ORIGINAL RESEARCH Dose Titration of Pregabalin in Patients with Painful Diabetic Peripheral Neuropathy: Simulation Based on Observational Study Patients Enriched with Data from Randomized Studies Joe Alexander Jr . Roger A. Edwards . Luigi Manca . Roberto Grugni . Gianluca Bonfanti . Birol Emir . Edward Whalen . Stephen Watt . Bruce Parsons Received: December 20, 2017 Ó Springer Healthcare Ltd., part of Springer Nature 2018 ABSTRACT Introduction: Achieving a therapeutic response to pregabalin in patients with painful diabetic peripheral neuropathy (pDPN) requires ade- quate upward dose titration. Our goal was to identify relationships between titration and response to pregabalin in patients with pDPN. Methods: Data were integrated from nine ran- domized, placebo-controlled clinical trials as well as one 6-week open-label observational study conducted by 5808 physicians (2642 patients with pDPN) in standard outpatient settings in Germany. These studies evaluated pregabalin for treatment of pDPN. Using these data, we examined ‘‘what if’’ scenarios using a microsimulation platform that integrates data from randomized and observational sources as well as autoregressive–moving-average with exogenous inputs models that predict pain outcomes, taking into account weekly changes in pain, sleep interference, dose, and other patient characteristics that were unchanging. Results: Final pain levels were significantly dif- ferent depending on dose changes (P \0.0001), with greater proportions improving with upward titration regardless of baseline pain severity. Altogether, 78.5% of patients with pDPN had 0–1 dose change, and 15.2% had C 2 dose changes. Simulation demonstrated that the 4.8% of inad- equately titrated patients who did not improve/ very much improve their pain levels would have benefited from C 2 dose changes. Patient satis- faction with tolerability (range 90.3–96.2%) was similar, regardless of baseline pain severity, number of titrations, or extent of improvement, suggesting that tolerability did not influence treatment response patterns. Conclusion: Upward dose titration reduced pain in patients with pDPN who actually received it. Simulation also predicted pain reduction in an inadequately titrated nonre- sponder subgroup of patients had they actually received adequate titration. The decision not to uptitrate must have been driven by factors other than tolerability. Funding: Pfizer, Inc. Joe Alexander Jr and Roger A. Edwards co-first authors. Enhanced Content To view enhanced content for this article go to https://doi.org/10.6084/m9.figshare. 5798997. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12325- 018-0664-6) contains supplementary material, which is available to authorized users. J. Alexander Jr (&) Á B. Emir Á E. Whalen Á S. Watt Á B. Parsons Pfizer, New York, NY, USA e-mail: Joe.Alexander.Jr@pfizer.com R. A. Edwards Health Services Consulting Corporation, Boxborough, MA, USA L. Manca Á R. Grugni Á G. Bonfanti Fair Dynamics Consulting, Milan, Italy Adv Ther https://doi.org/10.1007/s12325-018-0664-6