The present study is a randomized, multi-center, open label, active controlled, comparative phase-III clinical trial to evaluate safety and efficacy of fixed dose combination of Glibenclamide 5 mg, Metformin 500 mg and Voglibose 0.2 mg/0.3 mg tablets of Sun Pharma Laboratories Limited, India for treatment in diabetic patients.
Subjects will be randomized to either twice daily FDC of Glibenclamide 5 mg, Metformin 500 mg and Voglibose 0.2 mg or twice daily Glibenclamide 5 mg, Metformin 850 mg as per the randomization list.Subject in either of group (Fixed dose combination Glibenclamide 5 mg, Metformin500 mg, Voglibose 0.2 mg or Glibenclamide 5 mg, Metformin 850 mg), whose PPBG reduction is insufficient at 12 weeks will be switched to Fixed dose combination Glibenclamide 5 mg, Metformin 500 mg, Voglibose 0.3 mg and Glibenclamide 5 mg, Metformin 1000 mg respectively while the others subjects with reduction of at least 15 mg/dl will continue their study medications (Fixed dose combination Glibenclamide 5 mg, Metformin 500 mg, Voglibose 0.2 mg and Glibenclamide 5 mg and Metformin 850 mg) up to 24 weeks. Change in HbA1c from baseline will be considered as primary outcome.Safety assessment will be done by evaluating any adverse/serious adverse events and laboratory parameters during entire study period.
This
was a phase III, randomized, multi-centric, parallel, open-label, active-controlled,
comparative trial conducted in 301 patients suffering with type 2 diabetes and who
were on stable dose of combination of Glibenclamide 5 mg and Metformin 500 mg
twice daily for at least 12 weeks at the time of screening. The study was
conducted in compliance with applicable regulatory requirements and the good
clinical practice guidelines. This study was designed to evaluate efficacy and
safety of fixed dose combination of Glibenclamide, Metformin and Voglibose
tablets in comparison to Glibenclamide and Metformin tablets in treated
patients. The
randomized patients of the treatment arms [FDC of Glibenclamide 5 mg, Metformin 500 mg and Voglibose 0.2 mg tablet and
combination of Glibenclamide 5 mg and Metformin 850 mg tablet] in this study
did not have any clinically significant differences in demographic and baseline
characteristics including disease characteristics like HbA1c, FBG and PPBG
measurements. Overall, the arms were comparable with respect to baseline
characteristics. 1. Primary
Efficacy End Point In
primary efficacy endpoint, reduction in HbA1c (%) from baseline to week 12 was
0.63 in fixed dose combination of Glibenclamide 5 mg + Metformin 500 mg +
Voglibose 0.2 mg arm (Test 1 arm) and 0.62 in Glibenclamide 5 mg + Metformin
850 mg arm (Comparator 1 arm). Similarly, reduction in HbA1c (%) from baseline
to week 24 was 0.85 in Test 1 arm and 0.76 in Comparator 1 arm. This decrease
in HbA1c value was statistically significant (p < 0.0001) at both week 12
and at week 24 from baseline in all the treatment groups. Between group results
were non-significant at week 12 and 24. The results on primary end point show
that Test 1 arm demonstrates higher reduction in HbA1c in comparison to
comparator 1 arm at week 12 and 24. Few
patients required dose escalation from week 12 onwards. Out of 129 patients in
Test 1 arm and 140 patients in Comparator 1 arm, 18 patients were up-titrated
from Test 1 arm to FDC of Glibenclamide 5 mg + Metformin 500 mg + Voglibose 0.3
mg (Test 2 arm) and 22 patients were up-titrated from Comparator 1 arm to
Glibenclamide 5 mg + Metformin 1000 mg (Comparator 2 arm). In the up-titrated patients, reduction in
HbA1c (%) from week 12 (baseline value) to week 24 was 0.1 in Test 2 arm and
0.28 in Comparator 2 arm. 2. Secondary
Efficacy End-Points Change
in PPBG (mg/dL) from baseline to week 12 was 48.23 in Test 1 arm and 39.22 in
Comparator 1 arm. Similarly, change in PPBG from baseline to week 24 was 63.63
in Test 1 arm and 54.34 in Comparator 1 arm. This decrease in PPBG value was
statistically significant (p < 0.0001) within groups and was non-significant
between groups. In the up-titrated patients, change in PPBG (mg/dL) from week
12 (baseline value) to week 24 was 29.17 in Test 2 arm and 42.13 in Comparator
2 arm. The higher reduction in PPBG in Test 1 arm can be attributed due to voglibose
component of the FDC. This can be more useful in Indian diabetic patients who
have high carbohydrate intake in diet. In
another end point, FBG (mg/dL), change from baseline to week 12 was 20.37 in Test
1 arm and 16.42 in Comparator 1 arm. Similarly, change in FBG from baseline to
week 24 was 26.58 in Test 1 arm and 22.42 Comparator 1 arm. This decrease in
FBG was statistically significant (p < 0.0001) within groups and was
non-significant between groups. In the up-titrated patients, change in FBG
(mg/dL) from week 12 (baseline value) to week 24 was 5.96 in Test 2 arm and 13.46
in Comparator 2 arm. Based
on this, we can conclude that Test 1 arm has demonstrated higher reduction in HbA1c,
PPBG and FBG in comparison to comparator 1 arm at week 12 and week 24 whereas Test
2 arm could not show the same over comparator 2 arm. Proportion
of participants with HbA1c reduction of at least 0.5% at the end of 24 weeks was
also one of the study endpoint. In Test 1 arm, it was observed that 93 patients
(83.78%) achieved reduction in HbA1c of at least 0.5% at the end of 24 weeks.
This was achieved early in 111 patients (86.05%) by week 12. Similarly, in
Comparator 1 arm, it was observed that 103 patients (87.29%) achieved reduction
in HbA1c of at least 0.5% at the end of 24 weeks. This was achieved early in
120 patients (85.71%) by week 12. In up-titrated patients, in Test 2 arm, it was observed that 12
patients (66.67%) achieved reduction in HbA1c of at least 0.5% at the end of 24
weeks. In Comparator 2 arm, it was observed that 14 patients (63.64%) achieved
reduction in HbA1c of at least 0.5% at the end of 24 weeks. Proportion
of participants with PPBG < 170 mg/dL at the end of 24 weeks was also
evaluated in this study. In fixed dose combination of Test 1 arm, it was
observed that 31 patients (27.93%) achieved PPBG < 170 mg/dL at the end of
24 weeks. This was achieved early in 20 patients (15.5%) by week 12. Similarly,
in Comparator 1 arm, it was observed that 31 patients (26.27%) achieved PPBG
< 170 mg/dL at the end of 24 weeks. This was achieved early in 22 patients
(15.71%) by week 12. In up-titrated patients, in Test 2 arm, it was observed
that 3 patients (16.67%) achieved PPBG < 170 mg/dL at the end of 24 weeks.
In Comparator 2 arm, it was observed that 4 patients (18.18%) achieved PPBG
< 170 mg/dL at the end of 24 weeks. Overall,
proportion of participants with HbA1c reduction of at least 0.5% at end of 24
weeks from baseline and proportion of participants with PPBG < 170 mg/dL at
the end of 24 weeks was observed in patients who continued to take study
medication as per randomization schedule and also in those patients who were
up-titrated to higher dose. As
per CGI-I scale, the disease condition of patients improved from week 12 after
administration of the study medication. There were only 34 cases of “no changeâ€
(17 in Test 1 and 11 in Comparator 1 arm), “minimally worse†(15 in Test 1 and
20 in Comparator 1 arm) and “Much worse†(02 in Test 1 and 03 in Comparator 1
arm) after 24 weeks of treatment. There were no cases of “very much worseâ€
patients by week 24 in this study. In up-titrated patients, there were only 07
cases of “no change†(00 in Test 2 and 04 in Comparator 2 arm), “minimally
worse†(01 in Test 1 and 01 in Comparator 1 arm) and “Much worse†(01 in Test
1) after 24 weeks of treatment. There
were no cases of “very much worse†patients by week 24 in this study. 3.
Bootstrapping of efficacy end points In order to evaluate effect of Voglibose as an
add on to Glibenclamide and Metformin combination it is necessary to compare
for reduction in HbA1c, PPBG and FBG in fixed dose combination of Glibenclamide
5 mg + Metformin 500 mg + Voglibose 0.2 mg arm against fixed dose combination
of Glibenclamide 5 mg + Metformin 500 mg + Placebo arm. Since, we did not
choose the comparator with placebo component on the basis of ethical ground we
evaluated this effect based on bootstrapping method. Results of bootstrapping
are as follows a.
Change
in HbA1c (%) from baseline to week 12 was reduction by 0.63 in fixed dose
combination of Glibenclamide 5 mg + Metformin 500 mg + Voglibose 0.2 mg arm (Test
1 arm) and increase by 0.01 in Glibenclamide 5 mg + Metformin 850 mg arm
(Comparator 1 arm). Similarly, reduction in HbA1c (%) from baseline to week 24
was 0.85 in Test 1 arm and 0.03 in Comparator arm. This decrease in HbA1c value
was statistically significant (p < 0.0001) within and between group at both
week 12 and at week 24 from baseline b.
Reduction
in PPBG from baseline to week 12 was 48.23 in fixed dose combination of
Glibenclamide 5 mg + Metformin 500 mg + Voglibose 0.2 mg arm (Test 1 arm) and 3.69
in Glibenclamide 5 mg + Metformin 850 mg arm (Comparator 1 arm). Similarly,
reduction in PPBG from baseline to week 24 was 63.63 in Test 1 arm and 5.85 in
Comparator arm. This decrease in PPBG value was statistically significant (p
< 0.0001) within and between group at both week 12 and at week 24 from
baseline c.
Change
in FBG from baseline to week 12 was reduction by 20.37 in fixed dose
combination of Glibenclamide 5 mg + Metformin 500 mg + Voglibose 0.2 mg arm (Test
1 arm) and increase by 3.12 in Glibenclamide 5 mg + Metformin 850 mg arm (Comparator
1 arm). Similarly, reduction in FBG from baseline to week 24 was 26.58 in Test 1
arm and 1.21 in Comparator arm. This decrease in PPBG value was statistically
significant (p < 0.0001) between group at both week 12 and at week 24 from
baseline Thus,
based on the adhoc analysis results FDC Glibenclamide 5 mg, Metformin 500 mg,
Voglibose 0.2 mg arm (Teat 1 arm) is found be superior than Glibenclamide 5 mg
and Metformin 850 mg (Comparator 1 arm) arm in Type 2 Diabetes patients after
receiving the treatment for 24 weeks. 4.
Safety Analysis There
were no serious adverse events reported in any of the randomized study
participants. One patient reported Hypoglycemia from Glibenclamide 5 mg and
Metformin 850 mg (Comparator 1 arm) and was withdrawn from the study by the
investigator due to safety reason. A
total of 23 TEAEs were reported in 18 patients during the study period. Out of 23
events, 20 events were reported by the 15 patients who received study
medication as per randomization schedule (Test 1 and Comparator 1) and 3 events
were reported by 3 patients who were up-titrated to higher dose (Test 2 and
Comparator 2) at week 12. Out of 20 events reported among Test 1 and Comparator 1
combined, 10 events were reported in Test 1 arm and 10 events were reported in
Comparator 1 arm. Out of 10 event in Test 1 arm, three were mild and seven were
moderate in nature. Only one event was possibly related and all 10 events were
resolved. In comparator 1 arm, seven were mild and three were moderate in
intensity. A total of three events were related and all 10 events were
resolved. In up-titrated patients, out
of 03 events reported, 01 event was reported in Test 2 arm and 02 events were
reported in Comparator 2 arm. All 03 events were not related to study drug of
which 01 event was mild in nature and 02 events were moderate in nature. All
the adverse events reported were recovered/resolved during the study period. The events reported from 0.7% to 2.1 % incidence in
Test 1 arm were Urinary Tract Infection, Upper Respiratory Tract Infection, Dyspepsia,
Nasopharyngitis, Back Pain, Headache and Cough. The events reported from 0.6% to
1.3% incidence in Comparator 1 arm were Pyrexia, Vertigo, Hyperchlorhydria,
Mouth Ulceration, Nausea, Salivary Gland Pain, Hypoglycemia, Arthralgia and
Back Pain. In up-titrated patients, the events reported with 4.8% incidence in
Test 2 arm was Upper Respiratory Tract Infection and the events reported with
4.5% incidence in Comparator 2 arm was Pyrexia and Pruritus. All the
arms were comparable with respect to other safety parameters also. The physical
examination, ECG, vital signs and laboratory findings were within acceptable or
non-significant range in both the arms. The Laboratory AEs did not vary
significantly between all the arms. Apart from the safety that is already known
for the study medications, no new safety findings were observed in the study. The
results of safety analysis showed that the incidence of TEAEs and ADRs were
comparable and acceptable in all the arms with no significant differences were
found in other safety parameters like vital signs, ECG, physical examination
and laboratory parameters. Based on above findings all the arms did not raise any
new & significant safety concerns and showed acceptable safety profile
in diabetic patients after receiving the treatment for 24 weeks. Overall, our results suggest that all four arms
individually have proved to be efficacious in diabetic patients after receiving
the treatment for 24 weeks. The fixed dose combination of Glibenclamide 5 mg, Metformin
500 mg, Voglibose 0.2 mg has demonstrated higher reduction in HbA1c, PPBG and
FBG in comparison with Glibenclamide 5 mg and Metformin 850 mg arm. The effect
on HbA1c, PPBG and FBG was non-significant between Test and Reference arms.
However, the effect on HbA1c, PPBG and FBG was significant between fixed dose
combination of Glibenclamide 5 mg, Metformin 500 mg, Voglibose 0.2 mg and fixed
dose combination of Glibenclamide 5 mg, Metformin 850 mg arm. The overall
safety profile of all the three arms was found to be similar and consistent
with those known safety events. Type 2 DM is a chronic disease which usually requires
lifelong therapy. Adherence to therapy is an important aspect in management of
such. Adherence to these therapies decline as the number of drugs in therapy
increases. Also, there are suggestions that single tablet treatment regimen was associated
with better adherence to antidiabetic therapy than one involving multiple
tablets. Initial combination therapy is also
recommended in management of T2DM in patients with HbA1C ≥ 1.5%. Hence, combining the drugs into a single
fixed dose combination provides patients with a convenient way of consuming
multiple drugs without increasing the number of tablets. As per USFDA and CDSCO guideline, the rationality of FDCs should be based on certain aspects such as
the drugs in the combination should act by different mechanisms, the
pharmacokinetics must not be widely different and the combination should not
have supra-additive toxicity of the ingredients. Our fixed dose combination of
Glibenclamide, Metformin, Voglibose (5 mg + 500 + 0.2 mg) and (5 mg + 500 mg +
0.3 mg) were designed considering the above guidelines and was found to be
efficacious and safe when studied in 301 diabetic patients. CONCLUSION: Based
on the efficacy and safety results observed in our clinical study, it can be
concluded that three drugs combination of Glibenclamide + Metformin + Voglibose
(5 mg + 500 mg + 0.2 mg) and (5 mg + 500 mg + 0.3 mg) strengths have comparable
efficacy to two drugs combination of Glibenclamide + Metformin (5 mg + 850 mg)
and (5 mg + 1000 mg), when used in higher strengths of Metformin in treatment of
Type 2 diabetes mellitus patients. Overall, the drug was safe and well
tolerated by patients.
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