Effects of TD-4208 on FEV1 in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Overview

Thirty-two subjects diagnosed with COPD were enrolled, received each study treatment and completed the follow-up assessments. During each of the four study periods, subjects were admitted to the clinic on Day -1 and housed overnight until after the last spirometry measurement. Serial pulmonary function tests were performed and PK (pharmacokinetics) samples collected up to 25 hours. Subjects were discharged from the clinic on Day 2 after evaluations.

Full Title of Study: “A Phase 2, Randomized, Double-Blind, Crossover Study to Examine the Pharmacodynamics, Safety and Tolerability, and Pharmacokinetics of Single Doses of TD-4208 in Subjects Diagnosed With Chronic Obstructive Pulmonary Disease”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: October 2011

Detailed Description

Subjects were assigned to one of the 4-treatment sequence groups presented in the table above according to a randomization schedule supplied by the Sponsor before study initiation. The randomization scheme did not include assignments for replacement subjects.

Subjects reported to their respective clinical research unit (CRU) on Admission/Day −1 for pre-randomization procedures and confirmation of eligibility (and continued eligibility for Periods 2 to 4). The unblinded pharmacist prepared and dispensed the nebulizers, according to the randomization schedule for each of the 4 periods. Dosing occurred in the morning, generally between 7 am and 9 am. For Periods 2 to 4, dosing occurred within ±30 minutes of the dosing time established in Period 1.

Study drug was administered in the respective CRU under the supervision of study personnel. Single doses of TD-4208, ipratropium bromide, and placebo were administered in the clinical research unit (CRU) under the supervision of study personnel. Care was taken to avoid eye contact with study drugs. Residual drug solution remaining in the nebulizer (ie, in mL) was measured and recorded.

The investigator or designee was responsible for maintaining accountability records for all study drug(s) in accordance with applicable government regulations and study procedures.

The accountability record included entries for receipt, distribution or dispensing, and destruction of the material(s). Unused and expired study drugs were to be disposed of in accordance with written instructions from the Sponsor.

Interventions

  • Drug: Placebo
  • Drug: TD-4208 700 μg
  • Drug: TD-4208 350 μg
  • Drug: Ipratropium 500 μg

Arms, Groups and Cohorts

  • Placebo Comparator: Placebo
    • Sequence 1: Period 1 = Placebo; Period 2 = TD-4208 700 μg; Period 3 = TD-4208 350 μg; Period 4 = Ipratropium 500 μg
  • Experimental: TD-4208 700 μg
    • Sequence 2: Period 1 = TD-4208 700 μg; Period 2 = Ipratropium 500 μg; Period 3 = Placebo; Period 4 = TD-4208 350 μg
  • Experimental: TD-4208 350 μg
    • Sequence 3: Period 1 = TD-4208 350 μg; Period 2 = Placebo; Period 3 = Ipratropium 500 μg; Period 4 = TD-4208 700 μg
  • Active Comparator: Ipratropium 500 μg
    • Sequence 4: Period 1 = Ipratropium 500 μg; Period 2 = TD-4208 350 μg; Period 3 = TD-4208 700 μg; Period 4 = Placebo

Clinical Trial Outcome Measures

Primary Measures

  • Change in peak forced expiratory volume in one second (FEV1) relative to baseline
    • Time Frame: From predose to 25 hours postdose

Secondary Measures

  • Area under the FEV1 vs. time curve, time-matched difference from placebo
    • Time Frame: From predose to 25 hours postdose
  • Area under the FEV1 vs. peak FEV1, time-matched difference from placebo
    • Time Frame: From predose to 25 hours postdose
  • Peak Expiratory Flow Rate (PEFR) from 25% to 75% of vital capacity (FEF25−75), as related to FEV1
    • Time Frame: From predose to 25 hours postdose
  • Forced Expiratory flow from 25% to 75% of vital capacity (FEF25−75), as related to FEV1
    • Time Frame: From predose to 25 hours postdose
  • Forced Vital Capacity (FVC)
    • Time Frame: From predose to 25 hours postdose
  • Area under the forced vital capacity (FVC) vs. time curve
    • Time Frame: From predose to 25 hours postdose
  • Safety and tolerability endpoints: adverse events
    • Time Frame: From randomization to the Period 4 Post-Study Follow-up Visit (up to 84 days)
  • Safety and tolerability endpoints: vital signs
    • Time Frame: From predose to 24 hours postdose
  • Safety and tolerability endpoints: ECG parameters
    • Time Frame: From predose to 24 hours postdose
  • Safety and tolerability endpoints: physical exam results
    • Time Frame: From predose to 24 hours postdose
  • Safety and tolerability endpoints: clinical lab results
    • Time Frame: From predose to 24 hours postdose
  • Plasma PK parameters: Cmax
    • Time Frame: From predose to 24 hours postdose
  • Plasma PK parameters: Area under the concentration-versus-time curve calculated from time zero to the last detectable time point (AUC0-t)
    • Time Frame: From predose to 24 hours postdose
  • Plasma PK parameters: terminal half-life (t½)
    • Time Frame: From predose to 24 hours postdose
  • Plasma PK parameters: Renal clearance calculated as Ae/AUC0-t (CLrenal)
    • Time Frame: From predose to 24 hours postdose
  • Urine PK parameters: Cmax
    • Time Frame: From predose to 24 hours postdose
  • Urine PK parameters: Area under the concentration-versus-time curve calculated from time zero to the last detectable time point (AUC0-t)
    • Time Frame: From predose to 24 hours postdose
  • Urine PK parameters: terminal half-life (t½)
    • Time Frame: From predose to 24 hours postdose
  • Urine PK parameters: Renal clearance calculated as Ae/AUC0-t (CLrenal)
    • Time Frame: From predose to 24 hours postdose
  • Metabolite profiling performed using plasma and urine samples
    • Time Frame: From predose to 24 hours postdose
  • Pharmacokinetic parameters (including Time to maximum concentration [Tmax])
    • Time Frame: From predose to 24 hours postdose
  • Observed maximum concentration (Cmax)
    • Time Frame: From predose to 24 hours postdose
  • Elimination half-life (t1/2)
    • Time Frame: From predose to 24 hours postdose
  • Area Under the Concentration-time curve (AUC) for TD-4208 in blood
    • Time Frame: From predose to 24 hours postdose
  • Area Under the Concentration-time curve (AUC) for TD-4208 in urine
    • Time Frame: From predose to 24 hours postdose

Participating in This Clinical Trial

Inclusion Criteria

  • Diagnosis of moderate stable Chronic Obstructive Pulmonary.
  • Disease with FEV1/FVC <0.7 at screening.
  • Woman of non-childbearing potential.
  • Female participants of childbearing potential must test negative for pregnancy and must be using a highly effective method of birth control during the study and for at least 1 month after completion of study dosing.
  • Female participants must not be breastfeeding.
  • Men must agree to use a highly effective method of birth control with partners of childbearing potential during the study and for 1 month after completion of study dosing.
  • Current or past smoking history >10 pack-years.
  • Must be capable of performing reproducible spirometry maneuvers.

Exclusion Criteria

  • History of significant respiratory disease other than COPD, and/ or requires daily long-term oxygen therapy.
  • Exacerbation of COPD, lung infection within 6 weeks prior to study.
  • Start of or change in dose of COPD treatment 4 weeks before study.
  • Daily using of maintenance systemic/inhaled corticosteroids (>1000 microgram of fluticasone propionate equivalent or >5 mg prednisone).
  • Use of bronchodilators or medication for the treatment of COPD, aspirin, anti-inflammatories for a specific time, prior to the first dose or is not willing to abstain from their use for the specified time periods prior to study dose administration.
  • Symptomatic prostrate hypertrophy, bladder neck obstruction, active cancer, narrow angle glaucoma.
  • Clinical significant hypersensitivity to medications.
  • Participants have an uncontrolled hematologic, immunologic, renal, neurologic, hepatic, endocrine or other disease that may place participant at risk.
  • Cerebrovascular, cardiovascular disease or abnormal ECG.
  • History of drug or alcohol abuse.

Gender Eligibility: All

Minimum Age: 40 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Theravance Biopharma
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Glenn Crater, M.D., Study Director, Theravance Biopharma, US, Inc.

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