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Multicenter, Randomized, Investigator-Masked Study Comparing Brimonidine Tartrate 0.1% and Timolol Maleate 0.5% as Adjunctive Therapies to Prostaglandin Analogues in Normal-Tension Glaucoma

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An Erratum to this article was published on 30 August 2017

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Abstract

Introduction

This study compared the efficacy and safety of adjunctive brimonidine tartrate 0.1% ophthalmic solution (brimonidine) and timolol maleate 0.5% ophthalmic solution (timolol) in prostaglandin analogue (PGA)-treated normal-tension glaucoma (NTG), assessing the non-inferiority of brimonidine in terms of intraocular pressure (IOP) reduction.

Methods

In this multicenter, randomized, investigator-masked, parallel-group, clinical study, adjunctive brimonidine or timolol was administered twice daily for 12 weeks in eyes with NTG that had been treated with PGA for at least 90 days and required additional treatment despite an IOP of 16 mmHg or less. IOP was measured on at least three visits before add-on therapy (mean baseline IOP), and at weeks 4, 8, and 12 after adjunctive administration. Systolic/diastolic blood pressure, pulse rate, and adverse events (AEs) were recorded at each visit.

Results

A total of 152 individuals were enrolled and 128 (84.2%) were eligible for efficacy analyses. IOP in both groups at each visit decreased significantly from baseline (P < 0.001). However, the difference in the change from baseline IOP at week 12 between the brimonidine (−1.05 ± 1.81 mmHg) and timolol (−1.41 ± 1.40 mmHg) groups was 0.36 mmHg (95% confidence interval [CI] [−0.21, 0.92]), which exceeded the value of the non-inferiority margin (0.75 mmHg). Baseline systolic/diastolic blood pressure decreased significantly in both groups at certain visits (P < 0.05), while baseline pulse rates decreased significantly in the timolol group (P < 0.001), with no significant differences in the brimonidine group. AE-related treatment discontinuation occurred in 2/71 (2.8%) and 2/75 (2.7%) patients in the brimonidine and timolol groups, respectively.

Conclusion

This study demonstrated an add-on effect of brimonidine to PGAs, although non-inferiority of brimonidine to timolol as adjunctive therapy in PGA-treated NTG in terms of IOP reduction was not observed. Brimonidine was associated with no adverse effects on pulse rate.

Funding

Senju Pharmaceutical Co., Ltd.

Trial registration

UMIN Clinical Trials Registry identifier, UMIN000014810.

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Change history

  • 30 August 2017

    An erratum to this article has been published.

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Acknowledgments

The current study and the article processing charges for this publication were provided by Senju Pharmaceutical Co., Ltd. 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. Editorial assistance was provided by David P. Figgitt PhD, Content Ed Net, with funding from Senju Pharmaceutical Co., Ltd.

Disclosures

Shiro Mizoue has received personal fees from Abbott Medical Optics Inc., Alcon Japan Ltd., KOWA Co., Ltd., KOWA Pharmaceutical Co., Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., R-Tech Ueno Ltd., Santen Pharmaceutical Co., Ltd., Senju Pharmaceutical Co., Ltd., Sucampo Pharma LLC., and has received grants from Abbott Medical Optics Inc., Alcon Japan Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Santen Pharmaceutical Co., Ltd., Senju Pharmaceutical Co., Ltd. Koji Nitta has received personal fees from Alcon Japan Ltd., Kaken Pharmaceutical Co., Ltd., KOWA Co., Ltd., KOWA Pharmaceutical Co., Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Senju Pharmaceutical Co., Ltd., and has received grants from Alcon Japan Ltd., Santen Pharmaceutical Co., Ltd., Senju Pharmaceutical Co., Ltd. Motohiro Shirakashi has received personal fees from Senju Pharmaceutical Co., Ltd., has received a grant from Alcon Japan Ltd., and has received non-financial support from Alcon Japan Ltd., KOWA Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd. Akiyoshi Nitta has received personal fees from Senju Pharmaceutical Co., Ltd. Shigeki Yamabayashi has received personal fees from Senju Pharmaceutical Co., Ltd., and has received a grant from Senju Pharmaceutical Co., Ltd. Tairo Kimura has received personal fees from Alcon Japan Ltd., KOWA Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Santen Pharmaceutical Co., Ltd. Toshihiko Ueda has received personal fees from KOWA Co., Ltd., KOWA Pharmaceutical Co., Ltd, and has received a grant from Senju Pharmaceutical Co., Ltd. Ryuji Takeda has received personal fees from Senju Pharmaceutical Co., Ltd. Shun Matsumoto has received personal fees from Alcon Japan Ltd., KOWA Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Senju Pharmaceutical Co., Ltd., and has received a grant from Senju Pharmaceutical Co., Ltd. Keiji Yoshikawa has received personal fees from Alcon Japan Ltd., KOWA Co., Ltd., KOWA Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., R-Tech Ueno Ltd., Santen Pharmaceutical Co., Ltd., Senju Pharmaceutical Co., Ltd, Sucampo Pharma LLC., has received a grant from Santen Pharmaceutical Co., Ltd., and has received non-financial support from Alcon Japan Ltd., KOWA Co., Ltd., KOWA Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd. The authors report no other conflicts of interest related to this work.

Compliance with Ethics Guidelines

All study-related documents, including the protocol and informed consent forms, were reviewed and approved by the ethics committee of Minami-Matsuyama Hospital (Matsuyama City, Ehime, Japan). Prior to participation in the study, all study participants were given an explanation of informed consent and consented to participation in the study by signing the informed consent form. The study was conducted in compliance with the ethical principles of the Declaration of Helsinki.

Data Availability

The datasets during and analyzed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Ophthalmology, Ehime University Graduate School of Medicine, Ehime, Japan

    Shiro Mizoue

  2. Department of Ophthalmology, Fukui-ken Saiseikai Hospital, Fukui, Japan

    Koji Nitta

  3. Kido Eye Clinic, Niigata, Japan

    Motohiro Shirakashi

  4. Nitta Ophthalmological Clinic, Gunma, Japan

    Akiyoshi Nitta

  5. Yamabayashi Eye Clinic, Aichi, Japan

    Shigeki Yamabayashi

  6. Ueno Eye Clinic, Tokyo, Japan

    Tairo Kimura

  7. Nihonmatsu Eye Hospital, Tokyo, Japan

    Toshihiko Ueda

  8. Faculty of Agriculture, Kindai University, Nara, Japan

    Ryuji Takeda

  9. Faculty of Health Science for Welfare, Kansai University of Welfare Sciences, Osaka, Japan

    Ryuji Takeda

  10. Department of Ophthalmology, Tokyo Teishin Hospital, Tokyo, Japan

    Shun Matsumoto

  11. Yoshikawa Eye Clinic, Tokyo, Japan

    Keiji Yoshikawa

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  1. Shiro Mizoue
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Correspondence to Shiro Mizoue.

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An erratum to this article is available at https://doi.org/10.1007/s12325-017-0607-7.

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Mizoue, S., Nitta, K., Shirakashi, M. et al. Multicenter, Randomized, Investigator-Masked Study Comparing Brimonidine Tartrate 0.1% and Timolol Maleate 0.5% as Adjunctive Therapies to Prostaglandin Analogues in Normal-Tension Glaucoma. Adv Ther 34, 1438–1448 (2017). https://doi.org/10.1007/s12325-017-0552-5

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  • DOI: https://doi.org/10.1007/s12325-017-0552-5

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