E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Stage 5 Chronic Kidney Disease (CKD) in subjects receiving hemodialysis who have left ventricular hypertrophy (LVH). |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064848 |
E.1.2 | Term | Chronic kidney disease |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049773 |
E.1.2 | Term | Left ventricular hypertrophy |
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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 investigate the effects of paricalcitol injection on progression or regression of LVH in subjects with Stage 5 CKD receiving hemodialysis compared to placebo, as assessed by comparing changes in LV Mass Index (LVMI) over 48 weeks measured by sequential cardiac magnetic resonance imaging (MRI). |
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E.2.2 | Secondary objectives of the trial |
To evaluate the following:
1. Echocardiographic assessment of diastolic function will be assessed by evaluating changes in diastolic mitral annular relaxation velocity (E') and changes in additional measures of diastolic function (IVRT, E/E', DT).
2. Changes in progression of aortic atherosclerosis, aortic compliance, left ventricular end-systolic volume index, left ventricular end-diastolic volume index and left ventricular ejection fraction from baseline to Week 24 and Week 48 as assessed by MRI imaging.
3. Changes in biological and inflammatory markers that have been linked to CVD in CKD subjects. Specifically, the markers to be evaluated will include plasma triiodothyronine (T3), interleukin-6 (IL-6), troponin-T, B-type natriuretic peptide (BNP) and high sensitivity C-reactive protein (hsCRP). |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
DNA and RNA samples from this protocol may be used to study genetic factors contributing to paricalcitol responses for both primary and secondary endpoints as well as safety response. Genetic studies may include genes related to the metabolism, transport, therapeutic response and adverse events of paricalcitol.
Please refer to section 5.3.5 of the study protocol for further information. |
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E.3 | Principal inclusion criteria |
To be eligible for participation, subjects must meet all of the following criteria: 1. Subject has voluntarily signed and dated an informed consent form, approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC), after the nature of the study has been explained and the subject has had the opportunity to ask questions. The informed consent must be signed before any study-specific procedures are performed. 2. Male or female subjects greater than 18 years. 3. Stage 5 CKD receiving chronic hemodialysis three times per week for ≥ 3 months and ≤ 12 months from date of Randomization (Day 1). 4. For entry into the Treatment Period the subject must satisfy the following criteria based on the Screening laboratory values: ● Serum iPTH value between 100-350 pg/mL. ● Serum calcium level between 8.4-10.5 mg/dL (2.1-2.6 mmol/L). ● Phosphate < 7 mg/dl. ● Serum albumin ≥ 3.0 g/dL (30 g/L). 5. For entry into the Treatment Period the subject must satisfy the following criteria based on the Screening echocardiogram: ● For females, LV ejection fraction ≥ 50% and septal wall thickness between 11-17 mm; and, ● For males, LV ejection fraction ≥ 50% and septal wall thickness between 12-18 mm. 6. If the subject is receiving RAAS inhibitors, the dose must have been stable for greater than one month prior to the Screening Period. If the subject is receiving RAAS inhibitors, the dose must have been stable for at least one months prior to the Screening Period. However, subject may have switched to different brands but at equivalent doses as determined by the study physician during the three months prior to the Screening Period. 7. Subject must have a technically adequate baseline cardiac MRI. 8. If female, subject is not breast feeding or is not pregnant (verified by negative serum pregnancy test prior to the Treatment Period); or is not of childbearing potential, defined as postmenopausal for at least one year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy); or is of childbearing potential and practicing one of the following methods of birth control: ● Double-barrier method (any two of the following: condoms, contraceptive sponge, diaphragm, vagina ring with spermicidal jellies or creams, or intrauterine device [IUD]) ● Hormonal contraceptives (oral, parenteral, or transdermal) for at least three months prior to and during study drug administration ● Maintains a monogamous relationship with a vasectomized partner ● Total abstinence from sexual intercourse during the study (minimum one complete menstrual cycle prior to study start). |
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E.4 | Principal exclusion criteria |
To be eligible for participation, subjects must not meet any of the following criteria: 1. Subject has been on active vitamin D therapy (e.g., calcitriol, parocalcitiol, doxercalciferol, alfacalcidol) within the previous 4 weeks prior to the Screening Period and/or for a total duration greater than three months since the start of dialysis. 2. Subject has a history of an allergic reaction or significant sensitivity to paricalcitol or to drugs similar to the study drug (i.e., vitamin D or vitamin D related compounds). 3. Subject is expected to receive an increased dose of RAAS inhibitor (ACEi, ARB or aldosterone inhibitor) during the course of the study. 4. Subject has clinically significant coronary artery disease (CAD) within 3 months prior to the Screening Period, defined as one of the following: ● Hospitalization for MI or unstable angina; or ● New onset angina with positive functional study or coronary angiogram revealing stenosis; or ● Coronary revascularization procedure. 5. Subject has major cardiac valve abnormality linked with LVH and/or diastolic dysfunction, defined as one of the following: ● Aortic valve area ≤ 1.5 cm2 or a mean gradient of > 20 mmHg; or ● Regurgitation lesions; more than moderate mitral regurgitation or more than moderate aortic regurgitation. 6. Subject has asymmetric septal hypertrophy defined as septal wall thickness/posterior wall thickness ratio > 1.5 based on screening echocardiogram. 7. Subject has had a severe cerebrovascular accident (CVA) within the last three months (e.g., hemorrhagic) prior to screening. 8. Full remission from a malignancy for less than one year except completely excised non-Melanoma skin cancer (e.g., basal or squamous carcinoma) or any history of bone metastasis. 9. Subject has co-morbid conditions (e.g., advanced malignancy, advanced liver disease) with a life expectancy less than one year. 10. Subject has received any investigational drug within 30 days prior to study drug administration or is currently enrolled in another clinical trial. 11. Subject has poorly controlled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 110 mmHg) at the Screening Visit (confirmed by repeat). 12. Subject has a history of renal artery stenosis, primary aldosteronism or pheochromocytoma. 13. Subject is taking calcitonin, bisphosphonates, cinacalcet, glucocorticoids (except topical or inhaled glucocorticoids), or other drugs that may affect calcium or bone metabolism, other than calcium containing phosphate binders or female subjects on stable (same dose and product for three months) estrogen and/or progestin therapy. 14. Subject is currently receiving immunosuppressant therapy and.or high doses (non maintaince therapy) of glucocorticoids (>5mg/day of prednisone or equivalent). 15. Subject is known to be HIV positive. 16. Use of known inhibitors (i.e., ketoconazole) or inducers (i.e., carbamazepine) of cytochrome P450 3A (CYP3A) within two weeks prior to study drug administration. 17. Subject is contraindicated for the MRI examination (i.e., pacemaker). 18. For any reason, subject is considered by the Investigator to be an unsuitable candidate to receive paricalcitol injection or is put at risk by study procedures. 19. Subject has a history of drug or alcohol abuse within six months prior to screening. 20. Subject weighs more than 340 pounds (154 kilograms). 21. Subject has had a liver transplant. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable is change from baseline in LVMI over 48 weeks measured by cardiac MRI. |
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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 | No |
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 | No |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
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 | 34 |
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 | Information not present in EudraCT |
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 |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
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 | 3 |