Supplemental Online Material

SUPPLEMENTAL ONLINE MATERIAL

Table S1. Approved and banned top selling metformin FDCs in India.

Figure S1. Excerpt from World Health Organization Guidelines for Registration of Fixed- dose Combination Medicinal Products - Annex 5. WHO Technical Report Series, No. 929. Geneva, World Health Organization, 2005.

Figure S2. Description and example of electronic search strategy in PubMed conducted 01 April 2016

Figure S3. Flowchart of search strategy and results of literature searches conducted on published trials of five FDCs

Figure S4. Description of clinical trial inclusion criteria

Table S2. Results from the literature search for metformin FDCs in patients with Type 2 diabetes from published clinical trials

Figure S5. Flowchart of search strategy and results of the clinical trial database searches conducted on unpublished trials of five FDCs

Table S3. Details of unpublished trials on metformin FDCs conducted on Type 2 diabetes patients

Table S4. Trials listed on USA and India clinical trials registries for metformin FDC clinical trials conducted on patients with Type 2 diabetes

Table S1. Approved and banned top selling metformin FDCs in India Fifty-two metformin FDCs have been approved by CDSCO over 20 years from February 1996 through to September 2016.1 Of these 52, 12 were approvals for the 5 top sellers and of the different dosages for the 5 top-sellers, 10 were banned in March 2016 by the government.2

Approved1 Banned2 3 approvals for Glimpiride + Metformin: None

Glimepiride 1mg/2mg + Metformin SR 500mg; 13/11/2002

Glimpiride 1mg/2mg + Metformin SR 1000mg; 08/06/2007

Glimepiride IP 0.5 mg + Metformin Hydrochloride ER 500 mg uncoated bilayered tablets (additional strength); 20/01/2014 1 approval for Glimepiride + Pioglitazone + Metformin: 7 banned

Glimepiride (1mg/2mg) + Pioglitazone (15mg) + Metformin S.O. 802 (500mg E.R) uncoated Tablet, as 3rd line treatment of type-II Glimepiride 1/2/1/2mg diabetes mellitus when diet, exercise and the single agents and Pioglitazone 7.5/7.5/7.5/7.5mg second line therapy with two drugs do nto result in adequate Metformin 1000/1000/500/500mg glycemic control; 16/08/2005 S.O. 806 Glimepiride 1/2/3mg Pioglitazone 15/15/15mg Metformin 1000/1000/1000mg

S.O. 807 Glimepiride 1/2mg Pioglitazone 15/15mg Metformin 850/850mg

S.O. 808 Glimepiride 2mg Pioglitazone 7.5mg Metformin 850mg

S.O. 809 Glimepiride 1mg Pioglitazone 7.5mg Metformin 850mg

S.O. 815 Glimepiride Pioglitazone Metformin

S.O. 823 Glimepiride 3mg Pioglitazone 15mg Metformin (SR) 500mg

1 http://cdsco.nic.in/writereaddata/latesapproved%20FDC%20list%20till%2030%20june%202017.pdf. 2 http://www.cdsco.nic.in/writereaddata/GSR705E.pdf

2 approvals for Glipizide + Metformin: 1 banned

Glipizide 2.5mg/5mg + Metformin 250mg/500mg tablet, for S.O. 816 non insulin dependent diabetes mellitus; 20/03/1998 Glipizide 2.5mg Metformin 400 mg Metformin 500mg CR + Glipizide 5mg CR Tablet, [indication not stated]; 17/12/2003 5 approvals for Glibenclamide + Metformin: None

Glibenclamide 2.5mg+Metformin 400mg Film coated Tablets, non insulin dependent diabites mallitus patients poorly controled with sulphonyluren or biguanide alone; 30/11/1995

Glibenclamide IP 2.5mg + Metformin IP 400mg film coated tablets, For the management of type II diabetes mellitus when single drug therapy, diet and exercise do not result in adequate glycemic control; 06/02/1996

Glibenclamide 5mg+ Metformin 500mg Tablets, non insulin dependent diabites mallitus patients poorly controlled with sulphonyluren or biguanide alone; 26/11/96

Glibenclamide 2.5mg/5mg+Metformin 500mg/500mg SR tablet, non insulin dependent diabites mallitus patients poorly controled with sulphonyluren or biguanide alone; 20/08/2004

Glibeneclamide 5mg + Metformin SR 850mg tablet (additional strength), non insulin dependent diabites mallitus patients poorly controled with sulphonyluren or biguanide alone; 15/02/07 1 approval for Gliclazide + Metformin: 2 banned

Gliclazide M.R. (30mg/60mg/80mg) + Metformin HCl S.O. 803 (500mg/500mg/500mg) ER Tablet, for type-II diabetes; Gliclazide 80 mg 27/04/2005 Metformin 325 mg

S.O. 1029 Gliclazide 40mg Metformin 400mg

Figure S1. Excerpt from World Health Organization. Guidelines for registration of fixed- dose combination medicinal products - Annex 5. WHO Technical Report Series, No. 929.

Geneva, World Health Organization, 2005.

6.6 Clinical efficacy and safety 6.6.1 General principles 6.6.1.1 The risk–benefit assessment for a new combination may be based on data generated using either the components given as single entity products concurrently or the FDC as a single FPP [finished pharmaceutical product]. 6.6.1.2 Any theoretical advantages of a particular combination should be confirmed by means of efficacy studies. The risk– benefit assessment should not be based on theoretical considerations only, or on extrapolation from other data. 6.6.1.3 If the actives in an FDC are intended to relieve different symptoms of a disease state, it is a prerequisite that these symptoms commonly occur simultaneously at a clinically relevant intensity and for a period of time such that simultaneous treatment is appropriate. Occurrence of the individual symptoms in isolation should not be indications for the FDC. 6.6.1.4 Clinical studies should be designed to determine whether the combination has an advantage over the component actives given alone in a substantial patient population. The data should demonstrate that each active contributes to the therapeutic effect of the combination. It may not be essential to show that all of the components have efficacy when administered as single entities; for example clavulanic acid has little or no antimicrobial activity when given alone, but it enhances the efficacy of beta-lactam antibiotics. 6.6.1.5 In situations where comparative clinical trials are not feasible, for example when monotherapy is inappropriate or is unethical, an aggregate of clinical and preclinical data may be substituted. Such data may include: 6.6.1.5.1 Historical clinical data, preferably at an exposure comparable to that for the proposed FDC. 6.6.1.5.2 Bridging pharmacokinetic data. 6.6.1.5.3 Preclinical pharmacology and/or toxicology data. 6.6.1.5.4 In vitro data (e.g. microbiological studies). 6.6.1.6 If the FDC is available in more than one strength or ratio of doses, there should be a risk–benefit assessment for each combination. 6.6.1.7 The choice of comparators for the purposes of safety and efficacy studies should be justified. They should normally represent the recognized treatment for the indication in question. As far as possible, comparators should be licensed products with well- established safety and efficacy profiles and of established quality. Unapproved or novel combinations should be avoided as comparators as they may introduce new efficacy or toxicity characteristics and thus complicate assessment of the combination under test. 6.6.1.8 If the combination is intended for long-term use, data on safety in patients will normally be required for 6 months or longer.

6.6.1.9 If one or more of the component actives has an established use and dosage regimen in indications unrelated to the indications of the FDC, existing experience as to its safety may nevertheless be taken into account, bearing in mind the relative doses for the two sets of indications. 6.6.1.10 End-points in clinical trials should be such as to characterize the advantages and disadvantages of the combination. For example, for a combination designed to reduce the development of drug resistance, end-points might include the frequency of new drug resistance as well as the overall clinical outcome. 6.6.1.11 Parallel group comparisons are one means of demonstrating a therapeutic effect. A parallel placebo group should be included if feasible and if consistent with the indications under treatment. Multifactorial designs are another means by which it may be possible to demonstrate that a combination is superior to the individual actives. 6.6.1.12 In some cases, studies have to be specifically designed to confirm the minimal effective dose and the usual effective dose of the combination. Multiple dose-effect studies may be necessary. 6.6.1.13 The design and analysis of studies of efficacy and safety should consider (among other things) whether the combination is indicated as first- or second-line therapy. 6.6.1.14 In general, all of the actives in a combination should have a similar duration of action. If this is not the case, the applicant should explain and justify the combination. 6.6.1.15 In general, the actives in a combination should have similar pharmacokinetics. If this is not the case, the applicant should explain and justify the combination. 6.6.1.16 If there is an increase in the number or severity of adverse reactions to the FDC as compared with those in response to the individual actives given alone, evidence and argument should be presented showing that the advantages of the combination outweigh the disadvantages. These should be included in the section of the submission entitled “Balancing the advantages and disadvantages of a new FDC”. 6.6.1.17 Data generated in clinical safety and efficacy studies should comply with the WHO

Guidelines for good clinical practice (GCP) for trials on pharmaceutical products (1995).

Figure S2. Description and example of electronic search strategy in PubMed conducted 01

April 2016

Simultaneously, five clinical trials databases were searched using the same criteria for relevant unpublished trials: United States’ National Institute of Health, Clinical Trials

Registry in India, WHO International Clinical Trials Registry Platform, UK Clinical Trials

Network, and EU Clinical Trials Register. This search strategy enabled a global search for published and unpublished clinical trials on these metformin FDCs while also allowing us to capture trials conducted specifically in India.

Example:

All fields: metformin AND glibenclamide

Limits: filters set to human, clinical trial

Search details: ("metformin"[MeSH Terms] OR "metformin"[All Fields]) AND

("glyburide"[MeSH Terms] OR "glyburide"[All Fields] OR "glibenclamide"[All Fields])

AND (Clinical Trial[ptyp] AND "humans"[MeSH Terms])

Figure S3. Flowchart of search strategy and results of literature searches conducted on published trials of five FDCs

Figure S4. Description of clinical trial inclusion criteria

The trials of primary interest were those evaluating the efficacy and safety in Type 2 diabetes of metformin FDCs compared with the individual FDC components dosed concomitantly as

SDFs. We also included trials comparing metformin FDCs with monotherapy, any other antidiabetic treatment, or with placebo in adults (>18 years) with Type 2 diabetes. Trials on healthy volunteers, in vitro or animal studies, all retrospective analyses, cost-effectiveness trials, investigative treatments for gestational diabetes or those conducted in children (<18 years) were excluded. Once the relevant trials were retrieved data were evaluated using a modified critical appraisal tool based on that used by the NHS Centre for Reviews and

Dissemination and the Research Council for Complementary Medicine.3,4 Selected results, such as study duration, number of patients, study arms, primary outcomes, sponsorship, and study country, were then extracted into an Excel file for further analysis.

3 Centre for Reviews and Dissemination. Undertaking systematic reviews of research on effectiveness: CRD's guidance for carrying out or commissioning reviews (2nd Edition). York, UK, Centre for Reviews and Dissemination, University of York, 2001. 4.

4 The Research Council for Complementary Medicine. Data Extraction and Appraisal templates. London, UK, The Research Council for Complementary Medicine, London South Bank University, 2011. http://www.rccm.org.uk/sites/default/files/files/DECA%20forms.pdf. Accessed 08 July 2016.

Table S2. Results from the literature search for metformin FDCs in patients with Type 2 diabetes from published clinical trials

Reference Study Design N Sex Blinding Duration Study description Intervention Country Funding/ Age of study Sponsorship FDC COMPONENTS: GLIMEPIRIDE + METFORMIN Charpentier double-dummy 372 M/W randomised 5 To compare the effect of (1) metformin + glimepiride France Hoechst 2001 parallel group 35-70y double- months glimepiride in combination placebo Marion multicentre blind with metformin with (2) glimepiride + metformin Roussel monotherapy of each drug on placebo glycaemic control in patients (3) glimepiride/metformin FDC with Type 2 diabetes. González- multicenter 152 M/W randomised 12 The aim of this study was to (1) glimepiride/metformin FDC Mexico Laboratorios Ortiz 2009 40-65y double- months compare the efficacy of (1mg/500mg) Silanes blind glimepiride/metformin (2) glibenclamide/metformin combination versus FDC (5mg/500mg) glibenclamide/metformin for reaching glycemic control in patients with uncontrolled Type 2 diabetes. Shimpi single center 28 M/W randomised 3 To compare the effect of (1) glimepiride/metformin FDC India Not listed 2009 parallel group >35y open-label months metformin in combination (2mg/1000mg) with glimepiride and (2) glibenclamide/metformin glibenclamide in patients with FDC (10mg/1000mg) Type 2 diabetes. FDC COMPONENTS: GLIMEPIRIDE + PIOGLITAZONE + METFORMIN Bell 2011 multicentric 101 M/W randomised 3 To compare the efficacy of a (1) metformin + insulin 70/30 India Not listed parallel group 18-80y open-label months fixed-dose triple oral diabetes (2) glimepiride/pioglitazone/met polypill containing 1 or 2 mg formin SR FDC (1mg or glimepiride, 500 mg SR 2mg/15mg/500mg) metformin, and 15 mg pioglitazone administered once daily with human insulin 70/30 mix and 500 mg metformin SR administered twice daily in insulin-naïve subjects with Type 2 diabetes inadequately controlled on a combination of glimepiride and metformin.

Meshram multicentric 101 M/W open-label 2 To determine the efficacy and (1) glimepiride/pioglitazone/met India Unichem 2005 >18y months tolerability of the triple drug formin SR FDC Laboratories combination glimepiride 2mg (2mg/15mg/500mg) Ltd. plus pioglitazone hydrochloride 15mg plus metformin SR 500mg for 8 weeks in 101 Indian patients with Type 2 diabetes. FDC COMPONENTS: GLIPIZIDE Goldstein multicentric 178 M/W randomised 4.5 To determine the efficacy and (1) glipizide (30mg) United Bristol- 2003 parallel-group avg: 56y double- months tolerability of (2) metformin (500mg) States Myers active- masked metformin/glipizide in patients (3) glipizide/metformin FDC Squibb controlled uncontrolled with sulfonylurea (5mg/500mg) monotherapy. Given for 1 week and titrated for 17 weeks to maintain glucose control. FDC COMPONENTS: GLIBENCLAMIDE Blonde parallel group 521 M/W randomised 4 To compare the efficacy, (1) glyburide (10mg) United Bristol- 2002 30-75y double- months safety and tolerability of a (2) metformin (500mg) States Myers blind FDC glyburide/ metformin in (3) glyburide/metformin FDC Squibb preparations with those of (2.5mg/500mg) glyburide and metformin alone (4) glyburide/metformin FDC in patients with Type 2 (5mg/500mg) diabetes inadequately controlled by sulphonylurea, diet and exercise. Blonde multicenter 304 M/W randomised 12 To evaluate metformin- (1) glibenclamide/metformin United Bristol- 2004 30-75y double- months glibenclamide combination FDC (2.5mg/500mg) States Myers blind tablets (Glucovance®) in 477 (2) glibenclamide/metformin Squibb patients with hyperglycaemia FDC (5mg/500mg) despite sulphonylurea therapy. Bruce 2006 multicenter 45 M/W randomised 5 To investigate the mechanisms (1) glibenclamide/metformin United Bristol- 3-arm 20-75y double- months of action of the blood glucose- FDC (Glucovance; States Myers parallel group blind lowering actions of the 1.25mg/250mg) Squibb combination tablets, in (2) metformin (500mg) comparison with metformin (3) glibenclamide (2.5mg) and glibenclamide monotherapies, using

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hyperglycaemic clamp methodology and an oral glucose tolerance test in patients with Type 2 diabetes. Brunetti multicenter 133 M/W randomised 6 To assess the efficacy and (1) glibenclamide/metformin Italy Not listed 2004 prospective 35-70y double- months safety profile of this new dose- FDC (5mg/400mg) crossover blind combination compared with (2) glibenclamide/metformin the standard glibenclamide FDC (2.5mg/400mg) 2.5mg/ metformin 400mg dose Each given for 3 months then regimen in patients with Type switched to the other treatment 2 diabetes and poor glycaemic for 3 months. control. Chien 2007 multicenter 76 M/W randomised 4 To evaluate the efficacy and (1) glyburide (5mg) Taiwan Orient 4-arm 30-75y double- months safety of glyburide/ metformin (2) metformin (500mg) Europharma parallel group blind combined tablet compared to (3) glyburide/metformin FDC Co. Ltd. glyburide or metformin alone (2.5mg/500mg) in patients with Type 2 (4) glyburide/metformin FDC diabetes. (5.0mg/500mg) Comaschi multicenter 196 M/W randomised 6 To compare the effectiveness (1) pioglitazone (Actos®; 15- Italy Takeda Italy 2007 parallel group ≥35y open-label months of co-administration of 30mg/day) + metformin or Comaschi pioglitazone with metformin sulfonylurea concomitant 2008 or a sulfonlyurea with a fixed- treatment dose combination of (2) glibenclamide/metformin metformin and glibenclamide FDC (Glibomet®; on glycemic control and β-cell 2.5mg/500mg) function in patients with Type 2 diabetes. Dailey III multicenter 261 M/W randomised 6 To assess the efficacy and (1) glyburide/metformin FDC + United Bristol- 2004 20-78y double- months safety of adding rosiglitazone rosiglitazone States Myers blind to an established regimen of (2) glyburide/metformin FDC + Squibb glyburide/metformin in placebo patients with Type 2 diabetes Started after a 3 month open- who had not achieved label lead-in phase. adequate glycemic control. Donahue 2-way 35 M/W randomised 0.5 To compare the effects of two (1) glibenclamide/metformin United Bristol- 2002 crossover 20-70y double- months different formulations of FDC (2.5mg/500mg) States Myers blind glibenclamide (glyburide) Squibb combined with metformin on

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postprandial glucose (2) glibenclamide (2.5mg) + excursions, and to assess their metformin (500mg) pharmacokinetics. concomitant treatment Two-hour postprandial plasma glucose excursion. Erle 1999 crossover 33 M/W randomised 6 To assess and compare the (1) glyburide/metformin FDC Italy Laboratori avg: 60y double- months effectiveness and safety of (Glibomet; 2.5mg/400mg) Guidotti blind preconstituted, fixed, (2) glyburide (Gliboral; 5mg) + SpA, Pisa combinations of low-dose placebo glyburide plus metformin with higher dose glyburide monotherapy in patients with Type 2 diabetes. Flores- crossover 19 W randomised 0.5 To compare two (1) glyburide/metformin FDC Mexico Not listed Murrieta avg: 49.6y months pharmaceutical formulations (Bieuglucon®; 2.5mg/500mg) 2003 manufactured in Mexico, the (2) glyburide/metformin FDC conventional tablet (Glucovance®; (Bieuglucon®) and the new 2.5mg/500mg) partially micronized Each given for 1 week then formulation (Glucovance®), in switched to the other treatment diabetic patients submitted to for 1 week. treatment with both formulations for 7 days. Garber 2002 parallel-group 533 M/W randomised 4 To prospectively evaluate the (1) placebo United Bristol- placebo- avg: 56.6y months efficacy and safety of (2) glyburide (Micronase®, States Myers controlled combination therapy using a 2.5mg) Squibb multicentre glyburide/metfomrin tablet as (3) metformin (500mg) study compared with metformin (4) glyburide/metformin FDC monotherapy and glyburide (1.25mg/250mg) monotherapy as an initial (5) glyburide/metformin FDC treatment in patients with Type (2.5mg/500mg) 2 diabetes. Started after a 2 week single- blind placebo lead-in phase. Garber 2003 multicenter 429 M/W randomised 4 To examine the efficacy of (1) glyburide/metformin FDC United Bristol- 3-arm parallel 20-78y double- months initial therapy with (1.25mg/250mg) States Myers group study blind glyburide/metformin tablets (2) metformin (500mg) Squibb compared with traditional (3) glyburide (2.5mg) glyburide or metformin Started after a 2 week placebo lead-in phase.

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monotherapy in patients with more severe hyperglycemia. Garber 2006 multicentre 280 M/W randomised 6 To evaluate the efficacy and (1) glibenclamide/metformin United Bristol- 20-70y double- months safety of metformin- FDC (2.5mg500mg) States Myers blind glibenclamide tablets vs. (2) rosiglitazone (4mg) + Squibb metformin plus rosiglitazone metformin (500mg) therapy in patients with Type 2 concomitant treatment diabetes inadequately Started after a 1 week open-label controlled on metformin metformin lead-in phase. monotherapy. González- multicenter 152 M/W randomised 12 The aim of this study was to (1) glimepiride/metformin Mexico Laboratorios Ortiz 2009 study 40-65y double- months compare the efficacy of (1mg/500 mg) Silanes blind glimepiride/metformin (2) glibenclamide/metformin combination versus (5mg/500 mg) glibenclamide/metformin for reaching glycemic control in patients with uncontrolled Type 2 diabetes. Marre 2002 multicentre 356 M/W double- 4 To evaluate the efficacy and (1) metformin (Glucophage®; France Merck Lipha parallel-group >18y blind months safety of two dosage strengths 500mg) Belgium study double- of a single tablet metformin– (2) glibenclamide (Daonil®; Netherlands blind glibenclamide (glyburide) 5mg) Denmark combination compared with (3) glibenclamide/metformin Portugal the respective monotherapies, FDC (Glucovance®; in patients with Type 2 2.5mg/500mg) diabetes inadequately (4) glibenclamide/metformin controlled by metformin FDC (Glucovance®; monotherapy. 5mg/500mg) Started after a 2 week run-in period. Medina phase IV study 122 M/W open-label 1 month To evaluate the effectiveness (1) glyburide/metformin Mexico Not listed Santillán 34-77y and safety of preconstituted (Glucovance®; 2002 fixed combinations of 1.25mg/250mg) glyburide plus metformin in (2) glyburide/metformin patients with Type 2 diabetes (Glucovance®; inadequately controlled with 2.5mg/500mg) monotherapy. (3) glyburide/metformin (Glucovance®; 5mg/500mg)

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Raptis 1996 crossover 30 M/W randomised 6 To examine the effects of the (1) glibenclamide/metformin Greece Not listed prospective avg: 60.8y open-label months FDC glibenclamide-metformin FDC (Daopar® and Sugan study 2.5mg and 400mg M®; 2.5mg/400mg) respectively, compared to the (2) glibenclamide/phenformin fixed combination FDC (Daopar® and Sugan glibenclamide-phenformin M®; 2.5mg/25mg ) 2.5mg and 25mg respectively, Each given for 3 months then on the homeostasis of blood switched to the other treatment glucose in patients with Type for 3 months. 2 diabetes. Shimpi single center 28 M/W randomised 3 To compare the effect of (1) glimepiride/metformin FDC India Not listed 2009 parallel group >35y open-label months metformin in combination (1mg/500mg) study with glimepiride and (2) glibenclamide/metformin glibenclamide in patients with FDC (5mg/500mg) Type 2 diabetes. Tosi 2003 crossover 80 M/W randomised 12 To compare efficacy and (1) glibenclamide (5mg) (n=22) Italy Guidotti 3-treatment avg: 57.3y months tolerability of combination (2) metformin (500mg) (n=22) Laboratories treatment with metformin and (3) glibenclamide/metformin Pisa, Italy sulfonylurea with each of these (2.5mg/400mg) (n=44) drugs alone in the treatment of After 1 week run in period. One type 2 diabetes. tablet twice daily. Crossover after 6 months. FDC COMPONENTS: GLICLAZIDE NONE N=participants completed; FDC=fixed dose combination; SR=slow release/sustained release; IR=immediate release; ER=extended release; T2DM=Type 2 Diabetes Mellitus

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Figure S5. Flowchart of search strategy and results of the clinical trial database searches conducted on unpublished trials of five FDCs

NIH = NIH clinical trials database (clinicaltrials.gov); CTRI = Clinical Trials Registry India; ICTRP = WHO International Clinical Trials Registry Platform; UKCTR = UK Clinical Trials Gateway; EUCTR = EU Clinical Trials Register

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Table S3. Details of unpublished trials on metformin FDCs conducted on Type 2 diabetes patients.

Expected Gender Primary Clinical Trial ID# Country of # Estimated Duration Age Status Intervention Outcome Sponsor [reference] Study Participants (months) (years) Measure(s) FDC COMPONENTS: GLIMEPIRIDE + METFOMRIN M/F (1) Glimepiride SDF NCT01457911[1] China 5 240 Recruiting HbA1c level Sanofi-Aventis (18-80y) (2) FDC (glimepiride/metformin) M/F (1) Glimepiride SDF NCT00924573[2] Japan 6 189 Completed HbA1c level Sanofi-Aventis (20-74y) (2) FDC (glimepiride/metformin) Laboratorios M/F (1) Metformin SDF endothelial NCT01429818[3] Mexico 2 16 Completed Silanes S.A. de (≥18y) (2) FDC (glimepiride/metformin) dysfunction C.V. (1) Metformin SDF HbA1c level, Laboratorios M/F NCT00941161[4] Mexico 3 28 Completed (2) Glimepiride SDF fasting plasma Silanes S.A. de (40-65y) (3) FDC (glimepiride/metformin) glucose C.V. Handok M/F (1) Metformin SDF NCT00612144[5] Korea 6 192 Unknown HbA1c level Pharmaceuticals (30-75y) (2) FDC (glimepiride/metformin) Co., Ltd. adiponectin M/F (1) FDC (glimepiride/metformin) NCT01204580[6] Indonesia 3 40 Completed (ADMA) Sanofi-Aventis (40-60y) (2) No comparator plasma level (1) FDC (brand 1) Handok M/F (glimepiride/metformin) patient NCT01444248[7] Korea 6 168 Completed Pharmaceuticals (18-75y) (2) FDC (brand 2) compliance (glimepiride/metformin) Co., Ltd. (1) FDC (dose 1) HbA1c level, Handok M/F (glimepiride/metformin) NCT00437554[8] Korea 4 188 Completed fasting plasma Pharmaceuticals (30-75y) (2) FDC (dose 2) (glimepiride/metformin) glucose Co., Ltd. HbA1c level, M/F (1) FDC (glimepiride/metformin) NCT01144728[9] Kazakhstan 4 172 Completed fasting plasma Sanofi-Aventis (35-75y) (2) No comparator glucose

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(1) Metformin SDF body weight, (2) FDC (dose 1) Services NCT01624116[10] Pakistan 1 161 M/F Completed (glimepiride/metformin) fructosamine Hospital, Lahore (3) FDC (dose 2) level (glimepiride/metformin) Lebanon, M/F (1) FDC (glimepiride/metformin) NCT01699932[11] Russia, 6 150 Recruiting HbA1c level Sanofi (≥18y) (2) No comparator Ukraine (1) FDC (dose 1) (glimepiride/metformin) (2) FDC (dose 2) (glimepiride/metformin) Abbott CTRI/2011/091/000266[ M/F India 6.5 104 Completed (3) FDC (dose 1) HbA1c level Healthcare Pvt 12]* (>18y) (glimepiride/pioglitazone/metf ormin) Ltd (4) FDC (dose 2) (glimepiride/pioglitazone/metf ormin) FDC COMPONENTS: GLIMEPIRIDE + PIOGLITAZONE + METFORMIN (1) FDC (dose 1) (glimepiride/pioglitazone/metf ormin) (2) FDC (dose 2) CTRI/2011/091/000266[ M/F Abbott India 6 104 Completed (glimepiride/pioglitazone/metf HbA1c level 12]* >18 ormin) Healthcare (3) FDC (dose 1) (glimepiride/metformin) (4) FDC (dose 2) (glimepiride/metformin) (1) FDC (glimepiride/pioglitazone/metf HbA1c level, CTRI/2011/09/002024[ M/F ormin) postprandial Abbott India 3 44 Completed 13] >18 (2) FDC plasma Healthcare (glimepiride/voglibose/metfor glucose min) CTRI/2011/06/001841[ M/F Abbott India 3 70 Suspended (1) Insulin + Metformin HbA1c level 14] >18 Healthcare

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(2) FDC (dose 1) (glimepiride/pioglitazone/metf ormin) (3) FDC (dose 2) (glimepiride/pioglitazone/metf ormin) FDC COMPONENTS: GLIPIZIDE + METFORMIN NONE FDC COMPONENTS: GLIBENCLAMIDE + METFORMIN (1) Metformin SDF United M/F Bristol-Myers NCT00035568[15] NR NR Completed (2) Glibenclamide SDF NR States 20-75 (3) FDC Squibb (glibenclamide/metformin) (1) Metformin + Genovate M/F NCT00541437[16] Taiwan NR 12 Completed Sulfonylurea NR Biotechnology 20-75 (2) FDC Co., Ltd. (glibenclamide/metformin) FDC COMPONENTS: GLICLAZIDE + METFOMRIN NONE * This trial is listed twice, under both glimepiride/metformin and glimepiride/pioglitazone/metformin as they compare the two treatments. NR=not reported

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Unpublished trials

Searches of the five clinical trial databases identified a total of 17 unpublished trials: glimepiride/metformin, 12; glimepiride/pioglitazone/metformin, 3; and glibenclamide/metformin, 2. No trials investigated glipizide/metformin or gliclazide/metformin. The NIH Clinical Trials database listed 2 studies of glibenclamide/metformin and 11 studies of glimepiride/metformin. The CTRI listed 1 clinical trial for glimepiride/metformin and 3 for glimepiride/pioglitazone/metformin. No additional trials were registered of the other combinations of interest in our review. Subsequent searches of the WHO International Clinical Trials Registry Platform, the UK Clinical Research

Network/ISRCTN and the EU Clinical Trials Register found no additional relevant trials.

Description of comparator arms in unpublished trials worldwide and in India

Of the 17 unpublished trials of metformin FDCs in diabetic patients: 13 examined glimepiride/metformin; five, glimepiride/pioglitazone/metformin; two, glibenclamide/metformin; none, glipizide/metformin. In India, there were three unpublished clinical trials of metformin FDCs on Type 2 diabetes patients. All three unpublished trials of this FDC were conducted by Abbott Healthcare in 44, 70, and 104 patients with Type 2 diabetes with a study duration of 3-6 months[12–14].

Evaluation of the 17 unpublished clinical trials against WHO FDC criteria (Table S7)

No trial results were posted on any of the clinical trial databases. Eight trials compared the

FDC to SDF monotherapy; none investigated concomitant SDF treatments (Table S7). None of the trials met the WHO criteria of several hundred patients or duration greater than six months. Most trials listed change in HbA1c level as the primary outcome; four trials listed

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other primary outcome measures in the trial protocol. The only study not conducted by a pharmaceutical company was a four-week study of 161 patients with Type 2 diabetes during

Ramadan in Pakistan. It compared a glimepiride/metformin FDC with a sitagliptin/metformin

FDC[10]. Of 12 glimepiride/metformin FDC trials, six were conducted in Asia (China, Japan,

Korea (3), Indonesia), two in Mexico, one in India, one in Pakistan, one in Kazakhstan, and one in Lebanon/Russia. The three trials that evaluated triple combination therapy

(glimepiride/pioglitazone/metformin) were all conducted in India[12–14]. Two trials compared different doses of glimepiride in the triple combination while the third compared the triple FDC to another triple FDC (glimepiride/voglibose/metformin). The two trials on glibenclamide/metformin were conducted in the United States and Taiwan, respectively[15,16]. The former compared the FDC to monotherapy (metformin or glibenclamide) and the latter FDC after concomitant treatment with a sulfonylurea plus metformin.

Involvement of multinational corporations (MNCs) and country of study

Of the 17 unpublished trials, only the Pakistan study was not conducted by a pharmaceutical company[10]. Sanofi-Aventis conducted five unpublished trials on the glimepiride

FDC[1,2,6,9,11]. Abbott Healthcare conducted three of the unpublished trials in India[12–14] investigating the triple combination FDC.

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Table S4. Trials listed on USA and India clinical trials registries for metformin FDC clinical trials conducted on patients with Type 2 Diabetes.

Clinical Study Design Start/End Status Interventions N Sex Phase Sponsor Location Trials ID No. Age (other) FDC COMPONENTS: GLIMEPIRIDE + METFORMIN NCT01457911 Evaluation of fixed dose randomized Oct 2011 - recruiting (1) glimepiride/metformin 240 M/F 3 Sanofi- China combination of parallel group Apr 2013 FDC (Amaryl M; 18-80y Aventis glimepiride and metformin open-label 1mg/250mg) in Chinese type 2 diabetes efficacy (2) glimepiride (Amaryl) patients inadequately controlled with metformin NCT00924573 Comparative study of randomized May 2009 completed (1) glimepiride/metformin 189 M/F 3 Sanofi- Japan HOE490 O (glimepiride parallel group - Mar 2010 (results on FDC (HOE490 O) 20-74y Aventis and metformin) compared double-blind corporate (2) glimepiride + placebo with placebo on top of efficacy website) glimepiride NCT01429818 Endothelial disfunction randomized Jul 2007 - completed (1) glimepiride/metformin 16 M/F 4 Laborato Mexico treatment with parallel group Jan 2008 FDC (Glimetal; ≥18y rios gimepiride/metformin double-blind 4mg/100mg) Silanes combination (Glimetal) in efficacy (2) metformin (Predial; S.A. de type 2 diabetes patients 100mg) C.V. NCT00941161 Effect of oral combination randomized Feb 2009 - completed (1) glimepride/metformin 28 M/F 4 Laborato Mexico therapy in a single dosage parallel group May 2010 long-acting FDC 40-65y rios form in patients with type double-blind (1g/2mg) Silanes 2 diabetes mellitus safety/ (2) metformin long acting S.A. de efficacy (1g) C.V. (3) glimepiride (2mg) NCT00612144 Study comparing efficacy randomized Dec 2007 - unknown (1) glimepiride/metformin 192 M/F 4 Handok Korea and safety of Amaryl M parallel group Mar 2009 FDC (Amaryl M) 30-75y Pharmac and metformin uptitraion open-label (2) metformin euticals to type 2 dm safety/ Co., Ltd. efficacy

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NCT01204580 ADIponectin and randomized Dec 2010 - completed (1) glimepiride/metformin 40 M/F 4 Sanofi- Indonesia asymmetric single group Mar 2012 FDC (Amaryl-M) 40-60y Aventis dimethylarginine (ADMA) open-label level in type-2 diabetes safety/ patients after 12 weeks of efficacy treatment with glimepiride and metformin fixed dose combination NCT01444248 Compare the compliance randomized Aug 2010 - completed (1) glimepiride/metformin 168 M/F 4 Handok Korea of patients treated with parallel group Dec 2011 FDC (Amaryl MEX; 18-75y Pharmac once-daily (od) or twice- open-label 4mg/1000mg) euticals daily (bid) glimepiride and safety/ (2) glimepiride/metformin Co., Ltd. metformin fixed efficacy FDC (Amaryl M; combination therapy 4mg/1000mg) NCT00437554 Phase III study for randomized Aug 2006 - completed (1) glimepiride + metformin 188 M/F 3 Handok Korea glimepiride + metformin parallel group Jul 2007 FDC (Amaryl M; 30-75y Pharmac hydrochloride (Amaryl M) double-blind 1mg/250 mg) euticals slow release (SR) safety/ (2) glimepiride + metformin Co., Ltd. efficacy FDC (Amaryl M SR; 2mg/500 mg) NCT01144728 Initiation and titration of single group May 2010 completed (1) glimepiride/metformin 172 M/F 4 Sanofi- Kazakhstan Amaryl open-label - Dec 2010 FDC 35-75y Aventis safety/ efficacy NCT01624116 Comparison of randomized Aug 2011 - completed (1) diet and lifestyle 161 M/F not Services Pakistan hypoglycaemic regimens parallel group Sep 2011 measures listed Hospital, during Ramadan fasting in open-label (2) metformin Lahore type 2 diabetes safety/ (3) glimepiride/metformin efficacy FDC (1mg/500mg) (4) sitagliptin/metformin FDC (50mg/500mg) NCT01699932 Efficacy and dafety of the non- Sep 2012 - recruiting (1) glimepiride/metformin 150 M/F 3 Sanofi Lebanon, (GLMET_R_0 fixed dose combination of randomized Mar 2014 FDC (Amaryl M®, ≥18y Russian 5823, U1111- glimepiride+metformin in single group HOE4900) Federation 1120-0058) type 2 diabetic patients open-label inadequately controlled efficacy

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CTRI/2011/09 A clinical trial to study the randomized Dec 2010 - completed (1) glimepiride/metformin 104 M/F 4 Abbott India 1/000266 effects of fixed dose open-label unknown SR FDC (1mg/500mg) >18y Healthca (TRIED 3- combination of multicentric (2) glimepiride/metformin re Pvt AHPL/06/10) glimepiride + metformin comparative SR FDC (2mg/500mg) Ltd SR + poglitazone vs fixed safety/ (3) glimepiride/pioglitazone dose combination of efficacy /metformin SR FDC glimepiride + metformin (1mg/15mg/500mg) SR in treatment of patients (4) glimepiride/pioglitazone with type 2 diabetes /metformin SR FDC inadequately controlled (2mg/15mg/1500mg) with monotherapy of either glimepiride or metformin plain/SR formulation FDC COMPONENTS: GLIMEPIRIDE + PIOGLITAZONE + METFORMIN CTRI/2011/09 A clinical trial to study the randomized Dec 2010 - completed (1) glimepiride/metformin 104 M/F 4 Abbott India 1/000266 effects of fixed dose open-label unknown SR FDC (1mg/500mg) >18y Healthca (TRIED 3- combination of multicentric (2) glimepiride/metformin re Pvt AHPL/06/10) glimepiride + metformin comparative SR FDC (2mg/500mg) Ltd SR + poglitazone vs fixed safety/ (3) glimepiride/pioglitazone dose combination of efficacy /metformin SR FDC glimepiride + metformin (1mg/15mg/500mg) SR in treatment of patients (4) glimepiride/pioglitazone with type 2 diabetes /metformin SR FDC inadequately controlled (2mg/15mg/1500mg) with monotherapy of either glimepiride or metformin plain/SR formulation CTRI/2011/09 To compare the safety and randomized Sep 2011 - completed (1) glimepiride/pioglitazone 44 M/F 4 Abbott India /002024 efficacy of two parallel group unknown /metformin SR >18y Healthca (VOGLIMET/ antidiabetic drugs in open-label (1mg/15mg/500mg) re Pvt APHL/01/11) treatment of patients with safety/efficacy (2) glimepiride/voglibose/m Ltd type II diabetes etformin SR (1mg/0.3mg/500mg)

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CTRI/2011/06 This study is done to randomized Jul 2011 - suspended (1) insulin 70/30 + 70 M/F not Abbott India /001841 assess effectiveness and parallel group unknown metformin >18y listed India (SCARC/2011 safety study of a three open-label (2) glimepiride/pioglitazone Limited /02) drug combination with a single centre /metformin SR two drug combination for safety/efficacy (1mg/15mg/500mg) the treatment of type 2 (3) glimepiride/pioglitazone diabetes mellitus in /metformin SR patients who have never (2mg/15mg/500mg) reveived insulin FDC COMPONENTS: GLIPIZIDE + METFORMIN NONE FDC COMPONENTS: GLIBENCLAMIDE + METFORMIN NCT00035568 A research study to assess interventional Feb 2002 - completed (1) glyburide/metformin M&F 4 Bristol- United (CV138-062) the mechanism by which Jun 2003 FDC (Glucovance) 20-75y Myers States glucovance, metformin, (2) metformin Squibb and glyburide work to (3) glyburide control glucose levels in patients with type 2 diabetes NCT00541437 Type 2 diabetes patients prospective May 2006 completed (1) switched from 12 M&F not Genovate Taiwan (GBL L-13) switched from sulfonylurea + 20-75y listed Biotechn sulfonylurea with metformin to ology metformin to glyburide/metformin Co., Ltd. glyburide/metformin FDC (GlucoMet®) combination tablet FDC COMPONENTS: GLICLAZIDE + METFORMIN NONE N=participants recruited; NCT=Clinical Trials Registry USA; CTRI=Clinical Trials Registry of India; LA=long-acting; SR=slow release; ER=extended release; PR=prolonged release

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Additional References (unpublished trials)

1 Abbott Healthcare Pvt., Ltd. A clinical trial to study the effects of fixed dose combinations of glimepiride + metformin SR + pioglitazone vs fixed dose combination of glimepiride + metformin SR in treatment of patients with Type 2 diabetes inadequately controlled with monotherapy of either glimepiride or metformin plain/SR formulation (CTRI/2011/091/000266) In: Clinical Trials Registry - India [Internet]. New Delhi: National Institute of Medical Statistics (India). 1980-2013. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=2774 (accessed April 2013). 2 Abbott Healthcare Pvt., Ltd. To compare the safety and efficacy of two antidiabetic drugs in treatment of patients with Type II diabetes (CTRI/2011/09/002024). In: Clinical Trials Registry - India [Internet]. New Delhi: National Institute of Medical Statistics (India). 1980-2013. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=3494 (accessed April 2013). 3 Abbott India Limited. This study is done to access effectiveness and safety study of a three drug combination with a two drug combination for the treatment of Type 2 diabetes mellitus in patients who have never received insulin (CTRI/2011/06/001841). In: Clinical Trials Registry - India [Internet]. New Delhi: National Institute of Medical Statistics (India). 1980-2013. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=2755 (accessed April 2013). 4 Services Hospital, Lahore. Comparison of hypoglycaemic regimens during Ramadan fasting in Type 2 diabetes (NCT01624116). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 1980-2013. http://clinicaltrials.gov/show/NCT01624116 (accessed April 2013). 5 Bristol-Myers Squibb. A research study to access the mechanism by which glucovance, metformin, and glyburide work to control glucose levels in patients with Type 2 diabetes (NCT00035568). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 1980-2013. http://clinicaltrials.gov/show/NCT00035568 (accessed April 2013). 6 Genovate Biotechnology Co., Ltd. Type 2 diabetes patients switched from sulfonylurea with metformin to glyburide/metformin combination tablet (NCT00541437). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 1980-2013. http://clinicaltrials.gov/show/NCT00541437 (accessed April 2013). 7 Sanofi. Evaluation of fixed dose combination of glimepiride and metformin in Chinese Type 2 diabetes patients inadequately controlled with metformin (NCT01457911). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 1980-2013. http://clinicaltrials.gov/show/NCT01457911 (accessed April 2013). 8 Sanofi. Comparative study of HOE490 O (glimepiride and metformin) compared with placebo on top of glimepiride (NCT00924573). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 1980-2013. http://clinicaltrials.gov/show/NCT00924573 (accessed April 2013). 9 Sanofi. ADIponectin and asymmetric dimethylarginine (ADMA) level in Type-2 diabetes patients after 12 weeks of treatment with glimepiride and metformin fixed dose combination (DIAGRAM) (NCT01204580). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 1980-2013. http://clinicaltrials.gov/show/NCT01204580 (accessed April 2013).

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10 Sanofi. Initiation and titration of Amaryl (AMIT KZ) (NCT01144728). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 1980-2013. http://clinicaltrials.gov/show/NCT01144728 (accessed April 2013). 11 Sanofi. Efficacy and safety of the fixed dose combination of glimepiride+metformin in Type 2 diabetic patients inadequately controlled (LEGEND) (NCT01699932). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 1980-2013. http://clinicaltrials.gov/show/NCT01699932 (accessed April 2013). 12 Laboratorios Silanes S.A. de C.V. Endothelial dysfunction treatment with glimepiride/metfomrin combination (Glimetal) in Type 2 diabetes patients (NCT01429818). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 1980-2013. http://clinicaltrials.gov/show/NCT01429818 (accessed April 2013). 13 Laboratorios Silanes S.A. de C.V. Effect of oral combination therapy in a single dosage form in patients with Type 2 diabetes mellitus (NCT00941161). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 1980-2013. http://clinicaltrials.gov/show/NCT00941161 (accessed April 2013). 14 Handok Pharmaceuticals Co., Ltd. Compare the compliance of patients treated with once-daily (od) or twice-daily (bid) glimepiride and metformin fixed dose combination therapy (NCT01444248). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 1980-2013. http://clinicaltrials.gov/show/NCT01444248 (accessed April 2013). 15 Handok Pharmaceuticals Co., Ltd. Study comparing efficacy and safety of Amaryl M and metformin uptitration to Type 2 DM (NCT00612144). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 1980-2013. http://clinicaltrials.gov/show/NCT00612144 (accessed April 2013). 16 Handok Pharmaceuticals Co., Ltd. Phase III study for glimepiride + metformin hydrochloride (Amaryl M) slow relsease (SR) (NCT00437554). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 1980-2013. http://clinicaltrials.gov/show/NCT00437554 (accessed April 2013).

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