Clinical trial NCT01356849: Evaluate the Efficacy and Safety of Once Daily Administration of Atrasentan Tablets (Low and High) Compared to Placebo in Reducing Residual Albuminuria in Type 2 Diabetic Patients With Nephropathy Who Are Treated With the Maximum Tolerated Labeled Dose of a Renin Angiotensin System (RAS) Inhibitor
Official title: RADAR: Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan - A Phase 2b, Prospective, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Safety and Efficacy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Kidney Disease
Diabetic Nephropathy
Keywords: Endothelin Receptor Antagonists
Proteinuria
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2011-05-20
Enrollment: 149
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Prospective, Randomized, Double-Blind, Placebo-Controlled Multicenter Study. The objective of the study is to evaluate the efficacy and safety of once daily administration of atrasentan tablets (low dose and high dose) compared to placebo in reducing residual albuminuria in Type 2 diabetic patients with nephropathy who are treated with the maximum tolerated labeled dose of a Renin Angiotensin System (RAS) inhibitor. If the patient is already receiving a maximum tolerated labeled daily dose of RAS inhibitor and a diuretic, he/she will complete 4 weeks of the Run-in Period on a dose that has not been adjusted. If the patient is currently not receiving a maximum labeled daily dose of a RAS inhibitor then the dose will be titrated up to the maximum tolerated labeled dose over the course of 4 to 8 weeks during the Run-in Period. It is expected that subjects not receiving a diuretic will have a diuretic added or titrated during this period to maximize RAS inhibition. Following titration to the maximum tolerated labeled dose, the patient will complete an additional 4 weeks of Run-In Period on an unchanged doses of RAS inhibitor and diuretics, unless medically contraindicated. The randomization will be stratified based on country where subjects are enrolled into the study, and the Week -1 Urinary Albumin to Creatinine Ratio (UACR) levels (\< or = 1000 mg/g \[113 mg/mmol\], or \> 1000 mg/g \[113 mg/mmol\]). Within each stratum, subjects will be randomly assigned in a 1:2:2 ratio to one of the following blinded treatment groups: Group A - Placebo once daily (QD) Group B - low dose atrasentan QD Group C - high dose atrasentan QD After the 12 weeks of study drug treatment, subjects will be followed up to 30 days.


Eligibility criteria: Inclusion Criteria:

* Patient is \> or = 18 years old.
* Patient has Type 2 diabetes and has been treated with at least one anti hyperglycemic medication within the 12 months prior to the Screening Period.
* Patient is currently receiving an angiotensin converting enzyme inhibitor (ACEi) or Angiotensin II receptor blocker (ARB) (Renin Angiotensin System (RAS) inhibitor).
* For entry in the Run-in Period the patient must satisfy the following criteria based on the Screening laboratory values:

  * Estimated glomerular filtration rate (eGFR) ≥ 30 and ≤ 75 mL/min/1.73m2 by Epidemiology Collaboration (EPI) formula
  * Urinary Albumin to Creatinine Ratio (UACR) \> or = 300 and \< or = 3500 mg/g as determined by the geometric mean of the two morning void urine specimens obtained at the Screening visit (UACR \> or = 34 mg/mmol and \< or = 396 mg/mmol)
  * Serum albumin \> or = 3.0 g/dL (30 g/L) - B-type Natriuretic Peptide (BNP) \< or = 200 pg/mL (57.8 pmol/L) \* Negative serum pregnancy test for female patients
  * Systolic Blood Pressure (SBP) \> or = 110 mmHg and \< or = 180 mmHg
  * Glucosylated hemoglobin A1c (HbA1c) \< or = 12%
* For entry in the Treatment Period the patient must satisfy the following criteria based on the last visit of the Run-in Period laboratory values:

  * Renin Angiotensin System (RAS) inhibitor at maximum tolerated labeled dose for the previous 4 weeks with no adjustments of dose
  * Diuretic at any dose unless medically contraindicated (with the exception of loop diuretics \> or = 120 mg QD of furosemide or \> or = 3.0 mg QD of bumetanide or \> or = 150 mg QD of ethacrynic acid or \> or = 60 mg QD of torasemide)
  * Urinary Albumin to Creatinine Ratio (UACR) \> or = 200 and \< or = 3500 mg/g as determined by the median of the three morning void urine specimens obtained prior to the Week -1 visit (UACR \> or = 23 mg/mmol and \< or = 396 mg/mmol)
  * Systolic blood pressure (SBP) \> or = 110 mmHg and \< or = 160 mmHg
  * Serum Potassium \< or = 5.5 mEq/L (5.5 mmol/L)
  * Negative serum pregnancy test for female patients

Exclusion Criteria:

* Patient has a history of moderate or severe edema, facial edema unrelated to trauma, or a history of myxedema in the prior 6 months to Screening.
* Patient is receiving loop diuretics \> or = 120 mg QD of furosemide or \> or = 3.0 mg QD of bumetanide or \> or = 150 mg QD of ethacrynic acid or \> or = 60 mg QD of torasemide.
* Patient has a history of pulmonary edema.
* Patient has a history of pulmonary hypertension, or any lung diseases requiring oxygen therapy (i.e., chronic obstructive pulmonary disease, emphysema, pulmonary fibrosis).
* Patient has a history of orthostatic hypotension within the past 6 months as defined by the presence of a supine-to-standing blood pressure decrease \> or = 20 mmHg systolic or \> or = 10 mmHg diastolic within 3 minutes of standing.

Primary outcomes:
measure: Change from baseline to Week 12 in Urinary Albumin to Creatinine Ratio (UACR)
timeFrame: Every two weeks for 12 weeks
Secondary outcomes:
measure: Differences in change from baseline to each post baseline measure for estimated glomerular filtration rate (eGFR)
timeFrame: Every two weeks for 12 weeks
measure: Differences in change from baseline to each post baseline measure for EQ-5D Index Score
timeFrame: Once a month for 3 months
measure: Differences in change from baseline to each post baseline measure for each of the Kidney Disease Quality of Life (KDQOL) Kidney Disease Targeted Scales
timeFrame: Once a month for 3 months
Other outcomes:
Locations:
city: Pell City
country: United States
facility: Site Reference ID/Investigator# 46345
state: Alabama
city: Tempe
country: United States
facility: Site Reference ID/Investigator# 46035
state: Arizona
city: Azusa
country: United States
facility: Site Reference ID/Investigator# 46016
state: California
city: Chula Vista
country: United States
facility: Site Reference ID/Investigator# 45992
state: California
city: La Mesa
country: United States
facility: Site Reference ID/Investigator# 46000
state: California
city: Lincoln
country: United States
facility: Site Reference ID/Investigator# 46038
state: California
city: Long Beach
country: United States
facility: Site Reference ID/Investigator# 45994
state: California
city: Los Angeles
country: United States
facility: Site Reference ID/Investigator# 45998
state: California
city: Los Gatos
country: United States
facility: Site Reference ID/Investigator# 47584
state: California
city: National City
country: United States
facility: Site Reference ID/Investigator# 64465
state: California
city: Orange
country: United States
facility: Site Reference ID/Investigator# 65862
state: California
city: Riverside
country: United States
facility: Site Reference ID/Investigator# 46019
state: California
city: Salinas
country: United States
facility: Site Reference ID/Investigator# 46110
state: California
city: Yuba City
country: United States
facility: Site Reference ID/Investigator# 46017
state: California
city: Westminster
country: United States
facility: Site Reference ID/Investigator# 46662
state: Colorado
city: Coral Gables
country: United States
facility: Site Reference ID/Investigator# 46033
state: Florida
city: Hialeah
country: United States
facility: Site Reference ID/Investigator# 45989
state: Florida
city: Lauderdale Lakes
country: United States
facility: Site Reference ID/Investigator# 46667
state: Florida
city: Miami
country: United States
facility: Site Reference ID/Investigator# 46123
state: Florida
city: Ocala
country: United States
facility: Site Reference ID/Investigator# 46115
state: Florida
city: Pembroke Pines
country: United States
facility: Site Reference ID/Investigator# 46664
state: Florida
city: Pembroke Pines
country: United States
facility: Site Reference ID/Investigator# 46031
state: Florida
city: Pembroke Pines
country: United States
facility: Site Reference ID/Investigator# 46040
state: Florida
city: Port Charlotte
country: United States
facility: Site Reference ID/Investigator# 46122
state: Florida
city: West Palm Beach
country: United States
facility: Site Reference ID/Investigator# 46015
state: Florida
city: Jonesboro
country: United States
facility: Site Reference ID/Investigator# 50482
state: Georgia
city: Meridian
country: United States
facility: Site Reference ID/Investigator# 46034
state: Idaho
city: Chicago
country: United States
facility: Site Reference ID/Investigator# 46666
state: Illinois
city: Evergreen Park
country: United States
facility: Site Reference ID/Investigator# 45996
state: Illinois
city: Gurnee
country: United States
facility: Site Reference ID/Investigator# 46002
state: Illinois
city: Shreveport
country: United States
facility: Site Reference ID/Investigator# 46111
state: Louisiana
city: Oxon Hill
country: United States
facility: Site Reference ID/Investigator# 46030
state: Maryland
city: Rockville
country: United States
facility: Site Reference ID/Investigator# 45991
state: Maryland
city: Novi
country: United States
facility: Site Reference ID/Investigator# 46025
state: Michigan
city: Brooklyn Center
country: United States
facility: Site Reference ID/Investigator# 46023
state: Minnesota
city: Farmington
country: United States
facility: Site Reference ID/Investigator# 46062
state: Missouri
city: Omaha
country: United States
facility: Site Reference ID/Investigator# 48942
state: Nebraska
city: Omaha
country: United States
facility: Site Reference ID/Investigator# 46349
state: Nebraska
city: Las Vegas
country: United States
facility: Site Reference ID/Investigator# 46116
state: Nevada
city: Albany
country: United States
facility: Site Reference ID/Investigator# 50483
state: New York
city: New Hyde Park
country: United States
facility: Site Reference ID/Investigator# 68328
state: New York
city: Asheville
country: United States
facility: Site Reference ID/Investigator# 65863
state: North Carolina
city: Greensboro
country: United States
facility: Site Reference ID/Investigator# 50529
state: North Carolina
city: Greenville
country: United States
facility: Site Reference ID/Investigator# 46129
state: North Carolina
city: Morehead City
country: United States
facility: Site Reference ID/Investigator# 46022
state: North Carolina
city: Doylestown
country: United States
facility: Site Reference ID/Investigator# 46224
state: Pennsylvania
city: Orangeburg
country: United States
facility: Site Reference ID/Investigator# 46028
state: South Carolina
city: Orangeburg
country: United States
facility: Site Reference ID/Investigator# 46702
state: South Carolina
city: Greenville
country: United States
facility: Site Reference ID/Investigator# 46024
state: Texas
city: Houston
country: United States
facility: Site Reference ID/Investigator# 46228
state: Texas
city: Houston
country: United States
facility: Site Reference ID/Investigator# 47068
state: Texas
city: Houston
country: United States
facility: Site Reference ID/Investigator# 64464
state: Texas
city: Mission
country: United States
facility: Site Reference ID/Investigator# 64483
state: Texas
city: San Antonio
country: United States
facility: Site Reference ID/Investigator# 46348
state: Texas
city: San Antonio
country: United States
facility: Site Reference ID/Investigator# 46063
state: Texas
city: San Antonio
country: United States
facility: Site Reference ID/Investigator# 68486
state: Texas
city: Bennington
country: United States
facility: Site Reference ID/Investigator# 46669
state: Vermont
city: Alexandria
country: United States
facility: Site Reference ID/Investigator# 46026
state: Virginia
city: Fairfax
country: United States
facility: Site Reference ID/Investigator# 46027
state: Virginia
city: Kitchener
country: Canada
facility: Site Reference ID/Investigator# 67762
city: Sarnia
country: Canada
facility: Site Reference ID/Investigator# 50526
city: Thornhill
country: Canada
facility: Site Reference ID/Investigator# 50525
city: Caguas
country: Puerto Rico
facility: Site Reference ID/Investigator# 47067
city: Manati
country: Puerto Rico
facility: Site Reference ID/Investigator# 50522
city: Ponce
country: Puerto Rico
facility: Site Reference ID/Investigator# 46352
city: Ponce
country: Puerto Rico
facility: Site Reference ID/Investigator# 46351
city: Ponce
country: Puerto Rico
facility: Site Reference ID/Investigator# 46133
city: Rio Piedras
country: Puerto Rico
facility: Site Reference ID/Investigator# 46131
city: San Juan
country: Puerto Rico
facility: Site Reference ID/Investigator# 46132
city: Santurce
country: Puerto Rico
facility: Site Reference ID/Investigator# 46230
city: Taichung City
country: Taiwan
facility: Site Reference ID/Investigator# 51566
city: Taichung
country: Taiwan
facility: Site Reference ID/Investigator# 51567
Study officials:
affiliation: AbbVie
name: Blai Coll, MD
role: STUDY_DIRECTOR
References:
citation: Lin CW, Mostafa NM, L Andress D, J Brennan J, Klein CE, Awni WM. Relationship Between Atrasentan Concentrations and Urinary Albumin to Creatinine Ratio in Western and Japanese Patients With Diabetic Nephropathy. Clin Ther. 2018 Feb;40(2):242-251. doi: 10.1016/j.clinthera.2017.07.011. Epub 2017 Jul 27.