Diabetes Clinical Trial
Official title:
A Prospective, Randomized, Probe Trial to Evaluate Whether,at Comparable Blood Pressure Control,Combined Therapy With ACEI BEN and ARB VAL Reduces Progression to ESRD More Effectively Than BEN or VAL Alone in High Risk Patients With Type 2 Diabetes and Overt Nephropathy
Nephropathy of type 2 diabetes is the leading cause of end stage renal disease (ESRD)
world-wide and is associated with a dramatic excess cardiovascular morbidity and mortality.
Two randomized trials found that angiotensin II receptor blockers (ARBs) reduce the
incidence of ESRD by about 30%, but have no appreciable effects on cardiovascular mortality.
Available data suggest that ACE inhibitors might be similarly renoprotective and even more
cardioprotective, but large scale trials on ACE inhibitors, alone or combined with ARBs, in
overt nephropathy of type 2 diabetes are missing.
This study will compare the effects, at comparable blood pressure control
(systolic/diastolic <130/80 mmHg), of dual renin-angiotensin-system (RAS) blockade by half
dose of benazepril and valsartan combination therapy as compared to single RAS blockade by
benazepril or valsartan alone at full dose, 20 mg and 160 mg respectively, on ESRD and
cardiovascular events in high-risk patients with type 2 diabetes and overt nephropathy,
defined as serum creatinine >1.8 mg/dl and < 3.2 mg/dl and spot morning urine albumin to
creatinine ratio >1000mg/g for the patients without previous ACE inhibitor and ARB therapy
and >500mg/g for the patients with previous ACE inhibitor or ARB therapy and no specific
contraindications to the study drugs. The relationships between renal and cardiovascular
outcomes will also be evaluated.
102 patients will be treated for at least 3 years. At comparable blood pressure control, the
study is expected to show a more effective reduction in ESRD and cardiovascular events with
combined than with single drug ACE inhibitor or ARB therapy. As compared to ARB, ACE
inhibitor therapy is expected to have a similar effect on ESRD, but a superior
cardioprotective effect. Applied to clinical practice, the findings should help reducing
renal and cardiovascular complications, and related treatment costs, of type 2 diabetes.
Introduction Nephropathy of type 2 diabetes is the leading cause of end stage renal disease
(ESRD). Currently, more than 50% of patients on renal replacement therapy in the US are
diabetics. The yearly incidence of diabetics progressing to ESRD and the proportion of ESRD
patients with diabetes is progressively increasing due to the progressively increasing
prevalence of type 2 diabetes worldwide.
Two large, multinational trials in overt nephropathy of type 2 diabetes found that
interruption of the renin angiotensin system (RAS) with angiotensin II receptor blockers
(ARBs) reduces the incidence of ESRD by about 30%, but has no appreciable effects on
cardiovascular mortality. On the basis of these findings, ARB therapy has become standard
treatment of patients with type 2 diabetes and nephropathy. However, despite ARB treatment,
about 7% of patients continue to progress to ESRD and 7% continue to die every year.
Large-scale randomized trials evaluating the nephro- and cardio-protective effects of RAS
inhibition with angiotensin-converting enzyme (ACE) inhibitors in overt nephropathy of type
2 diabetes are missing. However, studies in patients with type 1 diabetic nephropathy showed
that ACE inhibitor therapy may decrease progression to ESRD by 40% and cardiovascular
mortality by about 50%. Similar studies in non diabetic chronic nephropathies. consistently
found a 40-50% reduction in the risk of progression to ESRD with ACE inhibitors as compared
to non-RAS inhibitor therapy. Moreover, a meta-analysis of studies including type 2 diabetic
patients with different degree of renal involvement showed that ACE inhibitors and ARBs
sheared a similar renoprotective effect, but only ACE inhibitors significantly decreased the
cardiovascular mortality.
A recent trial in non diabetic nephropathies found that combined RAS inhibition with ARBs
and ACE inhibitors decreases progression to ESRD by 50% as compared to ARB or ACE inhibition
alone. Evidence that combined therapy more effectively than ACE inhibitor or ARB therapy
alone reduces albuminuria or proteinuria in patients with type 2 diabetes, suggests that a
similar renoprotective effect could be achieved also in overt nephropathy of type 2
diabetes. Indeed, short-term proteinuria reduction is a strong predictor of slower
progression of renal disease and reduced cardiovascular mortality in the long term.
A randomized trial powered to detect a reduced incidence of ESRD or cardiovascular mortality
with combined ARB and ACE inhibition as compared to ACE inhibition or ARB alone would
require several thousands of patients. However, identifying high risk patients who may
benefit the most of nephro- and cardio-protective therapy would allow to design an
adequately powered trial with remarkably less patients. By using a Bayesian decision-tree
analysis we identified, among patients included in the RENAAL study, a subgroup of high risk
patients with a baseline serum creatinine of 1.8 mg/dl or more and spot morning urine
albumin to creatinine ratio >1000mg/g or more. Of note, over 3.5 year follow-up, 70% of
these high-risk patients progressed to ESRD despite ARB therapy. Thus, the incidence of ESRD
was three-fold higher in high-risk patients (20%) than in the whole study group (6.8%). High
risk patients with these clinical characteristics are therefore the ideal target for
randomized clinical trials aimed to evaluate the effect of novel nephro- and, possibly,
cardio-protective treatments in overt nephropathy of type 2 diabetes.
Thus, whether dual more than single drug RAS blockade reduces the need for renal replacement
therapy in high risk patients with type 2 diabetes and whether ACE inhibitors shear with
ARBs a similar or even superior beneficial effect in this typology of patients is worth
investigating. This could be of clinical relevance in these terms: 1. Effective prevention
of ESRD in people with type 2 diabetes is expected to translate in a remarkable reduction in
costs for renal replacement therapy by chronic dialysis or kidney transplantation; 2. A
better definition of the cost/effectiveness profile of different study treatments may help
optimizing the allocation of available resources in order to achieve more effective
prevention at lower costs. 3. The definition of individual risk profiles may allows
identifying subjects at increased risk that may benefit the most of intensified treatment,
which should translate in a further optimization of the use of available resources at
population level. Moreover, in addition to verify whether dual RAS blockade by combined ACE
inhibitor and ARB treatment more effectively than single drug RAS blockade may prevent
progression to ESRD, the present study will offer the opportunity to compare the
renoprotective effects of equivalent doses of ACE inhibitors or ARBs.
Aims Primary To evaluate whether, at comparable blood pressure control, dual RAS blockade
with combined therapy with halved doses of benazepril (10 mg/day) and valsartan (160 mg/day)
reduces the incidence of ESRD more effectively than single drug RAS blockade by full doses
of valsartan (320 mg/day) given alone in high-risk patients with type 2 diabetes and overt
nephropathy.
Secondary
- To evaluate whether, at comparable blood pressure control, dual RAS blockade with
combined therapy with halved doses of benazepril (10 mg/day) and valsartan (160 mg/day)
reduces the incidence of ESRD more effectively than single drug RAS blockade by full
doses of benazepril (20 mg/day) given alone in high-risk patients with type 2 diabetes
and overt nephropathy.
- To evaluate whether, at comparable blood pressure control, the effects of benazepril
and valsartan therapy are similar or whether, alternatively, one of the two treatments
offers a superior protective effect against the progression to ESRD in the above study
population.
- To evaluate the effects of the three study treatments on the incidence of fatal and
non-fatal cardiovascular events, doubling of baseline serum creatinine, GFR decline and
proteinuria,
- To assess the relationships, in the study group as a whole and within each treatment
group, between renal outcome variables (ESRD, doubling serum creatinine, GFR decline,
proteinuria) and fatal and non-fatal cardiovascular events, between achieved blood
pressure or metabolic control and renal and/or cardiovascular outcome variables and
between achieved proteinuria reduction or residual follow-up proteinuria and renal
and/or cardiovascular outcome variables.
Design This will be a multicenter, Prospective, Randomized, Open label, Blinded End point
(PROBE) trial of 3-year treatment with halved doses of benazepril (10 mg/day) and valsartan
(160 mg/day) given in combination, or full doses of both benazepril (20 mg/day), or
valsartan (320 mg/day) given alone in 102 consenting patients >40 year old, with type 2
diabetes (WHO criteria), serum creatinine >1.8 mg/dl and < 3.5 mg/dl, spot morning urine
albumin to creatinine ratio >1000mg/g for the patients without previous ACE inhibitor and
ARB therapy and >500mg/g for the patients with previous ACE inhibitor or ARB therapy and no
specific contraindications to the study drugs. Primary efficacy variable will be ESRD and
primary comparison will be between the benazepril plus valsartan and valsartan alone groups.
The analysis will have an 80% power to detect (p=0.05, two-side test) a 50% difference in
ESRD incidence.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT05594446 -
Morphometric Study of the Legs and Feet of Diabetic Patients in Order to Collect Data Intended to be Used to Measure by Dynamometry the Pressures Exerted by Several Medical Compression Socks at the Level of the Forefoot
|
||
Completed |
NCT03975309 -
DHS MIND Metabolomics
|
||
Completed |
NCT01855399 -
Technologically Enhanced Coaching: A Program to Improve Diabetes Outcomes
|
N/A | |
Completed |
NCT01819129 -
Efficacy and Safety of FIAsp Compared to Insulin Aspart in Combination With Insulin Glargine and Metformin in Adults With Type 2 Diabetes
|
Phase 3 | |
Recruiting |
NCT04984226 -
Sodium Bicarbonate and Mitochondrial Energetics in Persons With CKD
|
Phase 2 | |
Recruiting |
NCT05007990 -
Caregiving Networks Across Disease Context and the Life Course
|
||
Active, not recruiting |
NCT04420936 -
Pragmatic Research in Healthcare Settings to Improve Diabetes and Obesity Prevention and Care for Our Program
|
N/A | |
Recruiting |
NCT03549559 -
Imaging Histone Deacetylase in the Heart
|
N/A | |
Completed |
NCT04903496 -
Clinical Characteristics and Disease Burden of Diabetic Patients Based on Tianjin Regional Database
|
||
Completed |
NCT01437592 -
Investigating the Pharmacokinetic Properties of NN1250 in Healthy Chinese Subjects
|
Phase 1 | |
Completed |
NCT01696266 -
An International Survey on Hypoglycaemia Among Insulin-treated Patients With Diabetes
|
||
Completed |
NCT04082585 -
Total Health Improvement Program Research Project
|
||
Completed |
NCT03390179 -
Hyperglycemic Response and Steroid Administration After Surgery (DexGlySurgery)
|
||
Not yet recruiting |
NCT05029804 -
Effect of Walking Exercise Training on Adherence to Disease Management and Metabolic Control in Diabetes
|
N/A | |
Recruiting |
NCT05294822 -
Autologous Regenerative Islet Transplantation for Insulin-dependent Diabetes
|
N/A | |
Completed |
NCT04427982 -
Dance and Diabetes/Prediabetes Self-Management
|
N/A | |
Completed |
NCT02356848 -
STEP UP to Avert Amputation in Diabetes
|
N/A | |
Completed |
NCT03292185 -
A Trial to Investigate the Single Dose Pharmacokinetics of Insulin Degludec/Liraglutide Compared With Insulin Degludec and Liraglutide in Healthy Chinese Subjects
|
Phase 1 | |
Active, not recruiting |
NCT05477368 -
Examining the Feasibility of Prolonged Ketone Supplement Drink Consumption in Adults With Type 2 Diabetes
|
N/A | |
Completed |
NCT04496401 -
PK Study in Diabetic Transplant récipients : From Twice-daily Tacrolimus to Once-daily Extended-release Tacrolimus
|
Phase 4 |