Safety and Efficacy of RLX030 in Pregnant Women With Pre- Eclampsia

An Adaptive Multicentre, Randomized, Partially Double-blind, Placebo-controlled Study to Assess the Safety, PK and PD/Efficacy of RLX030 in Women With Pre-eclampsia

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.

Study Overview

• Status: Terminated
• Conditions: Pre-eclampsia
• Intervention / Treatment: Drug: RLX030; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • MO
    • Modena, MO, Italy, 41100
      • Novartis Investigative Site
• United States
  • Alabama
    • Mobile, Alabama, United States, 36604
      • Novartis Investigative Site
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Novartis Investigative Site
    • Louisville, Kentucky, United States, 40202
      • Novartis Investigative Site
  • Texas
    • Galveston, Texas, United States, 77555-0587
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RLX030; In part 1, within each cohort, two (2) patients per cohort will be treated open label with RLX030 and two (2) patients will be treated double blind with RLX030 as intravenous infusion for 72 hours. There will be 3 cohorts in part 1 with different doses of RLX030. In part 2, there is no open label treatment on RLX030. In part 2, patients will be randomized in a double-blind fashion to this arm with the optimal dose of RLX030 as intravenous infusion for 72 hours as determined from part 1.	Drug: RLX030; RLX030 1 mg/mL vials
Placebo Comparator: Placebo; In part 1, equal number of subjects will be treated with matching placebo of RLX030 as intravenous infusion for 72 hours in 3 cohorts. In part 2, patients will be treated with matching placebo of RLX030 as intravenous infusion for 72 hours	Drug: Placebo; Placebo to RLX030 as intravenous infusion for 72 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Prior to delivery until 4-6 weeks post partum (maximum of 8 weeks)
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.	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)
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.	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)
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)	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)
Decrease in Utero-placental Blood Flow (Part 1)	Blood flow to the fetus was monitored using via a Doppler.	During treatment period of a maximum 72 hours infusion prior to delivery and up to delivery in part 1 (maximum of 3 weeks)
Change in Fetal Heart Rate (Part 1)	Heart rate of fetus was monitored continuously throughout 72 hour treatment period using a cardiotocograph.	During treatment period of a maximum 72 hours infusion prior to delivery and up to delivery in part 1 (maximum of 3 weeks)
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	Blood concentrations of RLX-030 was assayed to determine this PK parameter.	Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1
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.	Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1
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.	Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1
Pharmacokinetics of RLX030: Terminal Elimination Half-life (T1/2)- Part 1	Blood concentrations of RLX-030 was assayed to determine this PK parameter.	Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1
Pharmacokinetics of RLX030: Mean Residence Time (MRT)	Blood concentrations of RLX-030 was assayed to determine this PK parameter.	Baseline, 2, 6, 24,48,72, 76, 80 and 90 hours after initiation of infusion during part 1

Secondary Outcome Measures

Outcome Measure	Time Frame
Mean Number of Days Before Delivery	From randomization until delivery (maximum of 3 weeks)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: March 27, 2012
• First Submitted That Met QC Criteria: March 27, 2012
• First Posted (Estimate): March 29, 2012

Study Record Updates

• Last Update Posted (Estimate): November 5, 2015
• Last Update Submitted That Met QC Criteria: October 12, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: Pharmacokinetics; hemodynamics; Pre-eclampsia; human recombinant RLX030
• Additional Relevant MeSH Terms: Pregnancy Complications; Hypertension, Pregnancy-Induced; Eclampsia; Pre-Eclampsia
• Other Study ID Numbers: CRLX030A2205; 2011-001617-14 (EudraCT Number)