|LETTER TO EDITOR
|Ahead of print publication
Time to bring the background therapy to forefront
Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India
|Date of Submission||22-May-2021|
|Date of Acceptance||04-Jun-2021|
Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
We have had two great Phase 3 trials with two new drugs over the past few months. But, one issue that plagues both these trials is the issue of an inadequate background therapy. In ADVOCATE trial for avocapan, the steroids were tapered too rapidly and almost stopped by week 21, there were no repeat doses of rituximab beyond the induction for 4 weeks and no maintenance therapy prescribed, neither was cyclophosphamide given according to the European vasculitis group protocol, more so the mean daily dosage in avocapan group was 4 mg at week 52. Hence, the trial actually compared avocapan and low-dose steroids with inadequate treatment and found it superior. The AURORA trial did allow a mycophenolate mofetil (MMF) dose of 2 g in all its patients, but here also the steroids were tapered directly to 20 mg of prednisone equivalent by day 3 and tapered to 2.5 mg prednisone by month 4. Increasing MMF to 3 g, which is the usual target dose for induction in lupus nephritis, required the consent/approval of a medical expert. This reduces the chances of the patient to be on full-dose MMF and prevents the placebo group from receiving the true standard.
When you are comparing an immunosuppressive drug with a placebo, it is of utmost importance that both groups get a standard of care treatment. Getting inadequate treatment exposes the placebo group to higher chances of relapse and treatment failure as they do not have the additional immunosuppressive agent to fall back on, and these trial designs put the placebo group at a disadvantage from the onset. Both the trials swayed away from what is practiced clinically in terms of both dosages and duration of their background therapy. No clinician would stop steroids in a patient of ANCA vasculitis at week 21 or taper steroids to 20 or 25 mg at day 3 of treatment in patients with proliferative lupus nephritis.
We need to have a standardized treatment protocol for most of our diseases where the minimum and maximum doses and duration of the background therapy should be clearly stated, or it must be necessary to validate your background therapy to be equally effective in terms of remission, failure, and relapse rates. Having a Pre-defined Standardized background therapy is the need of the hour to provide a level playing field to the placebo when comparing it with a newer immunomodulator.
These drugs do offer hope to increase the scarce armamentarium of treatment we have in managing these difficult to treat disorders that not only have high mortality and morbidity but also greatly impact the quality of life but overestimating the utility of any new therapy by demeaning the standard of care can have grievous consequences given the cost of therapy and lack of knowledge about long-term side effects of these drugs.
A criterion to judge any new drug in a trial should always be the adequacy of background therapy and should be essential while designing a trial to assess a new drug.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Jayne DR, Merkel PA, Schall TJ, Bekker P, ADVOCATE Study Group. Avacopan for the treatment of ANCA-Associated Vasculitis. N Engl J Med 2021;384:599-609.
Rovin BH, Teng YK, Ginzler EM, Arriens C, Caster DJ, Romero-Diaz J, et al.
Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): A double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2021;397:2070-80.