Phase 2
Completed N=11
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
Source: ClinicalTrials.gov NCT02497937 ↗Enrolled (actual)
11
Serious AEs
4.6%
Results posted
Sep 2018
Primary outcomePrimary: Change From Baseline in the Diffusing Capacity of the Lung for Carbon Monoxide (DLco) on Pulmonary Gas Transfer (Site: Mayo) — 0.6; 1.4; -0.4; 0.6 mL/mmHg/min
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Change From Baseline in the Diffusing Capacity of the Lung for Carbon Monoxide (DLco) on Pulmonary Gas Transfer (Site: Mayo) |
0.6; 1.4; -0.4; 0.6; -1.0; 0.4 | — |
| PRIMARY Change From Baseline in the Diffusing Capacity of the Lung for DLco on Pulmonary Gas Transfer (Site: Hennepin) |
1.3; 1.0; 1.5; 0.1; 0.2; -0.3 | — |
| SECONDARY Change From Baseline in Diffusing Capacity of the Lung for Nitric Oxide (DLno) and Membrane Conductance (DM) |
2.1; 3.5; -2.3; 5.0; -6.0; 2.4 | — |
| SECONDARY Change From Baseline in Capillary Blood Volume (Vc) |
1.6; 10.4; -2.6; -0.2; -0.1; 3.0 | — |
| SECONDARY Change From Baseline in DLco Following Exercise and Following an Intravenous Saline Infusion (Site: Mayo) |
0.6; 1.4; -0.8; -0.7; 0.4; 1.6 | — |
| SECONDARY Change From Baseline in DLco Following Exercise and Following an Intravenous Saline Infusion (Site: Hennepin) |
1.3; 1.0; 0.7; 0.8; 1.2; 0.4 | — |
| SECONDARY Change From Baseline in the Ventilation/Volume of Carbon Dioxide Production (VE/VCO2) Ratio |
1.3; 0.3; 1.6; 1.8; 0.7; -4.5 | — |
| SECONDARY Change From Baseline in Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 Second (FEV1), Forced Expiratory Flows (FEF) 25-75, FEF50 and FEF75 |
-0.0; -0.1; -0.0; -0.0; -0.1; -0.0 | — |
| SECONDARY Change From Baseline in Functional Residual Capacity (FRC) |
— | — |
| SECONDARY Change From Baseline in End-expiratory Lung Volume (EELV) Measured by Body Plethysmograph |
— | — |
| SECONDARY Change From Baseline in Dyspnea Score |
0.5; 0.5; 0.2; -0.2; 0.2; -0.2 | — |
| SECONDARY Respiratory Rate Over Time Continuously Measured by Body Sensor (Site: Mayo Only) |
22.9; 13.3; 15.3; 16.8; 15.4; 17.7 | — |
| SECONDARY Change From Baseline in Systolic Blood Pressure(SBP) and Diastolic Blood Pressure (DBP) |
-6.8; 2.5; -7.8; -2.5; -8.8; 0.0 | — |
| SECONDARY Change From Baseline in Heart Rate |
-7.0; 5.2; -5.8; -2.8; -2.4; -0.8 | — |
| SECONDARY Change From Baseline in Respiration Rate |
0.6; 1.0; -0.2; 0.7; 0.2; 2.0 | — |
| SECONDARY Change From Baseline in Temperature |
-0.2; -0.0; -0.1; -0.0; 0.0; -0.0 | — |
| SECONDARY Change From Baseline in Percent Oxygen in Blood |
0.0; -0.3; 1.3; -1.2; 0.7; -0.7 | — |
| SECONDARY Number of Participants With Abnormal Electrocardiogram (ECG) Findings |
5; 6; 0; 0; 5; 6 | — |
| SECONDARY Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST), Creatine Kinase, Gamma Glutamyl Transferase (GGT) Values |
-1.8; -5.5; -1.2; -6.2; 2.8; -3.6 | — |
| SECONDARY Change From Baseline in Albumin and Total Protein Values |
-1.6; -0.5; -0.6; -0.3; -0.4; -0.2 | — |
| SECONDARY Change From Baseline in Chemistry: Calcium, Chloride, Glucose, Potassium, Sodium, Urea/Blood Urea Nitrogen (BUN) |
0.01497; -0.06653; 0.05988; -0.05822; -0.05489; 0.00998 | — |
| SECONDARY Change From Baseline in Creatinine, Direct Bilirubin, Total Bilirubin, Uric Acid |
-8.1328; 11.4920; -13.2600; -9.4293; -6.0112; -2.6520 | — |
| SECONDARY Change From Baseline in Digoxin Level |
-0.17080; 0.38430; 0.17080; 0.25620; 0.12810; 0.25620 | — |
| SECONDARY Change From Baseline in Troponin I Levels and Type I Collagen Cross-linked C-telopeptide |
-0.0044; -0.0007; -0.0118; -0.0008; -0.0112; -0.0056 | — |
| SECONDARY Change From Baseline in Chemistry: N-terminal Pro-Brain Natriuretic Peptide |
-279.0; 214.2; -347.7; -121.6 | — |
| SECONDARY Change From Baseline in Hematology: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, White Blood Cell (WBC) Count, Total Neutrophils |
0.004; 0.007; 0.000; 0.010; -0.002; 0.002 | — |
| SECONDARY Change From Baseline in Hematocrit |
-0.0084; -0.0092; -0.0086; -0.0045; 0.0046; -0.0138 | — |
| SECONDARY Change From Baseline in Hemoglobin |
-1.0; -4.3; 0.8; -2.2; 1.6; -3.8 | — |
| SECONDARY Change From Baseline in Mean Corpuscle Volume |
0.20; 0.97; -0.92; 0.55; 0.04; 0.08 | — |
| SECONDARY Change From Baseline in Red Blood Cell Count (RBC) and Reticulocytes |
-0.100; -0.160; -0.056; -0.083; 0.014; -0.146 | — |
| SECONDARY Change From Baseline in Mean Corpuscle Hemoglobin Concentration |
8.0; -3.0; 13.7; -8.0; -1.0; 2.7 | — |
| SECONDARY Change From Baseline in Mean Corpuscle Hemoglobin |
0.70; 0.20; 0.70; -0.20; 0.00; 0.27 | — |
| SECONDARY Number of Participants With All Adverse Events (AE) and Serious Adverse Events (SAE) |
5; 7; 0; 1 | — |
| SECONDARY Change From Baseline in Participant Reported Health Status (SF-36) Acute Score |
3.0; 1.2; 1.0; -0.4; -0.5; 3.7 | — |
| SECONDARY Area Under the Concentration Time Curve (AUC) Time Zero to the Last Time of the Last Quantifiable Concentration (AUC(0-t)), AUC Over the Dosing Interval After First and Last Dose (AUC(0-tau)) and AUCall for GSK2798745 |
128.3513; 202.2948; 137.7473; 274.0828; 127.9049; 174.7273 | — |
| SECONDARY Maximum Drug Concentration (Cmax) for GSK2798745 |
10.214; 15.687; 10.017; 15.428 | — |
| SECONDARY Time to Maximum Observed Plasma Concentration (Tmax) for GSK2798745 |
3.0; 3.0; 3.0; 2.0 | — |
| SECONDARY Elimination Half Life (T½) for GSK2798745 |
— | — |
Eligibility Criteria
Inclusion Criteria
- >=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 =18 and 2x Upper Limit of Normal (ULN) and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin 450 millisecond (msec) or QTc > 480 msec in subjects with Bundle Branch Block.
- History or current evidence of any serious or clinically significant gastrointestinal, renal, endocrine, neurologic, hematologic or other condition that is uncontrolled on permitted therapies or that would, in the opinion of the investigator or the GlaxoSmithKline (GSK) medical monitor, make the subject unsuitable for inclusion in this study.
- 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.
- History of drug/substance abuse within the past 2 years.
- History of alcohol abuse within 6 months of the study. Defined as an average weekly alcohol consumption of >14 drinks for men or >7 drinks for women. One drink is equivalent to 12 grams (g) of alcohol: approximately 12 ounces (360 milliliters [mL]) of beer, 5 ounces (150 mL) of wine, or 1.5 ounces of (45 mL) 80 proof distilled spirits.
- 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 investigator or Medical Monitor, contraindicates their participation.
- Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months of screening. For potent immunosuppressive agents, subjects with presence of hepatitis B core antibody (HBcAb) should also be excluded.
- A positive pre-study drug/alcohol screen.
- Use of another investigational product in a clinical study within the following time period prior to the first administration of study medication in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
- Exposure to more than 4 investigational medicinal products within 12 months prior to the first administration of study medication.
Data sourced from ClinicalTrials.gov (NCT02497937). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.