| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061835 |
| E.1.2 | Term | Diabetic nephropathy |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| 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-04634817 compared to placebo in the reduction of
albuminuria following 12 weeks of treatment 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-04634817 following 12 weeks of treatment.
To evaluate the effect of PF-04634817 on renal function.
To evaluate the pharmacodynamic profile of PF-04634817 following 12 weeks of treatment.
To evaluate the pharmacokinetics of PF-04634817 in subjects with type 2 diabetes and overt nephropathy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the
study:
1. Male or female subjects ≥18 years.
2. Female subjects who are of non-child bearing potential (ie, meet at least one of the following criteria):
- Have medically confirmed ovarian failure OR
- Are medically confirmed to be postmenopausal (cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause) OR
- Have undergone hysterectomy or bilateral oophorectomy.
3. Clinical diagnosis of type 2 diabetes together with stages 3a, 3b or 4 CKD, based on an eGFR of 20-75 mL/min/1.73m2.
4. Documented history of persistent, overt albuminuria; defined as a UACR ≥300 mg/g (≥33.9 mg/mmol) or UPCR ≥390 mg/g (44.1 mg/mmol), or equivalent, for 3 months or longer.
5. Stable background therapy of RAAS inhibition (ie, an ACE inhibitor and/or an ARB, which may also include an aldosterone antagonist in double RAAS but not triple RAAS inhibitor therapy) for at least 3 months before screening and to be maintained for the duration of the study.
6. Resting BP ≤165/105 mm Hg (mean of triplicate measurements).
Subjects with resting BP >135/85 but ≤165/105 (mean of triplicate
measurements)must be being treated with at least one antihypertensive
medication in addition to ACEi or ARB and have been on a stable dose(s)
for at least 35 days prior to the first dose of the investigational product
(Visit 2).
7. Evidence of a personally signed and dated informed consent document
indicating that the subject has been informed of all pertinent aspects of
the study.
8. Willing and able to comply with scheduled visits, treatment plan,
laboratory tests and other trial procedures. |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
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 albuminuria >6.5 g/day.
5. Subjects who have serum albumin <2.0 g/dL (<20 g/L).
6. Subjects with poorly controlled diabetes mellitus, defined as HbA1C >10.5%.
7. Subjects on direct renin inhibitor therapy (aliskiren, Tekturna/Rasilez or Valturna).
8. Subjects receiving or likely to receive during the study any moderatestrong
inhibitors or inducers of cytochrome P450 3A4 eg, itraconazole,
erythromycin, ketoconazole, protease inhibitors, verapamil or diltiazem.
9. Any history or current evidence of previously untreated or
inadequately treated active or latent infection with Mycobacterium
tuberculosis. To be considered eligible for inclusion, subjects should
have:
Negative QuantiFERON Gold In-Tube test performed at screening
• This is required unless the subject has been adequately treated for
active or latent Tuberculosis (TB) or a negative QuantiFERON Gold In-
Tube test was previously performed and documented within 3 months
prior to screening.
• A negative tuberculin skin test is one that is <5 mm induration and it
can be substituted for the QuantiFERON Gold In-Tube test if the test is
reported as indeterminate after 2 successive attempts.
AND
• In countries included in this study with a high rate of TB and/or a high
rate of multi-drug resistant TB (Argentina, Hong Kong, India, Korea,
without changes suggestive of active TB infection, unless previously
performed and documented within 3 months prior to screening.
OR
• No history of TB infection unless one of the following is determined by
the investigator.
• Subject with prior or current latent TB has no evidence of active TB
and must be taking or have completed an adequate course of therapy for
latent TB (9 months of isoniazid in a locale where rates of primary multidrug
resistant TB are <5% or an alternative regimen recognized by the
World Health Organization) and a chest radiograph is negative for active
disease: the chest radiograph must be obtained at screening or, if
previously performed and documented, within 3 months prior to
screening.
• Subject with prior active TB has no current evidence of active disease
and has completed an adequate course of therapy for active TB (a multidrug
regime recognized by the World Health Organization) and a chest
radiograph is negative for active disease; the chest radiograph must be
performed at screening or, if previously performed and documented,
within 3 months prior to screening.
10. Known history of human immunodeficiency (HIV) based on
documented history with positive serological test, or positive HIV
serological test at screening. (Note: a documented negative HIV test
within 12 months of screening is acceptable and does not need to be
repeated).
11. Significant allergy or known intolerance to CCR2 or CCR5 inhibitors
or any ingredient in the formulations.
12. Current history of congestive heart failure (NYHA class III or IV) or
unstable angina. A history of myocardial infarction, stroke or transient
ischemic attack in the previous 6 months.
13. Any 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, judged to be
relevant and clinically-significant by the investigator.
14. Family history of prolonged QT syndrome, or who themselves have a
QTc >450 msec for males or >470 msec for females, a QRS >120 msec,
or any clinically significant ischemic changes as assessed by the
investigator by 12-lead supine ECG at screening. The ECG should be
repeated two more times and the average of the three QTc or QRS values
should be used to determine the subject's eligibility. Preference is for QT
to be corrected using Fridericia's correction, although Bazett's correction
can also be used.
15. Subjects currently experiencing any clinically significant or unstable
medical condition, as judged by the investigator, 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.
For exclusion criteria 16-21 please refer to Protocol Section 4.2. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Urinary albumin:creatinine ratio (UACR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Urinary albumin:creatinine ratio (UACR).
Urinary protein:creatinine ratio (UPCR).
Estimated glomerular filtration rate (eGFR) using the abbreviated (4 variable) Modification of Diet in Renal Disease (MDRD) formula.
Estimated glomerular filtration rate (eGFR) using the eGFRcystatin formula.
Serum creatinine.
Serum cystatin C.
Plasma glycosylated hemoglobin (HbA1c).
An assessment of PF-04634817 exposure. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Urinary albumin:creatinine ratio (UACR) at Weeks 4, 8, 12 and 16.
Urinary protein:creatinine ratio (UPCR) at Weeks 4, 8, 12 and 16.
Estimated glomerular filtration rate (eGFR) using the abbreviated (4 variable) Modification of Diet in Renal Disease (MDRD) formula at Week 1 (Day 7), and Weeks 4, 8, 12 and 16.
Estimated glomerular filtration rate (eGFR) using the eGFRcystatin formula at Weeks 12 and 16.
Serum creatinine at Week 1 (Day 7), and Weeks 4, 8, 12 and 16.
Serum cystatin C at Weeks 12 and 16.
Plasma glycosylated hemoglobin (HbA1c) at Weeks 4, 8, 12 and 16.
An assessment of PF-04634817 exposure at Weeks 0, 1, 4, 8 and 12. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Italy |
| Romania |
| Argentina |
| Australia |
| Brazil |
| Germany |
| Hong Kong |
| India |
| Korea, Republic of |
| Malaysia |
| Spain |
| Peru |
| Poland |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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