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Sonar trial
1. The Study Of Diabetic
Nephropathy With AtraSentan
(SONAR Trial)
Prem Mohan Jha
10/29/2019 1
2. Published in THE LANCET Journal,
VOLUME 393, ISSUE 10184, P1937-1947,
MAY 11, 2019
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3. INDTRODUCTION
• Endothelin receptor antagonists reduces albuminuria
and blood pressure, like ACEi & ARBs.
• But it also causes sodium retention, which may leads
to increased risk of heart failure in patients with
chronic kidney disease and diabetes.
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4. INDTRODUCTION
• A previous trial (ASCEND Trial, published in 2012) using
Avosentan, a non-selective endothelin receptor antagonist, in
patients with diabetes and chronic kidney disease, was
Stopped Prematurely because of an increased incidence of
heart failure.
• ATRASENTAN is a selective Endothelin-A receptor Antagonist.
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8. STUDY DESIGN
Double - Blind
Randomised
Placebo-controlled Trial
Done in 689 sites
41 countries.
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9. INCLUSION CRITERIAS
1. Adults aged between 18-85 years with T2DM
2. eGFR of 25-75 ml/min/1.73m2 of BSA
3. UACR of 300-5000 mg/gm
4. Serum albumin of at least 2.5 mg/dl
5. BNP concentration of <200 pg/ml
6. Serum potassium of 3.5-5.0 mg/dl
7. SBP of 110-180 mmHg
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10. INCLUSION CRITERIAS
8. Treatment with a stable, recommended (or
maximally tolerated) dose of an ACEI or ARB was
required for at least 4 weeks before entry into the
enrichment period.
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11. EXCLUSION CRITERIAS
1. A diagnosed case of or previous hospitalization for heart
failure
2. H/o severe peripheral or facial edema
3. T1DM
4. H/o Pulmonary hypertension, pulmonary fibrosis, or any
lung disease requiring oxygen therapy
5. Non-diabetic kidney disease
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12. PROCEDURE
The eligible patients enterered a 4 week run in period followed by
6-weeks of Enrichment period, during which they received open-
label treatment with Atrasentan at dose of 0.75mg/day.
The Enrichment period was used To Identify Atrasentan
Responders.
Defined as patients with at least a 30% reduction in UACR, who did not
have substantial fluid retention, and did not have an increase in
s.creatinine of >0.5 mg/dl or >20% from baseline.
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13. PROCEDURE
• After 6 weeks, all responders who continued to meet eligible
criteria were Randomly assigned to continue atrasentan 0.75mg
daily or switch to placebo.
• After randomisation, in-person study visits were done after 1
month and 3 months, then every 3 months thereafter.
• And a last follow-up visit was done 45 days after the last dose of
study drug to assess effects and adverse effects of drug.
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17. PRIMARY OUTCOMES
• Efficacy of atrasentan in delaying the
progression of CKD, defined as the time from
randomization to the first occurrence of any of
the following components of a composite:
– Doubling of serum creatinine
– Onset of end stage renal disease (eGFR < 15
ml/min, chronic dialysis,renal transplantation)
– Death from kidney failure.
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18. SECONDARY OUTCOMES
• Time to at least 50% eGFR reduction.
• Time to Cardio-renal Composite Endpoint consisted of
– Doubling of serum creatinine,
– ESRD
– CV death (including CV death and presumed CV death)
– Nonfatal myocardial infarction (MI; heart attack)
– Nonfatal stroke.
• Time to First Occurrence of a Component of Composite Renal
Endpoint for All Randomized Participants (responders and non-
responders combined) renal endpoint in all randomly assigned
patients.
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19. RESULTS
• Between May 17, 2013, and July 13, 2017, 11,087 patients
were screened; 5117 entered the enrichment period, and
4711 completed the enrichment period.
• Of these, 2648 patients were responders and were randomly
assigned to the atrasentan group (n=1325) or placebo group
(n=1323).
• Responders who entered the double-blind treatment period
were followed up for a median period of 2.2 years.
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20. BASELINE CHARACTERISTICS
Remarkably, 75% of them were men, with about a third being Asian but
only 5% being black.
Mean duration of diabetes was about 16 years, and
a third of them had retinopathy.
The mean blood pressure was not bad (~ 136/75) and
ARBs:ACEi were used in a 2:1 ratio overall.
Mean GFR was ~ 45 and the median ACR was 800 mg/g.
During follow-up, 260 (19.6%) of 1325 patients in the atrasentan group and 251
(19.0%) of 1323 in the placebo group discontinued treatment prematurely.
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30. 10/29/2019 30
ATRACENTAN PLACEBO P VALUE
Rates Of Hospital
Admission For
Heart Failure
3.5% 2.6% 0.208
Death 4.4% 3.9% 0.650
ATRASENTAN PLACEBO P VALUE
Mean Rate Of
Change In eGFR
-2.4 ml/min/1.73
m2 per year
-3.1 ml/min/1.73
m2 per year
0.00049
31. Adverse Events During Trial Period
• Significantly more frequently among people treated with
atrasentan versus placebo (36.3 vs 32.6%), as did the
treatment-emergent adverse events of fluid retention (36.6 vs
32.3%) and anemia (18.5 vs 10.3%).
• The higher adverse events with atrasentan occurred despite
selection of patients at low risk of these outcomes (eg low
BNP) and the ‘enrichment’ period which screened out
patients who had immediate adverse events.
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33. DISCUSSION
• Guidelines recommended use of ACEi and ARBs as well as
optimised BP and glycemic control to minimise renal risk
in patients with T2DM & albuminuria.
• However, Increased expression of Endothelin-1 has also
been implicated in progressive loss of renal function
these patients.
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34. DISCUSSION
• Increase in renal endothelin-1 in DKD is stimulated by
multiple factors, like acidosis, angiotensin-2,
dyslipidemia, hypoxia, growth factors, inflammatory
cytokines, oxidative stress, insulin and hyperglycemia.
• In turn, endothelin-1 exerts multiple patho-physiological
effects, including injury to vasculature (enhanced vaso-
reactivity and pro-coagulation), podocytes (nephron
shedding, cytoskeletal dysruption and proteinuria),
tubulointerstitial fibrosis, mesangial proliferation and
maxtrix expansion, as well as promoting inflamatory cell
infilteration.
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35. DISCUSSION
• In experimental studies, ET-receptor antagonists
improved renal morphology & function, and reduced
proteinuria through multiple mechanisms, including
attenuated damage to mesangial cells, podocytes, renal
tubules and glycocalyx, & also reduces BP.
• The findings from this trial support the value of
atrasentan in protecting kidney function in carefully
selected patients with T2DM & CKD, who are responders
to an initial reduction in albuminuria with short term ET-
receptor blockers.
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36. Limitations Of This Trial
1. Early termination – because the rate of the primary
composite outcome was much lower than
expected, so, sponsor decided to stop the trial
prematurely.
2. 19% patients discontinued their assigned
treatment, which might have affected the benefit-
risk estimation.
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37. SUMMARY
This trial supported a potential role of Atrasentan, a
selective ET-receptor antagonist, in protecting renal
function In Carefully Selected Patients with T2DM at
high risk of developing ESRD.
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