A Phase 1, Open Label, Placebo-Controlled Study to Evaluate the Effect of GSK1349572 on Iohexol and Para-Aminohippurate Clearance in Healthy Subjects

This study has been completed.
Sponsor:
Collaborators:
Shionogi
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT01214993
First received: October 1, 2010
Last updated: June 7, 2012
Last verified: June 2012
  Purpose

The current study is designed to confirm the mechanism behind the increase in serum creatinine observed during GSK1349572 therapy; specifically, the study will determine whether GSK1349572 has any effect on glomerular filtration rate (GFR) or effective renal plasma flow. Absent such effects, one may conclude that the small increases in serum creatinine observed are due to the inhibition of the tubular secretion of creatinine via organic cation transporter 2 (OCT2) consistent with in vitro data. .


Condition Intervention Phase
Infections, Human Immunodeficiency Virus and Tuberculosis
Drug: GSK1349572
Drug: Placebo
Drug: Iohexol Injection
Drug: Para-aminohippurate infusion
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1, Open Label, Placebo-Controlled Study to Evaluate the Effect of GSK1349572 on Iohexol and Para-Aminohippurate Clearance in Healthy Subjects

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • Glomerular Filtration Rate (GFR) as measured by iohexol plasma clearance at days -1, 7 and 14 [ Time Frame: 14 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Serum creatinine, creatinine clearance (CrCL) as measured by 24-hour urine collection, and extra-glomerular creatinine excretion (EGCE) at days -1, 7, 14 and follow-up [ Time Frame: 24 days ] [ Designated as safety issue: Yes ]
  • Serum concentrations of Cystatin-C, 24-hour urinary excretions of albumin, total protein, beta2-microblobulin, N-acetyl-beta-d-glucosaminidase (NAG) and retinol binding protein at days -1, 7, 14 and at follow-up [ Time Frame: 24 days ] [ Designated as safety issue: Yes ]
  • Effective renal plasma flow (ERPF) as measured by plasma clearance of Para Aminohippurate (PAH) at days -1, 7 and 14 [ Time Frame: 14 days ] [ Designated as safety issue: Yes ]
  • Safety and tolerability parameters, including adverse event, concurrent medication, clinical laboratory and vital signs assessments. [ Time Frame: 24 days ] [ Designated as safety issue: No ]
  • Day 14 GSK1349572 PK parameters including area under the concentration curve (AUC)(0-tau), AUC(0-24), concentration (C)max, C0, and Ctau. [ Time Frame: day 14 ] [ Designated as safety issue: No ]

Enrollment: 38
Study Start Date: October 2010
Study Completion Date: November 2010
Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment A
There will be a screening visit within 30 days prior to the first dose of study drug. In this treatment arm, all subjects will receive GSK1349572 50mg (two 25mg tablets) q24h for 14 days. Subjects will also receive iohexol and PAH infusions on Days -1, 7 and 14. There will be a follow-up visit 7-10 days after the last dose of study medication.
Drug: GSK1349572
GSK1349572 is an experimental drug in the integrase inhibitor class of drugs to treat human immunodeficiency virus (HIV)
Drug: Iohexol Injection
Iohexol is an FDA approved radiologic contrast medium
Other Name: OMNIPAQUE
Drug: Para-aminohippurate infusion
Para-aminohippurate is an agent to measure effective renal plasma flow.
Experimental: Treatment B
There will be a screening visit within 30 days prior to the first dose of study drug. In this treatment arm, all subjects will receive GSK1349572 50mg (two 25mg tablets) q12h for 14 days. Subjects will also receive iohexol and PAH infusions on Days -1, 7 and 14. There will be a follow-up visit 7-10 days after the last dose of study medication.
Drug: GSK1349572
GSK1349572 is an experimental drug in the integrase inhibitor class of drugs to treat human immunodeficiency virus (HIV)
Drug: Iohexol Injection
Iohexol is an FDA approved radiologic contrast medium
Other Name: OMNIPAQUE
Drug: Para-aminohippurate infusion
Para-aminohippurate is an agent to measure effective renal plasma flow.
Placebo Comparator: Treatment C
There will be a screening visit within 30 days prior to the first dose of study drug. In this treatment arm, all subjects will receive placebo q24h for 14 days. Subjects will also receive iohexol and PAH infusions on Days -1, 7 and 14. There will be a follow-up visit 7-10 days after the last dose of study medication.
Drug: Placebo
Placebo is a tablet with no drug in it.
Drug: Iohexol Injection
Iohexol is an FDA approved radiologic contrast medium
Other Name: OMNIPAQUE
Drug: Para-aminohippurate infusion
Para-aminohippurate is an agent to measure effective renal plasma flow.

Detailed Description:

GSK1349572 is an integrase inhibitor being developed for the treatment of human immunodeficiency virus (HIV)-1 infection by GlaxoSmithKline (GSK) on behalf of Shionogi-ViiV Healthcare LLC. In healthy subjects and in dose-ranging clinical trials of GSK1349572, subjects showed a small, reversible increase in serum creatinine concentrations as compared to the control groups; this occurred early during study drug administration and did not progress over time. In vitro data demonstrate that GSK1349572 inhibits the organic cation transporter (OCT2), which mediates the tubular secretion of creatinine; drugs such as cimetidine with similar effects on OCT2 lead to a nonpathological increase in creatinine with no effect on glomerular filtration rate (GFR). The current study is designed to confirm the mechanism behind the increase in serum creatinine observed during GSK1349572 therapy; specifically, the study will determine whether GSK1349572 has any effect on GFR or effective renal plasma flow. Absent such effects, one may conclude that the small increases in serum creatinine observed are due to the inhibition of the tubular secretion of creatinine via OCT2.

Subjects will be given GSK1349572 50mg once daily, 50mg twice daily or placebo once daily for 14 days. Changes in the subject's GFR will be measured through administration of iohexol and effective renal plasma flow will be measured using Para-Aminohippurate (PAH) on days -1, 7 and 14. Changes in serum creatinine and other renal biomarkers will be evaluated at baseline and at various time points throughout the study.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects with normal renal function defined as creatinine clearance greater than or equal to 80 mL/min/1.73m2 measured by 24 urine collection
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and bilirubin less than or equal to 1.5x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
  • Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent.
  • A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 pmol/L) is confirmatory]. OR Child-bearing potential and agrees to use one of the contraception methods listed in the protocol for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until the follow-up visit.
  • Body weight greater than or equal to 50 kg for males and 45 kg for females and body mass index (BMI) within the range 18.5- 31.0 kg/m2 (inclusive).
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

  • The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
  • The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  • History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation. A subject with any history of allergic reaction to contrast media should not be enrolled.
  • 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, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
  • If heparin is used during PK sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.
  • History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >14 drinks/week for men or >7 drinks/week for women. One drink is equivalent to (12 g alcohol) = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits.
  • Has a history or regular use of tobacco- or nicotine-containing products within 3 months prior to screening.
  • Consumption of red wine, seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication.
  • Pregnant females as determined by positive serum or urine human chorionic gonadotrophin (hCG) test at screening or prior to dosing.
  • Lactating females.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Subjects with a pre-existing condition interfering with normal gastrointestinal anatomy or motility, hepatic and/or renal function, that could interfere with the absorption, metabolism, and/or excretion of the study drugs. Subjects with a history of cholecystectomy, peptic ulceration, inflammatory bowel disease or pancreatitis should be excluded.
  • History/evidence of clinically significant pulmonary disease.
  • History of significant renal or hepatobiliary diseases. Subjects with a history of nephrolithiasis will be excluded.
  • Any subject with evidence of microalbuminuria at screening defined as albumin-to-creatinine ratio in a random spot urine ≥ 0.03 mg/mg OR 30 mg/g.
  • History of severe or serious psychiatric disease ever requiring hospitalization, history of suicidal ideation or suicidal attempt, or undergoing psychiatric treatment will be excluded from study participation.
  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
  • A positive test for HIV antibody.
  • History of Gilbert's disease.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
  • The subject's systolic blood pressure is outside the range of 90-140mmHg, or diastolic blood pressure is outside the range of 45-90mmHg or heart rate is outside the range of 50-100bpm for female subjects or 45-100 bpm for male subjects.
  • Exclusion criteria for screening ECG per protocol
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01214993

Locations
United States, Minnesota
GSK Investigational Site
Minneapolis, Minnesota, United States, 55404
Sponsors and Collaborators
ViiV Healthcare
Shionogi
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials ViiV Healthcare
  More Information

No publications provided

Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT01214993     History of Changes
Other Study ID Numbers: 114819
Study First Received: October 1, 2010
Last Updated: June 7, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by ViiV Healthcare:
GSK1349572
para-aminohippurate
iohexol

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immunologic Deficiency Syndromes
Tuberculosis
Actinomycetales Infections
Bacterial Infections
Gram-Positive Bacterial Infections
Immune System Diseases
Lentivirus Infections
Mycobacterium Infections
Retroviridae Infections
RNA Virus Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Dolutegravir
Iohexol
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Contrast Media
Diagnostic Uses of Chemicals
Enzyme Inhibitors
HIV Integrase Inhibitors
Integrase Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014