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Repeat Dose Safety Study for Compound to Treat Anemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00840320
First received: February 9, 2009
Last updated: February 28, 2013
Last verified: February 2013
  Purpose

The purpose of this study is to characterize the safety and tolerability of repeat doses of compound 1278863A in healthy subjects.


Condition Intervention Phase
Kidney Disease
Drug: 1278863
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Basic Science
Official Title: A Phase I, Randomized, Single-Blind, Placebo-Controlled, Dose-Escalation Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Repeat Oral Doses of 1278863A in Healthy Subjects

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • adverse events reporting [ Time Frame: throughout study ] [ Designated as safety issue: Yes ]
  • Safety Labs (hematology) [ Time Frame: Screening, Days -1, 1-3, 5, 7, 9, 11, 14-18, 21, 25, 28 ] [ Designated as safety issue: Yes ]
  • vital signs (blood pressure and heart rate) [ Time Frame: Days 1-15, 28 ] [ Designated as safety issue: No ]
  • 12-lead ECG [ Time Frame: Screening, Days 1-2, 4, 6, 8, 10, 12, 14, 28 ] [ Designated as safety issue: Yes ]
  • dual-lead cardiac monitoring (telemetry monitoring) [ Time Frame: Days -1 to 3, 14 ] [ Designated as safety issue: Yes ]
  • clinical monitoring/observation [ Time Frame: throughout ] [ Designated as safety issue: Yes ]
  • Safety Labs (Chemistry) [ Time Frame: Screening, Days -1, 1-3, 7, 10, 14-15, 17, 21, 28 ] [ Designated as safety issue: Yes ]
  • Safety Labs (Urinalysis) [ Time Frame: Screening, Days -1, 1-3, 7, 10, 14-15, 17, 21, 28 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • AUC(0-∞) on Day 1, AUC(0-τ), Cmax, tmax and t1/2, on Days 1 and 14 [ Time Frame: Days 1-2, 4, 6, 8, 10, 12, 14-18 ] [ Designated as safety issue: No ]
  • Trough plasma concentrations at the end of the dosing interval [ Time Frame: Days 2, 4, 6, 8, 10 and 12 ] [ Designated as safety issue: No ]
  • Hemoglobin actual values, rate of rise, maximum change from baseline, and rate of decline following stopping of dosing [ Time Frame: Days 1, 7, 14, 21, 28 ] [ Designated as safety issue: No ]
  • Fetal hemoglobin actual values, change from baseline, and percent of total hemoglobin [ Time Frame: Days 1, 7, 14, 21, 28 ] [ Designated as safety issue: No ]
  • Actual values and change from baseline in erythropoietin [ Time Frame: Days 1-4, 7, 14-15, 18, 21 ] [ Designated as safety issue: No ]
  • Actual values and change from baseline in absolute VEGF [ Time Frame: Days 1-2, 14-15, 18, 21 ] [ Designated as safety issue: No ]
  • Actual values and change from baseline in hepcidin [ Time Frame: Days 1-2, 7, 14-15, 18, 21 ] [ Designated as safety issue: No ]
  • Actual values and change from baseline in total iron binding capacity (TIBC) [ Time Frame: Screening, Days 1, 7, 14, 18, 21 ] [ Designated as safety issue: No ]
  • Actual values and change from baseline in transferring saturation (%) [ Time Frame: Days 1, 7, 14, 18, 21 ] [ Designated as safety issue: No ]

Enrollment: 24
Study Start Date: March 2009
Study Completion Date: September 2009
Primary Completion Date: September 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Repeat doses of active at escalating doses
Drug: 1278863
15mg, 25mg, 50mg, 150mg
Placebo Comparator: 2
Repeat doses of placebo
Drug: Placebo
matching placebo

Detailed Description:

Compound 1278863A is a novel small molecule agent, which stimulates erythropoiesis through inhibition of hypoxia-inducible factor (HIF)-prolyl hydroxylases (EGLNs). This compound is being developed for the treatment of anemia. Compound 111427 was the first administration of compound 1278863A to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses up to 300 mg in healthy adult subjects. This study, PHI112842, will be the first administration of compound 1278863A to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of repeat oral doses up to 300 mg for 14 days in healthy adult subjects. At least 6 subjects will complete each cohort. Multiple blood samples for pharmacokinetic analyses will be obtained post-dose in each cohort. Safety will be assessed by measurement of vital signs, cardiac monitoring, collection of adverse event assessments and laboratory safety tests. Blood samples will be collected for pharmacodynamic analyses.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Healthy as determined by a responsible physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
  2. Male or female between 18 and 55 years of age, inclusive.
  3. A female subject must be of non-childbearing potential.
  4. Male subjects must agree to use one of the acceptable contraception methods listed in the protocol
  5. Body weight greater than or equal to 50 kg and BMI within the range 19 - 31 kg/m2 (inclusive).
  6. Capable of giving written informed consent
  7. QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block.

Exclusion Criteria:

  1. The subject has a positive pre-study drug screen.
  2. A hemoglobin value at screening is:

    • Male subjects or post-menopausal females: > 15.5 g/dL
    • Female subjects: > 14.5 g/dL
  3. The values of hematological parameters at screening are:

    MCV: outside the reference range and clinically significant deemed by the investigator and GSK Medical Monitor

  4. The values of the following tests at screening are:

    • TIBC: outside the reference range
    • Serum iron: outside the reference range
    • Serum ferritin: outside the reference range
  5. A value at screening is greater than the upper limit of reference range for the following clinical laboratory parameters: AST, ALT, direct bilirubin.
  6. Clinically significant abnormal CPK determined by the investigator and GSK Medical Monitor.
  7. Calculated creatinine clearance: < 60mL/min
  8. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
  9. A positive test for HIV antibody.
  10. History of drug abuse or dependence within 6 months of the study.
  11. History of regular alcohol consumption within 6 months of the study
  12. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
  13. 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 drug
  14. History of sensitivity to any of the study drugs, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
  15. History of sensitivity to heparin or heparin-induced thrombocytopenia. (if the clinical research unit uses heparin to maintain intravenous cannula patency)
  16. Subjects with a pre-existing condition interfering with normal gastrointestinal anatomy or motility, and/or hepatic function that could interfere with the absorption, metabolism, and/or excretion of the study drugs.
  17. History of peptic ulcer disease.
  18. History of malignancy tumor. Non-melanoma skin cancer that has been definitely removed is allowed.
  19. Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.
  20. Lactating females.
  21. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
  22. Unwillingness or inability to follow the procedures, or lifestyle and/or dietary restrictions outlined in the protocol.
  23. Consumption of red wine, seville oranges, grapefruit or grapefruit juice, exotic citrus fruits, grapefruit hybrids or fruit juices of the prohibited fruits from 7 days prior to the first dose of study medication
  24. 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).
  25. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  26. Subject is mentally or legally incapacitated.
  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: NCT00840320

Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00840320     History of Changes
Other Study ID Numbers: 112842, PHI112842
Study First Received: February 9, 2009
Last Updated: February 28, 2013
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration

Keywords provided by GlaxoSmithKline:
Safety
tolerability

Additional relevant MeSH terms:
Kidney Diseases
Urologic Diseases

ClinicalTrials.gov processed this record on November 25, 2014