Chronic Heart Failure
Conditions
Keywords
Serelaxin,, Chronic heart failure,, Spiroergometry,, Troponin,, New York Heart Association (NYHA) functional Class II/III,, Left ventricular ejection fraction,
Brief summary
This was a multicenter, randomized, double-blind, crossover, placebo-controlled, Phase II clinical study that evaluated the effect of serelaxin versus placebo (both in addition to SoC) on the release of hs-cTnI, in patients with CHF after an exercise testing session.
Interventions
DRUGSerelaxin
Serelaxin will be administered as a continuous i.v. infusion according to a weight-range adjusted dosing regimen
DRUGPlacebo
Matching placebo i.v infusion
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Male or female ≥ 18 years of age, with body weight ≤ 160 Kg * Diagnosis of stable CHF: * New York Heart Association (NYHA) functional Class II/III. * Receiving guideline-recommended treatment for CHF. * Left ventricular ejection fraction \< 45%, obtained within the last 3 months prior to screening. * NT-proBNP \> 300 ng/L in sinus rhythm or \> 900 ng/L if not in sinus rhythm (determined locally). * Ability to exercise for at least 10 to 12 minutes based on investigator's judgment. * Systolic BP ≥ 125 mmHg at randomization * Renal function defined as an eGFR of ≥ 25 mL/min/1.73 m\^2 at screening (sMDRD formula). Key
Exclusion criteria
* Dyspnea primarily due to non-cardiac causes. * Increased risk of developing hypotension during vasodilator therapy according to investigators judgement. * Any contraindication for exercise testing and spirometry. * Stopping of the spiroergometry at screening according to the stopping rules, unless the patient has reached maximum exercise capacity defined as carbon dioxide production/oxygen consumption (VCO2/VO2) \> 1.05. * Change in guideline-recommended CHF treatment within 1 month prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean of High Sensitivity Cardiac Troponin I (Hs-cTnI) Concentration After Exercise Compared to Placebo | Baseline, up to 7 hours after the start of an exercise testing session on treatment period 1 (Day 1) and treatment period 2 (Day 15+/- 1) | This cardiac biomarker measurement was obtained to determine plasma concentrations following a cardiac stress test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean of High Sensitivity Cardiac Troponin I (Hs-cTnI) Concentrations After Exercise Compared to Placebo at 4 and 5 Hours | 4 and 5 hours after exercise testing session | This cardiac biomarker measurement was obtained to determine plasma concentrations following a cardiac stress test. |
| Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | Baseline, up to 7 hours after the start of an exercise testing session on treatment period 1 (Day 1) and treatment period 2 (Day 15 +/- 1) | This cardiac biomarker measurement was obtained to determine plasma concentrations following a cardiac stress test. |
| Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | Baseline, up to 7 hours after the start of an exercise testing session on treatment period 1 (Day 1) and treatment period 2 (Day 15 +/- 1) | This cardiac biomarker measurement was obtained to determine plasma concentrations following a cardiac stress test. |
Countries
Germany, Switzerland, United Kingdom
Participant flow
Recruitment details
There were total 11 centers from 3 countries. (Germany-6, Switzerland-1, and the United Kingdom-4).
Participants by arm
| Arm | Count |
|---|---|
| Serelaxin-Placebo Subjects received serelaxin in Treatment Period 1 and placebo in Treatment Period 2.
Serelaxin was administered as a continuous i.v. infusion according to a weight-range adjusted dosing regimen. Matching placebo was administered as an i.v infusion. | 14 |
| Placebo-Serelaxin Subjects received placebo in Treatment Period 1 and serelaxin in Treatment Period 2.
Serelaxin was administered as a continuous i.v. infusion according to a weight-range adjusted dosing regimen. Matching placebo was administered as an i.v infusion. | 12 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Non-availability of IMP | 1 | 1 |
| Overall Study | Systolic blood pressure < 125 mmHg | 1 | 1 |
Baseline characteristics
| Characteristic | Serelaxin-Placebo | Placebo-Serelaxin | Total |
|---|---|---|---|
| Age, Continuous | 74.7 years STANDARD_DEVIATION 7.62 | 66.5 years STANDARD_DEVIATION 13.89 | 70.9 years STANDARD_DEVIATION 11.51 |
| Childbearing status | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 13 Participants | 10 Participants | 23 Participants |
| Weight (kg) | 84.5 kilogram (kg) STANDARD_DEVIATION 14.19 | 83.9 kilogram (kg) STANDARD_DEVIATION 17.85 | 84.2 kilogram (kg) STANDARD_DEVIATION 15.65 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 | 0 / 22 |
| other Total, other adverse events | 7 / 20 | 6 / 20 | 12 / 22 |
| serious Total, serious adverse events | 0 / 20 | 1 / 20 | 1 / 22 |
Outcome results
Primary
Geometric Mean of High Sensitivity Cardiac Troponin I (Hs-cTnI) Concentration After Exercise Compared to Placebo
This cardiac biomarker measurement was obtained to determine plasma concentrations following a cardiac stress test.
Time frame: Baseline, up to 7 hours after the start of an exercise testing session on treatment period 1 (Day 1) and treatment period 2 (Day 15+/- 1)
Population: The primary analysis of mixed model repeated measures was not performed because the validation of the primary endpoint variable hs-cTnI assay (Singulex Erenna®) was not completed because of the early termination of the study and, therefore, hs-cTnI was not analyzed.
Secondary
Geometric Mean of High Sensitivity Cardiac Troponin I (Hs-cTnI) Concentrations After Exercise Compared to Placebo at 4 and 5 Hours
This cardiac biomarker measurement was obtained to determine plasma concentrations following a cardiac stress test.
Time frame: 4 and 5 hours after exercise testing session
Population: The objective was not analyzed because the validation of the hs-cTnI Singulex Erenna® assay was not completed because of the early termination of the study.
Secondary
Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo
This cardiac biomarker measurement was obtained to determine plasma concentrations following a cardiac stress test.
Time frame: Baseline, up to 7 hours after the start of an exercise testing session on treatment period 1 (Day 1) and treatment period 2 (Day 15 +/- 1)
Population: The full analysis set (FAS) consisted of all randomized patients.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Serelaxin-Placebo | Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | 180 minutes | 13.5302 pg/mL | Standard Deviation 0.62107 |
| Serelaxin-Placebo | Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | 300 minutes | 13.6103 pg/mL | Standard Deviation 0.63614 |
| Serelaxin-Placebo | Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | 132 minutes | 13.5729 pg/mL | Standard Deviation 0.62057 |
| Serelaxin-Placebo | Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | 360 minutes | 13.6687 pg/mL | Standard Deviation 0.65735 |
| Serelaxin-Placebo | Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | 240 minutes | 13.5673 pg/mL | Standard Deviation 0.68419 |
| Serelaxin-Placebo | Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | 420 minutes | 13.6533 pg/mL | Standard Deviation 0.64776 |
| Serelaxin-Placebo | Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | Baseline | 13.5026 pg/mL | Standard Deviation 0.64893 |
| Placebo-Serelaxin | Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | 420 minutes | 13.7399 pg/mL | Standard Deviation 0.57361 |
| Placebo-Serelaxin | Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | Baseline | 13.6217 pg/mL | Standard Deviation 0.60192 |
| Placebo-Serelaxin | Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | 132 minutes | 13.7076 pg/mL | Standard Deviation 0.61612 |
| Placebo-Serelaxin | Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | 180 minutes | 13.6777 pg/mL | Standard Deviation 0.61118 |
| Placebo-Serelaxin | Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | 240 minutes | 13.7011 pg/mL | Standard Deviation 0.58471 |
| Placebo-Serelaxin | Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | 300 minutes | 13.7129 pg/mL | Standard Deviation 0.57832 |
| Placebo-Serelaxin | Log-transformed Concentration of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations Compared to Placebo | 360 minutes | 13.7213 pg/mL | Standard Deviation 0.57366 |
Secondary
Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo
This cardiac biomarker measurement was obtained to determine plasma concentrations following a cardiac stress test.
Time frame: Baseline, up to 7 hours after the start of an exercise testing session on treatment period 1 (Day 1) and treatment period 2 (Day 15 +/- 1)
Population: The full analysis set (FAS) consisted of all randomized patients. Patients were analyzed according to the treatment they had been assigned to at randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Serelaxin-Placebo | Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | 240 minutes | 8.7718 ng/mL | Standard Deviation 0.63971 |
| Serelaxin-Placebo | Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | Baseline | 8.8256 ng/mL | Standard Deviation 0.67027 |
| Serelaxin-Placebo | Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | 300 minutes | 8.7309 ng/mL | Standard Deviation 0.62177 |
| Serelaxin-Placebo | Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | 360 minutes | 8.7692 ng/mL | Standard Deviation 0.6492 |
| Serelaxin-Placebo | Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | 180 minutes | 8.7897 ng/mL | Standard Deviation 0.62835 |
| Serelaxin-Placebo | Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | 420 minutes | 8.7669 ng/mL | Standard Deviation 0.65793 |
| Serelaxin-Placebo | Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | 132 minutes | 8.8644 ng/mL | Standard Deviation 0.63646 |
| Placebo-Serelaxin | Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | 420 minutes | 8.7329 ng/mL | Standard Deviation 0.63139 |
| Placebo-Serelaxin | Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | Baseline | 8.8810 ng/mL | Standard Deviation 0.64372 |
| Placebo-Serelaxin | Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | 132 minutes | 8.8409 ng/mL | Standard Deviation 0.67261 |
| Placebo-Serelaxin | Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | 180 minutes | 8.7955 ng/mL | Standard Deviation 0.62729 |
| Placebo-Serelaxin | Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | 240 minutes | 8.8662 ng/mL | Standard Deviation 0.58565 |
| Placebo-Serelaxin | Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | 360 minutes | 8.8088 ng/mL | Standard Deviation 0.59672 |
| Placebo-Serelaxin | Log-transformed Concentration Values of Heart-type Fatty Acid-binding Protein (H-FABP) Concentrations Compared to Placebo | 300 minutes | 8.7202 ng/mL | Standard Deviation 0.6589 |