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Effects of Intravenous Bendavia™ on Reperfusion Injury in Patients Undergoing Angioplasty of the Renal Artery (EVOLVE)

Primary Purpose

Renal Artery Obstruction, Hypertension, Renovascular, Ischemia Reperfusion Injury

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Bendavia
Placebo
Sponsored by
Stealth BioTherapeutics Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Renal Artery Obstruction focused on measuring elamipretide

Eligibility Criteria

40 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • ≥40 and ≤80 years old.
  • Patients with hypertension (systolic blood pressure [BP] >155 mm Hg) and/or requiring 2 or more antihypertensive medications: no restrictions will be placed on antihypertensive agents, although loop diuretics will be temporarily changed to diluting site agents (eg, hydrochlorothiazide, indapamide, metolazone) prior to each blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) study performed during the trial, unless, in the judgment of the Investigator, the change represents a hazard to the patient. ARAS patients will be identified based upon radiologic and clinical criteria suggestive of renovascular hypertension and/or hemodynamically significant renovascular disease >60% lumen occlusion (determined by quantitative computed tomography angiography or Doppler ultrasound velocity >200 cm/sec).
  • Have an estimated glomerular filtration rate of ≥15 ml/min/1.73 m2 calculated using the Modification of Diet in Renal Disease (MDRD) formula.
  • Have no contraindications to angiography such as severe contrast allergy.
  • Have no contraindications to non-contrast magnetic resonance evaluations such as a pacemaker or magnetically active metal fragments.
  • Able to comply with protocol.
  • Women of childbearing age must:
  • Have a negative pregnancy serum human chorionic gonadotropin test prior to receiving study drug.
  • Agree to use two forms of contraception for 3 months following receipt of the study drug.
  • Men who are sexually active and able to father a child, must agree to use one of the birth control methods listed below for the entire study and for at least 2 months after receiving the study drug:
  • Barrier methods (such as a condom or diaphragm) used with a spermicide.
  • Hormonal methods used by his partner, such as birth control pills, patches, injections, vaginal ring, or implants.
  • Intrauterine device (IUD) used by his partner.
  • Abstinence (no sex).
  • Competent and able to provide written informed consent

Exclusion Criteria:

  • Advanced chronic kidney disease defined as either Stage 5 or end-stage renal disease requiring dialysis.
  • Have other clinically significant abnormalities or laboratory results that would, in the opinion of the investigators, compromise the safety of the patient including evidence of diabetic ketoacidosis, paraproteinemia, or triglycerides above 600 mg/dL.
  • Clinically significant medical conditions within the six months before administration of Bendavia (e.g., cancer, stroke, myocardial infarction, active angina, congestive heart failure) that would, in the opinion of the investigators, compromise the safety of the patient.
  • Have received an investigational drug within thirty (30) days of baseline.
  • Have a serum sodium <135 mmol/L on the day of, and prior to, the PTRA.
  • Are pregnant or breast feeding.

Sites / Locations

  • Mayo Clinic

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Bendavia

Placebo

Arm Description

Bendavia, intravenous infusion, 0.05 mg/kg/hr for a maximum duration of 4 hours.

Placebo (no active drug), intravenous infusion, for a maximum duration of 4 hours.

Outcomes

Primary Outcome Measures

Change in Mean Glomerular Filtration Rate (GFR), as Measured by Iothalamate Clearance, at Baseline (Pre-percutaneous Renal Artery Angioplasty and 8 Weeks Post-PTRA.
Change in mean glomerular filtration rate (GFR), as measured by iothalamate clearance, from baseline (pre-percutaneous renal artery angioplasty, or pre-PTRA) and 8 weeks post-PTRA..

Secondary Outcome Measures

Change in Mean Glomerular Flow Rate as Measured Using Multi-Detector Computed Tomography (MDCT) at Baseline (Pre-PTRA) and 8 Weeks Post-PTRA.
Change in mean glomerular flow rate as measured using Multi-Detector Computed Tomography (MDCT) at baseline (pre-PTRA) and 8 weeks post-PTRA, stented quantifiable scanned kidneys.
Change in Mean Regional Perfusion as Measured by MDCT at Baseline (Pre-PTRA) and 8 Weeks Post-PTRA
Change in mean regional perfusion as measured by Multi-Detector Computed Tomography (MDCT) Baseline (pre-PTRA) and 8 weeks post-PTRA for stented quantifiable scanned kidneys.
Change in Mean Renal Blood Flow as Measured Using Multi-Detector Computed Tomography (MDCT) at Baseline (Pre-PTRA) and 8 Weeks Post-PTRA
Change in mean renal blood flow (ml/minute) as measured using Multi-Detector Computed Tomography (MDCT) at Baseline (pre-PTRA) and 8 weeks post-PTRA for stented quantifiable scanned kidneys
Change in Mean Renal Volume as Measured by Multi-Detector Computed Tomography (MDCT) at Baseline (Pre-PTRA) and 8 Weeks Post-PTRA.
Change in mean renal volume as measured by Multi-Detector Computed Tomography (MDCT) at Baseline (pre-PTRA) and 8 weeks post-PTRA.
Mean Change in Renal Oxygenation, Axial Aspect, in Stented Kidneys From Baseline (Pre-PTRA), and 27 Hours Post-PTRA and 8 Weeks Post-PTRA
Mean change in renal oxygenation, axial aspect, in stented kidneys between baseline (pre-PTRA), and 27 hours post-PTRA and 8 weeks post-PTRA as measured by calculation of fractional hypoxia using blood oxygenation level-dependent magnetic resonance (BOLD-MR) imaging.
Mean Change in Renal Oxygenation, Coronal Aspect, in Stented Kidneys Between Baseline Pre-PTRA, 27 Hours Post-PTRA and 8 Weeks Post-PTRA
Mean change in renal oxygenation, coronal aspect, in stented kidneys between baseline (pre-PTRA) and 27 hours post-PTRA or 8 weeks post-PTRA, as measured by calculation of fractional hypoxia using blood oxygenation level-dependent magnetic resonance (BOLD-MR) imaging, with and without Bendavia
Mean Change in Systolic Blood Pressure Values (mmHg) From Pre-PTRA, Immediately Post-PTRA, 27 Hours and 8 (+4) Weeks Post-PTRA
Mean Change in Diastolic Blood Pressure
Mean Change in Diastolic Blood Pressure (DBP) values (mmHg) from baseline (pre-PTRA), immediately post-PTRA, 27 hours and 8 weeks post-PTRA, with and without Bendavia.

Full Information

First Posted
December 19, 2012
Last Updated
August 10, 2020
Sponsor
Stealth BioTherapeutics Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01755858
Brief Title
Effects of Intravenous Bendavia™ on Reperfusion Injury in Patients Undergoing Angioplasty of the Renal Artery
Acronym
EVOLVE
Official Title
A Phase 2a, Placebo-controlled Trial to Evaluate the Impact of Intravenous Bendavia™ on Ischemia Reperfusion Injury in Atherosclerotic Renal Artery Stenosis in Patients Undergoing Percutaneous Transluminal Angioplasty of the Renal Artery
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Terminated
Study Start Date
December 2012 (undefined)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
May 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Stealth BioTherapeutics Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This was a Phase 2a prospective, single center, randomized, double-blind, placebo-controlled study designed to assess the efficacy, pharmacokinetics, safety and tolerability of IV elamipretide for reduction of reperfusion injury in subjects with Atherosclerotic Renal Artery Stenosis (ARAS), who are undergoing percutaneous transluminal angioplasty of the renal artery (PTRA).
Detailed Description
This was a Phase 2a prospective, single center, randomized, double-blind, placebo-controlled study designed to assess the efficacy, pharmacokinetics, safety and tolerability of IV elamipretide for reduction of reperfusion injury in subjects with ARAS, who are undergoing percutaneous transluminal angioplasty of the renal artery (PTRA). The randomization (1:1 active:placebo) was stratified by a diagnosis of diabetes mellitus. Participants received either 0.05 mg/kg/h elamipretide or matching placebo, administered as an IV infusion at 60 mL/h infused 30 minutes before and continued 3 hours after PTRA of the renal artery. After completion of the PTRA and stenting, subjects were to receive standard treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Artery Obstruction, Hypertension, Renovascular, Ischemia Reperfusion Injury
Keywords
elamipretide

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Bendavia
Arm Type
Experimental
Arm Description
Bendavia, intravenous infusion, 0.05 mg/kg/hr for a maximum duration of 4 hours.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo (no active drug), intravenous infusion, for a maximum duration of 4 hours.
Intervention Type
Drug
Intervention Name(s)
Bendavia
Other Intervention Name(s)
MTP-131, Elamipretide
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Change in Mean Glomerular Filtration Rate (GFR), as Measured by Iothalamate Clearance, at Baseline (Pre-percutaneous Renal Artery Angioplasty and 8 Weeks Post-PTRA.
Description
Change in mean glomerular filtration rate (GFR), as measured by iothalamate clearance, from baseline (pre-percutaneous renal artery angioplasty, or pre-PTRA) and 8 weeks post-PTRA..
Time Frame
Baseline (pre-PTRA) and 8 weeks post-PTRA
Secondary Outcome Measure Information:
Title
Change in Mean Glomerular Flow Rate as Measured Using Multi-Detector Computed Tomography (MDCT) at Baseline (Pre-PTRA) and 8 Weeks Post-PTRA.
Description
Change in mean glomerular flow rate as measured using Multi-Detector Computed Tomography (MDCT) at baseline (pre-PTRA) and 8 weeks post-PTRA, stented quantifiable scanned kidneys.
Time Frame
Baseline (pre-PTRA) and 8 weeks post-PTRA
Title
Change in Mean Regional Perfusion as Measured by MDCT at Baseline (Pre-PTRA) and 8 Weeks Post-PTRA
Description
Change in mean regional perfusion as measured by Multi-Detector Computed Tomography (MDCT) Baseline (pre-PTRA) and 8 weeks post-PTRA for stented quantifiable scanned kidneys.
Time Frame
Baseline (pre-PTRA) and 8 weeks post-PTRA
Title
Change in Mean Renal Blood Flow as Measured Using Multi-Detector Computed Tomography (MDCT) at Baseline (Pre-PTRA) and 8 Weeks Post-PTRA
Description
Change in mean renal blood flow (ml/minute) as measured using Multi-Detector Computed Tomography (MDCT) at Baseline (pre-PTRA) and 8 weeks post-PTRA for stented quantifiable scanned kidneys
Time Frame
Baseline (pre-PTRA) and 8 weeks post-PTRA
Title
Change in Mean Renal Volume as Measured by Multi-Detector Computed Tomography (MDCT) at Baseline (Pre-PTRA) and 8 Weeks Post-PTRA.
Description
Change in mean renal volume as measured by Multi-Detector Computed Tomography (MDCT) at Baseline (pre-PTRA) and 8 weeks post-PTRA.
Time Frame
Baseline (Pre-PTRA) and 8 (+4) weeks post-PTRA
Title
Mean Change in Renal Oxygenation, Axial Aspect, in Stented Kidneys From Baseline (Pre-PTRA), and 27 Hours Post-PTRA and 8 Weeks Post-PTRA
Description
Mean change in renal oxygenation, axial aspect, in stented kidneys between baseline (pre-PTRA), and 27 hours post-PTRA and 8 weeks post-PTRA as measured by calculation of fractional hypoxia using blood oxygenation level-dependent magnetic resonance (BOLD-MR) imaging.
Time Frame
Baseline (Pre-PTRA) , 27 hours post-PTRA and 8 weeks post-PTRA
Title
Mean Change in Renal Oxygenation, Coronal Aspect, in Stented Kidneys Between Baseline Pre-PTRA, 27 Hours Post-PTRA and 8 Weeks Post-PTRA
Description
Mean change in renal oxygenation, coronal aspect, in stented kidneys between baseline (pre-PTRA) and 27 hours post-PTRA or 8 weeks post-PTRA, as measured by calculation of fractional hypoxia using blood oxygenation level-dependent magnetic resonance (BOLD-MR) imaging, with and without Bendavia
Time Frame
27H post PTRA and 8 weeks Post PTRA
Title
Mean Change in Systolic Blood Pressure Values (mmHg) From Pre-PTRA, Immediately Post-PTRA, 27 Hours and 8 (+4) Weeks Post-PTRA
Time Frame
Pre-PTRA and 27 hours post-PTRA and 8 weeks post-PTRA
Title
Mean Change in Diastolic Blood Pressure
Description
Mean Change in Diastolic Blood Pressure (DBP) values (mmHg) from baseline (pre-PTRA), immediately post-PTRA, 27 hours and 8 weeks post-PTRA, with and without Bendavia.
Time Frame
Pre-PTRA, immediately post-PTRA, 27 hours post-PTRA and 8 weeks post-PTRA

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: ≥40 and ≤80 years old. Patients with hypertension (systolic blood pressure [BP] >155 mm Hg) and/or requiring 2 or more antihypertensive medications: no restrictions will be placed on antihypertensive agents, although loop diuretics will be temporarily changed to diluting site agents (eg, hydrochlorothiazide, indapamide, metolazone) prior to each blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) study performed during the trial, unless, in the judgment of the Investigator, the change represents a hazard to the patient. ARAS patients will be identified based upon radiologic and clinical criteria suggestive of renovascular hypertension and/or hemodynamically significant renovascular disease >60% lumen occlusion (determined by quantitative computed tomography angiography or Doppler ultrasound velocity >200 cm/sec). Have an estimated glomerular filtration rate of ≥15 ml/min/1.73 m2 calculated using the Modification of Diet in Renal Disease (MDRD) formula. Have no contraindications to angiography such as severe contrast allergy. Have no contraindications to non-contrast magnetic resonance evaluations such as a pacemaker or magnetically active metal fragments. Able to comply with protocol. Women of childbearing age must: Have a negative pregnancy serum human chorionic gonadotropin test prior to receiving study drug. Agree to use two forms of contraception for 3 months following receipt of the study drug. Men who are sexually active and able to father a child, must agree to use one of the birth control methods listed below for the entire study and for at least 2 months after receiving the study drug: Barrier methods (such as a condom or diaphragm) used with a spermicide. Hormonal methods used by his partner, such as birth control pills, patches, injections, vaginal ring, or implants. Intrauterine device (IUD) used by his partner. Abstinence (no sex). Competent and able to provide written informed consent Exclusion Criteria: Advanced chronic kidney disease defined as either Stage 5 or end-stage renal disease requiring dialysis. Have other clinically significant abnormalities or laboratory results that would, in the opinion of the investigators, compromise the safety of the patient including evidence of diabetic ketoacidosis, paraproteinemia, or triglycerides above 600 mg/dL. Clinically significant medical conditions within the six months before administration of Bendavia (e.g., cancer, stroke, myocardial infarction, active angina, congestive heart failure) that would, in the opinion of the investigators, compromise the safety of the patient. Have received an investigational drug within thirty (30) days of baseline. Have a serum sodium <135 mmol/L on the day of, and prior to, the PTRA. Are pregnant or breast feeding.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephen C Textor, MD
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Richard Straube, MD
Organizational Affiliation
Stealth BioTherapeutics Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
28916603
Citation
Saad A, Herrmann SMS, Eirin A, Ferguson CM, Glockner JF, Bjarnason H, McKusick MA, Misra S, Lerman LO, Textor SC. Phase 2a Clinical Trial of Mitochondrial Protection (Elamipretide) During Stent Revascularization in Patients With Atherosclerotic Renal Artery Stenosis. Circ Cardiovasc Interv. 2017 Sep;10(9):e005487. doi: 10.1161/CIRCINTERVENTIONS.117.005487.
Results Reference
derived

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Effects of Intravenous Bendavia™ on Reperfusion Injury in Patients Undergoing Angioplasty of the Renal Artery

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