- Email: [email protected]
Termination of Acute Stroke Studies Involving Selfotel Treatment
THE LANCET
4000 mg/dL). Small bowel enteroclysis was normal. Body weight was 38 kg (height 171 cm). After 3 months of tetracycline an increase of weight of 25 kg was noted. However, duodenal and intra-abdominal lymphoma were unchanged and IgA did not return to normal. Seven courses of polychemotherapy (cychophosphamide, doxorubicin, vincristine, prednisone) from November, 1992, to June, 1993, did not cause lymphoma regression. IgA did, alone, return to normal. Furthermore, the lymphoma was still detectable after administration of four courses of vinblastine, etoposide, epirubicin, and prednisone, and after abdominal irradiation (18 Gy). Diagnostic re-evaluation in May, 1995, showed gastric metaplasia in the duodenal bulb infected with Helicobacter pylori and infiltrates of IPSID with monoclonal heavy-chain rearrangement. Omeprazole, amoxicillin, and clarithromycin were given for 7 days. For the first time the patient became symptom-free. Diagnostic work-up including endoscopic ultrasound and abdominal computed tomography in November, 1995, and March, 1996, confirmed complete lymphoma regression. Alkan and colleagues reported in this journal the disappearance of salivary gland MALT lymphoma after Helicobacter pylori eradication.4 Contrary to their findings, in our study Helicobacter pylori infection was located in (metaplastic) gastric mucosa where it is known to be associated with the development of MALT-type lymphoma. 1
2
3
4
Wotherspoon AC, Doglioni C, Diss TC, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 1993; 342: 575–77. Bayerdörffer E, Neubauer A, Rudolph B, et al. Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. Lancet 1995; 345: 1591–94. Roggero E, Zucca E, Pinotti G, et al. Eradication of Helicobacter pylori infection in primary gastric low-grade gastric lymphoma of mucosaassociated lymphoid tissue. Ann Intern Med 1995; 122: 767–69. Alkan S, Karcher DS, Newman MA, Cohen P. Regression of salivary gland MALT lymphoma after treatment for Helicobacter pylori. Lancet 1996; 348: 268–69.
Medical Department II, Klinikum Aschaffenburg, Akademisches Lehrkrankenhaus der Universität Würzburg, D-63739 Aschaffenburg, Germany (W Fischbach); Medical Department II, Kliniken des MainTaunus-Kreises; and Institute for Pathology, University of Würzburg
Termination of Acute Stroke Studies Involving Selfotel Treatment Stephen M Davis, Gregory W Albers, Hans-Christoph Diener, Kennedy R Lees, John Norris (ASSIST Steering Committee)
Selfotel, a selective competitive N-methyl-D-aspartate antagonist, has neuroprotective efficacy in animal models of focal and global ischaemia and traumatic brain injury. In these models, selfotel was shown to reduce ischaemia-induced neuronal cell death and infarct size, and to attenuate neuronal injury.1 In a phase II study, an intravenous bolus dose of 1·5 mg/kg administered within 6 h of onset of acute ischaemic stroke was safe and potentially effective.2,3 To determine whether selfotel improved the outcome of acute ischaemic stroke and severe traumatic brain injury, two multinational placebo-controlled trials for each indication were initiated. After review of the aggregate data from the four trials and considering both safety and potential benefit, an independent Data and Safety Monitoring Board (DSMB) recommended that enrolment in the selfotel programme be suspended and that the trials be terminated. We report the results from these two stroke trials. The ASSIST (Acute Stroke Studies Involving Selfotel Treatment) programme involved two trials, one conducted in
32
Europe, Australia, Argentina, and Canada (Protocol 10 IC/STE1), and the other in the USA and Israel (Protocol 07). The hypothesis tested in these double-blind, randomised, placebo-controlled trials was that 1·5 mg/kg selfotel administered intravenously within 6 h of stroke onset would improve functional outcome at 3 months defined as the proportion of patients reaching a score of at least 60 on the Barthel Index (BI). Patient accrual began in September, 1994. By December, 1995, 509 patients had been enrolled in the two trials and data from 476 patients (389 in Protocol 10 IC/STE1 and 87 in Protocol 07) were in the database. Of these, 328 patients had 3-month outcome data available for analysis (274 in Protocol 10 IC/STE1 and 54 in Protocol 07). Comparison of baseline demographic variables showed that the treatment groups were well-matched for sex, initial stroke severity (based on the Scandinavian Stroke Scale [SSS]4), and time from stroke onset to therapy:
Male (%) Mean (SD) age Mean (SD) baseline SSS Mean (SD) time to treatment
Selfotel (n=237)
Placebo (n=239)
130 (54·9) 70·2 (9·9) 12·5 (5·0) 4 h 32 min (1 h 6 min)
141 (60·0) 68·7 (10·2) 12·6 (4·6) 4 h 29 min (1 h 8 min)
The overall mortality rate at the time enrolment was suspended was 22% (103/476). The mortality rate from all causes was 24% (58/237) in the selfotel group compared with 19% (45/239) in the placebo group. This difference was not significant (RR=1·3; 95% CI 0·92–1·83; p=0·15). However, review of individual case fatalities by the DSMB raised concern over an imbalance against selfotel in the number of deaths related to brain insult. The mortality from brainrelated events (primarily cerebral oedema and progression of stroke) was 13% in the selfotel group and 5% in the placebo group (p=0·003). To determine whether the benefit of selfotel treatment might outweigh any potential risk, the probability of demonstrating efficacy based on the primary outcome variable (the proportion of patients achieving a BI of at least 60 at day 90), was calculated with a Bayesian approach on the observed rates of BI at least 60.5 The proportion of patients with a BI score at least 60 was 47% (78/166) in the selfotel group and 49% (80/162) in the placebo group. For the individual trials, the proportion of patients with a BI score at least 60 in Protocol 10 IC/STE1 was 47% (64/137) and 51% (70/137) in the selfotel and placebo groups respectively, and 48% (14/29) in the selfotel group and 40% (10/25) in the placebo group in Protocol 07. The probability of demonstrating efficacy in the individual trials had they proceeded was 0·28 (n=274) and 0·82 (n=54) in Protocols 10 IC/STE1 and 07, respectively. It was considered that the apparent high probability of success in the latter trial may have reflected the small sample size. This work was funded by Ciba-Geigy Ltd, Basel, Switzerland. 1
2
3
4 5
Markabi S. Selfotel (CGS 19755): the preliminary clinical experience. In: Krieglstein J, Oberpichler-Schwenk H, eds. Pharmacology of cerebral ischemia. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH, 1994: 635–42. Grotta J, Clark W, Coull B, et al. Safety and tolerability of glutamate antagonist CGS 19755 (selfotel) in patients with acute ischemic stroke: results of a phase IIa randomized trial. Stroke 1995; 26: 602–05. Clark WM, et al. Randomized trial of CGS 19755, a glutamate antagonist, in acute ischemic stroke treatment. Neurology 1994; 44 (suppl 2): A270. Scandinavian Stroke Study Group. Multicenter trial of hemodilution in stroke-background and study protocol. Stroke 1985; 16: 885–90. Spiegelhalter DJ, et al. Monitoring clinical trials: conditional or predictive power? Control Clin Trials 1986; 7: 8–17.
Department of Neurology, Melbourne Neuroscience Centre, The Royal Melbourne Hospital, Victoria 3050, Australia (Stephen Davis)
Vol 349 • January 4, 1997
4000 mg/dL). Small bowel enteroclysis was normal. Body weight was 38 kg (height 171 cm). After 3 months of tetracycline an increase of weight of 25 kg was noted. However, duodenal and intra-abdominal lymphoma were unchanged and IgA did not return to normal. Seven courses of polychemotherapy (cychophosphamide, doxorubicin, vincristine, prednisone) from November, 1992, to June, 1993, did not cause lymphoma regression. IgA did, alone, return to normal. Furthermore, the lymphoma was still detectable after administration of four courses of vinblastine, etoposide, epirubicin, and prednisone, and after abdominal irradiation (18 Gy). Diagnostic re-evaluation in May, 1995, showed gastric metaplasia in the duodenal bulb infected with Helicobacter pylori and infiltrates of IPSID with monoclonal heavy-chain rearrangement. Omeprazole, amoxicillin, and clarithromycin were given for 7 days. For the first time the patient became symptom-free. Diagnostic work-up including endoscopic ultrasound and abdominal computed tomography in November, 1995, and March, 1996, confirmed complete lymphoma regression. Alkan and colleagues reported in this journal the disappearance of salivary gland MALT lymphoma after Helicobacter pylori eradication.4 Contrary to their findings, in our study Helicobacter pylori infection was located in (metaplastic) gastric mucosa where it is known to be associated with the development of MALT-type lymphoma. 1
2
3
4
Wotherspoon AC, Doglioni C, Diss TC, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 1993; 342: 575–77. Bayerdörffer E, Neubauer A, Rudolph B, et al. Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. Lancet 1995; 345: 1591–94. Roggero E, Zucca E, Pinotti G, et al. Eradication of Helicobacter pylori infection in primary gastric low-grade gastric lymphoma of mucosaassociated lymphoid tissue. Ann Intern Med 1995; 122: 767–69. Alkan S, Karcher DS, Newman MA, Cohen P. Regression of salivary gland MALT lymphoma after treatment for Helicobacter pylori. Lancet 1996; 348: 268–69.
Medical Department II, Klinikum Aschaffenburg, Akademisches Lehrkrankenhaus der Universität Würzburg, D-63739 Aschaffenburg, Germany (W Fischbach); Medical Department II, Kliniken des MainTaunus-Kreises; and Institute for Pathology, University of Würzburg
Termination of Acute Stroke Studies Involving Selfotel Treatment Stephen M Davis, Gregory W Albers, Hans-Christoph Diener, Kennedy R Lees, John Norris (ASSIST Steering Committee)
Selfotel, a selective competitive N-methyl-D-aspartate antagonist, has neuroprotective efficacy in animal models of focal and global ischaemia and traumatic brain injury. In these models, selfotel was shown to reduce ischaemia-induced neuronal cell death and infarct size, and to attenuate neuronal injury.1 In a phase II study, an intravenous bolus dose of 1·5 mg/kg administered within 6 h of onset of acute ischaemic stroke was safe and potentially effective.2,3 To determine whether selfotel improved the outcome of acute ischaemic stroke and severe traumatic brain injury, two multinational placebo-controlled trials for each indication were initiated. After review of the aggregate data from the four trials and considering both safety and potential benefit, an independent Data and Safety Monitoring Board (DSMB) recommended that enrolment in the selfotel programme be suspended and that the trials be terminated. We report the results from these two stroke trials. The ASSIST (Acute Stroke Studies Involving Selfotel Treatment) programme involved two trials, one conducted in
32
Europe, Australia, Argentina, and Canada (Protocol 10 IC/STE1), and the other in the USA and Israel (Protocol 07). The hypothesis tested in these double-blind, randomised, placebo-controlled trials was that 1·5 mg/kg selfotel administered intravenously within 6 h of stroke onset would improve functional outcome at 3 months defined as the proportion of patients reaching a score of at least 60 on the Barthel Index (BI). Patient accrual began in September, 1994. By December, 1995, 509 patients had been enrolled in the two trials and data from 476 patients (389 in Protocol 10 IC/STE1 and 87 in Protocol 07) were in the database. Of these, 328 patients had 3-month outcome data available for analysis (274 in Protocol 10 IC/STE1 and 54 in Protocol 07). Comparison of baseline demographic variables showed that the treatment groups were well-matched for sex, initial stroke severity (based on the Scandinavian Stroke Scale [SSS]4), and time from stroke onset to therapy:
Male (%) Mean (SD) age Mean (SD) baseline SSS Mean (SD) time to treatment
Selfotel (n=237)
Placebo (n=239)
130 (54·9) 70·2 (9·9) 12·5 (5·0) 4 h 32 min (1 h 6 min)
141 (60·0) 68·7 (10·2) 12·6 (4·6) 4 h 29 min (1 h 8 min)
The overall mortality rate at the time enrolment was suspended was 22% (103/476). The mortality rate from all causes was 24% (58/237) in the selfotel group compared with 19% (45/239) in the placebo group. This difference was not significant (RR=1·3; 95% CI 0·92–1·83; p=0·15). However, review of individual case fatalities by the DSMB raised concern over an imbalance against selfotel in the number of deaths related to brain insult. The mortality from brainrelated events (primarily cerebral oedema and progression of stroke) was 13% in the selfotel group and 5% in the placebo group (p=0·003). To determine whether the benefit of selfotel treatment might outweigh any potential risk, the probability of demonstrating efficacy based on the primary outcome variable (the proportion of patients achieving a BI of at least 60 at day 90), was calculated with a Bayesian approach on the observed rates of BI at least 60.5 The proportion of patients with a BI score at least 60 was 47% (78/166) in the selfotel group and 49% (80/162) in the placebo group. For the individual trials, the proportion of patients with a BI score at least 60 in Protocol 10 IC/STE1 was 47% (64/137) and 51% (70/137) in the selfotel and placebo groups respectively, and 48% (14/29) in the selfotel group and 40% (10/25) in the placebo group in Protocol 07. The probability of demonstrating efficacy in the individual trials had they proceeded was 0·28 (n=274) and 0·82 (n=54) in Protocols 10 IC/STE1 and 07, respectively. It was considered that the apparent high probability of success in the latter trial may have reflected the small sample size. This work was funded by Ciba-Geigy Ltd, Basel, Switzerland. 1
2
3
4 5
Markabi S. Selfotel (CGS 19755): the preliminary clinical experience. In: Krieglstein J, Oberpichler-Schwenk H, eds. Pharmacology of cerebral ischemia. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH, 1994: 635–42. Grotta J, Clark W, Coull B, et al. Safety and tolerability of glutamate antagonist CGS 19755 (selfotel) in patients with acute ischemic stroke: results of a phase IIa randomized trial. Stroke 1995; 26: 602–05. Clark WM, et al. Randomized trial of CGS 19755, a glutamate antagonist, in acute ischemic stroke treatment. Neurology 1994; 44 (suppl 2): A270. Scandinavian Stroke Study Group. Multicenter trial of hemodilution in stroke-background and study protocol. Stroke 1985; 16: 885–90. Spiegelhalter DJ, et al. Monitoring clinical trials: conditional or predictive power? Control Clin Trials 1986; 7: 8–17.
Department of Neurology, Melbourne Neuroscience Centre, The Royal Melbourne Hospital, Victoria 3050, Australia (Stephen Davis)
Vol 349 • January 4, 1997