Efficacy of the Nanodropper Device on Intraocular Pressure in Patients With Glaucoma
Phase: NA
Conditions: Glaucoma, Ocular Hypertension, Open Angle Glaucoma
Sponsor: University of California, San Francisco

RANDOMIZED TRIAL TO EVALUATE THE EFFICAY OF THE 
NANODROPPER DEVICE ON INTRAOCULAR PRESSURE IN PATIENTS 
WITH GLAUCOMA
Protocol Number: 
20-32530
NCT Number: 
NCT05273385 
Document Date: 
11/02/2020
Intervention: 
Efficacy of the Nanodropper Device on Intraocular Pressure 
in Patients With Glaucoma

Nanodropper Glaucoma Trial Study Overview  
  
Study Title: Efficacy of the Nanodropper Device on Pupillary Dilation in Clinic and Intraocular 
Pressure Reduction in Patients with Glaucoma. (Nanodropper Glaucoma trial)   
  
Principal Investigator:  
Julius Oatts, M.D., Associate Professor of Ophthalmology. UCSF, 
San Francisco, CA.  
Phone: 415.353.2800 e-mail: Julius.Oatts@ucsf.edu  
Co-Investigator:   
Ying Han, M.D.- Ph.D., Professor of Ophthalmology. UCSF, San 
Francisco, CA.  
Phone: 415.353.2800 e-mail: ying.han@ucsf.edu   
Study Coordinator:  
Mariko Costantini  
Phone:  510.646.2065 e-mail: mari.costantini@ucsf.edu   
  
STUDY SUMMARY  
  
Introduction: Nanodropper is an eye dropper adapter that dispenses smaller eye drops. 
Eye drops from standard of care (SOC) dropper bottles are up to 5x larger than what the 
human eye can absorb (7-10 µL). Therefore, every time a patient administers an eye 
drop, they lose approximately 80% of their medication to wasted overflow and/or 
systematic absorption. The Nanodropper device elutes 10.4 µL per drop, which may 
reduce medical waste and reduce systemic side effects while maintaining efficacy.  
  
Purpose: To determine non-inferiority of the Nanodropper adaptor for intraocular 
pressure (IOP) control in glaucoma patients compared to SOC dropper bottles.   
  
Study Design: The study will include four visits: recruitment visit, baseline visit 
following a wash-out period of 4-5 weeks (± 1 week), 1-month follow-up (± 1 week), 
and 3-month follow-up (± 1 week). A random sample of 80 participants from UCSF will 
be selected to participate in the “Nanodropper Glaucoma” study, which will entail use 
of Nanodropper to administer eyedrops and IOP measurements at follow-up visits.  
  
Table 1: Schedule for examination and treatment  
  
Recruitment  
  
Baseline  
  
1-Month Follow-
Up  
(± 7 days)  
3-Month Follow-
Up  
(±7 days)  
Consent  
X  
  
  
  
Randomization  
  
X  
  
  
Nanodropper 
Instruction  
  
X  
  
  
IOP Measurement  
X  
X  
X  
X  
Conjunctival 
Grading  
  
X  
  
X  
Survey  
  
  
  
X  
  

Page Break  
Study Population:  
Inclusion Criteria:  
1. 
18 years old or older  
2. 
Diagnosis of open-angle glaucoma (OAG) or ocular hypertension 
(OHT)  
3. 
Use of prostaglandin analogue (PGA) eye drop  
4. 
Stable disease status (no visual field loss progression or increase in 
IOP-lowering medications in the last 6 months)  
Exclusion Criteria:  
1. 
Uncontrolled glaucoma  
2. 
Have had eye surgery (including laser procedures) within the past 
six months  
3. 
Have a diagnosis of acute angle-closure glaucoma and/or other 
retinal diseases  
4. 
Use of non-PGA class of IOP-lowering medication  
Randomization (40 patients per group):  
Group 1: administer eyedrops with SOC dropper bottles for three months   
Group 2: administer eyedrops using Nanodropper for three months  
   
Participants will be supplied a Nanodropper device free of charge.   
Outcomes:  
Intraocular Pressure (IOP)  
Goldman applanation tonometry will be performed at each study visit by a masked and 
experienced ophthalmologist. The time of IOP measurement will be also recorded. The 
tonometer will be calibrated monthly. Pneumotonometer application tonometry will also be 
performed at each study visit by a masked and experienced ophthalmologist. The time of IOP 
measurement will also be recorded and the Pneumotonometer will be calibrated monthly.  
The order of testing will always be applanation right eye, applanation left eye; pneumotonometry right 
eye, pneumotonometry left eye  
  
End-of study Survey  
The following open-ended questions will be administered to participants randomized 
to the Nanodropper group at the end of the 3-month study.  
1. Would you consider using the Nanodropper for your regular eye drop use in the 
future? (yes/no)  
2. Did you find the Nanodropper easy to use? (yes/no)  
3. Did using the Nanodropper cause more irritation compared to normal eye drop 
bottles? (yes/no)  
Conjunctival Grading  
Conjunctival grading will be performed by a masked ophthalmologist at the baseline 
and 3 month study visits. Grading will be performed as described in the following 
citation, with redness graded on a scale of 0-100 using the 5-picture validated scale 
(which will be printed on photographic paper in a size of 3.8x5.7 cmand used for 

comparison). Time between grade and last eye drop administration at the 3 month end 
point will be measured as well.  
  
  
 

Non-Inferiority of Nanodropper for 
Intraocular Pressure Control   
 
 
Statistical Analysis Plan 
 
1.  Administrative Information 
 
Trial registration:   
ClinicalTrials.gov 
Funder: 
UCSF Internal Funding 
SAP Version: 
Version 1 
A revision history for this document is included at the end. 
 
 
Protocol Version: 
Refers to Protocol Version 
Contributors: 
Statisticians responsible:  
Jeremy Keenan1 
 
Principal Investigators:  
 
Jeremy Keenan1 
Julius Oatts2 
Ying Han2 
 
1 Francis I. Proctor Foundation for Research in Ophthalmology, 
University of California, San Francisco, USA 
2Department of Ophthalmology, University of California, San 
Francisco, USA 
 
 
 
 
 

SAP Table of Contents 
 
The content of this Statistical Analysis Plan meets the requirements stated by the US Food and 
Drug Administration and conforms to the American Statistical Association’s Ethical Guidelines. 
This SAP was organized following guidelines proposed in:  
 
Gamble C, Krishan A, Stocken D, Lewis S, Juszczak E, Doré C, et al. Guidelines for the 
Content of Statistical Analysis Plans in Clinical Trials. JAMA. 2017;318: 2337–2343. PMID: 
29260229. 
 
 
 

2.  Introduction 
2.1. Background and rationale 
Topical ophthalmic medications in the form of eye drops are widely used for diagnostic and 
therapeutic purposes. The human eye can only absorb 7-10 μL of fluid, but the average volume 
dispensed from commercially available eye dropper bottles is approximately 50 μL. Given this, 
every time a patient administers an eye drop, they lose approximately 80% of their medication 
to wasted overflow and/or systemic absorption. Besides generating waste, larger eye dropper 
volumes may also increase the likelihood of local and systemic adverse medication effects, 
especially since topical medications that reach the nasolacrimal duct and nasopharynx can be 
absorbed systemically through the mucosa, avoiding first-pass metabolism. Major systemic side 
effects have been reported in children including bradycardia, hypotension, and asthma attacks 
after topical beta-blocker use and anticholinergic symptoms and psychosis following topical 
cycloplegia. Locally, preservatives found in eye drops are known to cause adverse eye 
symptoms and irritation. 
 
Instillation of a smaller volume eye drop could limit medication waste and reduce systemic and 
local side effects, although the efficacy of smaller volume eye drops has not been well 
characterized. The aim of this study was to evaluate the effectiveness of a novel small volume 
eye drop adapter, Nanodropper, which administers 10.4 μL eye drops when used for pupillary 
dilation and cycloplegia in children.  
 
2.2. Objectives 
1: To determine if the use of Nanodropper eye adapter is non-inferior for intraocular pressure 
(IOP) control to standard of care (SOC) eye drop bottles. 
 
3.  Study Methods 
3.1. Trial design 
The study will be a randomized trial to evaluate the non-inferiority of Nanodropper eye drop 
adapter versus SOC eye drops. 
 
3.2. Randomization 
Participants (including both eyes for every participant) will be randomized 1:1 to two groups 
using RedCap with an imported allocation table from R with the following code. Note the 
important thing here is the seed, which will be chosen at random by non-masked study 
personnel. The person doing the randomization will not share the seed with anyone who is 
masked. The person doing the randomization will share the R script (and randomization list) 
with a member of the DSMC as a backup. 
 
 
 

library(blockrand) 
library(tidyverse) 
  
set.seed(1234*** will be replaced with random number) 
randomlist <- blockrand(n=90, num.levels=2, block.sizes = 4:6) %>% 
  mutate(tx=case_when(treatment=="A" ~ "nanodropper", 
                      treatment=="B" ~ "standard", 
                      TRUE ~ NA_character_), 
         redcap_copypaste=paste0(id, ", ", tx)) 
write_csv(randomlist, "randomlist_forpractice.csv") 
 
 
 
Group 1: administer eyedrops with SOC bottles for three months  
Group 2: administer eyedrops using Nanodropper for three months  
 
3.3. Sample size 
The trial’s target enrollment will be 80 participants. Sample size was determined based on a 
power calculation to reach significance for one outcome at a p-value = 0.05 for 80% statistical 
power. R code for Power calculation included below: 
  
Library(SampleSize4ClinicalTrials) 
ssc_meancomp(design=3L, ratio=1, alpha=0.025, power=0.8, sd=3, 
theta=0, delta=2) 
 
Assuming 10% loss to follow up, 80 participants are needed.  
 
3.4. Statistical framework 
For the primary prespecified analysis, we propose a non-inferiority analysis with a margin of 
error of 2 mmHg. 
 
3.5. Statistical interim analyses and stopping guidance 
This is a small trial with four study visits to evaluate the non-inferiority of Nanodropper eye 
adapter. Interim analyses will not be performed. 
 
3.6. Timing of the final analysis 
The final analysis will take place when study data has been measured and collected on all study 
participants. If the trial is stopped for safety concerns or complications before the full sample, 
the final analysis will include all outcomes among patients who have been enrolled at the time 
the trial is stopped. 
4.  Statistical Principles 
4.1. Confidence intervals and P-values 
 

The trial will report 95% confidence intervals for the mean/pseudomedian of each group, 
together with boxplots and other descriptive statistics.  
 
4.2. Missing data 
We will report the number of individuals with missing outcomes, together with relevant 
covariates. The primary analysis will be a complete case analysis only including those who do 
not have missing data.  
5.  Trial Population 
5.1. Screening data 
We will report the number of patients screened and characteristics to the extent they are 
available to assess representativeness of the enrolled study population. 
 
5.2. Eligibility 
See the trial protocol for eligibility criteria. 
 
5.3. Recruitment  
We will report the number of participants screened, enrolled, randomized, and measured, along 
with reasons for exclusion at each step following CONSORT guidelines. 
 
5.4. Withdrawal/follow-up  
We will report the proportion of patients who withdraw from the trial, along with reasons. We will 
report this information in the trial’s CONSORT flow chart.   
 
5.5. Baseline patient characteristics  
We will summarize patient characteristics by arm, including: age, sex, intraocular pressure 
(IOP), and ocular diagnoses at the time of enrollment. 
 
6.  Analysis 
6.1. Outcome definitions and analysis methods 
Outcome: The primary outcome will be intraocular pressure (IOP) at each follow-up time point. 
 
Analysis: We propose to compare the mean IOP for SOC vs Nanodropper groups at each 
follow-up timepoint (1 and 3 month visits).  
6.2. Additional analyses 
Additional analyses may be added. If so, these analyses will be addended to the SAP prior to 
the analysis being performed. 

6.3. Harms 
Adverse events and serious adverse events (SAEs) will be reported to a Data and Safety 
Monitoring Board, with SAEs being reported within 24 hours. These events will be tabulated by 
study arm. The counts of adverse events and serious adverse events will be analyzed using chi-
square tests between study and control eyes. However, we note that conservative statistical 
analyses are not necessarily appropriate in analysis of safety signals and that the DSMB may 
recommend discontinuation due to evidence of safety without achieving a 0.05 threshold for 
significance. In publication, we propose to not report statistical significance for these analyses. 
 
6.4. Statistical software 
Analyses will be conducted using R version 4 or later.  
7.  References 
1. Non-Inferiority Clinical Trials to Establish Effectiveness Guidance for Industry. (2016). 
U.S.Department of Health and Human Services Food and Drug Administration. Retrieved 
from https://www.fda.gov/regulatory-information/search-fda-guidance-documents/non-
inferiority-clinical-trials.