Clinical trial NCT00920764: A Study of Atrasentan on Reducing Albuminuria in Type 2 Diabetic Nephropathy Treated With Renin-Angiotensin System Inhibitors
Official title: A Phase 2a, Prospective, Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Safety and Efficacy of Atrasentan on Reducing Albuminuria in Type 2 Diabetic Nephropathy Subjects Who Are Currently Being Treated With an Renin-Angiotensin System Inhibitor
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Kidney Disease
Diabetic Nephropathy
Keywords: CKD Stages 3&4
Endothelin antagonist
Proteinuria
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2009-06-15
Enrollment: 92
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: The study objective is to investigate the effects of three low doses of atrasentan on urinary albumin/creatinine ratio (UACR) levels in subjects with Type 2 diabetic nephropathy.

Patients with Type 2 diabetes with nephropathy must be receiving a renin-angiotensin system inhibitor, such as an Angiotensin converting enzyme inhibitor (ACEi) or an Angiotensin II Receptor Blocker (ARB) for participation in this study. ACEi and ARB treatment are the standard of care for the management of proteinuria in Chronic Kidney Disease (CKD) patients.


Eligibility criteria: Inclusion Criteria:

* 1.Subject is \>= 18 years old.
* 2.Subject has voluntarily signed and dated an informed consent form, approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC), after the nature of the study has been explained and the subject has had the opportunity to ask questions. The informed consent must be signed before any study-specific procedures are performed.
* 3.Subject has Type 2 diabetes and has been treated with at least one anti-hyperglycemic medication within the 12 months prior to the Screening Phase.
* 4.Subject has been receiving a stable dose (i.e., same type and regimen) of angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blocking agents (ARB) for at least 2 months prior to the Screening Phase.
* 5.If female, subject must be not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy). The reason for non-childbearing potential must be specified in the subject's eCRF.
* 6.If male, subject must be surgically sterile or if sexually active and of childbearing potential, the site must document the lack of desire for future procreation and subject must agree to use a condom and a second reliable barrier of contraception from the Screening Visit through two months following completion of their participation in the study.
* 7.For entry into the Treatment Phase the subject must satisfy the following criteria based on Screening laboratory values:

  * a.Estimated GFR \> 20 mL/min/1.73 m2 by simplified MDRD formula
  * b.UACR between 100 and 3000 mg/g as determined at the initial Screening visit or by the mean of the 2 morning void urine specimens obtained prior to the second Screening visit.
  * c.Serum albumin \> 3.0 g/dL.
  * d.HbA1c \<= 10%.
  * e.Pro-BNP \<= 500pg/mL.
  * f.Negative urine pregnancy test for female subjects.

Exclusion Criteria:

* 1.Subject has a history of significant peripheral edema (2 + or greater), or facial edema unrelated to trauma, or a history of myxedema in the 6 months prior to Screening.
* 2.Subject receiving loop diuretics \> 30 mg BID of furosemide or \> 0.5 mg BID of bumetanide or \> 25 mg BID of ethacrynic acid.
* 3.Subject has a history of pulmonary edema.
* 4.Subject has a history of pulmonary hypertension, chronic obstructive pulmonary disease, emphysema, pulmonary fibrous disease, asthma or other lung disease that requires oxygen.
* 5.Subject has a documented history of heart failure, defined as New York Heart Association (NYHA) Class II, III or IV heart failure.
* 6.Subject has a body mass index (BMI) \> 40.
* 7.Subject has elevated liver enzymes (ALT and/or AST) \> 1.5 x the upper limit of normal (ULN).
* 8.Subject has a hemoglobin \< 9.5 g/dL.
* 9.Subject has a history of an allergic reaction or significant sensitivity to atrasentan or its excipients.
* 10.Subject has a history of a chronic gastrointestinal disease, which in the Investigator's opinion may cause significant GI malabsorption.
* 11.Subject has a history of secondary hypertension (i.e., renal artery stenosis, primary aldosteronism or pheochromocytoma).
* 12.Subject has poorly controlled hypertension (systolic blood pressure ≥ 160 mmHg and or diastolic blood pressure ≥ 90 mmHg) or hypotension (systolic blood pressure \<= 90 mmHg).
* 13.Subject has significant comorbidities (e.g., advanced malignancy, advanced liver disease) with a life expectancy less than 1 year.
* 14.Subject is expected to receive an increased dose of current RAAS inhibitor (ACEi, ARB, renin or aldosterone inhibitor) during the course of the study. Conversions from one product to another (e.g., ACEi to ARB) must be at equivalent doses.
* 15.Subject has clinically significant coronary artery disease (CAD) within 3 months prior to the Screening Period, defined as one of the following:

  * Hospitalization for MI or unstable angina; or
  * New onset angina with positive functional study or coronary angiogram revealing stenosis; or
  * Coronary revascularization procedure.
* 16.Subject has a history of viral or bacterial infection within 4 weeks of Screening or HIV infection.
* 17.Subject has scheduled or planned surgery with general anesthesia within 12 weeks of Screening Visit.
* 18.Subject has a history of drug or alcohol abuse within 6 months prior to the Screening Visit.
* 19.Subject has evidence of poor compliance with diet or medication that may interfere, in the Investigator's opinion, with adherence to the protocol.
* 20.Subject has received any investigational drug within 30 days prior to study drug administration.
* 21.For any reason, subject is considered by the Investigator to be an unsuitable candidate to receive atrasentan oral solution or is put at risk by study procedures

Primary outcomes:
measure: Mean change from baseline to each post-baseline observation on UACR over the course of treatment period versus standard of care
timeFrame: Week 8 visit or final assessment
Secondary outcomes:
measure: Proportion of subjects achieving at least a 25% reduction in final UACR levels from baseline
timeFrame: Week 8 visit or final assessment
measure: Proportion of subjects achieving at least a 40% reduction in final UACR levels from baseline
timeFrame: Week 8 visit or final assessment
measure: Change from baseline to the final value in UACR, estimated glomerular filtration rate (eGFR), Neutrophil Gelatinase-Associated Lipocalin (NGAL)
timeFrame: Week 8 visit or final assessment
measure: Change from baseline to each weekly measurement in NGAL
timeFrame: Week 8 visit or final assessment
Other outcomes:
Locations:
city: Tempe
country: United States
facility: Site Reference ID/Investigator# 19386
state: Arizona
city: Azusa
country: United States
facility: Site Reference ID/Investigator# 25043
state: California
city: Los Angeles
country: United States
facility: Site Reference ID/Investigator# 23308
state: California
city: Los Angeles
country: United States
facility: Site Reference ID/Investigator# 25430
state: California
city: San Diego
country: United States
facility: Site Reference ID/Investigator# 20421
state: California
city: San Diego
country: United States
facility: Site Reference ID/Investigator# 22442
state: California
city: Whittier
country: United States
facility: Site Reference ID/Investigator# 21061
state: California
city: Yuba City
country: United States
facility: Site Reference ID/Investigator# 16572
state: California
city: Coral Gables
country: United States
facility: Site Reference ID/Investigator# 26142
state: Florida
city: Hudson
country: United States
facility: Site Reference ID/Investigator# 16567
state: Florida
city: Pembroke Pines
country: United States
facility: Site Reference ID/Investigator# 16577
state: Florida
city: Pembroke Pines
country: United States
facility: Site Reference ID/Investigator# 25242
state: Florida
city: Rockville
country: United States
facility: Site Reference ID/Investigator# 16569
state: Maryland
city: Omaha
country: United States
facility: Site Reference ID/Investigator# 16574
state: Nebraska
city: Buffalo
country: United States
facility: Site Reference ID/Investigator# 20221
state: New York
city: Greenville
country: United States
facility: Site Reference ID/Investigator# 16576
state: North Carolina
city: Morehead City
country: United States
facility: Site Reference ID/Investigator# 16573
state: North Carolina
city: Statesville
country: United States
facility: Site Reference ID/Investigator# 26143
state: North Carolina
city: Bethlehem
country: United States
facility: Site Reference ID/Investigator# 19383
state: Pennsylvania
city: Orangeburg
country: United States
facility: Site Reference ID/Investigator# 26365
state: South Carolina
city: San Antonio
country: United States
facility: Site Reference ID/Investigator# 16571
state: Texas
city: San Antonio
country: United States
facility: Site Reference ID/Investigator# 16566
state: Texas
city: San Antonio
country: United States
facility: Site Reference ID/Investigator# 19384
state: Texas
city: Fairfax
country: United States
facility: Site Reference ID/Investigator# 24542
state: Virginia
city: Las Piedras
country: Puerto Rico
facility: Site Reference ID/Investigator# 16564
city: Ponce
country: Puerto Rico
facility: Site Reference ID/Investigator# 19381
city: San Juan
country: Puerto Rico
facility: Site Reference ID/Investigator# 16563
city: San Juan
country: Puerto Rico
facility: Site Reference ID/Investigator# 16562
Study officials:
affiliation: AbbVie
name: Dennis Andress
role: STUDY_DIRECTOR
References:
citation: Perez-Gomez MV, Sanchez-Nino MD, Sanz AB, Martin-Cleary C, Ruiz-Ortega M, Egido J, Navarro-Gonzalez JF, Ortiz A, Fernandez-Fernandez B. Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade. J Clin Med. 2015 Jun 18;4(6):1325-47. doi: 10.3390/jcm4061325.