The PRIMO Study: Paricalcitol Capsules Benefits Renal Failure Induced Cardiac Morbidity in Subjects With Chronic Kidney Disease Stage 3/4

Study Overview
=================
Brief Summary
-----------------
To evaluate the effects of paricalcitol capsules on cardiac structure and function over 48 weeks in patients with Stage 3/4 chronic kidney disease (CKD) who had left ventricular hypertrophy (LVH).

Detailed Description
-----------------
Patients who met the inclusion criteria and did not meet any of the exclusion criteria were randomized in a 1:1 ratio to each treatment group to receive paricalcitol capsules or placebo. A stratified randomization scheme was used to ensure balance among treatment groups with respect to country, gender, and baseline renin angiotensin-aldosterone system (RAAS) inhibitor use (yes/no). Participants who completed the 48-Week Treatment Period could continue on in the ongoing Long-term Follow-up Period that was to last 18 months, with study visits at 6 months, 12 months and 18 months post Treatment Week 48 Visit. Participants did not receive study drug, nor were they to have undergone echocardiogram/MRI procedures during the Long-term Follow-up Period.

Official Title
-----------------
The PRIMO Study: Paricalcitol Capsules Benefits in Renal Failure Induced Cardiac Morbidity in Subjects With Chronic Kidney Disease Stage 3/4

Conditions
-----------------
Chronic Kidney Disease, Left Ventricular Hypertrophy

Intervention / Treatment
-----------------
* Drug: paricalcitol
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Estimated glomerular filtration rate (GFR) between 15-60 mL/min/1.73 m^2 Serum intact parathyroid hormone (iPTH) value between 50-300 pg/mL Corrected serum calcium level 8.0-10.0 mg/dL (2.0-2.5 mmol/L) Phosphorous level less than or equal to 5.2 mg/dL (1.68 mmol/L) Serum albumin greater than or equal to 3.0 g/dL (30 g/L) Echocardiogram results of: Females: Left ventricular (LV) ejection fraction greater than or equal to 50% and septal wall thickness between 11-17 mm; and, Males: LV ejection fraction greater than or equal to 50% and septal wall thickness between 12-18 mm If the subject is receiving renin-angiotensin-aldosterone system (RAAS) inhibitors the dose must have been stable for greater than one month prior to the Screening Period. However, the subject may have switched to different brands but at equivalent doses as determined by the study physician during the month prior to the Screening Period. Subject must have a technically adequate baseline cardiac magnetic resonance imaging (MRI). Exclusion Criteria: Subject has previously been on active vitamin D therapy within the four weeks prior to the Screening Period Pregnant or lactating females Subject is expected to initiate renal replacement therapy within one year Subject is taking calcitonin, bisphosphonates, cinacalcet, glucocorticoids (except topical or inhaled glucocorticoids) Subject had clinically significant coronary artery disease (CAD) within 3 months prior to the Screening Period, defined as either hospitalization for myocardial infarction (MI) or unstable angina; new onset angina with positive functional study or coronary angiogram revealing stenosis; or coronary revascularization procedure. Subject had major cardiac valve abnormality linked with LVH and/or diastolic dysfunction, defined as either aortic valve area ≤ 1.5 cm^2 or a mean gradient of > 20 mmHg; or regurgitation lesions; more than moderate mitral regurgitation, or more than moderate aortic regurgitation. Subject had asymmetric septal hypertrophy defined as septal wall thickness/posterior wall thickness ratio > 1.5 based on screening echocardiogram. Subject had a severe cerebrovascular accident (CVA) within the last 3 months (e.g., hemorrhagic) prior to screening. Subject had full remission from a malignancy for less than 1 year except completely excised non-melanoma skin cancer (e.g., basal or squamous carcinoma) or any history of bone metastasis. Subject had comorbid conditions (e.g., advanced malignancy, advanced liver disease) with a life expectancy less than 1 year.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paricalcitol<br>Participants received paricalcitol capsules 2 µg once a day (two 1 µg paricalcitol capsules), for up to 48 weeks. Participants who completed the 48-week Treatment Period could continue in the Long-term Follow-up Period for an additional 18 months. Participants did not receive study drug during the Long-term Follow-up Period. | Drug: paricalcitol<br>* 2 µg capsule<br>* Other names: Zemplar;|
| Placebo Comparator: Placebo<br>Participants received 2 placebo capsules once a day for up to 48 weeks. Participants who completed the 48-week Treatment Period could continue in the Long-term Follow-up Period for an additional 18 months. Participants did not receive study drug during the Long-term Follow-up Period. | Drug: placebo<br>* placebo capsule<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Left Ventricular Mass Index (LVMI) Over 48 Weeks Measured by Cardiac Magnetic Resonance Imaging (MRI) | The Central Cardiac MRI Core Laboratory (CCL) interpreted and analyzed all cardiac MRI data. Left Ventricular Mass (LVM) was normalized to the participant's height by the following equation to obtain LVMI: LVM (grams) divided by height (meters)^2.7. | Baseline to 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Diastolic Mitral Annular Relaxation Velocity (E') | Diastolic mitral annular relaxation velocity (lateral E wave velocity; E') is a measure of diastolic function. | Baseline to 48 weeks | 
| Change in Ratio of Peak E Wave Velocity to Lateral E Wave Velocity (E/E') | The ratio of peak E wave velocity to lateral E wave velocity (E/E') is a measure of diastolic function. | Baseline to 48 weeks | 
| Change in E-wave Deceleration Time (DT) | E-wave deceleration time (DT) is a measure of diastolic function. | Baseline to 48 weeks | 
| Change in Isovolumetric Relaxation Time (IVRT) | Isovolumetric relaxation time (IVRT) is a measure of diastolic function. | Baseline to 48 weeks | 
| Change in Left Atrial Volume | Left atrial volume is a measure of diastolic function. | Baseline to 48 weeks | 
| Change in Plasma Triiodothyronine (T3) | Plasma triiodothyronine (T3) is a biological and inflammatory marker. | Baseline to 48 weeks | 
| Change in Interleukin-6 (IL-6) | Interleukin-6 (IL-6) is a biological and inflammatory marker. | Baseline to 48 weeks | 
| Change in Troponin-T | Troponin-T is a biological and inflammatory marker. | Baseline to 48 weeks | 
| Change in B-type Natriuretic Peptide (BNP) | B-type natriuretic peptide (BNP) is a biological and inflammatory marker. | Baseline to 48 weeks | 
| Change in High Sensitivity C-reactive Protein (hsCRP) | High sensitivity C-reactive protein (hsCRP) is a biological and inflammatory marker. | Baseline to 48 weeks | 
| Change in Progression of Thoraco-abdominal Aortic Plaque Volume | Change from baseline to Week 48 in thoraco-abdominal aortic plaque volume. | Baseline to 48 weeks | 
| Change in Progression of Thoraco-abdominal Aortic Wall Volume | Change from baseline to Week 48 in thoraco-abdominal aortic wall volume | Baseline to 48 weeks | 
| Change in Progression of Aortic Compliance | Change from baseline to Week 48 in aortic compliance. | Baseline to 48 weeks | 
| Change in Progression of Left Ventricular End-systolic Volume Index | Change from baseline to Week 48 in left ventricular end-systolic volume index. | Baseline to 48 weeks | 
| Change in Progression of Left Ventricular End-diastolic Volume Index | Change from baseline to Week 48 in left ventricular end-diastolic volume index. | Baseline to 48 weeks | 
| Change in Progression of Left Ventricular Ejection Fraction | Change from baseline to Week 48 in left ventricular ejection fraction. | Baseline to 48 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
paricalcitol, Zemplar, PRIMO, Chronic Kidney Disease Stage 3B/4