If this message is not displayed correctly, click here.

Late Breaking Clinical Trials

June 4, 2017

 

Content

 

NEFIGAN Trial
Novel targeted-release formulation of budesonide reduced proteinuria in IGAN patients

New insights from the COSMOS study
12% mortality reduction, if serum phosphate levels are brought into the target range of 3.6 to 5.2 mg/dL

Whom to treat – and not to treat – with immunosuppressive drugs?
High serum levels of Gd-IgA1 predict poor renal outcomes in IgAN

Results of the EXCITE trial
A home-based exercise program significantly improves physical performance in dialysis patients

Active Vitamin D does not prevent cardiovascular disease
J-DAVID Trial shows no benefit

AURA-LV trial shows promising results!
Complete remission of lupus nephritis is three times more likely with voclosporin

 


 

NEFIGAN Trial
Novel targeted-release formulation of budesonide reduced proteinuria in IGAN patients

According to a study that has been published in The Lancet and will be presented and discussed at the "Lancet session" at the ERA-EDTA Congress today a novel targeted-release formulation of budesonide (TRF-budesonide) could become the first specific treatment for IgA nephropathy. It targets the intestinal mucosal immunity upstream of disease manifestation, while limiting systemic glucocorticoid absorption. This means the medication has less side-effects than other steroids.

After the STOP IgAN study [1] showed that intensified, supportive therapy (i.e. maximized antihypertensive medication) was nearly as effective as immunosuppression, the NEFIGAN Trial evaluated optimized renin-angiotensin system (RAS) blockade plus TRF-budesonide versus intensified RAS blockade alone. "We wanted to know if the additional therapy with TRF-budesonide leads to a better disease control", explained lead investigator, Bengt Fellström, Uppsala, Sweden. "Our rationale was that this novel targeted therapy for IGAN patients that blocks disease manifestation could further improve outcomes."

The study results are promising, indeed: Overall, at 9 months TRF-budesonide (16 mg/day plus 8 mg/day) was associated with a 24.4% decrease from baseline in mean urine protein creatinine ratio. For patients in the 16 mg/day TRF budesonide group, proteinuria in the form of UPCR and 24-h urine protein excretion both decreased by about 30%, compared with the placebo-treated group. A meta-analysis [2] showed that proteinuria reduction is significantly associated with outcomes in end-stage renal disease.

This trial showed that 9 months' treatment with TRF budesonide resulted in reduced proteinuria and stabilized eGFR in patients with IgA nephropathy at risk of progression to end-stage renal disease. Besides, the total incidence of treatment-emergent adverse events was similar across treatment groups. "The observed beneficial effect was additive to optimized RAS blockade and supports the use of TRF-budesonide as adjunct therapy in patients with IgA nephropathy with persistent proteinuria", concluded Professor Fellström.

[1] Rauen T, Eitner F, Fitzner C et al. N Engl J Med 2015;373: 2225–36
[2] Lambers Heerspink HJ, Tighiouart H, Sang Y et al. Am J Kidney Dis 2014; 64: 860–66

 


 

New insights from the COSMOS study
12% mortality reduction, if serum phosphate levels are brought into the target range of 3.6 to 5.2 mg/dL

High phosphate concentrations are associated with an increased incidence of cardiovascular complications and mortality in the general population and especially in patients with chronic kidney disease (CKD). As the kidney has a key role in phosphate regulation, phosphate homeostasis is disturbed in patients with kidney disease. Many dialysis patients develop hyperphosphataemia, which is associated with poor clinical outcomes as epidemiological data consistently indicate.

The COSMOS study (Current management of secondary hyperparathyroidism: A multicentre observational study), a 3-year, open cohort, prospective observational study conducted in 6,797 HD patients randomly selected from 227 centres of 20 European countries studied in this analyses the association between reductions in serum phosphate during 6 periods of 6 months and the relative risk of mortality likewise the influence of two days (midweek) and three days (post-weekend) interdialytic period on serum phosphate levels and survival.

The study shows the reduction of serum phosphate (-1.1 mg/dL) from mean serum phosphate values of 6.5 mg/dL towards the COSMOS serum phosphate safest target ranges (3.6 to 5.2 mg/d, in which the lowest mortality risk was observed), was associated with 12% reduction in the relative risk of mortality. In addition, it shows that the timing of blood withdrawal influences not only serum phosphate levels – significant higher post-weekend (p>0.001) –, but also the association between serum phosphate levels (including their safest ranges) and the lowest risk of mortality, a matter of great importance as the upper levels of the serum phosphate safest ranges are currently used to guide the management of hyperphosphataemia, mainly modifying the phosphate binding agents prescription.

Prof Jorge Cannata-Andia, (Chairman), and Dr Jose Luis Fernández (Project Manager) of COSMOS said; "For the first time, using a COSMOS analyses which mimics as much as possible what happens in randomized clinical trials, it was found that the reduction of serum phosphorus in dialysis patients may render the expected benefits, as it is associated to better survival." In addition, the analyses showed that the time of blood withdrawal (related to the extent of the intradialytic period) matters as influences not only serum phosphate but also its association with survival. This aspect should be considered in future guidelines for its important clinical implications.

 


 

Whom to treat – and not to treat – with immunosuppressive drugs?
High serum levels of Gd-IgA1 predict poor renal outcomes in IgAN

Glomerulonephritides (GN) constitute the third most common defined cause of kidney failure or end-stage renal disease (ESRD) in Europe, after diabetic and hypertensive nephropathy. A 'glomerulonephritis' is an inflammation of the kidneys, which predominantly affects the glomeruli (the filtering capsules of the kidneys). IgA Nephropathy (IgA nephritis/IgAN) is the most common of the idiopathic glomerulo-nephritides, and is the most common reason for younger adults to need dialysis. Central in the pathogenesis of IgAN is deposition of galactose-deficient IgA1 (Gd-IgA1) in glomeruli and this triggers inflammation.

For more than 50 years, an anti-inflammatory, immunosuppressive treatment has been used in the treatment of glomerulonephritis. Drugs such as the well-known corticosteroids have been used as well as other immunosuppressive substances and even cytotoxic drugs. But all these treatments go along with severe side-effects. The STOP-IgAN study [1], a randomized clinical trial (RCT), showed that supportive therapy (i.e. maximized antihypertensive and antiproteinuric medication) might be as effective in many patients, although immunosuppression seemed to be beneficial for some IgAN patients as indicated by the higher number of patients achieving full clinical remission.

The question is now, how to stratify the patients wisely: i.e. how to decide which patients should, and should not, be treated with immunosuppression. So far, few biomarkers have been suggested to predict the risk of progression in IgAN patients. Now the working group of Jürgen Floege et al., Aachen, Germany, has shown that higher serum levels of Gd-IgA1 predict poor renal outcomes in IgAN.

The authors of one of the 'late breaking clinical study' abstracts of the ERA-EDTA congress in Madrid analyzed Gd-IgA1 levels in those patients from the STOP-IgAN study who did not respond to supportive therapy. Among the 104 non-responders, baseline Gd-IgA1 levels were higher in those who developed ESRD, who had an eGFR-loss above 30 ml/min/1.73 m2 at the end of the trial, or who failed to reach full clinical remission. "The findings suggest that patients with high Gd-IgA1 are high-risk patients, and that the pre-treatment Gd-IgA1 level might be a good biomarker to stratify those patients who are in need of more intense treatment", explained lead investigator Professor Floege.

[1] Rauen T, Eitner F, Fitzner C et al. N Engl J Med. 2015 Dec 3; 373(23): 2225–36

 


 

Results of the EXCITE trial
A home-based exercise program significantly improves physical performance in dialysis patients

"Mens sana in corpore sano." The Roman poet Juvenal knew 2000 years ago that physical health goes hand in hand with mental health. Physical activity reduces cardiovascular risk, not only in the general population, but also in high-risk patients. As far as dialysis patients are concerned, the effects of some kinds of physical activity have been investigated only in hemodialysis patients in small, single-center studies involving supervised exercise during the dialysis session or in hospital. There is no question that the fact that all these studies were performed during dialysis sessions represents a strong limitation on patient empowerment. Indeed, home-based, extra-dialysis physical exercise programs would considerably enhance feasibility and adherence.

The aim of the randomized, controlled EXCITE (EXerCise Introduction To Enhance performance in dialysis) clinical trial [1] was therefore to test the effects on physical performance in dialysis patients of a low-intensity, easy-to-implement, home-exercise program. 296 hemodialysis patients were randomly assigned to the active arm (exercise, n=145) or the control arm (n=151), according to their New York Heart Association classification. Physical performance was assessed by the Six Minute Walking Test and the Sit-to-stand-to-sit Test. These tests were performed in hospital at baseline and after 6 months. Patients randomized to the active arm were prescribed physical exercise to be performed at home, scheduled according to the baseline performance tests.

At baseline, patients in the active group and those in the control group were perfectly comparable, indicating that randomization was successful. After 6 months, patients in the active group had a remarkable improvement in their performance either for the Six Minute Walking Test or the Sit-to-stand-to-sit Test, while no changes were recorded in the control group. Not surprisingly, changes in cognitive function and in quality of social interaction items of the KDQOL-SF were significantly more favorable in the exercise group than in the control arm.

The EXCITE trial included a post-trial observation period (36 months), during which data on death, cardiovascular events and hospitalizations were collected. During follow-up, 134 events were recorded. In 126 cases, hospitalization was the first event, followed by death in 38 cases, whereas in 8 cases patients died without hospitalization. Statistical analyses showed that during the trial (follow-up 6 months: short-term risk) the risk of hospitalization was significantly reduced in the exercise arm compared to the control arm. The same analysis extended to the post-trial observation period (36 months: long-term risk) confirmed the risk reduction (-29%) for hospitalization. Furthermore, in analyses taking into account adherence to the walking exercise program, the subgroup with high adherence exhibited the lowest risk of hospitalization compared to the control arm and to patients with low adherence. Separate analysis for mortality showed no significant difference between the groups.

"In conclusion, these results indicate that a simple, personalized, home-based, low-intensity exercise program managed by dialysis staff improves physical performance and quality of life, and reduces short- and long-term risk of hospitalization in patients who maintain a high adherence", explained lead investigator Professor Francesca Mallamaci.

 


 

Active Vitamin D does not prevent cardiovascular disease
J-DAVID Trial shows no benefit

Activation of vitamin D is severely impaired in patients with advanced stages of chronic kidney disease, particularly those on hemodialysis. Observational studies have shown that the use of vitamin D receptor activators (VDRAs) was associated with lower risk of death from all-cause and cardiovascular disease (CVD) in dialysis [1] – even populations regardless of serum parathyroid hormone (PTH) level. Therefore, the prospective randomized Japan Dialysis Active Vitamin D (J-DAVID) trial was initiated to test the hypothesis, if dialysis patients with normal PTH level would benefit from a VDRA therapy. 976 patients were enrolled and randomized to treatment with oral VDRA or treatment without VDRAs. The risk of CVD events was the primary endpoint of this study, all-cause mortality was the secondary endpoint.

Today, the study results have been presented at the ERA-EDTA Congress in Madrid as one of the Congress's 'late breaking clinical trial'. As Professor Tetsuo Shoji, Osaka, Japan, pointed out, the study showed no beneficial effect for this therapy. On the contrary, the cardiovascular risk of the treated patients was even a little bit higher, although it was not significant (p=0.127), by intention-to-treat analysis.

One can only speculate about the reasons, why the therapy was not effective. VDRAs are known to raise serum calcium and FGF23 levels, which are both associated with higher cardiovascular risk. "Thus, these effects might have outweighed potential beneficial effects of the supplementation of active vitamin D", explained Professor Shoij. Also other RCTs (e.g. PRIMO or OPERA [2, 3]) that tested VDRAs in predialysis patients with elevated PTH had disappointed before.

"Based on our results there is no rationale for a VDRA therapy in dialysis patients with normal PTH", concluded Professor Shoji.

[1] Teng M et al. J Am Soc Nephrol 2005; 16: 1115–25
[2] Thadhani R et al. JAMA 2012; 307: 674–84
[3] Wang AY et al. J Am Soc Nephrol 2014; 25: 175–86

 


 

AURA-LV trial shows promising results!
Complete remission of lupus nephritis is three times more likely with voclosporin

Treatment with low-dose Voclosporin for 48 weeks trebles the chance of complete remission of lupus nephritis compared to placebo in patients receiving recommended standard immunosuppressive therapy. Voclosporin was well tolerated with no adverse effects on renal function, blood pressure or serum electrolytes.

These are the results of the multicentre, randomized, double-blind, placebo-controlled phase 2 AURA-LV trial. Presenting the 'late breaking clinical study' during ERA-EDTA Congress 2017, lead investigator Dr James Tumlin said: "This study demonstrates that Voclosporin has positive additive effects on Lupus nephritis concurrent with a rapid reduction of oral steroids. These promising data are a basis for a phase 3 study to validate the efficacy of low-dose Voclosporin in lupus nephritis."

Voclosporin is a novel calcineurin inhibitor (CNI) intended for the treatment of autoimmune diseases such as lupus nephritis. In this long-term condition the patient’s immune system attacks the kidneys, causing protein leakage in the urine, swelling of the tissues, and kidney damage that may progress to kidney failure.

The AURA-LV trial enrolled 265 patients with active lupus nephritis in 20 countries. Patients were randomized to placebo, or low-dose voclosporin (23.7 mg twice daily), or high-dose voclosporin (39.5 mg twice daily). All patients received background treatment with mycophenolate mofetil 2 g/day and rapidly tapering doses of steroids.

At Week 48, patients receiving low-dose voclosporin were three times more likely to achieve complete remission compared to the placebo group (OR: 3.21, p<0.001; high dose 2.10, p=0.026). There were no significant differences between the study groups in kidney function, blood pressure, or blood levels of important electrolytes such as magnesium and potassium. Thirteen patients died during the study, most deaths occurring in the first two months. Causes of death were similar to those seen in other lupus nephritis studies and were all considered unrelated to voclosporin by investigators.

 

About ERA-EDTA

With almost 7,000 members, the ERA-EDTA ("European Renal Association – European Dialysis and Transplant Association") is one of the biggest nephrology associations worldwide and one of the most important and prestigious European Medical Associations. It supports basic and clinical research in the fields of clinical nephrology, dialysis, renal transplantation and related subjects. It also supports a number of studies as well as research groups and has founded a special "Fellowship Programme" for young investigators as well as grant programmes. In order to involve young nephrologists in all activities ERA-EDTA has the Young Nephrologists’ Platform (YNP), a very active committee whose board includes members who are 40 years old or younger. Besides, it has established various working groups to promote the collaboration of nephrologists with other medical disciplines (e.g. cardiology, immunology). Furthermore, a "European Renal Best Practice" (ERBP) advisory board was established by the ERA-EDTA to draw up and publish guidelines and position statements. Another important goal of the ERA-EDTA is education: several series of CME-courses as well as the annual congress offer an attractive scientific programme to cover the need of continuous medical education for doctors working in the fields of nephrology, dialysis and transplantation. The association’s journals, NDT (Nephrology, Dialysis, Transplantation) and ckj (Clinical Kidney Journal), are currently the leading nephrology journals in Europe; furthermore NDT-Educational is the online educational journal, open for free to all uses, of the Society as well as the very important and useful feature of NDT-Educational “Literature Review”. The ERA-EDTA Registry is a large epidemiologic database comparing countries by assessing nephrology practice throughout Europe. ENP, the European Nephrology Portal, is the latest new initiative of ERA-EDTA: here all those interested in the activities of the Society can find everything that is done, all in one place! Finally, ERA-EDTA is member of the European Kidney Health Alliance (EKHA), a consortium of patients, nurses, foundations all related to renal issues that actively interacts with the European Parliament. For more information please visit www.era-edta.org

Press Office ERA-EDTA
albersconcept | Dr. Bettina Albers | Jakobstraße 38 | D-99423 Weimar | Germany

If you don't want to receive this newsletter anymore, click here to unsubscribe.