Safety and Efficacy Study of Fixed Dose Combination of Three Antidiabetic Drugs in Comparison to Two Antidiabetic Drugs in Patients with Type 2 Diabetes

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.

DISCUSSION AND OVERALLCONCLUSIONThiswas a phase III, randomized, multi-centric, parallel, open-label, active-controlled,comparative trial conducted in 301 patients suffering with type 2 diabetes and whowere on stable dose of combination of Glibenclamide 5 mg and Metformin 500 mgtwice daily for at least 12 weeks at the time of screening. The study wasconducted in compliance with applicable regulatory requirements and the goodclinical practice guidelines. This study was designed to evaluate efficacy andsafety of fixed dose combination of Glibenclamide, Metformin and Voglibosetablets in comparison to Glibenclamide and Metformin tablets in treatedpatients.

Therandomized patients of the treatment arms [FDC of Glibenclamide 5 mg, Metformin 500 mg and Voglibose 0.2 mg tablet andcombination of Glibenclamide 5 mg and Metformin 850 mg tablet] in this studydid not have any clinically significant differences in demographic and baselinecharacteristics including disease characteristics like HbA1c, FBG and PPBGmeasurements. Overall, the arms were comparable with respect to baselinecharacteristics.

1. PrimaryEfficacy End Point

Inprimary efficacy endpoint, reduction in HbA1c (%) from baseline to week 12 was0.63 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 + Metformin850 mg arm (Comparator 1 arm). Similarly, reduction in HbA1c (%) from baselineto week 24 was 0.85 in Test 1 arm and 0.76 in Comparator 1 arm. This decreasein HbA1c value was statistically significant (p < 0.0001) at both week 12and at week 24 from baseline in all the treatment groups. Between group resultswere non-significant at week 12 and 24. The results on primary end point showthat Test 1 arm demonstrates higher reduction in HbA1c in comparison tocomparator 1 arm at week 12 and 24.

Fewpatients required dose escalation from week 12 onwards. Out of 129 patients inTest 1 arm and 140 patients in Comparator 1 arm, 18 patients were up-titratedfrom Test 1 arm to FDC of Glibenclamide 5 mg + Metformin 500 mg + Voglibose 0.3mg (Test 2 arm) and 22 patients were up-titrated from Comparator 1 arm toGlibenclamide 5 mg + Metformin 1000 mg (Comparator 2 arm).  In the up-titrated patients, reduction inHbA1c (%) from week 12 (baseline value) to week 24 was 0.1 in Test 2 arm and0.28 in Comparator 2 arm.

 2. SecondaryEfficacy End-Points

Changein PPBG (mg/dL) from baseline to week 12 was 48.23 in Test 1 arm and 39.22 inComparator 1 arm. Similarly, change in PPBG from baseline to week 24 was 63.63in Test 1 arm and 54.34 in Comparator 1 arm. This decrease in PPBG value wasstatistically significant (p < 0.0001) within groups and was non-significantbetween groups. In the up-titrated patients, change in PPBG (mg/dL) from week12 (baseline value) to week 24 was 29.17 in Test 2 arm and 42.13 in Comparator2 arm. The higher reduction in PPBG in Test 1 arm can be attributed due to voglibosecomponent of the FDC. This can be more useful in Indian diabetic patients whohave high carbohydrate intake in diet.

Inanother end point, FBG (mg/dL), change from baseline to week 12 was 20.37 in Test1 arm and 16.42 in Comparator 1 arm. Similarly, change in FBG from baseline toweek 24 was 26.58 in Test 1 arm and 22.42 Comparator 1 arm. This decrease inFBG was statistically significant (p < 0.0001) within groups and wasnon-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 13.46in Comparator 2 arm.

Basedon 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 Test2 arm could not show the same over comparator 2 arm.

Proportionof participants with HbA1c reduction of at least 0.5% at the end of 24 weeks wasalso 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, inComparator 1 arm, it was observed that 103 patients (87.29%) achieved reductionin HbA1c of at least 0.5% at the end of 24 weeks. This was achieved early in120 patients (85.71%) by week 12. In up-titrated patients, in Test 2 arm, it was observed that 12patients (66.67%) achieved reduction in HbA1c of at least 0.5% at the end of 24weeks. In Comparator 2 arm, it was observed that 14 patients (63.64%) achievedreduction in HbA1c of at least 0.5% at the end of 24 weeks.

Proportionof participants with PPBG < 170 mg/dL at the end of 24 weeks was alsoevaluated in this study. In fixed dose combination of Test 1 arm, it wasobserved that 31 patients (27.93%) achieved PPBG < 170 mg/dL at the end of24 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 observedthat 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 24weeks from baseline and proportion of participants with PPBG < 170 mg/dL atthe end of 24 weeks was observed in patients who continued to take studymedication as per randomization schedule and also in those patients who wereup-titrated to higher dose.

Asper CGI-I scale, the disease condition of patients improved from week 12 afteradministration 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 and20 in Comparator 1 arm) and “Much worse†(02 in Test 1 and 03 in Comparator 1arm) 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 07cases of “no change†(00 in Test 2 and 04 in Comparator 2 arm), “minimallyworse†(01 in Test 1 and 01 in Comparator 1 arm) and “Much worse†(01 in Test1) after 24 weeks of treatment. Therewere 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 anadd on to Glibenclamide and Metformin combination it is necessary to comparefor reduction in HbA1c, PPBG and FBG in fixed dose combination of Glibenclamide5 mg + Metformin 500 mg + Voglibose 0.2 mg arm against fixed dose combinationof Glibenclamide 5 mg + Metformin 500 mg + Placebo arm. Since, we did notchoose the comparator with placebo component on the basis of ethical ground weevaluated this effect based on bootstrapping method. Results of bootstrappingare as follows

**a.**Changein HbA1c (%) from baseline to week 12 was reduction by 0.63 in fixed dosecombination of Glibenclamide 5 mg + Metformin 500 mg + Voglibose 0.2 mg arm (Test1 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 24was 0.85 in Test 1 arm and 0.03 in Comparator arm. This decrease in HbA1c valuewas statistically significant (p < 0.0001) within and between group at bothweek 12 and at week 24 from baseline

**b.**Reductionin PPBG from baseline to week 12 was 48.23 in fixed dose combination ofGlibenclamide 5 mg + Metformin 500 mg + Voglibose 0.2 mg arm (Test 1 arm) and 3.69in 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 inComparator arm. This decrease in PPBG value was statistically significant (p< 0.0001) within and between group at both week 12 and at week 24 frombaseline

**c.**Changein FBG from baseline to week 12 was reduction by 20.37 in fixed dosecombination of Glibenclamide 5 mg + Metformin 500 mg + Voglibose 0.2 mg arm (Test1 arm) and increase by 3.12 in Glibenclamide 5 mg + Metformin 850 mg arm (Comparator1 arm). Similarly, reduction in FBG from baseline to week 24 was 26.58 in Test 1arm and 1.21 in Comparator arm. This decrease in PPBG value was statisticallysignificant (p < 0.0001) between group at both week 12 and at week 24 frombaseline

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 mgand Metformin 850 mg (Comparator 1 arm) arm in Type 2 Diabetes patients afterreceiving the treatment for 24 weeks.

**4.**Safety Analysis

Therewere no serious adverse events reported in any of the randomized studyparticipants. One patient reported Hypoglycemia from Glibenclamide 5 mg andMetformin 850 mg (Comparator 1 arm) and was withdrawn from the study by theinvestigator due to safety reason. Atotal of 23 TEAEs were reported in 18 patients during the study period. Out of 23events, 20 events were reported by the 15 patients who received studymedication as per randomization schedule (Test 1 and Comparator 1) and 3 eventswere reported by 3 patients who were up-titrated to higher dose (Test 2 andComparator 2) at week 12.

Out of 20 events reported among Test 1 and Comparator 1combined, 10 events were reported in Test 1 arm and 10 events were reported inComparator 1 arm. Out of 10 event in Test 1 arm, three were mild and seven weremoderate in nature. Only one event was possibly related and all 10 events wereresolved. In comparator 1 arm, seven were mild and three were moderate inintensity. A total of three events were related and all 10 events wereresolved. In up-titrated patients, outof 03 events reported, 01 event was reported in Test 2 arm and 02 events werereported in Comparator 2 arm. All 03 events were not related to study drug ofwhich 01 event was mild in nature and 02 events were moderate in nature. Allthe adverse events reported were recovered/resolved during the study period.

The events reported from 0.7% to 2.1 % incidence inTest 1 arm were Urinary Tract Infection, Upper Respiratory Tract Infection, Dyspepsia,Nasopharyngitis, Back Pain, Headache and Cough. The events reported from 0.6% to1.3% incidence in Comparator 1 arm were Pyrexia, Vertigo, Hyperchlorhydria,Mouth Ulceration, Nausea, Salivary Gland Pain, Hypoglycemia, Arthralgia andBack Pain. In up-titrated patients, the events reported with 4.8% incidence inTest 2 arm was Upper Respiratory Tract Infection and the events reported with4.5% incidence in Comparator 2 arm was Pyrexia and Pruritus.

All thearms were comparable with respect to other safety parameters also. The physicalexamination, ECG, vital signs and laboratory findings were within acceptable ornon-significant range in both the arms. The Laboratory AEs did not varysignificantly between all the arms. Apart from the safety that is already knownfor the study medications, no new safety findings were observed in the study. Theresults of safety analysis showed that the incidence of TEAEs and ADRs werecomparable and acceptable in all the arms with no significant differences werefound in other safety parameters like vital signs, ECG, physical examinationand laboratory parameters. Based on above findings all the arms did not raise anynew & significant safety concerns and showed acceptable safety profilein diabetic patients after receiving the treatment for 24 weeks.

Overall, our results suggest that all four armsindividually have proved to be efficacious in diabetic patients after receivingthe treatment for 24 weeks. The fixed dose combination of Glibenclamide 5 mg, Metformin500 mg, Voglibose 0.2 mg has demonstrated higher reduction in HbA1c, PPBG andFBG in comparison with Glibenclamide 5 mg and Metformin 850 mg arm. The effecton HbA1c, PPBG and FBG was non-significant between Test and Reference arms.However, the effect on HbA1c, PPBG and FBG was significant between fixed dosecombination of Glibenclamide 5 mg, Metformin 500 mg, Voglibose 0.2 mg and fixeddose combination of Glibenclamide 5 mg, Metformin 850 mg arm. The overallsafety profile of all the three arms was found to be similar and consistentwith those known safety events.

Type 2 DM is a chronic disease which usually requireslifelong therapy. Adherence to therapy is an important aspect in management ofsuch. Adherence to these therapies decline as the number of drugs in therapyincreases. Also, there are suggestions that single tablet treatment regimen was associatedwith better adherence to antidiabetic therapy than one involving multipletablets.  Initial combination therapy is alsorecommended in management of T2DM in patients with HbA1C ≥ 1.5%.  Hence, combining the drugs into a singlefixed dose combination provides patients with a convenient way of consumingmultiple drugs without increasing the number of tablets. As per USFDA and CDSCO guideline, the rationality of FDCs should be based on certain aspects such asthe drugs in the combination should act by different mechanisms, thepharmacokinetics must not be widely different and the combination should nothave supra-additive toxicity of the ingredients. Our fixed dose combination ofGlibenclamide, 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 beefficacious and safe when studied in 301 diabetic patients.

CONCLUSION:

Basedon the efficacy and safety results observed in our clinical study, it can beconcluded 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 comparableefficacy 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 ofType 2 diabetes mellitus patients. Overall, the drug was safe and welltolerated by patients.