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

• Change in Diastolic Mitral Annular Relaxation Velocity (E') [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  Diastolic mitral annular relaxation velocity (lateral E wave velocity; E') is a measure of diastolic function.
• Change in Ratio of Peak E Wave Velocity to Lateral E Wave Velocity (E/E') [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  The ratio of peak E wave velocity to lateral E wave velocity (E/E') is a measure of diastolic function.
• Change in E-wave Deceleration Time (DT) [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  E-wave deceleration time (DT) is a measure of diastolic function.
• Change in Isovolumetric Relaxation Time (IVRT) [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  Isovolumetric relaxation time (IVRT) is a measure of diastolic function.
• Change in Left Atrial Volume [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  Left atrial volume is a measure of diastolic function.
• Change in Plasma Triiodothyronine (T3) [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  Plasma triiodothyronine (T3) is a biological and inflammatory marker.
• Change in Interleukin-6 (IL-6) [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  Interleukin-6 (IL-6) is a biological and inflammatory marker.
• Change in Troponin-T [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  Troponin-T is a biological and inflammatory marker.
• Change in B-type Natriuretic Peptide (BNP) [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  B-type natriuretic peptide (BNP) is a biological and inflammatory marker.
• Change in High Sensitivity C-reactive Protein (hsCRP) [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  High sensitivity C-reactive protein (hsCRP) is a biological and inflammatory marker.
• Change in Progression of Thoraco-abdominal Aortic Plaque Volume [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  Change from baseline to Week 48 in thoraco-abdominal aortic plaque volume.
• Change in Progression of Thoraco-abdominal Aortic Wall Volume [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  Change from baseline to Week 48 in thoraco-abdominal aortic wall volume
• Change in Progression of Aortic Compliance [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  Change from baseline to Week 48 in aortic compliance.
• Change in Progression of Left Ventricular End-systolic Volume Index [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  Change from baseline to Week 48 in left ventricular end-systolic volume index.
• Change in Progression of Left Ventricular End-diastolic Volume Index [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  Change from baseline to Week 48 in left ventricular end-diastolic volume index.
• Change in Progression of Left Ventricular Ejection Fraction [ Time Frame: Baseline to 48 weeks ] [ Designated as safety issue: No ]
  Change from baseline to Week 48 in left ventricular ejection fraction.

• Improvement of Diastolic Function parameters by echocardiogram. [ Time Frame: 48 weeks ]
• Changes in inflammatory biomarkers [ Time Frame: 48 weeks ]
• Health Care Resource Utilization [ Time Frame: 48 weeks ]
• Hospitalizations [ Time Frame: 48 weeks ]
• Mortality [ Time Frame: 48 weeks ]

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).

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.

• Chronic Kidney Disease
• Left Ventricular Hypertrophy

• Drug: paricalcitol
  2 µg capsule
  Other Names:

  • ABT-358
  • Zemplar
• Drug: placebo
  placebo capsule

• Experimental: Paricalcitol
  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.
  Intervention: Drug: paricalcitol
• Placebo Comparator: Placebo
  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.
  Intervention: Drug: placebo

• Tamez H, Zoccali C, Packham D, Wenger J, Bhan I, Appelbaum E, Pritchett Y, Chang Y, Agarwal R, Wanner C, Lloyd-Jones D, Cannata J, Thompson BT, Andress D, Zhang W, Singh B, Zehnder D, Pachika A, Manning WJ, Shah A, Solomon SD, Thadhani R. Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease. Am Heart J. 2012 Dec;164(6):902-9.e2. doi: 10.1016/j.ahj.2012.09.018. Epub 2012 Oct 29.
• Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J, Tamez H, Bhan I, Agarwal R, Zoccali C, Wanner C, Lloyd-Jones D, Cannata J, Thompson BT, Andress D, Zhang W, Packham D, Singh B, Zehnder D, Shah A, Pachika A, Manning WJ, Solomon SD. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA. 2012 Feb 15;307(7):674-84.
• Thadhani R, Appelbaum E, Chang Y, Pritchett Y, Bhan I, Agarwal R, Zoccali C, Wanner C, Lloyd-Jones D, Cannata J, Thompson T, Audhya P, Andress D, Zhang W, Ye J, Packham D, Singh B, Zehnder D, Manning WJ, Pachika A, Solomon SD. Vitamin D receptor activation and left ventricular hypertrophy in advanced kidney disease. Am J Nephrol. 2011;33(2):139-49. Epub 2011 Jan 18.
• Thadhani R. Targeted ablation of the vitamin D 1alpha-hydroxylase gene: getting to the heart of the matter. Kidney Int. 2008 Jul;74(2):141-3.

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.