Chronic Kidney Disease, Left Ventricular Hypertrophy
Conditions
Keywords
paricalcitol, Zemplar, PRIMO, Chronic Kidney Disease Stage 3B/4
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.
Interventions
DRUGparicalcitol
2 µg capsule
DRUGplacebo
placebo capsule
Sponsors
Massachusetts General Hospital
AbbVie (prior sponsor, Abbott)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Left Ventricular Mass Index (LVMI) Over 48 Weeks Measured by Cardiac Magnetic Resonance Imaging (MRI) | Baseline to 48 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Ratio of Peak E Wave Velocity to Lateral E Wave Velocity (E/E') | Baseline to 48 weeks | 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) | Baseline to 48 weeks | E-wave deceleration time (DT) is a measure of diastolic function. |
| Change in Isovolumetric Relaxation Time (IVRT) | Baseline to 48 weeks | Isovolumetric relaxation time (IVRT) is a measure of diastolic function. |
| Change in Left Atrial Volume | Baseline to 48 weeks | Left atrial volume is a measure of diastolic function. |
| Change in Plasma Triiodothyronine (T3) | Baseline to 48 weeks | Plasma triiodothyronine (T3) is a biological and inflammatory marker. |
| Change in Interleukin-6 (IL-6) | Baseline to 48 weeks | Interleukin-6 (IL-6) is a biological and inflammatory marker. |
| Change in Troponin-T | Baseline to 48 weeks | Troponin-T is a biological and inflammatory marker. |
| Change in Diastolic Mitral Annular Relaxation Velocity (E') | Baseline to 48 weeks | Diastolic mitral annular relaxation velocity (lateral E wave velocity; E') is a measure of diastolic function. |
| Change in High Sensitivity C-reactive Protein (hsCRP) | Baseline to 48 weeks | High sensitivity C-reactive protein (hsCRP) is a biological and inflammatory marker. |
| Change in Progression of Thoraco-abdominal Aortic Plaque Volume | Baseline to 48 weeks | Change from baseline to Week 48 in thoraco-abdominal aortic plaque volume. |
| Change in Progression of Thoraco-abdominal Aortic Wall Volume | Baseline to 48 weeks | Change from baseline to Week 48 in thoraco-abdominal aortic wall volume |
| Change in Progression of Aortic Compliance | Baseline to 48 weeks | Change from baseline to Week 48 in aortic compliance. |
| Change in Progression of Left Ventricular End-systolic Volume Index | Baseline to 48 weeks | Change from baseline to Week 48 in left ventricular end-systolic volume index. |
| Change in Progression of Left Ventricular End-diastolic Volume Index | Baseline to 48 weeks | Change from baseline to Week 48 in left ventricular end-diastolic volume index. |
| Change in Progression of Left Ventricular Ejection Fraction | Baseline to 48 weeks | Change from baseline to Week 48 in left ventricular ejection fraction. |
| Change in B-type Natriuretic Peptide (BNP) | Baseline to 48 weeks | B-type natriuretic peptide (BNP) is a biological and inflammatory marker. |
Countries
Australia, Czechia, Germany, Italy, Poland, Puerto Rico, Romania, Russia, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled in the study at US and ex-US investigative sites. Recruitment began in March 2008 and ended in December 2009. The study population consisted of participants with Stage 3/4 chronic kidney disease who had a diagnosis of left ventricular hypertrophy confirmed by echocardiogram and cardiac magnetic resonance imaging.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 115 |
| 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. | 112 |
| Total | 227 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Long-term Follow-up Period | Adverse Event | 2 | 2 |
| Long-term Follow-up Period | Lost to Follow-up | 5 | 1 |
| Long-term Follow-up Period | Other | 0 | 1 |
| Long-term Follow-up Period | Withdrawal by Subject | 8 | 2 |
| Treatment Period | Adverse Event | 6 | 2 |
| Treatment Period | Change in RAAS inhibitor therapy | 5 | 2 |
| Treatment Period | Lost to Follow-up | 1 | 3 |
| Treatment Period | Other Reason | 2 | 3 |
| Treatment Period | Required dialysis | 4 | 1 |
| Treatment Period | Unable to dose reduce per protocol | 4 | 1 |
| Treatment Period | Withdrawal by Subject | 5 | 9 |
Baseline characteristics
| Characteristic | Paricalcitol | Placebo | Total |
|---|---|---|---|
| Age at Beginning of Long term Follow-up Period | 64.6 years STANDARD_DEVIATION 11.01 | 66.5 years STANDARD_DEVIATION 12.09 | 65.6 years STANDARD_DEVIATION 11.58 |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 59 Participants | 61 Participants | 120 Participants |
| Age, Categorical Between 18 and 65 years | 56 Participants | 51 Participants | 107 Participants |
| Age Continuous | 64.3 years STANDARD_DEVIATION 11.3 | 65.7 years STANDARD_DEVIATION 12.2 | 65.0 years STANDARD_DEVIATION 11.75 |
| Baseline RAAS Status No | 25 participants | 25 participants | 50 participants |
| Baseline RAAS Status Yes | 90 participants | 87 participants | 177 participants |
| Diabetic Status None | 52 participants | 55 participants | 107 participants |
| Diabetic Status Type I | 4 participants | 1 participants | 5 participants |
| Diabetic Status Type II | 59 participants | 56 participants | 115 participants |
| Gender at Beginning of Long term Follow-up Period Female | 20 participants | 25 participants | 45 participants |
| Gender at Beginning of Long term Follow-up Period Male | 45 participants | 47 participants | 92 participants |
| Sex: Female, Male Female | 36 Participants | 33 Participants | 69 Participants |
| Sex: Female, Male Male | 79 Participants | 79 Participants | 158 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 75 / 115 | 68 / 112 | 4 / 65 | 8 / 72 |
| serious Total, serious adverse events | 20 / 115 | 20 / 112 | 18 / 65 | 13 / 72 |
Outcome results
Primary
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.
Time frame: Baseline to 48 weeks
Population: The analysis was based on the intent-to-treat (ITT) population, defined as all randomized participants who took at least one dose of study drug, with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change From Baseline in Left Ventricular Mass Index (LVMI) Over 48 Weeks Measured by Cardiac Magnetic Resonance Imaging (MRI) | 0.34 grams/meter^2.7 | Standard Error 0.248 |
| Placebo | Change From Baseline in Left Ventricular Mass Index (LVMI) Over 48 Weeks Measured by Cardiac Magnetic Resonance Imaging (MRI) | -0.07 grams/meter^2.7 | Standard Error 0.246 |
p-value: 0.145Mixed Models Analysis
Secondary
Change in B-type Natriuretic Peptide (BNP)
B-type natriuretic peptide (BNP) is a biological and inflammatory marker.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in B-type Natriuretic Peptide (BNP) | 0.19 log nanograms/liter | Standard Error 0.086 |
| Placebo | Change in B-type Natriuretic Peptide (BNP) | 0.35 log nanograms/liter | Standard Error 0.085 |
Secondary
Change in Diastolic Mitral Annular Relaxation Velocity (E')
Diastolic mitral annular relaxation velocity (lateral E wave velocity; E') is a measure of diastolic function.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in Diastolic Mitral Annular Relaxation Velocity (E') | -0.01 centimeters/second | Standard Error 0.314 |
| Placebo | Change in Diastolic Mitral Annular Relaxation Velocity (E') | -0.30 centimeters/second | Standard Error 0.323 |
Secondary
Change in E-wave Deceleration Time (DT)
E-wave deceleration time (DT) is a measure of diastolic function.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in E-wave Deceleration Time (DT) | 0.01 seconds | Standard Error 0.004 |
| Placebo | Change in E-wave Deceleration Time (DT) | -0.00 seconds | Standard Error 0.005 |
Secondary
Change in High Sensitivity C-reactive Protein (hsCRP)
High sensitivity C-reactive protein (hsCRP) is a biological and inflammatory marker.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in High Sensitivity C-reactive Protein (hsCRP) | 1.49 milligrams/liter | Standard Error 1.658 |
| Placebo | Change in High Sensitivity C-reactive Protein (hsCRP) | 1.06 milligrams/liter | Standard Error 1.623 |
Secondary
Change in Interleukin-6 (IL-6)
Interleukin-6 (IL-6) is a biological and inflammatory marker.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in Interleukin-6 (IL-6) | 0.27 nanograms/liter | Standard Error 0.844 |
| Placebo | Change in Interleukin-6 (IL-6) | -0.85 nanograms/liter | Standard Error 0.847 |
Secondary
Change in Isovolumetric Relaxation Time (IVRT)
Isovolumetric relaxation time (IVRT) is a measure of diastolic function.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in Isovolumetric Relaxation Time (IVRT) | 0.00 seconds | Standard Error 0.002 |
| Placebo | Change in Isovolumetric Relaxation Time (IVRT) | -0.00 seconds | Standard Error 0.002 |
Secondary
Change in Left Atrial Volume
Left atrial volume is a measure of diastolic function.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in Left Atrial Volume | -4.94 milliliters | Standard Error 1.159 |
| Placebo | Change in Left Atrial Volume | -0.92 milliliters | Standard Error 1.193 |
Secondary
Change in Plasma Triiodothyronine (T3)
Plasma triiodothyronine (T3) is a biological and inflammatory marker.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in Plasma Triiodothyronine (T3) | 0.07 nanomoles/liter | Standard Error 0.036 |
| Placebo | Change in Plasma Triiodothyronine (T3) | 0.12 nanomoles/liter | Standard Error 0.036 |
Secondary
Change in Progression of Aortic Compliance
Change from baseline to Week 48 in aortic compliance.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in Progression of Aortic Compliance | -7.24 10^-4 cm^2/mmHg | Standard Error 5.011 |
| Placebo | Change in Progression of Aortic Compliance | -5.79 10^-4 cm^2/mmHg | Standard Error 4.958 |
Secondary
Change in Progression of Left Ventricular Ejection Fraction
Change from baseline to Week 48 in left ventricular ejection fraction.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in Progression of Left Ventricular Ejection Fraction | 0.62 percent | Standard Error 0.773 |
| Placebo | Change in Progression of Left Ventricular Ejection Fraction | -0.54 percent | Standard Error 0.771 |
Secondary
Change in Progression of Left Ventricular End-diastolic Volume Index
Change from baseline to Week 48 in left ventricular end-diastolic volume index.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in Progression of Left Ventricular End-diastolic Volume Index | 0.30 milliliters/meter^2.7 | Standard Error 0.48 |
| Placebo | Change in Progression of Left Ventricular End-diastolic Volume Index | -0.36 milliliters/meter^2.7 | Standard Error 0.478 |
Secondary
Change in Progression of Left Ventricular End-systolic Volume Index
Change from baseline to Week 48 in left ventricular end-systolic volume index.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in Progression of Left Ventricular End-systolic Volume Index | 0.58 milliliters/meter^2.7 | Standard Error 0.42 |
| Placebo | Change in Progression of Left Ventricular End-systolic Volume Index | 0.57 milliliters/meter^2.7 | Standard Error 0.412 |
Secondary
Change in Progression of Thoraco-abdominal Aortic Plaque Volume
Change from baseline to Week 48 in thoraco-abdominal aortic plaque volume.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in Progression of Thoraco-abdominal Aortic Plaque Volume | -0.02 milliliters | Standard Error 0.002 |
| Placebo | Change in Progression of Thoraco-abdominal Aortic Plaque Volume | -0.03 milliliters | Standard Error 0.002 |
Secondary
Change in Progression of Thoraco-abdominal Aortic Wall Volume
Change from baseline to Week 48 in thoraco-abdominal aortic wall volume
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in Progression of Thoraco-abdominal Aortic Wall Volume | -0.07 milliliters | Standard Error 0.023 |
| Placebo | Change in Progression of Thoraco-abdominal Aortic Wall Volume | -0.10 milliliters | Standard Error 0.024 |
Secondary
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.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in Ratio of Peak E Wave Velocity to Lateral E Wave Velocity (E/E') | 0.16 ratio | Standard Error 0.58 |
| Placebo | Change in Ratio of Peak E Wave Velocity to Lateral E Wave Velocity (E/E') | -0.33 ratio | Standard Error 0.601 |
Secondary
Change in Troponin-T
Troponin-T is a biological and inflammatory marker.
Time frame: Baseline to 48 weeks
Population: The intent-to-treat (ITT) population, participants with available data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol | Change in Troponin-T | 0.01 micrograms/liter | Standard Error 0.002 |
| Placebo | Change in Troponin-T | 0.00 micrograms/liter | Standard Error 0.002 |