Clinical trial NCT02754570
Conditions: Glaucoma, Open-angle Hypertension, Ocular
Keywords: Open-angle glaucoma Ocular hypertension Latanoprost Pilocarpine
Sponsor: University of Colorado, Denver
Start date: 2016-07-01; Completion date: 2018-02-21
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The aim of this study will be to determine the effects of pilocarpine as an adjunct medication to latanoprost monotherapy at multiple intervals throughout a 24-hour period and compare these effects to latanoprost alone.

Detailed description:
This study plans to learn more about the effect of pilocarpine on intraocular pressure and ocular perfusion pressure for a full twenty-four hour period.

In this study, the investigators seek to better characterize the knowledge base of the intraocular pressure (IOP) lowering effects of pilocarpine in patients with open angle glaucoma or ocular hypertension who are currently taking latanoprost. The goal is to define the potential additive effect of pilocarpine throughout a 24-hour period, not only for IOP, but for ocular perfusion pressure (defined as 2/3\[diastolicBP + 1/3(systolicBP - diastolicBP)\] - IOP). These data will allow to expand current knowledge of the effects of pilocarpine and help determine if this medication has a useful role as an adjunctive treatment in glaucoma.

Arms: arm 1: Subjects with open-angle glaucoma and ocular hypertension that are currently taking latanoprost
Interventions: intervention 1: Pilocarpine
Intervention descriptions: intervention 1: Pilocarpine will be administered 4 times in addition to latanoprost.

Protocol documents:
Prot_SAP_000.pdf: 
            
 
SARC Protocol
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Scientific Advisory and Review Committee (SARC) Protocol
COMIRB # 15-1972
Protocol Title: The Diurnal and Nocturnal Effect of Pilocarpine on Intraocular Pressure and Ocular 
Perfusion Pressure
Version Date: 06Jan2017
Principal Investigator: Leonard K. Seibold, MD
I.   Hypothesis and Specific Aims  
     
We hypothesize that pilocarpine will achieve a decrease in intraocular pressure and increase in ocular 
perfusion pressure throughout the diurnal and nocturnal periods. The aim of this study will be to 
determine the effects of pilocarpine as an adjunct medication to ophthalmic prostaglandin analogue 
(PGA) monotherapy at multiple intervals throughout a 24-hour period and compare these effects to 
ophthalmic prostaglandin analogue alone. 
II.  Background and Significance 
 
Intraocular pressure (IOP) is a major risk factor for the development of glaucoma. In addition, it remains 
the only modifiable factor in the prevention and subsequent treatment of glaucomatous optic neuropathy.1 
Most clinicians only take a single IOP measurement during a patient visit that will typically occur once 
every four months.  These snapshots in time are likely inadequate for the optimal management of 
glaucoma and may miss actual peak values.  Diurnal IOP curves, consisting of serial IOP measurements, 
can provide a better estimate of each patient’s individual IOP variation throughout the day.  However 
diurnal curves fail to determine IOP values during another crucial time, the nocturnal period.  
Glaucomatous eyes have been shown to have different IOP curves during the nocturnal period compared 
to healthy controls.2 In addition, different classes of glaucoma drugs have variable IOP lowering effects 
during the nocturnal hours compared to the diurnal/wake period.3 Therefore it is crucial to determine an 
accurate IOP curve for each medication throughout a 24 hour time period.  
Pilocarpine hydrochloride ophthalmic 2% is a commercially available, topical anti-cholinergic, FDA 
approved for treatment of glaucoma and ocular hypertension.  Pilocarpine has a long history of use after 
FDA approval in 1974, but there is a paucity of data detailing its efficacy over a 24 hour period. One early 
study found average IOP lowering efficacy to be on the order of 20% from baseline over the diurnal 
period only.4 The nocturnal effects of pilocarpine are poorly defined with only one study evaluating the 24 
hour effects on IOP.5 This study found a significant IOP lowering effect from pilocarpine throughout a 24 
hour period, but this was in exfoliation glaucoma patients only. Pilocarpine’s relatively short duration of 
action requires frequent daily dosing of 3 to 4 times per day making it a seldom chosen option for first line 
therapy compared to once daily dosed medications.  However it is often considered as an adjunct to more 
easily administered medications such as the prostaglandin analogues (ie. Latanoprost, bimatoprost, 
travoprost, or tafluprost).  It is in this real world clinical scenario that we wish to study this medication’s 
effects. 
COMIRB
APPROVED
10-Mar-2017


            
 
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V-01.06.17
In this study, we seek to better characterize the knowledge base of the IOP lowering effects of 
pilocarpine.  We plan to determine the IOP lowering effects in patients with open angle glaucoma or 
ocular hypertension who are currently taking PGA monotherapy. Our goal is to define the potential 
additive effect of pilocarpine throughout a 24-hour period, not only for IOP, but for ocular perfusion 
pressure as well. Ocular perfusion pressure was defined as 2/3[diastolicBP + 1/3(systolicBP - diastolicBP)] - 
IOP. These data will allow us to expand current knowledge of the effects of pilocarpine and help determine 
if this medication has a useful role as an adjunctive treatment in glaucoma
III.  Preliminary Studies  
      
Our group has completed similar studies of the 24-hour effects of other glaucoma medications, including 
Travatan Z and Simbrinza.  These protocols were reviewed and approved by SARC and COMIRB in 2012 
and 2014 respectively and completed less than a year after approval.  The results from the Travatan Z 
study were published in the American Journal of Ophthalmology, PMID 24182742. The results from the 
second trial are being analyzed and prepared for manuscript submission (COMIRB # 14-0362).
IV. Research Design and Methods  
A.
Study Design Details
This is a single site, investigator-initiated, prospective, clinical, open-label study of the 24-hour IOP 
lowering effects of pilocarpine.  Patients with open angle glaucoma (including pigment dispersion 
glaucoma and pseudoexfoliation glaucoma) or ocular hypertension who are currently on monotherapy 
with a prostaglandin analogue (PGA: latanoprost, bimatoprost, travoprost, or tafluprost) will be recruited 
at their regularly scheduled ophthalmology exam visits.   A study coordinator will discuss study details 
and commitments and obtain informed consent from subjects on the same day or later date during visit 1.    
The CTRC nurses will be trained by an ophthalmic technician (lead technician in our study group with 
experience in training others) with previous expertise with the pneumotonometer.  This will include a 30 
minute hands-on demonstration with the instrument and accompanying written instructions.  The nurse 
must then demonstrate proficiency at obtaining an accurate and reproducible IOP measurement as 
determined by a performance evaluation from the training technician.  In addition, the instrument records 
IOP waveforms and standard deviation values that will be reviewed during the study to ensure accuracy 
of measurements.  The use of this device is very simple and straightforward and new technicians are 
frequently proficient with its use after a brief 30 minute introduction as outlined above.  
Subjects will be asked to participate in three separate study visits.  The first study visit will involve 
enrollment of subjects into the study after meeting inclusion criteria and reviewing the risks and 
requirements of the study.  Informed consent will be obtained and urine pregnancy test performed where 
applicable.  On the second study visit, baseline IOP measurements will be taken while on PGA 
monotherapy.  The purpose of this 24-hour visit will be to establish individual baseline IOP and OPP while 
on PGA therapy before pilocarpine is administered at visit 3. Patients will check in at the inpatient Clinical 
Translational Research Center (CTRC) on the 12th floor of Anschutz Inpatient Pavilion at 09:30.  
Intraocular pressure of both eyes and blood pressure measurements will then be taken every 2 hours for 
a 24-hour period.  Measurements during the diurnal period of 0600 to 2200 will be in the normal upright 
position (total of 8 measurements: 0700, 0900, 1100, 1300, 1500, 1700, 1900, 2100).  Starting with the 
measurements after 2200, patients will be measured in the supine position during the nocturnal period 
(total of 4 measurements: 2300, 0100, 0300, 0500).  Patients will self-dose with their current prescribed 
PGA at 2000.   This dose will be observed by study staff.  After the last measurement in a 24-hour period, 
subjects will be free to leave the CTRC.  Meals will be provided to subjects through the CTRC inpatient 
food services during their stay.  Visit 1 and 2 may be combined with consent being obtained prior to any 
study procedures taking place.  
A second 24-hour visit (visit #3) will be performed at any point over the next 4 weeks.  This time period 
was chosen to allow convenient scheduling for the patient and CTRC unit.  Visit 3 will proceed as Visit 2 
with IOP, BP and pulse measured every 2 hours for a 24 hour period.  In addition, a dose of pilocarpine 


            
 
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V-01.06.17
2% will be administered by nursing staff at 0600, 1000, 1600, and 2200. Due to the relative lack of 
additional efficacy with extended use, no period of prolonged use of pilocarpine is needed prior to this 
visit. Patients will self-dose with current prescribed PGA at their usual dosing time similar to visit #2.  At 
the conclusion of study visit #3, the subjects participation will be complete, and they will return to their 
prior treatment regimen and follow up with their treating ophthalmologist for further recommendations.
B.
Sample size justification and analytical plan
A statistical consultation was made with the Colorado Biostatistics Consortium.  Their recommendations 
are as follows: The sample size calculations were based on the assumption that the mean difference in 
IOP will be 1.9 mmHg. The sample sizes required to detect this difference using a paired t test with 80% 
or 90% power using two assumed standard deviations are:
 
                  
SD = 3.0         SD = 4.0
80% power               22                    37
90% power               29                    49
Based on these power calculations, we have decided to use a sample size of 30. Due to the repeated 
measures of IOP and BP over each study visit, mixed models will be utilized to compare IOP and OPP 
across all time points.
C.
Primary Outcome Measure(s)
The primary outcome measure will be the change in intraocular pressure and ocular perfusion pressure 
after the addition of pilocarpine to PGA monotherapy at multiple time points throughout a 24-hour period.
Subject Recruitment and Consent (Visit #1)
 2nd Study Visit:
24-hour IOP and BP measurements 
(PGA only)
  3rd Study Visit:
24-hour IOP and BP measurements
(PGA plus pilocarpine)
Study End


            
 
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V.  Human Subjects  
A.
Inclusion Criteria
- Current confirmed diagnosis of open angle glaucoma or ocular hypertension including pigment 
dispersion glaucoma and pseudoexfoliation glaucoma.  
- Current use of topical PGA (latanoprost, bimatoprost, travoprost, or tafluprost) once a day in both eyes 
for at least 6 weeks
- Age ≥ 18 years, of either gender, or any race/ethnicity
B.
Exclusion Criteria
- Females who are currently pregnant or planning to become pregnant during the study period
- Diagnosis of any other form of glaucoma other than open-angle
- Intraocular pressure readings of <14mmHg in either eye when measured during routine office visit in      
the past 12 months.  
- Schaffer angle grade < 2 in either eye by gonioscopy
- Intraocular surgery within 6 months or laser within 3 months
- History of retinal tear or detachment in either eye
- Active iritis in either eye as determined by most recent eye examination
- Patients who smoke or have irregular daily sleep patterns
- Patients who have started or changed glucocorticoids therapy in the last 3 months
- Patients who are currently using medical or recreational marijuana 
- Any use of a non-FDA approved medication for glaucoma in the last 3 months
- History of allergy to pilocarpine
- History of allergy to proparacaine ophthalmic solution
C.
Anticipated risks 
Intraocular pressure: Measurement will be performed using an FDA approved pneumotonometer device.  
This measurement requires the use of a topical anesthetic drop (proparacaine 0.5%) before 
measurement.  The pressure is obtained by placing a probe onto the corneal surface for approximately 5-
10 seconds per eye and requires the subject’s cooperation in remaining motionless.  All measurements 
will be performed by trained CTRC nursing staff.  During awake hours (0600 – 2200), the measurements 
will be taken in the upright position.  During sleep hours (2200 - 0600), subjects will be awakened gently 
and measurements taken in the resting, supine position to more closely approximate typical sleeping 
posture and IOP.  
The pneumotonometer and associated topical anesthesia are both used routinely in everyday 
ophthalmologic examinations for IOP measurement.  Risks associated with these measurements include 
ocular surface irritation and minor corneal abrasion.  There is also a small risk of hypersensitivity with 
topical anesthesia (proparacaine).  Patients may experience a mild stinging or blurring of vision that is 
brief and self-limited.   Rare risk of allergic reaction may occur causing diffuse epithelial keratitis.  The risk 
of corneal abrasion during intraocular pressure measurement using a Pneumotonometer is small and 
estimated at 1/3,000.  This risk is no greater than that encountered in every day ocular exams as part of 
routine work-ups.  Any persistent or significant pain or discomfort sustained during or after IOP 
measurements will be assessed by slit lamp examination and will be addressed as per clinical standards.  
Any antibiotics eye drops and lubricating eye drops needed to treat a corneal abrasion will be provided at 
no cost to the subject.  Clinical follow up until resolution of the corneal abrasion will also be done by the 
eye clinic at no cost to the subject.  Subjects will also be at risk for sleep loss due to the frequency of IOP 
checks during the nighttime hours.  This cannot be avoided due to the nature of the study.  However, 
sleep disturbance will be minimized by very brief testing measurements that can be performed in dim 
lighting with accuracy.


            
 
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Blood pressure:  Measurement will be performed using an automated, electronic FDA approved 
sphygmomanometer.  There are no significant risks associated with the use of this device.  
Pregnancy Test: All women of childbearing potential (who are not postmenopausal for at least 1 year or 
surgically sterile) will undergo a urine pregnancy test prior to the start of study medication.  Any positive 
results will result in exclusion from the study.  [Quidel Corp QuickVue hCG urine test]
Study Medication: All subjects will receive 4 doses of pilocarpine 2% in both eyes during the third study 
visit.  The study medications have been FDA approved for the reduction of elevated intraocular pressure 
in patients with open-angle glaucoma or ocular hypertension.  The inclusion criteria were designed to 
include only this population.  Therefore, the medication will be used in a manner that is in complete 
accordance with the labeled indications and dosing recommendations. 
There are some possible adverse effects and reactions with the study medication, pilocarpine 2%, as 
outlined in the drug information sheet.  We anticipate a low occurrence of these, as the study participants 
will only be receiving a total of 4 doses of the study medication.  
The most frequently reported adverse reactions occurring in ≥ 5% of patients in the pilocarpine 2% 
populations were: headache/browache, accommodative change, blurred vision, eye irritation, visual 
impairment (dim, dark, or "jumping" vision), and eye pain.  
Precautions include:  

Night Driving
o
Caution is advised with night driving and when hazardous activities are undertaken in 
poor illumination.

Accommodative Spasm
o
Pilocarpine Hydrochloride Ophthalmic Solution may cause problems when changing 
focus between near objects and distant objects. Do not drive or use machinery if vision is 
not clear.

Contact Lens Wear
o
Contact lens should be removed prior to the instillation of Pilocarpine Hydrochloride 
Ophthalmic Solution. Wait 10 minutes after dosing before reinserting contact lenses.
Contraindications to the use of pilocarpine: None  
Safety stopping rules will also be put into place to hold or stop the study until further review if either of the 
following occurs:

>3 corneal abrasion related to the study protocol

>2 episodes of bacterial keratitis related to the study protocol
Individual subject stopping will occur if a subjects becomes intolerant to study testing, intolerant to study 
eye drops, or develops a corneal abrasion during testing,
D.
Describe plan to minimize risk
All patients will receive full disclosure of these possible adverse events and be monitored during the study 
for any occurrences. To minimize systemic absorption, patients will be instructed on proper eye drop 
administration including closing of the eyelids and punctual occlusion after administration.  The exclusion 
criteria have been designed in a manner to eliminate subjects with a high risk of adverse events.  All 
women of childbearing age will take a urine pregnancy test at visit 1 prior to starting the first overnight 
visit.  Any significant adverse events or patient intolerance will be evaluated by the study coordinator 
and/or the PI and result in removal from the study.   Subjects will be able to contact the study coordinator 
during business hours and have access to the Rocky Mountain Lions Eye Institute after hours call center 
and on call ophthalmologists for any concerns that arise after normal business hours.  Any evaluation, 


            
 
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diagnosis, and treatment of adverse events related to the medication will be provided at no charge to the 
subject until the event is resolved.  Subjects will be advised of potential for sleep deprivation after Visits 2 
& 3 and suggested options of arranging transportation or staying at facility to sleep longer if needed to 
drive.  
The PI will review all reported adverse events and stop individual subjects or the study as defined in risks 
section.  As the ocular medications in this study are all FDA approved and being used on-label, a 
separate safety officer will not be utilized.  
E.
Describe the potential benefits of the study
This study is designed with the intention to further elucidate the 24-hour effects of pilocarpine on 
intraocular pressure and ocular perfusion pressure.  Prior work regarding nocturnal effects of other 
medications (PGAs, CAIs, AAs) has been published. This will be the first known 24hr IOP study of 
pilocarpine as an adjunct to PGA therapy. A better understanding of the effects of this drug on intraocular 
and blood pressure will contribute to physician’s ability to prescribe appropriate and effective therapy for 
glaucoma and ocular hypertension. The results of this study will help better determine the effect of this 
medication in the overnight hours.
VI.  References
1. Coleman AL, Miglior S. Risk factors for glaucoma onset and progression. Surv Ophthalmol. 2008 
Nov;53 Suppl1:S3-10.
2. Drance SM. Diurnal Variation of Intraocular Pressure in Treated Glaucoma. Significance in Patients 
with Chronic Simple Glaucoma. Arch Ophthalmol. 1963 Sep;70:302-11.
3. Liu JH, Kripke DF, Weinreb RN. Comparison of the nocturnal effects of once-daily timolol and 
latanoprost on intraocular pressure. Am J Ophthalmol. 2004 Sep;138:389-95.
4. Harris LS, Galin MA. Dose response analysis of pilocarpine induced ocular hypotension. Arch 
Ophthalmol 1970;84:605-8.
5.  Konstas AG, Lake S, Maltezos AC, Holmes KT, Stewart WC. Twenty-four hour intraocular pressure 
reduction with latanoprost compared with pilocarpine as third-line therapy in exfoliation glaucoma. Eye. 
2001 Feb;15(Pt 1):59-62.