Minocycline to Treat Central Retinal Vein Occlusion

• Sponsor: National Eye Institute (NEI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01468844
• Collaborator: (none)
• Enrollment: 6
• Locations: 2
• Arms: 2
• Actual Duration (Months): 40.7
• Patients Per Site: 3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Background:

• Central retinal vein occlusion (CRVO) is a blockage of the main vein that carries blood away from the retina in the back of the eye. It can lead to macular edema, a swelling of the retina that is a common source of vision loss. Studies suggest that inflammation might be a cause. Minocycline is a drug that might help prevent cells involved in inflammation from becoming activated. It is approved for use as an antibiotic, but it has not yet been tested to see if it can treat CRVO.

Objectives:

• To test the safety and effectiveness of minocycline as a treatment for central retinal vein occlusion.

Eligibility:

• Individuals at least 18 years of age who have central retinal vein occlusion in at least one eye, with vision between 20/32 and 20/200.

Design:

• This study lasts 2 years, with at least 25 visits.

• Participants will be screened with a physical exam and medical history. They will also have blood tests and an eye exam. One eye will be selected as the study eye to receive the medicine.

• Participants will take minocycline or a placebo pill twice a day, about 12 hours apart, for 2 years.

• Participants will have monthly visits for blood tests and full eye exams to study the effect of the treatment. Other exams may include thyroid tests and eye imaging studies. Those in the study may also receive injections of a drug to prevent the growth of new blood vessels in the eye.

Condition or Disease	Intervention/Treatment	Phase
Retinal Vein Occlusion	Drug: Minocycline; Drug: Placebo; Drug: Bevacizumab	Phase 1/Phase 2

Detailed Description

Objective:

Retinal vein occlusions (RVOs) are significant sources of vision loss, affecting mostly healthy people over 55 years of age. The common source of vision loss is the macular edema accompanying the retinal injury. Very recently, studies employing monthly anti-vascular endothelial growth factor (VEGF) treatments have demonstrated a benefit to this line of treatment; however, the duration of effectiveness appears to be short lived and the length of time needed for these monthly injections remains unknown. A histologic study of human retinas with retinal vein occlusions found the presence of activated microglia. Microglia are capable of migrating through the retina to sites of inflammation to associate closely with neurons and the vasculature, and are key cellular players in the mediation of processes of chronic inflammation. For these reasons, microglia represent a promising cellular target for forms of therapy that limit the deleterious inflammatory changes found in vein occlusions. Minocycline, a second-generation tetracycline, has been shown to exhibit anti-inflammatory properties, including microglial inhibition. The objective of this study is to investigate the safety and potential efficacy of minocycline as a microglia inhibitor in participants with central retinal vein occlusion (CRVO).

Study Population:

A minimum of 10 and a maximum of 20 participants who meet the eligibility criteria may be enrolled. Eligibility criteria include: foveal center-involved macular edema secondary to a CRVO, retinal thickness in the central subfield >350 microns as measured by optical coherence tomography (OCT); and visual acuity (VA) between 20/32 and 20/200 in the study eye.

Design:

In this pilot, double-masked, randomized multi-center study, participants will receive monthly bevacizumab injections for the first three months, followed by PRN dosing. In addition, participants will take an oral dose of 100 mg of minocycline or placebo twice daily for 24 months. During each monthly visit, participants will have their visual acuity measured and will undergo OCT testing to measure retinal thickness. At the Month 3 visit and thereafter, participants will be evaluated for improvement and worsening and will be eligible for additional bevacizumab treatment and/or investigational product (IP) depending on which criteria they fulfill. Additionally, at Month 12, participants will also be evaluated for no improvement.

Outcome Measures:

The primary outcome is the difference in mean change in best-corrected visual acuity (BCVA), as measured in ETDRS letters, between the minocycline and placebo groups in the study eye at 12 months compared to baseline. Secondary outcomes include the difference between the minocycline and placebo groups in the number of intravitreal bevacizumab injections between 12 and 24 months and baseline, changes in mean macular sensitivity as measured by microperimetry at 3, 6, 12, 18 and 24 months compared to baseline, the mean change in BCVA at 24 months compared to baseline, changes in retinal thickness as measured by OCT at 6, 12, 18 and 24 months compared to baseline, number of participants improving greater than or equal to 1 logOCT scale step at 12 and 24 months compared to baseline, as well as and changes in fluid leakage in the macula as demonstrated by fluorescein angiography at 12 and 24 months compared to baseline. Safety outcomes include the number of participant withdrawals, number and severity of systemic and ocular toxicities and the number of adverse events (AEs).

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Pilot Study for the Evaluation of Minocycline as a Microglia Inhibitor in the Treatment of Central Retinal Vein Occlusions
• Actual Study Start Date: Dec 21, 2011
• Actual Primary Completion Date: Mar 4, 2015
• Actual Study Completion Date: May 13, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Minocycline Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months	Drug: Minocycline; 100 mg pink opaque capsule; Drug: Bevacizumab; 1.25 mg bevacizumab injection
Placebo Comparator: Placebo Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months	Drug: Placebo; Placebo; Drug: Bevacizumab; 1.25 mg bevacizumab injection

Outcome Measures

Primary Outcome Measures

1. The Primary Outcome is the Comparison Between the Minocycline and Placebo Groups of the Mean Change in Best-corrected Visual Acuity (BCVA) in the Study Eye at 12 Months Compared to Baseline. [Baseline to Month 12]

   The primary outcome measure is the mean change in best-corrected visual acuity (BCVA), as measured in ETDRS letters in the study eye at 12 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 12 months.

Secondary Outcome Measures

1. Number of Participants Improving ≥ 1 logOCT Scale Step in the Study Eye at 12 Months Compared to Baseline [Baseline to Month 12]

   Improvement of ≥ 1 logOCT scale step is defined as a decrease of ≥ 1-step on the logOCT scale. A 1-step decrease is equivalent to at least a 20% improvement of central macular thickness.

2. Number of Participants Improving ≥ 1 logOCT Scale Step in the Study Eye at 24 Months Compared to Baseline [Baseline to Month 24]

   Improvement of ≥ 1 logOCT scale step is defined as a decrease of ≥ 1-step on the logOCT scale. A 1-step decrease is equivalent to at least a 20% improvement of central macular thickness.

3. Number of Bevacizumab Injections From Baseline to 12 Months [Baseline to Month 12]

   The outcome measure is the number of bevacizumab injections administered to participants between baseline and 12 months.

4. Number of Bevacizumab Injections From Baseline to 24 Months [Baseline to Month 24]

   The outcome measure is the number of bevacizumab injections administered to participants between baseline and 24 months.

5. Changes in Mean Macular Sensitivity in the Study Eye as Measured by Microperimetry at 3 Months Compared to Baseline [Baseline to Month 3]

   The outcome measure is the mean change in macular sensitivity in the study eye at 3 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 3 months.

6. Changes in Mean Macular Sensitivity in the Study Eye as Measured by Microperimetry at 6 Months Compared to Baseline [Baseline to Month 6]

   The outcome measure is the mean change in macular sensitivity in the study eye at 6 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 6 months.

7. Changes in Mean Macular Sensitivity in the Study Eye as Measured by Microperimetry at 12 Months Compared to Baseline [Baseline to Month 12]

   The outcome measure is the mean change in macular sensitivity in the study eye at 12 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 12 months.

8. Changes in Mean Macular Sensitivity in the Study Eye as Measured by Microperimetry at 18 Months Compared to Baseline [Baseline to Month 18]

   The outcome measure is the mean change in macular sensitivity in the study eye at 18 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 18 months.

9. Changes in Mean Macular Sensitivity in the Study Eye as Measured by Microperimetry at 24 Months Compared to Baseline [Baseline to Month 24]

   The outcome measure is the mean change in macular sensitivity in the study eye at 24 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 24 months.

10. Mean Change in the ETDRS BCVA in the Study Eye at 24 Months Compared to Baseline [Baseline to Month 24]

    The outcome measure is the mean change in best-corrected visual acuity (BCVA), as measured in ETDRS letters in the study eye at 24 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 24 months.

11. Changes in Retinal Thickness in the Study Eye as Measured by Optical Coherence Tomography (OCT) at 6 Months Compared to Baseline [Baseline to Month 6]

    The outcome measure is the mean change in central retinal thickness in the study eye at 6 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 6 months.

12. Changes in Retinal Thickness in the Study Eye as Measured by Optical Coherence Tomography (OCT) at 12 Months Compared to Baseline [Baseline to Month 12]

    The outcome measure is the mean change in central retinal thickness in the study eye at 12 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 12 months.

13. Changes in Retinal Thickness in the Study Eye as Measured by Optical Coherence Tomography (OCT) at 18 Months Compared to Baseline [Baseline to Month 18]

    The outcome measure is the difference in the mean change in central retinal thickness in the study eye at 18 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 18 months.

14. Changes in Retinal Thickness in the Study Eye as Measured by Optical Coherence Tomography (OCT) at 24 Months Compared to Baseline [Baseline to Month 24]

    The outcome measure is the mean change in central retinal thickness in the study eye at 24 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 24 months.

15. Changes in Fluid Leakage in the Macula of the Study Eye as Demonstrated by Fluorescein Angiography at 12 Months Compared to Baseline [Baseline to Month 12]

    The outcome measure is the number of participants experiencing changes in fluid leakage in the macula of the study eye as demonstrated by fluorescein angiography at 12 months compared to baseline. The counts presented are the number of participants experiencing decrease, increase, or no change in fluid leakage from baseline.

16. Changes in Fluid Leakage in the Macula of the Study Eye as Demonstrated by Fluorescein Angiography at 24 Months Compared to Baseline. [Baseline to Month 24]

    The outcome measure is the the number of participants experiencing changes in fluid leakage in the macula of the study eye as demonstrated by fluorescein angiography at 24 months compared to baseline. The counts presented are the number of participants experiencing decrease, increase, or no change in fluid leakage from baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

To be eligible, the following participant-level inclusion criteria must be met, where applicable:

• Participant is 18 years of age or older.

• Participant must understand and sign the protocol s informed consent document.

• Female participants of childbearing potential must not be pregnant or breast-feeding and must be willing to undergo serum (BRC sites only) and urine pregnancy tests throughout the study.

• For the NEI Site: Female participants of childbearing potential and male participants able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse or must agree to practice two acceptable methods of contraception throughout the course of the study and for one week after study medication discontinuation (based on the half life of minocycline which is 11-22 hours). Acceptable methods of contraception include:

• hormonal contraception (i.e., birth control pills*, injected hormones, dermal patch or vaginal ring),

• intrauterine device,

• barrier methods (diaphragm, condom) with spermicide, or

• surgical sterilization (hysterectomy or tubal ligation).

• Oral birth control pills must be used with caution as minocycline decreases the effectiveness of some oral contraceptives. Participants already taking oral contraceptives may continue to use them, but must agree to use at least one other method of birth control while on study.

• For the BRC Sites: Female participants of childbearing potential and male participants able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, or be completely abstinent from intercourse. Male participants or male partners (of female participants) who have not had a vasectomy or are not abstinent are required to use a condom with spermicide throughout the course of the study and for one week after study medication discontinuation (based on the half life of minocycline which is 11-22 hours). Female participants of childbearing potential or female partners (of male participants) of childbearing potential must practice one of the below acceptable methods of contraception throughout the course of the study and for one week after study medication discontinuation:

• hormonal contraception (i.e., birth control pills*, injected hormones, dermal patch or vaginal ring),

• intrauterine device,

• barrier methods (e.g., diaphragm) with spermicide, or

• surgical sterilization (hysterectomy or tubal ligation).

Abstinence is only acceptable when it is the participant s preferred and usual lifestyle choice. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

*Oral birth control pills must be used with caution as minocycline decreases the effectiveness of some oral contraceptives. Participants already taking oral contraceptives may continue to use them, but must agree to use at least one other method of birth control while on study.

It should be noted that two forms of contraception (as specified above) will be used by sexually active participants for the duration of the study and for one week after study medication discontinuation.

• Participants must agree to notify the study investigator or coordinator if any of their doctors initiate a new medication during the course of this study.

• Participant must have normal renal function and liver function, or have mild abnormalities not above grade 1 as defined by the Common Terminology Criteria for AEs v4.0 (CTCAE).

• Participant must agree to minimize exposure to sunlight or artificial UV rays and to wear protective clothing, sunglasses, and sunscreen (minimum SPF 15) if s/he must be out in the sun.

• Participant has at least one eye that meets the study eye criteria listed in the Study Eye Eligibility Criteria below.

EXCLUSION CRITERIA:

A participant is not eligible if any of the following exclusion criteria are present.

• Participant is in another investigational study and actively receiving investigational product for CRVOs.

• Participant is unable to comply with study procedures or follow-up visits.

• Participant has a known hypersensitivity to sodium fluorescein dye.

• Participant has a condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure and glycemic control).

• Participant has a history of chronic renal failure requiring dialysis or kidney transplant.

• Participant has a history of chronic hepatitis or liver failure.

• Participant has an allergy or hypersensitivity to minocycline or any drug in the tetracycline family.

• Participant is currently taking a tetracycline medication.

• Participant is taking any medication that could adversely interact with minocycline such as methoxyflurane.

• Participant has a blood pressure of >180/110 (systolic above 180 OR diastolic above 110).

--If blood pressure is brought below 180/110 by anti-hypertensive treatment, the participant can become eligible.

• Participant is currently being treated with systemic anti-VEGF agents or systemic steroids.

• Participant had a cerebral vascular event (CVA) or myocardial infarction (MI) within three months prior study entry.

• Participant has a history of thyroid cancer.

STUDY EYE ELIGIBILITY CRITERIA:

The participant must have at least one eye meeting all inclusion criteria and none of the exclusion criteria listed below.

STUDY EYE INCLUSION CRITERIA:

• The study eye has a best-corrected ETDRS visual acuity score between 78 and 34 letters (i.e., between 20/32 and 20/200)

• The study eye shows definite retinal thickening due to a CRVO based on clinical examination involving the center of the macula that is not refractory to further therapy as based on the investigator s clinical judgment. CRVO is defined as an eye that had retinal hemorrhage or other biomicroscopic evidence of RVO (e.g., telangiectatic capillary bed) and a dilated (or previously dilated) venous system in at least three quadrants of the retina drained by the affected vein.

• The study eye has retinal thickness in the central subfield on baseline OCT measurement > 350 microns, as measured by Zeiss Cirrus spectral domain OCT, or an equivalent retinal thickness on a similar OCT machine.

• The study eye has media clarity and pupillary dilation sufficient for adequate fundus photographs. Furthermore, the participant must be able to cooperate during the procedure for accurate fundus photographs.

STUDY EYE EXCLUSION CRITERIA:

• Macular edema is considered to be due to a cause other than CRVO.

--An eye should not be considered eligible if:

• The macular edema is considered to be related to cataract extraction or

• Clinical examination and/or OCT suggest that vitreoretinal interface disease (e.g., a taut posterior hyaloid or epiretinal membrane) is the primary cause of the macular edema or

• Clinical examination, medical history and/or fluorescein angiography suggest that diabetic retinopathy is the primary cause of the edema.

• The study eye has a history of a recurrent RVO.

• The study eye has a history of RVO present for >18 months.

• A brisk afferent pupillary defect (APD) is present in the study eye.

• An ocular condition (other than RVO) is present such that, in the opinion of the investigator, visual acuity would not improve from resolution of macular edema (e.g., foveal atrophy, pigmentary changes, dense subfoveal hard exudates, laser scar at fovea, non-retinal condition).

• An ocular condition (other than RVO) is present that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, Irvine-Gass Syndrome, etc.).

• A substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by three lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if eye was otherwise normal) is present in the study eye.

• The study eye has had panretinal or sectoral scatter photocoagulation (PRP) within four months prior to study entry.

• The study eye has had pars plana vitrectomy within six months prior to study entry.

• The study eye has undergone major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within three months prior to study entry.

• A yttrium aluminum garnet (YAG) capsulotomy has been performed on the study eye within two months prior to study entry.

• The study eye has had treatment <3 months prior to study entry of intravitreal or periocular steroid injections.

• The study eye has had treatment < 28 days prior to study entry of intravitreal anti-VEGF agents.

STUDY EYE SELECTION CRITERIA IN CASES OF BILATERAL DISEASE:

If both eyes of a participant meet the criteria described above, the study eye will be determined at the investigator's discretion.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892
2	Bristol Eye Hospital	Bristol		United Kingdom

Sponsors and Collaborators

• National Eye Institute (NEI)

Investigators

• Principal Investigator: Catherine A Cukras, M.D., National Eye Institute (NEI)

Study Documents (Full-Text)

• Study Protocol - Sep 19, 2018
• Statistical Analysis Plan - Apr 14, 2020

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Brown DM, Campochiaro PA, Singh RP, Li Z, Gray S, Saroj N, Rundle AC, Rubio RG, Murahashi WY; CRUISE Investigators. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010 Jun;117(6):1124-1133.e1. doi: 10.1016/j.ophtha.2010.02.022. Epub 2010 Apr 9.
• Klein R, Klein BE, Moss SE, Meuer SM. The epidemiology of retinal vein occlusion: the Beaver Dam Eye Study. Trans Am Ophthalmol Soc. 2000;98:133-41; discussion 141-3.
• Mitchell P, Smith W, Chang A. Prevalence and associations of retinal vein occlusion in Australia. The Blue Mountains Eye Study. Arch Ophthalmol. 1996 Oct;114(10):1243-7.

• Responsible Party: National Eye Institute (NEI)
• ClinicalTrials.gov Identifier: NCT01468844
• Other Study ID Numbers: 110264; 11-EI-0264
• First Posted: Nov 10, 2011
• Last Update Posted: Mar 17, 2021
• Last Verified: Feb 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by National Eye Institute (NEI): Visual Acuity; Retinal Vein Occlusion; Central Retinal Vein Occlusion; CRVO
• Additional relevant MeSH terms: Retinal Vein Occlusion; Minocycline; Bevacizumab

Study Results

Participant Flow

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo
Period Title: Overall Study
STARTED	4	2
COMPLETED	2	2
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Minocycline	Placebo	Total
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo	Total of all reporting groups
Overall Participants	4	2	6
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	1 25%	1 50%	2 33.3%
>=65 years	3 75%	1 50%	4 66.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	71.0 (8.8)	66.0 (11.1)	69.3 (8.8)
Sex: Female, Male (Count of Participants)
Female	1 25%	1 50%	2 33.3%
Male	3 75%	1 50%	4 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 50%	1 16.7%
Not Hispanic or Latino	4 100%	1 50%	5 83.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 25%	0 0%	1 16.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	3 75%	2 100%	5 83.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	The Primary Outcome is the Comparison Between the Minocycline and Placebo Groups of the Mean Change in Best-corrected Visual Acuity (BCVA) in the Study Eye at 12 Months Compared to Baseline.
Description	The primary outcome measure is the mean change in best-corrected visual acuity (BCVA), as measured in ETDRS letters in the study eye at 12 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 12 months.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

The primary outcome analysis population includes those participants who were exposed to IP and were followed up for at least 12 months. One participant in the minocycline group was excluded from the analysis because their Month 12 data was not recorded due to their withdrawal from the study prior to Month 12, and one participant in the placebo group was excluded due to missing ETDRS BCVA letters data at baseline.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months. Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months. Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	3	1
Mean (Standard Deviation) [ETDRS letters]	13.3 (7.0)	-2.0 (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean difference between the minocycline and placebo arms in change in BCVA in the study eye at Month 12 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	15.3
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Minocycline - Placebo

2. Secondary Outcome

Title	Number of Participants Improving ≥ 1 logOCT Scale Step in the Study Eye at 12 Months Compared to Baseline
Description	Improvement of ≥ 1 logOCT scale step is defined as a decrease of ≥ 1-step on the logOCT scale. A 1-step decrease is equivalent to at least a 20% improvement of central macular thickness.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol. One participant in the minocycline group was excluded from the analysis because their Month 12 data was not recorded due to their withdrawal from the study prior to Month 12.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months. Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	3	2
Count of Participants [Participants]	2 50%	2 100%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The difference between the minocycline and placebo treatment arms in number of participants improving ≥ 1 logOCT scale step in the study eye at Month 12 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Number of Participants
	Estimated Value	0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Minocycline - Placebo

3. Secondary Outcome

Title	Number of Participants Improving ≥ 1 logOCT Scale Step in the Study Eye at 24 Months Compared to Baseline
Description	Improvement of ≥ 1 logOCT scale step is defined as a decrease of ≥ 1-step on the logOCT scale. A 1-step decrease is equivalent to at least a 20% improvement of central macular thickness.
Time Frame	Baseline to Month 24

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol. Two participants in the minocycline group were excluded because their Month 24 data was not recorded due to their withdrawal from the study prior to Month 24.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months. Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	2	2
Count of Participants [Participants]	2 50%	2 100%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The difference between the minocycline and placebo treatment arms in number of participants improving ≥ 1 logOCT scale step in the study eye at Month 24 compared to baseline is reported
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Number of Participants
	Estimated Value	0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Minocycline - Placebo

4. Secondary Outcome

Title	Number of Bevacizumab Injections From Baseline to 12 Months
Description	The outcome measure is the number of bevacizumab injections administered to participants between baseline and 12 months.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	4	2
Mean (Standard Deviation) [injections]	5.5 (4.4)	10.5 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean difference between the minocycline and placebo treatment arms in number of bevacizumab injections received from baseline to Month 12 is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 2.3
	Estimation Comments	Difference = Minocycline - Placebo

5. Secondary Outcome

Title	Number of Bevacizumab Injections From Baseline to 24 Months
Description	The outcome measure is the number of bevacizumab injections administered to participants between baseline and 24 months.
Time Frame	Baseline to Month 24

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	4	2
Mean (Standard Deviation) [injections]	7.8 (8.8)	16.0 (0.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean difference between the minocycline and placebo treatment arms in number of bevacizumab injections received from baseline to Month 24 is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-8.2
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 4.4
	Estimation Comments	Difference = Minocycline - Placebo

6. Secondary Outcome

Title	Changes in Mean Macular Sensitivity in the Study Eye as Measured by Microperimetry at 3 Months Compared to Baseline
Description	The outcome measure is the mean change in macular sensitivity in the study eye at 3 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 3 months.
Time Frame	Baseline to Month 3

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol. One participant in the minocycline group was excluded due to missing macular sensitivity data at Month 3.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	3	2
Mean (Standard Deviation) [db]	0.8 (2.2)	3.4 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean difference between the minocycline and placebo groups in the change in macular sensitivity in the study eye at Month 3 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 1.3
	Estimation Comments	Difference = Minocycline - Placebo

7. Secondary Outcome

Title	Changes in Mean Macular Sensitivity in the Study Eye as Measured by Microperimetry at 6 Months Compared to Baseline
Description	The outcome measure is the mean change in macular sensitivity in the study eye at 6 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 6 months.
Time Frame	Baseline to Month 6

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol. One participant in the minocycline group was excluded from the analysis because their Month 6 data was not recorded due to withdrawal from the study prior to Month 6.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	3	2
Mean (Standard Deviation) [db]	0.3 (2.8)	1.1 (4.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean difference between the minocycline and placebo groups in the change in macular sensitivity in the study eye at Month 6 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 3.5
	Estimation Comments	Difference = Minocycline - Placebo

8. Secondary Outcome

Title	Changes in Mean Macular Sensitivity in the Study Eye as Measured by Microperimetry at 12 Months Compared to Baseline
Description	The outcome measure is the mean change in macular sensitivity in the study eye at 12 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 12 months.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol. One participant in the minocycline group was excluded from the analysis because their Month 12 data was not recorded due to withdrawal from the study prior to Month 12.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	3	2
Mean (Standard Deviation) [db]	-1.7 (5.5)	1.3 (0.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean difference between the minocycline and placebo groups in the change in macular sensitivity in the study eye at Month 12 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 3.2
	Estimation Comments	Difference = Minocycline - Placebo

9. Secondary Outcome

Title	Changes in Mean Macular Sensitivity in the Study Eye as Measured by Microperimetry at 18 Months Compared to Baseline
Description	The outcome measure is the mean change in macular sensitivity in the study eye at 18 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 18 months.
Time Frame	Baseline to Month 18

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol. Two participants in the minocycline group were excluded from the analysis because their Month 18 data was not recorded due to withdrawal from the study prior to Month 18.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	2	2
Mean (Standard Deviation) [db]	-0.9 (4.0)	4.5 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean difference between the minocycline and placebo groups in the change in macular sensitivity in the study eye at Month 18 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.4
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 2.8
	Estimation Comments	Difference = Minocycline - Placebo

10. Secondary Outcome

Title	Changes in Mean Macular Sensitivity in the Study Eye as Measured by Microperimetry at 24 Months Compared to Baseline
Description	The outcome measure is the mean change in macular sensitivity in the study eye at 24 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 24 months.
Time Frame	Baseline to Month 24

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol. Two participants in the minocycline group were excluded from the analysis because their Month 24 data was not recorded due to withdrawal from the study prior to Month 24.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	2	2
Mean (Standard Deviation) [db]	-1.5 (3.3)	3.9 (4.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean difference between the minocycline and placebo groups in the change in macular sensitivity in the study eye at Month 24 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.4
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 3.8
	Estimation Comments	Difference = Minocycline - Placebo

11. Secondary Outcome

Title	Mean Change in the ETDRS BCVA in the Study Eye at 24 Months Compared to Baseline
Description	The outcome measure is the mean change in best-corrected visual acuity (BCVA), as measured in ETDRS letters in the study eye at 24 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 24 months.
Time Frame	Baseline to Month 24

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol. Two participants in the minocycline group were excluded from the analysis because their Month 24 data was not recorded due to withdrawal from the study prior to Month 24, and one participant in the placebo group was excluded due to missing baseline BCVA data.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	2	1
Mean (Standard Deviation) [ETDRS letters]	13 (0.0)	-17.0 (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean difference between the minocycline and placebo arms in change in BCVA in the study eye at Month 24 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	30.0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Minocycline - Placebo

12. Secondary Outcome

Title	Changes in Retinal Thickness in the Study Eye as Measured by Optical Coherence Tomography (OCT) at 6 Months Compared to Baseline
Description	The outcome measure is the mean change in central retinal thickness in the study eye at 6 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 6 months.
Time Frame	Baseline to Month 6

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol. One participant in the minocycline group was excluded from the analysis because their Month 6 data was not recorded due to withdrawal from the study prior to Month 6.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	3	2
Mean (Standard Deviation) [micrometers]	-272.7 (117.0)	-312.0 (128.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean difference between the minocycline and placebo treatment arms in change in retinal thickness as measured by OCT in the study eye at Month 6 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	39.3
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 113.3
	Estimation Comments	Difference = Minocycline - Placebo

13. Secondary Outcome

Title	Changes in Retinal Thickness in the Study Eye as Measured by Optical Coherence Tomography (OCT) at 12 Months Compared to Baseline
Description	The outcome measure is the mean change in central retinal thickness in the study eye at 12 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 12 months.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol. One participant in the minocycline group was excluded from the analysis because their Month 12 data was not recorded due to withdrawal from the study prior to Month 12.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	3	2
Mean (Standard Deviation) [micrometers]	-145.3 (259.1)	-458.5 (313.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean difference between the minocycline and placebo treatment arms in change in retinal thickness as measured by OCT in the study eye at Month 12 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	313.2
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 267.3
	Estimation Comments	Difference = Minocycline - Placebo

14. Secondary Outcome

Title	Changes in Retinal Thickness in the Study Eye as Measured by Optical Coherence Tomography (OCT) at 18 Months Compared to Baseline
Description	The outcome measure is the difference in the mean change in central retinal thickness in the study eye at 18 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 18 months.
Time Frame	Baseline to Month 18

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol. Two participants in the minocycline group were excluded from the analysis because their Month 18 data was not recorded due to withdrawal from the study prior to Month 18.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	2	2
Mean (Standard Deviation) [micrometers]	-52.0 (169.7)	-480.5 (118.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean difference between the minocycline and placebo treatment arms in change in retinal thickness as measured by OCT in the study eye at Month 18 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	428.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 146.2
	Estimation Comments	Difference = Minocycline - Placebo

15. Secondary Outcome

Title	Changes in Retinal Thickness in the Study Eye as Measured by Optical Coherence Tomography (OCT) at 24 Months Compared to Baseline
Description	The outcome measure is the mean change in central retinal thickness in the study eye at 24 months compared to baseline. Values presented represent mean and standard deviation of change from baseline at 24 months.
Time Frame	Baseline to Month 24

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol. Two participants in the minocycline group were excluded from the analysis because their Month 24 data was not recorded due to withdrawal from the study prior to Month 24.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	2	2
Mean (Standard Deviation) [micrometers]	-227.0 (84.9)	-346.0 (41.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean difference between the minocycline and placebo treatment arms in change in retinal thickness as measured by OCT in the study eye at Month 24 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	119.0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 66.6
	Estimation Comments	Difference = Minocycline - Placebo

16. Secondary Outcome

Title	Changes in Fluid Leakage in the Macula of the Study Eye as Demonstrated by Fluorescein Angiography at 12 Months Compared to Baseline
Description	The outcome measure is the number of participants experiencing changes in fluid leakage in the macula of the study eye as demonstrated by fluorescein angiography at 12 months compared to baseline. The counts presented are the number of participants experiencing decrease, increase, or no change in fluid leakage from baseline.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol. Two participants in the minocycline group were excluded from the analysis: one because their Month 12 data was not recorded due to withdrawal from the study prior to Month 12, and one due to missing data for fluid leakage at the Month 12 visit.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	2	2
Decrease	2 50%	1 50%
Increase	0 0%	1 50%
No Change	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The difference between the minocycline and treatment arms in the number of participants experiencing a decrease in fluid leakage at Month 12 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Number of Participants
	Estimated Value	1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Minocycline - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The difference between the minocycline and treatment arms in the number of participants experiencing an increase in fluid leakage at Month 12 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Number of Participants
	Estimated Value	-1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Minocycline - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The difference between the minocycline and treatment arms in the number of participants experiencing no change in fluid leakage at Month 12 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Number of Participants
	Estimated Value	0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Minocycline - Placebo

17. Secondary Outcome

Title	Changes in Fluid Leakage in the Macula of the Study Eye as Demonstrated by Fluorescein Angiography at 24 Months Compared to Baseline.
Description	The outcome measure is the the number of participants experiencing changes in fluid leakage in the macula of the study eye as demonstrated by fluorescein angiography at 24 months compared to baseline. The counts presented are the number of participants experiencing decrease, increase, or no change in fluid leakage from baseline.
Time Frame	Baseline to Month 24

Outcome Measure Data

Analysis Population Description

The secondary outcomes are based on the safety population, which includes all participants who were exposed to IP, regardless of adherence to protocol. Two participants in the minocycline group were excluded from the analysis because their Month 24 data was not recorded due to withdrawal from the study prior to Month 24, and one participant in the placebo group was excluded due to missing data for fluid leakage at the Month 24 visit.

Arm/Group Title	Minocycline	Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule Bevacizumab: 1.25 mg bevacizumab injection
Measure Participants	2	1
Decrease	2 50%	1 50%
Increase	0 0%	0 0%
No Change	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The difference between the minocycline and treatment arms in the number of participants experiencing a decrease in fluid leakage at Month 24 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Number of Participants
	Estimated Value	1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Minocycline - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The difference between the minocycline and treatment arms in the number of participants experiencing an increase in fluid leakage at Month 24 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Number of Participants
	Estimated Value	0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Minocycline - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Minocycline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The difference between the minocycline and treatment arms in the number of participants experiencing no change in fluid leakage at Month 24 compared to baseline is reported.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Number of Participants
	Estimated Value	0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Minocycline - Placebo

Adverse Events

Time Frame	24 months
Arm/Group Title	Minocycline		Placebo
Arm/Group Description	Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months Minocycline: 100 mg pink opaque capsule		Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months Placebo: Placebo
All Cause Mortality
	Minocycline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/2 (0%)
Serious Adverse Events
	Minocycline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/4 (25%)		1/2 (50%)
General disorders
Systemic inflammatory response syndrome	1/4 (25%)	1	0/2 (0%)	0
Infections and infestations
Klebsiella bacteraemia	1/4 (25%)	1	0/2 (0%)	0
Nervous system disorders
Cerebellar artery thrombosis	0/4 (0%)	0	1/2 (50%)	1
Other (Not Including Serious) Adverse Events
	Minocycline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		2/2 (100%)
Cardiac disorders
Acute myocardial infarction	1/4 (25%)	1	0/2 (0%)	0
Endocrine disorders
Hypothyroidism	1/4 (25%)	1	0/2 (0%)	0
Eye disorders
Punctate keratitis	2/4 (50%)	4	0/2 (0%)	0
Conjunctival haemorrhage	1/4 (25%)	1	1/2 (50%)	2
Diplopia	1/4 (25%)	2	0/2 (0%)	0
Angle closure glaucoma	1/4 (25%)	1	0/2 (0%)	0
Blepharitis	0/4 (0%)	0	1/2 (50%)	1
Eye pain	1/4 (25%)	1	0/2 (0%)	0
Eyelid ptosis	1/4 (25%)	1	0/2 (0%)	0
Macular fibrosis	1/4 (25%)	1	0/2 (0%)	0
Vitreous haemorrhage	1/4 (25%)	1	0/2 (0%)	0
Retinal pigmentation	1/4 (25%)	1	0/2 (0%)	0
Gastrointestinal disorders
Vomiting	1/4 (25%)	4	0/2 (0%)	0
Abdominal discomfort	1/4 (25%)	1	1/2 (50%)	1
Abdominal pain	0/4 (0%)	0	1/2 (50%)	1
Constipation	1/4 (25%)	1	0/2 (0%)	0
Diarrhoea	1/4 (25%)	1	0/2 (0%)	0
Dysphagia	0/4 (0%)	0	1/2 (50%)	1
General disorders
Fatigue	2/4 (50%)	2	0/2 (0%)	0
Oedema peripheral	1/4 (25%)	1	0/2 (0%)	0
Infections and infestations
Nasopharyngitis	1/4 (25%)	1	2/2 (100%)	3
Urinary Tract Infection	0/4 (0%)	0	1/2 (50%)	2
Gastroenteritis viral	0/4 (0%)	0	1/2 (50%)	1
Influenza	0/4 (0%)	0	1/2 (50%)	1
Respiratory tract infection	1/4 (25%)	1	0/2 (0%)	0
Sinusitis	1/4 (25%)	1	0/2 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/4 (0%)	0	1/2 (50%)	1
Investigations
Aspartate aminotransferase increased	1/4 (25%)	1	1/2 (50%)	1
Blood pressure increased	1/4 (25%)	1	0/2 (0%)	0
Blood thyroid stimulating hormone abnormal	1/4 (25%)	1	0/2 (0%)	0
Blood thyroid stimulating hormone increased	1/4 (25%)	1	0/2 (0%)	0
Haemoglobin decreased	0/4 (0%)	0	1/2 (50%)	1
International normalised ratio decreased	1/4 (25%)	1	0/2 (0%)	0
International normalised ratio increased	1/4 (25%)	1	0/2 (0%)	0
Liver function test increased	1/4 (25%)	1	0/2 (0%)	0
Prostatic specific antigen increased	0/4 (0%)	0	1/2 (50%)	1
Renal function test abnormal	1/4 (25%)	1	0/2 (0%)	0
Transaminases increased	1/4 (25%)	1	0/2 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	2/4 (50%)	2	0/2 (0%)	0
Hyperkalaemia	1/4 (25%)	1	0/2 (0%)	0
Type 2 diabetes mellitus	1/4 (25%)	1	0/2 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle twitching	1/4 (25%)	1	0/2 (0%)	0
Neck pain	1/4 (25%)	1	0/2 (0%)	0
Osteoarthritis	1/4 (25%)	1	0/2 (0%)	0
Pain in extremity	0/4 (0%)	0	1/2 (50%)	1
Pain in jaw	0/4 (0%)	0	1/2 (50%)	1
Nervous system disorders
Dizziness	1/4 (25%)	1	2/2 (100%)	2
Dizziness postural	0/4 (0%)	0	1/2 (50%)	1
Headache	0/4 (0%)	0	1/2 (50%)	1
Tension headache	0/4 (0%)	0	1/2 (50%)	1
Renal and urinary disorders
Nephrolithiasis	1/4 (25%)	1	0/2 (0%)	0
Reproductive system and breast disorders
Vulvovaginal pruritus	0/4 (0%)	0	1/2 (50%)	1
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/4 (25%)	2	0/2 (0%)	0
Oropharyngeal pain	0/4 (0%)	0	1/2 (50%)	1
Sinus congestion	0/4 (0%)	0	1/2 (50%)	1
Skin and subcutaneous tissue disorders
Skin hyperpigmentation	3/4 (75%)	3	0/2 (0%)	0
Surgical and medical procedures
Sinus operation	1/4 (25%)	1	0/2 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.