ONGOING CLINICAL TRIALS

TREATMENT OF IgA NEPHROPATHY WITH ANGIOTENSIN CONVERTING ENZYMES INHIBITORS (ACE-I): DESIGN OF A PROSPECTIVE RANDOMIZED MULTICENTER TRIAL

COORDINATOR Rosanna Coppo MD

REFERENCE Angiotensin-converting enzyme inhibitors (ACE-Is) in young patients with IgA nephropathy: effects against deterioration of renal function (European Biomed project EEC Concerted Action BMH4-97-2487 (OG 12-SSMI) Biomedicine and Health Research, (Nephrol Dial Transplant 1999;14:840-841) [PDF]

Acronym: IgACE

TEXT OF PROTOCOL
ABSTRACT: Although several experimental in vitro studies and clinical observations suggest that ACE-inhibitors (ACE-I) are a very promising treatment for IgA nephropathy (IgAN), meta-analysis of published data is not yet conclusive. Therefore, a European double-blinded, prospective, randomized therapeutic trial was designed to evaluate ACE-I treatment benefits on a group of young IgAN patients (<35 years old) with persistent moderate proteinuria (>1<3.5 g/day/1.73 m2) and fair renal function (creatinine clearance >50 ml/min/1.73 m2). Enrolled patients are randomly assigned to Benazepril (0.2 mg/Kg/day) or placebo treatment. A 3-4 year follow up is proposed to patients. The end point is a 30% decrease in GFR evaluated by means of centralized HPLC measurement of creatinine clearance. Recruitment period ends on December 2003 and follow-up periods ends on December 2004.

PARTICIPATING CENTRES
P. Cochat, Lyon (France), F. Coelho Rosa, Lisboa (Portugal), T. Linné, Stockholm (Sweden), G. Lama, Napoli, (Italy), S. Maringhini, Palermo (Italy), C. Pecoraro, Napoli (Italy), G. B. Capasso, Napoli (Italy), R. Penza, Bari (Italy), G. Rizzoni, Roma (Italy), M.Giani, Milano (Italy), A. Amore, Torino-Regina Margherita (Italy), G. De Petri, Crema (Italy), G. Rattalino, Torino-Martini (Italy), S. Ferrero, Asti (Italy), E. Ragazzoni, Borgomanero, Novara, (Italy), P. Stratta, Torino-Molinette (Italy), S. Carozzi, Savona, (Italy), D. Roccatello, Torino, (Italy), GC. Lavoratti, Firenze, (Italy), S. Li Volti, Catania, (Italy), M. Dugo, Treviso (Italy), H. Guldenring, Dresden, (Germany), D. Weitzel, Wiesbaden, (Germany), M. Soergel, Marburg (Germany).

BACKGROUND AND RATIONALE
According to EDTA Registry, IgAN represents 1.5% of renal diseases of all patients in dialysis in Europe (6). In the 17% of patients who start dialysis because of an evolutive IgAN the disease appears in the first youth, before 20 years of age. Therefore, every treatment proved to be effective in the first decades of life will give the greatest benefit in modifying the natural history of the disease.
Clinical indicators of evolutive course are represented by significant proteinuria and arterial hypertension (7). Although several therapeutic modalities have been proposed, so far no therapy displayed a proved efficacy in all patients, allowing to draw a therapeutic scheme with uniformly recognised validity. Proteinuria is considered a therapeutic target because it may, itself, induce renal damage and decrease in proteinuria significantly correlated with effective reno-protection.
Steroids have been recently positively re-evaluated . Without under-estimating the obtained results, some questions remain open, in addition to the possible side effects of steroids and immunosuppressive drugs, which are certainly indicated in patients with evolutive behaviour (13). One of the main doubts however is if a steroids cycle, eventually repeated, is the appropriate therapy for a nephropathy characterised by a pathogenic mechanism probably constantly operating along several decades (14).
Several experimental in vitro data and clinical observations have suggested that Angiotensin converting enzyme inhibitors (ACE-I) could be an elective treatment for IgAN, inducing the reduction of glomerular hypertension and of proteinuria (15). On the other hand, it is true that this treatment does not seem effective in the totality of patients and only a subgroup (between 30-50% of cases), seems to show relevant results (16-17). At the moment, no controlled evidences exist that ACE-I slow down the progression of IgAN: neither the meta-analysis of specific data (18), nor the recently published sub-analysis of IgAN patients enrolled in REIN study (19) reported significant evidences.
Basing on these premises the need of a controlled prospective study emerges, to evaluate the effects of ACE-I on a group of young IgAN patients, with the purpose of a future use of these drugs selectively only in the sub-group with the best probability of success deviating the cases resistant to this treatment to other drugs (e.i. cortisone, fish-oil or new drugs).

OBJECTIVES
The primary objective of this study is the evaluation of ACE-I treatment effects on a group of young IgAN patients with persistent moderate proteinuria and good renal function, in order to investigate the impact on long-term renal survival and the possibility to induce a complete disease remission (proteinuria <0.2 g/day/1.73 m2) by statistical survival analysis of Benazepril treated patients vs. placebo treated (20).
Moreover, the study intends to evaluate some genetic (e.i. polymorphisms of HLA, Ig switch region, ACE, Ang II receptor, adducin, Na/H pump genes, cytochines or involved immunologic factors as TGF-b, PAI-1, mannose binding protein, uteroglobin genes), immunologic (e.i. serum macromolecular IgA, IgA and mixed IgA/IgG immune complexes, IgA1 with altered glycosylation and abnormal electric charge, uteroglobin levels), histologic factors (renal biopsies analysis by Laser Scanning Microscopy), to clarify their role in the modulation of the final response to ACE-I treatment. Since hypertension represents one of the main progression factors to chronic renal failure, the role of this parameter in the IgAN course will be evaluated by 24 hours Ambulatory Blood Pressure Monitoring (ABPM) for all patients involved in the study.

CLINICAL TRIAL DESIGN
This study is a double-blinded, prospective, centrally-randomized therapeutic trial with informed consent of enrolled patients and Ethical Committee approval. It begun as a Concerted Action of the European Community Biomedicine and Health Research (20) ended in 2000 and pursuing now as a collaborative multicenter study. This trial involves at the moment 40 Centers in Europe. Patients enrolment started in April 1998 and it will last until December 2003.
The study consists of a 3 months period in which patients are clinically monitored, to accomplish inclusion and exclusion criteria (run-in phase) and blood pressure is brought back to normal values when needed. After this period, patients are randomized to receive ACE-I treatment (Benazepril 0.2 mg/Kg/day) or placebo. Considering the importance of blood pressure control in slowing renal failure progression, patients having medium systolic or diastolic pressure higher than 95th percentile (corrected for patient age) during two consecutive visits must be treated for hypertension (Nifedipine Retard to 3 mg/Kg/day and/or Atenolol to 1.5 mg/Kg/day).

INCLUSION CRITERIA
All patients with biopsy-proven IgAN (presence of dominant or co-dominant IgA mesangial deposits) of either sex who give their informed consent and who fulfil the following inclusion criteria can be included in the study:
• age >3<35 years at the moment of enrolment;
• proteinuria persistently >1<3.5 g/day/1.73 m2 at least in the previous 3 months;
• Creatinine clearance (CrCl) >50 ml/min/1.73 m2.

EXCLUSION CRITERIA
• Presence of secondary IgAN forms (i.e Henoch-Schoenlein purpura, Lupus, Celiac disease, chronic liver and pulmonary diseases).
• Steroids and/or other anti-inflammatory, immunomodulatory, cytostatic and ACE-I drugs used in the last 6 months before enrolment;
• Renovascular hypertension, heart block, collagen vascular disease, diabetes, impaired hepatic function, history of angioneurotic edema, leukopenia and significant haematological diseases, chronic cough.
• Hypersensitivity to ACE-I.
• Pregnancy or unwilling to use appropriate measures to avoid pregnancy during the study.
• Uncontrolled arterial hypertension.
• Need for treatment with diuretics because of edema.

WITHDRAWAL AND DROP-OUT CRITERIA
Patients will be withdrawn from the trial because of:
• 30% decrease of CrCl values in comparison with baseline values.
• Persistent increase of proteinuria to >3.5 g/die/1.73 m2.
• Withdrawal of consent.
• Serum albumin values <20 g/l without infections.
• Pregnancy, presence of unwanted side effects.
• Pills assumption <75% of the prescribed dose.

TREATMENT ALLOCATION
Patients are randomly allocated to Benazepril or placebo treatment through an appropriate software in the Coordinating Center (“Regina Margherita” Hospital). This concealed randomization is performed by A. Piccoli, University of Padua, according to 2 strata, on the basis of Cr Cl < or >70 ml/min/1.73 m2 .
The enrolment period duration is 5 years and will end in December 2003. The study estimates a clinical observation of the patients in treatment for 6 years (1 year minimum treatment). The end of the trial is December 2004.

TRIAL PROCEDURES
Patients considered eligible on the basis of the inclusion/exclusion criteria are provided with information concerning the study and asked for informed consent. Before entering the treatment phase, all patients are monitored for a period of three months (run-in phase), in order to confirm the validity of inclusion criteria and to provide baseline values:
Analyses will be performed at 1, 3, 6, 12 months of the first year follow-up phase and then every 4 months till the end of the trial (December 2004).
At each visit, the patients will be asked about their height, weight, blood pressure, clinical symptoms, possible treatment complications and drug consumption.

STATISTICAL ANALYSIS
Survival to 30% loss of initial CrCl as primary end point: hypothesis of 95% end points in the treatment group vs. 80% in the placebo group at 6 years follow-up (5 years recruitment), a 10% drop out (20).

Data analysis
The statistical analysis will be performed according to the following modality:
• CrCl as continuous variable: covariance and variance analysis with repeated measures of all evaluated parameters.
• Univariate (log-rank test) and multivariate (Cox model) survival analysis, assuming a definitive 30% decrease in initial CrCl as end point.
• Proteinuria and systolic/diastolic pressure as continuous variable: covariance and variance analysis with repeated measures of all evaluated parameters.
• Univariate (log-rank test) and multivariate (Cox model) survival analysis, assuming the complete disease remission (proteinuria <0.2g/day/1.73 m2) as end point.

BIOLOGICAL SAMPLES COLLECTION
All the biological samples, essential for the evaluation of the possible role of genetic, immunologic and serologic factors conditioning the clinical course and the response to ACE-I treatment, have to be collected at baseline (3rd month of run-in phase) and then once a year until the end of the study (December 2004). Moreover, the histological evaluation of renal biopsies will be performed by Confocal Laser Scanning Microscopy.
In particular, the samples to collect are:
• 10 ml of peripheral blood (EDTA as anticoagulant) for genetic studies.
• 3 ml of serum and 3x10 ml of fresh urines for immunologic and serologic analyses.
• 3 ml of serum and 10 ml of 24 hours urines for centralized HPLC creatinine clearance and proteinuria.
• 3 ml of plasma for C3d polymorphism.
• Cryostat sections from the renal biopsy specimen: 5 slides, 2 sections or more each (thickness 12-15 microns) for the Confocal Laser Scanning Microscopy analysis.
Frozen biological samples must be sent to Torino Coordinating Center, that will support all the shipment expenses.

ABPM REPORTS
Continuous Ambulatory Blood Pressure Measurement (ABPM) must be evaluated for all enrolled patients at baseline level (3rd month of run-in phase), 1 month follow-up and then once a year until the end of the trial. It should be performed for 24 hours with 15 minutes intervals during the day (6 a.m., 10 p.m.) and 30 minutes during the night. The reports have to be mailed to Torino Center.

STUDY COORDINATOR
Further information requests and/or intention to participate the study can be communicated to the Study Coordinator, who will send the detailed protocol and operative instructions:

Dr. Rosanna Coppo
Nephrology, Dialysis and Unit
“Regina Margherita” Children’s Hospital
P.zza Polonia 94, 10126 Torino (Italy)
Tel:+39-011-3135361 – +39-011-3135848
Fax:+39-011-6635543
e-mail: nefrologia@oirmsantanna.piemonte.it

REFERENCES

1. D’Amico G. The commonest glomerulonephritis in the world: IgA nephropathy. Q J Med 1987; 64: 707-727.
2. Koyama A, Igarashi M, Kobayashi M. Members and Coworkers of the Research Group on Progressive Renal Diseases. Natural history and risk factors for immunoglobulin A nephropathy in Japan. Am J Kidney Dis 1997; 4: 526-532.
3. D’Amico G, Imbasciati E, Barbiano di Belgioioso G, et al. Idiopathic IgA mesangial nephropathy. Clinical and histological study on 374 patients. Medicine 1985; 64: 49-60.
4. Chaveau D, Droz D. Follow-up evaluation of the first patients with IgA nephropathy described at Necker Hospital. Contrib Nephrol, Benè MC, Faure GC, Kessler M (eds): IgA Nephropathy: the 24th year. Basel, Karger 1993; 104: 1-5.
5. Rekola S, Bergstrand A, Butch H. Deterioration rate in hypertensive IgA nephropathy: comparison of a converting enzyme inhibitor and beta-blocking agents. Nephron 1991; 59: 57-60.
6. Fassbinder W, Brunner FP, Brynger H, Ehrich JHH, Geerlings W, Raine AEG, Rizzoni G, Selwood NH, Tufveson G, Wing AG. Combined report of regular dialysis and transplantation in Europe, XX, 1989. Nephrol Dial Transplant 1991; 6 (Suppl. 1): 5-35.
7. Hogg RJ. Prognostic indicators and treatment of childhood IgA nephropathy. Contrib Nephrol. IgA Nephroathy: pathogenesis and treatment. Clarkson AR [ed], Basel, Karger 1995; 111: 194-200.
8. Hogg RJ. A randomized, placebo controlled, multicenter trial evaluating alternate-day prednisone and fish oil supplement in young patients with immunoglobulin nephropathy. Scientific Planning Committee of the IgA Nephropathy Study. Am J Kidney Dis 1995; 24: 792-796.
9. Dillon JJ. Treating IgA nephropathy. J Am Soc Nephrol 2001; 12:846-847Kobayashi Y, Hiki Y, Kokubo T, Horii A, Tateno S. Steroid therapy during the early stage of IgA nephropathy. Nephron 1996; 72: 237-242.
10. KobayashiY, Hiki Y, Fujii K, Kurokawa A, Tateno S. Moderately proteinuric IgA nephropathy. prognostic prediction of individual clinical course and steroid therapy in progressive cases. Nephron 1989; 53: 250-256
11. Pozzi C, Bolasco PG, Fogazzi GB, Andrulli A, Altieri P, Ponticelli C, Locatelli F. Corticosteroids in IgA nephropathy: a randomized controlled trial. Lancet 1999; 353: 883-887.
12. Locatelli F, Pozzi C, Del Vecchio L, Andrulli S, Pani A, Fogazzi G, Altieri P, Ponticelli C. Combined treatment with steroids and azathioprine in IgA nephropathy: design of a randomised multicentre trial. J Nephrol 1999; 12: 308-311
13. Roccatello D, Ferro M, Coppo R, Mazzucco G, Quattrocchio G, Piccoli G. Treatment of rapidly progressive IgA nephropathy. Contrib Nephrol 1995; 111: 177-182; discussion 182-183
14. Coppo R, Emancipator S. Pathogenesis of IgA nephropathy: established observations, new insights and perspectives in treatment. J Nephrol 1994; 7: 5-15
15. Remuzzi A, Perticucci E, Ruggenenti P, Mosconi L, Limonta M, Remuzzi G. Angiotensin converting enzyme inhibition improves glomerular size-selectivity in IgA nephropathy. Kidney Int 1991; 39: 1247-1273.
16. Maschio G, Alberti D, Janin G, Locatelli F, Mann JFE, Motolese M, Ponticelli C, Ritz E, Zucchelli P. Effect of the Angiotensin-Converting-Enzyme Inhibitor Benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996; 334: 939-945.
17. Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999; 354: 359-364
18. Dillon JJ. ACE inhibitor therapy: a meta-analysis. J Am Soc Nephrol 1998; 9: 86A
19. Ruggenenti P, Perna A, Gherardi G, Benini R, Remuzzi G. Chronic proteinuric nephropathies: outcomes and response to treatment in a prospective cohort of 352 patients with different patterns of renal injury. Am J Kidney Dis 2000; 35: 1155-1165.
20. Coppo R, Peruzzi L. Moderately proteinuric IgA Nephropathy in the Young. Biomedical and Health Research series, Amsterdam, IOS Press, Volume 44, 2000
21. Cattran D, Greenwood BS, Math M, Ritchie MD Long-term benefits of angiotensin-converting enzyme inhibitor therapy in patients with severe immunoglobulin A nephropathy : a comparison to patients receiving treatment with other antihypertensive agents and to patients receiving no therapy. Am J Kid Dis 1994; 23: 247-254
22. Ruggenenti P, Perna A, Gherardi G, Benini R, Remuzzi G Chronic proteinuric nephropathies: outcomes and response to treatment in a prospective cohort of 352 patients with different patterns of renal injury. Am J Kidney Dis 2000; 35: 1155-65
23. Nolin L, Courteau M Management of IgA nephropathy: evidence-based recommendations. Kidney Int 1999; 55: S-56-S-62
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_ The results of ACE-I in nephropathies of different origins reported by the AIRPI (16) and REIN (15,17) studies, raised a proper effect of scientific satisfaction, which however, left some anti-scientific a-dynamic a-criticism. The AIRP study showed that benazepril reduced the risk of doubling serum creatinine in 53% of cases particularly in patients with heavy proteinuria, >3 g/day. Similar data were reported by REIN using ramipril, with reduced rate of renal function decline by 50% again in patients with proteinuria >3 g/day, while the benefit was not statistically significant in patients with proteinuria <2 g/day (24). It should be noted, however, that these studies involved a heterogeneous group of patients with either glomerular, vascular or tubulo-interstitial changes. On the contrary, the sub-analysis of IgAN patients enrolled in the REIN trial, designed for proteinuric nephropathies, recently reported that in 75 IgAN patients with proteinuria > 1 g/day, meanly 3 g/day, ACE-I induced a 35% reduction in GFR decline, but the effect was without statistical significance (22).
It is quite clear that ACE-I is the drug to be selected in hypertensive IgAN patients: Rekola et al (5) showed an advantage of ACE-I therapy over beta-blockers in IgAN and other retrospective data (21) have further supported the notion that ACE-I should be considered the preferred modality in patients with IgAN and proteinuria > 1 g/day.
A recent meta-analysis of ACE-I results in 240 adult IgAN patients (18) showed that in 7 studies (3 short-term, one randomized prospective and 3 retrospective in hypertensive patients), ACE-I decreased proteinuria but it was significant in 4/7 reports only. For what it is concerning the renoprotective effect, although some benefits were observed in terms of decreasing the decline of renal function, the meta-analysis concluded that differences in control therapies and deficiencies in study design prevented definitive conclusions regarding the benefits of ACE-I therapy in IgAN, and that a prospective controlled study is warranted.
Indeed, the report of the Canadian Society of Nephrology (23) concerning the evidence-based recommendations about the management of IgAN concludes that patients with proteinuria >3 g/day, mild glomerular changes only and preserved renal function (ClCl >70 ml/min) should be treated with prednisolone. In patients with progressive disease (CrCl <70 ml/min) fish-oil should be given. Those with hypertension should be treated with ACE-I. Conversely, no evidence-based recommendations have been found-out for IgAN with moderate proteinuria and normal renal function. Similar conclusions have been drawn by the recently published evidence-based assessment of treatment options for children with IgA nephropathies (24).
In conclusion, the benefit of ACE-I in moderately proteinuric IgAN is supposed by almost each Nephrologist but not yet proved. And we must add that it is not sure that it will be proved by this or other trials, for several reasons. First of all the benefit seems quite clear when patients have >3 g/day proteinuria, while the decrease in urinary protein excretion (20 to 60%) in patients with lower amounts – eg from 2.2 to 1.6 g/day proteinuria – does not inequivocably lead to renoprotection. As recently stated by Dillon (9) the proteinuria reduction in IgAN is modest, and patients who lose 4.4 or 4.8 ml/min /year (as reported in unselected nephropahties) eventually develop end- stage renal failure.
Before claiming the usefulness of a drug, its effectiveness should be proved, or data must be available to correctly calculate the additional benefit of other interventions, eg extremely good BP control to get patients into the normal-low BP range, or adding Angiotensin receptor antagonists (AT1RA), or hepatic 3-methyl-glutaryl coenzime A (HMG-CoA), fish-oil, recombinant uteroglobin, or even prescribe aggressive therapy, as corticosteroids and anti cytokines.
We need a study defining the effect great or low as it could be, in order to further clearly find out if ACE-I at conventional doses is good enough or which other strategy might be beneficially applied to these IgAN patients to efficiently prevent renal function loss.