Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00498537 |
| Other study ID # |
0024 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
July 6, 2007 |
| Last updated |
October 16, 2008 |
| Start date |
January 2003 |
| Est. completion date |
June 2006 |
Study information
| Verified date |
May 2008 |
| Source |
VA Office of Research and Development |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Federal Government |
| Study type |
Interventional
|
Clinical Trial Summary
Introduction: Aldosterone seems to have deleterious effects on the kidneys. Many animal
studies and few clinical trials now have shown that suppression of aldosterone by
aldosterone receptor blockers ameliorated these effects.
Method: In a double-blind, cross over study, 24 patients with diabetic nephropathy who were
already receiving either ACE inhibitor(lisinopril 20-40 mg/day ) or ARB( losartan 25-100
mg/day )were given spironolactone( 25 mg during the first month and 50 mg during the second
and third month if serum K remained ok) or matching placebo with 1 month of washout in
between. All patients were from a single center and exclusively male veterans. Blood
pressure, serum creatinine, serum K and spot urine protein/creatinine were measured at the
beginning and end of each study period. The study was started in May of 2003 and completed
in May 2006.
Description:
Spironolactone for reducing proteinuria and progression of renal failure in diabetic
nephropathy
Introduction:
Diabetic nephropathy is the leading cause of ESRD in USA now and accounts for 40% of all new
patients that begins renal replacement therapy each year. The number of new patients
starting chronic dialysis therapy is 70,000 each year and is increasing. This number does
not include patients who decline dialysis therapy or die soon after starting dialysis. The
economic and human cost of diabetic nephropathy is therefore enormous.
Aggressive control of blood pressure especially with ACE-inhibitor had been shown to reduce
proteinuria and progression of renal dysfunction in both type 1 and type 2 diabetics. Use of
ACE-inhibitor reduced proteinuria even in normotensive diabetics with microalbuminuria.
However even with optimal use of ACE-Inhibitor the progression of renal dysfunction is not
completely stopped. Other additional treatment strategies therefore need to be explored.
Studies in animals and small pilot studies in humans have shown that nondihydropyridine
calcium channel blockers (e.g. diltiazem or verapamil) may have additional protective effect
in reducing proteinuria when used in conjunction with ACE-inhibitor. Use of angiotensin
receptor blockers along with ACE-inhibitors also had been tried but results are not
dependable because of the short sample size.
While angiotensin plays the major role in glomerular hemodynamics there is increasing
evidence that aldosterone plays a significant role in renal hemodynamics independent of
angiotensin. In a remnant kidney model in the rat Greene et al showed that there was greater
than 10-fold rise in aldosterone in the remnant kidney rats (REM) compared to SHAM operated
ones. As expected, the proteinuria, hypertension and glomerulosclerosis in the REM rats were
attenuated with treatment with ACE-inhibitor and angiotensin receptor blockers (REM AIIA).
However when these rats (REM AIIA) were treated with aldosterone infusion the proteinuria,
hypertension and glomerulosclerosis seen were similar to REM alone rats, suggesting
deleterious renal hemodynamic effects of aldosterone independent of angiotensin II. Use of
spironolactone in these rats transiently reduced proteinuria and lowered arterial pressure.
Previous experiment in remnant kidney model also showed that adrenalectomy with adequate
glucocorticoid replacement reduced the proteinuria and other evidence of renal injury
usually seen in REM rats. Similarly heparin administration provides remarkably complete
protection from injury in remnant kidney model. Although this effect could be due to any of
several actions of heparin (anticoagulant and hemodynamic), it could be due to known
suppressive action of heparin on aldosterone synthesis.
In stroke-prone spontaneously hypertensive rats (SHRSP), renal vascular injury causing
proteinuria and malignant nephrosclerotic lesions were markedly reduced by treatment with
spironolactone, an aldosterone receptor blocker. The effect of spironolactone alone was
comparable to effect of treatment with captopril, an ACE-inhibitor. In further studies Rocha
et al had shown that the ameliorating effect of ACE-inhibition in the SHRSP rats could be
fully reversed by infusion of aldosterone, suggesting a major role for aldosterone in the
vascular injury in these rats as well. Importantly the deleterious effect of aldosterone and
the protective effect of spironolactone against end organ damage in SHRSP rats appeared to
be independent of the blood pressure effects.
In another experiment, the Wistar-Furth rat, an inbred strain resistant to actions of
mineralocorticoids, was used to study the concept that mineralocorticoids contribute to
progressive renal injury. Renal damage, as evidenced by albuminuria and glomerulosclerosis,
in response to 5/6 nephrectomy was markedly less in Wistar-Furth rats compared to Wistar
rats. Treatment of hypertension seen in the nephrectomized Wistar rats did not protect them
from renal injury suggesting again that mineralocorticoid mediated deleterious effect was
independent of the blood pressure effect.
Hyperaldosteronism has been noted as a component of clinical chronic renal insufficiency of
various etiologies. In a cross sectional study of patients with mild to moderate renal
insufficiency Hene et al observed that level of serum aldosterone increased as creatinine
clearance fell below 70 cc/min and went up as high as 3-4 fold the baseline. Similarly in a
study of 9 patients with average inulin clearance of 27cc/min, Bauer and Reams noted plasma
aldosterone level to be four fold greater than normal. The significance of this
Hyperaldosteronism as to the progression of the renal insufficiency had not been studied
systematically, but in one longitudinal study Walker noted a significant correlation between
aldosterone level and rate of progression of renal failure. In this longitudinal study of
131 diabetic cohort, Walker noted that hypertension, plasma angiotensin II and aldosterone
were independent predictors of accelerated loss of renal function.
Although the distal tubule is considered the target for aldosterone action, aldosterone
receptors had been found in myocardium, vascular smooth muscle cells and glomeruli .In vitro
studies of cultured mesangial cells revealed increased production of type IV collagen after
incubation with aldosterone. In a double blind controlled study MacFadyen and colleagues
observed that spironolactone treatment reduced circulating levels of procollagen type III
N-terminal amino peptide, a marker of vascular collagen turnover. Weber and other
investigators have observed that aldosterone caused myocardial fibrosis and this effect
could be ameliorated by treatment with spironolactone. In addition to the classical genomic
action through the type 1 mineralocorticoid receptor, aldosterone is now known to have
significant non-genomic mediated action in many different tissues including kidney tubules
and vascular smooth muscle cells. Aldosterone also up regulates Angiotensin II membrane
receptors thereby multiplying the vascular effect of Ang II. This upregulation was inhibited
by treatment with spironolactone. These findings are consistent with a synergistic action
between Ang II and aldosterone in the production of vascular injury as first proposed by
Masson et al almost 4 decades ago.
The use of ACE inhibitors may strongly inhibit the RAAS, but their suppressive effect on
aldosterone production may not be satisfactory. Indeed, in hypertension as well as in CHF,
continuous treatment with ACE inhibitor did not produce a sufficient decrease in plasma
aldosterone level, which remained high or increases eventually during long term use. In one
study, patients treated with hefty doses of captopril (300 mg/day) had a doubling of the
plasma aldosterone level at the end of 12 months of therapy despite marked decrease in ANG
II level. The reasons for the unsatisfactory suppressive effect of ACE inhibitors on plasma
aldosterone could be partly due to tachyphylaxis and also very likely due to predominance of
the non-RAAS component of the control system for aldosterone production. Urinary clearance
of aldosterone may also be reduced in CHF and CRF. On the basis of these understandings,
spironolactone (25-50 mg a day) was used in a large multi-centered randomized controlled
trial for treatment of congestive heart failure who already were receiving standard therapy
with Ace inhibitors, diuretics and digoxin. The study was terminated in midway because
interim analysis showed 30% reduction in mortality in the spironolactone treated group as
opposed to the control. Of note, the incidence of hyperkalemia in the treatment group was
only 1.7% as opposed to 1% in the placebo group. The incidence of gynecomastia was also
modest (10% Vs 1%) in spite of use of other drugs like digoxin that are known also to cause
gynecomastia.
Planned Study:
For this study we will recruit patients from the renal clinic at the VA medical center and
also some patients from the primary care clinics at the same hospital. The study will be a
double blind control study using each patient as his own control after a period of wash out
phase.
Inclusion criteria
Patients with diabetic nephropathy (with proteinuria exceeding 100 mg per day while on ace
inhibitor ) who are already being treated with ACE-Inhibitor at maximum tolerated dose. For
lisinopril this dose usually will be 20-40 mg per day. Patients who are on angiotensin
receptor blocker ( ARB ) due to inability to tolerate ace inhibitor ( e.g. due to cough )
will be also considered for the study provided they stay on the same ARB at same dose
throughout the study period.
Exclusion criteria:
Serum creatinine greater than 2.0 mg/dl Serum K greater than 5.0 meq/L Patients who need to
use spironolactone for some other reasons Life expectancy less than 1 year For this pilot
phase of the study we will investigate 30 patients (see attached sample size calculation)
equally divided into control and treatment groups. Patients will be randomly allocated to
the different groups by using computer generated randomization sequence. After 3 months on
study medication (or placebo) the study group of patients will be switched to the placebo
group and vice versa. Thus each patient will be his own control. There will be a month of
wash out period in between this change over.
Study drug:
Study drug will be spironolactone. The starting dose will be 25 mg orally every day, which
will be increased to 50 mg every day, if tolerated after 4 weeks. A matching placebo will be
used for the placebo group. The VA pharmacy will prepare and provide the study drug as well
as the placebo. The pharmacy will create and maintain the randomization numbers in a safe
place so that the investigators and the study nurses remain blind to the whole randomization
process all throughout the study period.
Protocol of lab studies and follow up:
All patients will be seen by one of the investigator and have a brief history and physical
examination prior to randomization. All patients will have their blood pressured measured by
a study nurse in a sitting position (average of two BP readings taken at 5 minutes interval
will be recorded). Patients will be weighed at each visit also.
The study related visits would be prior to randomization, day of randomization, at 1 month
and at 3 month in study.
The cycle will be repeated again for each patient after one month washout period after which
their study drug will be reversed (placebo to study and study to placebo)
All patients will have the following lab studies at the beginning (prior to randomization),
at 1 month and at 3 month clinic visits:
Renal panel 24 hours urine for protein and creatinine Renal panel can be done in between the
prescribed study visits for clinical reasons.
All patients will be continued on their other usual medication during the study period and
changes will be made as deemed necessary by the clinicians taking care of patients. As far
as possible the dose of ace inhibitor (or angiotensin receptor blocker) will be kept the
same as at the beginning of randomization. Doses of calcium channel blocker (if they are on
it) will also not be changed as much as possible during the study.
