- Email: [email protected]
Safety and efficacy of vigabatrin and carbamazepine
6-mercaptopurine. The 11 Crohn’s patients were followed on an intentionto-treat basis for a median of 11·5 months. Eight patients had taken mycophenolate mofetil for 6 months or longer, and four of these patients were taking the drug for longer than 12 months. Patients were prescribed mycophenolate mofetil 2 g daily, which in one case was increased to 3 g after no response was seen at 3 months. Two of 11 patients with Crohn’s colitis had complete response (CDAI <150) and three had partial responses (CDAI decline <100 points), but only three of the original Crohn’s patients maintained remission (one complete, two partial). Three of 11 patients who responded at 3 months1 have relapsed, two stopped therapy at 3 months because they did not respond, and one patient stopped therapy because of intolerable nausea and vomiting. We used mycophenolate mofetil instead of azathioprine or 6mercaptopurine because of adverse events associated with azathioprine and 6-mercaptopurine and the slow onset of their effect. However, the initial favourable complete (75%) and partial (17%) response rates that we reported at 3 months1 were not sustained beyond 6 months in most patients with severe Crohn’s disease. Apart from the fact that we have used the treatment in a group of patients with severe inflammatory bowel disease, there are pharmacokinetic and pharmacodynamic issues that may affect efficacy (and safety) in the longer term. First, mycophenolic acid is highly bound to human albumin (>98% in healthy individuals), and the pharmacological activity of mycophenolic acid is thought to be a function of unbound drug concentration.4 There is probably more free mycophenolic acid and thus active drug available in sicker Crohn’s patients with low albumin. Second, Sanquer and colleagues5 report that the efficiency of mycophenolate mofetil, as an inhibitor of inosine monophosphate dehydrogenase, is reduced with time and moreover that there is substantial stimulation of inosine monophosphate dehydrogenase activity after 2 years’ mycophenolate mofetil treatment in renal transplant patients. We agree with Lowry and colleagues’ conclusion2 that “the safety and efficacy of mycophenolate mofetil as maintenance therapy of Crohn’s disease should be addressed”. We need to know more about the pharmacokinetics and pharmacodynamics of this therapy in inflammatory bowel disease patients before it can be advocated as an alternative therapy to azathioprine or 6-mercaptopurine. Our subsequent
THE LANCET • Vol 354 • October 16, 1999
experience and pharmacodynamic data of longer-term use in renal transplant patients are not so promising. Graham L Radford-Smith, Paul Taylor, *Timothy H J Florin Brisbane Inflammatory Bowel Diseases Research Centre, Department of Medicine, University of Queensland, St Lucia 4072, Queensland, Australia (e-mail: [email protected]) 1
Florin T, Roberts R, Watson M, Radford-Smith G. Treatment of steroid refractory inflammatory bowel disease (IBD) with mycophenolate mofetil (MMF). Aust NZ J Med 1998; 28: 344–45. 2 Lowry P, Sandborn W, Lipsky J. Mycophenolate mofetil for Crohn’s disease? Lancet 1999; 354: 3–4. 3 Neurath M, Wanitschke R, Peters M, Krummenauer F, Buschenfelde MZ, Schlaak J. Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn’s disease. Gut 1999; 44: 625–28. 4 Nowak I, Shaw LM. Mycophenolic acid binding to human serum albumin: characterization and relation to pharmacodynamics. Clin Chem 1995; 41: 1011–17. 5 Sanquer S, Breil M, Baron C, Dhamane D, Astier A, Lang P. Induction of inosine monophosphate dehydrogenase activity after long-term treatment with mycophenolate mofetil. Clin Pharmacol Ther 1999; 65: 640–48.
Safety and efficacy of vigabatrin and carbamazepine Sir—David Chadwick and colleagues (July 3, p 13)1 conclude that vigabatrin is less effective but better tolerated than carbamazepine in the treatment of newly diagnosed partial epilepsy and that therefore vigabatrin cannot be recommended as a first-line drug for monotherapy in this group of patients. However, although they mention the risk of developing concentric visual field defects on vigabatrin, this safety issue has not been taken into account in their recommendations, which seem solely based on their study results. The occurrence of severe symptomatic concentric visual field defects has been reported in patients since 1997.2 The prevalence of symptomless field defects under vigabatrin is estimated at about 30%.3 Evidence suggests that visual field defects are irreversible even after discontinuation of vigabatrin. The precise mechanism of action is unclear but Baulac and colleagues 4 h a v e suggested a direct toxic effect by ␥aminobutyric acid on the retina. Severe symptomatic visual field defects implies functional blindness, but the functional impact of symptomless defects should also not
be underestimated. Symptomless here merely means that the patient is not aware of the defect, but that interference with normal functioning might have started much earlier. Moreover, before visual field defects become symptomatic, in the sense of being recognised by the patient, the defect must be substantial. There is, however, no rationale for waiting until symptomless visual defects become symptomatic because irreversible harm will have been done. The Committee for Proprietary Medicinal Products (CPMP) reviewed the benefit/risk profile of vigabatrin with special emphasis on this safety issue. As was indicated in a letter to doctors issued by the marketing authorisation holder, the indication for vigabatrin should be restricted to addon therapy in both adults and children, but only after all other appropriate drug combinations have failed. The risk/benefit profile for vigabatrin as monotherapy, taking into account Chadwick’s findings is negative. For infantile spasms the benefit/risk profile is regarded as acceptable since alternatives with a more favourable profile are lacking. Safeguards for early detection of visual field defects by periodic perimetry are recommended, although in young children validated methods for detecting visual field defects need to be developed. *A J A Elferink, M Toivonen, H van Bronswijk, on behalf of CPMP *Medicines Evaluation Board, PO Box 16229, 2500 BE The Hague, Netherlands; National Agency for Medicines, Finland 1
Chadwick D, Vigabatrin European Monotherapy Study Group. Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised double-blind study. Lancet 1999; 354: 13–19. 2 Eke T, Talbot JF, Lawden MC. Severe persistent visual field constriction associated with vigabatrin. BMJ 1998; 314: 180–81. 3 Revised SPC of Sabril, June, 1999. 4 Baulac M, Bordmann JP, Lanoé Y. Severe visual field construction and side-effects of GBA-mimetic antiepileptic agents. Lancet 1998; 352: 546.
Author’s reply Sir—I welcome the comments from A J A Elferink and colleagues. Because my colleagues and I had undertaken a randomised controlled trial (RCT), we felt it best to restrict our comments to conclusions that can reasonably be drawn from the entirety of RCTs comparing vigabatrin and carbamazepine as monotherapy. RCTs are sensitive to comparisons of short to medium term efficacy and tolerability. Issues such as chronic toxicity and
1387
safety require long-term follow-up of patients, which is not always practical in the context of RCT, and are more easily investigated in observational studies. These long-term outcomes are of considerable relevance to epilepsy in view of the chronic nature of the condition. It is also noteworthy that: (1) RCTs designed to demonstrate efficacy will never have the power to detect rare but potentially serious sideeffects; and (2) there are considerable ethical difficulties about investigating teratogenicity and other adverse events in RCTs. Regulatory agencies inevitably have access to more post-marketing safety related data than do groups of investigators, and are thus in a better position to overview efficacy evidence from RCTs along with chronic toxicity data. We do not disagree with the CPMP’s conclusions that vigabatrin should now be a drug of last resort for the treatment of partial epilepsy, when it will usually be given as a combined therapy rather than monotherapy. We hoped that our discussion had given a reasonably balanced view, but it is important to recognise that much of the compelling evidence indicating a causal relation between longer term exposure to vigabatrin and the occurrence of typical constrictive visual field defects only became public knowledge during the time that our report was within the editorial process. Although there is still some doubt about the frequency of symptomless and symptomatic visual field defects, and the factors that may determine frequency, we agree, especially in view of the probable irreversibility of defects, that vigabatrin should not be used routinely in patients with partial epilepsy. The position of children with infantile spasms is, however, much more difficult, with the drawbacks to monitoring visual fields in young children. This issue highlights an important principle for those undertaking systematic reviews of the effects of treatments—and the Cochrane Collaboration in particular. The methodologies for summarising RCTs are well developed, but the methods for summarising evidence from nonrandomised studies are far less certain. Despite these methodological uncertainties, important safety data are likely to arise from nonrandomised studies, and these data should be incorporated into systematic reviews. David Chadwick Neurological Science, Walton Centre for Neurology and Neurosurgery, Liverpool L9 7LJ, UK
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Immunotherapy with Mycobacterium vaccae Sir—The study on M y c o b a c t e r i u m vaccae in patients with pulmonary tuberculosis reported by the Durban Immunotherapy Trial Group (July 10, p 116)1 concludes that M vaccae has no benefit when added to standard antituberculosis chemotherapy. This result may be a premature conclusion because of a flaw in the trial in that only one dose of M vaccae was given. We have monitored the immunological effects of M vaccae on patients with cancer and concluded that repeated vaccination is required to induce a change in the cytokine pattern to that of a Th1 or cellmediated response, which in turn is associated with objective clinical responses and increased survival. 2,3 It is likely that African patients with tuberculosis and probable entrenched Th2 dominant responses would also need a multiple vaccination schedule to achieve clinical benefit, which is reasonable to expect if a sustained Th1 response is achieved. Minor changes in the starting conditions, especially in the number of doses administered, readily explain successes and failure with apparent similar vaccines used in cancer treatment and may be the case in the immunotherapy of chronic infectious diseases such as tuberculosis.4 A G Dalgleish Division of Oncology, Department of Cellular and Molecular Sciences, St George’s Hospital Medical School, London SW17 ORE, UK 1
Durban Immunotherapy Trial Group. Immunotherapy with Mycobacterium vaccae in patients with newly diagnosed pulmonary tuberculosis: a randomised controlled trial. Lancet 1999; 354: 116–19. 2 Hrouda D, Baban B, Dunsmuir WD, Kirby RS, Dalgleish AG. Immunotherapy of advanced prostate cancer: a phase I/II trial using Mycobacterium vaccae (SLR-172). Br J Urol 1998; 82: 568–73. 3 Maraveyas A, Baban B, Kennard D, et al. Possible improved survival of patients with stage IV AJCC melanoma receiving SRL 172 immunotherapy: correlation with induction of increased levels of intracellular interleukin 2 in peripheral blood lymphocytes. Ann Oncol 1999; 101: 817–27. 4 Dalgleish AG. The relevance of non-linear mathematics (chaos theory) to the treatment of cancer; the role of the immune response and the potential for vaccines. QJM 1999; 92: 347–59.
multiple doses of M vaccae as an adjunct to conventional chemotherapy in patients with newly diagnosed pulmonary tuberculosis. At the time of starting the study, evidence from previous studies1–4 indicated that a single dose would be sufficient. The references cited by Dalgleish that favour multiple doses of M vaccae were all fairly recent and published long after the start of our study. Furthermore, all studies mentioned referred to cancer immunotherapy, which cannot serve as a model for the hypothesis we aimed to investigate.1 We acknowledged the possibility that multiple doses may be an important variable to investigate, however, in the case of tuberculosis we believe that the timing of the administration of M vaccae, might be a more important issue to consider for future studies. The appropriate time point might be at the point of sputum-smear conversion when the bacillary load would have been substantially decreased and the immunological perturbation attendant on a continuous bacillary load reduced sufficiently to unmask the effect of immunotherapy. In support of this statement, as we pointed out, is the Romanian M vaccae immunotherapy study1 in which intervention was given at 1 month from the start of chemotherapy and in which a significantly higher conversion rate was documented at 2 months. 3 The difference was, however, not sustained at the end of short-course chemotherapy. It is important to point out that the potential to drive a predominant type-1 response in advanced multicavitatory pulmonary tuberculosis might not equate to faster sputum conversion, especially when compared with the best chemotherapeutic regimens available for treating the disease. The evidence from work in animals, in which rabbits with cavitatory pulmonary tuberculosis were exposed to M vaccae immunotherapy, and no effect was shown,5 supports the contention that such pathological variables may need to be accommodated in future immunotherapeutic constructs. We do not agree that our trial was flawed, rather we addressed a question on the basis of available evidence at the time of the design of the trial and this showed no additional benefit with a single dose of M vaccae in adjunctive therapy over short-course chemotherapy for tuberculosis.
Authors’ reply
*P C Onyebujoh, J B Levin, P B Fourie
Sir—A G Dalgleish challenges the neutral outcome of our trial. He questions the wisdom of a trial design and the use of a single dose rather than
*National Tuberculosis Research Programme, Medical Research Council, Private Bag X385, 001 Pretoria, South Africa; and Division for Biostatistics, Center for Epidemiological Research in South Africa, Medical Research Council, Pretoria
THE LANCET • Vol 354 • October 16, 1999
THE LANCET • Vol 354 • October 16, 1999
experience and pharmacodynamic data of longer-term use in renal transplant patients are not so promising. Graham L Radford-Smith, Paul Taylor, *Timothy H J Florin Brisbane Inflammatory Bowel Diseases Research Centre, Department of Medicine, University of Queensland, St Lucia 4072, Queensland, Australia (e-mail: [email protected]) 1
Florin T, Roberts R, Watson M, Radford-Smith G. Treatment of steroid refractory inflammatory bowel disease (IBD) with mycophenolate mofetil (MMF). Aust NZ J Med 1998; 28: 344–45. 2 Lowry P, Sandborn W, Lipsky J. Mycophenolate mofetil for Crohn’s disease? Lancet 1999; 354: 3–4. 3 Neurath M, Wanitschke R, Peters M, Krummenauer F, Buschenfelde MZ, Schlaak J. Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn’s disease. Gut 1999; 44: 625–28. 4 Nowak I, Shaw LM. Mycophenolic acid binding to human serum albumin: characterization and relation to pharmacodynamics. Clin Chem 1995; 41: 1011–17. 5 Sanquer S, Breil M, Baron C, Dhamane D, Astier A, Lang P. Induction of inosine monophosphate dehydrogenase activity after long-term treatment with mycophenolate mofetil. Clin Pharmacol Ther 1999; 65: 640–48.
Safety and efficacy of vigabatrin and carbamazepine Sir—David Chadwick and colleagues (July 3, p 13)1 conclude that vigabatrin is less effective but better tolerated than carbamazepine in the treatment of newly diagnosed partial epilepsy and that therefore vigabatrin cannot be recommended as a first-line drug for monotherapy in this group of patients. However, although they mention the risk of developing concentric visual field defects on vigabatrin, this safety issue has not been taken into account in their recommendations, which seem solely based on their study results. The occurrence of severe symptomatic concentric visual field defects has been reported in patients since 1997.2 The prevalence of symptomless field defects under vigabatrin is estimated at about 30%.3 Evidence suggests that visual field defects are irreversible even after discontinuation of vigabatrin. The precise mechanism of action is unclear but Baulac and colleagues 4 h a v e suggested a direct toxic effect by ␥aminobutyric acid on the retina. Severe symptomatic visual field defects implies functional blindness, but the functional impact of symptomless defects should also not
be underestimated. Symptomless here merely means that the patient is not aware of the defect, but that interference with normal functioning might have started much earlier. Moreover, before visual field defects become symptomatic, in the sense of being recognised by the patient, the defect must be substantial. There is, however, no rationale for waiting until symptomless visual defects become symptomatic because irreversible harm will have been done. The Committee for Proprietary Medicinal Products (CPMP) reviewed the benefit/risk profile of vigabatrin with special emphasis on this safety issue. As was indicated in a letter to doctors issued by the marketing authorisation holder, the indication for vigabatrin should be restricted to addon therapy in both adults and children, but only after all other appropriate drug combinations have failed. The risk/benefit profile for vigabatrin as monotherapy, taking into account Chadwick’s findings is negative. For infantile spasms the benefit/risk profile is regarded as acceptable since alternatives with a more favourable profile are lacking. Safeguards for early detection of visual field defects by periodic perimetry are recommended, although in young children validated methods for detecting visual field defects need to be developed. *A J A Elferink, M Toivonen, H van Bronswijk, on behalf of CPMP *Medicines Evaluation Board, PO Box 16229, 2500 BE The Hague, Netherlands; National Agency for Medicines, Finland 1
Chadwick D, Vigabatrin European Monotherapy Study Group. Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised double-blind study. Lancet 1999; 354: 13–19. 2 Eke T, Talbot JF, Lawden MC. Severe persistent visual field constriction associated with vigabatrin. BMJ 1998; 314: 180–81. 3 Revised SPC of Sabril, June, 1999. 4 Baulac M, Bordmann JP, Lanoé Y. Severe visual field construction and side-effects of GBA-mimetic antiepileptic agents. Lancet 1998; 352: 546.
Author’s reply Sir—I welcome the comments from A J A Elferink and colleagues. Because my colleagues and I had undertaken a randomised controlled trial (RCT), we felt it best to restrict our comments to conclusions that can reasonably be drawn from the entirety of RCTs comparing vigabatrin and carbamazepine as monotherapy. RCTs are sensitive to comparisons of short to medium term efficacy and tolerability. Issues such as chronic toxicity and
1387
safety require long-term follow-up of patients, which is not always practical in the context of RCT, and are more easily investigated in observational studies. These long-term outcomes are of considerable relevance to epilepsy in view of the chronic nature of the condition. It is also noteworthy that: (1) RCTs designed to demonstrate efficacy will never have the power to detect rare but potentially serious sideeffects; and (2) there are considerable ethical difficulties about investigating teratogenicity and other adverse events in RCTs. Regulatory agencies inevitably have access to more post-marketing safety related data than do groups of investigators, and are thus in a better position to overview efficacy evidence from RCTs along with chronic toxicity data. We do not disagree with the CPMP’s conclusions that vigabatrin should now be a drug of last resort for the treatment of partial epilepsy, when it will usually be given as a combined therapy rather than monotherapy. We hoped that our discussion had given a reasonably balanced view, but it is important to recognise that much of the compelling evidence indicating a causal relation between longer term exposure to vigabatrin and the occurrence of typical constrictive visual field defects only became public knowledge during the time that our report was within the editorial process. Although there is still some doubt about the frequency of symptomless and symptomatic visual field defects, and the factors that may determine frequency, we agree, especially in view of the probable irreversibility of defects, that vigabatrin should not be used routinely in patients with partial epilepsy. The position of children with infantile spasms is, however, much more difficult, with the drawbacks to monitoring visual fields in young children. This issue highlights an important principle for those undertaking systematic reviews of the effects of treatments—and the Cochrane Collaboration in particular. The methodologies for summarising RCTs are well developed, but the methods for summarising evidence from nonrandomised studies are far less certain. Despite these methodological uncertainties, important safety data are likely to arise from nonrandomised studies, and these data should be incorporated into systematic reviews. David Chadwick Neurological Science, Walton Centre for Neurology and Neurosurgery, Liverpool L9 7LJ, UK
1388
Immunotherapy with Mycobacterium vaccae Sir—The study on M y c o b a c t e r i u m vaccae in patients with pulmonary tuberculosis reported by the Durban Immunotherapy Trial Group (July 10, p 116)1 concludes that M vaccae has no benefit when added to standard antituberculosis chemotherapy. This result may be a premature conclusion because of a flaw in the trial in that only one dose of M vaccae was given. We have monitored the immunological effects of M vaccae on patients with cancer and concluded that repeated vaccination is required to induce a change in the cytokine pattern to that of a Th1 or cellmediated response, which in turn is associated with objective clinical responses and increased survival. 2,3 It is likely that African patients with tuberculosis and probable entrenched Th2 dominant responses would also need a multiple vaccination schedule to achieve clinical benefit, which is reasonable to expect if a sustained Th1 response is achieved. Minor changes in the starting conditions, especially in the number of doses administered, readily explain successes and failure with apparent similar vaccines used in cancer treatment and may be the case in the immunotherapy of chronic infectious diseases such as tuberculosis.4 A G Dalgleish Division of Oncology, Department of Cellular and Molecular Sciences, St George’s Hospital Medical School, London SW17 ORE, UK 1
Durban Immunotherapy Trial Group. Immunotherapy with Mycobacterium vaccae in patients with newly diagnosed pulmonary tuberculosis: a randomised controlled trial. Lancet 1999; 354: 116–19. 2 Hrouda D, Baban B, Dunsmuir WD, Kirby RS, Dalgleish AG. Immunotherapy of advanced prostate cancer: a phase I/II trial using Mycobacterium vaccae (SLR-172). Br J Urol 1998; 82: 568–73. 3 Maraveyas A, Baban B, Kennard D, et al. Possible improved survival of patients with stage IV AJCC melanoma receiving SRL 172 immunotherapy: correlation with induction of increased levels of intracellular interleukin 2 in peripheral blood lymphocytes. Ann Oncol 1999; 101: 817–27. 4 Dalgleish AG. The relevance of non-linear mathematics (chaos theory) to the treatment of cancer; the role of the immune response and the potential for vaccines. QJM 1999; 92: 347–59.
multiple doses of M vaccae as an adjunct to conventional chemotherapy in patients with newly diagnosed pulmonary tuberculosis. At the time of starting the study, evidence from previous studies1–4 indicated that a single dose would be sufficient. The references cited by Dalgleish that favour multiple doses of M vaccae were all fairly recent and published long after the start of our study. Furthermore, all studies mentioned referred to cancer immunotherapy, which cannot serve as a model for the hypothesis we aimed to investigate.1 We acknowledged the possibility that multiple doses may be an important variable to investigate, however, in the case of tuberculosis we believe that the timing of the administration of M vaccae, might be a more important issue to consider for future studies. The appropriate time point might be at the point of sputum-smear conversion when the bacillary load would have been substantially decreased and the immunological perturbation attendant on a continuous bacillary load reduced sufficiently to unmask the effect of immunotherapy. In support of this statement, as we pointed out, is the Romanian M vaccae immunotherapy study1 in which intervention was given at 1 month from the start of chemotherapy and in which a significantly higher conversion rate was documented at 2 months. 3 The difference was, however, not sustained at the end of short-course chemotherapy. It is important to point out that the potential to drive a predominant type-1 response in advanced multicavitatory pulmonary tuberculosis might not equate to faster sputum conversion, especially when compared with the best chemotherapeutic regimens available for treating the disease. The evidence from work in animals, in which rabbits with cavitatory pulmonary tuberculosis were exposed to M vaccae immunotherapy, and no effect was shown,5 supports the contention that such pathological variables may need to be accommodated in future immunotherapeutic constructs. We do not agree that our trial was flawed, rather we addressed a question on the basis of available evidence at the time of the design of the trial and this showed no additional benefit with a single dose of M vaccae in adjunctive therapy over short-course chemotherapy for tuberculosis.
Authors’ reply
*P C Onyebujoh, J B Levin, P B Fourie
Sir—A G Dalgleish challenges the neutral outcome of our trial. He questions the wisdom of a trial design and the use of a single dose rather than
*National Tuberculosis Research Programme, Medical Research Council, Private Bag X385, 001 Pretoria, South Africa; and Division for Biostatistics, Center for Epidemiological Research in South Africa, Medical Research Council, Pretoria
THE LANCET • Vol 354 • October 16, 1999