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A Dose Ascending, Study To Examine The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of GSK233705B.

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ClinicalTrials.gov Identifier: NCT00453479
Recruitment Status : Completed
First Posted : March 29, 2007
Results First Posted : February 8, 2018
Last Update Posted : March 12, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
GSK233705 is a high-affinity specific muscarinic receptor (mAChR) antagonist which is being developed for the treatment of chronic obstructive pulmonary disease. This is a randomised, double-blind, placebo-controlled, dose ascending, parallel group study to examine the safety, tolerability, pharmacokinetics and pharmacodynamics of twice daily inhaled doses of GSK233705B for 7 days, in COPD subjects.

Condition or disease Intervention/treatment Phase
Pulmonary Disease, Chronic Obstructive Drug: GSK233705B Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Primary Purpose: Diagnostic
Official Title: A Randomised, Double-blind, Placebo-controlled, Dose Ascending, 2-cohort, Parallel Group Study to Examine the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Twice-daily Inhaled Doses of GSK233705B Formulated With the Excipient Magnesium Stearate in COPD Subjects for 7-days.
Actual Study Start Date : March 28, 2007
Actual Primary Completion Date : October 11, 2007
Actual Study Completion Date : October 11, 2007

Resource links provided by the National Library of Medicine

MedlinePlus related topics: COPD




Primary Outcome Measures :
  1. Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) [ Time Frame: Up to follow-up (approximately 45 days) ]
    An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

  2. Summary of Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [ Time Frame: Up to Day 7 (24 hours post-dose) ]
    Blood pressure was measured subsequent to 12 lead electrocardiogram (ECG). Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on Baseline (triplicate), 15, 30 minutes, 1.5, 4, 8 and 24 hours on Day 1 and 7.

  3. Summary of Mean Heart Rate [ Time Frame: Up to Day 7 (24 hour post dose) ]
    Heart rate was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on Baseline (triplicate), 15, 30 minutes, 1.5, 4, 8 and 24 hours on Day 1 and 7.

  4. Maximum Value of SBP and DBP (0-4 Hour) for the Morning Dose [ Time Frame: Up to Day 7 (0-4 hour) ]
    Blood pressure was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.

  5. Maximum Value of Heart Rate (0-4 Hour) for the Morning Dose [ Time Frame: Up to Day 7 (0-4 hour) ]
    Heart rate was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.

  6. Weighted Mean of SBP and DBP (0-4 Hour) for the Morning Dose [ Time Frame: Up to Day 7 (0-4 hour) ]
    Blood pressure was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.

  7. Weighted Mean of Heart Rate (0-4 Hour) for the Morning Dose [ Time Frame: Up to Day 7 (0-4 hour) ]
    Heart rate was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.

  8. Number of Participants With Abnormal 12-lead ECG Findings [ Time Frame: Up to Day 7 (24 hour post dose) ]
    Single measurements were taken at all time points. The pre-dose values were classed as Baseline. Data for number of participants with normal, abnormal not clinically significant and abnormal clinically significant is presented. It was assessed on Baseline (triplicate), 15, 30 minutes, 1.5, 4, 8 and 24 hours on Day 1 and 7.

  9. Maximum Value (0-4 Hour) for the Morning Dose of ECG Parameters Corrected According to Fredericia's Formula (QTcF) and Corrected According to Bazett's Formula (QTc B) [ Time Frame: Up to Day 7 (0-4 hour) ]
    Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.

  10. Weighted Mean (0-4 h) for the Morning Dose of ECG Parameters QTcF and QTc B [ Time Frame: Up to Day 7 (0-4 hour) ]
    Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.

  11. Summary of Mean Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) [ Time Frame: Up to Day 7 (24-hour post dose) ]
    It was assessed on 1, 2, 4, 9, 12 and 24 hours on Days 1 and 7. Also on Day 7, it was measured on 0 hour (Baseline). At all time points 3 measurements were taken and formal statistical analysis was carried out on the derived maximum readings. Data for adjusted mean is presented as least square mean.

  12. Number of Participants Who Used Rescue Medication [ Time Frame: Up to Day 7 ]
    Inhaled salbutamol was used as a rescue medication. Participants were required to keep a diary of their rescue medication (total number of salbutamol doses taken) over the entire 7-day treatment period. Diaries were reviewed by the Investigator when participants were admitted to the unit on Days 1, 2, 7 and 8.

  13. Number of Participants With Abnormalities in Chemistry Data of Clinical Concern [ Time Frame: Up to Day 7 ]
    Clinical chemistry parameters included urea, potassium, aspartate aminotransferase (AST), total bilirubin, creatinine, creatine kinase, chloride, alanine aminotransferase (ALT), uric acid, glucose, gamma glutamyltransferase (GGT), albumin, sodium, phosphorus inorganic, calcium, alkaline phosphatase (ALP) and total protein. It was assessed on Day 1 (pre-dose, 24 hours) and Day 7 (pre-dose, 24 hours). Data for parameters with above and below the potential clinical concern (PCI) is provided.

  14. Number of Participants With Abnormalities in Hematology Data of Clinical Concern [ Time Frame: Up to Day 7 ]
    Hematology parameters included platelet count, red blood cell (RBC) count, mean corpuscular volume (MCV), total neutrophils, white blood cell (WBC) count (absolute), mean corpuscular hemoglobin (MCH), lymphocytes, mean corpuscular hemoglobin concentration (MCHC), monocytes, hemoglobin, eosinophils, hematocrit and basophils. It was assessed on Day 1 (pre-dose, 24 hours) and Day 7 (pre-dose, 24 hours). Data for parameters with above and below the PCI is provided.

  15. Summary of Microscopy Data for Participants With Abnormal Urinalysis Dipstick Results [ Time Frame: Up to Day 7 (pre dose) ]
    Urinalysis parameters included protein, blood, ketones, glucose, bilirubin, urobilinogen, leukocyte esterase, specific gravity, nitrites and pH. Sediment microscopy was performed only on urine samples showing an abnormality on the dipstick. Microscopy was performed for: WBC, RBC, hyaline casts, granular casts and cellular casts. It was assessed on Day 1 (pre-dose, 24 hours) and Day 7 (pre-dose, 24 hours).

  16. Summary of Mean (0-24 Hour) and Maximum (0-24 Hour) Heart Rate Measured Using 24 Hour Using Holter ECG Data [ Time Frame: Up to Day 7 ]
    Holter monitors were switched on immediately prior to dosing (up to 15mins pre-dose) so as to capture Holter ECG data from the 24 hour period following dosing. It was assessed on Day 1 and 7.


Secondary Outcome Measures :
  1. Plasma Concentrations of GSK233705 [ Time Frame: Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose ]
    Blood samples were collected at indicated time points. 12 hour pharmacokinetic (PK) sampling was before evening dose.

  2. Urine Concentrations of GSK233705 [ Time Frame: Day 1 and 7 throughout 24 hours ]
    Urine GSK233705 pharmacokinetic excretion rate-time data is presented. Urine samples were collected throughout study and consolidated data is presented as 0-12 hours and 12-24 hours. 12 hour pharmacokinetic sampling was before evening dose.

  3. Derived Plasma PK Parameters-area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC0-tau) [ Time Frame: Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose ]
    Blood samples were collected at indicated time points. 12 hour PK sampling was before evening dose. Data presented for morning samples.

  4. Derived Plasma PK Parameters-area Under Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-t) [ Time Frame: Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose ]
    Blood samples were collected at indicated time points. 12 hour PK sampling was before evening dose. Data presented for morning sample as adjusted geometric mean.

  5. Derived PK Plasma Parameters-area Under Concentration-maximum Observed Plasma Concentration (Cmax) [ Time Frame: Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose ]
    Blood samples were collected at indicated time points. 12 hour PK sampling was before evening dose. Data presented for morning and evening samples as adjusted geometric mean.

  6. Derived PK Plasma Parameters-area Under Concentration-time of Maximum Observed Plasma Concentration (T-max), Half-life (T-half) and Last Time Point Where the Concentration is Above the Limit of Quantification (T-last) [ Time Frame: Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose ]
    Blood samples were collected at indicated time points. 12 hour PK sampling was before evening dose. Data presented for morning and evening samples.

  7. Derived Urine Pharmacokinetic (PK) Parameters-area Under the Plasma Concentration-amount of Drug Excreted Unchanged in Urine (Ae) [ Time Frame: Day 1 and 7 throughout 24 hours ]
    Urine GSK233705 pharmacokinetic excretion rate-time data is presented. Urine samples were collected throughout study and consolidated data presented as AM dose and PM dose. 12 hour pharmacokinetic sampling was before evening dose.

  8. Derived Urine PK Parameters-area Under Concentration-fraction of Dose Excreted Unchanged in Urine (Fe) [ Time Frame: Day 1 and 7 throughout 24 hours ]
    Urine GSK233705 pharmacokinetic excretion rate-time data is presented. Urine samples were collected throughout study and consolidated data presented as 0-12 hours and 12-24 hours. 12 hour pharmacokinetic sampling was before evening dose.

  9. Derived Urine PK Parameters-area Under Concentration-renal Clearance (Clr) [ Time Frame: Day 1 and 7 throughout 24 hours ]
    Urine GSK233705 pharmacokinetic excretion rate-time data is presented. Urine samples were collected throughout study. 12 hour pharmacokinetic sampling was before evening dose.



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Ages Eligible for Study:   40 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men or women who are between 40 and 75 years of age
  • Female subjects must be of non-childbearing
  • Subject diagnosed with COPD
  • Body Mass Index 18.0 - 32.0 kg/m2 (inclusive)
  • Subject is a smoker or an ex-smoker
  • Subject has post-bronchodilator (200µg salbutamol) FEV1 of = 40% to = 80% of predicted normal.
  • Subject has FEV1/FVC < 0.7 post-bronchodilator (200µg salbutamol).
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
  • Subject is available to complete all study measurements and procedures.
  • Subjects have a 24hour holter recording that is within normal limits and does not demonstrate any clinically important abnormality that, in the opinion of the investigator, would make the subject unsuitable for participation in the study.

Exclusion Criteria:

  • Subjects who have a past or present disease, which as judged by the Investigator and the Medical Monitor, may affect the outcome of this study.
  • The subject has a positive pre-study alcohol screen.
  • The subject has a positive pre-study drug screen.
  • History of alcohol/drug abuse or dependence within 12 months of the study: Abuse
  • The subject has a positive pregnancy test.
  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
  • Subject has tested positive for HIV
  • The subject has participated in a clinical trial and has received a drug or a new chemical entity within 60 days or 5 half-lives
  • Exposure to more than three new chemical entities (NCE) within 10 months prior to the first dosing day or one NCE within 3 months prior to the first dosing day.
  • The subject has donated a unit (400ml) of blood within 60 days of screening, or, intends to donate during the study.
  • The subject has a known allergy or hypersensitivity to ipratropium bromide, atropine and any of its derivatives or milk protein/lactose.
  • 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 physician responsible, contraindicates their participation
  • Subject has prostate hypertrophy or narrow angle glaucoma

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00453479


Locations
Netherlands
GSK Investigational Site
Eindhoven, Netherlands, 5623 EJ
GSK Investigational Site
Harderwijk, Netherlands, 3844 DG
GSK Investigational Site
Utrecht, Netherlands, 3584 CJ
GSK Investigational Site
Zuidlaren, Netherlands, 9471 GP
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline

Additional Information:
Study Data/Documents: Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: AC2108378
For additional information about this study please refer to the GSK Clinical Study Register
Clinical Study Report  This link exits the ClinicalTrials.gov site
Identifier: AC2108378
For additional information about this study please refer to the GSK Clinical Study Register
Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: AC2108378
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: AC2108378
For additional information about this study please refer to the GSK Clinical Study Register
Informed Consent Form  This link exits the ClinicalTrials.gov site
Identifier: AC2108378
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: AC2108378
For additional information about this study please refer to the GSK Clinical Study Register
Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: AC2108378
For additional information about this study please refer to the GSK Clinical Study Register

Publications:
This study has not been published in the scientific literature.

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00453479     History of Changes
Other Study ID Numbers: AC2108378
First Posted: March 29, 2007    Key Record Dates
Results First Posted: February 8, 2018
Last Update Posted: March 12, 2018
Last Verified: July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
URL: http://

Keywords provided by GlaxoSmithKline:
muscarinic receptor,
bronchodilators
Chronic obstructive pulmonary disease,

Additional relevant MeSH terms:
Lung Diseases
Chronic Disease
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases
Disease Attributes
Pathologic Processes
Lung Diseases, Obstructive