Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT00502268 |
| Other study ID # |
SBPTH-CC1 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
February 2008 |
| Est. completion date |
July 2009 |
Study information
| Verified date |
December 2020 |
| Source |
Southeast Renal Research Institute |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Arterial calcification within the coronaries and other vessels is greatly accelerated among
patients with chronic or end-stage kidney disease. The mechanisms leading to increased
calcification are unknown, but include hyperphosphatemia, hyperparathyroidism and altered
vitamin D metabolism. Moreover, recent data demonstrates that circulating carboxy fragments
of PTH (7-84) are physiologic antagonists of intact PTH (1-84) and may directly contribute to
vascular calcification. Current PTH assays no not distinguish between intact and carboxy PTH
fragments leading to an overestimation of intact PTH levels. Because second generation PTH
assays detect both 1-84 and 7-84 PTH fragments, the use of vitamin D analogues to treat
secondary hyperparathyroidism could lead to excessive suppression of 1-84 and a preponderance
of carboxy PTH fragments. Moreover, increased administration of vitamin D analogues amy
contribute to vascular calcifications. To investigate these questions, we plan to investigate
the effect of managing new ESRD patients using conventional and third generation PTH assays
on vitamin D administration and the development of coronary calcification. Hypothesis #1:
Clinical management of secondary hyperparathyroidism in new hemodialysis patients using the
Scantibodies 1-84/7-84 PTH ratio for one year will reduce the amount of Vitamin D
administration resulting in reduced coronary calcification compared to patients in which PTH
management is accomplished by conventional, second generation PTH assay.
Description:
Patients with chronic renal failure are at increased risk for vascular calcification and
cardiovascular complications. For example, data from the USRDS database demonstrates that 42%
of all deaths among chronic dialysis patients are cardiovascular in origin with 22% of those
deaths due to arrhythmias or overt acute myocardial infarction. While numerous factors
including hypertension, hyperlipidemia and diabetes contribute to both renal failure and
coronary disease, recent studies find that patients with CKD experience an accelerated rate
of coronary calcification. Medial calcification reduces compliance of medium to large elastic
arteries such as the aorta and common carotids. The resulting loss of elasticity is thought
to contribute to the high prevalence of systolic hypertension and left ventricular
hypertrophy (LVH) among patients with ESRD 15.
The type of vascular calcification associated with diabetes and ESRD is histologically
distinct from that found in atherosclerotic plaques. In patients with CKD or diabetes calcium
deposits are concentric and uniformly distributed within the medial layer of the vessel wall.
The deposition of calcium does not require the presence of atherosclerotic lesions and occurs
in the absence of intimal hyperplasia. Infiltration of the adventia by T cells and activated
macrophages leads to expression of bone morphogenetic protein 2 (BMP-2) and osteopontin (OPN)
by pericytic myofibroblasts. In diabetics, BMP-2 expression is enhanced by the simultaneous
upregulation of two BMP-2 associated transcription factors Msx1 and Msx2 3. The resulting
transcription of BMP-2 genes leads to mineralization of non-endochondrial matrix. The
expression of OPN is a consistent feature of medial calcification 4. Osteopontin or "bone
bridge" is a highly phosphorylated glycoprotein that binds calcium and integrin receptors.
The expression of osteopontin can be stimulated by vitamin D and increased circulating levels
of phosphate.
Moreover, physiologic concentrations of 1, 25, dihydroxyvitamin D increases calcium
deposition in cultured vascular smooth muscle cells and is associated with reduced expression
of PTH related peptide (1-34 PTH) suggesting that amino PTH fragments are not only involved
in regulating bone turnover, but also function to prevent dystrophic vascular calcification.
Indeed, these observations raise the question of whether carboxy PTH fragments can accelerate
vascular calcification.
Because second generation PTH assays detect both 1-84 and 7-84 PTH fragments, the use of
vitamin D analogues to treat secondary hyperparathyroidism could lead to excessive
suppression of 1-84 and a preponderance of carboxy PTH fragments. As observed by Jono et.al
accumulation of 7-84 could contribute to excessive vascular calcification. We hypothesize
that limiting the accumulation of 7-84 PTH fragments by maintaining a 1-84/7-84 ratio above
1.6 will reduce the amount of vitamin D analogues administered and ultimately reduce the
development of coronary calcification. To investigate this hypothesis, we propose to
prospectively treat 50 patients with 1, 25 dihydroxyvitamin D2 where doses are determined by
maintaining a 1-84/7-84 ration > 1.6 or by maintaining intact PTH levels between 150-350
pg/ml using existing second generation PTH assays.
4.0 Hypothesis & Objectives
4.1 Hypothesis #1: Clinical management of secondary hyperparathyroidism in new hemodialysis
patients using the Scantibodies 1-84/7-84 PTH ratio for one year will reduce the amount of
Vitamin D administration resulting in reduced coronary calcification compared to patients in
which PTH management is accomplished by conventional, second generation PTH assay.
4.1a Specific Aim #1 Specific Aim #1 will compare the amount of coronary calcification and
the percentage of patients with at least one coronary lesion > 50% luminal obstruction at
baseline and after one-year therapy following randomization to one of two treatment groups.
[Group 1] Patients randomized to group 1 will have the administration of 1alpha OH vitamin D2
(Hectorol) targeted to achieve serum PTH levels between 150-300 ng/ml using a Bayer Centaur
iPTH assay.
[Group 2] Patients randomized to group 2 will have the administration of vitamin D analogues
targeted to achieve a ratio of 1-84/7-84 PTH fragments between ranges of 1.4-1.6 using the
Scantibodies IRMA PTH assay. (Hectorol).
Rationale: Coronary calcification is a frequent complication of end stage renal disease
(ESRD) with recent estimates of up to 80% of chronic hemodialysis patients exhibiting
moderate to severe vascular calcification 1. Numerous clinical factors have been associated
with the development of arterial calcification including hyperphosphatemia 2, diabetes
mellitus 3 and calcium containing phosphate binders 4. More recently, the increased use of
vitamin D analogues to treat secondary hyperparathyroidism has been implicated as a major
contributor to vascular calcification among ESRD patients.
These clinical practices are complicated by the observation that carboxy fragments of PTH
(e.g. 7-84) cross react with second generation PTH assays. Because carboxy PTH fragments are
either inert or antagonize functional bio-intact PTH (1-84), clinicians have used excessive
doses of vitamin D analogues to regulate PTH levels. Moreover, there are animal model studies
that suggest that carboxy PTH fragments directly contribute to vascular calcification 16.We
propose that clinical decision making using the incomplete information provided the currently
available second generation PTH assays leads to excessive vitamin D administration and
subsequent acceleration of coronary calcification.
Anticipated Results: We anticipate that prolonged (1 year) management of PTH levels using a
second generation of PTH assays will lead to an increase in the total administered dose of
vitamin D analogues. Moreover, this increase in vitamin D administration will result in
increased coronary calcification at the end of one year of therapy. Conversely, maintaining a
1-84/7-84 PTH ratio between 1.4-1.6 using the Scantibodies third generation assay will reduce
the amount of administered vitamin D analogues and subsequently reduce the amount of coronary
calcification at one year.
