Determining Distal Outflow Tract Function in Open Angle Glaucoma as a Predictive Test for the Success of Ab Interno Trabeculectomy
Phase: NA
Conditions: Open Angle Glaucoma, Pseudoexfoliation Glaucoma
Sponsor: Wuerzburg University Hospital

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page 1 of 15 
 Research Proposal 
 
1. Title: Determining Distal Outflow Tract Function in Open Angle Glaucoma as a 
Predictive Test for the Success of Ab Interno Trabeculectomy 
Protocol: Version 1.0 / 07.04.2021 
Institution: University of Würzburg, Department of Ophthalmology 
2. Investigators  
a. Raoul Verma-Fuehring, MD 
vermafuehr_r@ukw.de  
 
b. Daniel Kampik, PhD 
kampik_d@ukw.de  
 
3. Signature 
 
 
___________________                                    
R. Verma-Fuehring 
 
 
 
 
 
4. 
Rationale 
4.1.1. Narrative / Project Narrative 
Post-trabecular outflow resistance in glaucoma was described only recently and remains poorly 
understood. The outcome of two commonly performed microincisional glaucoma surgeries, ab 
interno trabeculectomy (AIT) and trabecular bypass stent implantation (TBS) depends on a 
patent distal outflow system with a normal post-trabecular outflow resistance. The failure rate 
of AIT is between 10 to 35% and that of TBS is even higher [1,2].  
The proposed research will determine the post-trabecular outflow resistance by 
comparing the drop of intraocular pressure (IOP) after a noninvasive trabeculopuncture (TP) to 
the IOP achieved after the subsequent AIT. Predicting surgical success by assessing the distal 

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outflow resistance will avoid unnecessary AIT by triaging patients with a negative test directly 
to the group of higher risk epibulbar glaucoma surgeries. 
 
4.2. 
Studienziele / Major Goals of the Project 
To create a non-invasive predictive test (TP) for distal outflow tract function after AIT in 
individuals with open angle glaucoma (OAG). We hypothesize that the IOP drop by a presurgical 
TP predicts the success of trabecular ablation in AIT. The results of this study will allow 
surgeons to use TP to select the proper procedure for a given glaucoma patient.  
 
4.3. 
Hintergrund / Background and Significance 
Open angle glaucoma is a leading cause of irreversible blindness. 42% of patients eventually 
become blind in one eye [3]. The annual costs of glaucoma in the US are $2.5 B. Most OAG is 
treated with eye drops, but even the latest prostaglandin analogs offer continuous-treatment 
success rates of 10% at one year [4]. 59% of patients continue to lose vision during initial 
medical treatment [5], and 32% [6] need surgery within one year.  
One of the microincisional glaucoma surgeries, ab interno trabeculectomy with the 
trabectome, has a low risk and effectively lowers IOP but only in approximately 65% [7]-85% [8] 
of patients after 12 months. The six-month success rate of AIT is about 90% [8]. In this process, 
the nasal 180 degrees circumference of the trabecular meshwork is ablated. After AIT, the 
aqueous humor can directly enter the drainage system [9,10]. We perform close to 600 AITs 
per year in our center. Similarly, the insertion of trabecular bypass stents (TBS, iStent, Glaukos 
Corp, San Clemente, California, USA) creates a direct connection between the anterior chamber 
and Schlemm’s canal using a nitinol implant.  
Failure of AIT or TBS to lower the IOP indicates a non-functioning distal drainage system 
located downstream of the trabecular meshwork. Despite systematic outcome analyses, no 
clinical features have been identified to predict failure nor is there a preoperative test that 
assesses the distal drainage system. Having a predictive test of surgical success for AIT or TBS 
would dramatically reduce unnecessary treatments and avoid vision loss that continues in 
patients with failed procedures until a secondary, more invasive surgery is chosen.  
TP could be such a test. It uses a common ophthalmic neodymium-YAG laser to create a 
small, temporary opening in the trabecular meshwork thereby increasing conventional outflow 
and lowering IOP for up to a few weeks [11]. The IOP drop caused by TP has to be related to the 
IOP drop caused by permanent surgical removal of the trabecular meshwork in AIT or by 
implantation of a TBS.  
 

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4.4. 
Vorstudien / Preliminary Studies 
Many studies were performed on trabeculopuncture at the dawn of laser eye surgery in the 
mid-1970s. We provide a summary of key studies and list laser type, settings, and results (Table 
1).  
Table 1: Summary of trabeculopuncture studies with laser type, settings, and results. 
Laser 
Paper 
Technique 
Time to trough IOP drop pre-TP post- TP comment 
Q-Switched 
ruby 
Krasnov 
1973 [11] 
Spots: not described 
Spot size: 0.25 - 0.5 mm 
Energy: 0.2 J 
1 week - 6 
months 
 
 
8.6 
32.4 
23.8 
-in vivo  human 
eyes 
Argon 
Ticho 
1978 [12] 
Spots: 50 
Spot size: 100 µm 
Duration: 0.1s 
Energy: 1-3 W 
Wave: continuous 
< 30 days 
 
 
 
- in vivo primate 
eyes 
 
Argon 
Wickham 
& 
Worthen 
1979 [13] 
 
Spots: 150 / 100 
Spot size: 50 µm 
Duration: 0.01 s / 0.02 s 
Energy: 2 - 3 W 
Wave: continuous  
 
Spots: 150 
Spot size: 50 µm 
Duration: 0.1 s 
Energy: 0.1-0.15W 
Wave: pulsed 
4-5 years 
 
“The lowest lOPs 
are seen at four 
and 
five years, when 
the sample size 
had decreased 
greatly.” 
12.0 
36.0 
24.0 
- in vivo human 
eyes 
- protocol is 
more akin to 
argon laser 
trabeculoplasty 
Excimer 
Töteberg-
Harms 
2011 [14] 
Spots: 10 
Spot size: 0.5 mm 
Duration: 60 ns 
Energy: 1.2 mJ 
Wavelength: 308 nm 
IOP measurement 
only once after 12 
months 
8.8 
25.3 
16.5 
- in vivo human 
eyes 
- very large TP 
spots (200-μm) 
Table 1 continued: YAG-Laser trials 
Nd:YAG 
Epstein 
1985 [15] 
 
Spots: 4-6 
Energy: 2-6 mJ 
24h 
5.5 
25.5 
20.0 
- in vivo human 
eyes 
- tonography 
was performed 
Nd:YAG 
Melamed 
1985 [16] 
Spots: 4 
Spot size: 20 µm 
Duration: 14 ns 
Energy: 5-7 mJ 
Immediate effect 
10.0 
20.5 
9.8 
- in vivo primate 
eyes 

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Nd:YAG 
Melamed 
1987[17] 
Spots: 4 (one in each 
quadrant) 
Energy: 40 mJ 
1h 
10.0 
25.6 
19.1 
- in vivo human 
eyes 
- tonography 
was performed 
Nd:YAG 
Del Priore 
1988 [18] 
Spots: 10 
Energy: 10 mJ 
1 month 
10.2 
28.9 
21.7 
- in vivo human 
eyes 
1 year 
10.6 
 
 
Nd:YAG 
Fukuchi 
1993 [19] 
Spots: 65 
Spot size: 20 µm 
Energy: 1 - 2.5 mJ 
Single-pulse mode 
Differs from 1 to 
12 months 
16.0 
31.0 
15.0 
- in vivo human 
eyes 
- ALT had failed 
before TP 
 
 
 
averages 9.0 (33%) 
27.3±4.9 18.9±4.8 
 
 
To this date, there have been no studies comparing TP to AIT but the implantation of a TBS is 
similar to TP in that it creates a hole-shaped opening in the TM maintained by the implant [20].  
Both establish a connection between the anterior chamber and Schlemm’s canal. Because of 
the proliferation of the TM, the opening in TP closes within weeks to months while the 
trabecular bypass stent can reduce IOP considerably longer [21]. At one week, the mean IOP 
reduction from baseline is about 8% after AIT and 6% after TBS injection (Table 2). Based on 
this data, we estimate a reduction of the six-month AIT success rate by at least 40% if TP shows 
no significant IOP reduction after one week. 
 

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Table 2 - Studies comparing trabecular bypass stent (TBS) and ab interno trabeculectomy 
(AIT) 
Paper pre 
TBS 
1d post 
TBS 
1w post 
TBS 
3m post 
TBS 
pre AIT 
1d post 
AIT 
1w post 
AIT 
3m post 
AIT 
[22] 
17.6 
19.8 
16.8 
15.5 
17.4 
17.7 
19.0 
14.4 
[23] 
16.7 
18.3 
16.2 
14.5 
17.2 
14.5 
17.2 
14.8 
[24] 
17.8 
16.4 
16.7 
14.4 
19.8 
16.9 
17.8 
13.2 
[25] 
16.7 
- 
16.0 
14.1 
18.2 
- 
15.3 
13.4 
[2] 
18.3 
- 
15.5 
13.2 
18.3 
- 
13.1 
14.6 
[26] 
16.2 
14.8 
- 
14.1* 
15.8 
12.9 
- 
13.8* 
mean 
17.22 
17.33 
16.24 
14.3 
17.78 
15.50 
16.48 
14.0 
numbers in mmHg,  d = day, w = week, m = month, * = only 6 months data 
 
4.5. 
Nutzen-Risiko-Abwägung / Risk-Benefit Evaluation 
Trabeculopuncture is a low-risk procedure that is usually performed at the nasal trabecular 
meshwork, the same site that is later to be ablated 180° using a trabectome (AIT). Its side 
effects are comparable to those of similar laser treatments such as selective laser 
trabeculoplasty or peripheral laser iridotomy. TP is described by patients to be almost painless 
[11]. Previous studies have shown only minor complications including blood reflux into the 
anterior chamber, mild iritis, and temporary visual impairment [18,19]. These events have no 
impact on the subsequent AIT. 
The primary benefit to our patients in participating in this trial is that TP lowers the IOP 
instantly. However, this effect is not sustained. The main purpose is to develop a test that 
predicts the success of AIT. This test will reduce both risks and costs by avoiding unnecessary 
surgery. 
The failure of AIT, a minimally invasive procedure, requires a traditional filtering surgery 
(trabeculectomy) or a glaucoma drainage device, both of which have an approximately 20 
times higher risk of serious complications and subsequent surgeries. If the probability of 
success can be determined beforehand, the surgical risk can be much reduced and unnecessary 

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procedures can be avoided. The target IOP at which glaucoma stops progressing would be 
achieved sooner and there would be fewer sick days.  
There will be decreased costs from fewer procedures, fewer hospitalizations and fewer 
patient visits. In Germany, the annual treatment cost per glaucoma patient ranges from 918 € - 
1194 €, depending on the severity of the glaucoma [27]. The prevalence of OAG in Germany 
among adults aged 40 to 80 years old is about 2.51 % [28,29]. This implies that the estimated 
total cost of glaucoma treatment in Germany is about 875 MM € per year (35 MM Germans 
between 40 - 80 years of age, prevalence 2.5 %, average cost of 1000 € per patient per year). 
The average costs for a standard glaucoma procedure in local anesthesia are about 2800 € 
according to Diagnosis Related Groups (C06Z G-DRG). In 2019, over 10,000 AIT or equivalent 
procedures were performed [31]. A one-year success rate of 70 % leads to 3000 unsuccessful 
interventions. Consequently, a simple predictive test like TP could save about 8.5 MM € 
annually by avoiding 2800 € for 3000 redundant interventions. 
 
5. 
Objektive & Hypothese / Objective & Hypothesis 
We expect an unsatisfactory drop in IOP and post-trabecular outflow resistance after TP to be 
associated with AIT failure. The primary endpoint will be the final IOP. The post-trabecular 
outflow resistance (R) will however also be measured. The outflow resistance is defined as 
reciprocal value of the outflow facility C (µL/(min*mmHg)) 
 
Null hypothesis (H0): The amount of IOP reduction after TP (ΔIOPTP) is not correlated to the IOP 
reduction after AIT (IOPAIT). 
Alternative hypothesis (H1): The amount of IOP reduction after TP (ΔIOPTP) is correlated to the 
IOP reduction after AIT (IOPAIT).  
 
6. 
Study Design/ Studiendesign 
6.1. 
Studiendesign / Research design 
This clinical trial is designed as a monocentric, longitudinal prospective, one-armed, cohort 
study.  
6.2. 
Untersuchungen und Eingriffe / Examination and Procedures 
The protocol is as follows: 
1. Patients with an IOP equal to or above 21 mmHg who qualify for AIT will be identified 
(see inclusion criteria below). A comprehensive eye exam will then be performed 
followed by an explanation of the risks and benefits of TP. Informed consent forms for 
both TP and AIT will then be signed.  

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2. IOP and outflow facility will be then measured with a pneumatonometer (Model 30, 
Reichert, Buffalo, NY, United States).  
3. As is common practice before glaucoma surgeries, glaucoma drops will be stopped two 
days prior to surgery.   
4. On the day before surgery, trabeculopuncture will be performed with a Q-switched 
Nd:YAG Laser (VISUALS YAGIII, Zeiss, Oberkochen, Germany) by placing four 
trabeculotomies with a trabeculoplasty lens (Ocular Latina SLT Gonio Laser, Ocular 
Instruments Inc., Bellevue, USA) 40 degrees apart along the nasal 120 degrees of the 
trabecular meshwork (energy per shot = 4 mJ, single-shot mode, 4 shots per TP, total 
energy < 100 mJ). The procedure will be carried out only by physicians experienced with 
this laser. Because this laser is low risk and easy to use, first-year resident physicians are 
familiar with this device and use it daily after their first six months of training. 
5. IOP and outflow facility will then be measured two hours after TP.  
6. AIT will subsequently be performed within two days of admission. 
7. At their one week follow-up visit, IOP and outflow facility will be measured with a 
pneumatonometer. The measurements will also be repeated one and three months 
after the AIT procedure. 
Recruitment is planned for about six months. For each individual the period of participation will 
be approximately three months with the total course of the study being 12 months.  
 
7. 
Studienpopulation / Human Subjects 
Glaucoma patients with open angle glaucoma (OAG) who qualify for AIT are recruited in our 
glaucoma clinic at the University Hospital Würzburg. 
The inclusion criteria are as described previously [1,2,8,32] and consist of: 
● worsening glaucoma as evidenced by  
○ uncontrolled IOP while using maximally tolerated medical therapy or 
○ progressive thinning of retinal nerve fiber layer by Spectral Domain OCT (p < 
0.05) or 
○ visual field progression: new glaucoma-associated peripheral defects or 
extension of preexisting defects or 
● visually significant cataract and indication to reduce IOP or glaucoma medication 
burden by combining cataract surgery with AIT 
● individuals ≥ 18 years of age 
● diagnosis of open angle glaucoma including  
○ primary open angle glaucoma 
○ pigmentary glaucoma 
○ pseudoexfoliation glaucoma  
 
 
 

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The exclusion criteria are:  
● diagnosis of  
○ neovascular glaucoma 
○ angle-closure glaucoma 
○ uncontrolled uveitis 
● prior glaucoma surgery 
● preexisting conditions affecting the episcleral venous pressure 
○ Grave’s ophthalmopathy 
○ Sturge-Weber syndrome  
○ arteriovenous fistulas (carotid-cavernous fistula) 
 
8. 
Individueller Studienablauf / Individual Course of Study  
Recruitment in 
glaucoma clinic  
day 0 
- 
detailed discussion of study 
- 
information leaflet  
- 
informed consent 
- 
schedule appointment within 14 days 
Admission for 
surgery 
within 2 weeks 
- 
additional questions answered 
- 
best corrected visual acuity (BCVA) 
measured 
- 
IOP and outflow facility measurements  
- 
TP with YAG-Laser 
- 
AIT / Phaco-AIT 
Follow-up #1 
Follow-up #2 
Follow-up #3 
1 week after AIT 
1 month after AIT 
3 months after AIT 
- 
BCVA 
- 
eye exam 
- 
IOP and outflow facility measurements  
 
BCVA: The best corrected visual acuity is assessed using a number chart at 5 meters. 
IOP and outflow facility: The  IOP measurement is performed using a pneumatonometer. The 
cornea anesthetized using Oxybuprocain eye drops. Next, the probe is placed on the central 
cornea and the IOP is measured. 
 
TP: The patient’s eye is anaesthetized using Oxybuprocain eye drops. A trabeculoplasty lens is 
placed on the eye using contact gel and four trabeculopunctures are carried out along the nasal 
trabecular meshwork with the aid of an Nd:YAG laser. 
 

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AIT/Phaco-AIT: The procedure is performed in the operation theatre in either local or general 
anesthesia. A trabectome is used to excise the trabecular meshwork around 180 degrees 
nasally. If applicable (Phaco-AIT), the patient will also undergo a lensectomy followed by an 
intraocular lens insertion.  
8.1. 
Medikation / Medications  
Postoperative drops after TP/AIT 
● dexamethasone drops four times daily, reduced weekly by one drop  
● ofloxacin eye drops four times daily for seven days 
● glaucoma drops may be restarted depending on postoperative IOP (but not when IOP < 
20 mmHg in the first month) 
 
9. 
Unerwünschte Ereignisse (AE) und schwerwiegende unerwünschte 
Ereignisse (SAE) / Adverse Events (AE) and Serious Adverse Events (SAE) 
9.1. 
Definition / Definition of AE and SAE 
Adverse events 
● after trabeculopuncture 
○ persistent IOP elevation by more than 30% above baseline  
○ hyphema 
○ corneal erosion 
● after AIT 
○ persistent IOP elevation by more than 30% above baseline  
○ cystoid macular edema 
 
Serious adverse events 
● after TP 
○ uncontrolled IOP elevation by more than 30% above baseline using maximal 
glaucoma medication 
● after AIT 
○ uncontrolled IOP elevation  by more than 30% above baseline using maximum 
glaucoma medication 
○ persistent hyphema of more than 50% for five days or longer 
○ IOL sub-/luxation 
○ endophthalmitis 
 
 

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9.2. 
Medizinische Maßnahmen / Treatment Plan of AEs & SAEs 
AE 
Treatment 
IOP elevation by more than 30% above 
baseline after TP 
1x apraclonidine eye drops 
- 
IOP check in 1 h 
if no decrease 
- 
additional pressure lowering drops 
(miotic, beta-blocker, prostaglandin 
agonist, carbonic anhydrase inhibitor) 
- 
IOP check in 1 h 
if no decrease  
- 
oral acetazolamide 1 g, then 500 mg 
three times per day (if no 
contraindications) 
if no decrease 
- 
see glaucoma section SOP (“Therapie 
Glaukomverdacht und Glaukom”) 
hyphema 
observe and reassure that there is no active 
bleeding, 
blood will be removed during AIT 
corneal erosion 
lubricating eye drops + ointment 
 
if large, antibiotic eye drops four times daily 
for three days 
IOP elevation by more than 30% above 
baseline after AIT 
 
initiate one of prior glaucoma drops  
 
if no decrease 
- 
additional pressure lowering  drops 
- 
(miotic, betablocker, prostaglandin 
agonist, carbonic anhydrase inhibitor) 
- 
IOP check in 1 h 
if no decrease  
- 
oral acetazolamide 1 g, then 500 mg 
three times per day 
if no decrease 
- 
see glaucoma section SOP (“Therapie 
Glaukomverdacht und Glaukom”) 
- 
 
SAE 
Treatment 

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uncontrolled IOP elevation by more than 30% 
above baseline using maximal glaucoma 
medications after TP 
see glaucoma section SOP (“Therapie 
Glaukomverdacht und Glaukom”), 
 
perform glaucoma surgery sooner 
uncontrolled IOP elevation by more than 30% 
above baseline using maximal glaucoma 
medication after AIT 
see glaucoma section SOP (“Therapie 
Glaukomverdacht und Glaukom”), 
consider additional glaucoma surgery 
- 
micro-shunt implant (Preserflo) 
- 
filtering surgery (trabeculectomy) 
- 
tube shunt (Ahmed, Baerveldt) 
persistent hyphema 
anterior chamber lavage 
IOL sub-/luxation 
IOL-reposition or implantation of new IOL 
postoperative endophthalmitis 
follow “UKW Augenklinik SOP - 
Endophthalmitis” 
 
10. 
Biometrische Aspekte / Biometrics and Data Analysis 
Surgical success is defined as IOP reduction by at least 20% after AIT, which equals an increase 
in outflow facility of approximately 25% according to the Goldmann equation. Individuals are 
assigned retrospectively to one of two groups, responders and non-responders, depending on 
the surgical success of AIT. This study is a pilot study and we aim to recruit as many patients as 
possible, within the allotted time frame, to increase the power and validity/generalisability of 
results. The statistical analysis calculates a sample size of 55 individuals.  
Changes in IOP and outflow resistance are to be compared between groups using a 
Student’s t-Test. A predictive parameter P, defined as Rtp/Rbaseline, will be used as a preoperative 
test to measure the distal outflow resistance of the individual’s eye. Eyes with a P value of  0.75 
or greater will be considered to have an increased distal outflow resistance and therefore, 
potential non-responders to AIT treatment. In this case, mere ablation of TM is predicted to 
result in an insufficiently decreased postoperative IOP.  
For all our statistical analyses, a p-value of 0.05 or less will be considered statistically 
significant. 
 

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11. 
Datenmanagement / Data Management 
Patient data and data analyses are saved in an access-protected, access-logged online UKW 
drive. Signed paper documents of informed consent are filed and locked.  
 
12. 
Ethische und Rechtliche Aspekte / Ethical and Legal Aspects 
The study conforms to the Declaration of Helsinki and the guidelines of Good Clinical Practice 
(ICH-GCP 1997). The European General Data Protection Regulation (EU GDPR  2016/679) is 
likewise respected.  
 
 

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13. 
Referenzen / References 
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generation trabecular bypass (iStent inject) to ab interno trabeculectomy (Trabectome) by exact 
matching. Graefes Arch Clin Exp Ophthalmol. 2020. doi:10.1007/s00417-020-04933-z 
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