Dose Titration of Pregabalin in Patients with Painful Diabetic Peripheral Neuropathy: Simulation Based on Observational Study Patients Enriched with Data from Randomized Studies

Abstract

Introduction

Achieving a therapeutic response to pregabalin in patients with painful diabetic peripheral neuropathy (pDPN) requires adequate 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 randomized, 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 different 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 ≥ 2 dose changes. Simulation demonstrated that the 4.8% of inadequately titrated patients who did not improve/very much improve their pain levels would have benefited from ≥ 2 dose changes. Patient satisfaction 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 nonresponder 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.

Plain Language Summary

Pregabalin is approved in the United States and Europe for treatment of neuropathic pain (NeP) associated with diabetic peripheral neuropathy (pDPN). A microsimulation platform was used to integrate actual patient data from randomized placebo-controlled clinical trials with data from a large observational study in Germany, with the goal of evaluating the effects of pregabalin dose changes on therapeutic response for NeP associated with pDPN. Upward dose titration was associated with significantly better treatment outcomes. Tolerability did not appear to be a significant influence on treatment response patterns or the decision not to titrate dose. Simulations of patients with pDPN who were inadequately titrated suggested that they may have achieved improved treatment outcomes with titration.

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Acknowledgements

Funding

All of these analyses and article processing charges were funded by Pfizer.

Medical Writing and Editorial Assistance

Editorial support in the form of copy editing and formatting was provided by Ray Beck Jr, PhD, of Engage Scientific Solutions and was funded by Pfizer.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Disclosures

Joe Alexander Jr is an employee of Pfizer. Birol Emir is an employee of Pfizer. Bruce Parsons is an employee of Pfizer. Stephen Watt is an employee of Pfizer. Edward Whalen is an employee of Pfizer. Roger A. Edwards is an employee of Health Services Consulting Corporation who was a paid consultant by Pfizer in connection with this study and development of this manuscript. Luigi Manca is an employee of Fair Dynamics Consulting. Roberto Grugni is an employee of Fair Dynamics Consulting. Gianluca Bonfanti is an employee of Fair Dynamics Consulting. These mentioned employees of Fair Dynamics Consulting were paid subcontractors to Health Services Consulting Corporation in connection with this study and development of this manuscript.

Compliance with Ethics Guidelines

This article is based on pooled data derived from previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Data Availability

The datasets generated and/or analyzed during the current study are not publicly available due to restrictions on public distribution, but are available from the corresponding author on reasonable request and with permission from Pfizer.

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Correspondence to Joe Alexander Jr.

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Joe Alexander Jr and Roger A. Edwards co-first authors.

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Alexander, J., Edwards, R.A., Manca, L. et al. Dose Titration of Pregabalin in Patients with Painful Diabetic Peripheral Neuropathy: Simulation Based on Observational Study Patients Enriched with Data from Randomized Studies. Adv Ther 35, 382–394 (2018). https://doi.org/10.1007/s12325-018-0664-6

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Keywords

  • Dose titration
  • Microsimulation
  • Pregabalin
  • pDPN