1INSERM Unit 507 and Service de Néphrologie, Hôpital Necker, Paris, France and 2Department of Nephrology and Dialysis, Azienda Ospedale di Lecco, Ospedale A. Manzoni, Lecco, Italy
Correspondence and offprint requests to: Tilman B. Drüeke, MD, FRCP, Unité 507 de Inserm et Service de Néphrologie, Hôpital Necker, 161 rue de Sèvres, 75743 Paris Cedex 15, France. Email: drueke{at}necker.fr
Keywords: discontinuation; financial reasons; research project; stopping
Recently, a multicentre clinical trial set up by nephrology groups in several countries in the European Union, under the instigation and with the active logistical support of the Zambon group in Italy, has been stopped at its very start, for undeclared reasons. In fact, the week before the first patients were to start their treatment protocol, the investigators were informed that the study was cancelled.
The purpose of the study was to examine possible beneficial effects of the antioxidant drug N-acetylcysteine (NAC), marketed by Zambon, on the anaemia of chronic haemodialysis patients. In particular, the intention was to test the hypothesis that patients receiving NAC might require less recombinant human epoetin to maintain blood haemoglobin at a constant level than patients receiving no NAC supplementation. It is not uncommon that uraemic patients exhibit a less than normal response to epoetin. These patients must therefore be considered as partially resistant to the hormones action. Their management requires upward adjustments of the weekly epoetin dose. One of the factors involved in the anaemia of patients with chronic kidney disease and epoetin hyporesponsiveness is oxidative stress, which is caused by an increased production of free oxygen radicals, diminished antioxidant defense, or both. This condition represents an increased relative risk for atherosclerosis and cardiovascular disease in patients with chronic renal failure. NAC, which is a water-soluble molecule, was shown to exert a marked antioxidant activity in pre-clinical studies conducted both in vitro and in vivo, as well as in clinical trials [14]. Specifically, NAC is capable of directly scavenging reactive oxygen species [1], and may act to rescue glutathione, a potent tripeptide within the intracellular pool of antioxidant molecules, by promoting the synthesis of GSH, a ubiquitous endogenous thiol with antioxidant properties [3]. We have demonstrated recently that NAC reduces in vitro phagocyte oxidative responses induced by advanced oxidation protein products (AOPP) in normal monocytes and normal as well as uraemic polymorphonuclear neutrophils [4]. It is important to note that NAC is used at present as an antidote in cases of acetaminophen poisoning, due to its antioxidant properties [5].
The NAC anaemia study planned in chronic haemodialysis patients was set up as a prospective, randomised, placebo-controlled and double-blind clinical trial. More than 30 European centres had agreed to participate. After study approval by ethical committees in each participating country, 264 patients had been recruited and had given informed consent. Regular blood sampling was scheduled for centralised routine laboratory determinations in Glasgow, UK, and research laboratory determinations in Paris, France. The protocol was about to start in February/March 2003 when the clinical investigators received short notice from the company that the study was cancelled. The company did not provide a written rationale or further details about the decision.
This abrupt discontinuation of the study closely resembles the procedure that has been adopted recently for the CONVINCE trial, which was also stopped to save money, as reported in an Editorial in JAMA [6]. The authors of this article point out that the commercial interruption of ongoing medical research is not unprecedented. We agree with them that this practice, when not motivated by safety considerations, questionable efficacy, ethical reasons or insufficient study power, constitutes a broken pact with researchers and patients. Clinical trials initiated by Industry cannot be handled like purely commercial transactions. Patients who have given their consent to participate in a trial testing a marketable product expose themselves to an unknown risk. They do this either for a potential personal benefit, by altruism for the improvement of health of other persons affected by the same or similar diseases, or for the advancement of science [6]. Therefore, the early discontinuation of trials for commercial reasons can be considered to represent a violation of the Declarations of Helsinki [7] and present legislation on bioethics in participating countries.
Finally, we are left with speculations about the possible reasons that may have motivated the interruption of the NAC anaemia trial. They include major changes in production and marketing priorities of the company, loss of confidence in the hypothetical usefulness of NAC in patients with chronic kidney disease, and an uncertain benefit with this or similar NAC indications since the drug is already commercially available. It is difficult to envisage the hypothesis of loss of confidence in the usefulness of NAC for the decision to cancel the trial. The potential benefit of NAC supplementation for CKD patients has considerably increased with a recent report by Tepel et al. [8], showing that treatment of chronic haemodialysis patients with NAC reduced composite cardiovascular endpoints such as fatal and non-fatal myocardial infarction, cardiovascular disease death, need for coronary angioplasty or coronary bypass surgery, ischaemic stroke, peripheral vascular disease with amputation, or need for angioplasty. This report was published 2 months before the present trial was interrupted. Although the trial was not powered to allow detection of individual cardiovascular endpoints including mortality, its positive results should have rather encouraged the Zambon group to conduct the present trial.
In conclusion, the discontinuation of the NAC anaemia trial for reasons, as yet unknown to us, is unacceptable in our opinion, once the patients had been asked to participate and had given informed consent. The study outcome was promising and the results of the trial might have been in our opinion beneficial for these patients and other patients with chronic kidney disease. This type of motivation for the interruption of a clinical trial is highly questionable.
Conflict of interest statement. T. B. Drueke, B. Descamps-Latscha and F. Locatelli report having served as consultants to Zambon, Milan, Italy and T. B. Drueke and B. Descamps-Latscha having received research funding from that company.
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