Clinical trial NCT04352660
Conditions: Open Angle Glaucoma
Keywords: trabeculectomy, mitomycin-C, glaucoma
Sponsor: University of California, San Diego
Start date: 2016-05-23; Completion date: 2019-04-14
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Trabeculectomy is routinely used as a surgical treatment for open angle glaucoma. Success of trabeculectomy is greatly augmented by the use of antimetabolites to inhibit wound healing, specifically Mitomycin C (MMC). MMC can be applied to the eye at various sites, concentrations and times. This study aims to compare the two application routes that are commonly employed: subconjunctival pre-operative injection and intraoperative direct scleral application in terms of IOP lowering effect, bleb appearance and complications.

Detailed description:
Trabeculectomy is widely used as a surgical treatment of uncontrolled open glaucoma. Success of trabeculectomy at halting or slowing glaucoma progression primarily relies on the extent of conjunctival and sclera wound healing. The success rates of trabeculectomy increased dramatically with the introduction of anti-metabolites. For more than two decades mitomycin-c (MMC), a chemotherapeutic agent capable of decreasing fibroblast activity and modulating wound healing at the bleb, has been used with trabeculectomy. The complications of MMC are well known and several studies have described various methods of application based on exposure time, dose and surface area. Numerous retrospective and prospective studies have compared the efficacy of MMC applied beneath the conjunctival flap with soaked sponges versus intrascleral application. In 2008, Lee et al. first described an alternative route of application: subconjunctival injection of MMC directly into the intra-Tenon area. Seventy-six eyes with primary and secondary open angle glaucoma underwent trabeculectomy with this approach and were followed for one year post-operatively. Eighty-six percent of eyes achieved an IOP \<21 mm Hg and 57% an IOP\<14 mm Hg at one year without adjunctive drops. Transient complications included hyphema, bleb leak and choroidal detachment. The advantages of injected MMC are primarily in controlling the exact dosage and area of application and reduced surgical time. Lim et al. retrospectively reviewed the outcomes of trabeculectomy in 57 eyes using sponge application directly to the sclera versus intra-tenon injection. IOP was significantly lower in the injection group at 1 month, 1, 2, and 3 years. Trabeculectomy success (IOP\<21mm Hg or IOP \>20% below baseline without medications or additional surgery) was greater in the injection group at 3 years. The sponge group experienced more encapsulated blebs but complication rates were similar in both groups. To date, there have been no prospective studies comparing the IOP-lowering efficacy and safety of intra-tenon injection versus direct scleral application of MMC.

Arms: arm 1: MMC delivered by preoperative subconjunctival injection arm 2: MMC delivered by intraoperative direct scleral application with impregnated cellulose sponges
Interventions: intervention 1: Mitomycin-C injection intervention 2: Mitomycin-C sponge
Intervention descriptions: intervention 1: MMC delivered by preoperative subconjunctival injection intervention 2: MMC delivered by intraoperative direct scleral application with impregnated cellulose sponges

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
Subconjunctival Versus Direct Mitomycin C in Trabeculectomy 
NCT04352660 
Document Date: May 5, 2020 
 


 
 
Biomedical IRB Application Instructions 
Page 1 
 
 
UCSD Human Research Protections Program 
New Biomedical Application 
RESEARCH PLAN 
Instructions for completing the Research Plan are available on the HRPP website. 
The headings on this set of instructions correspond to the headings of the Research Plan. 
General Instructions: Enter a response for all topic headings.  
Enter “Not Applicable” rather than leaving an item blank if the item does not apply to this project. 
Version date: 9/30/2013 
1. 
PROJECT TITLE 
 
Subconjunctival versus direct scleral application of Mitomycin-C injection in trabeculectomy 
2. 
PRINCIPAL INVESTIGATOR  
Robert Weinreb MD, Jiun Do MD PhD 
 
3. 
FACILITIES 
Shiley Eye Institute, Secondary investigators: Brandon Wong MD, Benjamin Y. Xu MD, Andrew Camp MD, 
Philip Ngai MD, Derek Welsbie MD PhD 
 
4. 
ESTIMATED DURATION OF THE STUDY 
We estimate from the beginning of the study through the end of data analysis will take less than 18 months 
 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph) 
Trabeculectomy is routinely used as a surgical treatment for open angle glaucoma. Success of trabeculectomy is 
greatly augmented by the use of antimetabolites to inhibit wound healing, specifically Mitomycin C (MMC). 
MMC can be applied to the eye at various sites, concentrations, and times. This study aims to compare the two 
application routes that are commonly employed: subconjunctival pre-operative injection and intraoperative 
direct scleral application in terms of IOP lowering effect, bleb appearance and complications. 
 
6. 
SPECIFIC AIMS 
To describe differences in IOP lowering effect, bleb appearance and complications over a 6-month post-operative 
course between patients receiving subconjunctival MMC vs direct sclera application during trabeculectomy 
 
7. 
BACKGROUND AND SIGNIFICANCE 
Trabeculectomy is widely used as a surgical treatment of uncontrolled open glaucoma. Success of 
trabeculectomy at halting or slowing glaucoma progression primarily relies on the extent of conjunctival and 
sclera wound healing (1).  The success rates of trabeculectomy increased dramatically with the introduction of 
anti-metabolites (2-4). For more than two decades mitomycin-c (MMC), a chemotherapeutic agent capable of 
decreasing fibroblast activity and modulating wound healing at the bleb, has been used with trabeculectomy. 
The complications of MMC are well known and several studies have described various methods of application 
based on exposure time, dose and surface area. Numerous retrospective and prospective studies have compared 
the efficacy of MMC applied beneath the conjunctival flap with soaked sponges versus intrascleral application 
(5-9). In 2008 Lee et al first described an alternative route of application: subconjunctival injection of MMC 
directly into the intra-Tenon area (11). Seventy-six eyes with primary and secondary open angle glaucoma 
underwent trabeculectomy with this approach and were followed for one year post-operatively. Eighty-six 
percent of eyes achieved an IOP <21 mm Hg and 57% an IOP<14 mm Hg at one year without adjunctive drops. 
Transient complications included hyphema, bleb leak and choroidal detachment.  The advantages of injected 
MMC are primarily in controlling the exact dosage and area of application and reduced surgical time. Lim et al 
retrospectively reviewed the outcomes of trabeculectomy in 57 eyes using sponge application directly to the 


 
 
Biomedical IRB Application Instructions 
Page 2 
sclera versus intra-tenon injection (10).  IOP was significantly lower in the injection group at 1 month, 1, 2 and 
3 years. Trabeculectomy success (IOP<21mm Hg or IOP >20% below baseline without medications or 
additional surgery) was greater in the injection group at 3 years. The sponge group experienced more 
encapsulated blebs and complication rates were similar in both groups.  To date, there have been no prospective 
studies comparing the IOP-lowering efficacy and safety of intra-tenon injection versus direct sceral application 
of MMC. 
8. 
PROGRESS REPORT 
 
n/a 
9. 
RESEARCH DESIGN AND METHODS 
 
This study will be a prospective randomized study of eyes with medically uncontrolled open angle glaucoma in 
whom trabeculectomy is indicated (high intraocular pressure, worsening visual field, or optic nerve head 
changes). Evaluated preoperative data will include age, gender, IOP, best corrected visual acuity, and number 
of antiglaucoma medications. Patients with pathologic myopia (refractive error of >6 Diopters) will be 
excluded.  To detect a minimum difference of 3mmHg in IOP between the two groups we will require 50 
patients in each group. This assumes a standard deviation of measurements of 5mmHg which is in agreement 
with previous literature. The patients will be randomized using a random number generator found at 
http://www.graphpad.com/quickcalcs/randomize1/.  The surgeons who perform the trabeculectomies and 
administer the MMC will not be masked. Masking of the surgeon would require injection of a vehicle (balanced 
salt solution) which would incur additional risks (subconjunctival hemorrhage).  There will be masking during 
the follow-up post-operative appointments. An examiner who was not present during surgery and blind to the 
group assignments will be conduct all of the post-operative exams and perform this portion of data collection. 
 
Patients will by random selection receive either 1) subconjunctival injection of MMC (0.15ml of 0.2mg/ml 
solutions) in the immediate pre-operative period or 2) direct scleral application for 1-2 minutes intraoperatively 
(0.4 mg/ml in cellulose sponges). The primary outcome in the study will be postoperative IOP measured at 1 
day, 1 and 6 weeks, 3 months and 6 months; it is standard of care to examine patients on these post-operative 
dates. Surgical success will be defined as an IOP value of <21 mm Hg and at least a 30% reduction in IOP 
without IOP lowering drops. Secondary outcomes will include an IOP<21 mm Hg and 30% reduction with 
adjunctive antiglaucoma drops, appearance of the bleb using the Indiana Bleb Appearance Grading Scale 
(IBAGS) and complication rates. At each follow-up visit the bleb will graded during physical exam using the 
IBAGS based on height, extent, vascularity, and Seidel. A masked examiner blinded to the patient’s group 
assignment will perform the post-operative examinations and collect the above data. 
 
For statistical analysis, continuous variables will be reported as means and standard deviations or 95% 
confidence intervals; significance will be determined by paired t-test within groups, two-sample t-test between 
groups, or Mann-Whitney U-test. Categorical variables will be reported as counts and percentages; differences 
will be tested using Fisher’s exact test. Analyses will be conducted using RStudio (RStudio Team, 2016, 
Boston, Massachusetts, Boston, ISA). 
 
10. 
HUMAN SUBJECTS 
Patients undergoing primary trabeculectomy will be recruited from the Shiley Eye Institute by Dr Weinreb, Dr 
Do, Dr Wong, and Dr Xu 
 
11. 
RECRUITMENT AND PROCEDURES PREPARATORY TO RESEARCH 
 


 
 
Biomedical IRB Application Instructions 
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None 
12. 
INFORMED CONSENT 
All patients will be consented for trabeculectomy with MMC- the route of application of which will be 
randomized. The patients will also be consented for participation in the study with explanation of the study’s 
purpose. 
 
13. 
ALTERNATIVES TO STUDY PARTICIPATION 
Patients may opt to not have trabeculectomy, to undergo an alternative surgical glaucoma procedure, or to 
undergo trabeculectomy with MMC without randomization and without inclusion in the study. 
 
14. 
POTENTIAL RISKS 
 
Risks of trabeculectomy and MMC application include pain, infection, loss of eye, loss of vision, need for more 
surgery, hypotony, uncontrolled high IOP, retinal detachment, maculopathy, corneal edema, risk of loss of 
confidentiality. It is standard practice to deliver MMC during trabeculectomy by either route discussed above; 
all patients excluding high myopes receive MMC during trabeculectomy at Shiley Eye Institute.  As it is our 
standard practice to always give MMC to trabeculectomy patients there is no added risk 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
 
None 
16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND MANAGEMENT 
Every reasonable effort will be made to keep records confidential. To protect privacy, the information obtained 
as a result of participation in this research will not be included with any medical records and will be kept in a 
locked cabinet. Information from which patients may be personally identified will be maintained in a 
confidential, secure location at the Shiley Eye Center, accessible only by authorized members of the study, and 
will not be disclosed to third parties except as described in the consent form, or as may be required by law.  
 
17. POTENTIAL BENEFITS 
 
A better understanding of optimal delivery of MMC will benefit future patients requiring 
trabeculectomy who require maximal IOP lowering. 
18. RISK/BENEFIT RATIO 
It is standard practice to deliver MMC during trabeculectomy by either route discussed above; all patients 
excluding high myopes receive MMC during trabeculectomy at Shiley Eye Institute.  As it is our standard 
practice to always give MMC to trabeculectomy patients there is no added risk.  
 
19. EXPENSE TO PARTICIPANT 
None 
 
20. COMPENSATION FOR PARTICIPATION 
None 
 
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
The research team will be responsible for randomizing patients, consenting patients, collecting all –preoperative 
patient data as well as all subsequent post-operative measurements during follow-up visits. The research team will 
be responsible for all statistical analysis. 
 


 
 
Biomedical IRB Application Instructions 
Page 4 
22. BIBLIOGRAPHY 
1. 
Mills R, Weinreb RN (eds). Glaucoma Surgery Techniques. San Francisco: American Academy of 
Ophthalmology, 1991.   
2. 
Lin ZJ Li Y Cheng JW Intraoperative mitomycin C versus intraoperative 5-fluorouracil for 
trabeculectomy: a systematic review and meta-analysis. J Ocul Pharmacol Ther . 2012; 28: 166–
173.[CrossRef] [PubMed] 
3. 
Cheng JW Cai JP Li Y Intraoperative mitomycin C for nonpenetrating glaucoma surgery: a systematic 
review and meta-analysis. J Glaucoma . 2011; 20: 322–326. [CrossRef] [PubMed] 
4. 
Cheng JW Xi GL Wei RL Efficacy and tolerability of nonpenetrating glaucoma surgery augmented with 
mitomycin C in treatment of open-angle glaucoma: a meta-analysis. Can J Ophthalmol . 2009; 44: 76–
82. [CrossRef] [PubMed] 
5. 
Subconjunctival Versus Intrascleral Application of Mitomycin C During Trabeculectomy Miaomiao 
Zhang; Bin Li; Wei Liu; Jianrong Wang; Xinyi Wu Investigative Ophthalmology & Visual Science July 
2014, Vol.55, 4639-4644. doi:10.1167/iovs.14-14159 
6. 
Agarwal HC, Saigal D, Sihota R. Assessing the role of subconjunctival versus intrascleral application of 
mitomycin-C in high-risk trabeculectomies. Indian J Ophthalmol . 2001; 49: 91–95. [PubMed] 
7.. 
Tressler, CS Cyrlin MN Rosenshein JS. Subconjunctival versus intrascleral mitomycin-C in 
trabeculectomy. Ophthalmic Surg Lasers . 1996; 27: 661–666. [PubMed] 
8. 
Prata JA Minckler DS Baerveldt G. Site of mitomycin C application during trabeculectomy. J 
Glaucoma . 1994; 3: 296–301. [CrossRef] [PubMed] 
9. 
Vass C Menapace R Strenn K Episcleral versus combined episcleral and intrascleral application of 
mitomycin-C in trabeculectomy. Ophthalmic Surg Lasers . 1998; 29: 714–721. [PubMed] 
10. 
 American Glaucoma Society (AGS) 23rd Annual Meeting: Abstract 19. Presented March 2, 2013. 
11. 
Lee, et al. Trabeculectomy surgery augmented with intra-Tenon injection of mitomycin C. Acta 
OphthalmologicaVolume 86, Issue 8, 28 June 2008. 
 
 
 
23. FUNDING SUPPORT FOR THIS STUDY 
No funding. 
 
24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
 
 
25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 
 
 


 
 
Biomedical IRB Application Instructions 
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26. IMPACT ON STAFF 
 
None 
27. CONFLICT OF INTEREST 
none 
 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES 
 
 
29. OTHER APPROVALS/REGULATED MATERIALS 
 
 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT