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Active control trials: Endpoints beyond conventional efficacy and tolerability measures
Reviews / Epilepsy Research 68 (2006) 19–94 Sooriyarachchi, M.R., Whitehead, J., 1998. A method for sequential analysis of survival data with nonproportional hazards. Biometrics 54, 1072–1084. Whitehead, J., 2001. Monotherapy trials: sequential design. Epilepsy Res. 45, 81–87. Whitehead, J., Todd, S., 2004. The double triangular test in practice. Pharmaceut. Stat. 3, 39–49.
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of efficacy and tolerability) as an additional endpoint, there has been relatively little effort to investigate additional aspects that could be relevant for the long-term well being of the patients (Perucca et al., 2000).
2. Quality of life, mood and cognition doi:10.1016/j.eplepsyres.2005.09.025 Active control trials: Endpoints beyond conventional efficacy and tolerability measures Emilio Perucca Abstract Clinical trial endpoints often extend beyond conventional efficacy and tolerability measures. While it is generally assumed that seizure control without major adverse drug effects is by far the most important determinant of quality of life, other factors also are important. Pharmacokinetic endpoints could also provide relevant information for optimal drug use. Outcome measures could reveal drug effects on mood, headache, and sleep disorders, as well as overall quality of life and seizure severity. Contents 1. 2. 3. 4.
Active control trials: endpoints beyond conventional efficacy and tolerability measures . . . 73 Quality of life, mood and cognition . . . . . . 73 Pharmacokinetic endpoints . . . . . . . . . . . . . . 73 Other measures . . . . . . . . . . . . . . . . . . . . . . . . 74 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Few would argue that the main objective in treating epilepsy is to ensure a quality of life unaffected by health constraints. While it is generally assumed that seizure control without major adverse drug effects is by far the most important determinant of quality of life, other factors can be at least as important. In particular, there is now extensive evidence that depression is highly prevalent among people with epilepsy, and that the presence or absence of depressive symptoms may outweigh the impact of seizures in determining the patients’ perception of well being (Boylan et al., 2004; Johnson et al., 2004). If different treatments affect mood differentially, randomized trials that only investigate seizure counts and adverse events may fail to identify differences in a major component of clinical outcome. Similar considerations can be made with respect to potential effects of AEDs on cognition, which may go easily undetected unless specialized testing is performed, and yet impact significantly on patients’ well being. Depression also affects patients perceptions of seizures (Cramer et al., 2003). Based on these considerations, an argument could be made for incorporating, in long-term active control trials, not only an assessment of mood and cognitive function, but also a global measure of health-related quality of life.
3. Pharmacokinetic endpoints 1. Active control trials: endpoints beyond conventional efficacy and tolerability measures The vast majority of randomized controlled trials of AEDs in newly diagnosed epilepsy have used, as efficacy endpoints, measures derived from seizure counts and, almost invariably, assessment of tolerability has been based on spontaneously reported adverse events and routine laboratory tests (Perucca and Tomson, 2000). Although most studies also incorporated retention on the allocated treatment (a combined measure
Pharmacokinetic endpoints are rarely considered in randomized active control trials (and in the extension phases of such trials), but they could also provide relevant information for the optimal use of the treatments being investigated. Because the need for therapeutic drug monitoring (TDM) is regarded as an unfavorable feature for the marketing of a new AED (Perucca, 2000), measurements of serum drug concentrations have been rarely performed in long-term trials of new AEDs, resulting in inadequate exploration of concentration-response relationships
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Reviews / Epilepsy Research 68 (2006) 19–94
and failure to identify situations associated with important pharmacokinetic changes. For example, the fact that lamotrigine levels are still infrequently monitored in routine practice may explain the long latency between the introduction of this drug in the market and recognition that its blood levels decrease to a clinically significant extent during pregnancy (Pennell et al., 2004) or intake of oral contraceptive steroids (Sabers et al., 2003). A recent study did identify a clear relationship between serum lamotrigine levels and adverse effects (Hirsch et al., 2004). 4. Other measures Long-term active control trials offer unique opportunities to investigate other non-conventional outcome measures, which may provide clues about potential usefulness of AEDs in other indications, or potential concerns for chronic toxicity. For example, careful monitoring of specific outcome measures could reveal signals of favorable (or unfavorable) effects of the administered treatments on associated morbidities, including alterations of mood, headache, neuropathic pain and sleep disorders. Many older generation AEDs can adversely affect the metabolism of some vitamins, hormones, serum lipids and other substrates (Eiris Punal et al., 1999; Battino et al., 2000; Bramswig et al., 2003). Randomized long-term trials would be ideal in allowing an unbiased assessment of the comparative effects of different AEDs on these measures. Finally, provisions could be made for incorporating a prospective comparison of the direct and indirect costs of the administered treatments, including the utilization of health resources, into study designs. The use of standard health economic (pharmacoeconomic) analyses is an essential component in modern drug development. Payors of all types, including health authorities and formulary managers, require at least a model of the expected net gain in health outcomes with a new drug. These data are increasingly used for rational decisions for allocation of health resources.
Boylan, L.S., Flint, L.A., Labovitz, D.L., Jackson, S.C., Starner, K., Devinsky, O., 2004. Depression but not seizure frequency predicts quality of life in treatment-resistant epilepsy. Neurology 62, 258–261. Bramswig, S., Sudhop, T., Luers, C., Von Bergmann, K., Berthold, H.K., 2003. Lipoprotein-a concentration increases during treatment with carbamazepine. Epilepsia 44, 457–460. Cramer, J.A., Blum, D., Reed, M., Fanning, K., for the Epilepsy Impact Project Group, 2003. The influence of comorbid depression on seizure severity. Epilepsia 44, 1578–1584. Eiris Punal, J., Del Rio-Garma, M., Del Rio-Garma, M.C., LojoRocamonde, S., Novo-Rodriguez, I., Castro-Cago, M., 1999. Long-term treatment of children with epilepsy with valproate and carbamazepine may cause subclinical hyperhyroidism. Epilepsia 40, 1761–1766. Johnson, E.K., Jones, J.E., Seidenberg, M., Hermann, B.P., 2004. The relative impact of anxiety, depression, and clinical seizure features on health-related quality of life in epilepsy. Epilepsia 45, 544–550. Hirsch, L.J., Weintraub, D., Du, Y., Buchsbaum, R., Spencer, H.T., Hager, M., Straka, T., Bazil, C.W., Adams, D.J., Resor Jr., S.R., Morrell, M.J., 2004. Correlating serum lamotrigine concentrations with tolerability in patients with epilepsy. Neurology 63, 1022–1026. Pennell, P.B., Newport, D.J., Stowe, Z.N., Helmers, S.L., Montgomery, J.Q., Henry, T.R., 2004. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology 62, 292–295. Perucca, E., Tomson, T., 2000. Monotherapy trials with the new antiepileptic drugs: study designs, practical relevance and ethical implications. Epilepsy Res. 33, 247–262. Perucca, E., Beghi, E., Shorvon, S., Tomson, T., 2000. Assessing risk to benefit ratio in antiepileptic drug therapy. Epilepsy Res. 41, 107–139. Perucca, E., 2000. Is there a role for therapeutic drug monitoring of new anticonvulsants? Clin. Pharmacokin. 38, 191–204. Sabers, A., Ohman, I., Christensen, J., Tomson, T., 2003. Oral contraceptives reduce lamotrigine plasma levels. Neurology 6, 570–571.
doi:10.1016/j.eplepsyres.2005.09.026
Historical control withdrawal to monotherapy Jacqueline French Abstract
Reference Battino, D., Dukes, M.N.G., Perucca, E., 2000. Anticonvulsants. In: Dukes, M.N.G., Aronson, J.K. (Eds.), Meyler’s Side Effects of Drugs, fourteenth ed. Elsevier Science B.V., Amsterdam, pp. 164–197.
The design of clinical trials can be explained in terms of selection of a control group. Two options have included (a) using an active comparator, usually a standard drug such as carbamazepine (active control) or (b) using a placebo or low-dose control.
73
of efficacy and tolerability) as an additional endpoint, there has been relatively little effort to investigate additional aspects that could be relevant for the long-term well being of the patients (Perucca et al., 2000).
2. Quality of life, mood and cognition doi:10.1016/j.eplepsyres.2005.09.025 Active control trials: Endpoints beyond conventional efficacy and tolerability measures Emilio Perucca Abstract Clinical trial endpoints often extend beyond conventional efficacy and tolerability measures. While it is generally assumed that seizure control without major adverse drug effects is by far the most important determinant of quality of life, other factors also are important. Pharmacokinetic endpoints could also provide relevant information for optimal drug use. Outcome measures could reveal drug effects on mood, headache, and sleep disorders, as well as overall quality of life and seizure severity. Contents 1. 2. 3. 4.
Active control trials: endpoints beyond conventional efficacy and tolerability measures . . . 73 Quality of life, mood and cognition . . . . . . 73 Pharmacokinetic endpoints . . . . . . . . . . . . . . 73 Other measures . . . . . . . . . . . . . . . . . . . . . . . . 74 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Few would argue that the main objective in treating epilepsy is to ensure a quality of life unaffected by health constraints. While it is generally assumed that seizure control without major adverse drug effects is by far the most important determinant of quality of life, other factors can be at least as important. In particular, there is now extensive evidence that depression is highly prevalent among people with epilepsy, and that the presence or absence of depressive symptoms may outweigh the impact of seizures in determining the patients’ perception of well being (Boylan et al., 2004; Johnson et al., 2004). If different treatments affect mood differentially, randomized trials that only investigate seizure counts and adverse events may fail to identify differences in a major component of clinical outcome. Similar considerations can be made with respect to potential effects of AEDs on cognition, which may go easily undetected unless specialized testing is performed, and yet impact significantly on patients’ well being. Depression also affects patients perceptions of seizures (Cramer et al., 2003). Based on these considerations, an argument could be made for incorporating, in long-term active control trials, not only an assessment of mood and cognitive function, but also a global measure of health-related quality of life.
3. Pharmacokinetic endpoints 1. Active control trials: endpoints beyond conventional efficacy and tolerability measures The vast majority of randomized controlled trials of AEDs in newly diagnosed epilepsy have used, as efficacy endpoints, measures derived from seizure counts and, almost invariably, assessment of tolerability has been based on spontaneously reported adverse events and routine laboratory tests (Perucca and Tomson, 2000). Although most studies also incorporated retention on the allocated treatment (a combined measure
Pharmacokinetic endpoints are rarely considered in randomized active control trials (and in the extension phases of such trials), but they could also provide relevant information for the optimal use of the treatments being investigated. Because the need for therapeutic drug monitoring (TDM) is regarded as an unfavorable feature for the marketing of a new AED (Perucca, 2000), measurements of serum drug concentrations have been rarely performed in long-term trials of new AEDs, resulting in inadequate exploration of concentration-response relationships
74
Reviews / Epilepsy Research 68 (2006) 19–94
and failure to identify situations associated with important pharmacokinetic changes. For example, the fact that lamotrigine levels are still infrequently monitored in routine practice may explain the long latency between the introduction of this drug in the market and recognition that its blood levels decrease to a clinically significant extent during pregnancy (Pennell et al., 2004) or intake of oral contraceptive steroids (Sabers et al., 2003). A recent study did identify a clear relationship between serum lamotrigine levels and adverse effects (Hirsch et al., 2004). 4. Other measures Long-term active control trials offer unique opportunities to investigate other non-conventional outcome measures, which may provide clues about potential usefulness of AEDs in other indications, or potential concerns for chronic toxicity. For example, careful monitoring of specific outcome measures could reveal signals of favorable (or unfavorable) effects of the administered treatments on associated morbidities, including alterations of mood, headache, neuropathic pain and sleep disorders. Many older generation AEDs can adversely affect the metabolism of some vitamins, hormones, serum lipids and other substrates (Eiris Punal et al., 1999; Battino et al., 2000; Bramswig et al., 2003). Randomized long-term trials would be ideal in allowing an unbiased assessment of the comparative effects of different AEDs on these measures. Finally, provisions could be made for incorporating a prospective comparison of the direct and indirect costs of the administered treatments, including the utilization of health resources, into study designs. The use of standard health economic (pharmacoeconomic) analyses is an essential component in modern drug development. Payors of all types, including health authorities and formulary managers, require at least a model of the expected net gain in health outcomes with a new drug. These data are increasingly used for rational decisions for allocation of health resources.
Boylan, L.S., Flint, L.A., Labovitz, D.L., Jackson, S.C., Starner, K., Devinsky, O., 2004. Depression but not seizure frequency predicts quality of life in treatment-resistant epilepsy. Neurology 62, 258–261. Bramswig, S., Sudhop, T., Luers, C., Von Bergmann, K., Berthold, H.K., 2003. Lipoprotein-a concentration increases during treatment with carbamazepine. Epilepsia 44, 457–460. Cramer, J.A., Blum, D., Reed, M., Fanning, K., for the Epilepsy Impact Project Group, 2003. The influence of comorbid depression on seizure severity. Epilepsia 44, 1578–1584. Eiris Punal, J., Del Rio-Garma, M., Del Rio-Garma, M.C., LojoRocamonde, S., Novo-Rodriguez, I., Castro-Cago, M., 1999. Long-term treatment of children with epilepsy with valproate and carbamazepine may cause subclinical hyperhyroidism. Epilepsia 40, 1761–1766. Johnson, E.K., Jones, J.E., Seidenberg, M., Hermann, B.P., 2004. The relative impact of anxiety, depression, and clinical seizure features on health-related quality of life in epilepsy. Epilepsia 45, 544–550. Hirsch, L.J., Weintraub, D., Du, Y., Buchsbaum, R., Spencer, H.T., Hager, M., Straka, T., Bazil, C.W., Adams, D.J., Resor Jr., S.R., Morrell, M.J., 2004. Correlating serum lamotrigine concentrations with tolerability in patients with epilepsy. Neurology 63, 1022–1026. Pennell, P.B., Newport, D.J., Stowe, Z.N., Helmers, S.L., Montgomery, J.Q., Henry, T.R., 2004. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology 62, 292–295. Perucca, E., Tomson, T., 2000. Monotherapy trials with the new antiepileptic drugs: study designs, practical relevance and ethical implications. Epilepsy Res. 33, 247–262. Perucca, E., Beghi, E., Shorvon, S., Tomson, T., 2000. Assessing risk to benefit ratio in antiepileptic drug therapy. Epilepsy Res. 41, 107–139. Perucca, E., 2000. Is there a role for therapeutic drug monitoring of new anticonvulsants? Clin. Pharmacokin. 38, 191–204. Sabers, A., Ohman, I., Christensen, J., Tomson, T., 2003. Oral contraceptives reduce lamotrigine plasma levels. Neurology 6, 570–571.
doi:10.1016/j.eplepsyres.2005.09.026
Historical control withdrawal to monotherapy Jacqueline French Abstract
Reference Battino, D., Dukes, M.N.G., Perucca, E., 2000. Anticonvulsants. In: Dukes, M.N.G., Aronson, J.K. (Eds.), Meyler’s Side Effects of Drugs, fourteenth ed. Elsevier Science B.V., Amsterdam, pp. 164–197.
The design of clinical trials can be explained in terms of selection of a control group. Two options have included (a) using an active comparator, usually a standard drug such as carbamazepine (active control) or (b) using a placebo or low-dose control.