ASN 2016: Late Breaking Clinical Trials

Written by Meguid El Nahas on Sunday, 20 November 2016. Posted in OLA Blog

ASN 2016: Late Breaking Clinical Trials

Prof Arif Khwaja Reporting from Chicago:

Late Breaking Clinical Trials


LEADER study looking at Liraglutatide on renal outcomes in patients with T2DM. This was a huge study with over 8000 patients with T2DM at higher CV risk who were randomised to placebo or Liraglutaide. The primary endpoint were major adverse cardiovascular events (MACE) and in the paper published this year in NEJM liraglutide was associated with a significant reduction in MACE. Today the secondary renal endpoints were presented - a composite of doubling of serum creatinine, ESRD, new onset macroalbuminuria and development of microalbuminuria. There was a significant reduction in the renal composite endpoint with Liraglutide which was completely driven by less new onset macroalbuminuria in CKD3 patients. No difference in any of the other endpoints including eGFR decline. As this was a placebo controlled trial the HbA1c in the the liraglutide group was significantly lower. I am not sure how surprising this is - we were taught at medical school that good glycemic control reduces the risk of nephropathy and increasing albuminuria is often the 1st sign of nephropathy - thus impossible to know if there is a drug specific effect or simply a lowering HBA1C effect.

The next study was the REMAIN study from UK which looked at the effect of early remote ischaemic preconditioning (RIPC) and late remote preconditioning on outcomes in live related transplantation. RIPC was done by 5 minutes inflation of BP cuff on upper arm followed by 5 minutes deflation for 5 cycles done either the day before theatre or on the morning of the transplant - and done prior to anaesthetic agents being given ( in contrast to the negative RIPC studies done before cardiac surgery). Controls underwent the same procedure but the cuff was inflated to only 40mmHg.
The primary endpoint was difference in mGFR at 1 year - and this was negative. The secondary endpoints were death, eGFR and graft survival at 5 years. Strangely in the early RIPC group there was a significant reduction in death and an improvement in eGFR at 5 years. Mortality at 5 years was 3% in the RIPC group and 8% in the control group. The authors recommend that we should start doing RIPC routinely in live transplants on the grounds that it is cheap, safe and easily deliverable. That maybe the case but I would add a word of caution - unsurprisingly the event rate was extremely low - patients with live related transplants do very well and though the percentage reduction in patient survival was statistically significant the absolute effect was probably very small - as a member of the audience pointed out nearly all liver recipients should be alive at 5 years. Secondly the eGFR improvement was seen at 1 year and persisted through to 5 years - yet there was no mGFR difference at 1 year which suggests to me that the eGFR result may not be ‘real’. To me it would have been much more interesting to do the study in deceased donor transplants particularly in this with a prolonged cold ischaemia time.

The 3rd study (HARMONY) from Germany evaluated whether ATG could enable rapid steroid withdrawal in low risks kidney transplant patients. Patients were randomised to 3 groups i) Tac, MMF, pred + Basiliximab ii) Tac MMF, Basiliximab with steroid withdrawal at 1 week iii)ATG, Tac, MMF and pred withdrawal at 1 week. The real purpose of the study was to see if this would reduce the incidence of new onset diabetes after transplantation (NODAT).
The primary endpoint was biopsy proven acute rejection (BPAR) and there was no difference between all three groups. Steroid withdrawal in both the basiliximab and ATG group halved the incidence of NODAT as compared to the steroid group. Astonishingly the NODAT occurred in 40% of the steroid group - which may partially be explained by the fact that tacrolimus levels were kept slightly higher in this study- nevertheless this is an incredibly high rate of NODAT and the rate of NODAT in the steroid free arm in this study (around 20%) is comparable to the rate seen in studies using low dose tac with prednisolone - see ELITE-SYMPHONY study
So the study suggests that in low risk, caucasian transplant patients steroids can be withdrawn after one week with standard basiliximab therapy. This is associated with no excess of rejection and a reduction in NODAT. The study is available online in the Lancet. www.thelancet.com/journals/lancet/articl...(16)32187-0/fulltext

4th study was the AURA-LN study that looked at adding a new CNI (Voclosporin low and high dose) to standard care (MMF+prednisolone) in class 3,4 and 5 Lupus. 24 week data was presented. Complete remission was defined as a composite endpoint of reduction proteinuria (<0.5g/24 hours) stabilisation of eGFR. Secondly endpoints included SLE activity scores such as SLENAI-SLEDAI. Voclospotin therapy was associated statistically significant impact on all primary and secondary endpoints with a phase 3 study being planned. Important to know that this positive outcome was driven completely by reduction in proteinuria with Voclosporin.
My caveats - i) patients had good kidney function - median eGFR was 100mls/min at baseline and so may not represent aggressive lupus ii) proteinuria remains a surrogate in lupus - and using a CNI will reduce proteinuria in any condition (via reduction in renal perfusion or stabilising actin cytoskeleton in the podocyte or both) - so in the absence of a repeat renal biopsy its very difficult to know if this is a genuine disease modifying effect or just improvement of a surrogate. I guess if there was a rebound rise in proteinuria after stopping the voclosporin then that would suggest that the effect is largely haemodynamic rather than disease modifying.
The SOLD study from new zealand looked at the impact of lowering dialyse Na (135mm vs 140mm) on Left ventricular mass index - no impact all at 1 year but further analyses planned. Authors postulate that LV mass is as much determined by uraemia as fluid overload.

the final study (DUET study ) compared irbesratan to a combined endothelin receptor antagonist and ARB (Sparsentan). it was an 8 week phase 2 study in a small no of patients so the conclusions are somewhat limited. Unsurprisingly combination therapy was associated with lower BP and proteinuria at 8 weeks.

Meguid El Nahas

Professor Meguid El Nahas PhD, FRCP

Chief Editor, OLA Director

Professor El Nahas was born in Cairo, Egypt and undertook his undergraduate medical education in...
Posted: 4 months 6 days ago by elnahas #21157
elnahas's Avatar
Many years ago when asked about what wins a presidential election Bill Clinton said: "Its the economy stupid..." meaning a better economy makes a president re-electable...

Now to LEADER and Liraglutide...can we say: "Its the Blood pressure stupid"...?!

as systolic BP was lower in the Liraglutide arm and this is know to reduce MACES....as well as delay macroalbuminuria?!

This was previously nicely demonstrated by Rossing and his colleagues in Denmark where in multivariate analysis the benefical effect of Liraglutide on albuminuria in DN could be explained by changes in systolic BP:
www.ncbi.nlm.nih.gov/pubmed/27753201
Posted: 4 months 6 days ago by elnahas #21158
elnahas's Avatar
and also concerns have been expressed about GLP-1 receptor agonists and the increased risk of pancreatitis and pancreatic cancer?!
Posted: 4 months 6 days ago by arif.khwaja #21159
arif.khwaja's Avatar
It might be a BP effect though the difference in systolic BP was small and the diastolic BP was significantly higher in liraglutide
Posted: 4 months 5 days ago by elnahas #21162
elnahas's Avatar
At the ASN meeting late-breaking clinical trials session the voclosporin Phase IIB randomized controlled trial in proliferative Lupus Nephritis showed a significant improvement in proteinuria remission rates when voclosporin was added to MMF , compared to MMF alone.Both groups received similar doses of steroids. The trial was short term only so the relapse rate was not assessed. Few African-American subjects were enrolled. There was no cyclosporine or tacrolimus arms included , so we do not know if voclosporin is more effective than other calcineurin inhibitors. Deaths were increased in the voclosporin group, but these were confined to a few centers outside the USA. Other safety signals were not observed. Repeat biopsies were not done to confirm disease remission.
Triple therapy of Lupus Nephritis (Voclosporin, MMF and steroids) may be effective but we do not know whether it is equivalent or superior to triple regimens that include cyclosporine or tacrolimus, whether the safety profile is advantageous, whether it will be effective in all ancestral groups, and wheteher itvaffirds long term disease rather than just proteinuria remissions. We look forward to Phase III pivotal trials in Lupus Nephritis with this interesting new calcineurin inhibitor.

Dick Glassock
Posted: 4 months 5 days ago by elnahas #21163
elnahas's Avatar
Dick,

any CNI reduces albuminuria through their renal hemodynamic effects as well as their effects on the podocytes; this is a class effect, predictable and reversible.

Whether reduction of albuminuria in LN impacts on longterm outcomes in terms of long term functional improvement and renal survival are mute points...it is most likely that proteinuria reduction in LN is an irrelevance!?
Posted: 2 months 3 days ago by nsolomons #21270
nsolomons's Avatar
There are a couple of indirect outcomes that suggest that the reduction in proteinuria are not simply haemodynamic both of which were reported in the ASN presentation:

1- The anti ds DNA was significantly reduced in the vocloporin arm compared to the control
2- The SLEDAI reduction was significantly greater in voclosporin treated patients. When renal parameters were removed from SLEDAI, the reduction remained

The 48 week data will be reported Q1 this year, giving us more information on duration of remission and safety.
Posted: 2 months 2 days ago by elnahas #21271
elnahas's Avatar
Thank you Neil for clarifications.

Add your comments

Please login in to join the discussion