Diabetes MellitusPhase 4SGLT2iPGxNCT02462421

Pharmacogenetics of SGLT2 Inhibitors

A Phase 4 study testing Canagliflozin in people with Diabetes Mellitus and Gout, run by University of Maryland, Baltimore.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

Who is it for?: Ages 21 years and olderHealthy volunteers can take part
Conditions the study is for: Diabetes Mellitus, Gout, Hyperuricemia
What is being tested?: Canagliflozin
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 30 participants
Where: No sites listed yet
Study dates: 1 Jun 2015to 31 Dec 2021
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 21 years and older
All sexes
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

Of Amish descent
Age 21 or older
BMI 18-40 kg/m2

Who cannot join

Known allergy to canagliflozin
History of diabetes, random glucose greater than 200 mg/dL, or HbA1c greater than or equal to 6.5%
Currently taking diuretics, antihypertensive medication, uric acid lowering medications, or other medication that the investigator judges will make interpretation of the results difficult
Significant debilitating chronic cardiac, hepatic, pulmonary, or renal disease or other diseases that the investigator judges will make interpretation of the results difficult or increase the risk of participation
Seizure disorder
Positive urine human chorionic gonadotropin (hCG) test or known pregnancy within 3 months of the start of the study

Show all 12Show fewer

Estimated glomerular filtration rate less than 60 mL/min
Currently breast feeding or breast feeding within 3 month of the start of the study
Liver function tests greater than 2 times the upper limit of normal
Hematocrit less than 35%
Currently symptomatic for urinary tract or yeast infection or history of two or more urinary tract or yeast infections in the past 12 months.
Abnormal thyroid stimulating hormone (TSH)

About this study

Official title: Pharmacogenetics of Sodium-dependent Glucose Transporter-2 (SGLT2) Inhibitors

Sodium-dependent glucose transporter-2 (SGLT2) inhibitors are a new class of anti-diabetic drugs, which increase urinary glucose excretion thereby promoting weight loss and decreasing plasma glucose levels. We hypothesize that the pharmacodynamic response to SGLT2 inhibitors (specifically canagliflozin) varies among individuals, and that a proportion of this inter-individual variation can be explained by genetic variation. This is a pilot study in healthy, non-diabetic subjects in whom glucose and other related metabolites in the urine and plasma will be measured before and after administration of a single dose of canagliflozin. This will allow us to characterize the inter-individual variation in the pharmacodynamic response to canagliflozin as well as determine if changes in glucose and other related metabolite levels are associated with variants in various candidate genes.

Read the detailed description

Sodium-dependent glucose transporters (SGLTs) are a family of glucose transporters expressed on the apical surface of epithelial cells in the intestines and kidneys. Their function is to actively transport glucose across epithelia into the blood. Members of the SGLT-family of transporters include sodium-dependent glucose transporters-1, -2, -3, and -4 (SGLT1, SGLT2, SGLT3 and SGLT4), with SGLT2 being the primary glucose transporter in the kidney. SGLT2 inhibitors are a new class of anti-diabetic drug approved as treatments for type 2 diabetes (T2DM). These drugs inhibit SGLT2-mediated reabsorption of glucose in the renal proximal tubule -- thereby increasing urinary glucose excretion and decreasing plasma glucose levels. We hypothesize that the pharmacodynamic response to SGLT2 inhibitors (specifically canagliflozin) varies among individuals, and that a proportion of this inter-individual variation can be explained by genetic variation. To explore this hypothesis, we will conduct a pilot study in healthy, non-diabetic subjects in whom glucose and other related metabolites in the urine and plasma will be measured before and after administration of a single dose of canagliflozin. This will allow us to characterize the inter-individual variation in the pharmacodynamic response to canagliflozin as well as determine if changes in glucose and other related metabolite levels are associated with variants in candidate genes (SGLT3, SGLT4, and glucose transporter-2 (abbreviated as either GLUT9 or SLC2A9)).

Conditions: Diabetes Mellitus, Gout, Hyperuricemia
Being tested: Canagliflozin
Keywords: SGLT2, SLC5A2, SLC5A4, SLC5A9, SLC2A9, GLUT9, SGLT3, SGLT4, pharmacogenomics
Medical subject headings: Diabetes Mellitus, Gout, Hyperuricemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

CanagliflozinDrug
Also called Invokana
A single dose of canagliflozin (300 mg, p.o.) will be administered prior to assessing pharmacodynamic response.

Study groups in NCT02462421
Study group	Role	What they receive
Wild type genotype	Active comparator	Research subjects with wild type genotypes at three candidate genes encoding sodium-dependent glucose transporter-3, sodium-dependent glucose transporter-4, and glucose transporter-9 (abbreviated as SLC5A4, SLC5A9, SLC2A9, respectively) will be studied before and after canagliflozin treatment. Receives: Drug: Canagliflozin
Nonsense mutation in SLC5A4	Experimental	Research subjects who are homozygous for nonsense mutation in SLC5A4 (sodium-dependent glucose transporter-3) will be studied before and after canagliflozin treatment. Receives: Drug: Canagliflozin
Nonsense mutation in SLC5A9	Experimental	Research subjects who are homozygous for nonsense mutation in SLC5A9 (sodium-dependent glucose transporter-4) will be studied before and after canagliflozin treatment. Receives: Drug: Canagliflozin
Missense variant in SLC2A9	Experimental	Research subjects who are homozygous for nonsynonymous variant in glucose transporter-9 (SLC2A9) will be studied before and after canagliflozin treatment. Receives: Drug: Canagliflozin

What is being measured

The primary outcome is the main question the study is designed to answer.

Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin)
The pharmacodynamic response to canagliflozin will be assessed by measuring the increase in 24 hour urinary glucose excretion.
Measured: 24 hours after administration of canagliflozin
Change in Fractional Excretion of Uric Acid (the Difference Between Data After Administration of Canagliflozin Minus Data Before Administration of Canagliflozin)
For the study arm focused on individuals with a genetic variant in SLC2A9, the pharmacodynamic response to canagliflozin will be assessed by measuring the absolute change in fractional excretion of uric acid in the urine. Fractional excretion of uric acid represents the fraction of the calculated filtered uric acid load (serum uric acid level multiplied by the measured creatinine clearance rate) that was excreted in the urine.
Measured: 24 hour urine collection after administration of canagliflozin

Secondary outcomes (4)

Canagliflozin-induced Change in Urinary Excretion of Sodium
The pharmacodynamic response to canagliflozin will be assessed by measuring the % increase in 24 hour urinary excretion of sodium.
Measured: 24 hours after administration of canagliflozin
Canagliflozin-induced Change in Serum Creatinine
The pharmacodynamic response to canagliflozin will be assessed by measuring changes in serum creatinine
Measured: 24 hours after administration of canagliflozin
Canagliflozin-induced Change in Serum Uric Acid
The pharmacodynamic response to canagliflozin will be assessed by measuring changes in serum uric acid level
Measured: 24 hours after administration of canagliflozin
Canagliflozin-induced Change in Fasting Plasma Glucose
The magnitude of the change in fasting plasma glucose 24 hours after administration of canagliflozin (300 mg)
Measured: 24 hrs

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1 Jun 201531 Dec 2021

First posted4 Jun 2015 (estimated)
Study start1 Jun 2015
Primary completion31 Dec 2021
Study completion31 Dec 2021

Why it stopped: Did not meet recruitment targets.

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Diabetes MellitusStudies of the same condition, open and under way.
More trials run by University of Maryland, BaltimoreThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Basic science
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Enrolment: 30 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02462421
Sponsor's protocol ID: HP-00058350
Other IDs: R21DK105401
Acronym: SGLT2iPGx
Status last verified: Jul 2022
First submitted: 24 Apr 2015
Last updated: 2 Aug 2022
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
Individual data sharing: No: Individual participant data will not be shared in order to protect confidentiality of research subjects.

Publications

Taylor SI, Montasser ME, Yuen AH, Fan H, Yazdi ZS, Whitlatch HB, Mitchell BD, Shuldiner AR, Muniyappa R, Streeten EA, Beitelshees AL. Acute pharmacodynamic responses to exenatide: Drug-induced increases in insulin secretion and glucose effectiveness. medRxiv [Preprint]. 2023 May 3:2023.03.15.23287166. doi: 10.1101/2023.03.15.23287166.
PubMed 36993363
Taylor SI, Cherng HR, Yazdi ZS, Montasser ME, Whitlatch HB, Mitchell BD, Shuldiner AR, Streeten EA, Beitelshees AL. Pharmacogenetics of SGLT2 Inhibitors: Validation of a sex-agnostic pharmacodynamic biomarker. medRxiv [Preprint]. 2023 Jun 12:2023.03.07.23286875. doi: 10.1101/2023.03.07.23286875.
PubMed 36945579

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

Official record

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Study at a glance

From the registry record, last updated by the sponsor on 2 Aug 2022. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Pharmacogenetics of Sodium-dependent Glucose Transporter-2 (SGLT2) Inhibitors
ClinicalTrials.gov ID: NCT02462421
Acronym / sponsor ID: SGLT2iPGx / HP-00058350
Conditions: Diabetes Mellitus, Gout, Hyperuricemia
Keywords: SGLT2, SLC5A2, SLC5A4, SLC5A9, SLC2A9, GLUT9, SGLT3, SGLT4
Phase: Phase 4
Study type: Interventional
Recruitment status: TerminatedReason stopped: Did not meet recruitment targets.
Enrolment: 30 participants (actual)
Lead sponsor: University of Maryland, BaltimoreUniversity, hospital or other
Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study start: 1 Jun 2015 (actual)
Primary completion: 31 Dec 2021 (actual)
Study completion: 31 Dec 2021 (actual)
First posted: 4 Jun 2015 (estimated)
Results: Posted 1 Aug 2022

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Basic science
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Number of arms: 4

Arm	Type	Receives
Wild type genotype	Active comparator	Drug: CanagliflozinResearch subjects with wild type genotypes at three candidate genes encoding sodium-dependent glucose transporter-3, sodium-dependent glucose transporter-4, and glucose transporter-9 (abbreviated as SLC5A4, SLC5A9, SLC2A9, respectively) will be studied before and after canagliflozin treatment.
Nonsense mutation in SLC5A4	Experimental	Drug: CanagliflozinResearch subjects who are homozygous for nonsense mutation in SLC5A4 (sodium-dependent glucose transporter-3) will be studied before and after canagliflozin treatment.
Nonsense mutation in SLC5A9	Experimental	Drug: CanagliflozinResearch subjects who are homozygous for nonsense mutation in SLC5A9 (sodium-dependent glucose transporter-4) will be studied before and after canagliflozin treatment.
Missense variant in SLC2A9	Experimental	Drug: CanagliflozinResearch subjects who are homozygous for nonsynonymous variant in glucose transporter-9 (SLC2A9) will be studied before and after canagliflozin treatment.

Who may qualify

Ages: 21 years and older
Sex: All
Healthy volunteers: Accepted
Age groups: Adult, Older adult

Key inclusion criteria (3 listed)

Of Amish descent
Age 21 or older
BMI 18-40 kg/m2

Key exclusion criteria (12 listed)

Known allergy to canagliflozin
History of diabetes, random glucose greater than 200 mg/dL, or HbA1c greater than or equal to 6.5%
Currently taking diuretics, antihypertensive medication, uric acid lowering medications, or other medication that the investigator judges will make interpretation of the results difficult
Significant debilitating chronic cardiac, hepatic, pulmonary, or renal disease or other diseases that the investigator judges will make interpretation of the results difficult or increase the risk of participation
Seizure disorder

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
CanagliflozinAlso: InvokanaA single dose of canagliflozin (300 mg, p.o.) will be administered prior to assessing pharmacodynamic response.	Drug	Missense variant in SLC2A9, Nonsense mutation in SLC5A4, Nonsense mutation in SLC5A9, Wild type genotype

Primary outcome

Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin)
Time frame: 24 hours after administration of canagliflozin
The pharmacodynamic response to canagliflozin will be assessed by measuring the increase in 24 hour urinary glucose excretion.
Change in Fractional Excretion of Uric Acid (the Difference Between Data After Administration of Canagliflozin Minus Data Before Administration of Canagliflozin)
Time frame: 24 hour urine collection after administration of canagliflozin
For the study arm focused on individuals with a genetic variant in SLC2A9, the pharmacodynamic response to canagliflozin will be assessed by measuring the absolute change in fractional excretion of uric acid in the urine. Fractional excretion of uric acid represents the fraction of the calculated filtered uric acid load (serum uric acid level multiplied by the measured creatinine clearance rate) that was excreted in the urine.

4 secondary outcomes

Canagliflozin-induced Change in Urinary Excretion of Sodium
Time frame: 24 hours after administration of canagliflozin
Canagliflozin-induced Change in Serum Creatinine
Time frame: 24 hours after administration of canagliflozin
Canagliflozin-induced Change in Serum Uric Acid
Time frame: 24 hours after administration of canagliflozin
Canagliflozin-induced Change in Fasting Plasma Glucose
Time frame: 24 hrs

Results and safety

Results posted to the registry on 1 Aug 2022, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Wild Type Genotype	13	13
Nonsense Mutation in SLC5A4	4	4
Nonsense Mutation in SLC5A9	6	6
Missense Variant in SLC2A9	7	7

Primary outcome: Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin)

Time frame: 24 hours after administration of canagliflozin. Mean (Standard Error). Unit: glucose (g)/creatinine (g)

Measure	Wild Type Genotype n = 13	Nonsense Mutation in SLC5A4 n = 4	Nonsense Mutation in SLC5A9 n = 6	Missense Variant in SLC2A9 n = 7	Total Population n = 30
Value	37.6 (2.1)	37.1 (3.3)	39.1 (2.5)	36.9 (2.7)	37.7 (1.2)

Wild Type Genotype vs Nonsense Mutation in SLC5A4: p = 0.92, t-test, 2 sided
Wild Type Genotype vs Nonsense Mutation in SLC5A9: p = 0.63, t-test, 2 sided
Wild Type Genotype vs Missense Variant in SLC2A9: p = 0.86, t-test, 2 sided

Population analysed: The entire population of 30 research participants comprised the database for this analysis.

Primary outcome: Change in Fractional Excretion of Uric Acid (the Difference Between Data After Administration of Canagliflozin Minus Data Before Administration of Canagliflozin)

Time frame: 24 hour urine collection after administration of canagliflozin. Mean (Standard Error). Unit: absolute change in fractional excretion

Measure	Wild Type Genotype n = 13	Nonsense Mutation in SLC5A4 n = 4	Nonsense Mutation in SLC5A9 n = 6	Missense Variant in SLC2A9 n = 7	Total Population n = 30
Value	0.25 (0.02)	0.25 (0.02)	0.28 (0.04)	0.38 (0.05)	0.29 (0.02)

Wild Type Genotype vs Missense Variant in SLC2A9: p = 0.04, t-test, 2 sided

Population analysed: Data from all 30 patients are summarized. The primary statistical analysis is based on comparison of the 13 "wild type" genotype versus the 7 patients who are homozygous for the variant in SLC2A9 (GLUT9).

4 secondary outcomes are reported in the full results.

Adverse events

Time frame: Participants received a single dose of canagliflozin (300 mg). The primary assessment of adverse events was during the 48 hours in which people were actively participating in the clinical trial (encompassing the two 24-hour urine collections).. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Total Population of Participants in the Clinical Trial	0 of 30 (0%)	2 of 30 (6.7%)	0 of 30

Limitations and caveats (from the sponsor): Small sample size: We had hoped to recruit more participants, but the need to collect two 24 hour urine samples turned out to be a major obstacle. Small pilot study conducted in healthy volunteers rather than the target population for SGLT2 inhibitors. Genetic studiy conducted in a Founder Population (Old Order Amish living in Lancaster County). Lancaster Amish chosen because of the availability of genotyping data and existence of infrastructure enabling genotype-directed "call-back" studies.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 2 Aug 2022.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 36993363Taylor SI, Montasser ME, Yuen AH, Fan H, Yazdi ZS, Whitlatch HB, Mitchell BD, Shuldiner AR, Muniyappa R, Streeten EA, Beitelshees AL. Acute pharmacodynamic responses to exenatide: Drug-induced increases in insulin secretion and glucose effectiveness. medRxiv [Preprint]. 2023 May 3:2023.03.15.23287166. doi: 10.1101/2023.03.15.23287166.
Derived from this study: PubMed 36945579Taylor SI, Cherng HR, Yazdi ZS, Montasser ME, Whitlatch HB, Mitchell BD, Shuldiner AR, Streeten EA, Beitelshees AL. Pharmacogenetics of SGLT2 Inhibitors: Validation of a sex-agnostic pharmacodynamic biomarker. medRxiv [Preprint]. 2023 Jun 12:2023.03.07.23286875. doi: 10.1101/2023.03.07.23286875.
Individual participant dataSharing planned: No. Individual participant data will not be shared in order to protect confidentiality of research subjects.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Simeon I Taylor, MD, PhD study chair

University of Maryland, Baltimore

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Canagliflozin in people with Diabetes Mellitus and Gout, run by University of Maryland, Baltimore.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 2 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 1 Aug 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin) (time frame: 24 hours after administration of canagliflozin). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02462421, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Aug 2022.