Chronic Kidney Disease, Diabetic Nephropathy
Conditions
Keywords
Type 2 Diabetic Nephropathy
Brief summary
The study objective was to evaluate the safety of paricalcitol capsules and the efficacy of paricalcitol capsules for albuminuria reduction in patients with Chronic Kidney Disease (CKD) who have Type 2 diabetic nephropathy and are receiving optimal angiotensin converting enzyme (ACE) inhibitor and/or angiotensin II receptor blocker (ARB) therapy.
Interventions
DRUGZemplar (paricalcitol ) capsules
Group 2 - paricalcitol 1 mcg capsules once daily (one paricalcitol 1 mcg capsule once daily and one matching placebo capsule once daily)
DRUGZemplar (paricalcitol) capsules
Group 3 - paricalcitol 2 mcg capsules once daily (two paricalcitol 1 mcg capsules once daily)
DRUGPlacebo
Group 1 - Placebo once daily (two placebo capsules once daily)
Sponsors
Abbott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female participant \>= 20 years old. * Participant has Type 2 Diabetes Mellitus and has been treated with at least one anti-hyperglycemic medication within the 12 months prior to the Screening Phase * Participant has been receiving a stable dose (i.e., same type and regimen) of ACEi and/or ARB for at least three months prior to the Screening Phase. However, participant may have switched to different brands but at equivalent doses during the three months prior to the Screening Phase. * Participant is not expected to begin dialysis for at least 6 months. * If female, participant is not breast feeding or is not pregnant. * For entry into the Treatment Phase, the participant must satisfy the following criteria based on the Screening laboratory values: * Estimated glomerular filtration rate (GFR) between 15-90 mL/min/1.73m2 by simplified Modification in Diet in Renal Disease (MDRD) formula * Urinary albumin to creatinine ratio (UACR) between 100 and 3000 mg/g as determined by the mean of the three first morning void urine specimens obtained within one week of each other * Corrected serum calcium level \<= 9.8 mg/dL * intact parathyroid hormone (iPTH) value between 35-500 pg/mL * Glycosylated hemoglobin A1c (HbA1c) \<= 12% * Serum albumin \> 3.0 g/dL * Negative urine pregnancy test for female participants
Exclusion criteria
* Participant has previously been on prescription-based vitamin D therapy within the six months prior to the Screening Phase. * Participant has a history of an allergic reaction or significant sensitivity to paricalcitol or to drugs similar to the study drug. * Participant has primary glomerulonephritis or secondary nephritis in addition to diabetic nephropathy. * Participant has had acute renal failure within 12 weeks of the Screening Phase, defined as an acute rise (of \>= 0.5 mg/dL) in serum creatinine to \> 4 mg/dL. * Participant has chronic gastrointestinal disease. * Participant has secondary hypertension. * Participant has poorly controlled hypertension. * Participant has a history of kidney stones. * Participant has a history of drug or alcohol abuse within six months prior to the Screening Phase. * Participant has evidence of poor compliance with diet or medication. * Participant has received any investigational drug within 30 days prior to study drug administration. * Participant is taking calcitonin, bisphosphonates, cinacalcet, glucocorticoids (except topical glucocorticoids), or other drugs that may affect calcium, or bone metabolism, other than calcium containing phosphate binder or female participants on stable (same dose and product for three months) estrogen and/or progestin therapy. * For any reason, participant is considered by the Investigator to be an unsuitable candidate to receive paricalcitol capsules or is put at risk by study procedures. * Participant is known to be human immunodeficiency virus (HIV) positive. * Participant has used known inhibitors or inducers of cytochrome P450 3A (CYP3A) within two weeks prior to study drug administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to the Last On-treatment Measurement in Urine Albumin to Creatinine Ratio (UACR) Levels Determined From the First Morning Void (FMV) Urine Collections Comparing Placebo to the Combined Paricalcitol Treatment Groups (1 Mcg and 2 Mcg). | Baseline (within 1 week prior to first treatment) through 24 weeks of treatment | UACR is defined as the ratio: milligram of albumin per gram of creatinine. Baseline UACR was determined as the mean of the 3 UACR measurements from FMV urine collections obtained within 1 week prior to the day of the first dose of study drug. The last on-treatment measurement was the mean of the 3 UACR measurements obtained from FMV urine collections obtained within 1 week of the final week of treatment. The UACR data were log transformed prior to analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving a 15% or Greater Reduction From Baseline to Last On-treatment Urine Albumin to Creatinine Ratio (UACR) Levels. | Baseline (within 1 week prior to first treatment) through 24 weeks of treatment | Number of participants whose last on-treatment albumin to creatinine ratio (UACR) value was reduced at least 15% from the baseline value. Albumin values were determined from 24-hour urine collections from the baseline and last on-treatment visits. |
| Change From Baseline to the Last On-treatment Measurement in Albumin Levels Determined From 24-hour Urine Collection. | Baseline (within 1 week prior to first treatment) through 24 weeks of treatment | The change is mean change from baseline to the last on-treatment value, with the data being log transformed prior to analysis. Albumin values were determined from 24-hour urine collections from the baseline and last on-treatment visits. |
| Change From Baseline to the Last On-treatment Observation in Intact Parathyroid Hormone (iPTH) Levels. | Baseline (screening period) through 24 weeks of treatment | Change is mean change in picograms of iPTH per milliliter of serum. |
Countries
Germany, Greece, Italy, Netherlands, Poland, Portugal, Puerto Rico, Spain, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Paricalcitol 1 Mcg One paricalcitol 1 mcg capsule and one matching placebo capsule per dose | 93 |
| Paricalcitol 2 Mcg Two paricalcitol 1 mcg capsules per dose | 95 |
| Placebo Two placebo capsules per dose | 93 |
| Total | 281 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative | 2 | 0 | 0 |
| Overall Study | Adverse Event | 4 | 9 | 2 |
| Overall Study | Death | 0 | 3 | 0 |
| Overall Study | Did not satisfy entry criteria | 1 | 3 | 2 |
| Overall Study | Lost to Follow-up | 1 | 2 | 4 |
| Overall Study | Protocol deviation | 4 | 7 | 2 |
| Overall Study | Required dialysis | 1 | 0 | 0 |
| Overall Study | Sponsor request | 1 | 0 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 7 |
Baseline characteristics
| Characteristic | Paricalcitol 1 Mcg | Paricalcitol 2 Mcg | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 48 Participants | 48 Participants | 49 Participants | 145 Participants |
| Age, Categorical Between 18 and 65 years | 45 Participants | 47 Participants | 44 Participants | 136 Participants |
| Age Continuous | 64.0 years STANDARD_DEVIATION 10.15 | 64.7 years STANDARD_DEVIATION 9.92 | 64.5 years STANDARD_DEVIATION 11.23 | 64.4 years STANDARD_DEVIATION 10.41 |
| Region of Enrollment Germany | 4 participants | 8 participants | 1 participants | 13 participants |
| Region of Enrollment Greece | 1 participants | 3 participants | 1 participants | 5 participants |
| Region of Enrollment Italy | 4 participants | 1 participants | 3 participants | 8 participants |
| Region of Enrollment Netherlands | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Poland | 4 participants | 4 participants | 4 participants | 12 participants |
| Region of Enrollment Portugal | 2 participants | 2 participants | 0 participants | 4 participants |
| Region of Enrollment Spain | 11 participants | 3 participants | 9 participants | 23 participants |
| Region of Enrollment Taiwan | 10 participants | 14 participants | 10 participants | 34 participants |
| Region of Enrollment United States | 57 participants | 60 participants | 64 participants | 181 participants |
| Sex: Female, Male Female | 27 Participants | 26 Participants | 33 Participants | 86 Participants |
| Sex: Female, Male Male | 66 Participants | 69 Participants | 60 Participants | 195 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 38 / 93 | 46 / 95 | 46 / 93 |
| serious Total, serious adverse events | 13 / 93 | 19 / 95 | 12 / 93 |
Outcome results
Primary
Change From Baseline to the Last On-treatment Measurement in Urine Albumin to Creatinine Ratio (UACR) Levels Determined From the First Morning Void (FMV) Urine Collections Comparing Placebo to the Combined Paricalcitol Treatment Groups (1 Mcg and 2 Mcg).
UACR is defined as the ratio: milligram of albumin per gram of creatinine. Baseline UACR was determined as the mean of the 3 UACR measurements from FMV urine collections obtained within 1 week prior to the day of the first dose of study drug. The last on-treatment measurement was the mean of the 3 UACR measurements obtained from FMV urine collections obtained within 1 week of the final week of treatment. The UACR data were log transformed prior to analysis.
Time frame: Baseline (within 1 week prior to first treatment) through 24 weeks of treatment
Population: Intent-to-treat population, which was all randomized participants who received at least 1 dose of study drug. Subjects without both a baseline and last on-treatment measurement were excluded from the primary efficacy analysis. As such, sample size was N=88 for placebo, N=92 for 1 mcg and for 2 mcg paricalcitol, and N=184 for combined paricalcitol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to the Last On-treatment Measurement in Urine Albumin to Creatinine Ratio (UACR) Levels Determined From the First Morning Void (FMV) Urine Collections Comparing Placebo to the Combined Paricalcitol Treatment Groups (1 Mcg and 2 Mcg). | -0.03 log milligram/gram creatinine | Standard Deviation 0.61 |
| Combined Paricalcitol 1 Mcg and 2 Mcg | Change From Baseline to the Last On-treatment Measurement in Urine Albumin to Creatinine Ratio (UACR) Levels Determined From the First Morning Void (FMV) Urine Collections Comparing Placebo to the Combined Paricalcitol Treatment Groups (1 Mcg and 2 Mcg). | -0.18 log milligram/gram creatinine | Standard Deviation 0.7 |
| Paricalcitol 1 Mcg | Change From Baseline to the Last On-treatment Measurement in Urine Albumin to Creatinine Ratio (UACR) Levels Determined From the First Morning Void (FMV) Urine Collections Comparing Placebo to the Combined Paricalcitol Treatment Groups (1 Mcg and 2 Mcg). | -0.15 log milligram/gram creatinine | Standard Deviation 0.72 |
| Paricalcitol 2 Mcg | Change From Baseline to the Last On-treatment Measurement in Urine Albumin to Creatinine Ratio (UACR) Levels Determined From the First Morning Void (FMV) Urine Collections Comparing Placebo to the Combined Paricalcitol Treatment Groups (1 Mcg and 2 Mcg). | -0.22 log milligram/gram creatinine | Standard Deviation 0.69 |
p-value: 0.071ANCOVA
p-value: 0.229ANCOVA
p-value: 0.053ANCOVA
Secondary
Change From Baseline to the Last On-treatment Measurement in Albumin Levels Determined From 24-hour Urine Collection.
The change is mean change from baseline to the last on-treatment value, with the data being log transformed prior to analysis. Albumin values were determined from 24-hour urine collections from the baseline and last on-treatment visits.
Time frame: Baseline (within 1 week prior to first treatment) through 24 weeks of treatment
Population: Intent-to-treat population, which was all randomized subjects who received at least one dose of study drug. Subjects who did not have both a baseline measurement and a last on-treatment visit value were excluded from the analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to the Last On-treatment Measurement in Albumin Levels Determined From 24-hour Urine Collection. | -0.10 log milligrams of albumin per 24 hours | Standard Deviation 0.73 |
| Combined Paricalcitol 1 Mcg and 2 Mcg | Change From Baseline to the Last On-treatment Measurement in Albumin Levels Determined From 24-hour Urine Collection. | -0.44 log milligrams of albumin per 24 hours | Standard Deviation 0.9 |
| Paricalcitol 1 Mcg | Change From Baseline to the Last On-treatment Measurement in Albumin Levels Determined From 24-hour Urine Collection. | -0.08 log milligrams of albumin per 24 hours | Standard Deviation 0.73 |
p-value: 0.85595% CI: [-0.26, 0.22]ANCOVA
p-value: 0.00995% CI: [-0.57, -0.08]ANCOVA
Secondary
Change From Baseline to the Last On-treatment Observation in Intact Parathyroid Hormone (iPTH) Levels.
Change is mean change in picograms of iPTH per milliliter of serum.
Time frame: Baseline (screening period) through 24 weeks of treatment
Population: Intent-to-treat population, which was all randomized subjects who received at least one dose of study drug. Subjects who did not have both a baseline and a last on-treatment measurement were excluded from the analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to the Last On-treatment Observation in Intact Parathyroid Hormone (iPTH) Levels. | -26.7 picogram/milliliter | Standard Deviation 55.2 |
| Combined Paricalcitol 1 Mcg and 2 Mcg | Change From Baseline to the Last On-treatment Observation in Intact Parathyroid Hormone (iPTH) Levels. | -50.7 picogram/milliliter | Standard Deviation 63.1 |
| Paricalcitol 1 Mcg | Change From Baseline to the Last On-treatment Observation in Intact Parathyroid Hormone (iPTH) Levels. | 18.3 picogram/milliliter | Standard Deviation 55.3 |
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
Secondary
Number of Participants Achieving a 15% or Greater Reduction From Baseline to Last On-treatment Urine Albumin to Creatinine Ratio (UACR) Levels.
Number of participants whose last on-treatment albumin to creatinine ratio (UACR) value was reduced at least 15% from the baseline value. Albumin values were determined from 24-hour urine collections from the baseline and last on-treatment visits.
Time frame: Baseline (within 1 week prior to first treatment) through 24 weeks of treatment
Population: Intent-to-treat population, which was all randomized subjects who received at least one dose of study drug. Subjects who did not have both a baseline measurement and a last on-treatment visit value were excluded from the analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants Achieving a 15% or Greater Reduction From Baseline to Last On-treatment Urine Albumin to Creatinine Ratio (UACR) Levels. | 48 Participants |
| Combined Paricalcitol 1 Mcg and 2 Mcg | Number of Participants Achieving a 15% or Greater Reduction From Baseline to Last On-treatment Urine Albumin to Creatinine Ratio (UACR) Levels. | 51 Participants |
| Paricalcitol 1 Mcg | Number of Participants Achieving a 15% or Greater Reduction From Baseline to Last On-treatment Urine Albumin to Creatinine Ratio (UACR) Levels. | 35 Participants |
p-value: 0.102Fisher Exact
p-value: 0.038Fisher Exact