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Diabetes Mellitus, Type 2Phase 1NCT01571661

A First-time-in-human Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ascending Doses of GSK189075A in Healthy Subjects and in Subjects With Type 2 Diabetes Mellitus

A Phase 1 study testing GSK189075A in people with Diabetes Mellitus, Type 2, run by GlaxoSmithKline.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This is a double blind, randomised, placebo controlled, single dose escalation, first-time-in-human, 5-way crossover study to assess the safety, tolerability, pharmacokinetic and pharmacodynamic parameters of ascending doses of GSK189075A in healthy subjects (Part A). Single doses will be given to 10 healthy subjects. Read more about this study

Who is it for?
Ages 18 to 60 yearsHealthy volunteers can take part
Conditions the study is for
Diabetes Mellitus, Type 2
What is being tested?
GSK189075A
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
16 participants
Where
No sites listed yet
Study dates
Sep 2004to Jan 2005
Phase
Phase 1
Are there results?
None posted in the registry

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 18 to 60 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • Women must be of non-childbearing potential. Non-childbearing potential is defined as: Post-menopausal females defined as being amenorrhoeic for greater than one year with an appropriate clinical profile, e.g., age appropriate, history of vasomotor symptoms. However, if indicated, this should be confirmed by estradiol and FSH levels consistent with menopause (according to local laboratory ranges) Pre-menopausal females with a documented (medical report verification) hysterectomy or tubal ligation.
  • A negative pre-study urine drug screen. A minimum list of drugs that will be screened includes amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
  • Negative results for hepatitis C antibodies, hepatitis B surface antigen and HIV at screening, or have documented negative test results within the last 6 months.
  • Signed and dated written informed consent prior to admission to the study.
  • The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions.
  • Subjects with the following clinical laboratory values: ALT and AST < 2 times the upper limit of normal at screening and prior to the first dose; fasting triglycerides < 400mg/dL at screening and prior to first dose; bilirubin < 1.5 times the upper limit of normal at screening and prior to the first dose (total; subjects above this limit may only be included if direct bilirubin is within normal limits).
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  • Other values must be within the normal range or not clinically significant at screening and check-in. Abnormal values, deemed clinically significant by the principal investigator, must be cleared by the medical monitor at GSK.
  • Additional inclusion criteria for subjects in Part A: A subject will be eligible for inclusion in Part A of this study only if all of the following criteria apply: Healthy adult subjects aged 18 to 55 years inclusive, male and female subjects of non-childbearing potential.
  • Body weight greater than or equal to 50kg for men and greater than or equal to 45kg for women and BMI within the range 19.0 to 30.0kg/m2 inclusive.
  • Healthy as judged by responsible physician. No clinically significant abnormality identified on the medical or laboratory evaluation, including 12-lead ECG. A subject with a clinically significant abnormality, or laboratory parameters outside the reference range for this age group may be included only if the Investigator and Sponsor's Medical Monitor considers that the finding will not introduce additional risk factors and will not interfere with the study procedures.
  • Part B: A subject will be eligible for inclusion in Part B of this study only if all of the following criteria are met: Subjects with documented type 2 diabetes mellitus diagnosis (diagnosed not less than 6 months; HbA1c less than or equal to 10 % and FPG < 280 mg/dL at screening) who are either controlled by diet alone or monotherapy for a minimum of 3 months with either oral sulfonylureas, rosiglitazone, metformin, or acarbose. They must be willing/able to discontinue these medications during each dosing occasion for up to 72 hours (from check-in into the research unit until released after the last study assessment for each dosing period).
  • Adult men and women between 30 - 60 years inclusive. Women must be of non-childbearing potential.
  • BMI within the range 22 35kg/m2 inclusive.
  • Subjects taking stable regimens of medications commonly used as prevention in diabetics (aspirin, ACE inhibitors, and statins) will be allowed if their dose regimen(s) remain constant throughout the study period. Concurrent usage of prescribed medications other than the medications listed above may be allowed to continue only with Sponsor's consent.
  • No significant concomitant health problems other than type 2 diabetes mellitus and otherwise healthy as judged by a responsible physician.
  • Systolic/Diastolic blood pressure: greater than or equal to 80/60 mmHg and less than or equal to 150/95 mmHg at screening.

Who cannot join

  • History or presence of allergy to the study drug or drugs of this class or a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation.
  • History or presence of gastrointestinal, hepatic or renal disease, or other condition known to interfere with the absorption, distribution, metabolism or excretion of drugs. Any acute gastrointestinal illness within 2 weeks prior to dosing.
  • Use of diuretics, systemic corticosteroids, or any other medication that may result in electrolyte depletion, within 3 weeks of any scheduled dose.
  • Blood electrolyte (K, Na, Cl, Mg or Ca or bicarbonate) values outside of the reference range at screening and admission. No deviation will be permitted unless there has been discussion on an individual basis between sponsor and investigator for the following parameters: sodium, potassium, chloride, bicarbonate, calcium and magnesium.
  • If participation in the study will result in the subject having donated more than 1,500mL blood (males) or 1,000mL (females) in the previous 12 months and 6. where participation in study would result in donation of blood in excess of 550mL within a 56-day period.
  • As a result of the medical interview, physical examination for screening investigations, the Physician Responsible considers the volunteer unfit for the study.
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  • They have suffered a urinary tract or bladder infection within 4 weeks of the start of the study.
  • Abuse of alcohol
  • Significant renal disease
  • Any clinically significant abnormality identified on the medical or laboratory evaluation, including 12-lead ECG and 24 h Holter monitoring. A subject with a clinically significant abnormality or laboratory parameters outside the reference range for this age group may be included only if the Investigator and Sponsor's Medical Monitor consider that the finding will not introduce additional risk factors and will not interfere with the study procedures
  • Participation in a study trial with any drug of new chemical entity within 90 days prior to the start of the study.
  • Male subject unwilling to abstain from, or use a condom during sexual intercourse with a pregnant or lactating female; or male subject unwilling to use a condom plus another form of contraception (e.g., spermicide, IUD, birth control pills taken by female partner, diaphragm with spermicide) during sexual intercourse with a female who could become pregnant. Any male subject unwilling to adhere to the above contraceptive criteria from administration of study medication until completion of follow-up procedures.
  • Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication and until released after the last study assessment after the last dosing period, unless in the opinion of the Investigator and Sponsor the medication will not interfere with the study procedures or compromise subject safety.
  • Part A: A subject will not be eligible for inclusion in Part A of this study if the following applies: Past or present disease, which as judged by the Investigator, may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, haematological disease, neurological disease and endocrine disease.
  • Part B: A subject will not be eligible for inclusion in Part A of this study if any of the following criteria apply: Currently requiring insulin therapy, or has been on insulin therapy for the previous 3 months prior to the screening examination.
  • Medically unable or unwilling to discontinue their oral antidiabetic medications for up to 72 hours (from check-in into the research unit until released after the last study assessment for each dosing period).
  • Past or present disease (other than type 2 diabetes mellitus) as judged by the Investigator, which may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, haematological disease, neurological disease and endocrine disease.

About this study

Official title: A Double Blind, Randomized, Placebo Controlled, Single-dose Escalation, First-time-in-human Crossover Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ascending Doses of GSK189075A in Healthy Subjects and in Subjects With Type 2 Diabetes Mellitus

This is a double blind, randomised, placebo controlled, single dose escalation, first-time-in-human, 5-way crossover study to assess the safety, tolerability, pharmacokinetic and pharmacodynamic parameters of ascending doses of GSK189075A in healthy subjects (Part A). Single doses will be given to 10 healthy subjects. The planned doses are 20mg, 50mg, 150mg, 500mg, and 1000mg. Each subject will receive 4 of the 5 active doses and a placebo separated by a washout of 5-10 days. A second cohort of 6 subjects with type 2 diabetes mellitus will receive 2 active doses and a placebo along with oral glucose in a three-way, randomised, placebo controlled, crossover design to assess glucose lowering following GSK189075A administration (Part B). Blood samples will be taken throughout the study day for pharmacokinetic analysis of prodrug and metabolites. Safety will be assessed by measurement of blood glucose, blood pressure, heart rate, ECGs, laboratory safety screens, and collection of adverse events.

Being tested
GSK189075A, Placebo
Keywords
KGT-1142, safety, pharmacokinetics, single-dose escalation, tolerability
Medical subject headings
Diabetes Mellitus, Type 2

What participants receive

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

  • GSK189075ADrug

    20mg, 50mg, 150mg, 500mg, 1000mg or Placebo

  • PlaceboOther

    Placebo

Study groups in NCT01571661
Study groupRoleWhat they receive
Part A Treatment 1ExperimentalGSK189075A 20mg
Receives: Drug: GSK189075A
Part A Treatment 2ExperimentalGSK189075A 50mg
Receives: Drug: GSK189075A
Part A Treatment 3ExperimentalGSK189075A 150mg
Receives: Drug: GSK189075A
Part A Treatment 4ExperimentalGSK189075A 500mg
Receives: Drug: GSK189075A
Part A Treatment 5ExperimentalGSK189075A 1000mg
Receives: Drug: GSK189075A
PlaceboPlacebo comparatorPlacebo
Receives: Other: Placebo
Part B Low doseExperimentallow dose chosen from Part A
Receives: Drug: GSK189075A
Part B High DoseExperimentalhigh dose chosen from Part A
Receives: Drug: GSK189075A

What is being measured

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

  1. Safety and tolerability change from baseline in laboratory assessments

    Hematology, Clinical Chemistry, Urinalysis

    Measured: Part A: Approximately 58 days and Part B: Approximately 38 days.

  2. Safety and tolerability change from baseline in electrocardiaogram (ECG) reading

    12-lead ECG and continuous ECG monitoring.

    Measured: Part A: Approximately 58 days and Part B: Approximately 38 days.

  3. Safety and tolerability change from baseline in fluid intake

    urine output, and the number of micturations will be recorded.

    Measured: FPart A: Approximately 58 days and Part B: Approximately 38 days.

  4. Safety and tolerability change from baseline in electrolytes

    Blood electrolyte concentrations (Na, K, Cl, Ca, Mg and bicarbonate)

    Measured: Part A: Approximately 58 days and Part B: Approximately 38 days.

  5. Safety and Tolerability change from baseline in creatinine clearance

    creatinine clearance (24-hours [h])

    Measured: Part A: Approximately 58 days and Part B: Approximately 38 days.

  6. Composite of pharmacokinetic parameters of GSK189075A, GSK189074A, and GSK279782A

    Area under the plasma concentration-time curve [AUC(0 last)], Area under the plasma concentration-time curve [AUC(0-infinity)], Maximum observed plasma concentration (Cmax), Time to maximum observed plasma concentration (tmax), Plasma elimination half-life (t1/2), Area under the plasma concentration-time curve for the metabolite [AUCm(0-last)]/ Area under the plasma concentration-time curve for the parent [AUCp(0-last)], and AUCm(0-infinity)/AUCp(0-infinity) ratios.

    Measured: Part A: up to 24 hours post dose for five periods. Part B: For 24 hours post dose for 3 periods. Collected at the following: pre-dose, and 10 min, 20 min, 30 min, 45 min, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, , 8, 12, 16 and 24h post-dose.

  7. Parts A and B: plasma glucose concentrations in healthy subjects

    Measured: Part A: up to 24 hours post dose for five periods. Part B: For 24 hours post dose for 3 periods.

  8. Parts A and B: Urine chemistry lab measurements

    Urine samples for creatinine, glucose, and electrolytes (Na, K, Cl) measurements will be obtained.

    Measured: measurements will be obtained pre-dose, and over the following intervals: 0-2, 2-4, 4-6, 6-8, 8-12, and 12-24h during the dosing period.

  9. Part B: Plasma glucose and insulin concentrations concentrations in subjects with type 2 diabetes mellitus following a 50g oral glucose challenge.

    Measured: On day -2 predose and at 0.5, 1, 1.5, 2, 4, 4.5, 5, 6, 8, 10, 12 and 24h.

  10. Safety and Tolerability as assessed by numbers of adverse events

    number of adverse events collected during study

    Measured: Part A: Approximately 58 days and Part B: Approximately 38 days.

  11. Safety and Tolerability as assessed by change from baseline in vital sign measurements

    Blood pressure and heart rate.

    Measured: Part A: Approximately 58 days and Part B: Approximately 38 days.

  12. urine glucose concentrations in subjects with type 2 diabetes mellitus following a 50g oral glucose challenge.

    Measured: On day -2 predose and at 0.5, 1, 1.5, 2, 4, 4.5, 5, 6, 8, 10, 12 and 24h.

Timeline

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

  1. First posted5 Apr 2012 (estimated)
  2. Study startSep 2004
  3. Primary completionJan 2005
  4. Study completionJan 2005

Resources

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 1
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
16 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01571661
Sponsor's protocol ID
KG219017
Status last verified
Apr 2012
First submitted
15 Mar 2012
Last updated
5 Apr 2012
Results posted
No
Data monitoring committee
No

Publications

  • Kapur A, O'Connor-Semmes R, Hussey EK, Dobbins RL, Tao W, Hompesch M, Smith GA, Polli JW, James CD Jr, Mikoshiba I, Nunez DJ. First human dose-escalation study with remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitus. BMC Pharmacol Toxicol. 2013 May 13;14:26. doi: 10.1186/2050-6511-14-26.

    PubMed 23668634

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing GSK189075A in people with Diabetes Mellitus, Type 2, run by GlaxoSmithKline.

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 16 inclusion and 17 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: finished, as of the sponsor's last update on 5 Apr 2012. 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. Some participants in this study may receive a placebo. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

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

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

Safety and tolerability change from baseline in laboratory assessments (time frame: Part A: Approximately 58 days and Part B: Approximately 38 days.). The study lists 12 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 NCT01571661, which also lists 1 linked publication.

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 5 Apr 2012.

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