safety assessments included monitoring of adverse events
(AEs), hypoglycaemia and liver function tests.
Blood samples were taken at screening, baseline and
during the treatment period for measurement of HbA1c
(weeks 12 and 20), lipids (weeks 4, 10 and 20) and liver
function tests (weeks 2, 6, 16 and 20). HbA1c and lipids were
measured at a central laboratory. Liver function tests were
measured at each centre’s laboratory.
Participants were assigned a glucometer to measure blood
glucose. They were trained to identify symptoms of hypoglycaemia and to document these in a diary card, together
with the accompanying blood glucose reading. Participants
also recorded their fasting blood glucose for at least 4 days in
the week preceding a potential up-titration visit. Glucometer
readings were examined by investigators and categorized
using American Diabetes Association working group criteria
for hypoglycaemia [13]. All values ≤ 3.9 mmol/l were
recorded as hypoglycaemia, regardless of symptoms.
The AE information was collected from the start of
treatment until the last follow-up contact. Drug compliance
was determined by counting returned tablets.
Change from baseline in HbA1c and percentage change
from baseline in LDL cholesterol were separately analysed
for the observed case dataset using a mixed model for
repeated measures with restricted maximum likelihood
estimation. The baseline values for HbA1c and LDL cholesterol were included as covariates in the respective models. In
case of drop-out, HbA1c and LDL cholesterol values at the
early withdrawal visit were included in the analysis. Analyses
were performed using SAS v. 9.2 or later.
HbA1c results were reported as percentages and converted
to mmol/mol as follows: HbA1c (mmol/mol)=[HbA1c (%)
2.15]910.93. Standard deviation and change from baseline
values in mmol/mol were calculated by multiplying the
percentage value by 10.93.
Safety variables were summarized descriptively.
Compliance was defined as: 100 9 total number of tablets
consumed/(days of study drug exposure)*(number of tablets
prescribed per day).
Results
Study population
Statistical methods
A non-inferiority hypothesis was used to show that participants taking the combination were not disadvantaged
compared with participants taking the separate agents.
Assessment of non-inferiority was based on the two-sided
95% CI for the difference between groups for each coprimary endpoint. If the upper limit of the 95% CI for the
difference in change from baseline to week 20 for HbA1c was
< 3.3 mmol/mol (< 0.3%), and percentage change from baseline to week 20 in LDL cholesterol was < 6%, then non-inferiority was to be concluded. Non-inferiority margins were selected based on regulatory guidance for diabetes [14] and previous lipid studies [15]. A sample size of 191 evaluable participants in each group provided 90% power for the comparison between groups for change from baseline in HbA1c (based on a non-inferiority margin of 0.3% assuming standard deviation of 0.9%) and 83% power for the comparison between groups for percentage change from baseline in LDL cholesterol (based on a non-inferiority margin of 6% assuming standard deviation of 20%) and a one-sided test with 2.5% significance level. Assuming up to 10% of participants would be nonevaluable, 424 participants were to be randomized (212 per group). The primary non-inferiority analysis was conducted on the per-protocol population (all participants without major protocol deviations). Analysis of the intention-to-treat population (all randomized participants with at least one postbaseline HbA1c or LDL cholesterol value) was conducted as a sensitivity analysis. The safety population comprised all participants who took at least one dose of study drug. 1086 A total of 427 participants were randomized (215 and 212 in combination and reference groups, respectively) and 393 (92%) participants completed the study (Fig. 1). Over 90% of participants were included in the per-protocol populations for the analysis of HbA1c (391/427, 92%) and LDL cholesterol (393/427, 92%). The most common reasons for exclusion from per-protocol populations were incorrect dose titration (six and seven participants in the combination and reference groups, respectively) and inadequate treatment compliance (four and six participants, respectively; Fig. 1). The two groups were well matched with regard to demographic and baseline characteristics (Table 1). In both groups, mean age was 57–58 years and there was a predominance of women (59 and 64%, respectively). Exposure and treatment compliance At the end of the 20-week treatment period or at premature discontinuation, 19 and 20% of participants in the combination and reference groups, respectively, remained on the lowest combination of glimepiride/atorvastatin 1/10 mg and 10% of participants in each group were on the highest combination of 4/20 mg (Table S1). Glimepiride 4 mg, irrespective of atorvastatin dose, was received by 42 and 44% of participants, respectively, with 34 and 35% of participants titrated to this dose at week 6. Atorvastatin 20 mg was received by 19 and 21% of participants, respectively, with 10 and 14% of participants titrated to this dose at week 6. Compliance with study drug was 98% in each group. ª 2015 Diabetes UK 768 assessed for eligibility 427 randomised Analysis Follow-up Enrollment DIABETICMedicine Allocation Research article 341 excluded • 327 did not meet eligibility criteria • 11 withdrew consent • 3 other reasons 215 allocated to combination group • 215 received allocated intervention 212 allocated to reference group • 212 received allocated intervention 199 completed the study to Week 20 16 discontinued prematurely: • 1 down-titration of study drug • 1 change in treatment f ... Purchase answer to see full attachment

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