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1.
J Am Soc Nephrol ; 28(9): 2756-2767, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28400446

ABSTRACT

Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%; P=0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%; P=0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.


Subject(s)
Aniline Compounds/therapeutic use , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy , Glucocorticoids/therapeutic use , Nipecotic Acids/therapeutic use , Prednisone/therapeutic use , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , Adult , Aged , Aniline Compounds/adverse effects , Cyclophosphamide/therapeutic use , Double-Blind Method , Drug Therapy, Combination/adverse effects , Female , Glucocorticoids/administration & dosage , Glucocorticoids/adverse effects , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Nipecotic Acids/adverse effects , Prednisone/administration & dosage , Prednisone/adverse effects , Rituximab/therapeutic use , Severity of Illness Index
2.
Nephrol Dial Transplant ; 31(12): 2108-2114, 2016 12.
Article in English | MEDLINE | ID: mdl-26769682

ABSTRACT

BACKGROUND: Primary membranous nephropathy is associated with variable clinical course ranging from spontaneous remission to slow progression to end stage renal failure. Achieving remission confers better renal survival in primary membranous nephropathy (PMN). Longer term outcomes such as patient survival and relapse of active disease remain poorly understood. METHODS: We performed a retrospective study of 128 consecutive adult patients diagnosed with biopsy proven PMN at a single UK centre between 1980 and 2010. These patients were followed prospectively over a median of 128 months. We assessed impact of persistent disease and relapse on Stage 5 chronic kidney disease (CKD-5) and patient survival and present longer term cumulative incidences of different end points. RESULTS: One hundred patients achieved partial remission (PartRem) and 28 patients did not achieve remission (NoRem). Nine per cent of patients achieving first remission developed CKD-5 and 75% of those with NoRem developed CKD-5 [hazard ratio (HR) 0.07, 95% confidence interval 0.03-0.19). Relapse following PartRem occurred in 31 patients (31%) during follow-up and was significantly associated with progression to CKD-5. Progression to CKD-5 was strongly associated with death (47 versus 6%, HR 23.4; P < 0.01). Cumulative incidence at 15 years following first presentation included: death, 14%; CKD-5, 28%; and relapse 40% (in patients who achieved first remission). CONCLUSIONS: Our data strongly suggest that mortality in PMN is seen in patients with disease progression to CKD-5. Achieving remission is strongly associated with improved renal survival after first presentation and following relapse. We suggest that patients who achieve remission should be followed up in longer term, and better strategies to help improve outcomes are needed in clinical practice.


Subject(s)
Glomerulonephritis, Membranous/pathology , Kidney Failure, Chronic/pathology , Adolescent , Adult , Disease Progression , Female , Glomerular Filtration Rate , Glomerulonephritis, Membranous/mortality , Glomerulonephritis, Membranous/therapy , Humans , Kaplan-Meier Estimate , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/therapy , Male , Middle Aged , Proportional Hazards Models , Proteinuria/mortality , Proteinuria/pathology , Proteinuria/therapy , Recurrence , Retrospective Studies , Treatment Outcome
4.
Pharmacoeconomics ; 32(12): 1171-83, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25059204

ABSTRACT

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of rituximab (Roche Products) to submit evidence of the clinical and cost effectiveness of rituximab in combination with corticosteroids for treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology, based upon the manufacturer's submission to NICE. The evidence was derived mainly from a double-blind, phase III, placebo-controlled trial of rituximab in patients with new or relapsed 'severe' AAV, which compared a rituximab treatment regimen with an oral cyclophosphamide treatment regimen. Intravenous cyclophosphamide is also commonly used but was not included in the pivotal trial. The evidence showed that rituximab is noninferior to oral cyclophosphamide in terms of induction of remission in adults with AAV and de novo disease, and is superior to oral cyclophosphamide in terms of remission in adults who have relapsed once on cyclophosphamide. The ERG concluded that the results of the manufacturer's economic evaluation could not be considered robust, because of errors and because the full range of relevant treatment sequences were not modelled. The ERG amended the manufacturer's model and demonstrated that rituximab was likely to represent a cost-effective addition to the treatment sequence if given after cyclophosphamide treatment.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Technology Assessment, Biomedical , Administration, Oral , Adrenal Cortex Hormones/administration & dosage , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Clinical Trials, Phase III as Topic , Cost-Benefit Analysis , Cyclophosphamide/administration & dosage , Cyclophosphamide/therapeutic use , Drug Therapy, Combination , Humans , Rituximab
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