Chronic Heart Failure
Conditions
Keywords
Chronic Heart Failure, CHF, Heart Failure, HF, Immunogenicity, Anti-bodies, Hypersensitivity, Serelaxin, RELAX-REPEAT
Brief summary
The purpose of this study was to assess the safety of repeat doses of serelaxin in chronic heart failure.
Interventions
DRUGRLX030 (serelaxin)
RLX030 (serelaxin) was administered according to a weight-range adjusted dosing regimen at a nominal dose of 30 μg/kg/day as a continuous IV infusion for 48 hours.
DRUGPlacebo
Matching placebo of serelaxin was administered as a continuous IV infusion for 48 hours.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Body weight of ≤ 160 kg. * Subjects with compensated CHF (NYHA Class II - III) at time of screening with a prior documented history of chronic heart failure. * NT-proBNP \>300 pg/ml (according to central measurement) at visit 1. * Subjects treated with appropriate and guideline-indicated CHF standard of care. * Ability to comply with all requirements, including ability to receive at least a 48 hour infusion plus follow-up time required for each dosing visit. Key
Exclusion criteria
* Current acute decompensated HF * Any major solid organ transplant recipient or planned anticipated organ transplant within 1 year. * Documented history of untreated ventricular arrhythmia with syncopal episodes, ventricular tachycardia, or ventricular fibrillation without ICD (implantable cardioverter defibrillator) with significant hemodynamic consequences within the 3 months prior to screening. * Presence of hemodynamically significant mitral and /or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation: including significant left ventricular outflow obstruction (e.g., obstructive hypertrophic cardiomyopathy, severe aortic stenosis) * Subjects with severe renal impairment defined as pre-randomization eGFR \< 30 ml/min/1.73m2 calculated using the sMDRD equation and/or those receiving current or planned dialysis or ultrafiltration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Chronic Heart Failure (CHF) Who Develop Anti-serelaxin Antibodies at Any Time Following Repeat Administration of IV Continuous Infusions of Serelaxin Administered for up to 48 Hours in 16 Weeks | 16 weeks | A patient is considered antibody positive during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were positive. A patient is considered antibody negative during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were negative. A patient's antibody status is considered to be undetermined during the study if it is not defined as positive or negative. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Antibody Titers in Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies (Neutralizing, Non-neutralizing or Both) at Any Time Following 3 Repeated Infusions and at Week 4, Week 8 and Week 12 | Week 4, Week 8, Week 12 | — |
| Percentage of Participants With Chronic Heart Failure With Positive Antibody Status Who Develop Non-neutralizing Anti-serelaxin Antibodies Following 3 Repeated Infusions (i.e. at Week 4, Week 8, and Week 12) | At Week 4, Week 8, Week 12 | A patient is considered antibody positive during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were positive. n = the total number of subjects with evaluable antibody status after specified number of infusions |
| Number of Participants With Adverse Events Such as Adjudicated Potential Hypersensitivity or Infusion Reactions | 16 weeks | Incidence rate of special interest, indicative of hypersensitivity reactions which occur during and after administration of repeated infusions of serelaxin relative to placebo in subjects with chronic heart failure is reported. Hypersensitivity reactions or infusion reactions can be headache, nausea, fever, chills, dizziness, flush, pruritus, chest and/or back pain. |
| Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16 | Randomization to Week 4, Week 4 to Week 8, Week 8 to Week 12, week 12 to week 16 | A patient is considered antibody positive during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were positive. Each time period is defined as the time frame from study drug initiation (or the visit if there is no infusion) to prior to study drug initiation of the next period (or the visit if no there is no infusion). n= The total number of subjects with evaluable antibody status during the defined period. |
| Pharmacokinetics of RLXL030: Actual Concentrations at Steady State (Css) | pre-infusion and 24, 48 hours post each infusion | Concentration at steady state (Css) was estimated using C48 or C24 for patients who received the intended rate of infusion for at least 24hours. n: Number of patients with valid PK parameters available |
| Pharmacokinetics of RLX030: Cmax Steady State (Cmaxss) Concentration at 48 Hours | 48 hours post each infusion | This analysis was not done due to sparse PK sampling. |
| Pharmacokinetics of RLX030: Clearance of Serelaxin (CL) | 48 hours post each infusion | Clearance (CL) was calculated using concentration at steady state (Css) and the actual delivered dose rate. n: Number of patients with valid PK parameters available within 48 hours post each infusion. |
| Pharmacokinetics of RLX030: Area Under the Plasma Concentration Time Curve From Time Zero up to 48 Hours Post Dose (AUC 0-48) | pre-infusion and 8, 24 and 48 hours post each infusion. | Due to sparse PK sampling, AUC 0-48 hours was not analyzed. |
Countries
Australia, Czechia, Finland, Germany, Italy, Netherlands, Norway, Romania, Russia, Spain, Sweden, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
A total of 323 patients were randomized to the serelaxin or placebo treatment in a 2:1 ratio. 2 patients from serelaxin were mis-randomized, hence 321 received study drug.
Participants by arm
| Arm | Count |
|---|---|
| RLX030 (Serelaxin) Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8 | 213 |
| Placebo Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8 | 108 |
| Total | 321 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Non-Compliance With Study Treatment | 1 | 0 |
| Overall Study | Patient/Guardian Decision | 3 | 1 |
| Overall Study | Protocol Deviation | 1 | 0 |
| Overall Study | Technical Problems | 2 | 0 |
Baseline characteristics
| Characteristic | RLX030 (Serelaxin) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 66.7 Years STANDARD_DEVIATION 8.99 | 65.2 Years STANDARD_DEVIATION 11.18 | 66.2 Years STANDARD_DEVIATION 9.79 |
| Sex: Female, Male Female | 46 Participants | 26 Participants | 72 Participants |
| Sex: Female, Male Male | 167 Participants | 82 Participants | 249 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 65 / 212 | 39 / 108 |
| serious Total, serious adverse events | 30 / 212 | 15 / 108 |
Outcome results
Primary
Percentage of Participants With Chronic Heart Failure (CHF) Who Develop Anti-serelaxin Antibodies at Any Time Following Repeat Administration of IV Continuous Infusions of Serelaxin Administered for up to 48 Hours in 16 Weeks
A patient is considered antibody positive during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were positive. A patient is considered antibody negative during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were negative. A patient's antibody status is considered to be undetermined during the study if it is not defined as positive or negative.
Time frame: 16 weeks
Population: Safety Set: All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment. In this reported analysis, patients with undetermined antibody status are excluded from analysis population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RLX030 (Serelaxin) | Percentage of Participants With Chronic Heart Failure (CHF) Who Develop Anti-serelaxin Antibodies at Any Time Following Repeat Administration of IV Continuous Infusions of Serelaxin Administered for up to 48 Hours in 16 Weeks | Positive | 0.50 Percentage of participants |
| RLX030 (Serelaxin) | Percentage of Participants With Chronic Heart Failure (CHF) Who Develop Anti-serelaxin Antibodies at Any Time Following Repeat Administration of IV Continuous Infusions of Serelaxin Administered for up to 48 Hours in 16 Weeks | Negative | 99.50 Percentage of participants |
| Placebo | Percentage of Participants With Chronic Heart Failure (CHF) Who Develop Anti-serelaxin Antibodies at Any Time Following Repeat Administration of IV Continuous Infusions of Serelaxin Administered for up to 48 Hours in 16 Weeks | Positive | 0.00 Percentage of participants |
| Placebo | Percentage of Participants With Chronic Heart Failure (CHF) Who Develop Anti-serelaxin Antibodies at Any Time Following Repeat Administration of IV Continuous Infusions of Serelaxin Administered for up to 48 Hours in 16 Weeks | Negative | 100 Percentage of participants |
Comparison: Difference in percentage of patients with positive antibody statusp-value: >0.999990% CI: [-9.38, 10.38]Fisher Exact
Comparison: Difference in percentage of patients with negative antibody status90% CI: [-10.38, 9.38]
Secondary
Antibody Titers in Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies (Neutralizing, Non-neutralizing or Both) at Any Time Following 3 Repeated Infusions and at Week 4, Week 8 and Week 12
Time frame: Week 4, Week 8, Week 12
Population: Safety set:All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| RLX030 (Serelaxin) | Antibody Titers in Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies (Neutralizing, Non-neutralizing or Both) at Any Time Following 3 Repeated Infusions and at Week 4, Week 8 and Week 12 | NA In international Units |
Secondary
Number of Participants With Adverse Events Such as Adjudicated Potential Hypersensitivity or Infusion Reactions
Incidence rate of special interest, indicative of hypersensitivity reactions which occur during and after administration of repeated infusions of serelaxin relative to placebo in subjects with chronic heart failure is reported. Hypersensitivity reactions or infusion reactions can be headache, nausea, fever, chills, dizziness, flush, pruritus, chest and/or back pain.
Time frame: 16 weeks
Population: Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RLX030 (Serelaxin) | Number of Participants With Adverse Events Such as Adjudicated Potential Hypersensitivity or Infusion Reactions | Submitted for adjudication | 32 Participants |
| RLX030 (Serelaxin) | Number of Participants With Adverse Events Such as Adjudicated Potential Hypersensitivity or Infusion Reactions | Confirmed with no hypersensitivity reactions | 32 Participants |
| RLX030 (Serelaxin) | Number of Participants With Adverse Events Such as Adjudicated Potential Hypersensitivity or Infusion Reactions | Hypersensitivity reactions confirmed | 0 Participants |
| Placebo | Number of Participants With Adverse Events Such as Adjudicated Potential Hypersensitivity or Infusion Reactions | Submitted for adjudication | 14 Participants |
| Placebo | Number of Participants With Adverse Events Such as Adjudicated Potential Hypersensitivity or Infusion Reactions | Confirmed with no hypersensitivity reactions | 14 Participants |
| Placebo | Number of Participants With Adverse Events Such as Adjudicated Potential Hypersensitivity or Infusion Reactions | Hypersensitivity reactions confirmed | 0 Participants |
Secondary
Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16
A patient is considered antibody positive during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were positive. Each time period is defined as the time frame from study drug initiation (or the visit if there is no infusion) to prior to study drug initiation of the next period (or the visit if no there is no infusion). n= The total number of subjects with evaluable antibody status during the defined period.
Time frame: Randomization to Week 4, Week 4 to Week 8, Week 8 to Week 12, week 12 to week 16
Population: All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RLX030 (Serelaxin) | Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16 | Randomization to week 4 (n= 209, 107) | 0.48 Percentage of patients |
| RLX030 (Serelaxin) | Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16 | Week 8 to week 12 (n= 204, 107) | 0.49 Percentage of patients |
| RLX030 (Serelaxin) | Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16 | Week 4 to week 8 (n= 204, 108) | 0.49 Percentage of patients |
| RLX030 (Serelaxin) | Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16 | Week 12 to week 16 (n= 2, 2) | 0 Percentage of patients |
| Placebo | Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16 | Week 4 to week 8 (n= 204, 108) | 0.00 Percentage of patients |
| Placebo | Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16 | Randomization to week 4 (n= 209, 107) | 0.00 Percentage of patients |
| Placebo | Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16 | Week 12 to week 16 (n= 2, 2) | 0 Percentage of patients |
| Placebo | Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16 | Week 8 to week 12 (n= 204, 107) | 0.00 Percentage of patients |
Secondary
Percentage of Participants With Chronic Heart Failure With Positive Antibody Status Who Develop Non-neutralizing Anti-serelaxin Antibodies Following 3 Repeated Infusions (i.e. at Week 4, Week 8, and Week 12)
A patient is considered antibody positive during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were positive. n = the total number of subjects with evaluable antibody status after specified number of infusions
Time frame: At Week 4, Week 8, Week 12
Population: All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RLX030 (Serelaxin) | Percentage of Participants With Chronic Heart Failure With Positive Antibody Status Who Develop Non-neutralizing Anti-serelaxin Antibodies Following 3 Repeated Infusions (i.e. at Week 4, Week 8, and Week 12) | after 1 infusion (at week 4) [n=209,108] | 0.48 Percentage of participants |
| RLX030 (Serelaxin) | Percentage of Participants With Chronic Heart Failure With Positive Antibody Status Who Develop Non-neutralizing Anti-serelaxin Antibodies Following 3 Repeated Infusions (i.e. at Week 4, Week 8, and Week 12) | after 2 infusions (at week 8) [n=200,106] | 0.50 Percentage of participants |
| RLX030 (Serelaxin) | Percentage of Participants With Chronic Heart Failure With Positive Antibody Status Who Develop Non-neutralizing Anti-serelaxin Antibodies Following 3 Repeated Infusions (i.e. at Week 4, Week 8, and Week 12) | after 3 infusions (at week 12) [n=184, 102] | 0.54 Percentage of participants |
| Placebo | Percentage of Participants With Chronic Heart Failure With Positive Antibody Status Who Develop Non-neutralizing Anti-serelaxin Antibodies Following 3 Repeated Infusions (i.e. at Week 4, Week 8, and Week 12) | after 1 infusion (at week 4) [n=209,108] | 0.0 Percentage of participants |
| Placebo | Percentage of Participants With Chronic Heart Failure With Positive Antibody Status Who Develop Non-neutralizing Anti-serelaxin Antibodies Following 3 Repeated Infusions (i.e. at Week 4, Week 8, and Week 12) | after 2 infusions (at week 8) [n=200,106] | 0.0 Percentage of participants |
| Placebo | Percentage of Participants With Chronic Heart Failure With Positive Antibody Status Who Develop Non-neutralizing Anti-serelaxin Antibodies Following 3 Repeated Infusions (i.e. at Week 4, Week 8, and Week 12) | after 3 infusions (at week 12) [n=184, 102] | 0.0 Percentage of participants |
Secondary
Pharmacokinetics of RLX030: Area Under the Plasma Concentration Time Curve From Time Zero up to 48 Hours Post Dose (AUC 0-48)
Due to sparse PK sampling, AUC 0-48 hours was not analyzed.
Time frame: pre-infusion and 8, 24 and 48 hours post each infusion.
Population: Due to sparse PK sampling, this analysis was not done.
Secondary
Pharmacokinetics of RLX030: Clearance of Serelaxin (CL)
Clearance (CL) was calculated using concentration at steady state (Css) and the actual delivered dose rate. n: Number of patients with valid PK parameters available within 48 hours post each infusion.
Time frame: 48 hours post each infusion
Population: PK analysis set (PK) - All patients with at least one available valid (i.e. not flagged for exclusion) PK concentration measurement, who received any study drug and experienced no protocol deviations with relevant impact on PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RLX030 (Serelaxin) | Pharmacokinetics of RLX030: Clearance of Serelaxin (CL) | First Infusion (n= 173) | 106 mL/hr/kg | Standard Deviation 55.8 |
| RLX030 (Serelaxin) | Pharmacokinetics of RLX030: Clearance of Serelaxin (CL) | Second Infusion (n=173) | 97.4 mL/hr/kg | Standard Deviation 41.4 |
| RLX030 (Serelaxin) | Pharmacokinetics of RLX030: Clearance of Serelaxin (CL) | Third Infusion (n= 180) | 202 mL/hr/kg | Standard Deviation 1290 |
Secondary
Pharmacokinetics of RLX030: Cmax Steady State (Cmaxss) Concentration at 48 Hours
This analysis was not done due to sparse PK sampling.
Time frame: 48 hours post each infusion
Population: Due to sparse PK sampling, this analysis was not done.
Secondary
Pharmacokinetics of RLXL030: Actual Concentrations at Steady State (Css)
Concentration at steady state (Css) was estimated using C48 or C24 for patients who received the intended rate of infusion for at least 24hours. n: Number of patients with valid PK parameters available
Time frame: pre-infusion and 24, 48 hours post each infusion
Population: PK analysis set (PK) - All patients with at least one available valid (i.e. not flagged for exclusion) PK concentration measurement, who received any study drug and experienced no protocol deviations with relevant impact on PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RLX030 (Serelaxin) | Pharmacokinetics of RLXL030: Actual Concentrations at Steady State (Css) | Third (n = 181) | 38.9 ng/ml | Standard Deviation 95.2 |
| RLX030 (Serelaxin) | Pharmacokinetics of RLXL030: Actual Concentrations at Steady State (Css) | First infusion (n=174) | 31.6 ng/ml | Standard Deviation 70.1 |
| RLX030 (Serelaxin) | Pharmacokinetics of RLXL030: Actual Concentrations at Steady State (Css) | Second Infusion (n=174) | 53.5 ng/ml | Standard Deviation 234 |