Clinical Trials Register

Summary
EudraCT Number:	2010-021358-20
Sponsor's Protocol Code Number:	A7331011
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-04-18
Trial results	View 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

Denmark - DHMA

A.2

EudraCT number

2010-021358-20

A.3

Full title of the trial

A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP, MULTI-CENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ONCE-DAILY ADMINISTRATION OF A PHOSPHODIESTERASE 5 INHIBITOR (PF-00489791) IN ADULTS WITH TYPE 2 DIABETES AND OVERT NEPHROPATHY

A.3.1

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

A clinical trial to evaluate whether a potential new drug is an effective and safe way to make damaged kidneys work better in patients with type II diabetes

A.4.1

Sponsor's protocol code number

A7331011

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	Pfizer Inc.235 East 42nd Street, New York, NY 10017
B.1.3.4	Country	United States
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	Pfizer Inc.
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	Pfizer Inc.
B.5.2	Functional name of contact point	Clinical Trials.gov Call Center
B.5.3	Address:
B.5.3.1	Street Address	235 East 42nd Street
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	NY 10017
B.5.3.4	Country	United States
B.5.4	Telephone number	001800 7181021
B.5.5	Fax number	001303739 1119
B.5.6	E-mail	clinicaltrials.govcallcentre@pfizer.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.3.2	Product code	PF-00489791
D.3.4	Pharmaceutical form	Tablet
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.3.9.1	CAS number	853003-48-2
D.3.9.2	Current sponsor code	PF-00489791
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	10
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	Tablet
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 (CKD), also known as chronic renal disease

E.1.1.1

Medical condition in easily understood language

Type II diabetic patients with chronic kidney disease

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10064848
E.1.2	Term	Chronic kidney disease
E.1.2	System Organ Class	100000004857

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 evaluate the efficacy of PF-00489791 in the reduction of albuminuria in subjects with type 2 diabetes and overt nephropathy.

E.2.2

Secondary objectives of the trial

-To evaluate the safety and tolerability of PF-00489791 in subjects with type 2 diabetes and overt nephropathy.
- To evaluate the effect of PF-00489791 on serum creatinine, urinary TGFβ1, serum CRP and serum cystatin C in subjects with type 2 diabetes and overt nephropathy.
- To evaluate the pharmacokinetics of PF-00489791 in subjects with type 2 diabetes and overt nephropathy.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female subjects ≥18 years. Female subjects must be of non-child bearing potential, defined as:
- Postmenopausal (defined as amenorrheic for at least 2 years or amenorrheic for at least 1 year together with an FSH level >40 IU/L) or
- Surgically sterile (defined as having had a hysterectomy and/or bilateral oophorectomy). All other female subjects (including females with tubal ligations and females that do NOT have a documented hysterectomy) will be considered to be of childbearing potential.
2. Clinical diagnosis of type 2 diabetes together with stages 3a, 3b or 4 CKD, based on an eGFR of 25-59 mL/min/1.73m2. 3. A history of persistent, overt albuminuria; defined as a UACR ≥300 mg/g
(≥33.9 mg/mmol) or equivalent UPCR, total protein excretion or dipstick proteinuria, for greater than 3 months. A mean UACR ≥300 mg/g (≥33.9 mg/mmol) determined from 3 consecutive morning
first pass urine samples AND UACR ≥300 mg/g (≥33.9 mg/mmol) in at least 2 out of 3 of these consecutive samples during the screening period. 4. Stable background therapy of an ACE inhibitor or an ARB for at least 3 months before screening and to be maintained for the duration of the study. 5. Resting BP ≤150/100 mm Hg, with no history of BP >150/100 mm Hg on more than one occasion (when measured by a health care professional) in the previous 3 months.
6. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. 7. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures.

E.4

Principal exclusion criteria

1. Subjects with CKD resulting from type 1 diabetes or non-diabetic CKD. 2. Subjects who are diagnosed with autosomal dominant polycystic kidney disease (ADPCKD), severe peripheral vascular disease (PVD) or obstructive uropathy. 3. Subjects who have had a kidney transplant, or who require renal replacement therapy, or are expected to require such therapy within 6 months. 4. Subjects who have a history of proteinuria >10 g/day (or equivalent UACR or UPCR) or
serum albumin <20 g/L (<308.6 µmol/L). 5. Subjects with poorly controlled diabetes mellitus, defined as HbA1C >9%. 6. Subjects on combination ACE inhibitor/ARB therapy. 7. Subjects on renin inhibitor therapy (aliskiren, Tekturna/Rasilez) or aliskiren-containing
combination therapy (Valturna). 8. Subjects on aldosterone antagonist therapy (spironolactone or eplerenone). 9. Subjects receiving or likely to receive during the study any of the following medications: Other PDE5 inhibitors must be terminated at least 14 days prior to randomization (Visit 2) and must not be taken at any time during the study; Nitrates or nitric oxide donors on either regular or intermittent basis (oral, sublingual, buccal, transdermal, inhalation or aerosols);
α -adrenoceptor blockers; Moderate to strong inhibitors or inducers of cytochrome P450 3A4 eg, itraconazole, erythromycin, ketoconazole, protease inhibitors. 10. Significant allergy or known intolerance to PDE5 inhibitors or any ingredient in the formulations. 11. Increased susceptibility to vasodilators including those with left ventricular outflow
obstruction (eg, hypertrophic obstructive cardiomyopathy). 12. History of recurrent syncope, or evidence of low BP (<90 mm Hg systolic or <40 mm Hg diastolic) or symptomatic postural hypotension. This includes relevant postural symptoms associated with a fall in systolic BP ≥20 mm Hg or diastolic BP ≥10 mm Hg on standing. 13. History of congestive heart failure (NYHA class III or IV) or unstable angina, or a history of myocardial infarction, stroke or transient ischemic attack in the previous 6 months. 14. Loss of vision in one eye due to non-arteritic ischemic optic neuropathy (NAION) regardless of whether or not this event was temporally associated with the use of a PDE5
inhibitor. 15. Hereditary degenerative retinal disorders (eg, retinitis pigmentosa). 16. Risk of priapism eg, sickle cell disease, multiple myeloma and myeloproliferative disorders (eg, myeloid leukemia, polycythaemia, thrombocythaemia). 17. Any relevant clinically significant abnormalities on physical examination or clinically
significant laboratory tests, including subjects with moderate liver function tests abnormalities >1.5 times the upper limit of normal. 18. Subjects with a family history of prolonged QT syndrome, or who themselves have a QTc of >450 msec at screening, or any clinically significant ischemic changes as assessed
by the investigator by supine 12-lead supine ECG at screening (preference is for QT to be corrected using Fridericia’s correction).
19. Subjects currently experiencing any clinically significant or unstable medical condition that might limit their ability to complete the study, or to comply with the requirements of the protocol, including: dermatologic disease, hematological disease, pulmonary disease,
hepatic disease, gastrointestinal disease, genitourinary disease, endocrine disease, neurological disease and psychiatric disease.
20. Any malignancy not considered cured (except basal cell carcinoma of the skin). A subject is considered cured if there has been no evidence of cancer recurrence in the previous 5 years.
21. Blood donation in the previous 4 weeks, or stated intention to donate blood or blood products during the period of the study or within 1 month following completion of the study. 22. Subjects who are investigational site staff members or subjects who are Pfizer employees
directly involved in the conduct of the study. 23. Participation in other studies within the previous 30 days, or five times the plasma half-life (if known) of the investigational drug (whichever is longer) before the current study begins and/or during study participation. 24. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this
study.

E.5 End points

E.5.1

Primary end point(s)

Urinary albumin:creatinine ratio (UACR) at Week 12.

E.5.1.1

Timepoint(s) of evaluation of this end point

Urinary albumin:creatinine ratio (UACR) at Week 12.

E.5.2

Secondary end point(s)

- UACR at Weeks 3, 6 and 16.
- Urinary protein:creatinine ratio (UPCR) at Weeks 3, 6, 12 and 16.
- Estimated glomerular filtration rate (eGFR) using the abbreviated (4 variable)
Modification of Diet in Renal Disease (MDRD) formula at Weeks 3, 6, 12 and 16.
-Systolic, diastolic and mean BP at Weeks 3, 6, 12 and 16.
- Serum creatinine at Weeks 3, 6, 12 and 16.
- Urinary TGFβ1 at Weeks 3, 6, 12 and 16.
- Serum C-reactive protein (CRP) at Weeks 12 and 16.
- Serum cystatin C at Weeks 12 and 16.
-An assessment of the pharmacokinetic parameters of PF-00489791.

E.5.2.1

Timepoint(s) of evaluation of this end point

• UACR at Weeks 3, 6 and 16.
• Urinary protein:creatinine ratio (UPCR) at Weeks 3, 6, 12 and 16.
• Estimated glomerular filtration rate (eGFR) using the abbreviated (4 variable) Modification of Diet in Renal Disease (MDRD) formula at Weeks 3, 6, 12 and 16.
• Systolic, diastolic and mean BP at Weeks 3, 6, 12 and 16.
• Serum creatinine at Weeks 3, 6, 12 and 16.
• Urinary TGFβ1 at Weeks 3, 6, 12 and 16.
• Serum highly sensitive C-reactive protein (hs-CRP) at Weeks 12 and 16.
• Serum cystatin C at Weeks 12 and 16.

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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

Yes

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

Canada

Denmark

Hong Kong

India

Korea, Republic of

Malaysia

Mexico

Poland

Serbia

Slovakia

South Africa

Sweden

United Kingdom

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 Subject Last Visit

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

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1