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

• ClinicalTrials.gov Identifier: NCT01566630
• Recruitment Status: Terminated
• First Posted: March 29, 2012
• Results First Posted: November 5, 2015
• Last Update Posted: November 5, 2015
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Pre-eclampsia	Drug: Placebo; Drug: RLX030	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 3 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: May 2013
• Actual Primary Completion Date: August 2014
• Actual Study Completion Date: August 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Number of Patients With Adverse Events, Serious Adverse and Death During Part 1 of the Study [ Time Frame: 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.
2. Change From Baseline in Maternal Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) in Part 1of the Study (Part 1) [ 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) ]
   Maternal safety assessment to monitor pre-eclampsia by checking blood pressure during 72 hour treatment period as well as post-dose.
3. Change From Baseline in Mean Maternal Arterial Pressure (Part 1) [ 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) ]
   Maternal safety assessment to monitor pre-eclampsia by checking mean arterial pressure during 72 hour treatment period as well as post-dose.
4. Change From Baseline on Maternal Proteinuria (Part 1) [ 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) ]
   Pre-eclampsia was monitored by checking levels of protein in urine and by urinary protein/creatinine ratio (UPCR)
5. Decrease in Utero-placental Blood Flow (Part 1) [ 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) ]
   Blood flow to the fetus was monitored using via a Doppler.
6. Change in Fetal Heart Rate (Part 1) [ 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) ]
   Heart rate of fetus was monitored continuously throughout 72 hour treatment period using a cardiotocograph.
7. Improvement in Renal Function Assessed by Increase in Creatinine Clearance [ Time Frame: From randomization until 4-6 weeks post partum (maximum 8 weeks) ]
8. Rate of Spontaneous Delivery and/or Mode of Delivery [ Time Frame: From randomization to delivery (maximum of 3 weeks) ]
9. Number of Patients With Absence of Anti-serelaxin Antibodies [ Time Frame: From Randomization until 4-6 weeks post partum (maximum of 8 weeks) ]
10. 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 ) ]
11. Number of Patients With Abnormalities in Fetal Cardiotocography and Biophysical Profile [ Time Frame: Randomization to delivery (maximum of 3 weeks) ]
12. Pharmacokinetics of RLX030: Area Under the Blood Concentration-time Curve From Time Zero to Infinity (AUCinf)-Part 1 [ Time Frame: 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.
13. Pharmacokinetics of RLX030: Area Under the Blood Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast)-Part 1 [ Time Frame: 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.
14. Pharmacokinetics of RLX030: Blood Concentration at 24 Hour (C 0-24h) After Administration- Part 1 [ Time Frame: 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.
15. Pharmacokinetics of RLX030: Terminal Elimination Half-life (T1/2)- Part 1 [ Time Frame: 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.
16. Pharmacokinetics of RLX030: Mean Residence Time (MRT) [ Time Frame: 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 Outcome Measures :

1. Mean Number of Days Before Delivery [ Time Frame: From randomization until delivery (maximum of 3 weeks) ]

Eligibility Criteria

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

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).

Contacts and Locations

Locations

United States, Alabama

Novartis Investigative Site

Mobile, Alabama, United States, 36604

United States, Kentucky

Novartis Investigative Site

Lexington, Kentucky, United States, 40503

Novartis Investigative Site

Louisville, Kentucky, United States, 40202

United States, Texas

Novartis Investigative Site

Galveston, Texas, United States, 77555-0587

Italy

Novartis Investigative Site

Modena, MO, Italy, 41100

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01566630
• Other Study ID Numbers: CRLX030A2205; 2011-001617-14 ( EudraCT Number )
• First Posted: March 29, 2012
• Results First Posted: November 5, 2015
• Last Update Posted: November 5, 2015
• Last Verified: October 2015

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

human recombinant RLX030; Pre-eclampsia; hemodynamics; Pharmacokinetics

Additional relevant MeSH terms:

Eclampsia; Pre-Eclampsia; Hypertension, Pregnancy-Induced; Pregnancy Complications