Clinical trial NCT02156843: Pyridorin in Diabetic Nephropathy
Official title: A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Safety and Efficacy of Pyridorin (Pyridoxamine Dihydrochloride) in Subjects With Nephropathy Due to Type 2 Diabetes (PIONEER)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Diabetic Nephropathy
Diabetic Kidney Disease
Keywords: Diabetic Kidney Disease
Nephropathy
Diabetic Nephropathy
Kidney Disease
Type 2 Diabetes
Lead sponsor: NephroGenex, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Collaborative Study Group (CSG)
name: Medpace, Inc.
First posted: 2014-06-05
Enrollment: 328
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 purpose of this study is to evaluate the safety and efficacy of oral Pyridorin 300 mg BID in reducing the rate of progression of nephropathy due to type 2 diabetes mellitus.

Detailed description: This is a randomized, double-blind, placebo-controlled, multi-center Phase 3 study to evaluate the safety and efficacy of Pyridorin 300 mg BID (twice daily, every 12 hours) in subjects with nephropathy due to type 2 diabetes mellitus. In this study, nephropathy is defined as a Serum Creatinine (SCr) \>= 1.3 (≥1.25) mg/dL (111 umol/L) for female and \>=1.5 (≥1.45) mg/dL (128 umol/L) for male subjects and a 24-hour urine collection protein/creatinine ration (PCR) \>=1200 mg/g (136 mg/mmol), and if applicable for PS Phase, at Visit 1S or 1.1S a 24-urine collection PCR ≥600 mg/g (68 mg/mmol). Subjects must have a baseline SCr \< 3.0 mg/dL (265 umol/L) and must be on previously established standard of care at screening.

Eligibility criteria: Inclusion Criteria:

Patients meeting all of the following criteria will be eligible to participate in the study:

1. Patients who have given voluntary written informed consent to participate in this study prior to conducting Screening (Visit 1) procedures;
2. Patients 18 years of age or older with a diagnosis of type 2 diabetes;
3. Women of childbearing potential (WOCBP) who agree to use appropriate birth control (double-barrier methods, hormonal contraceptives, or intrauterine device) for the duration of the study (women of childbearing potential is defined as all women who are not surgically sterile or are not at least 1 year post menopausal). All women of childbearing potential must have a negative serum pregnancy test at Visit 1;
4. All men (unless surgically sterile, as defined below) who have sexual intercourse with a WOCBP must agree and commit to use a highly effective method of contraception for the duration of the study (defined as the time of the signing of the informed consent form through the conclusion of patient participation). Highly effective methods of contraception include:

   i. Male subjects agreeing that they and their female spouse/partners will use adequate contraception (2 forms of birth control, one of which must be barrier method) or be of non-childbearing potential.

   ii. To be considered surgically sterilized, a male partner must have had a vasectomy at least 24 weeks before Visit 1;
5. At Visit 1, patients must have a history of overt diabetic nephropathy, as defined by the following:

   * A SCr measurement ≥1.3 (≥1.25)mg/dL (111 µmol/L) for females or ≥1.5 (≥1.45) mg/dL (128 µmol/L) for males;
   * At Visit 1 or 1.1 24-hour urine collection PCR \>1200 mg/g (130 mg/µmol) and, if applicable for PS phase, at Visit 1S or 1.1S a 24-urine collection PCR \>600 mg/g (67 mg/µmol)
   * For eligibility determination, laboratory reported values of PCR will be rounded up to 2 significant digits (e.g. ≥1150 mg/g to 1200 mg/g; ≥595 mg/g to 600 mg/g),
6. Patients must have a SCr measurement \<3.0 mg/dL (265 µmol/L);
7. Patients must have an eGFR of ≥20 mL/min/1.73m2, using the 4-variable Modification of Diet in Renal Disease equation in which eGFR = 175 x (SCr(mg/dL))-1.154 x (Age(years))-0.203 x (0.742 if female) x (1.212 if African American);
8. Patient must have a second screening SCr measurement at Visit 1.1 or 1.1S taken 1 week (± 2 days) after screening (Visit 1 or 1S). The value of the second screening SCr measurement must be \<3.0 mg/dL (265 µmol/L) for both genders and within 25% of the first screening measurement;
9. Patients must be taking a single ACE-I or ARB at a constant dose for at least 26 weeks prior to Visit 1, where the dose of the ACE-I or the ARB is considered appropriate for that patient (can be zero to max dose approved by the FDA) and it is anticipated that the same dose can and will be maintained throughout the course of the study;
10. Patients taking any blood pressure medications in addition to an ACE-I or ARB, including diuretics, must be on a stable dose for 13 weeks prior to Visit 1 (and Visit 1S if applicable) with a seated blood pressure of ≤ 150/90 mmHg;
11. Patients not taking any blood pressure medications, including diuretics, other than an ACE-I or ARB must have a seated blood pressure ≤ 150/90 mmHg at Visit 1 (and Visit 1S if applicable) and a seated blood pressure considered appropriate for the patient and one that can be sustained throughout the study.

Exclusion Criteria:

Patients are excluded from participation in the study if any of the following criteria apply

1. Patients with type 1 diabetes or MODY (a monogenic form of diabetes);
2. Patients with a diagnosis of chronic kidney disease other than diabetic renal disease with or without hypertensive renal disease
3. Patients receiving a renin inhibitor or an aldosterone antagonist or a combination of an ACE-I and an ARB within 26 weeks of Visit 1
4. Patients with a history of solid organ transplantation
5. Patients with a history of myocardial infarction, coronary re-vascularization procedures (including percutaneous transluminal coronary angioplasty), stroke, or transient ischemic attack within 30 days prior to Visit 1
6. Patients with a diagnosis of New York Heart Association Class III or IV congestive heart failure at any time
7. Patients with a history of being treated for neoplastic disease (except basal or squamous cell carcinoma of the skin) within 5 years prior to Visit 1
8. Patients with any history of dialysis within 2 years prior to Visit 1
9. Patients in whom dialysis or renal transplantation is anticipated by their physician within 1 year after Visit 1
10. Patients who used SCr-altering drugs within 30 days prior to Visit 1
11. Patients who require systemic immunosuppression therapy for \>2 weeks (except for inhalant steroids)
12. Patients with clinically significant liver disease or transaminase (alanine aminotransferase and aspartate aminotransferase) levels \>2.5 × the upper limit of normal (ULN) measured at Visit 1.1 or Visit 1.1S
13. Patients with bilirubin levels \>1.5 × ULN measured at Visit 1.1 or Visit 1.1S
14. Patients with a history of allergic or other adverse response to vitamin B preparations
15. Patients who require \>50 mg of vitamin B6 daily
16. Patients who have an active history of dysphagia or swallowing disorders
17. Patients with a history of hypersensitivity to Pyridorin or any of the excipients (non-active ingredients) in the Pyridorin formulation
18. Patients who have taken pyridoxamine or any other investigational drug within 30 days prior to Visit 1, or have participated in a previous Pyridorin study or another interventional clinical study within 30 days prior to Visit 1
19. Patients with an active history of drug or alcohol abuse
20. Patients unlikely to comply with the study protocol (eg, an inability and unwillingness to participate in adequate training, an uncooperative attitude, inability to return for follow-up visits, or unlikelihood of completing the study)
21. Women who are lactating, pregnant, or intend to become pregnant during the course of the study
22. Persons employed with the sponsor, CRO, or one of the study investigative sites must be excluded from participation, even if they are not involved directly in the conduct of the study.

Primary outcomes:
measure: Time to composite endpoint of >=50% SCr increase from baseline or ESRD
timeFrame: Approximately 45 Months
Secondary outcomes:
measure: Time to the composite endpoint >=100% SCr increase or ESRD
timeFrame: Approximately 45 Months
Other outcomes:
measure: Change in serum cystatin-C
timeFrame: Change from baseline to Week 52 and from baseline to Week 104
measure: Change in urine protein/creatinine ratio (PCR)
timeFrame: From baseline to Week 52 and from baseline to Week 104
measure: Change in urinary transforming growth factor-beta (TGF-Beta) excretion
timeFrame: From baseline to Week 52 and from baseline to Week 104
measure: Change in SCr
timeFrame: From baseline to Week 52 and from baseline to Week 104
Locations:
city: Birmingham
country: United States
facility: CSG Investigational Site (#157)
state: Alabama
city: Phoenix
country: United States
facility: CSG Investigational Site (#130)
state: Arizona
city: Phoenix
country: United States
facility: CSG Investigational Site (#150)
state: Arizona
city: Prescott
country: United States
facility: CSG Investigational Site (#145)
state: Arizona
city: Tucson
country: United States
facility: CSG Investigational Site (#142)
state: Arizona
city: Los Angeles
country: United States
facility: CSG Investigational Site (#160)
state: California
city: Riverside
country: United States
facility: CSG Investigational Site (#143)
state: California
city: Roseville
country: United States
facility: CSG Investigational Site (#159)
state: California
city: Arvada
country: United States
facility: CSG Investigational Site (#153)
state: Colorado
city: Aurora
country: United States
facility: CSG Investigational Site (#118)
state: Colorado
city: Westminster
country: United States
facility: CSG Investigational Site (#120)
state: Colorado
city: Waterbury
country: United States
facility: CSG Investigational Site (#158)
state: Connecticut
city: Columbus
country: United States
facility: CSG Investigational Site (#156)
state: Georgia
city: Chicago
country: United States
facility: CSG Investigational Site (#113)
state: Illinois
city: Michigan City
country: United States
facility: CSG Investigational Site (#102)
state: Indiana
city: New Orleans
country: United States
facility: CSG Investigational Site (#115)
state: Louisiana
city: Greenbelt
country: United States
facility: CSG Investigational Site (#147)
state: Maryland
city: Boston
country: United States
facility: CSG Investigational Site (#117)
state: Massachusetts
city: Springfield
country: United States
facility: CSG Investigational Site (#114)
state: Massachusetts
city: Detroit
country: United States
facility: CSG Investigational Site (#111)
state: Michigan
city: Pontiac
country: United States
facility: CSG Investigational Site (#134)
state: Michigan
city: Kansas City
country: United States
facility: CSG Investigational Site (#162)
state: Missouri
city: Kansas City
country: United States
facility: CSG Investigational Site (#152)
state: Missouri
city: Las Vegas
country: United States
facility: CSG Investigational Site (#141)
state: Nevada
city: Buffalo
country: United States
facility: CSG Investigational Site (#128)
state: New York
city: Northport
country: United States
facility: CSG Investigational Site (#136)
state: New York
city: West Nyack
country: United States
facility: CSG Investigational Site (#154)
state: New York
city: Asheville
country: United States
facility: CSG Investigational Site (#108)
state: North Carolina
city: Charlotte
country: United States
facility: CSG Investigational Site (#116)
state: North Carolina
city: Durham
country: United States
facility: CSG Investigational Site (#125)
state: North Carolina
city: New Bern
country: United States
facility: CSG Investigational Site (#155)
state: North Carolina
city: Winston-Salem
country: United States
facility: CSG Investigational Site (#127)
state: North Carolina
city: Cincinnati
country: United States
facility: CSG Investigational Site (#124)
state: Ohio
city: Cleveland
country: United States
facility: CSG Investigational Site (#151)
state: Ohio
city: Cleveland
country: United States
facility: CSG Investigational Site (#123)
state: Ohio
city: Columbus
country: United States
facility: CSG Investigational Site (#106)
state: Ohio
city: Parma Heights
country: United States
facility: CSG Investigational Site (#148)
state: Ohio
city: Philadelphia
country: United States
facility: CSG Investigational Site (#101)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: CSG Investigational Site (#149)
state: Pennsylvania
city: Providence
country: United States
facility: CSG Investigational Site (#146)
state: Rhode Island
city: Chattanooga
country: United States
facility: CSG Investigational Site (#131)
state: Tennessee
city: Nashville
country: United States
facility: CSG Investigational Site (#105)
state: Tennessee
city: Dallas
country: United States
facility: CSG Investigational Site (#119)
state: Texas
city: Houston
country: United States
facility: CSG Investigational Site (#139)
state: Texas
city: Houston
country: United States
facility: CSG Investigational Site (#133)
state: Texas
city: Midland
country: United States
facility: CSG Investigational Site (#109)
state: Texas
city: Salt Lake City
country: United States
facility: CSG Investigational Site (#132)
state: Utah
city: Burlington
country: United States
facility: CSG Investigational Site (#107)
state: Vermont
city: Charlottesville
country: United States
facility: CSG Investigational Site (#129)
state: Virginia
city: Fairfax
country: United States
facility: CSG Investigational Site (#137)
state: Virginia
city: Fairfax
country: United States
facility: CSG Investigational Site (#103)
state: Virginia
city: Hampton
country: United States
facility: CSG Investigational Site (#104)
state: Virginia
city: Richmond
country: United States
facility: CSG Investigational Site (#144)
state: Virginia
city: Spokane
country: United States
facility: CSG Investigational Site (#121)
state: Washington
city: Milwaukee
country: United States
facility: CSG Investigational Site (#122)
state: Wisconsin
city: Camperdown
country: Australia
facility: CSG Investigational Site (#205)
state: New South Wales
city: Gosford
country: Australia
facility: CSG Investigational Site (#201)
state: New South Wales
city: Liverpool
country: Australia
facility: CSG Investigational Site (#206)
state: New South Wales
city: St. Leonards
country: Australia
facility: CSG Investigational Site (#208)
state: New South Wales
city: Adelaide
country: Australia
facility: CSG Investigative Site (#204)
state: South Australia
city: Footscray
country: Australia
facility: CSG Investigational Site (#207)
state: Victoria
city: Reservoir
country: Australia
facility: CSG Investigational Site (#200)
state: Victoria
city: Richmond
country: Australia
facility: CSG Investigational Site (#202)
state: Victoria
city: Parkville
country: Australia
facility: CSG Investigational Site (#209)
city: Plovdiv
country: Bulgaria
facility: CSG Investigational Site (#757)
city: Sofia
country: Bulgaria
facility: CSG Investigational Site (# 750)
city: Sofia
country: Bulgaria
facility: CSG Investigational Site (# 755)
city: Sofia
country: Bulgaria
facility: CSG Investigational Site (# 756)
city: Sofia
country: Bulgaria
facility: CSG Investigational Site (#751)
city: Sofia
country: Bulgaria
facility: CSG Investigational Site (#752)
city: Sofia
country: Bulgaria
facility: CSG Investigational Site (#753)
city: Stara Zagora
country: Bulgaria
facility: CSG Investigational Site (#754)
city: Grenoble
country: France
facility: CSG Investigational Site (#801)
state: Cedex
city: Paris
country: France
facility: CSG Investigational Site (#802)
state: Cedex
city: Boulogne Sur Mer
country: France
facility: CSG Investigational Site (#800)
city: Colmar
country: France
facility: CSG Investigational Site (#803)
city: Montpellier
country: France
facility: CSG Investigational Site (#806)
city: Rhone
country: France
facility: CSG Investigational Site (#804)
city: Valenciennes
country: France
facility: CSG Investigational Site (#805)
city: Aschaffenburg
country: Germany
facility: CSG Investigational Site (#709)
city: Berlin
country: Germany
facility: CSG Investigative Site (#702)
city: Elsterwerda
country: Germany
facility: CSG Investigational Site (#706)
city: Heidelberg
country: Germany
facility: CSG Investigational Site (#703)
city: Herzberg
country: Germany
facility: CSG Investigational Site (#707)
city: Hoyerswerda
country: Germany
facility: CSG Investigational Site (#701)
city: Mainz
country: Germany
facility: CSG Investigational Site (#708)
city: Munchen
country: Germany
facility: CSG Investigational Site (#700)
city: Hong Kong
country: Hong Kong
facility: CSG Investigational Site (#400)
city: Kwai Chung
country: Hong Kong
facility: CSG Investigational Site (#402)
city: Sha Tin
country: Hong Kong
facility: CSG Investigational Site (#401)
city: Balatonfuered
country: Hungary
facility: CSG Investigational Site (#501)
city: Budapest
country: Hungary
facility: CSG Investigational Site (#509)
city: Budapest
country: Hungary
facility: CSG Investigational Site (#513)
city: Budapest
country: Hungary
facility: CSG Investigational Site (#505)
city: Debrecen
country: Hungary
facility: CSG Investigational Site (#507)
city: Gyula
country: Hungary
facility: CSG Investigational Site (#508)
city: Hatvan
country: Hungary
facility: CSG Investigational Site (#502)
city: Kaposvar
country: Hungary
facility: CSG Investigational Site (#504)
city: Kisvarda
country: Hungary
facility: CSG Investigational Site (#510)
city: Pecs
country: Hungary
facility: CSG Investigational Site (#506)
city: Szekesfehervar
country: Hungary
facility: CSG Investigational Site (#514)
city: Szikszo
country: Hungary
facility: CSG Investigational Site (#500)
city: Zalaegerszeg
country: Hungary
facility: CSG Investigational Site (#503)
city: Safed
country: Israel
facility: CSG Investigational Site (#308)
state: Zefad
city: Ashkelon
country: Israel
facility: CSG Investigational Site (#307)
city: Beer Sheva
country: Israel
facility: CSG Investigational Site (#313)
city: Haifa
country: Israel
facility: CSG Investigational Site (#300)
city: Holon
country: Israel
facility: CSG Investigational Site (#304)
city: Jerusalem
country: Israel
facility: CSG Investigational Site (#306)
city: Jerusalem
country: Israel
facility: CSG Investigational Site (#314)
city: Kfar Saba
country: Israel
facility: CSG Investigational Site (#309)
city: Nahariya
country: Israel
facility: CSG Investigational Site (#302)
city: Petah Tikva
country: Israel
facility: CSG Investigational Site (#312)
city: Poriya
country: Israel
facility: CSG Investigational Site (#315)
city: Rishon Le-Zion
country: Israel
facility: CSG Investigational Site (#311)
city: Tel Aviv
country: Israel
facility: CSG Investigational Site (#305)
city: Tel Aviv
country: Israel
facility: CSG Investigational Site (#303)
city: Tel Hasomer
country: Israel
facility: CSG Investigational Site (#310)
city: Zerifin
country: Israel
facility: CSG Investigational Site (#301)
city: Phoenix
country: Mauritius
facility: CSG Investigational Site (# 850)
city: Bydgoszcz
country: Poland
facility: CSG Investigational Site (#651)
city: Chojnice
country: Poland
facility: CSG Investigational Site (#655)
city: Kielce
country: Poland
facility: CSG Investigational Site (#653)
city: Nowy Sacz
country: Poland
facility: CSG Investigational Site (#657)
city: Poznan
country: Poland
facility: CSG Investigational Site (#652)
city: Poznan
country: Poland
facility: CSG Investigational Site (#656)
city: Rio Piedras
country: Puerto Rico
facility: CSG Investigational Site (#112)
city: San Juan
country: Puerto Rico
facility: CSG Investigational Site (#110)
city: Toa Baja
country: Puerto Rico
facility: CSG Investigational Site (#135)
city: San Sebastian de los Reyes
country: Spain
facility: CSG Investigational Site (#601)
state: Madrid
city: Barcelona
country: Spain
facility: CSG Investigational Site (#605)
city: Barcelona
country: Spain
facility: CSG Investigational Site (#606)
city: Barcelona
country: Spain
facility: CSG Investigational Site (#603)
city: Barcelona
country: Spain
facility: CSG Investigational Site (#604)
city: Girona
country: Spain
facility: CSG Investigational Site (#600)
city: Lleida
country: Spain
facility: CSG Investigational Site (# 607)
city: Valencia
country: Spain
facility: CSG Investigational Site (#602)
Study officials:
affiliation: The Collaborative Study Group (CSG) [Co-Chair]
name: Jamie Dwyer, MD
role: STUDY_CHAIR
affiliation: The Collaborative Study Group (CSG)
name: Julia B. Lewis, MD
role: STUDY_CHAIR
References: