Last updated on July 2019

Study to Evaluate Safety and Efficacy of Dapagliflozin and Saxagliptin in Patients With Type 2 Diabetes Mellitus Aged 10 to Below 18 Years Old


Brief description of study

The purpose of this research study is to evaluate the efficacy and safety of the drugs dapagliflozin and saxagliptin in patients with Type 2 Diabetes who are aged 10 to below 18 years old and are currently taking metformin, insulin, or both drugs.

Dapagliflozin and saxagliptin are both approved for use in patients with Type 2 Diabetes aged 18 years or older. This study will assess how well dapagliflozin and saxagliptin work by finding out how these treatments affect blood glucose (sugar) levels compared to placebo (a pill that contains no active drug), in children and adolescents. Dapagliflozin and saxagliptin are considered investigational products in this study since while they have been approved for use in adults (patients 18 years or older), they haven't been approved for children and adolescents due to lack of clinical studies in this specific population.

Patients with Type 2 Diabetes have higher levels of blood glucose (sugar) than patients who do not have this disease. The high level of sugar in the blood can lead to serious short-term and long-term medical problems. The main goal of treating diabetic patients is to lower blood glucose to a normal level. Lowering and controlling blood glucose help prevent or delay complications of diabetes, such as heart disease, kidney, eye and nerve diseases, and the possibility of amputation.

Dapagliflozin is a drug that helps to reduce blood glucose (sugar) levels by helping the kidneys to remove excess glucose from the blood and excrete it in the urine. It prevents the kidneys from returning glucose from the urine back into the bloodstream.

Saxagliptin increases insulin production when blood glucose levels are high. Insulin is a hormone made by the pancreas that allows the body to use sugar (glucose) from the food that is eaten for energy or to store glucose for future use. Saxagliptin helps to improve blood sugar levels in response to a meal and between meals if blood glucose levels are not lowered effectively. Saxagliptin does not work when the blood glucose is low. Saxagliptin also helps to decrease the amount of sugar made by the body. Together, these processes reduce blood glucose levels and help to control Type 2 Diabetes.

Dapagliflozin (alone or in combination with other antidiabetic drugs) has been shown to be effective in lowering blood glucose in adults with Type 2 Diabetes and is available for use in adults (patients 18 years or older) in approximately 40 countries worldwide including the USA and Europe. Dapagliflozin has not yet been studied in children (pediatric patients).

Saxagliptin (alone or in combination with other antidiabetic drugs) has been shown to be effective in lowering blood glucose in adults with Type 2 Diabetes and is available for use in adults (patients 18 years or older) in approximately 90 countries worldwide. Saxagliptin also has not yet been studied in children (pediatric patients).

The subject will either receive one of the active study drugs or a placebo (a pill that looks identical but contains inactive drug). This study will be double blind; this means that neither the subject, nor the study doctor will know which treatment the subject will receive.

Which treatment the subject receives is decided by a computer, purely by chance; this is called a "random assignment".

For this study, there will first be a screening phase of up to 6 weeks, followed by a 2 week lead in phase. Thereafter there will be a 26 week short-term treatment phase (week 1-week 26), and a 26 week long-term treatment phase (week 27-week 52). Following this there will be a follow-up telephone call on week 56 and a post study visit at week 104.

At day 1 visit after the lead in phase the subject will be randomly assigned to receive one of 3 treatments: dapagliflozin 5 mg, saxagliptin 2.5 mg or placebo in a blinded manner. This treatment will continue up to week 14. Then after week 14, and until the end of the study, the subject will be assigned to receive one of the following 5 treatments: dapagliflozin 5 mg, dapagliflozin 10 mg, saxagliptin 2.5 mg, saxagliptin 5 mg or placebo in a blinded manner. The drugs assigned after week 14 will be the same drugs as at Day 1, but some of the groups will receive them at a higher dose.

After completion of the 26-week short-term phase, the subject will enter a 26 week long-term phase. The same treatment that the subject had been assigned to at week 14 visit will be continued. This long-term phase is primarily designed to provide additional information on how well dapagliflozin and saxagliptin are tolerated.

Following the treatment phases, there will be a follow-up telephone call at week 56.

The subject will be asked to visit the clinic at week 104 again for a final evaluation of the physical development (based on the stage of puberty).

Detailed Study Description

In pediatric Type 2 Diabetes Mellitus (T2DM) subjects on diet and exercise and metformin, or insulin, or metformin and insulin:

The primary research hypothesis for dapagliflozin is whether addition of dapagliflozin, including up-titration if needed, results in a greater mean reduction from baseline in glycosylated hemoglobin (HbA1c) as compared to placebo when each are administered over 26 weeks of oral double-blind add-on treatment.

The primary research hypothesis for saxagliptin is whether addition of saxagliptin, including up-titration if needed, results in a greater mean reduction from baseline in HbA1c as compared to placebo when each are administered over 26 weeks of oral double-blind add-on treatment.

Study Design: The proposed study is a 26-week Phase 3b, multicenter, randomized, placebo-controlled, double-blind, parallel group study with a 26-week safety extension period to evaluate the safety and efficacy of dapagliflozin (5 mg and 10 mg), and, separately, saxagliptin (2.5 mg and 5 mg) in pediatric subjects with T2DM, and an additional post study visit at Week 104 for assessment of measures of growth and maturity. Approximately 243 pediatric subjects will be randomized in a 1:1:1 ratio to receive dapagliflozin 5 mg, saxagliptin 2.5 mg, or placebo. Approximately 81 subjects will be randomized to each treatment arm.

After a 26-week, double-blind, ST treatment period, the primary efficacy endpoint will be assessed. This will be followed by a 26-week, site- and subject-blind LT safety extension period. Dapagliflozin and, separately, saxagliptin will be compared against the single shared placebo comparator.

Measures of growth and maturity will be assessed at the Week 104 post study visit.

Subjects will be required to have been treated with diet and exercise and a stable dose of at least 1000 mg metformin (IR or XR) for a minimum of 8 weeks, or a stable baseline dose of insulin for a minimum of 8 weeks, or a stable combination of at least 1000 mg metformin and insulin for a minimum of 8 weeks prior to randomization. At least 50% of subjects will be on a stable baseline dose of metformin, with or without concurrent insulin therapy. At least 30% of total subjects will be between the ages of 10 and 14 years and at least one third, but no more than two thirds, female subjects.

During the 2-week lead-in period, subjects will be instructed on a diet and exercise program (in accordance with the American Diabetes Association [ADA] or similar local guidelines) to be followed for the study duration. Subjects will maintain their baseline types and/or doses of antidiabetic therapy throughout the study (2-week lead-in, 26-week double-blind ST treatment period, and the 26-week blinded safety extension LT treatment period). If applicable, investigators will encourage subjects to keep their insulin doses stable. Down-titration of insulin will be allowed only as necessary to prevent hypoglycemia and will be at the discretion of the Investigator. Home glucose meters to monitor glucose control will be dispensed to subjects and self-blood glucose monitoring (SBGM) requirements and procedures will be explained. Subjects will also be instructed on the use of the subject diary to record self-monitored glucose levels and daily insulin dose, if applicable. Subjects will also receive a blood ketone meter for testing when DKA is suspected.

After the lead-in period, eligible subjects with HbA1c of 6.5% to 10.5% at screening will be randomized 1:1:1 to receive oral, double-blind, dapagliflozin 5 mg (approximately 81 subjects), saxagliptin 2.5 mg (approximately 81 subjects), or placebo (approximately 81 subjects). Randomization will be stratified based on baseline anti-diabetes treatment regimen (stable baseline dose of metformin (IR or XR), a stable baseline dose of insulin, or a stable combination of metformin and insulin), gender, and age (10 to below 15 years of age, 15 to below 18 years of age).

A blinded HbA1c assessment will be performed at Week 12. All subjects with Week 12 HbA1c values < 7% will remain on previously assigned randomized treatment (dapagliflozin 5 mg, or saxagliptin 2.5 mg, or placebo) after the Week 12 assessment. Subjects assigned to the dapagliflozin treatment arm at Day 1 Randomization with Week 12 HbA1c values >= 7% will be re-randomized in a 1:1 ratio to continue on the low-dose treatment (dapagliflozin 5 mg) or up-titrate to the high-dose treatment (dapagliflozin 10 mg) after the Week 12 assessment. Similarly, subjects assigned to the saxagliptin treatment arm at Day 1 Randomization with Week 12 HbA1c values >= 7% will be re randomized in a 1:1 ratio to continue on the low-dose treatment (saxagliptin 2.5 mg) or up-titrate to the high-dose treatment (saxagliptin 5 mg) after the Week 12 assessment. Subjects assigned to the placebo treatment arm at Day 1 Randomization with Week 12 HbA1c values >= 7% will continue on placebo treatment. To maintain the blinding of treatments as well as HbA1c results, all placebo subjects and all subjects taking saxagliptin or dapagliflozin with an HbA1c < 7% at week 12 will go through a dummy 2nd randomization process that will be indistinguishable (for the subjects and site personnel) from the actual 2nd randomization. During the Week 14 visit, blinded study drug will be dispensed to all subjects in accordance with new treatment assignments based on Week 12 HbA1c assessments.

After completion of the ST treatment period, all subjects will enter the LT treatment period. All subjects, including those randomized to receive placebo, will continue with their randomized study medication assigned after the Week 12 assessment in the site- and subject blind LT treatment period. Adverse events (AEs) and serious adverse events (SAEs) will be assessed during a Week 56 phone visit.

Subjects who discontinue study drug before the end of the study treatment period will enter a non-treatment, follow up phase, in which subjects will follow their visit schedules with modified assessments until study completion. Subjects will attend a post-study visit at Week 104, for assessment of measures of growth and maturity.

Discontinued subjects will not be replaced. Samples for analysis of plasma levels of dapagliflozin, saxagliptin and its metabolite 5-Hydroxy saxagliptin (5 OH saxagliptin) will be collected pre-dose and approximately 2 hours post-dose (+/- 1 hour) during the Week 6, 12, 20, and 26 visits.

Samples for analysis of plasma glucose will be collected pre-dose during the Day 1 visit, and pre-dose and approximately 2 hours post-dose (+/- 1 hour) during the Week 6, 12, 20, and 26 visits.

Plasma samples for analysis of dipeptidyl peptidase-4 (DPP-4) activity will be collected pre-dose during the Day 1 visit, and at 2 (+/-1) hours post-dose during the Week 6, 12, 20, and 26 visits.

All plasma samples will be drawn in the fasting condition. During the course of the trial, subjects may be eligible for the addition of open-label rescue medication to their blinded treatment regimen in order to treat ongoing hyperglycemia. Insulin may be used as rescue, at the Investigator's discretion.

Pre-specified glycemic criteria, based upon self-monitored blood glucose (SMBG) FPG, or single central laboratory FPG and repeat confirmatory FPG have been established during the treatment period, starting at Week 6, and up to but not including the Week 52 visit, to determine eligibility for open-label rescue medication.

Sample Size:

The sample size for this study was selected to be consistent with the research hypotheses.

Dapagliflozin and saxagliptin will be compared with placebo separately. The Bonferroni method to control the type 1 error rate across two comparisons with respect to the two groups of research hypotheses (dapagliflozin vs placebo and saxagliptin vs placebo) will be used. No comparisons between saxagliptin and dapagliflozin will be performed.

The sample size for this study is based on the ability to detect a 0.5% improvement over placebo for dapagliflozin and saxagliptin in change from baseline in HbA1c at Week 26 (ST) with at least 80% power for each comparison at a two sided alpha level of 0.025. Assuming a standard deviation of 0.9% for change from baseline HbA1c at Week 26, a total of 237 pediatric subjects will be randomized in a 1:1:1 ratio to receive dapagliflozin 5 mg (79 subjects), saxagliptin 2.5 mg (79 subjects), or placebo (79 subjects) respectively. Assuming that 2% of subjects do not have a baseline and at least one post-baseline assessment, a total of approximately 243 subjects will be randomized. Randomization will be stratified based on the baseline anti-diabetic treatment regimen (stable baseline dose of metformin [IR or XR]), a stable baseline dose of insulin, or a stable combination of metformin [IR or XR] and insulin), gender, and age (10 to below 15 years of age, 15 to below 18 years of age).

The anticipated difference of 0.5% between each study drug (saxagliptin and dapagliflozin) and placebo used in sample size estimation is consistent with estimates that were obtained in adult clinical trials with saxagliptin or dapagliflozin as add on to anti-diabetic medication where the primary endpoint was improvement in HbA1c after 24 weeks treatment. The standard deviation estimate of 0.9% is consistent with estimates obtained in these adult studies as well as with published estimates from pediatric trials of other anti-diabetic medications.

Analyses

Dapagliflozin and saxagliptin will be summarized separately. A common placebo group will be included in each summary.

In addition, within the analyses of saxagliptin, the overall (combined low-dose and high-dose) efficacy and safety analyses will be repeated for the subgroup of subjects on a stable baseline dose of metformin (IR or XR) (with or without insulin). For these analyses, the saxagliptin treatment regimens will be combined into one group and compared to the (common) placebo group. P values corresponding to subgroup comparisons will be reported for the primary and secondary efficacy endpoints, and will be reported at the nominal significance level.

All efficacy analyses will be performed using the Randomized Subjects Data Set (all randomized subjects who receive at least one dose of study medication during the treatment period) unless otherwise specified.

The following treatment regimens are considered for analysis:

  • Low-dose/high-dose: Initial treatment of the low-dose followed by up-titrating to the high-dose for those who do not achieve the glycemic target of HbA1c <7% at week 12
  • Low-dose: Initial treatment of the low-dose followed by continuing treatment on the low-dose drug for those who do not achieve the glycemic target of HbA1c <7% at week 12 For each drug, the primary comparison between the low-dose/high-dose and placebo regimens will be tested at a two sided alpha level of 0.025.

The primary efficacy analysis will be performed using a weighted analysis of covariance (ANCOVA). Separate models will be used for saxagliptin and dapagliflozin analyses, and each analysis will include the (common) placebo control. Each model will have terms for baseline value, treatment group, and randomization strata.

For the comparison of the low-dose/high-dose treatment regimen versus placebo, all subjects who had HbA1c<7% at Week 12 and remained on the low-dose will get a weight of one. The subjects who had HbA1c >= 7% at Week 12 and continued on the low-dose will get a weight of 0. The subjects who had HbA1c>= 7% at Week 12 and received the high-dose will have a weight of 2. The subjects who withdrew from the study entirely before the second randomization and all placebo subjects will get a weight of one.

The intent-to-treat (ITT) estimand will be evaluated as the primary estimand. Missing values for Week 26 will be imputed using the multiple imputation method. The details of the imputation method will be presented in the statistical analysis plan. Point estimates and 95% confidence intervals will be calculated based on maximum likelihood for the adjusted mean changes within each treatment group as well as for the differences in adjusted mean changes between treatment groups.

To assess the robustness of the primary efficacy analysis for the change in HbA1c from baseline to Week 26, additional sensitivity analysis may be performed using the Evaluable Subjects Data Set if > 10% of the subjects in any treatment group in the Randomized Subjects Data Set have relevant protocol deviations.

The primary endpoint will also be compared between the low-dose treatment regimen and placebo. In addition, up titrating to high-dose and continuing on low-dose will be compared in the subset of saxagliptin and dapagliflozin subjects who had HbA1c >= 7% at Week 12. These analyses are described under secondary efficacy analyses.

Secondary efficacy analyses will also be performed separately for each drug (saxagliptin and dapagliflozin). For each drug, the following sequential testing order will be employed to control multiplicity of testing for the secondary objectives.

  1. Comparison of mean reduction in HbA1c from baseline at Week 26 between the low-dose treatment regimen and placebo
  2. Comparison of mean reduction in HbA1c from baseline at Week 26 between overall drug treatment and placebo
  3. Comparison of mean reduction in FPG from baseline at Week 26 between the low dose/high-dose treatment regimen and placebo
  4. Comparison of mean reduction in FPG from baseline at Week 26 between the low-dose treatment regimen and placebo
  5. Comparison of mean reduction in FPG from baseline at Week 26 between overall drug treatment and placebo
  6. Comparison of the percentage of subjects with baseline HbA1c>= 7% who achieve an HbA1c level < 7.0% at Week 26 between the low-dose/high-dose treatment regimen and placebo
  7. Comparison of the percentage of subjects with baseline HbA1c >= 7% who achieve an HbA1c level < 7.0% at Week 26 between the low-dose treatment regimen and placebo
  8. Comparison of the percentage of subjects with baseline HbA1c >= 7% who achieve an HbA1c level < 7.0% at Week 26 between overall drug treatment and placebo
  9. Comparison of mean reduction in HbA1c from baseline at Week 26 between the high dose and the low-dose in subjects who do not achieve an HbA1c < 7% at Week 12
  10. Comparison of mean reduction in FPG from baseline at Week 26 between the high dose and the low-dose in subjects who do not achieve an HbA1c < 7% at Week 12
  11. Comparison of the percentage of subjects with baseline HbA1c >= 7% who achieve an HbA1c level < 7.0% at Week 26 between the high-dose and the low-dose in subjects who do not achieve an HbA1c < 7% at Week 12 When the sequential testing stops for non-significance, nominal p-values and adjusted means will be provided for the remaining comparisons.

For each drug, weighted ANCOVA analysis will be performed for the change from baseline in HbA1c at Week 26 to compare the placebo and the low-dose treatment regimen. For this analysis, all subjects who had HbA1c < 7% at Week 12 and remained on the low-dose will get a weight of one. The subjects who had HbA1c >= 7% at Week 12 and continued on the low-dose will get a weight of 2. The subjects who had HbA1c >= 7% at Week 12 and received the high-dose will have a weight of 0. The subjects who withdrew from the study entirely before the second randomization and all placebo subjects will get a weight of one.

For subjects on saxagliptin and dapagliflozin and who had HbA1c >= 7% at Week 12, the change from baseline HbA1c at Week 26 (ST) will be compared between the subjects re-randomized to remain on the low-dose and the subjects who are re-randomized to the high- dose using an ANCOVA.

Change from baseline of HbA1c at Week 26 (ST) will be compared also using a repeated measures analysis between overall drug and placebo. For this analysis, both treatment regimens will be combined into one treatment group for each drug.

Change from baseline at Week 26 (ST) in FPG will be analyzed similar to the primary weighted analyses of change from baseline in HbA1c at Week 26.

The proportion of subjects achieving HbA1c < 7.0% at Week 26 (ST) will be analyzed using weighted logistic regression with adjustment for the baseline HbA1c measurement and the randomization strata. Weighting for the subjects will be applied similarly to a weighting in the analysis of change from baseline in HbA1c. Subjects with missing a response at Week 26 will be imputed by dichotomizing the imputed values of HbA1c at Week 26.

The assessment of safety will be based on the analyses of AEs, vital signs, physical examinations, electrocardiograms, hypoglycemia, DKA, safety laboratory evaluations, and measures of growth and maturity. All safety analyses will be performed using the Treated Subjects Data Set. Dapagliflozin and saxagliptin will be summarized separately. Treatment regimens (low-dose or low-dose/high-dose) will be combined for saxagliptin and dapagliflozin to provide the safety summary for overall saxagliptin and overall dapagliflozin compared to placebo. A common placebo group will be included in each summary.

Measures of growth, bone and maturation markers will also be summarized for the combined ST + LT + additional post study visit at Week 104.

Monitoring The Sponsor/designee representatives will review data centrally to identify potential issues to determine a schedule of on-site visits for targeted review of study records.

Representatives of the Sponsor (or designee) must be allowed to visit all study site locations periodically to assess the data quality and study integrity. On site they will review study records and directly compare them with source documents, discuss the conduct of the study with the Investigator, and verify that the facilities remain acceptable.

In addition, the study may be evaluated by the Sponsor (or designee) internal auditors and government inspectors who must be allowed access to Case Report Forms (CRFs), source documents, other study files, and study facilities. The Sponsor (or designee) audit reports will be kept confidential.

The investigator must notify the Sponsor (or designee) promptly of any inspections scheduled by regulatory authorities, and promptly forward copies of inspection reports to the Sponsor/designee.

Records Retention The investigator must retain all study records and source documents for the maximum period required by applicable regulations and guidelines, or institution procedures, or for the period specified by the Sponsor/designee, whichever is longer. The investigator must contact the Sponsor/designee prior to destroying any records associated with the study.

The Sponsor/designee will notify the Investigator when the study records are no longer needed.

If the Investigator withdraws from the study (e.g., relocation, retirement), the records shall be transferred to a mutually agreed upon designee (e.g., another investigator, IRB). Notice of such transfer will be given in writing to the Sponsor/designee.

Study Drug Records

It is the responsibility of the Investigator to ensure that a current disposition record of study drug (inventoried and dispensed) is maintained at the study site to include Investigational Products (IPs). Records or logs must comply with applicable regulations and guidelines and should include:

  • Amount received and placed in storage area
  • Amount currently in storage area
  • Label identification number or batch number
  • Amount dispensed to and returned by each subject, including unique subject identifiers
  • Amount transferred to another area/site for dispensing or storage
  • Non study disposition (e.g., lost, wasted)
  • Amount destroyed at study site, if applicable
  • Amount returned to the Sponsor/designee
  • Retain samples for bioavailability/bioequivalence, if applicable
  • Dates and initials of person responsible for IP dispensing/accountability, as per the Delegation of Authority Form The Sponsor/designee will provide forms to facilitate inventory control if the investigational site does not have an established system that meets these requirements.

Case Report Forms An investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the investigation on each individual treated or entered as a control in the investigation. Data that are derived from source documents and reported on the CRF must be consistent with the source documents or the discrepancies must be explained. Additional clinical information may be collected and analyzed in an effort to enhance understanding of product safety. Case report forms may be requested for AEs and/or laboratory abnormalities that are reported or identified during the course of the study.

For sites using the Sponsor/designee's Electronic Data Capture (EDC) tool, electronic CRFs will be prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will be reported on the electronic SAE form and Pregnancy Surveillance Form, respectively. If electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank only in those circumstances permitted by study-specific CRF completion guidelines provided by the Sponsor/designee.

The confidentiality of records that could identify subjects must be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).

The investigator will maintain a signature sheet to document signatures and initials of all persons authorized to make entries and/or corrections on CRFs.

The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the Investigator or qualified physician who is a co-investigator and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review and approval/signature is completed electronically through the Sponsor/designee's EDC tool. The investigator must retain a copy of the CRFs including records of the changes and corrections.

Each individual electronically signing electronic CRFs must meet Sponsor/designee training requirements and must only access the Sponsor/designee's EDC tool using the unique user account provided by the Sponsor/designee. User accounts are not to be shared or reassigned to other individuals.

Clinical Study Identifier: NCT03199053

Find a site near you

Start Over

Research Site

Saraland, AL United States
  Connect »

Research Site

Huntington Park, CA United States
  Connect »

Research Site

Long Beach, CA United States
  Connect »

Research Site

Sacramento, CA United States
  Connect »

Research Site

Washington, WA United States
  Connect »

Research Site

Doral, FL United States
  Connect »

Research Site

Hialeah, FL United States
  Connect »

Research Site

Miami, FL United States
  Connect »

Research Site

Pembroke Pines, FL United States
  Connect »

Research Site

Spring Hill, FL United States
  Connect »

Research Site

Atlanta, GA United States
  Connect »

Research Site

Norcross, GA United States
  Connect »

Research Site

Stockbridge, GA United States
  Connect »

Research Site

Idaho Falls, ID United States
  Connect »

Research Site

New Orleans, LA United States
  Connect »

Research Site

Springfield, MA United States
  Connect »

Research Site

Neptune, NJ United States
  Connect »

Research Site

New York, NY United States
  Connect »

Research Site

Charleston, SC United States
  Connect »

Research Site

Memphis, TN United States
  Connect »

Research Site

McAllen, TX United States
  Connect »

Research Site

San Antonio, TX United States
  Connect »

Research Site

Bellevue, WA United States
  Connect »

Research Site

Tacoma, WA United States
  Connect »

Research Site

Buenos Aires, Argentina
  Connect »

Research Site

Ciudad Autonoma de Buenos Aire, Argentina
  Connect »

Research Site

Ciudad de Buenos Aires, Argentina
  Connect »

Research Site

San Miguel de Tucumán, Argentina
  Connect »

Research Site

Blacktown, Australia
  Connect »

Research Site

Nedlands, Australia
  Connect »

Research Site

Brasilia, Brazil
  Connect »

Research Site

Campinas, Brazil
  Connect »

Research Site

Curitiba, Brazil
  Connect »

Research Site

Fortaleza, Brazil
  Connect »

Research Site

Goiânia, Brazil
  Connect »

Research Site

Marília, Brazil
  Connect »

Research Site

Passo Fundo, Brazil
  Connect »

Research Site

Porto Alegre, Brazil
  Connect »

Research Site

Ribeirão Preto, Brazil
  Connect »

Research Site

Santa Maria, Brazil
  Connect »

Research Site

Sao Paulo, Brazil
  Connect »

Research Site

Vancouver, BC Canada
  Connect »

Research Site

Toronto, ON Canada
  Connect »

Research Site

Montreal, QC Canada
  Connect »

Research Site

Antofagasta, Chile
  Connect »

Research Site

San Bernardo, Chile
  Connect »

Research Site

Armenia, Colombia
  Connect »

Research Site

Barranquilla, Colombia
  Connect »

Research Site

Bogotá, Colombia
  Connect »

Research Site

Seinäjoki, Finland
  Connect »

Research Site

Tampere, Finland
  Connect »

Research Site

Ahmedabad, India
  Connect »

Research Site

Aurangabad, India
  Connect »

Research Site

Bangalore, India
  Connect »

Research Site

Chandigarh, India
  Connect »

Research Site

Coimbatore, India
  Connect »

Research Site

Hyderabad, India
  Connect »

Research Site

Kozhikode, India
  Connect »

Research Site

Visakhapatnam, India
  Connect »

Research Site

Daejeon-si, Korea, Republic of
  Connect »

Research Site

Incheon, Korea, Republic of
  Connect »

Research Site

Seongnam-si, Korea, Republic of
  Connect »

Research Site

Seoul, Korea, Republic of
  Connect »

Research Site

Wonju-si, Korea, Republic of
  Connect »

Research Site

George Town, Malaysia
  Connect »

Research Site

Johor Bahru, Malaysia
  Connect »

Research Site

Kota Kinabalu, Malaysia
  Connect »

Research Site

Kuching, Malaysia
  Connect »

Research Site

Melaka, Malaysia
  Connect »

Research Site

Putrajaya, Malaysia
  Connect »

Research Site

Seri Manjung, Malaysia
  Connect »

Research Site

Taiping, Malaysia
  Connect »

Research Site

Boca del Rio, Mexico
  Connect »

Research Site

Cuernavaca, Mexico
  Connect »

Research Site

Guadalajara, Mexico
  Connect »

Research Site

Monterrey, Mexico
  Connect »

Research Site

México, D.F., Mexico
  Connect »

Research Site

San Juan del Rio, Mexico
  Connect »

Research Site

Veracruz, Mexico
  Connect »

Research Site

Auckland, New Zealand
  Connect »

Research Site

Grafton, New Zealand
  Connect »

Research Site

Havelock North, New Zealand
  Connect »

Research Site

Papatoetoe, New Zealand
  Connect »

Research Site

Tauranga, New Zealand
  Connect »

Research Site

Wellington, New Zealand
  Connect »

Research Site

Cebu City, Philippines
  Connect »

Research Site

Davao DEL SUR, Philippines
  Connect »

Research Site

Quezon City, Philippines
  Connect »

Research Site

San Fernando City, Philippines
  Connect »

Research Site

Bydgoszcz, Poland
  Connect »

Research Site

Rzeszów, Poland
  Connect »

Research Site

Warszawa, Poland
  Connect »

Research Site

Bucuresti, Romania
  Connect »

Research Site

Dobrosloveni, Romania
  Connect »

Research Site

Satu Mare, Romania
  Connect »

Research Site

Timisoara, Romania
  Connect »

Research Site

Barnaul, Russian Federation
  Connect »

Research Site

Izhevsk, Russian Federation
  Connect »

Research Site

Kemerovo, Russian Federation
  Connect »

Research Site

Moscow, Russian Federation
  Connect »

Research Site

Saint-Petersburg, Russian Federation
  Connect »

Research Site

Ufa, Russian Federation
  Connect »

Research Site

Vologda, Russian Federation
  Connect »

Research Site

Taichung, Taiwan
  Connect »

Research Site

Bangkok, Thailand
  Connect »

Research Site

Chiang Mai, Thailand
  Connect »

Research Site

Hat Yai, Thailand
  Connect »

Research Site

Eskisehir, Turkey
  Connect »

Research Site

Istanbul, Turkey
  Connect »

Research Site

Kurupelit, Turkey
  Connect »

Research Site

Chernivtsi, Ukraine
  Connect »

Research Site

Kharkiv, Ukraine
  Connect »

Research Site

Poltava, Ukraine
  Connect »

Research Site

Vinnitsya, Ukraine
  Connect »

Research Site

Zaporizhzhya, Ukraine
  Connect »

Research Site

Birmingham, United Kingdom
  Connect »

Research Site

London, United Kingdom
  Connect »

Research Site

Middlesbrough, United Kingdom
  Connect »

Research Site

Nottingham, United Kingdom
  Connect »

Research Site

San Miguel de Tucumán, Argentina
  Connect »

Research Site

Goiânia, Brazil
  Connect »

Research Site

Marília, Brazil
  Connect »

Research Site

Ribeirão Preto, Brazil
  Connect »

Research Site

Bogotá, Colombia
  Connect »

Research Site

Seinäjoki, Finland
  Connect »

Research Site

México, D.F., Mexico
  Connect »

Research Site

Rzeszów, Poland
  Connect »

Research Site

San Miguel de Tucumán, Argentina
  Connect »

Research Site

Goiânia, Brazil
  Connect »

Research Site

Marília, Brazil
  Connect »

Research Site

Ribeirão Preto, Brazil
  Connect »

Research Site

Bogotá, Colombia
  Connect »

Research Site

Seinäjoki, Finland
  Connect »

Research Site

México, D.F., Mexico
  Connect »

Research Site

Rzeszów, Poland
  Connect »

Research Site

San Miguel de Tucumán, Argentina
  Connect »

Research Site

Goiânia, Brazil
  Connect »

Research Site

Marília, Brazil
  Connect »

Research Site

Ribeirão Preto, Brazil
  Connect »

Research Site

Bogotá, Colombia
  Connect »

Research Site

Seinäjoki, Finland
  Connect »

Research Site

México, D.F., Mexico
  Connect »

Research Site

Rzeszów, Poland
  Connect »

Research Site

San Miguel de Tucumán, Argentina
  Connect »

Research Site

Goiânia, Brazil
  Connect »

Research Site

Marília, Brazil
  Connect »

Research Site

Ribeirão Preto, Brazil
  Connect »

Research Site

Bogotá, Colombia
  Connect »

Research Site

Seinäjoki, Finland
  Connect »

Research Site

México, D.F., Mexico
  Connect »

Research Site

Rzeszów, Poland
  Connect »

Research Site

San Miguel de Tucumán, Argentina
  Connect »

Research Site

Goiânia, Brazil
  Connect »

Research Site

Marília, Brazil
  Connect »

Research Site

Ribeirão Preto, Brazil
  Connect »

Research Site

Bogotá, Colombia
  Connect »

Research Site

Seinäjoki, Finland
  Connect »

Research Site

México, D.F., Mexico
  Connect »

Research Site

Rzeszów, Poland
  Connect »