Clinical trial NCT02805257
Conditions: Glaucoma Primary Open Angle Glaucoma Secondary Glaucoma Neovascular Glaucoma
Sponsor: University of California, San Francisco
Start date: 2016-06-01; Completion date: 2020-03-01
Enrollment: 119 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will determine the effectiveness of Mitomycin-C use in the glaucoma surgery Ahmed valve implantation. Approximately 100 patients will be enrolled, with half receiving the Mitomycin-C treatment and the other half receiving placebo treatment.

Detailed description:
Glaucoma is a leading cause irreversible blindness worldwide. Glaucoma valve surgeries such as Ahmed valve implantation, which are conventional surgeries performed to control intraocular pressure in eyes, are sometimes associated with complications due to fibrosis. Mitomycin-C is a commonly used antifibrotic agent used in glaucoma surgeries. This study will evaluate the effectiveness of Mitomycin-C injections intraoperatively and postoperatively.

Arms: arm 1: 0.1 ml of Mitomycin-C 0.4mg/ml injection intraoperatively and twice postoperatively. arm 2: 0.1ml Balanced Salt Solution injection intraoperatively and twice postoperatively.
Interventions: intervention 1: Mitomycin-C intervention 2: Balanced Salt Solution intervention 3: Ahmed Glaucoma Valve Implant
Intervention descriptions: intervention 1: Intraoperative and postoperative injections of mitomycin-c/Mitosol intervention 2: Intraoperative and postoperative injections of BSS intervention 3: Implantation of Ahmed Valve in study eye

Protocol documents:
Prot_000.pdf: 
 
1 
Ahmed with Mitomycin-C Comparison Trial  
(AMC trial) 
 
Manual of Operation 
NCT02805257 
December 12, 2017 
 
 
University of California, San Francisco 
Francis I. Proctor Foundation, University of California San Francisco 
Bascom-Palmer Eye Institute 
University of Colorado 
University of Maryland 
Zhongshan Ophthalmic Center 
Asociación para Evitar la Ceguera en México (APEC) 
 
Principal Investigators: 
Ying Han, MD, PhD1 
Steven J.  Gedde, MD2 
Malik Y Kahook, MD3  
Osamah Saeedi4 
Xing Liu, MD, PhD5 
Gabriel Lazcano, MD6 
 
 
 
 
 
 
 
 
 
 
 
1. University of California San Francisco, San Francisco, California 
2. Bascom-Palmer Eye Institute 
3. University of Colorado 
4. University of Maryland 
5. Zhongshan Ophthalmic Center 
6. Asociación para Evitar la Ceguera en México (APEC) 
 
Table of Content 


 
2 
 
 
 
1. Study Personnel, Collaboration Plan and Study Organizations ......................... 3 
2. Patient selection:  .................................................................................................. 3 
2.1 Inclusion Criteria: .............................................................................................................................................................. 3 
2.2 Exclusion Criteria: ............................................................................................................................................................. 3 
3. Randomization Scheme: ....................................................................................... 4 
4. Study Visits ........................................................................................................... 4 
4.1 Baseline Visit........................................................................................................................................................................ 4 
4.2 Surgery Visit  ........................................................................................................................................................................ 4 
4.3 Follow-Up Visits ................................................................................................................................................................. 4 
4. 4. Final Visit ............................................................................................................................................................................. 4 
5. Procedures ............................................................................................................ 5 
5.1 Masking .................................................................................................................................................................................. 5 
5.2 Mitosol®/MMC and BSS Sham preparation ........................................................................................................... 5 
5.3 Surgical Procedure ............................................................................................................................................................ 5 
5.4 Postoperative Mitosol®/MMC or BSS Sham Injection ....................................................................................... 5 
5.5 Postoperative medication management  .................................................................................................................. 6 
5.6 Examinations during each visit and study schedule ............................................................................................ 6 
6. Assessment of Primary and Secondary Outcomes ............................................ 7 
7. Management of Breach of Protocol ...................................................................... 9 
7.1 Instructions for the Patients .......................................................................................................................................... 9 
7.2  Unscheduled Visits ........................................................................................................................................................... 9 
7.3 Compliance with Protocol .............................................................................................................................................. 9 
7.4 Early Discontinuation of Patients ................................................................................................................................ 9 
7.5 Withdrawal Criteria .......................................................................................................................................................... 9 
7.6 Study Termination ............................................................................................................................................................. 9 
8. Diagnoses and Management of Adverse Events (AEs)      .................................10 
8.1 Definitions of Adverse Event ...................................................................................................................................... 10 
8.2. Manage Adverse Event ................................................................................................................................................ 10 
 
 
 


 
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1. Study Personnel, Collaboration Plan and Study Organizations 
This study will be a multicenter prospective single-masked, two-arm randomized clinical trial. Seven centers, 
including the University of California, San Francisco (UCSF), Bascom-Palmer Eye Institute (BPEI), University 
of Colorado, University of Maryland, Zhongshan Ophthalmic Center (ZOC) in China and Asociación para Evitar 
la Ceguera en México (APEC), will jointly enroll for this trial. To ensure the success of this study, we have 
partnered with UCSF’s Francis I. Proctor Foundation (F.I. Proctor Foundation), which is a center that 
specializes in ophthalmology research.  
 
All sites will be responsible for enrollment, implementation and follow up visits. The Proctor Foundation’s role is 
to serve as the coordinating center, supporting data management and data analysis. UCSF will take the lead 
on analysis, writing of study-related materials, and journal publications. UCSF will have the most current 
protocol, consent documents and HIPAA authorization for reference. UCSF has prepared the IRB application 
for this study. All modifications to the IRB of record will be communicated among sites. UCSF will ensure 
protection of all study-related data by using de-identified information over a secure server. All non-compliance 
with the study protocol or applicable requirements will be reported in accordance with local policy. There will be 
ongoing communication of problems, interim results, and study closure among all sites. 
 
Multicenter clinical trials require an organizational structure that provides efficient operations and facilitates 
communication. Investigators at the 6 Clinic Centers are responsible for screening potential study patients, 
enrolling eligible patients, and following the patients according to the study protocol. An independent Safety 
and Data Monitoring Committee (SDMC) will monitor all aspects of the study. The primary responsibility of the 
SDMC is to review the differences in failure rates and the occurrence of adverse events between treatment 
groups with a view of halting randomization early if treatment benefit or risk is so great for one treatment group 
that continuation of patient recruitment is deemed unethical. The SDMC will perform an interim analysis to 
assess for safety once 30% of study participants have completed the 6-month follow-up visit. The SDMC will 
be led by Philip Chen, MD at the University of Washington and Donald Budenz, MD, MPH at University of 
North Carolina at Chapel Hill (UNC). The Statistical Coordinating Center (SCC) will receive, edit, process, 
analyze, and store all de-Identified study data. The SCC will coordinate activities at the Clinic Centers and 
monitor adherence to the study protocol. The SCC is comprised of Jennifer Rose-Nussbaumer, MD and Travis 
Porco, PhD, MPH, both of whom are faculty at F.I. Proctor Foundation. The Steering Committee (SC) is 
composed of the principal investigators from each Clinic Center and this committee has overall responsibility 
for directing activities and formulating policies for the study. 
2. Patient selection:  
2.1 Inclusion Criteria: 
 Age 18 to 85 years old 
 Inadequately controlled glaucoma on maximum tolerated medical therapy with IOP ≥ 18 mm Hg 
 Ahmed Glaucoma Valve (AGV) implantation as the planned surgical procedure 
 For patients in whom 2 eyes are eligible for enrollment, only the first eligible eye to be implanted is 
enrolled. 
2.2 Exclusion Criteria: 
 Unwilling or unable to give consent, unwilling to accept randomization, or unable to return for scheduled 
protocol visits 
 Pregnant or nursing women 
 Previous cyclodestruction or glaucoma drainage device (GDD) surgery  
 Patients with nanophthalmos 
 Patients with Sturge-Weber syndrome or other conditions associated with elevated episcleral venous 
pressure 


 
4 
 Need for glaucoma surgery combined with other ocular procedures except cataract extraction (i.e., 
penetrating keratoplasty, or retinal surgery) or anticipated need for additional ocular surgery 
 Previous scleral buckling procedure or silicone oil present 
 Uveitic glaucoma, if patient have had active inflammation during last six months (we will include uveitic 
glaucoma patients if they haven’t had active inflammation for more than 6 months) 
3. Randomization Scheme: 
The study patients will be stratified by each Clinic Center into 3 categories based on type of glaucoma: (1) 
primary glaucomas, (2) secondary glaucomas (excluding neovascular glaucoma), and (3) neovascular 
glaucoma. Within each stratum, the patients will be randomized into two arms, either AGV with Mitosol® (for 
national centers) or Mitomycin-C (MMC) (for international centers) adjunctive treatment or AGV with Balanced 
Salt Solution (BSS) sham treatment. A randomization of 100 patients will be predetermined by the Proctor SCC 
before the trial starts based on block randomization using a computer program (Statistical package R; Version 
3.1; R Foundation for Statistical Computing, Vienna, Austria). This randomly permuted block scheme has 
varied block sizes between 2 and 6 with an equal number of patients randomized to each treatment group and 
within each stratum. 
 
During the trial, after informed consent is obtained and the SCC confirms patient eligibility, the local study 
coordinator (LSC) at each Clinic Center will assign the study participant an identification number (ID, alpha-
numeric code) that will serve as the patient’s ID on all study documents. The LSC at each center will login to 
the REDCap database and input the patient’s study ID. Randomization to AGV with Mitosol®/MMC adjunctive 
treatment or AGV with sham treatment occurs at the time when the patient is enrolled in the study using the 
REDCap database. Once the patient has been randomized to a treatment arm, they will remain in the intention 
to treat analysis. Clinical information will be collected via baseline patient forms, follow-up patient forms, final 
visit patient forms and adverse event forms. The data will be entered into REDCap database by LSCs. The 
SCC will not have identifiable patient information and de-identified information will be shared using a password 
that is only known by each Clinic Center.  
4. Study Visits 
4.1 Baseline Visit 
During this visit, eligible patients at each center will give informed consent and be enrolled in the study. A 
comprehensive eye exam including visual acuity (VA), intraocular pressure (IOP), gonioscopy, slit lamp exam, 
and dilated fundus exam will be performed, along with pachymetry, specular microscopy and perimetry, to 
establish a baseline. If diplopia exists, a basic motility test will also be performed. The baseline patient form will 
be completed.  
4.2 Surgery Visit  
The enrolled study participant will undergo either AGV with Mitosol®/MMC or BSS (sham) adjunctive treatment 
surgery. 
4.3 Follow-Up Visits 
During the postoperative Day 1, Week 1, Month 1, 2, 3 and 6 follow-up visits, VA, IOP, slit lamp exam, dilated 
fundus exam will be performed. The follow-up patient form will be completed. Mitosol®/MMC or BSS injection 
will be scheduled on postoperative week 1 and month 1.  
4. 4. Final Visit 
During the 12-month postoperative final visit, a comprehensive eye exam including VA, IOP, slit lamp exam, 
dilated fundus exam, specular microscopy and pachymetry will be performed. If diplopia exists, motility will be 
tested. The final status and follow-up patient forms will be completed.  


 
5 
5. Procedures 
5.1 Masking 
All study participants will be masked to their intervention. Surgeons will not be masked. Technicians performing 
study exams and imaging will be masked. The LSC at each Clinic Center will not be masked.  
5.2 Mitosol®/MMC and BSS Sham preparation 
Mitosol®/MMC (0.4mg/ml) will be prepared by the pharmacy within each Clinic Center. Prior to AGV surgery 
and follow-up appointments when Mitosol®/MMC or sham treatment is scheduled to be given, if the subject is 
in the Mitosol®/MMC arm, the LSC at each center will order Mitosol®/MMC. Mitosol®/MMC will be handled 
based on protocol for chemotherapy agents at each Clinic Center. If the subject is in the BSS arm, BSS will be 
either ordered or available in clinic depending on each Clinic Center’s set up.  
5.3 Surgical Procedure 
A standard technique for AGV implantation is used, while allowing the surgeon latitude to perform the 
procedure in a manner with which he or she feels comfortable. The type of anesthesia is at the surgeon’s 
discretion.  An Ahmed FP-7 is used in all cases, and implantation is performed in the superotemporal quadrant.  
Depending on the randomized treatment, Mitosol®/MMC (0.4 mg/ml) or BSS injection will be injected into the 
subconjunctival space at 8-9mm from limbus. After 1 minute, this area is then copiously irrigated with BSS. A 
fornix-based conjunctival flap will be used. Sufficient exposure is obtained in the superotemporal quadrant to 
permit placement of the Ahmed end plate.  A corneal traction suture may be used to rotate the globe 
inferonasally to improve exposure. After dissection, a 30-gauge cannula is used to prime the Ahmed valve. The 
Ahmed end plate is sutured to sclera at a measured distance 8-10 mm posterior to the limbus using the two 
fixation holes on the device. The type of nonabsorbable suture used for end plate fixation is determined by the 
surgeon. The tube is trimmed with an anterior bevel to extend 2-3 mm into the anterior chamber. A 23-gauge 
needle is used to enter the anterior chamber at the posterior limbus, parallel to the iris plane. The Ahmed tube 
is inserted through this entry incision and should be well positioned in the anterior chamber away from the 
corneal endothelium and above the iris plane. A donor patch graft composed of sclera, cornea, or pericardium 
is used to cover the limbal portion of the tube. The patch graft material and suture selected to fixate the patch 
graft are the surgeon’s choice. The conjunctiva and Tenon’s capsule are closed in keeping with the surgeon’s 
usual practice. A subconjunctival antibiotic and corticosteroid are injected at the end of the case. A cycloplegic-
mydriatic drop and steroid-antibiotic ointment may be instilled at the conclusion of the case, as determined by 
the surgeon in keeping with his or her usual practice. 
5.4 Postoperative Mitosol®/MMC or BSS Sham Injection 
Subconjunctival injection of Mitosol®/MMC (0.4mg/ml) or BSS for 0.1ml is scheduled in the region of the end 
plate at 1 week and 1 month. The injectable medication will be prepared at each Clinic Center based on 
treatment assignment. The doctors performing injections will be able to identify whether Mitosol®/MMC or BSS 
is being used. In order to perform the injection, the conjunctiva will be anesthetized first by applying a topical 
anesthetic (such as proparacaine). Cotton tips soaked with 4% lidocaine will be applied to conjunctiva over 
injection area. Then 0.1 ml of 1% lidocaine will be injected subconjunctivally, which usually results in formation 
of an elevated “blister.” Using a 30-gauge needle, another 0.1 ml Mitosol®/MMC (0.4%) or BSS, depending on 
treatment assignment, will be injected within the previously formed “blister” into a space between the 
conjunctiva and Tenon’s capsule. The eye will then be copiously irrigated with BBS.  
 
On postoperative week 1 visit, subconjunctival Mitosol®/MMC or BSS injection will be given depending on the 
treatment assignment. The injection will be held if any of the following conditions exist: IOP <5, wound 
dehiscence, choroidal detachment, shallow or flat anterior chamber, or conjunctiva over the plate of Ahmed 
valve is completely white and avascular (Figure 1). The patient will then be seen depending on the clinical 
situation. In that situation, injection will not be given within the postoperative month 1.   
 
On the visit scheduled for the 2nd injection at 1month postoperative follow-up, injection will be held if any of the 
following conditions exist: IOP <5, wound dehiscence, choroidal detachment, shallow or flat anterior chamber, 
or conjunctiva over the plate of Ahmed valve is completely white and avascular (Figure 1). The patient will then 


 
6 
be followed for a clinically appropriate interval for the complication, and the 2nd injection will be given if the 
complication is resolved at a follow-up visit before postoperative month 3. Should the complication persist 
beyond postoperative month 3, no 2nd injection will be administered.  
 
 
 
 
 
 
 
 
 
 
 
Figure 1:  
 
5.5 Postoperative medication management  
After the surgery, all subjects will receive an antibiotic drop to be used 4 times daily for 1 week, and a topical 
steroid (prednisolone acetate 1%) starting 4-6 times daily and tapered over 4 to 8 weeks depending on 
surgeon’s preference and degree of inflammation.  
Because early aqueous suppressant treatment may improve AGV implantation outcomes and reduce 
hypertensive phase frequency 21, 25, when IOP is above 10mmHg in either treatment arm, medications that 
primarily suppress aqueous humor production will be used according to the surgeon’s discretion. Medications 
that can be used for aqueous suppression include timolol 0.5%, dorzolamide 2%, brinzolamide 1%, or 
brimonidine 0.1% or 0.15% or 2%. If IOP is still not controlled, as determined by the treating physician, 
additional therapy, including oral systemic medical therapy, laser therapy or additional surgical therapy, may be 
performed.  
5.6 Examinations during each visit and study schedule 
A list of study measurements for scheduled follow-up visits is shown in Table 1. Baseline demographic and 
clinical information will be collected for enrolled patients at baseline visit.  The follow-up appointment schedule 
will be generated based on the date of surgery for each patient by REDCap. The study entry date is recorded 
as the date of surgery.  
Follow-up visits are scheduled 1 day, 1 week, 1 month, 2 months, 3 months, 6 months and 12 months 
postoperatively. Patients can be brought back sooner than the required study visits if there is a postoperative 
complication. The follow-up study form will be filled out for those visits. Adverse event forms may be completed 
if appropriate. All scheduled visits would be expected in normal postoperative care. Each examination includes 
measurement of Snellen VA, IOP, slit-lamp biomicroscopy, and ophthalmoloscopy.  Humphrey perimetry will 
be performed at the baseline visit to establish the severity of glaucoma. Early Treatment Diabetic Retiopathy 
The arrow points to the complete white and avascular conjunctiva over the plate of Ahmed valve.  


 
7 
Study (ETDRS) VA, pachymetry, and specular microscopy will be checked at baseline and at the 6-month and 
12-month follow-up visits.  
 
  
Table 1: Study Protocol 
 
Baseline 
1day 
1week 
1mo 
2mos 
3mos 
6mos 
12mos 
Mitosol®/MMC 
injection 
 
 
X* 
X* 
 
 
 
 
Snellen Acuity 
x 
x 
x 
x 
x 
x 
x 
x 
ETDRS Acuity 
x 
 
 
 
 
 
x 
x 
IOP (Applanation) 
x 
x 
x 
x 
x 
x 
x 
x 
Motility 
If diplopia 
present 
 
 
 
 
 
If diplopia 
present 
If diplopia 
present 
Pachymetry 
x 
 
 
 
 
 
x 
x 
Specular microscopy 
x 
 
 
 
 
 
x 
x 
Gonioscopy 
x 
 
 
 
 
 
 
 
SLE 
x 
x 
x 
x 
x 
x 
x 
x 
Ophthalmoscopy 
x 
x 
x 
x 
x 
x 
x 
x 
Perimetry 
x 
 
 
 
 
 
 
x 
 
 
* 1st Injection will be held for IOP <5, wound dehiscence, choroidal detachment, shallow or flat anterior chamber, or conjunctiva over the 
plate of Ahmed valve is completely white and avascular at postoperative week #1 visit. In that situation, injection will not be given within 
the postoperative month 1. 
 
On the visit scheduled for the 2nd injection at 1-month postoperative follow-up, injection will be held if any of the following conditions 
exist: IOP <5, wound dehiscence, choroidal detachment, shallow or flat anterior chamber, or conjunctiva over the plate of Ahmed valve 
is completely white and avascular. The patient will then be followed for a clinically appropriate interval for the complication, and the 2nd 
injection will be given if the complication is resolved at a follow-up visit before postoperative month 3. Should the complication persist 
beyond postoperative month 3, no 2nd injection will be administered.  
 
6. Assessment of Primary and Secondary Outcomes 
Technicians who perform the ocular tests should be masked to treatment assignment. The primary outcome of 
the study is IOP at postoperative 6 months. The secondary outcome is failure rate, which is defined by the 
following criteria: (1) IOP >21 mmHg or reduced < 20% from baseline at 12-month follow-up, (2) IOP ≤ 5 
mmHg at 12-month follow-up with best corrected VA decreased ≥ 2 lines from baseline, (3) use of oral anti-
hypertensive medication (acetazolamide or methazolamide), (4) loss of light perception vision, (5) reoperation 
for glaucoma, or (6) removal of implant. Successful repair of a retracted or occluded shunt will not be 
considered a failure, although all complications will be listed and analyzed. Eyes that have not failed and are 
not on supplemental medical therapy are considered complete successes. Eyes that have not failed but require 
supplemental medical therapy are defined as qualified successes.  
Two alternative IOP cutoffs, 18 mmHg and 15 mmHg, will also be used in secondary analyses as 
suggested by the World Glaucoma Association’s Guidelines on Design and Reporting of Surgical Trials.46 All 
other criteria for failure are the same as in the primary analysis as outlined above. 
Other outcome measures include VA, frequency of hypertensive phase (IOP increase to more than 21 mmHg 
in the first 6 months after surgery), number of topical medications and complication rates.  


 
8 
 
Visual Acuity. Distance VA is measured before pupil dilation, tonometry, gonioscopy, or other tests that could 
affect vision. Manifest refraction is performed before measurement of VA at the baseline examination and 12-
month follow-up visit. VA will be measured using two techniques. Snellen VA is measured at the baseline 
examination and every follow-up visit. The Early Treatment Diabetic Retinopathy Study (ETDRS) VA47 is tested 
at the baseline examination, 6-month and 12-month follow-up. The participating clinician will need to specify a 
cause for Snellen VA less than 20/30 at the baseline examination, or decrease in VA by 2 or more lines from 
baseline at the 6-month and 12-month follow-up. 
 
Intraocular Pressure. IOP will be measured at all visits. Goldmann applanation tonometry will be used to 
measure IOP, however, for patients with irregular corneal astigmatism, corneal scarring, or corneal edema, 
which affect accurate measurement, pneumatonometer or Tonopen (Reichert Technologies, Depew, NY) will 
be used. The right eye is to be measured first and the left eye measured second. Two consecutive 
measurements will be taken for the study eye. If the first 2 measurements differ by > 1 mm Hg, a third 
measurement will be taken. If the first 2 measurements differ by 1 mm Hg or less, the IOP for the given eye will 
be the average of the 2 readings. If the difference between the first 2 measurements is > 1 mm Hg, the IOP for 
the given eye will be the median of the 3 readings. Efforts will be made to schedule follow-up visits at similar 
time of the day to minimize the effect of diurnal IOP fluctuation.  
 
Pachymetry. Corneal thickness using ultrasound (contact) pachymetry will be performed on the central cornea 
at baseline examination, 6-month, and 12-month follow-up visit. Contact pachymetry will be performed after 
IOP measurement and before gonioscopy. 
 
Gonioscopy. Gonioscopy will be performed at the slit lamp at baseline examination using either a Zeiss-type 
indentation gonioprism or a Goldmann-type nonindentation gonioprism. The purpose of the preoperative 
examination of the anterior chamber angle is to document neovascularization, peripheral anterior synechiae, 
and to identify an appropriate implantation site for the tube. 
 
Motility Assessment. Transient diplopia is not uncommon after tube shunt surgery. The effect of local 
Mitosol®/MMC injection on nearby muscles is also unknown. To address this issue, a motility assessment is 
performed in all patients at baseline, 6-month and 12-month visits if diplopia is reported by patients.  
During each motility examination, the cover–uncover and alternate cover tests will be performed at primary 
gaze, upgaze, downgaze, left gaze, and right gaze for both distance and near targets. Any heterophoria or 
heterotropia will be documented. The deviation will be measured with a hand-held prism. In patients who are 
unable to fixate for cover testing, the deviation will be measured by centering the corneal light reflexes with a 
prism using the modified Krimsky method. 
 
Slit-Lamp Biomicroscopy. Examination of the anterior segment using slit-lamp biomicroscopy is performed at 
the baseline assessment to document preoperative status and at all follow-up examinations to detect any 
changes during the course of the study that may be attributable to the disease or treatment. Mitosol®/MMC 
may slow wound healing; therefore, the presence or absence of plate or/and tube exposure or wound 
dehiscence will be examined and documented at each visit. In addition, placement of tube shunt may lead to 
long-term damage to the cornea; therefore, tube position and length within the anterior chamber in relation to 
the cornea and iris on slit-lamp examination will be documented at each study visit.  
 
Ophthalmoscopy Examination. A dilated fundus examination will be performed at all visits. At the baseline 
examination, particular attention is paid to detect signs of proliferative retinopathy, retinal neovascularization, 
vitreous hemorrhage, or preretinal hemorrhage. At all postoperative follow-up visits, ophthalmoscopy is 
performed to evaluate posterior segment complications of surgery, such as serous choroidal effusions, 
suprachoroidal hemorrhage, or hypotony maculopathy.  
 
Specular Microscopy: Endothelial cell density will be assessed using specular microscopy performed on the 
central cornea at baseline examination, 6-month and 12-month follow-up visit. Three images are to be acquired 
and transmited to the SCC, and the best quality image will be selected for quantitative analysis of central 


 
9 
endothelial cell density, determined by manual cell count at a reading center.  
 
Perimetry. Visual field examinations will be assessed using automated perimetry (using either Humphrey 24-2 
full threshold program or Swedish Interactive Thresholding Algorithm [SITA] Standard, size III, white stimulus, 
Carl Zeiss Meditec, Dublin, CA). Visual field testing will be performed before tonometry, gonioscopy, or other 
technique that could affect vision. A visual field is attempted in any eye that has vision equal or better than 
finger counting at a distance of 2 feet. Perimetry will be performed before surgery (within 1 month of enrollment 
in the study) to establish the severity of glaucoma and one year after surgery. 
7. Management of Breach of Protocol 
7.1 Instructions for the Patients 
Patients will be instructed to strictly follow the study visit schedule and to report all changes in their condition to 
the Clinic Center. Patients will also be reminded to contact the study site if they are experiencing any 
difficulties during their study participation. Patients will be reminded of the importance of medication 
compliance during each postoperative visit and provided with written and oral instructions on the medication 
regimen.  
7.2  Unscheduled Visits 
Additional examinations may be performed as necessary to ensure the safety and well being of patients during 
the study period. Follow-up study forms should be completed for each unscheduled visit. An assessment of 
any adverse event should be completed. 
7.3 Compliance with Protocol 
Patients must be able to adhere to the study visit schedule. Patient screening and enrollment should strictly 
follow appropriate inclusion, exclusion, and treatment criteria as described in the protocol. At each study visit, 
patients will be asked if they have used their eye drops as instructed and whether they have used any 
concomitant medications/therapies or had any concurrent procedures since the previous visit. Patients should 
be scheduled for study visits as closely to the day specified in the visit schedule as possible. 
The investigator at each Clinic Center must adhere to the study protocol and randomization. Any 
violation of the protocol will be reported to the HSC to decide whether the corresponding study participant 
should stay in the trial. The SCC will be informed of the decision to allow for appropriate data management.   
7.4 Early Discontinuation of Patients 
Patients may voluntarily withdraw from the study at any time. Notification of early patient discontinuation from 
the study and the reason for discontinuation will be sent to the SCC and will be clearly documented on the 
appropriate case report form. 
7.5 Withdrawal Criteria 
The investigator should consider withdrawing a patient from the study early if any of the following criteria are 
met: 
1. Patient develops (or has an exacerbation of) a medical condition that, in the opinion of the investigator, 
would put the patient at an unacceptable medical risk by continuing study participation  
2. Patient develops (or has an exacerbation of) a medical condition that, in the opinion of the investigator, 
compromises the patient’s ability to participate in the study  
3. Patient is unwilling or unable to continue to comply with study procedures  
4. Patient is unwilling or unable to continue in the study  
Whenever possible, the decision to withdraw a patient from the study or study treatment should be discussed 
with SCC.  
7.6 Study Termination 
The study may be stopped at his/her study site at any time by the site investigator.  


 
10 
8. Diagnoses and Management of Adverse Events (AEs)      
8.1 Definitions of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient who has received AGV in this trial and 
that does not necessarily have a causal relationship with this treatment. However, progression of treatment 
indication including new or worsening of anticipated clinical signs or symptoms, which are collected as clinical 
efficacy variables and assessed as unequivocally associated with the disease progression and/or lack of 
efficacy, should NOT be reported as AEs unless the disease progression is greater than anticipated in the 
natural course of the disease. 
During each study visit, the subject will be questioned about AEs in a non-leading manner. All AEs, 
whether observed by the Investigator, elicited by the Investigator, or spontaneously reported by the subject, will 
be documented in the subject's chart and the AE form. 
8.2. Manage Adverse Event 
All AEs should be followed until they are resolved or until a stable clinical endpoint is reached. Each AE is to 
be classified by the Investigator as SERIOUS (SAE) or NONSERIOUS (NSAE). A SAE is any adverse event 
that results in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or 
prolongation of existing hospitalization, or a persistent or significant disability/incapacity.  
If a SAE occurs, the investigator at each study site must verbally and/or in writing notify their medical center or its 
designee within 24 hours of the occurrence of the SAE. The initial SAE report must be followed by a written report, 
signed by the investigator, and received by their medical center or its designee via fax within two working days. The 
investigator must provide written follow-up reports until the SAE or clinically significant AE has resolved or until a 
stable clinical endpoint is reached. Notification of an SAE or clinically significant AE must also be submitted to the 
Institutional Review Board (IRB)/Ethics Committee (EC) in accordance with its requirements. All AEs must be 
reported from the time that the subject provides informed consent through the last study visit.  

SAP_001.pdf: 
Ahmed with Mitomycin-C Comparison Trial  
(AMC trial) 
 
Statistical Analysis Plan 
NCT02805257 
December 12, 2017 
 
University of California, San Francisco 
Francis I. Proctor Foundation, University of California San Francisco 
Bascom-Palmer Eye Institute 
University of Maryland 
Tulane University 
Asociación para Evitar la Ceguera en México I.A.P. (APEC) 
Zhongshan Ophthalmic Center (ZOC) 
 
 
Principal Investigators: 
Ying Han, MD, PhD1 
 
Co Investigators: 
Steven J.  Gedde, MD2 
Osamah Saeedi, MD3 
Ramesh Ayyala, MD4 
Gabriel Lazcano Gómez, MD5 
Xing Liu, MD, PhD6 
 
 
 
 
 
 
 
 
 
 
1. University of California San Francisco, San Francisco, California 
2. Bascom-Palmer Eye Institute 
3. University of Maryland 
4. Tulane University 
5. Asociación para Evitar la Ceguera en México I.A.P.(APEC) 
6. Zhongshan Ophthalmic Center (ZOC)  


 
The Ahmed glaucoma valve (AGV) is one of the most commonly used glaucoma drainage devices (GDDs). 
AGV has a good safety profile compared to other glaucoma surgeries, but its application is limited by 
unsatisfactory long-term outcomes.1, 2 The body’s natural healing response leads to fibrotic scar tissue 
formation, encapsulating the device and blocking fluid outflow. Mitomycin C (MMC), an antifibrotic agent, has 
been broadly used intraoperatively in trabeculectomies to improve surgical outcomes. Unfortunately, 
intraoperative use of MMC in AGV has not been demonstrated to improve the success rate of this surgery.3, 4 
One explanation is that the AGV plate may serve as a constant stimulus for foreign body reaction, which may 
overcome the antifibrotic effect from a single intraoperative MMC use.3, 5 A proposed solution for this problem 
is to administer subsequent postoperative MMC injections during the recovery phase when fibrotic repair 
occurs. Interestingly, retrospective clinical studies indicate that combined intraoperative and postoperative 
application of antifibrotic agents significantly improves AGV surgical performance without compromising its 
safety profile.6, 7 However, no prospective study has been conducted. To further test the role of MMC in AGV 
use, we propose a multicenter prospective double-masked, two-arm randomized clinical trial. This study will 
examine initial surgical outcomes, including early and intermediate intraocular pressure (IOP) control and 
postoperative complications, and will serve as a pilot trial to prepare for a NIH-sponsored study to address 
longer term outcomes and complications in a larger cohort. 
 
Specific Aim 1: To compare the surgical outcomes at 12-month follow-up after AGV implantation 
between patients receiving adjunctive intraoperative and postoperative MMC therapy versus those 
receiving sham therapy. We hypothesize that adjunctive MMC application during and after AGV implantation 
improves IOP control and decreases the failure rate without compromising postoperative visual acuity at 6-
months follow-up.  
Specific Aim 2: To compare the frequency of hypertensive phase at 6-month follow-up after AGV 
implantation between patients receiving adjunctive MMC therapy and those receiving sham therapy. 
We hypothesize that adjunctive MMC application decreases the occurrence of the hypertensive phase.  
Specific Aim 3: To compare the rate of complications within 12-month follow-up between patients 
receiving adjunctive MMC therapy and those receiving sham therapy with AGV implantation.  We 
hypothesize that there will be a slight increase in non-serious postoperative complications, but not in vision 
threatening complications, in patients who receive MMC with AGV implantation compared to sham therapy.  
 
This study will be a multicenter prospective double-masked, two-arm randomized clinical trial. The primary 
objective is to compare the IOP in patients undergoing AGV with and without adjunctive MMC therapy. Six 
centers, including Bascom-Palmer Eye Institute, UCSF, University of Maryland, Tulane University, Zhongshan 
Ophthalmic Center (ZOC) in China, and Asociación para Evitar la Ceguera en México I.A.P.(APEC) in Mexico, 
will jointly enroll subjects for this trial. Study participants will be stratified prior to randomization into three 
groups: 1) Primary glaucoma, 2) Secondary glaucoma except Neovascular glaucoma, and 3) Neovascular 
glaucoma. Both participating surgeons and study participants will be masked to treatment assignment. 
Study participants will be randomized to one of two treatment arms: 1) AGV with MMC (0.4%) 
intraoperative application and postoperative injections, or 2) AGV with sham injection of balanced salt solution. 
Based on preliminary studies and clinic experience, a maximum of two postoperative MMC injections will be 
given.  
Specific Aim 1: To compare surgical outcomes at 12-month follow-up after AGV implantation between 
patients receiving adjunctive intraoperative and postoperative MMC therapy versus those receiving 
sham therapy. The primary goal of glaucoma surgery is to decrease IOP, therefore the primary outcome 
measure for our study is IOP at 12-months follow-up. Medication washout will not be considered before the 
final visit because IOP spike after medication washout may cause permanent damage for study participants 
due to the severity of glaucoma in patients who need AGV placement. A secondary outcome measure is rate 
of treatment failure. Failure will be defined as meeting any of the following criteria: (1) IOP >21 mmHg or 
reduced < 20% from baseline at 12-month follow-up, (2) IOP ≤ 5 at 12-month follow-up with best corrected 
visual acuity decreased ≥ 2 lines from baseline, (3) use of oral anti-hypertensive medication (acetazolamide or 
methazolamide), (4) loss of light perception vision, (5) reoperation for glaucoma, or (6) removal of implant. 
Eyes that have not failed and are not on supplemental topical medical therapy are considered complete 


successes.  Eyes that have not failed but require supplemental topical medical therapy are defined as qualified 
successes. The third outcome measures are the number of anti-glaucoma medications and the ETDRS visual 
acuity at 12-months follow-up.  
Specific Aim 2: To compare the frequency of the hypertensive phase at 6-month follow-up after AGV 
implantation between patients receiving adjunctive MMC therapy and those receiving sham therapy.  In 
this study, the hypertensive phase is defined as an IOP of more than 21 mmHg in the first 6 months after 
surgery.  
 
Specific Aim 3: To compare the rate of complications within 12-month follow-up between patients 
receiving adjunctive MMC therapy and those receiving sham therapy with AGV implantation. The 
application of MMC during trabeculectomy improves treatment success, but is associated with higher instances 
of postoperative complications.11-15 Thus it will be important to monitor for postoperative complications in the 
setting of MMC application. Both intraoperative and postoperative complications will be compared between the 
two arms. Intraoperative complications include hyphema and suprachoroidal hemorrhage. Early and late 
postoperative complications include tube occlusion with iris or vitreous, choroidal effusion, suprachoroidal 
hemorrhage, cystoid macular edema, shallow anterior chamber, hypotony maculopathy, endophthalmitis, 
cataract, diplopia, corneal edema, tube or shunt erosion, uveitis, and tube malposition.  
Because of potential corneal toxicity from MMC, corneal endothelial cell density (ECD) will be 
monitored. Significant endothelial cell loss has been reported during or immediately after trabeculectomy with 
MMC application. However, no progressive cell loss was observed postoperatively beyond 3 months.43-46 In 
this trial, central ECDs measured by specular microscopy and central corneal thickness by ultrasound 
pachymetry will be monitored at baseline, 6 months and 12 months postoperatively.  
 
Sample Size Calculation:  
Sample size calculation for this study is based on the primary outcome of IOP. In our retrospective 
study comparing AGV implant with intraoperative and postoperative antifibrotic agents versus AGV implant 
without these agents, we found approximately 4.0 mmHg lower mean IOP in the antifibrotic-agent treated 
groups with a standard error of 1.4 mmHg.7 With 50 patients per arm, we conservatively estimate that we 
would have at least 80% power to detect a 2 mmHg or more IOP difference between groups with a two-tailed 
alpha of 0.05, assuming a standard deviation in IOP of 3 mmHg and 15% loss to follow up. The criterion of 
detecting 2 mmHg difference in IOP has been used in several large glaucoma trials47,48 and the dropout rate of 
15% is decided based on recent glaucoma trial experience49.  We anticipate that stratification will not cause 
appreciable changes in sample size calculation.50 
 
Statistical Considerations:   
For specific aim 1, the primary outcome variable is IOP measured at 12 months. This will be analyzed 
using linear regression, considering the stratified randomization. Analysis will be two sided at alpha of 0.05. 
Secondarily, we will analyze success (as a binary outcome), the number of glaucoma medications, visual 
acuity, and time to failure. For specific aim 2, the occurrence of a hypertensive phase will be compared using 
logistic regression, adjusting for the stratified design. For specific aim 3, complications will be compared 
between groups using logistic regression. Tabulations of each complication will be prepared. The central ECD 
and pachymetry difference between the two arms will be compared at 6 and 12 months with linear regression, 
adjusting for the stratified design. Further details of the statistical plan will be provided in the Manual of 
Operations.  
  
Data Management and Sharing Plan:  
For this trial, the REDCap database platform will be used for data entry/collection. To save participating 
surgeons’ time, data will be collected via paper study forms, and then entered into the REDCap database via 
double data entry methods at the enrollment site during every visit. All data will be stored and transferred using 
a secure database server with de-identified information. To ensure the success of this study, we have 
partnered with UCSF’s F. I. Proctor Foundation, which is a center that specializes in ophthalmology research. 
The Proctor Foundation’s role is to serve as the coordinating center, supporting data management and data 
analysis. 
We will take steps to keep participants’ personal information confidential. Health information will be kept 
secure and separate from information that identifies participants. Upon enrollment, participants will be assigned 


a code that will be used instead of their name, medical record number or other personal identifying information. 
Electronic files for data analysis will contain only the participant code. Information may be released to others 
outside of the enrollment center, but information which could identify the participant will be kept secure. Data 
management and sharing plan will be fully discussed in the Manual of Operation. 
 
• 
low-up period to study long-term IOP control and late stage complications.