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      Can Matching-Adjusted Indirect Comparison Methods Mitigate Placebo Response Differences Among Patient Populations in Adjunctive Trials of Brivaracetam and Levetiracetam?

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          Abstract

          Background and objective

          Patients with focal seizures recruited into adjunctive antiepileptic drug (AED) trials have become more refractory and severe over time; concurrently, placebo responses have increased. To attempt to account for heterogeneity among trials, propensity-score weighted patient-level data were used to indirectly compare placebo responses reported in brivaracetam and levetiracetam trials.

          Methods

          Patient-level data from randomised, placebo-controlled brivaracetam (recruited 2007–2014) and levetiracetam (1993–1998) trials were pooled. Consistent inclusion/exclusion criteria were applied and outcomes were defined consistently. Potentially confounding baseline characteristics were adjusted for using propensity score weighting. Weighting success was assessed using placebo response.

          Results

          In total, 707 and 473 active drug and 399 and 253 placebo patients comprised the brivaracetam and levetiracetam groups, respectively. Before weighting, several baseline variables were significantly different between groups; after weighting, prior vagal nerve stimulation, co-morbid depression and co-morbid anxiety remained different. Before weighting, median seizure frequency reduction was 21.7 and 3.9% in the brivaracetam and levetiracetam placebo arms, respectively; after weighting, median reduction was 15.0 and 6.0%. The comparison of non-randomised groups could be biased by unobserved confounding factors and region of residence. Lifetime AED history was unavailable in the brivaracetam trials and excluded from analysis.

          Conclusions

          Placebo responses remained different between brivaracetam and levetiracetam trials after propensity score weighting, indicating the presence of residual confounding factors associated with placebo response in these trials. It therefore remains problematic to conduct reliable indirect comparisons of brivaracetam and levetiracetam given the current evidence base, which may apply to comparisons between other AED trials.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s40263-017-0462-8) contains supplementary material, which is available to authorized users.

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          Applied Logistic Regression

          David Hosmer Jr., Stanley Lemeshow, Rodney Sturdivant (2013)
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            Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304.

            H. Yang, David Squillacote, Dinesh Kataria … (2012)
            To assess efficacy and safety of once-daily 8 or 12 mg perampanel, a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, when added to concomitant antiepileptic drugs (AEDs) in the treatment of drug-resistant partial-onset seizures. This was a multicenter, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT00699972). Patients (≥12 years, with ongoing seizures despite 1-3 AEDs) were randomized (1:1:1) to once-daily perampanel 8 mg, 12 mg, or placebo. Following baseline (6 weeks), patients entered a 19-week double-blind phase: 6-week titration (2 mg/week increments to target dose) followed by a 13-week maintenance period. Percent change in seizure frequency was the primary endpoint; 50% responder rate was the primary endpoint for EU registration. Of 388 patients randomized and treated, 387 provided seizure frequency data. Using this intent-to-treat population over the double-blind phase, the median percent change in seizure frequency was -21.0%, -26.3%, and -34.5% for placebo and perampanel 8 and 12 mg, respectively (p = 0.0261 and p = 0.0158 for 8 and 12 mg vs placebo, respectively). Fifty percent responder rates during the maintenance period were 26.4%, 37.6%, and 36.1%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg; these differences were not statistically significant for 8 mg (p = 0.0760) or 12 mg (p = 0.0914). Sixty-eight (17.5%) patients discontinued, including 40 (10.3%) for adverse events. Most frequent treatment-emergent adverse events were dizziness, somnolence, irritability, headache, fall, and ataxia. This trial demonstrated that once-daily, adjunctive perampanel at doses of 8 or 12 mg improved seizure control in patients with uncontrolled partial-onset seizures. Doses of perampanel 8 and 12 mg were safe, and tolerability was acceptable. This study provides Class I evidence that once-daily 8 and 12 mg doses of adjunctive perampanel are effective in patients with uncontrolled partial-onset seizures.
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              Placebo response in studies of major depression: variable, substantial, and growing.

              Cathryn M. Gould, Robyn Sysko, Stuart N Seidman … (2002)
              Intense debate persists about the need for placebo-controlled groups in clinical trials of medications for major depressive disorder (MDD). There is continuing interest in the development of new medications, but because effective antidepressants are already available, ethical concerns have been raised about the need for placebo groups in new trials. To determine whether the characteristics of placebo control groups in antidepressant trials have changed over time. We searched MEDLINE and PsychLit for all controlled trials published in English between January 1981 and December 2000 in which adult outpatients with MDD were randomly assigned to receive medication or placebo. Seventy-five trials met our criteria for inclusion. Data were extracted from the articles by 2 of the authors and discrepancies were resolved via discussion and additional review by a third author. The mean (SD) proportion of patients in the placebo group who responded was 29.7% (8.3%) (range, 12.5%-51.8%). Most studies examined more than a single active medication, and, in the active medication group with the greatest response, the mean (SD) proportion of patients responding was 50.1% (9.0%) (range, 31.6%-70.4%). Both the proportion of patients responding to placebo and the proportion responding to medication were significantly positively correlated with the year of publication (for placebo: n = 75; r = 0.45; 95% confidence interval [CI], 0.25-0.61; P<.001; for medication: n = 75; r = 0.26; 95% CI, 0.03-0.46; P =.02). The association between year of publication and response rate was more statistically robust for placebo than medication. The response to placebo in published trials of antidepressant medication for MDD is highly variable and often substantial and has increased significantly in recent years, as has the response to medication. These observations support the view that the inclusion of a placebo group has major scientific importance in trials of new antidepressant medications and indicate that efforts should continue to minimize the risks of such studies so that they may be conducted in an ethically acceptable manner.
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                Author and article information

                Contributors
                Elyse Swallow: Elyse.Swallow@analysisgroup.com
                Anna Fang: Anna.Fang@analysisgroup.com
                James Signorovitch: James.Signorovitch@analysisgroup.com
                Jonathan Plumb: Jonathan.Plumb@ucb.com
                Simon Borghs:
                ORCID: http://orcid.org/0000-0003-1081-7981
                +44 1753 44 7813 , Simon.Borghs@ucb.com
                Journal
                Journal ID (nlm-ta): CNS Drugs
                Journal ID (iso-abbrev): CNS Drugs
                Title: CNS Drugs
                Publisher: Springer International Publishing (Cham )
                ISSN (Print): 1172-7047
                ISSN (Electronic): 1179-1934
                Publication date (Electronic): 30 August 2017
                Publication date PMC-release: 30 August 2017
                Publication date (Print): 2017
                Volume: 31
                Issue: 10
                Pages: 899-910
                Affiliations
                [1 ]ISNI 0000 0004 4660 9516, GRID grid.417986.5, Analysis Group, Inc., ; 111 Huntington Ave, Floor 14, Boston, MA USA
                [2 ]GRID grid.421932.f, UCB Pharma, ; Allee de la Recherche 60, 1070 Brussels, Belgium
                [3 ]GRID grid.418727.f, UCB Pharma Ltd, ; 208 Bath Rd, Slough, SL1 3WE UK
                Author information
                http://orcid.org/0000-0003-1081-7981
                Article
                Publisher ID: 462
                DOI: 10.1007/s40263-017-0462-8
                PMC ID: 5658476
                PubMed ID: 28856580
                SO-VID: 416adf85-186d-48f9-a95c-58371e51a8bd
                Copyright © © The Author(s) 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Funding
                Funded by: UCB Pharma
                Categories
                Subject: Original Research Article
                Custom metadata
                issue-copyright-statement © Springer International Publishing AG 2017

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