Pharmacokinetics, Pharmacodynamics, and Safety of Alogliptin in Children, Adolescents and Adults With Type 2 Diabetes Mellitus

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT00957268
First received: August 6, 2009
Last updated: January 26, 2015
Last verified: January 2015
  Purpose

The purpose of this study is to determine the pharmacokinetic and safety profile of alogliptin in children, adolescents, and adults with type 2 diabetes mellitus.


Condition Intervention Phase
Diabetes Mellitus, Type 2
Drug: Alogliptin
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: A Comparative, Randomized, Open-Label, Multi-Center, Single Dose Pharmacokinetic, Pharmacodynamic and Safety Study of Alogliptin (12.5 mg and 25 mg) Between Children, Adolescents, and Adults With Type 2 (Non-Insulin Dependent) Diabetes Mellitus

Resource links provided by NLM:


Further study details as provided by Takeda:

Primary Outcome Measures:
  • Cmax: Maximum Observed Plasma Concentration for Alogliptin [ Time Frame: 1 hour pre-dose and 1, 2, 4, 8, 12, 16, 24, 48, and 72 hours post-dose ] [ Designated as safety issue: No ]
    Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.

  • Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alogliptin [ Time Frame: 1 hour pre-dose and 1, 2, 4, 8, 12, 16, 24, 48, and 72 hours post-dose ] [ Designated as safety issue: No ]
    Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.

  • AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Alogliptin [ Time Frame: 1 hour pre-dose and 1, 2, 4, 8, 12, 16, 24, 48, and 72 hours post-dose ] [ Designated as safety issue: No ]
    AUC(0-inf) is measure of area under the curve over the dosing interval (tau) (AUC(0-tau]), where tau is the length of the dosing interval in this study).


Secondary Outcome Measures:
  • Area Under the Plasma Effect-Time Curve From Time 0 to 24 Hours Post-dose (AUEC[0-24]) of Dipeptidyl Peptidase-4 (DPP-4) Inhibition [ Time Frame: 1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose ] [ Designated as safety issue: No ]
    The area under the plasma effect-time curve from time 0 to 24 hours post-dose (AUEC[0-24]) of dipeptidyl peptidase-4 (DPP-4) inhibition was determined from the inhibition-time curve.

  • Maximum Observed Effect (Emax) of Dipeptidyl Peptidase-4 (DPP-4) Inhibition [ Time Frame: 1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose ] [ Designated as safety issue: No ]
    The maximum observed effect (Emax) of dipeptidyl peptidase-4 (DPP-4) inhibition was determined from the inhibition-time curve.

  • Time to Reach the Maximum Observed Effect of Dipeptidyl Peptidase-4 (DPP-4) Inhibition [ Time Frame: 1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose ] [ Designated as safety issue: No ]
    The time to reach the maximum observed effect of dipeptidyl peptidase-4 (DPP-4) inhibition was determined from the inhibition-time curve.

  • Observed Effect at 24 Hours Post-dose (E24) of Dipeptidyl Peptidase-4 (DPP-4) Inhibition [ Time Frame: 1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose ] [ Designated as safety issue: No ]
    The observed effect at 24 hours post-dose (E24) of dipeptidyl peptidase-4 (DPP-4) inhibition was determined from the inhibition-time curve.

  • Area Under the Plasma Effect-Time Curve From Time 0 to 24 Hours Post-dose (AUEC[0-24]) of the Baseline-corrected Glucagon-like Peptide-1 (GLP-1) Concentration [ Time Frame: 1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose ] [ Designated as safety issue: No ]
    The area under the plasma effect-time curve from time 0 to 24 hours post-dose (AUEC[0-24]) of baseline-corrected glucagon-like peptide-1 was determined from the concentration-time curve. Baseline-corrected glucagon-like peptide-1 concentrations were calculated as the post-dose concentration at each post-dose time point minus the baseline (pre-dose) concentration.

  • Maximum Observed Effect (Emax) of the Baseline-corrected Glucagon-like Peptide-1 (GLP-1) Concentration [ Time Frame: 1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose ] [ Designated as safety issue: No ]
    The maximum observed effect (Emax) of baseline-corrected glucagon-like peptide-1 was determined from the concentration-time curve. Baseline-corrected glucagon-like peptide-1 concentrations were calculated as the post-dose concentration at each post-dose time point minus the baseline (pre-dose) concentration.

  • Time to Reach the Maximum Observed Effect of the Baseline-corrected Glucagon-like Peptide-1 (GLP-1) Concentration [ Time Frame: 1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose ] [ Designated as safety issue: No ]
    The time to reach the maximum observed effect of baseline-corrected glucagon-like peptide-1 was determined from the concentration-time curve. Baseline-corrected glucagon-like peptide-1 concentrations were calculated as the post-dose concentration at each post-dose time point minus the baseline (pre-dose) concentration.

  • Observed Effect at 24 Hours Post-dose (E24) of the Baseline-corrected Glucagon-like Peptide-1 (GLP-1) Concentration [ Time Frame: 1 hour pre-dose and 2, 4, 8, 12, and 24 hours post-dose ] [ Designated as safety issue: No ]
    The observed effect at 24 hours post-dose (E24) of baseline-corrected glucagon-like peptide-1 was determined from the concentration-time curve. Baseline-corrected glucagon-like peptide-1 concentrations were calculated as the post-dose concentration at each post-dose time point minus the baseline (pre-dose) concentration.


Enrollment: 46
Study Start Date: September 2009
Study Completion Date: November 2013
Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Alogliptin 12.5 mg (age 10 to < 14 years)
Alogliptin 12.5 mg, tablets, orally, 1 dose only.
Drug: Alogliptin
Alogliptin tablets
Other Name: SYR-322
Experimental: Alogliptin 25 mg (age 10 to < 14 years)
Alogliptin 25 mg, tablets, orally, 1 dose only.
Drug: Alogliptin
Alogliptin tablets
Other Name: SYR-322
Experimental: Alogliptin 12.5 mg (age 14 to < 18 years)
Alogliptin 12.5 mg, tablets, orally, 1 dose only.
Drug: Alogliptin
Alogliptin tablets
Other Name: SYR-322
Experimental: Alogliptin 25 mg (age 14 to < 18 years)
Alogliptin 25 mg, tablets, orally, 1 dose only.
Drug: Alogliptin
Alogliptin tablets
Other Name: SYR-322
Experimental: Alogliptin 25 mg (age 18 to 65 years)
Alogliptin 25 mg, tablets, orally, 1 dose only.
Drug: Alogliptin
Alogliptin tablets
Other Name: SYR-322

Detailed Description:

Alogliptin is a selective, orally available inhibitor of dipeptidyl peptidase-4 being developed by Takeda Global Research & Development as a treatment for type 2 diabetes mellitus. Inhibition of dipeptidyl peptidase-4 (DPP-4) prolongs the action of 2 important incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These hormones are responsible for increasing insulin synthesis, regulating β-cell proliferation, inhibiting gastric emptying, and inhibiting glucagon secretion.

To date, alogliptin has not been studied in participants less than 18 years of age. As with adults, there is growing evidence of an increase in the prevalence of type 2 diabetes mellitus in children and adolescents.

This study is designed to determine the pharmacokinetic, pharmacodynamic, and safety profiles of alogliptin in children and adolescents with type 2 diabetes mellitus. These profiles will be compared with those of similarly matched adult participants with type 2 diabetes mellitus. Pharmacokinetic, pharmacodynamics, and safety endpoints will be analyzed.

  Eligibility

Ages Eligible for Study:   10 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria for children and adolescent participants only (Groups 1 and 2, respectively):

  1. Participant was male or female between 10 and 17 years of age.
  2. Participant or parent or legal guardian was capable of understanding and complying with the protocol requirements.
  3. Participant was capable of understanding an informed consent form (ICF) or assenting to participate. The parent or legal guardian of the participant must have been able to understand and sign an ICF prior to the initiation of any study procedures.
  4. Participant weighed at least 36 kg (79 pounds) and had a Screening body mass index (BMI) of at least 18 kg/m^2.
  5. Participants had a diagnosis of type 2 diabetes mellitus (T2DM) (non-insulin dependent) based on diagnostic criteria of the American Diabetes Association (ADA). Criteria included:

    1. Fasting plasma glucose level of ≥ 126 mg/dL where fasting is defined as no caloric intake for at least 8 hours, or
    2. 2-hour plasma glucose level of ≥ 200 mg/dL during an oral glucose tolerance test, or
    3. random plasma glucose level of ≥ 200 mg/dL, or
    4. glycated hemoglobin (HbA1c) ≥ 6.5%.
  6. Diagnosis could have been historical (documented), or participants could have been diagnosed for this study.
  7. Participants had a fasting serum C-peptide concentration ≥ 0.8 ng/mL (≥ 0.26 nmol/L) at the Screening Visit only.
  8. Participants may have been taking concomitant metformin if the dose was stable for at least 30 days prior to Day 1 (day of first dosing).

    Inclusion criteria for adult participants only (Group 3):

  9. Participant was male or female, and between 18 and 65 years of age, inclusive for gender and race matched adult participants with T2DM only.
  10. Participant was capable of understanding and complying with protocol requirements and was willing to sign the ICF prior to the initiation of any study procedures for gender and race matched adult participants with T2DM only.
  11. Participant weighed at least 50 kg (110 pounds) and had a Screening BMI between 23 kg/m^2 and 45 kg/m^2 (except for Asian or Asian-descendant participants for whom the range was between 20 kg/m^2 and 35 kg/m^2), inclusive for gender and race matched T2DM adult participants only.
  12. Participants had a diagnosis of T2DM (non-insulin dependent) based on diagnostic criteria of the ADA. Criteria included:

    1. Fasting plasma glucose level of ≥ 126 mg/dL where fasting is defined as no caloric intake for at least 8 hours, or
    2. 2-hour plasma glucose level of ≥ 200 mg/dL during an oral glucose tolerance test, or
    3. random plasma glucose level of ≥ 200 mg/dL, or
    4. HbA1c ≥ 6.5%.
  13. Diagnosis could have been historical (documented) or participants could have been diagnosed for this study.
  14. Participants may have been taking concomitant metformin if the dose was stable for at least 30 days prior to Day 1.
  15. Participants may have been taking statin or antihypertensive drugs if the dose was stable for at least 30 days prior to Day 1.

    Inclusion criteria for all participants (Groups 1, 2, and 3):

  16. Female participants of childbearing potential and male participants who were sexually active agreed to routinely use adequate contraception from Screening until 30 days after receiving the dose of study drug. NOTE: Women not of childbearing potential were defined as those who were surgically sterilized (hysterectomy, bilateral oophorectomy, tubal ligation) or who were postmenopausal (defined as at least 45 years of age and 1 year since last regular menses).
  17. Participant had a negative urine test result for selected substances of abuse (including alcohol and cotinine) at Screening and Check-in (Day -1).
  18. Participant had clinical chemistry, hematology, and complete urinalysis (fasted for at least 8 hours) results within the reference range for the testing laboratory (except results associated with T2DM) unless the out-of-range results were deemed not clinically meaningful by the investigator or sponsor.
  19. Participant had a negative test result for hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (anti-HCV), and no known history of human immunodeficiency virus.

Exclusion Criteria:

  1. Participant was currently participating in another investigational study or took an investigational drug within 30 days prior to Day 1.
  2. Participant received alogliptin previously.
  3. Participant was a study site employee, or was an immediate family member (ie, spouse, parent, child, or sibling) of a study site employee involved in conduct of this study.
  4. Participant received or donated blood or blood products within 30 days prior to Screening or planned to donate blood during the study.
  5. Participant had a known hypersensitivity to alogliptin or related compounds.
  6. Participant had a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as consumption of more than 4 alcoholic drinks per day) within 1 year prior to study Day 1.
  7. Participant had an acute, clinically significant illness (excluding T2DM) within 30 days prior to study Day 1.
  8. Participant had any other condition or prior therapy that, in the opinion of the investigator, would have made the participant unsuitable for the study.
  9. Participant had a history or clinical manifestations of significant metabolic (excluding T2DM), hematologic, pulmonary, cardiovascular, gastrointestinal, neurologic, hepatic, renal, urologic, immunologic, musculoskeletal, or psychiatric disorder.
  10. Participant had a hemoglobin value < 12 g/dL.
  11. Participant had a systolic blood pressure > 140 mm Hg or had a diastolic blood pressure > 90 mmHg at Screening or Check-in (Day -1).
  12. Adult participant had an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level greater than 2 times the upper limit of normal (ULN), active liver disease, or jaundice at the Screening Visit or on Check-in (Day -1).
  13. Pediatric participant had an ALT or AST level greater than 1.5 times the ULN at the Screening Visit or on Check-in (Day -1).
  14. Participant had a serum creatinine level > 1.5 mg/dL.
  15. Participant had a creatinine clearance (CrCl) < 50 mL/min (normalized to body surface area of 1.73 m^2).
  16. Participant had a history of abdominal surgery (except laparoscopic cholecystectomy or uncomplicated appendectomy) or thoracic or nonperipheral vascular surgery within 6 months prior to Day 1.
  17. Participant had a history or presence of a clinically significant abnormal 12-lead electrocardiogram (ECG) result as determined by the investigator or Takeda at Screening or Check-in (Day -1).
  18. Participant had a history of cancer, other than basal cell carcinoma or Stage I squamous cell carcinoma of the skin that had not been in remission for at least 5 years prior to the first dose of study drug.
  19. If female, participant was pregnant or lactating or intending to become pregnant before, during, or within 30 days after receiving study drug.
  20. If male, participant intended to impregnate others during the study or for 30 days after receiving study drug.
  21. Participant consumed or was unable to abstain from consumption of products containing alcohol, caffeine, or xanthine, and food or beverages containing grapefruit juice or Seville-type oranges within 72 hours prior to study Day 1 and for the duration of the study.
  22. Participant used any tobacco (ie, nicotine) products (including but not limited to cigarettes, pipe, cigar, chewing tobacco, nicotine patch, or nicotine gum) within 6 weeks prior to study Day 1, and was unwilling to abstain from these products for the duration of the study.
  23. Participant used any nutraceutical preparations within 28 days prior to study Day 1.
  24. Participant was currently taking ketoconazole, fluconazole, gemfibrozil, rifampin, or carbamazepine or taken within 28 days prior to Check-in (Day -1).
  25. Participant had poor peripheral venous access.
  26. Participant had a medical history of clinical or laboratory evidence to indicate a diagnosis of type 1 diabetes or secondary forms of diabetes, including maturity-onset diabetes of the young (MODY).
  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: NCT00957268

Locations
United States, Florida
Miami, Florida, United States
Pineallas Park, Florida, United States
United States, Kentucky
Louisville, Kentucky, United States
United States, North Carolina
Durham, North Carolina, United States
United States, Pennsylvania
Philadelphia, Pennsylvania, United States
United States, Tennessee
Memphis, Tennessee, United States
United States, Texas
San Antonio, Texas, United States
Sponsors and Collaborators
Takeda
Investigators
Study Director: VP Clinical Science Takeda
  More Information

No publications provided

Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT00957268     History of Changes
Other Study ID Numbers: SYR-322_104, 2009-011221-13, U1111-1111-7810
Study First Received: August 6, 2009
Results First Received: November 21, 2014
Last Updated: January 26, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Takeda:
Type 2 diabetes mellitus
Non-insulin dependent diabetes mellitus
Drug therapy
Pediatrics

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Alogliptin
Dipeptidyl-Peptidase IV Inhibitors
Enzyme Inhibitors
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Hypoglycemic Agents
Incretins
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protease Inhibitors

ClinicalTrials.gov processed this record on May 28, 2015