The PRIMO II Study: Paricalcitol Injection Benefits in Renal Failure Induced Cardiac Morbidity in Subjects With Chronic Kidney Disease (CKD) Stage 5

Clinical Study Protocol M10-221 The PRIMO II Study: Paricalcitol Injection Benefits in Renal Failure Induced Cardiac Morbidity in Subjects With Chronic Kidney Disease (CKD) Stage 5

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00616902

Acronym

PRIMO II

Enrollment

Registered

2008-02-15

Start date

2009-01-31

Completion date

2009-05-31

Last updated

2012-01-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Chronic Kidney Disease (CKD) Stage 5, Hypertrophy, Left Ventricular

Keywords

Zemplar, paricalcitol, PRIMO II

Brief summary

To evaluate the effects of paricalcitol injection on cardiac structure and function over 48 weeks in subjects with Stage 5 Chronic Kidney Disease (CKD) receiving hemodialysis who have left ventricular hypertrophy (LVH).

Interventions

DRUGparicalcitol injection 4 mcg/mL

Paricalcitol Injection 4 mcg/mL intravenously three times a week during dialysis

DRUGPlacebo Injection 4 mcg/mL

Placebo Injection 4 mcg/mL given intravenously three times a week during dialysis

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

Inclusion criteria

* Stage 5 CKD receiving chronic hemodialysis three times per week for \>= 3 months and \<= 12 months from date of Randomization (Day 1). * Serum intact parathyroid hormone (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). * Echocardiogram results: * For females, left ventricular (LV) ejection fraction \>= 50% and septal wall thickness between 11-17 mm. * For males, LV ejection fraction \>= 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. * A technically adequate baseline cardiac magnetic resonance imaging (MRI). * If female, subject is not breast feeding or is not pregnant, or is not of childbearing potential, defined as postmenopausal for at least one year or surgically sterile, or is of childbearing potential and practicing one of the following methods of birth control: * Double-barrier method * Hormonal contraceptives 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.

Exclusion criteria

* Subject has previously been on active vitamin D therapy (calcitriol, paricalcitol, doxercalciferol, alfacalcidol) for a total duration greater than three months since the start of dialysis. * Subject has a history of an allergic reaction or significant sensitivity to paricalcitol or to drugs similar to the study drug. * Subject is expected to receive an increased dose of RAAS inhibitor (Angiotensin converting enzyme inhibitor \[ACEi\], Angiotensin II receptor blocker \[ARB\] or aldosterone inhibitor) during the course of the study. * Subject has clinically significant coronary artery disease (CAD) within 3 months prior to the Screening Period, defined as one of the following: * Hospitalization for myocardial infarction (MI) or unstable angina; or * New onset angina with positive functional study or coronary angiogram revealing stenosis; or * Coronary revascularization procedure. * Subject has major cardiac valve abnormality linked with left ventricular hypertrophy (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. * Subject has asymmetric septal hypertrophy. * Subject has had a severe cerebrovascular accident (CVA) within the last three months (e.g., hemorrhagic) prior to screening. * 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. * Subject has co-morbid conditions. * Subject has received any investigational drug within 30 days prior to study drug administration or is currently enrolled in another clinical trial. * Subject has poorly controlled hypertension. * Subject has history of renal artery stenosis, primary aldosteronism or pheochromocytoma * Subject is taking calcitonin, bisphosphonates, cinacalcet, glucocorticoids (except topical or inhaled glucocorticoids) * Subject is currently receiving immunosuppressant therapy and/or high doses of glucocorticoids * Subject is known to be HIV positive. * Use of known inhibitors or inducers of cytochrome P450 3A (CYP3A) within two weeks prior to study drug administration * Subject is contraindicated for the MRI examination * Investigator considers subject unsuitable for any reason * Subject has a history of drug or alcohol abuse within six months prior to screening * Subject weighs more than 340 pounds (154 kg) * Subject has had a liver transplant

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, 24 Weeks, and 48 Weeks/Early Termination	Change from Baseline in left ventricular mass index (LVMI) over 48 weeks measured by cardiac MRI. The effects of paricalcitol injection on progression or regression of left ventricular hypertrophy (LVH) in participants with Stage 5 chronic kidney disease (CKD) on hemodialysis (HD) compared to placebo. Left Ventricular Mass is normalized to the participant's height by the following equation to obtain LVMI: LVM (g) divided by height (m)2.7. The primary comparison was between the 4 mcg paricalcitol injection and the placebo treatment groups in the change from baseline to Week 48.

Secondary

Measure	Time frame	Description
Change From Baseline in Evaluating Changes in the Additional Measure of Diastolic Function of Isovolumetric Relaxation Time (IVRT) Over 48 Weeks.	Baseline, 24 Weeks, and 48 Weeks/Early Termination	Isovolumetric relaxation time is a measure of diastolic heart function.
Change From Baseline in Evaluating Changes in the Additional Measure of Diastolic Function of Peak E-wave Velocity to Lateral E-wave Velocity (E/E') Over 48 Weeks.	Baseline, Week 24, and Week 48/Early Termination	The ratio of peak E-wave velocity to lateral e-wave velocity is a measure of diastolic heart function.
Change From Baseline in Evaluating Changes in the Additional Measure of Diastolic Function E-wave Deceleration Time (DT) Over 48 Weeks	Baseline, 24 Weeks, and 48 Weeks/Early Termination	E-wave deceleration time is a measure of diastolic heart function.
Change From Baseline in Biological Marker Triiodothyronine (T3).	Baseline and Early Termination Visit (4 Weeks, 5 Weeks, 7 Weeks, 8 Weeks, 14 Weeks, and 16 Weeks)	Plasma T3 is a circulating hormone that may have an effect on diastolic heart function and its level may be affected by treatment with paricalcitol. The study was terminated early (prior to any subject reaching Week 24). The values are for Baseline and Early Termination only. Each of the 12 randomized subjects terminated at different study weeks; therefore Early Termination cannot be defined as a specific week and varies for different subjects. Of the 12 subjects, 11 had early termination visits and 1 didn't. The final visit week range is 4-16.
Change From Baseline in the Echocardiographic Assessment of Diastolic Function Assessed by Evaluating Changes in Diastolic Mitral Annular Relaxation Velocity (E') Over 48 Weeks.	Baseline, 24 Weeks, and 48 Weeks/Early Termination	Mitral Annular relaxation velocity is a measure of diastolic heart function.
Change From Baseline in Biological Marker Plasma Interleukin-6 (IL-6) Over 48 Weeks	Baseline and Early Termination Visit (4 Weeks, 5 Weeks, 7 Weeks, 8 Weeks, 14 Weeks, and 16 Weeks)	Plasma IL-6 is a biomarker of inflammation that may have an effect on heart function and its level may be affected by treatment with paricalcitol. The study was terminated early (prior to any subject reaching Week 24). The values are for Baseline and Early Termination only. Each of the 12 randomized subjects terminated at different study weeks; therefore Early Termination cannot be defined as a specific week and varies for different subjects. Of the 12 subjects, 11 had early termination visits and 1 didn't. The final visit week range is 4-16.
Change From Baseline in Biological Marker Plasma High Sensitivity C-reactive Protein (hsCRP) Over 48 Weeks	Baseline and Early Termination Visit (4 Weeks, 5 Weeks, 7 Weeks, 8 Weeks, 14 Weeks, and 16 Weeks)	Plasma high sensitivity CRP is a biomarker of inflammation that may have an effect on heart function and its level may be affected by treatment with paricalcitol. The study was terminated early (prior to any subject reaching Week 24). The values are for Baseline and Early Termination only. Each of the 12 randomized subjects terminated at different study weeks; therefore Early Termination cannot be defined as a specific week and varies for different subjects. Of the 12 subjects, 11 had early termination visits and 1 didn't. The final visit week range is 4-16.
Change From Baseline in Biological Marker Plasma B-Type Natriuretic Peptide (BNP)	Baseline and Early Termination Visit (4 Weeks, 5 Weeks, 7 Weeks, 8 Weeks, 14 Weeks, and 16 Weeks)	Plasma BNP is a product from the heart that becomes elevated with an enlarged heart and its level may be affected by treatment with paricalcitol. The study was terminated early (prior to any subject reaching Week 24). The values are for Baseline and Early Termination only. Each of the 12 randomized subjects terminated at different study weeks; therefore Early Termination cannot be defined as a specific week and varies for different subjects. Of the 12 subjects, 11 had early termination visits and 1 didn't. The final visit week range is 4-16.
Change From Baseline in Biological Marker Plasma Troponin-T Over 48 Weeks	Baseline and Early Termination Visit (4 Weeks, 5 Weeks, 7 Weeks, 8 Weeks, 14 Weeks, and 16 Weeks)	Plasma troponin-t is a marker of heart damage and and its level may be affected by treatment with paricalcitol. The study was terminated early (prior to any subject reaching Week 24). The values are for Baseline and Early Termination only. Each of the 12 randomized subjects terminated at different study weeks; therefore Early Termination cannot be defined as a specific week and varies for different subjects. Of the 12 subjects, 11 had early termination visits and 1 didn't. The final visit week range is 4-16.

Countries

Australia, Czechia, Germany, Greece, Italy, Poland, Puerto Rico, Romania, Russia, Spain, Taiwan, United Kingdom, United States

Participant flow

Recruitment details

A total of 220 participants were to be randomized in a 1:1 ratio to each treatment group to receive paricalcitol injection or placebo at 75 US and ex-US sites. A stratified randomization scheme was used to ensure balance among treatment groups with respect to country, sex, and baseline Renin Angiotensin-Aldosterone System (RAAS) inhibitor use.

Pre-assignment details

The Screening Period consisted of 3 visits and occurred within 6 weeks prior to participant randomization and enrollment into the Treatment Period of the study. For enrollment, all screening labs and echocardiogram requirements had to be met. Also, a technically adequate cardiac MRI had to be obtained for participant to be randomized into study.

Participants by arm

Arm	Count
Paricalcitol Injection 4 Mcg/mL Paricalcitol Injection 4 mcg/mL given intravenously 3 times per week during dialysis.	6
Placebo Injection 4 Mcg/mL Placebo Injection 4 mcg/mL given intravenously 3 times per week during dialysis.	6
Total	12

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Termination of study	6	6

Baseline characteristics

Characteristic	Total	Placebo Injection 4 Mcg/mL	Paricalcitol Injection 4 Mcg/mL
Age Continuous	56.7 years STANDARD_DEVIATION 12.01	58.8 years STANDARD_DEVIATION 7.05	54.5 years STANDARD_DEVIATION 16.01
Age, Customized 40 - < 60 years	5 participants	2 participants	3 participants
Age, Customized < 40 years	1 participants	0 participants	1 participants
Age, Customized >= 60 years	6 participants	4 participants	2 participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	2 Participants	0 Participants	2 Participants
Race (NIH/OMB) Black or African American	3 Participants	2 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	7 Participants	4 Participants	3 Participants
Sex: Female, Male Female	7 Participants	3 Participants	4 Participants
Sex: Female, Male Male	5 Participants	3 Participants	2 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	3 / 6	3 / 6
serious Total, serious adverse events	0 / 6	0 / 6

Outcome results

Primary

Change From Baseline in Left Ventricular Mass Index (LVMI) Over 48 Weeks Measured by Cardiac Magnetic Resonance Imaging (MRI)

Change from Baseline in left ventricular mass index (LVMI) over 48 weeks measured by cardiac MRI. The effects of paricalcitol injection on progression or regression of left ventricular hypertrophy (LVH) in participants with Stage 5 chronic kidney disease (CKD) on hemodialysis (HD) compared to placebo. Left Ventricular Mass is normalized to the participant's height by the following equation to obtain LVMI: LVM (g) divided by height (m)2.7. The primary comparison was between the 4 mcg paricalcitol injection and the placebo treatment groups in the change from baseline to Week 48.

Time frame: Baseline, 24 Weeks, and 48 Weeks/Early Termination

Population: The Intent-To-Treat (ITT) population - all randomized participants who were administered at least one dose of study drug and the Evaluable population (a subset of ITT population and consists of those participants who have completed Week 24 visit). None of the participants completed 24 or 48 weeks.

Secondary

Change From Baseline in Biological Marker Plasma B-Type Natriuretic Peptide (BNP)

Plasma BNP is a product from the heart that becomes elevated with an enlarged heart and its level may be affected by treatment with paricalcitol. The study was terminated early (prior to any subject reaching Week 24). The values are for Baseline and Early Termination only. Each of the 12 randomized subjects terminated at different study weeks; therefore Early Termination cannot be defined as a specific week and varies for different subjects. Of the 12 subjects, 11 had early termination visits and 1 didn't. The final visit week range is 4-16.