Pre-eclampsia
Conditions
Keywords
human recombinant RLX030, Pre-eclampsia, hemodynamics, Pharmacokinetics
Brief summary
This study is designed in two parts. Part 1 will assess the safety and tolerability of different doses of RLX030 when given to pregnant women with pre- eclampsia (elevated blood pressure with protein in urine). Part 2 will assess whether an optimal dose of RLX030 can prolong pregnancy in women with pre-eclampsia.
Interventions
DRUGPlacebo
Placebo to RLX030 as intravenous infusion for 72 hours
DRUGRLX030
RLX030 1 mg/mL vials
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion criteria: * Written informed consent was obtained before any assessment was performed. * Women at 18 to 40 years of age with a pregnancy 28 weeks (0 days) and 33 weeks (+4 days) gestational age. Gestational age was based on mother's last menstruation; if last menstruation was unknown, an alternative method was used as applicable and was documented in the (electronic) Case Report/Record Form \[(e)CRF\]. * Women with a diagnosis of pre-eclampsia or superimposed pre-eclampsia requiring hospitalization. Pre-eclampsia was defined as new onset of hypertension (SBP ≥ 140 or DBP ≥ 90 mmHg) or gestational hypertension accompanied by proteinuria (\>= 0.3 g/24h) after 20 weeks of gestation. Superimposed pre-eclampsia was defined as chronic hypertension with new onset of proteinuria after 20 weeks of gestation. * Reassuring fetal testing (cardiotocography and biophysical profile) Key
Exclusion criteria
* Severe hypertension (SBP ≥ 160 mmHg or DBP ≥ 110 mmHg) and /or those receiving anti-hypertensive treatment at time of randomization. * Clinically relevant electrocardiogram (ECG) abnormalities at screening excluding those abnormalities commonly seen in pregnancy according to the Investigator. * Symptoms indicative of severe pre-eclampsia or HELLP syndrome (Hemolysis, Elevated Liver enzymes, and Low Platelet count) for which immediate delivery of the baby may be indicated. Symptoms include persistent CNS symptoms (severe headaches, visual changes, altered mentation), persistent right upper quadrant or epigastric pain, nausea or vomiting, severe thrombocytopenia (\<100,000/mm3) and abnormal (\> 2X upper limit of normal) liver enzymes (alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\]). * Eclampsia during current pregnancy, vaginal bleeding present at screening, abruptio placentae, oligohydramnios * Current diagnosis of a seizure disorder that requires chronic medication. * Pre-gestational diabetes (Type 1 or Type 2) with or without diabetic retinopathy. Diagnosis (previous or current) of gestational diabetes, regardless of treatment, was allowed * Known allergy to magnesium sulfate or steroids. * Multifetal gestation, known major fetal anomaly, intrauterine growth restriction (\<5th percentile).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of RLX030: Mean Residence Time (MRT) | Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1 | Blood concentrations of RLX-030 was assayed to determine this PK parameter. |
| Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study | Prior to delivery until 4-6 weeks post partum (maximum of 8 weeks) | Safety and tolerability was assessed by adverse events/serious adverse event and death monitoring. |
| Change From Baseline in Maternal Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) in Part 1of the Study (Part 1) | From baseline to during treatment period of a maximum 72 hours infusion prior to delivery until 4-6 weeks post partum in part 1 (maximum of 8 weeks) | Maternal safety assessment to monitor pre-eclampsia by checking blood pressure during 72 hour treatment period as well as post-dose. |
| Change From Baseline in Mean Maternal Arterial Pressure (Part 1) | From baseline to during treatment period of a maximum 72 hours infusion prior to delivery until 4-6 weeks post partum in part 1 (maximum of 8 weeks) | Maternal safety assessment to monitor pre-eclampsia by checking mean arterial pressure during 72 hour treatment period as well as post-dose. |
| Change From Baseline on Maternal Proteinuria (Part 1) | From baseline to during treatment period of a maximum 72 hours infusion prior to delivery until 4-6 weeks post partum in part 1 (maximum of 8 weeks) | Pre-eclampsia was monitored by checking levels of protein in urine and by urinary protein/creatinine ratio (UPCR) |
| Decrease in Utero-placental Blood Flow (Part 1) | During treatment period of a maximum 72 hours infusion prior to delivery and up to delivery in part 1 (maximum of 3 weeks) | Blood flow to the fetus was monitored using via a Doppler. |
| Change in Fetal Heart Rate (Part 1) | During treatment period of a maximum 72 hours infusion prior to delivery and up to delivery in part 1 (maximum of 3 weeks) | Heart rate of fetus was monitored continuously throughout 72 hour treatment period using a cardiotocograph. |
| Improvement in Renal Function Assessed by Increase in Creatinine Clearance | From randomization until 4-6 weeks post partum (maximum 8 weeks) | — |
| Rate of Spontaneous Delivery and/or Mode of Delivery | From randomization to delivery (maximum of 3 weeks) | — |
| Number of Patients With Absence of Anti-serelaxin Antibodies | From Randomization until 4-6 weeks post partum (maximum of 8 weeks) | — |
| Number of Patients With Abnormalities in Birth Weight, Gestational Age, Appearance, Pulse, Grimace, Activity, Respiration (APGAR) Score, Umbilical Cord Gases, and Days in Neonatal Intensive Care Unit (NICU) | up to 4 - 6 weeks post partum (maximum of 8 weeks ) | — |
| Number of Patients With Abnormalities in Fetal Cardiotocography and Biophysical Profile | Randomization to delivery (maximum of 3 weeks) | — |
| Pharmacokinetics of RLX030: Area Under the Blood Concentration-time Curve From Time Zero to Infinity (AUCinf)-Part 1 | Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1 | Blood concentrations of RLX-030 was assayed to determine this PK parameter. |
| Pharmacokinetics of RLX030: Area Under the Blood Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast)-Part 1 | Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1 | Blood concentrations of RLX-030 was assayed to determine this PK parameter. |
| Pharmacokinetics of RLX030: Blood Concentration at 24 Hour (C 0-24h) After Administration- Part 1 | Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1 | Blood concentrations of RLX-030 was assayed to determine this PK parameter. |
| Pharmacokinetics of RLX030: Terminal Elimination Half-life (T1/2)- Part 1 | Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1 | Blood concentrations of RLX-030 was assayed to determine this PK parameter. |
Secondary
| Measure | Time frame |
|---|---|
| Mean Number of Days Before Delivery | From randomization until delivery (maximum of 3 weeks) |
Countries
Italy, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| RLX030 Because premature termination of the study, only Cohort 1 part 1 had patients with early onset pre-eclampsia. As per planned treatment assigned, patients in this arm received open label serelaxin (RLX030) 15 μg/kg/day i.v. for 72 hours. | 2 |
| Placebo Because premature termination of the study, only Cohort 1 part 1 had patients with early onset pre-eclampsia. The randomized patient received matching placebo of serelaxin (RLX030) in a blinded manner. | 1 |
| Total | 3 |
Baseline characteristics
| Characteristic | RLX030 | Placebo | Total |
|---|---|---|---|
| Age, Customized Between age 18 to 40 years | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 2 / 2 | 1 / 1 | 0 / 1 |
| serious Total, serious adverse events | 2 / 2 | 2 / 2 | 1 / 1 | 1 / 1 |
Outcome results
Primary
Change From Baseline in Maternal Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) in Part 1of the Study (Part 1)
Maternal safety assessment to monitor pre-eclampsia by checking blood pressure during 72 hour treatment period as well as post-dose.
Time frame: From baseline to during treatment period of a maximum 72 hours infusion prior to delivery until 4-6 weeks post partum in part 1 (maximum of 8 weeks)
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Primary
Change From Baseline in Mean Maternal Arterial Pressure (Part 1)
Maternal safety assessment to monitor pre-eclampsia by checking mean arterial pressure during 72 hour treatment period as well as post-dose.
Time frame: From baseline to during treatment period of a maximum 72 hours infusion prior to delivery until 4-6 weeks post partum in part 1 (maximum of 8 weeks)
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Primary
Change From Baseline on Maternal Proteinuria (Part 1)
Pre-eclampsia was monitored by checking levels of protein in urine and by urinary protein/creatinine ratio (UPCR)
Time frame: From baseline to during treatment period of a maximum 72 hours infusion prior to delivery until 4-6 weeks post partum in part 1 (maximum of 8 weeks)
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Primary
Change in Fetal Heart Rate (Part 1)
Heart rate of fetus was monitored continuously throughout 72 hour treatment period using a cardiotocograph.
Time frame: During treatment period of a maximum 72 hours infusion prior to delivery and up to delivery in part 1 (maximum of 3 weeks)
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Primary
Decrease in Utero-placental Blood Flow (Part 1)
Blood flow to the fetus was monitored using via a Doppler.
Time frame: During treatment period of a maximum 72 hours infusion prior to delivery and up to delivery in part 1 (maximum of 3 weeks)
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Primary
Improvement in Renal Function Assessed by Increase in Creatinine Clearance
Time frame: From randomization until 4-6 weeks post partum (maximum 8 weeks)
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Primary
Number of Patients With Abnormalities in Birth Weight, Gestational Age, Appearance, Pulse, Grimace, Activity, Respiration (APGAR) Score, Umbilical Cord Gases, and Days in Neonatal Intensive Care Unit (NICU)
Time frame: up to 4 - 6 weeks post partum (maximum of 8 weeks )
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Primary
Number of Patients With Abnormalities in Fetal Cardiotocography and Biophysical Profile
Time frame: Randomization to delivery (maximum of 3 weeks)
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Primary
Number of Patients With Absence of Anti-serelaxin Antibodies
Time frame: From Randomization until 4-6 weeks post partum (maximum of 8 weeks)
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Primary
Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study
Safety and tolerability was assessed by adverse events/serious adverse event and death monitoring.
Time frame: Prior to delivery until 4-6 weeks post partum (maximum of 8 weeks)
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RLX030 - Maternal | Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study | Serious Adverse events | 2 Participants |
| RLX030 - Maternal | Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study | Non-serious AEs | 2 Participants |
| RLX030 - Maternal | Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study | Death | 0 Participants |
| Placebo - Maternal | Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study | Serious Adverse events | 1 Participants |
| Placebo - Maternal | Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study | Non-serious AEs | 1 Participants |
| Placebo - Maternal | Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study | Death | 0 Participants |
| RLX030- Neonates Born to Patients | Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study | Death | 0 Participants |
| RLX030- Neonates Born to Patients | Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study | Serious Adverse events | 2 Participants |
| RLX030- Neonates Born to Patients | Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study | Non-serious AEs | 2 Participants |
| Placebo- Neonates Born to Patients | Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study | Serious Adverse events | 1 Participants |
| Placebo- Neonates Born to Patients | Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study | Non-serious AEs | 0 Participants |
| Placebo- Neonates Born to Patients | Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study | Death | 0 Participants |
Primary
Pharmacokinetics of RLX030: Area Under the Blood Concentration-time Curve From Time Zero to Infinity (AUCinf)-Part 1
Blood concentrations of RLX-030 was assayed to determine this PK parameter.
Time frame: Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Primary
Pharmacokinetics of RLX030: Area Under the Blood Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast)-Part 1
Blood concentrations of RLX-030 was assayed to determine this PK parameter.
Time frame: Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Primary
Pharmacokinetics of RLX030: Blood Concentration at 24 Hour (C 0-24h) After Administration- Part 1
Blood concentrations of RLX-030 was assayed to determine this PK parameter.
Time frame: Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Primary
Pharmacokinetics of RLX030: Mean Residence Time (MRT)
Blood concentrations of RLX-030 was assayed to determine this PK parameter.
Time frame: Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Primary
Pharmacokinetics of RLX030: Terminal Elimination Half-life (T1/2)- Part 1
Blood concentrations of RLX-030 was assayed to determine this PK parameter.
Time frame: Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Primary
Rate of Spontaneous Delivery and/or Mode of Delivery
Time frame: From randomization to delivery (maximum of 3 weeks)
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed
Secondary
Mean Number of Days Before Delivery
Time frame: From randomization until delivery (maximum of 3 weeks)
Population: No formal analysis was performed as the study was terminated after three patients were enrolled and dosed