Web-based trial to evaluate the efficacy and safety of tolterodine ER 4 mg in participants with overactive bladder: REMOTE trial

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Abstract

Introduction

Participatory patient-centered, web-based methods could streamline and improve the convenience of clinical trial participation. We used an entirely web-based approach to conduct a randomized, placebo-controlled, Phase 4 (REMOTE) trial under an Investigational New Drug (IND) application to evaluate tolterodine extended release (ER) 4 mg for overactive bladder.

Methods

The trial was designed to replicate previous clinic-based trials of tolterodine ER but was conducted via the web from one clinical site overseen by physicians. Participants were recruited via the web, screened for eligibility using web-based questionnaires, had laboratory testing in their community, and entered a run-in phase requiring bladder e-diaries. Informed consent was obtained using an interactive web-based method with physician countersignature. Study medication was shipped directly to participants.

Results

With a goal of 283 randomized participants, 5157 registered on the trial website. Of 456 who passed initial screening, identification verification, and signed consent, 237 passed additional medical screening and were countersigned by the investigator. After laboratory testing, 118 entered the placebo run-in; only 18 passed e-diary assessments and were randomized to treatment. At week 12, the mean change from the baseline in micturitions/24 hours (primary endpoint) was − 2.4 for tolterodine ER versus − 0.8 for placebo [treatment difference (95% CI): − 1.6 (− 3.9, 0.6)].

Conclusion

The REMOTE trial is the first entirely web-based trial conducted under an IND application. The efficacy observed was consistent with results from conventional trials. With simplification of multi-step screening and testing, web-based trials or their component parts should provide a participant-friendly approach to many clinical trials.

Introduction

Participant recruitment is often a major barrier to the feasibility and timely completion of clinical trials. Trial participation is limited by the number of eligible participants who live near trial sites, especially for uncommon medical conditions. In addition, a requirement for multiple visits to the clinical site and a limited number of time slots can interfere with trial enrollment and completion. The operation of trial sites (i.e., site management, payments, and monitoring) accounts for most of the costs of conducting clinical trials [1]. A more efficient way of conducting clinical trials is needed to reduce their current cost.

In parallel with the contemporary challenges of clinical research, trends are emerging in healthcare that are driven largely by the proliferation of information on the Internet. The centralization of specialized healthcare services is enabling the decentralization of basic healthcare, such as improved access and convenience offered by health clinics in retail locations [2]. In parallel with these challenges, the proliferation of health information on the Internet is giving rise to the “e-patient” — a patient who is engaged, empowered, and online. In 2012, 59% of US adults searched for health information online [3]. The widespread use of mobile phones has decreased socioeconomic and age barriers to web access [4]. Groups of patients with common medical conditions and concerns are also organizing online to share data and initiate research activities [5].

Participatory patient-centered (PPC), web-based, clinical trials could increase patient access to clinical trials, streamline trial conduct, and facilitate rapid reporting of clinical signals and outcomes to regulators, healthcare providers, and patients. The key components of PPC web-based trials are listed in Fig. 1. More rapid recruitment and the potential to reduce clinical site costs is a strong incentive for pharmaceutical companies to conduct web-based trials, and greater availability and convenience will enable more patients to join PPC web-based trials.

After a favorable formal review by the US Food and Drug Administration (FDA), Pfizer Inc, in collaboration with Mytrus, Inc, (San Francisco, CA), conducted the Research on Electronic Monitoring of Overactive Bladder (OAB) Treatment Experience (REMOTE) trial. The REMOTE trial is, to our knowledge, the first randomized controlled trial under an FDA Investigational New Drug (IND) application that enrolled and managed study participants entirely remotely using the Internet and mobile-phone technology with no participant visits to investigator sites. Tolterodine extended release (ER), an FDA-approved antimuscarinic for the treatment of OAB with symptoms of urge urinary incontinence (UUI), urgency, and frequency, was chosen as the active treatment in the REMOTE trial because it has been in wide use with demonstrated efficacy and safety in previous site-based clinical trials that could be used for comparison [6], [7], [8], [9], [10], [11]. Additionally, OAB diagnosis and efficacy assessments are based on validated patient-reported outcome measures that are amenable to remote electronic data entry by patients.

Section snippets

Study design and participants

The REMOTE trial was an exploratory, randomized, double-blind, placebo-controlled, parallel-group, single-center, Phase 4 trial to test a novel web-based trial design for evaluating the efficacy and safety of tolterodine ER 4 mg in US participants with OAB (ClinicalTrials.gov ID: NCT01302938). The primary objective was to compare the efficacy of tolterodine ER versus placebo in participants with OAB after 12 weeks of treatment using a web-based trial design. The REMOTE trial protocol was based on

Results

The online participant recruitment process was initiated when a potential participant viewed the introductory web page describing the REMOTE trial. The potential participant could then decide to create an account, which would begin the screening process for determining eligibility for study enrollment. Of 20,901 individuals who viewed the introduction to the study on the website, 17,950 viewed the online informational video about the trial (Fig. 3). Of 7230 individuals who registered for

Discussion

The REMOTE trial represents the first clinical trial under an IND application to recruit, obtain electronically signed informed consent, and screen and manage patients entirely with web-based technology, with blinded study drug shipped to each participant's residence via overnight delivery and without any participant visits to an investigator study site. Of note, participants had access to the investigator site team of healthcare professionals 24 hours a day every day of the week. In addition,

Conclusions

The REMOTE trial is the first trial under an IND application to recruit and manage participants entirely with web-based technology and without any participant visits to the trial site. Although the small number of enrolled patients precluded the confirmation of the efficacy and safety of tolterodine ER, the findings were consistent with those of previous OAB studies. Many of the web-based components of the REMOTE trial worked well and may be applicable to future web-based trials and/or

Acknowledgments

Funding for this study was provided by Pfizer Inc. Mytrus, Inc. served as the coordinating center/trial site and developed online systems under guidance from Pfizer Inc. The statistical design was led by Amanda Darekar and the statistical analysis by Martin Carlsson. Study execution was supported by Perceptive Informatics, Inc. and Exco InTouch, Inc. Kenji Shimodaira and Kelsey Adams of Mytrus, Inc. assisted with the analysis of participant flow. Steven Bent, MD, served as the principal

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1

Dr. Orri's affiliation as of February 2014: Innovat Orri Pharma Consulting Ltd., Selangor, Malaysia.

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