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 |
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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 |
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E.1.3 | Condition being studied is a rare disease | No |
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 | No |
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. |
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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. |
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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 | No |
E.6.2 | Prophylaxis | No |
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 | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
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 | No |
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 |
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 | No |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |