Clinical Studies for Kidney Failure/Results

Trial Information

NADIR Study: A Study of Neorecormon (Epoetin Beta)in Anemic Patients With Diabetes and Chronic Renal Failure Who Are Not on Dialysis.

Status: Completed

Protocol Number: ML18730

Sponsor: Roche SAS

Company Division: Pharmaceutical

Official Scientific Title: NADIR study: Multicenter, open-label trial evaluating a simple NeoRecormon treatment regimen in anemic, non-dialysed diabetic patients with chronic renal failure (stages 2 to 5).

Brief Summary: This study will evaluate the effect on correction of anemia and quality of life of NeoRecormon in patients with diabetes who have chronic renal failure and are not receiving dialysis. The anticipated time on study treatment is <3 months and the target sample size is 100-500 individuals. Target sample size is 450.

Study Phase: IV

Study Design / Study Details:

• Purpose: Treatment
• Allocation: Non-Randomized
• Masking: open Label
• Control: Uncontrolled
• Assignment: Single Group
• Endpoints: Safety/Efficacy

Study Type:

Interventional

Condition: Anemia

Intervention Type: Drug

Intervention Name: epoetin beta[NeoRecormon]

Primary Outcome: 1. Efficacy: Proportion of patients achieving the treatment objective of hemoglobin >11g/dL after the 8-week anemia correction phase. Safety: local injection-site reactions (qualitative evaluation); and recording of adverse events

Key Secondary Outcomes: 1. Efficacy:(1)% of patients achieving Hb >11g/dL after 4 wk extension phase;(2)% of non-responding patients at wk 8 who achieve Hb >11g/dL at wk 12. Safety: Practicality and safety of auto-administration. Quality of life: SF 36 from baseline to wk 12.

Inclusion Criteria:

• adult patients 18-75 years of age;
• type 1 or 2 diabetes;
• chronic renal failure;
• anemia requiring treatment.

Exclusion Criteria:

• anemia due to a non-renal cause;
• poorly controlled hypertension;
• previous or current treatment with an ESA (Erythropoiesis Stimulating Agent);
• planned dialysis or organ transplant;
• history of cancer, except for basal cell cancer and cervical

Prospective Controlled Study of Posttransplant Diabetes

Purpose

Research participants will be asked to undergo complete medical history, physical examination and blood tests. The purpose of these tests is to determine whether persons are predisposed to develop diabetes mellitus after kidney transplantation and also to make an early diagnosis if a patient develops diabetes mellitus. Medical information collected as part of the standard transplant evaluation and posttransplant medical care may be incorporated into this study. It is important to realize that research subjects will not be given an experimental drug as part of this study.

After kidney transplantation, research subjects will be followed in the posttransplant clinic visits. The study will last up to 6 months. During this time the subjects may be asked to participate in clinical assessment visits (medical history and physical examination), and also during the third or fourth month after transplant will be asked to do a repeat glucose tolerance test.

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Condition	Intervention
Diabetes Mellitus Kidney Failure	Procedure: renal transplant

Search for New Methods to Detect Acute Renal Failure

Purpose

The purpose of this study is to find substances in the blood and urine that indicate that a person has kidney damage. It will identify proteins found only in patients with acute kidney failure but not in normal healthy people or in patients with volume depletion.

Adults and children who are at least 3 years old who fall into one of the following four categories may be eligible for this study:

1. Are healthy and have normal kidney function
2. Have volume depletion (this condition differs from acute kidney failure in that it is easily treated with fluids)
3. Are at high risk of kidney failure
4. Have acute kidney failure (kidney shutdown)

All study participants will have a history and physical examination. Up to four blood samples of 3 tablespoons each will be taken for laboratory analysis. Urine will be collected for analysis and to measure urine output. The participants' length of stay in the study varies. People with normal kidney function will be in the study for 1 day and patients with volume depletion will be studied 3 days. The length of hospitalization of patients at high risk of kidney failure or in acute kidney failure will depend on the patient's condition and medication requirements.

The results of this study may lead to the development of earlier and more accurate methods for diagnosing acute kidney failure. With earlier detection, treatment could be started earlier, possibly preventing further damage and helping recovery of injury that has already occurred.

...

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Condition
Kidney Failure

Detailed Description:

The mortality of acute renal failure (ARF) remains high despite advances in supportive care. There are no established effective drug therapies, and dialysis may promote renal injury via hypotension or neutrophil activation. Many agents [e.g., mannitol, furosemide, dopamine, atrial natrieuretic Peptide (ANP), Insulin-like Growth Factor (IGF-1), thyroid hormone, etc.] are effective in animal models but ineffective in treating or preventing human ARF. The failure of these agents in human ARF may be due to late enrollment into the trial; effective therapy will likely require earlier detection.

The objective of this clinical study is to identify new biomarkers of renal injury, progression or recovery by analyzing urinary proteins during ARF. We will enroll patients with ARF, patients at high risk of ARF, patients with volume depletion, patients with urinary tract infection, patients with chronic kidney disease, and normal subjects. The diagnosis of pre-renal versus renal ARF will be made by routine clinical and laboratory testing. The level of renal dysfunction will be determined by creatinine clearance. Those patients at high risk for ARF will be followed prospectively and will undergo additional testing if ARF does develop. Patients will also be studied after creatinine levels return to normal. We will attempt to identify proteins that are unique to patients with ARF, but not found in normal subjects or patients with volume depletion. It is hoped that some of these proteins may form the basis of new diagnostic tests for ARF.

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Niaspan in Diabetic Nephropathy

Purpose

The primary purpose of this study is to test the effectiveness and tolerability of Niaspan® to improve the levels of blood fats (“good” and “bad” cholesterol and triglyceride levels) in people who have kidney damage due to diabetes. A secondary goal is to test whether Niaspan® slows down further development of kidney damage.

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Condition	Intervention	Phase
Diabetes Mellitus, Type 2 Kidney Failure, Chronic Hyperlipidemia	Drug: Niaspan	Phase II

Further study details as provided by University of Miami:

<!-- primary outcomes --> Primary Outcome Measures:

• Change in HDL (high-density lipoprotein) concentration
  
• Change in proteinuria
  

<!-- secondary outcomes --> Secondary Outcome Measures:

• Change in LDL (low-density lipoprotein) concentration
  
• Change in LDL particle size
  
• Change in estimated GFR (glomerular filtration rate)
  
• Incidence of adverse events
  

Detailed Description:

Diabetic nephropathy is the leading cause of end stage kidney disease in the United States. Patients with chronic kidney disease have a markedly increased risk of death from cardiovascular disease, and traditional risk factors such as hyperlipidemia have been shown to be of critical importance.

Almost 90% of patients with diabetes and chronic kidney disease have lipid abnormalities. Here, we investigate whether Niaspan, taken in addition to lipid-lowering drugs referred to as "statins", will decrease LDL cholesterol and increase LDL particle size, increase HDL, reduce proteinuria, and reduce the speed of loss of renal function.

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Study of Patients With Acute Renal Failure on CVVH

Purpose

Acute kidney failure is common in children in the Pediatric Intensive Care Unit (PICU). You are being asked to participate in this study because your child is being treated for kidney failure with continuous veno-venous hemofiltration (CVVH). CVVH is a continuous, gentle form of removing excess fluids and small wastes from the blood, similar to kidney dialysis (artificial kidney). It is an accepted therapy for temporary support of kidney failure. In some patients with acute kidney failure, beginning CVVH is followed by a temporary decrease of urine output. The reason why this happens is currently unknown. The purpose of this study is to determine why this happens.

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Condition
Renal Failure

Detailed Description:

Acute renal failure is common in children in the pediatric intensive care unit. Renal replacement therapies such as peritoneal dialysis (PD), intermittent hemodialysis (IHD), and continuous venovenous hemofiltration (CVVH) have been used in the management of acute renal failure. CVVH is becoming increasingly utilized in pediatric acute renal failure. However, in patients who have acute renal failure, the institution of CVVH is often followed by a progression to oliguria or anuria. The underlying pathophysiology of this change is unknown. We believe that this progression is influenced by changes in the renin-angiotensin axis, cytokine response, and other modifiers of renal hemodynamics. By serially measuring components of those systems, this study will attempt to elucidate the pathophysiology of the decreased urine output seen with institution of CVVH. Once this process is understood, future studies should focus on prevention and treatment of this complication.

General Hypothesis

The decrease in urine output seen after the initiation of CVVH is associated with increased angiotensin converting enzyme (ACE) levels, increased renin activity, increased angiotensin II levels, increased atrial naturetic peptide (ANP) levels, increased endothelin-1 levels, increased arginine vasopressin (AVP) levels, and alterations of cytokine levels and modulators of apoptosis

FREEDOM: Following Rehabilitation, Economics and Everyday-Dialysis Outcome Measurements Study

Purpose

Purpose The purpose of this study is to compare the economical impact and clinical parameters of short daily hemodialysis using the NxStage® System One hemodialysis device with thrice-weekly conventional in-center dialysis using a matched cohort from the US Renal Data System (USRDS) database.

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Condition	Phase
Kidney Failure, Chronic End Stage Renal Disease, Requiring Dialysis	Phase IV

Detailed Description:

In the 21st century, nephrologists in the United States face many challenges including a forecast of decline in physician manpower. Challenges that are specific to hemodialysis (HD) include reimbursement constraints, a growing shortage of nurses and major technological advances in dialysis equipment.

There is a growing interest in alternative dialysis regimen and frequency, but a lack of patient incentive for self-care dialysis either in the center or in the home setting. The proposed phase 4 post-marketing study plans to explore whether daily HD is economically attractive compared with thrice weekly HD, while improving health-related quality of life and other dialysis adequacy measures. This project is unique as it provides a large prospective cohort of patients converted to daily HD, with a longitudinal follow up and an ability to compare to a matched cohort from the United States Renal Data Services. This study will help develop whether daily dialysis is economically attractive through the use of new technologies that reduce treatment costs and decrease hospitalization rates, with the long-term hope of increasing life expectancy. All patients will have the option to participate in the Quotidian Dialysis Registry, coordinated by the Lawson Health Research Institute (LHRI) in London, Ontario.

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Cystatin C as a Marker for Detecting Early Renal Dysfunction in a Pediatric Emergency Department (CARING)

Purpose

Acute renal failure (ARF) is a rare but serious complication of gastroenteritis and dehydration, the most common reason for pediatric emergency visits.

Renal function is determined by the glomerular filtration rate (GFR). Serum creatinine, the current marker of GFR, is insensitive and a late marker of ARF. Unfortunately, "gold standard" methods for measurement of GFR are impractical in the emergency setting. Recently, cystatin C (CysC) was introduced as superior marker for the measurement of GFR, particularly in children. A single random blood sample allows for accurate determination of GFR in the so-called "creatinine-blind" range and independent of the body composition. There is growing evidence that the determination of serum CysC concentration can detect ARF in adults earlier than serum creatinine or urinary fractional sodium excretion. No studies have examined this marker for the early detection of ARF in children at risk. We therefore propose a prospective study that compares CysC with other biomarkers of renal dysfunction for the early detection of ARF in children with dehydration due to gastroenteritis. Patients with minor trauma and a minimal likelihood of ARF will serve as a control. This study may establish CysC as an accurate and cost-effective marker for identifying patients at risk.

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Condition	Phase
Acute Renal Failure Gastroenteritis Dehydration	Phase I

 

 

How Vitamin D Analogues Affect Endothelial Cells in Patients on Dialysis

Purpose

Patients with chronic kidney disease and end stage renal disease have greater cardiovascular risk than the general population. Vitamin D analogues have been shown in observational studies to have mortality benefit for these patients. This study is designed to investigate doxercalciferol's effect on the vasculature (i.e. endothelial cell function) as a possible mechanism to explain the mortality benefit.

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Condition	Intervention	Phase
Hyperparathyroidism, Secondary Kidney Failure, Chronic Endothelial Cells Vitamin D	Drug: doxercalciferol	Phase IV

Autonomic Dysfunction and Inflammation in Chronic Hemodialysis Patients

Purpose

This study investigates the relationship between autonomic dysfunction and chronic inflammation in hemodialysis patients.

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Condition
Autonomic Dysfunction Chronic Renal Failure

RESULTS

 

Protocol BCI-CH-115: Effect of Oral 1α-Hydroxyvitamin D₂ on Elevated Blood Parathyroid Hormone Levels in Patients with Mild to Moderate Chronic Renal Failure

Hectorol® (doxercalciferol)

Drug Name	Generic Name	Therapeutic Area and FDA Approved Indications:	Approved U.S. Drug Label
Hectorol®	doxercalciferol capsules	Therapeutic Area: Chronic Kidney Disease FDA Approved Indications: Dialysis Patients: Hectorol® is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Pre-Dialysis Patients: Hectorol® is indicated for the treatment of secondary hyperparathyroidism in patients with Stage 3 or Stage 4 chronic kidney disease.	Prescribing Info for Hectorol® Capsules

These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert.

PUBLICATION (REFERENCE)

Publications

NAME OF SPONSOR/COMPANY:

Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142
Bone Care International, Inc., Middleton, WI 53652 (Bone Care was acquired by Genzyme Corporation July 2005)

TITLE OF STUDY:

Protocol BCI-CH-115: Effect of Oral 1α-Hydroxyvitamin D₂ on Elevated Blood Parathyroid Hormone Levels in Patients with Mild to Moderate Chronic Renal Failure

INVESTIGATORS AND STUDY CENTER(S):

This was a multicenter study conducted at three locations in the United States.

STUDIED PERIOD:

First patient enrolled: 03 November 1997
Last patient completed: 09 January 2000

PHASE OF DEVELOPMENT:

Phase 3

OBJECTIVES:

To establish the safety and efficacy of oral Hectorol® as a therapy for secondary hyperparathyroidism in pre-dialysis patients with mild to moderate chronic renal insufficiency (Stage 3 and Stage 4 Chronic Kidney Disease (CKD)).

METHODOLOGY:

This was a Phase 3, randomized, multi-center study. The study consisted of an 8-week Washout Period followed by a 24-week double-blind Treatment Period. During the 24-week double-blind period, patients were randomly assigned to either Hectorol or placebo.

NUMBER OF PATIENTS (PLANNED AND ANALYZED):

No. Enrolled: 40
No. Treated: 30 (15 Hectorol, 15 placebo)
No. Completed: 24 (13 Hectrol, 11 placebo)

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION:

Subjects were between the ages of 18 and 85 years, with elevated plasma iPTH (> 85 pg/mL), and serum creatinine between 1.8 to 5.0 mg/dL (for men) or 1.6 to 4.0 mg/dL (for women).

TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION:

Hectorol: 0.5 mcg soft gelatin capsules
The initial dose was 1 mcg per day.
Doses were taken orally every day before breakfast.

DURATION OF TREATMENT:

8-week Washout Period followed by 24-week Treatment Period.

REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION:

Placebo contained the same inactive ingredients in identical proportions and appearance to Hectorol.
Doses were taken orally every day before breakfast.

CRITERIA FOR EVALUATION:

Criteria for Evaluation - Efficacy:
Plasma iPTH was evaluated for evidence of the test drug’s efficacy. Bone-specific serum markers (e.g., bone-specific alkaline phosphatase (BSAP), serum osteocalcin) were also evaluated.

Criteria for Evaluation - Safety:
Serum and urine calcium were evaluated for safety. Additionally, adverse events were evaluated for safety.

STATISTICAL METHODS:
Comparisons were considered to be statistically significant if the two-sided p-value was ≤ 0.05. Missing values were imputed using last observation carried forward.

Statistical Methods - Efficacy:
Baseline values were defined as the mean of the data collected during Weeks -4 and 0 of the Washout Period. At each time point, descriptive statistics were calculated. Also, the significance of the mean difference from baseline at each time point was assessed by paired t-test.

At baseline and at each time point during the Treatment Period, the treatment groups were compared, and the significance of differences in means was assessed via a two-sample t-test. For certain parameters (plasma iPTH, BSAP, and serum osteocalcin), the data were also recalculated as a percent of baseline and the analyses were performed on these percentages. All of the above analyses were performed on an intent-to-treat basis.

Statistical Methods – Safety:
Baseline values were defined as the mean of the data collected during Weeks -4 and 0 of the Washout Period. At each time point, descriptive statistics were calculated. Also, the significance of the mean difference from baseline at each time point was assessed by paired t-test.

At baseline, and throughout the Treatment Period, the treatment groups were compared, and the significance of differences in means was assessed via a two-sample t-test. For serum calcium and serum phosphorus, the data were also recalculated as a percent of baseline and the analyses were performed on these percentages. All of the above analyses were performed on an intent-to-treat basis.

Adverse experiences were recorded, and their frequency determined for each treatment group. For each type of serious, unexpected adverse event or drug-related adverse experience, the treatment groups were compared with respect to the percent of patients experiencing the adverse effect by Fisher’s exact test.

SUMMARY / CONCLUSIONS

Summary / Conclusions - Demographics:
The 30 patients enrolled into the Treatment Period had ages between 52 and 84 years (mean = 68.4 years). Twenty-eight patients were men and two were women; 19 were African-American, 7 were Caucasian, and 4 were Hispanic.

Summary / Conclusions – Efficacy:
The intent-to-treat analysis included all 30 subjects who entered the Treatment Period (15 on Hectorol, 15 on placebo).

Average Prescribed Dose: The mean weekly dosage of study drug remained at the initial level of 1 mcg (2 capsules) for subjects receiving Hectorol until Week 4. Thereafter, the mean dose in the Hectorol group increased to 1.57 mcg/day by the end of the study. The dose in the placebo group increased to 4.93 mcg/day by the end of the study.

Plasma iPTH: At baseline, mean plasma iPTH was 220.2 pg/mL in the Hectorol group, and 185.3 pg/mL in the placebo group (p = 0.40). With initiation of Hectorol treatment, mean iPTH decreased to 97.3 pg/mL (p < 0.001 vs. baseline) at the end of the study. In contrast, mean iPTH remained unchanged from baseline levels in the placebo group throughout the entire Treatment Period, ending at 167.5 pg/mL (p = 0.16).

At the end of the Treatment Period, 13 (87%) of 15 subjects in the Hectorol group had achieved plasma iPTH suppression of ≥ 30% from baseline. Only one (7%) of the 15 subjects receiving placebo achieved iPTH suppression of ≥ 30% by the end of the study.

At the end of the study, mean reduction of iPTH from baseline was 53.9% for Hectorol subjects and 10.2% for placebo subjects (p < 0.001).

Osteocalcin: Baseline mean serum osteocalcin was 67.6 ng/mL in the Hectorol group and 67.0 ng/mL in the placebo group (p = 0.96). With Hectorol treatment, mean osteocalcin decreased to 46.9 ng/mL by the end of the study (p < 0.001). Mean osteocalcin levels trended slightly downward but remained statistically unchanged from baseline in the placebo group, reaching 60.8 ng/mL (p = 0.20) by the end of the study. No differences between the groups reached statistical significance during the Treatment Period.

Bone-Specific Alkaline Phosphatase (BSAP): Baseline mean serum BSAP was 25.3 U/L in the Hectorol group and 27.5 U/L in the placebo group (p = 0.40). After initiation of Hectorol treatment, mean BSAP decreased to 18.3 U/L by the end of the study (p < 0.001 vs. baseline). Mean BSAP in the placebo group was 25.5 U/L at the end of study (p = 0.27). The mean difference between the treatment groups was statistically significant at the end of the study (p = 0.004).

At the end of the study, mean reduction in BSAP from baseline was 26.3% for Hectorol subjects and 5.2% for placebo subjects (p = 0.01).

Summary / Conclusions – Safety Results:
Adverse Events: One-hundred thirty (130) treatment emergent adverse events occurred during the study with 47 events occurring in patients randomized to active treatment. One non-serious adverse event (nausea), reported in a subject who received Hectorol, was assessed as related to study drug (0.8%). All other treatment emergent adverse events were assessed as not related or probably not related to study drug. An analysis of the incidence rates for serious and non-serious adverse events by treatment group showed no significant differences.

One death occurred during the study in a patient randomized to placebo. The patient died at Week 15 of the study due to cardiorespiratory arrest. The Investigator determined the event as not related to study drug. Fifteen serious treatment emergent adverse events occurred in nine patients during the study. Seven serious adverse events (39%) occurred in four patients receiving Hectorol. All serious adverse events were considered not related to study drug.

No episodes of hypercalcemia (serum calcium > 10.7 mg/dL) occurred in the Hectorol group and one episode of hypercalcemia occurred in one subject in the placebo group. During the Treatment Period, there were 5 episodes of hyperphosphatemia (serum phosphorus > 5.0 mg/dL) in four patients receiving active treatment and 3 episodes in three patients receiving placebo treatment. No episodes of hypercalciuria (defined as 24-hour urine calcium excretion greater than 200 mg or fasting urine calcium/creatinine ratio above 0.25) occurred during the Treatment Period in either the active or placebo groups.

Serum Calcium: Baseline mean serum calcium was 8.62 mg/dL in the Hectorol group and 8.83 mg/dL in the placebo group (p = 0.28). At the end of the study, mean serum calcium was 9.11 mg/dL in the Hectorol group and 8.9 mg/dL in the placebo group (p = 0.32). The increase in mean serum calcium from baseline was significant only in patients treated with Hectorol (p = 0.01); however, mean serum calcium did not differ between the treatment groups at any time during the study (p > 0.14).

Serum Phosphorus: At baseline, mean serum phosphorus was 3.85 mg/dL in the Hectorol group and 3.73 mg/dL in the placebo group (p = 0.61). At the end of the study, mean serum phosphorus was 4.21 mg/dL in the Hectorol group and 3.64 mg/dL in the placebo group (p = 0.005). The increase in serum phosphorus relative to baseline was significant for the Hectorol group (p = 0.011). Serum phosphorus differed between Hectorol and placebo groups at Weeks 20 and 24 (p ≤ 0.02).

Urine Calcium: Baseline mean 24-hour urine calcium was 33.7 mg in patients treated with Hectorol and 37.8 mg in patients receiving placebo (p = 0.74). At the end of the study, mean urine calcium was 48.1 mg/24 hours in the Hectorol group and 34.8 mg/24 hours in the placebo group (p = 0.43). No statistically significant changes in 24-hour urine calcium relative to baseline levels were observed in either the Hectorol or placebo group throughout the Treatment Period. No differences between treatment groups reached statistical significance during the Treatment Period.

Clinical Chemistry, Hematology, Vital Signs: There were no clinically significant changes in other clinical chemistry or hematology laboratory parameters or vital signs.

CONCLUSION:

Hectorol (doxercalciferol capsules) is effective and safe for the management of secondary hyperparathyroidism in Stage 3 and Stage 4 CKD.

Based on report prepared on: 16 January 2002
Synopsis prepared on: 10 November 2006