Pyridorin in Diabetic Nephropathy

Diabetic Nephropathy Clinical Trial

— PIONEER  

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02156843
• Other study ID #: PYR-311
• Secondary ID: 2014-001641-24CS
• Status: Terminated
• Phase: Phase 3
• First received: May 28, 2014
• Last updated: March 8, 2016
• Start date: June 2014
• Est. completion date: March 2018

Study information

• Verified date: March 2016
• Source: NephroGenex, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationAustralia: Department of Health and Ageing Therapeutic Goods AdministrationFrance: Agence Nationale de Sécurité du Médicament et des produits de santéGermany: Federal Institute for Drugs and Medical DevicesHungary: National Institute of PharmacyHong Kong: Department of HealthIsrael: Ministry of HealthItaly: The Italian Medicines AgencySpain: Agencia Española de Medicamentos y Productos Sanitarios
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 328
• Est. completion date: March 2018
• Est. primary completion date: December 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetic Kidney Disease
• Diabetic Nephropathies
• Diabetic Nephropathy
• Kidney Diseases

Intervention

Drug:
• Pyridorin
300 mg BID (twice daily, every 12 hours), oral capsule taken until end stage renal disease or death occurs, or the study is terminated by the sponsor.
• Placebo
Placebo excipients without the active drug, oral capsule taken BID (twice daily, every 12 hours), until end stage renal disease or death occurs, or the study is terminated by the sponsor.

Locations

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

Sponsors (3)

Lead Sponsor	Collaborator
NephroGenex, Inc.	Collaborative Study Group (CSG), Medpace, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Bulgaria,  France,  Germany,  Hong Kong,  Hungary,  Israel,  Mauritius,  Poland,  Puerto Rico,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in serum cystatin-C		Change from baseline to Week 52 and from baseline to Week 104	No
Other	Change in urine protein/creatinine ratio (PCR)		From baseline to Week 52 and from baseline to Week 104	No
Other	Change in urinary transforming growth factor-beta (TGF-Beta) excretion		From baseline to Week 52 and from baseline to Week 104	No
Other	Change in SCr		From baseline to Week 52 and from baseline to Week 104	No
Primary	Time to composite endpoint of >=50% SCr increase from baseline or ESRD	Time to the composite endpoint consisting of the earliest event amongst a SCr increase of 50% from baseline that occurs during follow-up; or End Stage Renal Disease. ESRD is defined as the initiation of permanent dialysis, receiving a kidney transplant, or a SCr value >= 6.0 mg/dL (530 umol/L) with a second SCr confirmation value >=6.0 mg/dL (530 umol/L) obtained 4-6 weeks later. A confirmation of SCr value for subjects with ESRD and initiation of permanent dialysis or kidney transplant will not be collected.	Approximately 45 Months	No
Secondary	Time to the composite endpoint >=100% SCr increase or ESRD	A SCr increase of >=100% that occurs during follow-up; or ESRD	Approximately 45 Months	No