Post Edited (LLPLUV) : 6/28/2009 2:29:00 PM (GMT-6)
NADIR Study: A Study of Neorecormon (Epoetin Beta)in Anemic Patients With Diabetes and Chronic Renal Failure Who Are Not on Dialysis.
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:
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.
OBJECTIVES: I. Determine the maximum tolerated dose and safety of alpha-melanocyte stimulating hormone (alpha-MSH) in patients with acute renal failure.
II. Determine the safety and pharmacokinetics of alpha-MSH in patients at high risk of acute renal failure after renal transplantation.
III. Determine the safety and pharmacokinetics of alpha-MSH in patients with established ischemic acute renal failure.
IV. Determine the effect of alpha-MSH on interleukin-10 pharmacokinetics.
PROTOCOL ENTRY CRITERIA:
Group 1: Patients on chronic hemodialysis
Group 2: Patients at high risk of developing acute renal failure (ARF) after cadaveric renal transplantation Received high risk allograft Cadaveric kidneys with greater than 24 hours of cold ischemia time Donor had rising creatinine before organ procurement Donor over 60 years
Group 3: Patients with ischemic ARF due to hypotension, surgery, or trauma ARF severity index 20-60% Creatinine clearance 12-14 mL/min Rising creatinine of at least 0.5 mg/dL per day for 2 days without evidence of recovery despite standard supportive care No drug or contrast induced renal failure No oliguric renal failure (creatinine clearance 3-4 mL/min) No prior chronic renal failure Baseline creatinine greater than 2.5 mg/dL (males) or 2.0 mg/dL (females) No ARF due to bacterial or fungal sepsis, nephrotoxins, acute tubulointerstitial nephritis, cyclosporine toxicity, bilateral renal vascular disease, or systemic diseases (hepatorenal syndrome, glomerulonephritis, renal vasculitis, etc.)
Group 1: No recent immunosuppressive therapy Group 2 and 3: No prior renal transplantation No prior alpha-MSH Group 3: No prior dialysis for this episode of ARF No anticipated need for dialysis for at least 24 hours At least 12 hours since prior diuretics, mannitol, or dopamine At least 14 days since prior immunosuppressive drugs
No recent infection No known reaction to Terumo T175 dialyzer Not a prisoner Not pregnant or nursing No allergy to drugs used in study Not mentally impaired Group 3: No severe nonrenal medical condition that would interfere with the study (e.g., terminal cancer)
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.
Hemodialysis remains associated with a high mortality (approximately 22% per year) and many complications despite improvements over the last twenty years. Several nephrologists have suggested that increasing the frequency and amount of dialysis will result in improved outcomes. In fact, various forms of daily dialysis have been performed in over 300 patients in the last 30 years with improvements in blood pressure, quality-of-life, bone disease, and other complications of renal failure. Whether this form of treatment can be expanded to the 220,000 Americans on hemodialysis is unknown. The primary outcome of this study is to determine the effectiveness of nocturnal dialysis in hemodialysis patients in St. Louis. If the pilot study is effective, then participation in a larger, multicenter trial is expected. The endpoints measured are use of antihypertensive medications, improvement in secondary hyperparathyroidism and use of phosphorus binders, quality-of-life measured by SF-36 surveys, and improvement in physical function as measured by maximal oxygen uptake.
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:
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.
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.
The purpose of this study is to determine how the progressive loss of kidney function influences cardiovascular disease.
Currently, both the incidence and prevalence of chronic kidney disease leading to end-stage renal disease (ESRD) continue to increase at an alarming rate in the United States. According to the United States Renal Data System, in 2000 there were 370,000 prevalent ESRD patients, which was expected to grow to 610,000 by the year 2010. Furthermore, the adjusted death rate for all incident ESRD patients was 19.8 per 100 patient years at risk, with cardiovascular disease accounting for more than 50 percent of mortality in this patient population. Recent analyses demonstrate that there are at least 10.9 million people in the United States with chronic kidney disease and, that for this population, there are substantially increased cardiovascular risks, prompting the Surgeon General to include chronic kidney disease as a focus area for improving the nation's health in Healthy People 2010. The metabolic derangements accompanying progressive loss of kidney function lead to unique patterns of oxidative injury specific to the uremic state. For patients with chronic kidney disease, non-traditional risk factors for cardiovascular disease such as increased oxidative stress and inflammation may be especially important.
The broad goals of this study are to develop enhanced understanding of how the progressive loss of kidney function leads to increased oxidative stress, inflammation, and accelerated development of cardiovascular disease. The long-term objective of this proposal is to develop the data critical for a subsequent large scale, multicenter, randomized, controlled trial designed to alleviate oxidative stress, reduce inflammation, and reduce cardiovascular morbidity in patients with chronic kidney disease. The aims of this study are to determine in a prospective study the extent to which oxidative stress is a risk factor for cardiovascular events in patients with chronic kidney disease and to characterize the inter-relationships between oxidative stress and inflammation. A further aim is to determine in the longitudinal study is how progressive loss of kidney function influences oxidative stress propensity to inflammation and cardiovascular disease. An additional aim is to determine the effects of antioxidant therapy on biomarkers of oxidative stress, markers of inflammation and endothelium-dependent vascular function in patients with chronic kidney disease. This study incorporates a series of observational and interventional studies measuring the extent of cardiovascular disease with extensive ex vivo measures of biomarkers of oxidative stress and inflammation in patients with chronic kidney disease. Coordination between the clinical data and the ex vivo studies will be emphasized to achieve maximal understanding of the pathophysiology of uremic cardiovascular disease.
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.
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.
The purpose of this trial is to study the use of nesiritide in thoracic aneurysm repair to prevent acute renal failure.
The study hypothesis: Nesiritide, given prophylactically prior to surgery may prevent acute renal failure requiring dialysis and/or decrease mortality.
Acute renal failure is a major and serious complication of more than 200,000 cardiovascular surgeries performed on adult Americans annually (www.sts.org). The incidence of acute renal failure (ARF) after cardiac surgery (depending on criteria used to define ARF) is 1-5%, in the absence of preexisting renal dysfunction. The subset of patients with thoracic aortic aneurysm surgery have a higher risk for the development of postoperative ARF (25-40% - ARF defined as doubling of serum creatinine; 13% - ARF defined as requirement for dialysis). This risk is further increased by various peri-operative factors, especially cardiopulmonary bypass time. The overall postoperative mortality rate for cardiovascular surgery is 2.2%, but is much higher for thoracic aortic aneurysm surgery (8-10% for elective repair, 25-50% for ruptured thoracic aorta aneurysm repair). The major risk factor for thoracic aortic aneurysm surgery related mortality is post-operative ARF requiring dialysis. When thoracic aortic aneurysm surgery is complicated by acute renal failure, the mortality rate worsens to 50%.
Thus, identifying ways to prevent acute renal failure may have a major impact on the outcome of cardiovascular surgery. A retrospective study of the use of nesiritide in cardiovascular surgery patients by our group has demonstrated a tendency towards a decreased incidence of renal failure and mortality, when the medication is used prophylactically.
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.
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.
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
Patients developing kidney failure after open heart surgery experience an abrupt decrease in blood flow to the kidney. We hypothesize that administration of fenoldopam mesylate (a drug that increases blood flow to the kidney) to patients early in the course of their disease could reduce progression to dialysis-dependent acute renal failure. We also hypothesize that restoring blood flow could induce additional injury to the kidney through the release of reactive oxygen species. Therefore, patients in this protocol will be randomized to receive a fenoldopam or the anti-oxidant MESNA. We hypothesize that combination treatment with Fenoldopam and MESNA will decrease the incidence of death or dialysis at 21 days in patients with early post-operative acute renal failure.
The combination of fenoldopam mesylate and Intravenous MESNA reduces the level of reactive oxygen species released following restoration of renal blood flow in patients with ischemic ATN. Specific Aims
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.
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.
The purpose of this study is to determine if analysis of urine samples for specific markers can predict transplant rejection in people who have received kidney transplants.
Innovations in kidney transplantation have improved short-term outcomes for transplant patients. However, organ rejection remains as an important threat to the long-term survival of the transplanted organ. An increase in the serum creatinine level is often the first clinical indicator of kidney transplant rejection; however, this marker lacks sensitivity and specificity. Rejection is currently diagnosed using an invasive transplant biopsy procedure; in addition to being expensive, transplant biopsies can result in bleeding from the transplant and even graft loss. In early studies, it has been observed that significant increases in the levels of perforin, granzyme B, and CD3 messenger RNA (mRNA) in urinary cells signal the development of acute transplant rejection. The purpose of this study is to evaluate whether the noninvasive procedure of measuring perforin, granzyme B, and CD3 mRNA levels in urine samples can accurately diagnose and predict kidney transplant rejection, make transplant biopsy unnecessary, and provide an opportunity to initiate treatment for early rejection with the aim to minimize damage to the kidney.
This study will last 3 years post-transplant. There will be a total of 14 study visits. Blood and urine collection will occur at all visits. Additional visits may be necessary for those participants who develop abnormal kidney function.
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.
The purpose of this study is to assess the use of this Lap-Band system for the purpose of promoting weight loss in renal failure patients who do not qualify as transplant candidates because of excessive BMI's
The concern of transplant surgeons is that obese patients with high BMI's are more likely to experience post-transplantation complications than age-matched recipients . Nevertheless, the Summa transplant list contains numerous patients with renal failure that have BMI's above 35. These patients are not considered to be "active" transplant candidates because of their obesity and are not eligible to receive a kidney transplant.
Dr. Lal counsels these patients that they must lose weight in order to be considered active candidates for transplantation.
Weight loss for obese patients in renal failure is difficult. These patients must undergo hemodialysis three times weekly. Most of these patients do not, or physically cannot, engage in exercise activities. Many of these patients are burdened psychologically, and further behavioral responsibilities related to weight loss may overstress them. Repetitive diets or behavioral therapy in morbidly obese patients prior to transplantation have had disappointing results . Likewise, pharmacological management of obesity in these patients is largely unsuccessful. Noradrenergic appetite suppressants must be restricted because of stimulatory side-effects. Serotonergic agents have cardiovascular and pulmonary complications. Thermogenic agents are minimally effective .
The INAMED LAPBAND SYSTEM is an FDA-approved, surgically-placed device marketed to facilitate weight reduction in obese individuals. The LAPBAND is positioned laparoscopically around the stomach and requires an overnight hospitalization and an upper GI swallow the next morning. The device can be gradually adjusted to increase stomach constriction by the physician in an office setting so that the patient loses approximately 1-2 pounds per week over two years. These adjustments are performed on average 4-5 times during the first year and twice during the second year.
The purpose of this pilot study is to assess the utility of the LAPBAND in facilitating weight loss in obese renal failure patients awaiting transplantation and to document issues related to its use in these patients. The hope is that the LAPBAND will facilitate enough weight loss to reduce the patient's BMI to 35 or below after placement of the LAPBAND. If the patient reaches the intended goal of BMI of 35, they will be placed on the active renal transplant list and will be eligible for transplantation.
A secondary goal of this research is to follow those patients who successfully reach BMI's of 35 or less who are subsequently transplanted to determine any untoward effects of the LAPBAND upon transplantation success
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.
Muscle wasting is common in advanced chronic kidney disease (CKD) and adversely affects morbidity and mortality. In 2/3 of males with advanced CKD serum testosterone (TT) levels are reduced, and likely contributes to the wasting. As TT in relatively safe physiologic replacement doses, increases muscle mass in otherwise normal TT deficient subjects, we hypothesize that physiologic TT replacement will be effective in preventing and treating the loss of muscle mass and function in CKD patients, will improve quality of life and may reduce some cardiovascular disease (CVD) risk factors.
This study investigates the relationship between autonomic dysfunction and chronic inflammation in hemodialysis patients.
Protocol REN-002-01: Comparison of a Calcium-Free Phosphate Binder (Sevelamer) with a Calcium-Containing Phosphate Binder (Calcium Acetate) in the Treatment of Hyperphosphatemia in Children with Chronic Renal Failure
Renagel® (sevelamer hydrochloride)
Studied Indications or Disease
Approved U.S. Drug Label
chronic kidney disease
Name of Sponsor/Company
Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142Geltex Pharmaceuticals, Inc., Waltham, MA 02451, (Geltex Pharmaceuticals, Inc. was acquired by Genzyme Corporation December 2000)
Investigators and Study Center(s)
This was a multicenter study conducted at 11 sites in Germany.
First patient entered: 10 October 2001Last patient completed: 22 May 2003
Phase of Development
In pediatric patients with chronic kidney disease (CKD) (whether or not receiving dialysis therapy), to compare the effects of sevelamer and calcium acetate treatment on:
Serum phosphorus levels (hyperphosphatemia)
Serum calcium-phosphorus product levels
Plasma intact parathyroid hormone (iPTH) levels, cyclase inhibiting PTH (CIP) levels, cyclase activating PTH levels and CAP/CIP ratio (hyperparathyroidism)
Incidence of hypercalcemic episodes [(serum calcium > 11 mg/dL (2.75 mmol/L)]
In pediatric patients with CKD (whether or not receiving dialysis therapy), to compare the effects of sevelamer and calcium acetate treatment on:
Uremic dyslipidemia as measured by serum total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and lipoprotein (a) [Lp(a)]
Incidence and severity of adverse events
This was a phase 4, multicenter, open-label, randomized study in pediatric subjects with chronic kidney disease on or off dialysis (hemodialysis or peritoneal dialysis). Following a two-week initial washout period, pediatric patients with CKD were exposed to two eight-week treatment periods with sevelamer or calcium acetate in a crossover fashion with a two-week washout between treatment periods.
Number of Patients (Planned and Analyzed)
No. Enrolled, Randomized, and Treated: 44/40/34No. Completed: 23
Diagnosis and Main Criteria for Inclusion
Patients included in the study were male and female pediatric patients (aged 0 to 18 years) with chronic kidney disease [glomerular filtration rate > 20 and < 60 mL/min x 1.73 m2 OR on dialysis (hemodialysis or peritoneal dialysis)] and on constant dosages of phosphate-binder and calcitriol therapy on study entry. Patients, or parents, were required to give written informed consent prior to participation in the study.
Test Product, Dose, and Mode of Administration
Sevelamer hydrochloride (Renagel®): 400 mg tabletsSevelamer hydrochloride (Renagel®): 403 mg capsulesAdministered orally with meals
Duration of Treatment
The total study duration was 20 weeks including 8 weeks of sevelamer treatment, 8 weeks of calcium acetate treatment, and 2 weeks of washout before each treatment period.
Reference Therapy, Dose and Mode of Administration
Calcium acetate (Nephracetat®): 500 mg (tablets)Administered orally with meals
CRITERIA FOR EVALUATIONEfficacy
Efficacy was assessed by evaluating:
Effects on serum phosphorus levels
Number of hypercalemic episodes [(serum calcium > 11 mg/dL (2.75 mmol/L)]
Effects on the serum calcium-phosphorus product
Effects on plasma intact parathyroid hormone (iPTH) levels, cyclase inhibiting PTH (CIP) levels, cyclase activating PTH levels and CAP/CIP ratio (hyperparathyroidism)
Doses of phosphate binders
Influence on the uremic dyslipidemia as measured by: changes in serum level of cholesterol, HDL cholesterol, LDL cholesterol, triglycerides and Lp(a)
Safety was assessed by evaluating:
The incidence of adverse events
Changes in laboratory measurements
Changes in physical examinations and vital signs
For phosphorus, hyperparathyroidism [iPTH, CIP, CAP and CAP/CIP ratio], uremic dyslipidemia [TC, LDL, HDL, TG and Lp(a)], calcium, and calcium-phosphorus product, the values at each study visit and the change from baseline to the end of study treatment were summarized by treatment both within and across treatment sequence groups. The change from baseline was analyzed by mixed effect regression models with a subject random effect and treatment, period, and treatment-by-period fixed effects. For serum phosphorus, the 90% and 95% confidence intervals for the difference in phosphorus reduction between treatment groups was calculated based on the least squares means and mean squared error derived from this model.
The number of hypercalcemic episodes was summarized by treatment group both within and across treatment sequence groups. McNemar’s paired comparison test was used to compare the incidence of hypercalcemia for the two treatments.
The difference in incidence of treatment emergent adverse events (proportion of patients with one or more events) between the treatment groups and between the treatment sequences was tested using Fisher’s Exact test. Treatment emergent adverse events were defined as adverse events that started or worsened after the first study treatment was given.
The change in safety laboratories from start to end of a treatment period were tested using Wilcoxon’s signed rank test.
SUMMARY – CONCLUSIONSDemographics and Renal History
The patients had a mean age of 12 years and consisted of 65% males and 35% females. The majority of patients were Caucasian (92%) and the three most frequent causes of ESRD were malformations (45%), hereditary disease (20%) and glomerulopathies (27%).
A statistically significant reduction in serum phosphorus was observed during the eight weeks of treatment in both the sevelamer and the Ca acetate groups and in both sequence groups. Equivalence was established relative to the pre-specified equivalence bounds on the mean treatment difference of –0.34 to 0.34 based on the 90% confidence limits.
Mean PTH levels were similar at the beginning of each treatment period (sevelamer 48.61 pmol/L; Ca acetate 40.47 pmol/L) and did not change significantly during the treatment (sevelamer -2.73 pmol/L; Ca acetate 4.26 pmol/L). The difference between sevelamer and Ca acetate was not significant. Similar results were obtained for CAP, CIP and the CAP/CIP ratio.
Mean calcium-phosphorus product decreased significantly with sevelamer [79.7 to 62.6 mg2/dL2 (6.43 to 5.05 mmol2 /L2); p=0.0007] as well as with Ca acetate [75.8 to 61.9 mg2/dL2 (6.11 to 4.99 mmol2/L2 ); p=0.0015]. The difference between the two treatment groups was not significant.
Mean total cholesterol decreased significantly with sevelamer [231.8 to 173.4 mg/dL (5.99 to 4.48 mmol/L); p=0.0171], but not with Ca acetate treatment [231.4 to 208.2mg/dL (5.98 to 5.38 mmol/L); p=0.3213]. The difference between the two treatment groups was significant. A similar pattern was shown for LDL cholesterol. For HDL cholesterol, triglycerides, and lipoprotein (a), no significant changes were observed for either treatment.
The number of hypercalcemic episodes [defined as serum calcium >11mg/dL (2.75 mmol/L)] was statistically significantly higher with Ca acetate treatment than with sevelamer treatment (5 versus 0 episodes, respectively; p=0.0005).
Sevelamer was well tolerated in this group of children with chronic kidney disease. Overall, 30 patients (93.8%) in the sevelamer group experienced 119 adverse events (AEs) and 27 patients (90.0%) in the calcium acetate group experienced 113 AEs. The adverse events most frequently reported were gastro-intestinal (21 events in 13 patients for sevelamer; 26 events in 13 patients for calcium acetate). The most frequently occurring adverse events in the sevelamer group were acidosis (11 events in 11 patients), abdominal pain (10 events in 9 patients), hyperparathyroidism (8 events in 7 patients), and headache (6 events in 6 patients). In the calcium acetate group, the most frequent adverse events were nausea (11 events in 7 patients), and rhinitis (7 events in 6 patients). One case of acidosis was also reported for the calcium acetate group.
The Investigators assessed the relationship of all AEs in relation to the use of sevelamer or calcium acetate. In the sevelamer group, 22 adverse events in 14 patients (43.8%) were considered related to the use of study medication, and 17 adverse events in 10 patients (33.3%) in the calcium acetate group were considered related to the use of study medication. The most frequently reported adverse events with a relationship to study drug were: acidosis, aggravation of secondary hyperthyroidism, and nausea in the sevelamer group; and hypercalcemia in the calcium acetate group.
A total of 19 patients experienced 27 serious treatment emergent adverse events during the study. Eight patients (25.0%) experienced 10 serious adverse events during sevelamer treatment and 11 patients (36.6%) experienced 17 serious adverse events during calcium acetate treatment. The serious adverse events were mostly mild to moderate in intensity. All serious adverse events, except two, were considered not or remotely related to study treatment. The serious adverse event ‘acidosis’ was considered definitely related to sevelamer treatment and the serious adverse event ‘hypertension’ was considered possibly related to calcium acetate treatment. All patients recovered from the serious adverse events without sequelae.
In the sevelamer group, there was a statistically significant decrease from baseline in serum copper. This decrease was within the normal range and thus not considered clinically significant. Other laboratory assessments showed statistically significant changes in the treatment groups between the start and end of the treatment period. However, none of these assessments showed shifts from normal to clinically significant abnormal.
Laboratory values, physical exams and vital signs: There were no clinically significant changes in safety laboratory parameters. Furthermore, there were no clinically significant changes in vital signs or physical exam abnormalities.
Sevelamer and Ca acetate were equally effective in controlling serum phosphorus levels as well as the calcium phosphorus product. Both binders had no effect on PTH levels. In addition, sevelamer significantly reduced serum LDL cholesterol and serum total cholesterol. Sevelamer and Ca acetate were equally safe and well tolerated when used in children with CKD to reduce their hyperphosphatemia. Acidosis was more frequent and more often drug-related with sevelamer while hypercalcaemia [defined as serum calcium >11mg/dL (2.75 mmol/L)] was more frequent and more often drug-related with Ca acetate.
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
Therapeutic Area and FDA Approved Indications:
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.
NAME OF SPONSOR/COMPANY:
Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142Bone Care International, Inc., Middleton, WI 53652 (Bone Care was acquired by Genzyme Corporation July 2005)
TITLE OF STUDY:
INVESTIGATORS AND STUDY CENTER(S):
This was a multicenter study conducted at three locations in the United States.
First patient enrolled: 03 November 1997Last patient completed: 09 January 2000
PHASE OF DEVELOPMENT:
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)).
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 capsulesThe 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.
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 2002Synopsis prepared on: 10 November 2006