Effect of doxycycline vs placebo on retinal function and diabetic retinopathy progression in patients with severe nonproliferative or non-high-risk proliferative diabetic retinopathy: a randomized clinical trial

Ingrid U Scott; Gregory R Jackson; David A Quillen; Michael Larsen; Ronald Klein; Jason Liao; Stig Holfort; Inger Christine Munch; Thomas W Gardner

doi:10.1001/jamaophthalmol.2014.93

Effect of doxycycline vs placebo on retinal function and diabetic retinopathy progression in patients with severe nonproliferative or non-high-risk proliferative diabetic retinopathy: a randomized clinical trial

Ingrid U Scott, Gregory R Jackson, David A Quillen, Michael Larsen, Ronald Klein, Jason Liao, Stig Holfort, Inger Christine Munch, Thomas W Gardner

Department of Clinical Medicine

27 Citations (Scopus)

Abstract

OBJECTIVES To investigate, in a proof-of-concept clinical trial, whether low-dose oral doxycycline monohydrate can (1) slow the deterioration of, or improve, retinal function or (2) induce regression or slow the progression of DR in patients with severe nonproliferative DR (NPDR) or non-high-risk proliferative (PDR), and to determine the potential usefulness of visual function end points to expedite the feasibility of conducting proof-of-concept clinical trials in patients with DR. DESIGN, SETTING, AND PARTICIPANTS We conducted a randomized, double-masked, 24-month proof-of-concept clinical trial. Thirty patients (from hospital-based retina practices) with 1 or more eyes with severe NPDR or PDR less than Early Treatment Diabetic Retinopathy Study-defined high-risk PDR. INTERVENTIONS Patients were randomized to receive 50mg of doxycycline monohydrate or placebo daily for 24 months. MAIN OUTCOMES AND MEASURES Change at 24 months compared with baseline in functional factors (frequency doubling perimetry [FDP], Humphrey photopic Swedish Interactive Thresholding Algorithm 24-2 testing, contrast sensitivity, dark adaptation, visual acuity, and quality of life) and anatomic factors (Early Treatment Diabetic Retinopathy Study DR severity level, area of retinal thickening, central macular thickness, macular volume, and retinal vessel diameters). RESULTS From baseline to month 24, mean FDP foveal sensitivity decreased in the placebo group (-1.9 dB) and increased in the doxycycline group (+1.8 dB) (P = .02). A higher mean FDP foveal sensitivity in the doxycycline group compared with the placebo group was detected at 6 months (P = .04), and this significant difference persisted at 12 and 24 months. A difference between the groups was not detected with respect to the other visual function outcomes and all anatomic outcomes assessed. CONCLUSIONS AND RELEVANCE To our knowledge, this is the first observation suggesting a link between a low-dose oral anti-inflammatory agent and subclinical improvement in inner retinal function. Oral doxycycline may be a promising therapeutic strategy targeting the inflammatory component of DR. Furthermore, study results suggest that FDP, which primarily measures inner retinal function, is responsive to intervention and may be a useful clinical trial end point for proof-of-concept studies in patients with DR.

Original language	English
Journal	Archives of Ophthalmology
Volume	132
Issue number	5
Pages (from-to)	535-43
Number of pages	9
ISSN	0003-9950
DOIs	https://doi.org/10.1001/jamaophthalmol.2014.93
Publication status	Published - May 2014

Keywords

Adaptation, Ocular
Adult
Aged
Anti-Bacterial Agents
Contrast Sensitivity
Diabetic Retinopathy
Disease Progression
Dose-Response Relationship, Drug
Double-Blind Method
Doxycycline
Feasibility Studies
Female
Fluorescein Angiography
Follow-Up Studies
Fundus Oculi
Humans
Male
Middle Aged
Questionnaires
Retina
Retrospective Studies
Time Factors
Treatment Outcome
Visual Field Tests
Visual Fields
Vitreoretinopathy, Proliferative
Young Adult

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Scott, I. U., Jackson, G. R., Quillen, D. A., Larsen, M., Klein, R., Liao, J., Holfort, S., Munch, I. C., & Gardner, T. W. (2014). Effect of doxycycline vs placebo on retinal function and diabetic retinopathy progression in patients with severe nonproliferative or non-high-risk proliferative diabetic retinopathy: a randomized clinical trial. Archives of Ophthalmology, 132(5), 535-43. https://doi.org/10.1001/jamaophthalmol.2014.93

Effect of doxycycline vs placebo on retinal function and diabetic retinopathy progression in patients with severe nonproliferative or non-high-risk proliferative diabetic retinopathy : a randomized clinical trial. / Scott, Ingrid U; Jackson, Gregory R; Quillen, David A et al.

In: Archives of Ophthalmology, Vol. 132, No. 5, 05.2014, p. 535-43.

Research output: Contribution to journal › Journal article › Research › peer-review

Scott, IU, Jackson, GR, Quillen, DA, Larsen, M, Klein, R, Liao, J, Holfort, S, Munch, IC & Gardner, TW 2014, 'Effect of doxycycline vs placebo on retinal function and diabetic retinopathy progression in patients with severe nonproliferative or non-high-risk proliferative diabetic retinopathy: a randomized clinical trial', Archives of Ophthalmology, vol. 132, no. 5, pp. 535-43. https://doi.org/10.1001/jamaophthalmol.2014.93

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abstract = "OBJECTIVES To investigate, in a proof-of-concept clinical trial, whether low-dose oral doxycycline monohydrate can (1) slow the deterioration of, or improve, retinal function or (2) induce regression or slow the progression of DR in patients with severe nonproliferative DR (NPDR) or non-high-risk proliferative (PDR), and to determine the potential usefulness of visual function end points to expedite the feasibility of conducting proof-of-concept clinical trials in patients with DR. DESIGN, SETTING, AND PARTICIPANTS We conducted a randomized, double-masked, 24-month proof-of-concept clinical trial. Thirty patients (from hospital-based retina practices) with 1 or more eyes with severe NPDR or PDR less than Early Treatment Diabetic Retinopathy Study-defined high-risk PDR. INTERVENTIONS Patients were randomized to receive 50mg of doxycycline monohydrate or placebo daily for 24 months. MAIN OUTCOMES AND MEASURES Change at 24 months compared with baseline in functional factors (frequency doubling perimetry [FDP], Humphrey photopic Swedish Interactive Thresholding Algorithm 24-2 testing, contrast sensitivity, dark adaptation, visual acuity, and quality of life) and anatomic factors (Early Treatment Diabetic Retinopathy Study DR severity level, area of retinal thickening, central macular thickness, macular volume, and retinal vessel diameters). RESULTS From baseline to month 24, mean FDP foveal sensitivity decreased in the placebo group (-1.9 dB) and increased in the doxycycline group (+1.8 dB) (P = .02). A higher mean FDP foveal sensitivity in the doxycycline group compared with the placebo group was detected at 6 months (P = .04), and this significant difference persisted at 12 and 24 months. A difference between the groups was not detected with respect to the other visual function outcomes and all anatomic outcomes assessed. CONCLUSIONS AND RELEVANCE To our knowledge, this is the first observation suggesting a link between a low-dose oral anti-inflammatory agent and subclinical improvement in inner retinal function. Oral doxycycline may be a promising therapeutic strategy targeting the inflammatory component of DR. Furthermore, study results suggest that FDP, which primarily measures inner retinal function, is responsive to intervention and may be a useful clinical trial end point for proof-of-concept studies in patients with DR.",

keywords = "Adaptation, Ocular, Adult, Aged, Anti-Bacterial Agents, Contrast Sensitivity, Diabetic Retinopathy, Disease Progression, Dose-Response Relationship, Drug, Double-Blind Method, Doxycycline, Feasibility Studies, Female, Fluorescein Angiography, Follow-Up Studies, Fundus Oculi, Humans, Male, Middle Aged, Questionnaires, Retina, Retrospective Studies, Time Factors, Treatment Outcome, Visual Field Tests, Visual Fields, Vitreoretinopathy, Proliferative, Young Adult",

author = "Scott, {Ingrid U} and Jackson, {Gregory R} and Quillen, {David A} and Michael Larsen and Ronald Klein and Jason Liao and Stig Holfort and Munch, {Inger Christine} and Gardner, {Thomas W}",

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doi = "10.1001/jamaophthalmol.2014.93",

language = "English",

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T1 - Effect of doxycycline vs placebo on retinal function and diabetic retinopathy progression in patients with severe nonproliferative or non-high-risk proliferative diabetic retinopathy

T2 - a randomized clinical trial

AU - Scott, Ingrid U

AU - Jackson, Gregory R

AU - Quillen, David A

AU - Larsen, Michael

AU - Klein, Ronald

AU - Liao, Jason

AU - Holfort, Stig

AU - Munch, Inger Christine

AU - Gardner, Thomas W

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N2 - OBJECTIVES To investigate, in a proof-of-concept clinical trial, whether low-dose oral doxycycline monohydrate can (1) slow the deterioration of, or improve, retinal function or (2) induce regression or slow the progression of DR in patients with severe nonproliferative DR (NPDR) or non-high-risk proliferative (PDR), and to determine the potential usefulness of visual function end points to expedite the feasibility of conducting proof-of-concept clinical trials in patients with DR. DESIGN, SETTING, AND PARTICIPANTS We conducted a randomized, double-masked, 24-month proof-of-concept clinical trial. Thirty patients (from hospital-based retina practices) with 1 or more eyes with severe NPDR or PDR less than Early Treatment Diabetic Retinopathy Study-defined high-risk PDR. INTERVENTIONS Patients were randomized to receive 50mg of doxycycline monohydrate or placebo daily for 24 months. MAIN OUTCOMES AND MEASURES Change at 24 months compared with baseline in functional factors (frequency doubling perimetry [FDP], Humphrey photopic Swedish Interactive Thresholding Algorithm 24-2 testing, contrast sensitivity, dark adaptation, visual acuity, and quality of life) and anatomic factors (Early Treatment Diabetic Retinopathy Study DR severity level, area of retinal thickening, central macular thickness, macular volume, and retinal vessel diameters). RESULTS From baseline to month 24, mean FDP foveal sensitivity decreased in the placebo group (-1.9 dB) and increased in the doxycycline group (+1.8 dB) (P = .02). A higher mean FDP foveal sensitivity in the doxycycline group compared with the placebo group was detected at 6 months (P = .04), and this significant difference persisted at 12 and 24 months. A difference between the groups was not detected with respect to the other visual function outcomes and all anatomic outcomes assessed. CONCLUSIONS AND RELEVANCE To our knowledge, this is the first observation suggesting a link between a low-dose oral anti-inflammatory agent and subclinical improvement in inner retinal function. Oral doxycycline may be a promising therapeutic strategy targeting the inflammatory component of DR. Furthermore, study results suggest that FDP, which primarily measures inner retinal function, is responsive to intervention and may be a useful clinical trial end point for proof-of-concept studies in patients with DR.

AB - OBJECTIVES To investigate, in a proof-of-concept clinical trial, whether low-dose oral doxycycline monohydrate can (1) slow the deterioration of, or improve, retinal function or (2) induce regression or slow the progression of DR in patients with severe nonproliferative DR (NPDR) or non-high-risk proliferative (PDR), and to determine the potential usefulness of visual function end points to expedite the feasibility of conducting proof-of-concept clinical trials in patients with DR. DESIGN, SETTING, AND PARTICIPANTS We conducted a randomized, double-masked, 24-month proof-of-concept clinical trial. Thirty patients (from hospital-based retina practices) with 1 or more eyes with severe NPDR or PDR less than Early Treatment Diabetic Retinopathy Study-defined high-risk PDR. INTERVENTIONS Patients were randomized to receive 50mg of doxycycline monohydrate or placebo daily for 24 months. MAIN OUTCOMES AND MEASURES Change at 24 months compared with baseline in functional factors (frequency doubling perimetry [FDP], Humphrey photopic Swedish Interactive Thresholding Algorithm 24-2 testing, contrast sensitivity, dark adaptation, visual acuity, and quality of life) and anatomic factors (Early Treatment Diabetic Retinopathy Study DR severity level, area of retinal thickening, central macular thickness, macular volume, and retinal vessel diameters). RESULTS From baseline to month 24, mean FDP foveal sensitivity decreased in the placebo group (-1.9 dB) and increased in the doxycycline group (+1.8 dB) (P = .02). A higher mean FDP foveal sensitivity in the doxycycline group compared with the placebo group was detected at 6 months (P = .04), and this significant difference persisted at 12 and 24 months. A difference between the groups was not detected with respect to the other visual function outcomes and all anatomic outcomes assessed. CONCLUSIONS AND RELEVANCE To our knowledge, this is the first observation suggesting a link between a low-dose oral anti-inflammatory agent and subclinical improvement in inner retinal function. Oral doxycycline may be a promising therapeutic strategy targeting the inflammatory component of DR. Furthermore, study results suggest that FDP, which primarily measures inner retinal function, is responsive to intervention and may be a useful clinical trial end point for proof-of-concept studies in patients with DR.

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KW - Aged

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KW - Contrast Sensitivity

KW - Diabetic Retinopathy

KW - Disease Progression

KW - Dose-Response Relationship, Drug

KW - Double-Blind Method

KW - Doxycycline

KW - Feasibility Studies

KW - Female

KW - Fluorescein Angiography

KW - Follow-Up Studies

KW - Fundus Oculi

KW - Humans

KW - Male

KW - Middle Aged

KW - Questionnaires

KW - Retina

KW - Retrospective Studies

KW - Time Factors

KW - Treatment Outcome

KW - Visual Field Tests

KW - Visual Fields

KW - Vitreoretinopathy, Proliferative

KW - Young Adult

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