Vagus nerve stimulation as adjunctive therapy in patients with difficult-to-treat depression (RESTORE-LIFE): study protocol design and rationale of a real-world post-market study

Abstract

Background: Depressive illness is associated with significant adverse consequences for patients and their families, and for society. Clinical challenges are encountered in the management of patients suffering from depression whether they are designated difficult-to-treat or treatment-resistant. Prospective serial depression treatment trials have shown that less than 40% of patients with major depressive disorder remit with an initial pharmacotherapy trial, and a progressively smaller proportion of patients remit with each subsequent trial. For patients who suffer from difficult-to-treat depression (DTD), treatments should focus on patient-centred symptom control, patient functioning, and improving patient quality of life. Among the treatment options for patients with DTD is Vagus Nerve Stimulation (VNS) Therapy. VNS Therapy involves intermittent electrical stimulation of the left cervical vagus nerve and has been shown to be efficacious for long-term management of patients with DTD.

Methods: RESTORE-LIFE is a prospective, observational, multi-site, global post-market study intended to assess short-, mid-, and long-term effectiveness and efficiency outcomes in a 'real-world' setting among patients with DTD treated with adjunctive VNS Therapy. A minimum of 500 patients will be implanted with a VNS Therapy System at up to 80 global sites. Eligible patients will participate in a baseline visit between 1 and 6 weeks before device implant and will be followed for a minimum of 36 months and a maximum of 60 months. The diagnosis of depression and comorbid disorders will be determined using the Mini-International Neuropsychiatric Interview (MINI). The primary endpoint is response rate, defined as a decrease of ≥50% in Montgomery Åsberg Depression Rating Scale (MADRS) total score from baseline to 12 months post-implant.

Discussion: A standardized approach in the management of DTD may not be appropriate for the treatment of such a complex heterogenous patient population. This study has been designed to evaluate whether VNS Therapy meaningfully improves and sustains clinical and depressive symptom outcomes in patients with DTD. This study will investigate the durability of VNS response in DTD and utility of VNS for long-term disease management of DTD. In addition, the study results will potentially clarify clinical, functional, and health economic questions in a real-world patient population with DTD.

Trial registration: ClinicalTrials.gov NCT03320304. Registered 25 October 2017.

Keywords: Bipolar disorder; Difficult-to-treat depression; Major depressive disorder; RESTORE-LIFE; Real-world setting; Study design; Treatment-resistant depression; VNS; Vagus nerve stimulation therapy.

Conflict of interest statement

AHY’s independent research is funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London; the views expressed are those of AHY and not necessarily those of the NHS, the NIHR, or the Department of Health. AHY has received fees for lectures and advisory boards from AstraZeneca, Eli Lilly, Lundbeck, Sunovion, Servier, LivaNova, Janssen, Allegan, and Bionomics. AHY is a consultant to Johnson & Johnson and LivaNova. AHY has received honoraria for attending advisory boards and presenting talks at meetings organized by LivaNova.

MFJ is funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London; has received speaker honorarium fees and honoraria for attending advisory boards from AstraZeneca, Lundbeck, LivaNova, Janssen, Libbs, Daiichi-Sankyo, and Bionomics; is a consultant to Lundbeck, Johnson & Johnson and LivaNova; and has received honoraria for presenting talks at meetings organized by LivaNova.

RDZ is an employee and shareholder of LivaNova.

KD has been involved in advisory boards and speaker bureaus with Boehringer Ingelheim, Johnson & Johnson, LivaNova, Lundbeck, Pfizer, and Servier.

Figures

Fig. 1

schematic representation of the VNS therapy system. Study participants will be implanted with the VNS Therapy system that includes a small pulse generator surgically implanted subcutaneously in the thoracic area (usually the left side) and a thin, flexible wire called a lead that connects to the vagus nerve (Fig 1). Mild intermittent electrical stimulation is delivered to the vagus nerve eliciting action potentials in the vagal fibres that synapse in the brainstem. Clinicians are able to program the system using an external programming device relying on attentive patient-specific titration to select the right combination of adjustable parameters (output current, frequency, pulse width, and signal ON and OFF times) to attain full activation of the vagus nerve while minimizing stimulation-induced side effects. Additional information is provided in the VNS Therapy Physician’s Manual and the Implant Manual