Skip to main content

Advertisement

SpringerLink
Log in

A Phase II, Multicenter, Randomized, Placebo-Controlled, Double-Masked Trial of a Topical Estradiol Ophthalmic Formulation in Postmenopausal Women with Moderate-to-Severe Dry Eye Disease

  • Original Research
  • Published:
Advances in Therapy Aims and scope Submit manuscript

Abstract

Introduction

Dry eye disease (DED) is a multifactorial disorder of the ocular surface. The current phase II study was performed to assess the safety and dose regimen of a recently developed topical estradiol formulation for the treatment of DED.

Methods

A total of 104 postmenopausal women suffering from moderate-to-severe DED were included. Topical 17-β-estradiol-3-phosphate eye drops were administered in three different dosage groups (group 1, 0.05% twice daily; group 2, 0.1% morning, vehicle in the evening; group 3, 0.1% twice daily) and vehicle twice daily as control group for a total period of 3 months. Clinical signs including Schirmer’s test and corneal staining were assessed at baseline and at days 14, 30, 60, and 90. Symptoms of DED were measured using the symptom assessment in dry eye (SANDE) test at the same time points. Safety was assessed via frequency of adverse events.

Results

Schirmer’s test II wetting distance significantly increased in all four groups from baseline to day 90 without significant difference between groups (group 1, + 5.6 ± 6.7 mm/5 min; group 2, + 3.7 ± 4.2 mm/5 min; group 3, + 4.8 ± 4.5 mm/5 min; group 4, + 4.0 ± 5.3 mm/5 min). Statistical significance versus baseline was reached earlier in the treatment groups versus the control group. Corneal staining was significantly reduced after the 3-month treatment period with no significant difference between treatment groups. Staining of the inferior cornea, however, showed a significantly more pronounced decrease in the highest dose group compared to vehicle (p = 0.0463). Symptoms score as assessed with the SANDE test decreased at the end of the treatment period in all four groups. Estradiol eye drops showed a favorable safety profile.

Conclusion

Our results show that both estradiol eye drops and vehicle are safe and reduce signs and symptoms in postmenopausal women with moderate-to-severe DED. Although the study failed to reach the primary outcome to demonstrate a significant difference between the estradiol eye drops and vehicle in Schirmer’s test, improvement occurred earlier in the active groups compared to the control group. The data of the current study will serve as a basis for a larger phase III study to establish a potential therapeutic effect of topical estradiol eye drops.

Clinical Trial Registration

Clinicaltrials.gov registry NCT03821415.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Stapleton F, Alves M, Bunya VY, et al. TFOS DEWS II epidemiology report. Ocul Surf. 2017;15(3):334–65.

    Article  Google Scholar 

  2. Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017;15(3):575–628.

    Article  Google Scholar 

  3. Bron AJ, de Paiva CS, Chauhan SK, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017;15(3):438–510.

    Article  Google Scholar 

  4. Sullivan DA, Rocha EM, Aragona P, et al. TFOS DEWS II sex, gender, and hormones report. Ocul Surf. 2017;15(3):284–333.

    Article  Google Scholar 

  5. Rapoport Y, Singer JM, Ling JD, Gregory A, Kohanim S. A comprehensive review of sex disparities in symptoms, pathophysiology, and epidemiology of dry eye syndrome. Semin Ophthalmol. 2016;31(4):325–36.

    Article  Google Scholar 

  6. Rocha EM, Wickham LA, da Silveira LA, et al. Identification of androgen receptor protein and 5alpha-reductase mRNA in human ocular tissues. Br J Ophthalmol. 2000;84(1):76–84.

    Article  CAS  Google Scholar 

  7. Schirra F, Suzuki T, Dickinson DP, Townsend DJ, Gipson IK, Sullivan DA. Identification of steroidogenic enzyme mRNAs in the human lacrimal gland, meibomian gland, cornea, and conjunctiva. Cornea. 2006;25(4):438–42.

    Article  Google Scholar 

  8. Wickham LA, Gao J, Toda I, Rocha EM, Ono M, Sullivan DA. Identification of androgen, estrogen and progesterone receptor mRNAs in the eye. Acta Ophthalmol Scand. 2000;78(2):146–53.

    Article  CAS  Google Scholar 

  9. DEWS. Methodologies to diagnose and monitor dry eye disease: report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):108–52.

  10. Lemp MA. Report of the National Eye Institute/Industry workshop on clinical trials in dry eyes. CLAO J. 1995;21(4):221–32.

    CAS  PubMed  Google Scholar 

  11. Schaumberg DA, Buring JE, Sullivan DA, Dana MR. Hormone replacement therapy and dry eye syndrome. JAMA. 2001;286(17):2114–9.

    Article  CAS  Google Scholar 

  12. Esmaeli B, Harvey JT, Hewlett B. Immunohistochemical evidence for estrogen receptors in meibomian glands. Ophthalmology. 2000;107(1):180–4.

    Article  CAS  Google Scholar 

  13. Versura P, Giannaccare G, Campos EC. Sex-steroid imbalance in females and dry eye. Curr Eye Res. 2015;40(2):162–75.

    Article  CAS  Google Scholar 

  14. Coksuer H, Ozcura F, Oghan F, Haliloglu B, Coksuer C. Effects of estradiol-drospirenone on ocular and nasal functions in postmenopausal women. Climacteric. 2011;14(4):482–7.

    Article  CAS  Google Scholar 

  15. Altintas O, Caglar Y, Yuksel N, Demirci A, Karabas L. The effects of menopause and hormone replacement therapy on quality and quantity of tear, intraocular pressure and ocular blood flow. Ophthalmologica. 2004;218(2):120–9.

    Article  CAS  Google Scholar 

  16. Na KS, Jee DH, Han K, Park YG, Kim MS, Kim EC. The ocular benefits of estrogen replacement therapy: a population-based study in postmenopausal Korean women. PLoS One. 2014;9(9):e106473.

    Article  Google Scholar 

  17. Sator MO, Joura EA, Golaszewski T, et al. Treatment of menopausal keratoconjunctivitis sicca with topical oestradiol. Br J Obstet Gynaecol. 1998;105(1):100–2.

    Article  CAS  Google Scholar 

  18. Kumar V, Sur VP, Guha R, Konar A, Hazra S. Estrogen modulates corneal nociception and maintains corneal homeostasis in rat eye. Cornea. 2018;37(4):508–14.

    Article  Google Scholar 

  19. Situ P, Simpson TL. Interaction of corneal nociceptive stimulation and lacrimal secretion. Invest Ophthalmol Vis Sci. 2010;51(11):5640–5.

    Article  Google Scholar 

  20. Novack GD, Asbell P, Barabino S, et al. TFOS DEWS II clinical trial design report. Ocul Surf. 2017;15(3):629–49.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the participants of the study. We also want to thank all investigators that participated in the conduction of the present study, namely Prof. Dr. Chris Lohmann, Klinikum rechts der Isar, Klinik und Poliklinik für Augenheilkunde, Ismaninger Str. 22, 81675 München, Germany; Prof. Dr. med Frank Tost, Universitätsmedizin Greifswald, Klinik und Poliklinik für Augenheilkunde, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany; PD Dr. med. univ. Dr. med. FEBO Katrin Lorenz, Universitätsmedizin Mainz, Augenklinik und Poliklinik, Klinisches Studienzentrum, Langenbeckstr. 1, 55131 Mainz, Germany; Dr. Éva Czinege, Macro Klinika, 4281 Miskolc, Arany János tér 1., Hungary; Dr. Judit Láng, Dr. Láng Judit Ophthalmology private practice, 8000 Székesfehérvár Berényi út 23, Hungary.

Funding

The present study was sponsored by Redwood Pharma AB (publ), Stockholm, Sweden. The sponsor also funded the present journal’s Rapid Service Fee.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosures

Gerhard Garhöfer and Leopold Schmetterer are consultants for Redwood Pharma. Doreen Schmidl, László Szalai, and Orsolya G Kiss have nothing to disclose.

Compliance with Ethics Guidelines

A total of eight study centers participated in the trial. The study protocol was approved by all local ethics committees or institutional review boards as well as competent authorities and the study was performed in adherence to the guidelines of the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent was obtained from all study participants prior to performance of any study-related procedures.

Data Availability

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

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

    Doreen Schmidl, Leopold Schmetterer & Gerhard Garhöfer

  2. Óbudai Egészségügyi Centrum (OEC), Budapest, Hungary

    László Szalai

  3. Department of Ophthalmology, Érmellék Egészségcentrum, Baross utca 7, 4281, Létavértes, Hungary

    Orsolya G. Kiss

  4. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore

    Leopold Schmetterer

  5. School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore, Singapore

    Leopold Schmetterer

  6. SERI-NTU Advanced Ocular Engineering (STANCE), Singapore, Singapore

    Leopold Schmetterer

  7. Duke-NUS Medical School, Academic Clinical Program, Singapore, Singapore

    Leopold Schmetterer

  8. Center for Medical Physics and Biomedical Engineering, Medical University Vienna, Vienna, Austria

    Leopold Schmetterer

  9. Institute of Molecular and Clinical Ophthalmology, Basel, Switzerland

    Leopold Schmetterer

Authors
  1. Doreen Schmidl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. László Szalai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Orsolya G. Kiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leopold Schmetterer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gerhard Garhöfer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerhard Garhöfer.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file 1 (DOCX 171 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schmidl, D., Szalai, L., Kiss, O.G. et al. A Phase II, Multicenter, Randomized, Placebo-Controlled, Double-Masked Trial of a Topical Estradiol Ophthalmic Formulation in Postmenopausal Women with Moderate-to-Severe Dry Eye Disease. Adv Ther 38, 1975–1986 (2021). https://doi.org/10.1007/s12325-021-01680-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12325-021-01680-3

Keywords

Search

Navigation