A Study to Evaluate the Effect of the Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Blocker, GSK2798745, on Pulmonary Gas Transfer and Respiration in Patients With Congestive Heart Failure

NCT02497937 | Completed Phase 2 Results

• 1 other identifier: 201881
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 2

Brief Summary

This study is a single centre, randomised, double-blind, sponsor-unblinded, placebo-controlled, 2 by 2 crossover study in adults with heart failure. In blocking the TRPV4 ion channel and reducing pulmonary interstitial fluid, GSK2798745 may improve pulmonary function, respiration, and gas exchange as well as sleep-disordered breathing in patients with heart failure. Therefore, the current study is designed to investigate the effect of repeat administration of GSK2798745 on pulmonary gas exchange and pulmonary function. A sufficient number of subjects with heart failure will be enrolled so that 12 subjects complete the two study periods and critical assessments. Subjects will be randomised to receive either GSK2798745 or placebo once daily for a period of 7 days in one treatment period and alternate study medication in the second treatment period. Both the treatment periods will be separated by a washout period of at least 14-days. This study will consist of a Screening visit within 14 days of the start of Period I and two treatment periods wherein eligible subjects will be randomised to one of the two treatment sequences, a follow-up visit approximately 2 weeks after the completion of second study period. The total duration of the study is approximately 8 weeks from screening to follow-up visit.

Conditions

Heart Failure

Keywords

GSK2798745; TRPV4 Channel Blocker; Pharmacodynamics; Adults; Congestive Heart Failure

Outcome Measures

Primary Outcomes (2)

• Change From Baseline in the Diffusing Capacity of the Lung for Carbon Monoxide (DLco) on Pulmonary Gas Transfer (Site: Mayo)

  DLco is a measure of the ability of a gas to transfer from alveoli across the alveolar epithelium and capillary endothelium to the red blood cells. Changes in DLco reflect the alveolar-capillary membrane conductance. Acute pulmonary congestion causes a reduction in DLco. In participants with heart failure, decrease in DLco serves as a predictor of disease progression. An impairment in the diffusing capacity of the lung may be related to symptoms and exercise intolerance associated with heart failure. DLco was measured just prior to and after the 3- minute step test on Days -1, and 7 and just prior to and after an intravenous saline infusion on Day 5. Day -1 was Baseline and change from Baseline was calculated from Day -1 pre-exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as Baseline. Data of DLco (milliliter per millimeter of mercury per minute \[mL/mmHg/min\]) for Mayo site is presented.

  Baseline, Day 4, Day 5 and Day 7 of each treatment period

• Change From Baseline in the Diffusing Capacity of the Lung for DLco on Pulmonary Gas Transfer (Site: Hennepin)

  DLco is a measure of the ability of a gas to transfer from the alveoli across the alveolar epithelium and the capillary endothelium to the red blood cells. Changes in DLco reflect the alveolar-capillary membrane conductance. Acute pulmonary congestion cause a reduction in DLco. In participants with heart failure, decrease in DLco serves as a predictor of disease progression. An impairment in the diffusing capacity of the lung may be related to the symptoms and exercise intolerance associated with heart failure. DLco was measured just prior to and after the 3- minute step test on Days -1, and 7 and just prior to and after an intravenous saline infusion on Day 5. Day -1 was Baseline and change from Baseline was calculated from Day -1 Pre-Exercise of the respective period, except when calculating the post-infusion change from Baseline, where the pre-infusion value was used as the Baseline. Statistical analysis was not performed as the sample size was too small

  Baseline, Day 4, Day 5 and Day 7 of each treatment period

Secondary Outcomes (36)

• Change From Baseline in Diffusing Capacity of the Lung for Nitric Oxide (DLno) and Membrane Conductance (DM)

  Baseline, Day 4, Day 5 and Day 7 of each treatment period

• Change From Baseline in Capillary Blood Volume (Vc)

  Baseline, Day 4, Day 5 and Day 7 of each treatment period

• Change From Baseline in DLco Following Exercise and Following an Intravenous Saline Infusion (Site: Mayo)

  Baseline, Day 5 and Day 7 of each treatment period

• Change From Baseline in DLco Following Exercise and Following an Intravenous Saline Infusion (Site: Hennepin)

  Baseline, Day 5 and Day 7 of each treatment period

• Change From Baseline in the Ventilation/Volume of Carbon Dioxide Production (VE/VCO2) Ratio

  Baseline and Day 7 of each treatment period

Study Arms (1)

GSK2798745 and Placebo

EXPERIMENTAL

Each subject will be randomized to receive GSK2798745 2.4 milligrams (mg) and Placebo once daily for 7 days, each in one of the two treatment periods. Two treatment periods will be separated by a 14-day washout period.

Drug: GSK2798745; Drug: Placebo

Interventions

GSK2798745 DRUG

GSK2798745 will be supplied as granule filled capsule with unit dose strength of 2.4 mg to be administered orally with 240 mL water.

GSK2798745 and Placebo

Placebo DRUG

Placebo will be supplied as blend filled capsule to be administered orally with 240 mL water.

GSK2798745 and Placebo

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \>=21 years of age at the time of signing the informed consent form.
• Diagnosis of heart failure (New York Heart Association Class II-IV) for a minimum of 3 months prior to screening.
• Clinically stable with no changes in optimized guidance-directed medications and no hospitalizations for heart failure for at least 1 month prior to Screening.
• N-terminal pro-B-type Natriuretic Peptide (NT-proBNP) \>1000 picogram per milliliter (pg/mL) measured within 6 months prior to OR at Screening.
• Average DLco measurements outside the normal range (percent \[%\] predicted DLco \< 80%) during the Screening Period.
• Body mass index (BMI) \>=18 and \<=40 kilogram per meter square (kg/m\^2).
• Male or female of non-childbearing potential-
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.

You may not qualify if:

• History of acute coronary syndromes including unstable angina or myocardial infarction within 6 months of screening.
• Coronary revascularization including angioplasty and stenting within 6 months of Screening.
• History of stroke or seizure disorder within 5 years of Screening.
• Diagnosis of asthma.
• Diagnosis of chronic obstructive pulmonary disease (COPD) with FEV1 \<50% of predicted measured within 4 weeks of Screening.
• History of a condition that required radiation therapy to the thorax.
• History of any type of malignancy within the past five years with the exception of successfully treated basal cell cancer of the skin.
• Active ulcer disease or gastrointestinal bleeding.
• Current or chronic history of liver disease, known hepatic impairment, or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Alanine transaminase (ALT) \>2x Upper Limit of Normal (ULN) and bilirubin \>1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• QT interval corrected (QTc) \> 450 millisecond (msec) or QTc \> 480 msec in subjects with Bundle Branch Block.
• Use of medications specified for the treatment of COPD including short- and long acting bronchodilators (beta-agonists and anticholinergics) and inhaled glucocorticoids as well as oxygen therapy.
• Use of a listed prohibited medication within the restricted timeframe relative to the first dose of study medication.
• Use of a strong inhibitors or inducers of cytochrome P450 (CYP) 3A or p-glycoprotein.
• Current smoker.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (2)

GSK Investigational Site

Minneapolis, Minnesota, 55415, United States

Location

GSK Investigational Site

Rochester, Minnesota, 55905, United States

Location

MeSH Terms

Conditions

Heart Failure

Interventions

GSK2798745

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 13, 2015
• First Posted: July 15, 2015
• Study Start: April 13, 2016
• Primary Completion: August 21, 2017
• Study Completion: August 21, 2017
• Last Updated: September 5, 2018
• Results First Posted: September 5, 2018

Record last verified: 2018-04

Locations

US (2)