Clinical Trials Register

Summary
EudraCT Number:	2012-001563-78
Sponsor's Protocol Code Number:	402-C-1201
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-05-22
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2012-001563-78

A.3

Full title of the trial

A Double-Blind, Randomized, Placebo-Controlled Safety Study Evaluating the Effects of Bardoxolone Methyl on Residual Renal Function (RRF) in Patients with End-Stage Renal Disease (ESRD) and Type 2 Diabetes Mellitus (T2DM) on Peritoneal Dialysis (PD)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Comparing the effects (safety and efficacy) of the study drug, bardoxolone methyl, against placebo for patients with End-Stage Renal Disease and Type 2 diabetes on peritoneal dialysis

A.3.2

Name or abbreviated title of the trial where available

Effects of Bardoxolone Methyl on Residual Renal Function during PD

A.4.1

Sponsor's protocol code number

402-C-1201

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01576887

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Reata UK Limited
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Reata UK Limited
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Abbott Laboratories
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Reata UK Limited
B.5.2	Functional name of contact point	Kingsley Urakpo
B.5.3	Address:
B.5.3.1	Street Address	1 Bell Street
B.5.3.2	Town/ city	Maidenhead
B.5.3.3	Post code	SL6 1BU
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44(0)7769353163
B.5.5	Fax number	+441628 644330
B.5.6	E-mail	Kingsley.urakpo@uk.reatapharma.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Bardoxolone Methyl
D.3.2	Product code	RTA 402
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Bardoxolone Methyl
D.3.9.1	CAS number	218600534
D.3.9.2	Current sponsor code	RTA 402
D.3.9.3	Other descriptive name	CDDOMe, CDDOMethyl, NSC 713200
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic Kidney Disease in patients with type 2 diabetes mellitus on peritoneal dialysis

E.1.1.1

Medical condition in easily understood language

Diabetic patients with chronic kidney disease who are on peritoneal dialysis

E.1.1.2

Therapeutic area

Diseases [C] - Male diseases of the urinary and reproductive systems [C12]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	SOC
E.1.2	Classification code	10038359
E.1.2	Term	Renal and urinary disorders
E.1.2	System Organ Class	10038359 - Renal and urinary disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the safety and pharmacokinetic profile of 20 mg bardoxolone in patients with ESRD and T2DM on PD.

E.2.2

Secondary objectives of the trial

To assess the effect of bardoxolone methyl relative to placebo on RRF in patients with ESRD and T2DM on PD.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients must have ESRD and been on PD for longer than 3
months.
2. Patients must have had a diagnosis of T2DM prior to starting
dialysis.
3. Patients must have RRF, as defined by the mean of urea and
creatinine clearance on a 24 hour urine collection, ≥ 25 Liters/week/1.73 m2 documented in the four months prior to the Screen A visit.
4. Patients must have RRF, as defined by the mean of urea and
creatinine clearances on a 24 hour urine collection, ≥ 25
Liters/week/1.73 m2 at both the Screen A and Screen B visits.
5. The RRF value obtained at the Screen B visit must not be less
than 50% of the RRF value obtained at the Screen A visit.
6. Patients must be at least 18 years of age.
7. Patients must have a mean systolic blood pressure (SBP) on three readings at both Screen A and Screen B visits ≤ 160 mmHg and ≥ 90 mmHg.
8. Patients must have a mean diastolic blood pressure (DBP) on
three readings at both Screen A and Screen B visits < 100
mmHg and ≥ 40 mmHg.
9. Patients must be willing to practice methods of birth control (both males who have partners of childbearing potential and females of childbearing potential) during screening, while taking study drug and for at least 30 days after the last dose of study drug is ingested.
10. Patients must be willing and able to cooperate with all aspects of the protocol.
11. Patients must be willing and able to give written informed
consent to participate in the study. They must provide consent
for access to medical data according to appropriate local data
protection legislation and allow authorization to access medical
records that describe events captured in the endpoints.

E.4

Principal exclusion criteria

1. History of Autosomal Dominant Polycystic Kidney Disease
2. Currently active Systemic Lupus Erythematosus
3. History of Hepatitis B Surface Antigen +
4. History of Hepatitis C Antibody + being treated with antiviral therapy
5. History of an organ transplant
6. A planned renal transplant from a living donor during the study
7. History of hospitalization for congestive heart failure or pulmonary edema within 12 weeks before study randomization
8. History of cirrhosis of the liver
9. History of amyloidosis or light chain nephropathy
10. History of Hemoglobin A1c level > 11.0% (97 mmol/mol) within 12 weeks before study randomization
11. History of recently active cardiovascular disease defined as:
• Unstable angina pectoris within 12 weeks before study randomization
• Myocardial infarction, coronary artery bypass graft surgery, or
percutaneous transluminal coronary angioplasty/stent within 12
weeks before study randomization
• Cerebrovascular accident, including transient ischemic attack within 12 weeks before study randomization
12. History of diagnostic or interventional procedure that required
intravenous administration of an iodinated contrast agent or gadolinium within 12 weeks before study randomization
13. History of known severe obstructive valvular heart disease or severe obstructive hypertrophic cardiomyopathy
14. History of known 2o or 3o Atrioventricular block not successfully treated with a pacemaker
15. History of resuscitated sudden cardiac death
16. History of an automatic implantable defibrillator
17. QTc greater than 0.50 seconds on an ECG obtained during either Screen A or Screen B visits
18. A serum magnesium level less than 1.4 meq/L on either Screen A or Screen B visit laboratory test results
19. History of systemic immunosuppression for more than 15 days, cumulatively, within the 12 weeks before study randomization or anticipated need for more than 15 days of immunosuppression during the study (see section 5.4)
20. Total bilirubin, aspartate transaminase (AST), or alanine transaminase (ALT) level greater than the upper limit of normal (ULN) or alkaline phosphatase level greater than two times the ULN on either the Screen A or Screen B visit laboratory test results
21. Known hypersensitivity to any component of the study drug
22. Current history of drug or alcohol abuse, as assessed by the investigator
23. History of clinically significant infection requiring intravenous
administration of antibiotics or hospitalization within 12 weeks before study randomization
24. In patients who have been on peritoneal dialysis for ≥ 6 months, two or more episodes of peritonitis in the 6 months before study randomization. In patients who have been on peritoneal dialysis for <6 months, one episode of peritonitis before study randomization
25. History of a diagnosis or treatment of a malignancy in the past 5 years, excluding non-melanoma skin cancer and carcinoma in situ of the cervix
26. History of a clinical condition that, in the judgment of the investigator, could potentially pose a health risk to the patient while involved in the study
27. Patient is unable to communicate or cooperate with the investigator due to language problems, poor mental development, or impaired cerebral function
28. Participation in a clinical study involving any intervention within 30 days prior to Screen A visit, concurrent participation in such a study, or participation in a prior clinical study involving bardoxolone methyl in any form
29. Female patients who are pregnant, intend to become pregnant during the study, or are nursing

E.5 End points

E.5.1

Primary end point(s)

SAFETY ENDPOINTS
Frequency, intensity and relationship of study drug to adverse events and serious adverse events, as well as clinical and laboratory test result abnormalities.

PK ENDPOINTS
Assessment of bardoxolone methyl plasma concentration-time data.

E.5.1.1

Timepoint(s) of evaluation of this end point

SAFETY ENDPOINTS
Throughout study from study randomization (SR) visit until post treatment visit (V7)

PK ENDPOINTS
From visit 1 (V1) through visit 6 (V6)

E.5.2

Secondary end point(s)

EFFICACY ENDPOINTS
The mean change in RRF from baseline to month 6 as analyzed by the repeated measures model.

E.5.2.1

Timepoint(s) of evaluation of this end point

EFFICACY ENDPOINTS
Screening visits A and B and from visit 1 (V1) until visit 7 (V7)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

last visit of the last patient in the study

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After the completion of the study, patients will be treated in accordance with the usual standard of care.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-06-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-07-03

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2012-10-17

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