Evaluation of the Accuracy and Usability of the ACR | U.S. Urine Analysis Test System in the Lay User Hands
Phase: NA
Conditions: Albuminuria
Sponsor: Healthy.io Ltd.

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Evaluation of the Accuracy and Usability of the ACR | U.S. Urine Analysis Test System in 
the Lay User Hands 
 
Protocol ACR-US-MCU-01 
 
Issue day:  August 02, 2020 
Document No.:  ACR-US-MCU-01 
Version No.: 1.0 
 
APPROVALS: 
Name 
Position 
Date 
Signature 
Inbar Aviezer 
Clinical Trial Manager 
August 25, 2020 
 
Matan Ronen  
VP Product 
August 25, 2020 
 
 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are 
privileged or confidential and may not be disclosed unless such disclosure is required by law. In 
any event, persons to whom the information is disclosed must be informed that the information 
is privileged or confidential and may not be further disclosed by them. These restrictions on 
disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential. 
 
 

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ABBREVIATIONS & DEFINITIONS 
ACR Albumin to Creatinine Ratio 
AE Adverse Event 
eSource Electronic source documents  
GCP Good Clinical Practice 
IC Informed Consent  
ICH International Conference on Harmonization 
IEC Independent Ethics Committee 
IEC/IRB Independent Ethics Committee/Institutional Review Board   
IVD In-Vitro Diagnostic 
 
CKD Chronic Kidney Disease  
Optima - URiSCAN Optima Urine Analyzer  
 
 
 
 
 
 
 
 
 
 
 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          3 
 
STUDY SYNOPSIS 
Name of Device: 
ACR | U.S. Urine Analysis Test System (henceforth ACR | U.S.) 
Device Description: 
The ACR | U.S. Urine Analysis Test System is an in-vitro diagnostic, 
home-use device for the semi-quantitative measurement of the Albumin-
Creatinine Ratio (ACR). The device consists of a smartphone 
application, proprietary Color-Board and an ACR reagent strip. The 
device is available for prescription-use only. Results are intended to be 
used in conjunction with clinical evaluation as an aid in the assessment 
of kidney function. 
Patient Population:   
At least 250 male and female subjects, 18-80 years of age, patients with 
suspected or known urine detectable acute and chronic disease such as 
Diabetes Type 1/ Type 2, Hypertension, any kidney disease, subjects 
who are undergoing routine physical examinations, or healthy patients.  
Structure: 
A comparative, controlled, multi-centered, accuracy and usability study. 
Objectives: 
The objective of the study is to evaluate the performance of the ACR | 
U.S. in the hands of the potential lay user. 
 
Primary Endpoint:   
The degree of agreement of the ACR | U.S. (tested by a lay user) as 
compared to the URiSCAN Optima Urine Analyzer (tested by a 
healthcare professional), for the different concentrations (blocks) 
reported by the ACR | U.S. device. 
Secondary Endpoint: 
Evaluation of the ACR | U.S. usability, by potential lay user under actual 
use conditions of a simulated home environment. 

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Study Design: 
Eligible subjects meeting the pathological profile will be recruited at the 
designated site by the study personnel. Following subject consent, the 
subjects will be evaluated for eligibility based on their health condition 
and history.   
The ACR | U.S. kit, in its original packaging, along with the ACR | U.S. 
smartphone application will be provided to the subject in a simulated 
home- use environment. All subjects will be provided with a list of tasks 
to complete, including providing a urine sample and operating the ACR | 
U.S. device on both an iPhone 11 device and a Google Pixel 3a mobile 
phone. After completing the test, the lay user will complete a post-test 
questionnaire. The study observer will also complete a questionnaire to 
collect information regarding the lay users’ use of the ACR | U.S. 
The device use will be compared with identified risks to determine if the 
percentage of failures is acceptable. Additionally, measurable usability 
criteria for specific, critical steps will be evaluated. 
Following the usability test performed by the lay user, the subjects’ urine 
samples will be tested by the study staff using the URiSCAN Optima 
Urine Analyzer. These results will be considered as the “true value”. 
Data analysis: 
Results from the ACR | U.S. Urine Analysis Test System and the 
comparator device, the URiSCAN Optima Urine Analyzer, will be 
presented in tables listing the results in each group and the % exact 
match (agreement) and the % ±1 block match. 
Study Sponsor:   
Healthy.io Ltd. 
Principal  Investigators: 
Dr. Richard E Mills, Dr. Mitchell D. Efros,   
 

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1. 
INTRODUCTION 
1.1. 
Urinalysis and Albumin-to-Creatinine Ratio Overview 
Urinalysis is an array of tests performed on urine, and one of the most common methods of medical 
diagnosis. The target parameters that can be measured or quantified in a urinalysis test include many 
substances and cells, as well as other properties, such as specific gravity and pH. Urinalysis can be 
performed by using urine test strips, in which the test results can be measured on the basis of color 
changes. Other methods of urinalysis include light microscopy (1). 
An Albumin-Creatinine Ratio (ACR) urine test strip is a basic diagnostic tool used to determine 
pathological changes in a patient’s urine in standard urinalysis. A standard ACR urine test strip usually 
contains two different chemical pads or reagents which react (change color) when immersed in, and then 
removed from, a urine sample. The test can often be read after 60 seconds after immersion. Routine 
testing of the urine with ACR urine test strips is the first step in the diagnosis of a wide range of kidney 
diseases. The analysis includes testing for the Albumin and Creatinine, and then calculating the ratio 
between them. 
Albumin is the single-most important protein that is pathologically present in the urine in most chronic 
kidney diseases.  A properly-functioning kidney will permit extremely small amounts of Albumin to 
pass into urine, and thus even a minute presence – defined as a quantity greater than 30 mg/L – is a sign 
of a diseased or distressed kidney.  Creatinine is a byproduct of muscle metabolism released into the 
urine at a constant rate; its level in urine is an indication of urine concentration.  The Albumin-to-
Creatinine Ratio measurement is a widespread and effective screen for the early stages of CKD1, in most 
instances appearing before the reduction in the estimated glomerular filtration rate (or eGFR, which 
requires a blood test). 
ACR urine test strips can be used in many areas of the healthcare chain including screening for routine 
examinations, treatment monitoring, self-monitoring by patients and/or general preventive medicine. 
The ACR urine test is an effective measurement to identify patients with early stages of Chronic Kidney 
Disease (CKD), when patients are often asymptomatic, which can reduce the risks of cardiovascular 
disease, End-Stage Renal Failure (ESRF), and death that are the hallmarks of a malfunctioning kidney. 
According to the Henry Ford Health System, only 5% of the general Medicare population undergoes a 
 
1  
"Albumin-to-creatinine ratio (ACR) is the first method of preference to detect elevated protein."  
            See the National Kidney Foundation's website detailing the importance of the ACR test:  
https://www.kidney.org/kidneydisease/siemens_hcp_acr  

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screening urinalysis, while only 2% of high-risk subjects screened through a National Kidney 
Foundation initiative self-reported a history of kidney disease.2 
Healthy.io has developed the ACR | U.S. Urine Analysis Test System (ACR | U.S.). The ACR | U.S. is a 
semi-quantitative, prescription-based, in vitro diagnostic (IVD) home use device for the measurement of 
the ratio between albumin to creatinine in a urine sample using a single-wrapped ACR urine reagent 
strip (microalbumin/creatinine).   
Automatic analysis of urine test strips using automated urine test strip analyzers is a well-established 
practice in modern day urinalysis. It guarantees rapid, standardized measurement and immediate reliable 
documentation of the result. Most of these urine analyzers are based on the technology of reflectance 
photometry while additional technologies such as microscopy or flow cytometry exist (performed 
directly on the urine specimen). 
The basic elements of the reflectance photometry are based on the analysis of the intensity and color of 
light reflected from the reagent areas on a urinalysis test strip. Most of the automated urine analyzers are 
specifically intended for lab environments and are operated by professional users. In recent years, 
following the tremendous development in communication media (especially with mobile media) there is 
a shift from "in-clinic" testing to the home-use self-testing. This trend enables manufacturers to develop 
cost effective, reliable, easy-to-use, self-monitoring test methods, including urinalysis methods.  
Healthy.io Ltd. employs computer vision technology to turn smartphones into clinical-grade diagnostic 
devices. Previously, the company developed a smartphone application containing image recognition 
software that enables users to remotely and independently perform a urinalysis test, the DIP | U.S. 
(510(k) clearance number: K173327)3. The DIP | U.S. device is a prescription, home-use device 
intended for the analysis of six urine analytes. The company also developed a point of care, prescription-
only, professional-use smartphone application to test for microalbuminuria, the ACR | LAB device 
(510(k) clearance number: K182384)4. Building off this experience, Healthy.io developed the ACR | 
U.S. to test for the Albumin-Creatinine Ratio. Further details on the device components and 
functionality are described in the device description section below. 
 
2   
Chronic Kidney Disease. Henry Ford Health System. 2011. 
3   
See the 510(k) Substantial Equivalence Determination Decision Summary: 
https://www.accessdata.fda.gov/cdrh_docs/reviews/K173327.pdf  
4        https://www.accessdata.fda.gov/cdrh_docs/reviews/K182384.pdf 

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DEVICE DESCRIPTION 
1.2. 
General 
The ACR | U.S. is a prescription, in-vitro diagnostic, home-use device for the semi-quantitative 
measurement of the Albumin-Creatinine Ratio. The device comprises a kit with a urine receptacle, an 
ACR urine test strip, an absorbing pad, a Color-Board and a user manual. The device also consists of an 
easy-to-use smartphone application and image recognition algorithm. 
The ACR | U.S., while also a photometric based device, employs a computer vision technique, executed 
on various hardware platforms, in an uncontrolled lighting environment, used by an untrained user. The 
test has no pre-calibration step. The calibration and test are executed simultaneously during each test 
individually. This is executed via a Color-Board, which is part of the user kit. Performing test 
calibration eliminates lighting variances & camera disruptions and delivers a semi-quantitative 
measurement. 
The kit consists of five elements, which have been designed for easy usage in a home setting; 
1. 
Urine receptacle  
2. 
ACR urine test strip 
3. 
Absorbing pad 
4. 
Color-Board 
5. 
User manual 
 
1.3. 
System components  
• 
Urine receptacle 
The urine receptacle is comprised of a plastic cup which holds the subject's urine. It is designed to hold a 
sufficient amount of urine and allow for easy immersion of the test strip. 
 
 
 
 

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Image 1:  Closed Plastic Cup 
 
 
• 
ACR urine test strip 
A single-wrapped ACR urine reagent strip (microalbumin/creatinine). The strip consists of 3 chemical 
reagents, which change color after being immersed in a urine sample. One patch for albumin, another for 
creatinine and an additional compensation patch. 
Figure 2: Urine Test Strip 
 
 
 
 
 
 
 

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• 
                  Absorbing pad 
A single piece of standard absorbing material. It is designated to assist in absorbing remaining liquids 
from the strip after it has been immersed in the urine sample. 
 
• 
Color-Board 
A cardboard-based, high-quality printed Color-Board facilitates the image recognition process. Its main 
functions are: 
o 
Proper positioning of the urine strip in the frame.  
o 
Neutralization of the surrounding lighting and/or camera interruptions. 
o 
Providing a reference color spectrum for the strip reagent colors based on a data algorithm. 
 
Figure 3: Color-Board 
 
 
 
 
 
 
 
 
 
 
 
 
 

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• 
Smartphone app 
The smartphone application (supported by the iPhone 11 device running iOS 13 and Google Pixel 3a 
running OS 10) is designed to enable the following: 
o 
Device interface instructions for the user to ensure proper performance of the urinalysis test, 
avoiding key human errors. These include interactive video texts and sound instruction to guide the 
users through the testing procedure.  
o 
The software includes an augmented reality layer on the smartphone camera which guides users 
while taking the scan. This is a real-time analysis of the scan, which finds and centers the Color-Board 
within the camera frame. The software will also analyze the scan and evaluate if it meets the system 
boundary conditions for urinalysis measurement. If not, the software will instruct the user to take 
another scan which can be analyzed. 
o 
Presentation of urinalysis measurement result to a clinician for viewing and interpretation.  
• 
Software 
The ACR | U.S. smartphone algorithm is a cloud-based, image-processing system. Both albumin and 
creatinine analytes are analyzed based on a separate, unique set of eight target colors and a set of 
calculations which are completely independent from each other.  Once these two measurements are 
taken, the algorithm on the cloud will use these two numbers to calculate the subsequent Albumin-
Creatinine Ratio, which is measured in units of mg/g or mg/mmol.  
1.4. 
Intended Use 
The ACR | U.S. Urine Analysis Test System is an in-vitro diagnostic, home-use device for the semi-
quantitative measurement of the Albumin-Creatinine Ratio (ACR). The device consists of a smartphone 
application, proprietary Color-Board and an ACR reagent strip. The device is available for prescription-
use only. Results are intended to be used in conjunction with clinical evaluation as an aid in the 
assessment of kidney function. 
      
 
 
 

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Figure 4: Smartphone Application Screens 
  
 

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2. 
PERFORMANCE TESTING AND CLINICAL EVALUATION  
2.1. 
ACR | U.S. Performance Tests 
Healthy.io has designed a series of bench-testing experiments to verify the performances of the ACR | 
U.S. These tests have been designed according to the guidance provided by the Clinical and Laboratory 
Standards Institute (CLSI). 
● 
Precision: Comprises two separate tests - Repeatability and Reproducibility.  The precision 
studies are designed in accordance with guidance provided by Clinical and Laboratory Standards 
Institute document EP05-A3 – Evaluation of Precision of Quantitative Measurement Procedures; 
Approved Guideline – Third Edition.  
o 
Repeatability is defined as the closeness of the agreement between results of successive 
measurements of the same measure and carried out under the same conditions of measurement. 
o 
Reproducibility is defined as closeness of the agreement between the results of 
measurements of the same measure carried out under changed conditions of measurement over the 
course of multiple days.  
● 
  Interference: Testing of potential interfering substances with the ACR | U.S. was designed in 
accordance with guidance provided by the Clinical and Laboratory Standards Institute document EP07 – 
Interference Testing in Clinical Chemistry; Approved Guideline – Third Edition. 
● 
Limit of Detection: Testing of the ACR | U.S. assay’s detection was designed in accordance 
with guidance provided by Clinical and Laboratory Standards Institute (CLSI) document EP17-A2 – 
Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved 
Guideline – Second Edition. 
● 
Linearity: Testing the linearity of the ACR | U.S. was designed in accordance with guidance 
provided by the Clinical and Laboratory Standards Institute (CLSI) document EP06-A – Evaluation of 
Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline  
● 
Stability: The stability experiment is designed to evaluate the environmental conditions under 
which the ACR | U.S. is suitable for its intended use. This study was designed with the guidance 
provided by the Clinical and Laboratory Standards Institute (CLSI) document EP-25A Evaluation of In-
Vitro Diagnostics Reagents; Approved Guideline. 
● 
Additional Studies-  

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o 
Illumination Study: Healthy.io designed an experiment to test the ACR | U.S. under 
multiple lighting conditions.   
o 
Boundary Study: Healthy.io designed an experiment to test the physical boundaries 
(such as the phone's distance and angle in relation to the Color-Board) which would prevent the ACR | 
U.S. from capturing an accurate image that can be evaluated by the algorithm. 
o 
Multiple Phones and Operating Systems Study: Healthy.io designed an experiment to 
test the ACR | U.S. with multiple smartphone devices and operating systems versions (iOS and 
Android). 
o 
Timing Flex Study: Healthy.io designed an experiment to test the impact of different 
dipping times, assay-times, and strip wetting times on the ACR | U.S.   
2.2. 
Albumin-Creatinine Ratio Urinalysis Method Comparison Studies: 
The following table (Table 1.0) summarizes the method comparison studies conducted on several 
marketed lab urine analyzers and test strips with similar indications for use as the ACR | U.S. 
The key difference being that these studies were operated by lab professionals while the ACR | U.S. is 
intended for lay users who are operating the device at home. 
 
Table 1.0: Urinalysis analyzers method comparison studies summary: 
Study details 
Mission U120 Ultra Urine 
(K142391)5 
Uritek TC-201 Urine Analyzer 
(K152835)6 
URiSCAN Optima Urine 
Analyzer (K141874) 7 
No. of urine 
samples  
429 samples 
402 
351 
Urine sources 
Fresh  
Fresh 
Fresh 
 
5 See the 510(k) Substantial Equivalence Determination Decision Summary: 
https://www.accessdata.fda.gov/cdrh_docs/reviews/K142391.pdf  
6 See the 510(k) Substantial Equivalence Determination Decision Summary: 
https://www.accessdata.fda.gov/cdrh_docs/reviews/K152835.pdf  
7 See the 510(k) Substantial Equivalence Determination Decision Summary:   
https://www.accessdata.fda.gov/cdrh_docs/reviews/K141874.pdf 

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Study details 
Mission U120 Ultra Urine 
(K142391)5 
Uritek TC-201 Urine Analyzer 
(K152835)6 
URiSCAN Optima Urine 
Analyzer (K141874) 7 
Percentage of 
Contrived Samples 
Used 
12-13% 
9% 
0% 
Subjects medical 
history  
From 510k summary: 
"Test results may be used in 
screening urine specimens for 
microalbuminuria as an aid in 
the detection of patients at risk 
for developing kidney 
damage." 
From User Manual: 
"Patients with the highest risk 
of developing early kidney 
damage are those with diabetes 
and hypertension, followed by 
patients who have immune 
disorders or have been exposed 
to nephrotoxins." 
From the 510K summary: 
"Test results may be used in 
screening urine specimens for 
microalbuminuria as an aid in the 
detection of patients at risk for 
developing kidney damage.” 
From the 510K summary: 
“These measurements are useful 
in the evaluation of renal, urinary 
and metabolic disorders.” 
  
Compared 
predicate 
Clinitek Status Analyzer 
(K031947) 
Clinitek Status+ Analyzer (K091216) 
Clinitek Status (Siemens) 
(K091216) 
No. of strip lots 
3 
3 
3 

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3. 
RATIONALE FOR THE STUDY 
In addition to the analytical performance tests described above, method comparison and usability tests 
are crucial steps before companies are permitted to bring such a device to market. All marketed 
urinalysis devices and urine test strips for home use have performed method comparison and usability 
studies tested by the intended lay user. Normally in these studies, urine samples are collected and tested 
by a lay user, using the new home use device, and by a device operator or lab professional using the 
comparison device. The lay user test results are compared to the results obtained by testing the same 
urine sample on the comparison device. The method comparison and usability studies provide data on 
the accuracy and usability of the device, including the lay user's ability to understand and implement the 
user manual instructions and evaluate the ease of use of the device under actual use conditions (home 
environment). Moreover, the study provides valuable data originating from unhealthy subjects using 
mostly their real urine samples and can strengthen the results of the bench analytical tests. The urine 
samples should be sourced from pathological subjects simulating the "realistic clinical environment" or 
from healthy subjects, spiked samples to cover the entire color range of the analyte detection reagents. 
        
 
The ACR | U.S. method comparison study should include similar elements and be designed similarly to 
previously tested urinalysis analyzers. The study design is meant to demonstrate that the ACR | U.S. 
may be easily used by a lay person and the results are in agreement with another legally marketed urine 
analyzer device. 
 
4. 
OBJECTIVES  
The aim of the study is to evaluate the accuracy and usability performance of ACR | U.S. in the hands of 
the potential lay user. 
4.1. 
Primary Objective  
The primary objective of the study is to evaluate the % exact match (agreement) and the % ±1 block 
match (agreement) of ACR | U.S. (tested by the lay user) compared to the URiSCAN Optima Urine 
Analyzer (the comparator device, tested by a healthcare professional), for each tested concentration 
(block). 

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4.2. 
Secondary Objective  
The secondary objective of the study is to evaluate the ACR | U.S. usability, by potential lay users under 
actual use conditions (home environment).  
5. 
STUDY POPULATION 
5.1. 
General Considerations 
The study will recruit at least 250 subjects from multiple sites, including patients with a disease that 
normally represents itself with an abnormal concentration of albumin. Examples of such diseases 
include Diabetes Type I/Type II, Hypertension, any kidney disease etc., or healthy patients. All genders, 
all ethnicities, and subjects between 18-80 years of age will be recruited for the study. Subjects will be 
recruited from the study sites, and if appropriate, from the study center's database. Informed consent will 
be obtained from potential subjects according to local and national IRB requirements. Potential 
candidates will be screened according to the following inclusion/exclusion criteria. 
5.2. 
Inclusion Criteria 
● 
Males and Females 18-80 years of age. 
● 
Subjects diagnosed with a disease that normally represents itself with an abnormal concentration 
of albumin: 
o Diabetes Type I/Type II, 
o Hypertension, 
o any kidney disease, 
o other relevant conditions, 
● 
or, subjects who are healthy or pregnant. 
● 
Subject is familiar with the use of a smartphone. 
● 
Subject is capable of comprehending and following instructions in English. 
● 
Subject has facility with both hands. 
● 
Subject is capable and willing to adhere to the study procedures. 
● 
Subject is capable and willing to provide informed consent. 

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5.3. 
Exclusion criteria 
● 
Subject has dementia. 
● 
Subject has severe mental disorders. 
● 
Subject cannot collect urine in a receptacle. 
● 
Subject is visually impaired (cannot read the user manual). 
● 
Any additional reason the study physician believes disqualifies the subject from participating in the 
study. 
6. 
STUDY DESIGN  
The Method Comparison Test is a clinical study using actual human urine samples that will be 
collected in a lab-based hospital settingstrio.  These include urine samples from diseased 
subjects (e.g. patients with Type 1 and Type 2 Diabetes and Hypertension), as well as from 
patients who are undergoing routine physical examinations.  
6.1. 
Framework: 
● 
At least 250 patients will be recruited to participate 
● 
Up to 15% of the samples may be spiked urine samples in case of insufficient native samples in 
certain blocks 
● 
Multiple sites  
● 
2 mobile phones: iPhone 11 and Google Pixel 3a (per subject) 
● 
3 strip lots which will be used interchangeably throughout the experiment 
 
6.2. 
Population: The study is a comparative, controlled trial of subjects who will be recruited from a 
research clinic. The study population will consist of patients with a medical history of diabetes Type I, 
Type II, Hypertension, kidney disease and other ailments that represent the target population for urine 
testing or healthy patients. The intention is to recruit subjects with ailments that will cover all test 
analytes and all concentrations of these analytes. In the case that analytes and concentrations will not be 
covered by enrolled subjects, the study will be supplemented with spiked urine samples with the missing 
analytes and concentrations. However, the number of spiked samples will not exceed 15% of the total 
samples (all bins combined). Lay users will test their own urine with both smartphones and additionally 

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may be asked to test another spiked sample, that will be provided by the study staff as necessary and in 
accordance to protocol. 
6.3. 
Testing Methods: Subjects will be recruited for the clinical trials based on their ability to 
provide a urine sample and comfortably complete tasks using a smartphone. Each urine sample should 
be tested by a lay user on the ACR | U.S. app, and then transferred to a professional user to conduct the 
test on the Optima device. The professional user will be blinded to the results of the lay user until after 
they have completed the test using the Optima device. 
6.4. 
     Timing: Collection of a urine sample is performed by the patient as part of the study flow. 
Within 15 minutes from the time of patient’s test, testing on the comparator analyzer should be done.  
This is to best simulate the real-case usage of the ACR | U.S. test. The specimen should not be 
centrifuged or refrigerated in between tests.  
6.5. 
Analyzers: Each urine sample will be tested using the iPhone 11 and Google Pixel 3a devices 
running the ACR | U.S. application. Each test will be compared to the URiSCAN Optima Analyzer, the 
comparator device.  
6.6. 
Reagent Strips: To control for bias among the test strips, three lots of reagent strips will be used 
during the study. To enable an equal and unbiased distribution of the lots, one lot will be randomly 
selected by the professional user for the testing of each sample. Separate strips will be used in each test: 
with the ACR | U.S. and the Optima analyzer. 
6.7. 
Requirements: The Method Comparison Study must be conducted in accordance with Good 
Clinical Practice (GCP), according to 21 CFR Part 50, 54, 56, 812, ISO14155-1/2 and relevant local and 
national regulations (IRB or Helsinki EC approved). The Method Comparison Study shall comply with 
CLSI EP09c: Method Comparison and Bias Estimation Using Patient Samples; Approved Guidelines – 
Third Edition. Since the ACR | U.S. is classified as a urinalysis analyzer intended for lay users to test 
their urine in a home environment, the design of the device clinical comparative study should include 
parameters from both lab urinalysis analyzers and urine strip method comparison studies. The study 
design is mainly based on the above-mentioned method comparison studies in section 3.2 when used by 
a lay user and FDA recognized consensus standards CLSI EP09c and for usability testing of medical 
devices - ANSI/AAMI/IEC 62366-1:2015 Medical devices – Part 1: Application of usability engineering 
to medical devices. 
 

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7. 
STUDY PROCEDURES 
7.1. 
Study Procedures 
The study consists of 5 stages, including the familiarization period and the screening, pre-study and 
testing, performed on the same day:  
● 
Familiarization Period. 
● 
Screening.  
● 
Pre-study. 
● 
Quality Control. 
● 
Testing. 
● 
Post-Testing. 
 
•              Stage I – Familiarization Period 
Evaluating an analytical method requires sufficient time for the operators to become familiar with the 
device operation and the study protocol, and the standard therefore recommends a study familiarization 
period. During the familiarization period, the operators of the test and comparative method will become 
familiar with all aspects of set-up, operation, maintenance, quality control, and troubleshooting of both 
methods. This period will precede the study evaluation process and will coincide with the manufacturer's 
training performed during the Site Initiation Visit (SIV). During the SIV and familiarization period, 
routine laboratory quality control procedures will be run and up to 15 subjects will participate in a study 
simulation to ensure familiarity with the study protocol and all study procedures. After the SIV and 
familiarization period, the usability study will begin.  The test results from the subjects participating in 
the simulation study during the SIV and familiarization period will not be included in the final study 
results or the study statistical analyses. 
● 
Stage II – Screening 
Potential candidates will receive complete information describing the study and their role and 
will be encouraged to ask any questions regarding the study. The risks and requirements of this 
clinical research trial will be explained to each potential subject. Those volunteering to take part 
will read and sign the Informed Consent Form for participation in the clinical trial before any 

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study-related procedures are performed. The Informed consent signing will be in front of a 
study personnel, the principal investigator will review and will sign all source documents, 
informed consents, and results once a day. 
Upon obtaining the signed informed consent, inclusion and exclusion criteria will be reviewed to verify 
the subjects' eligibility.  
● 
Stage III – Pre-study 
Subjects who were found eligible to participate in the study and signed informed consent will be enrolled 
into the study and assigned a subject ID number, which will be used along with their initials for study 
record identification. 
Designated eSource forms will be completed with the subject's general details, including demographics, 
medical history, diagnosis and concomitant medications. 
● 
Stage IV – Quality Control 
Before each testing day, Quality Control will be performed using the YD Diagnostics - supplied Level 1 
and Level 2 Control solutions on all phones used in the study, using two strips from one lot that will be 
randomly selected.  
1. The professional user will use Level 1 Control solution to perform the QC test. 
2. The professional user will open the ACR | U.S. application on either the iPhone 11 or Google 
Pixel 3a device. 
3. Following the in-app instructions, the professional user will remove one strip and pipette the 
Level 1 control solution on the strip. The ACR | U.S. application will guide the user to scan the 
strip, uploading the data to the backend server for analysis.       
4. The professional user will then remove another strip, pipette Level 1 Control solution on the 
strip and scan it using the Optima device. 
5. The professional user will repeat steps 2-4, substituting the Level 1 Control solution with Level 
2 Control solution, and between the smartphone devices. 
6. The Quality Control will be considered as passing if the ACR | U.S. and the Optima reports the 
acceptable range as determined by the manufacturer. 
7. If the Quality Control test for either phone fails, the error will be identified, and the Quality 
Control procedure will be conducted again. 
 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          21 
 
● 
Stage V – Testing  
1) 
   The subject will perform the usability study tasks in a simulated home environment, e.g. in a 
dedicated and isolated room in the clinic simulating a home, where internet connection is available, and 
a restroom is nearby. The clinic will be set up so that the self-testing will allow the subject to perform 
the urinalysis test without outside influence and to simulate the home-use testing of the device.  
2) 
   The subject will be placed in the private room, with restroom accessibility and internet 
connectivity, to perform the urinalysis test and complete the task list found below. No training, 
assistance, feedback, or supplemental instructional materials, other than those described, will be 
provided to participants. The healthcare professional or other site staff will not be allowed to intervene 
or answer questions from the subjects during testing, although a 1-800 or clinical assistance phone 
number, which will be provided to the subject in actual use, will be made available to the subject in case 
contact is attempted by the subject.   
3) 
   The room will be prepared with a desk and chair. The ACR | U.S., in its original packaging will 
be placed on the desk. The device packaging contains the kit components and the user manual. An in-
app instructional guide containing the information most critical to safety and effectiveness is also 
provided in the form of a readable and understandable, visual, and textual guide on the device App. The 
patient labeling will be in the format intended for distribution to allow for a realistic evaluation of the 
labeling effectiveness. 
4) 
        The subjects will be asked to follow the device user manual and/or the in-app instructional 
guide and perform the following tasks: 
● 
Access the ACR | U.S. App on the smartphone. (iPhone 11 or the Google Pixel 3a) 
● 
Provide a urine sample in the urine receptacle (to the level marked on the cup) that is included in 
the ACR | U.S. kit. 
● 
Immerse the urine strip (provided in the ACR | U.S. kit) in the collected urine specimen for one 
second. 
● 
Place the urine strip on the designated area on the Color-Board and wait at least 75 seconds, but 
not more than 180 seconds. 
● 
Scan the urine strip and Color-Board with the smartphone App. 
● 
Send the test results to the study clinician using the smartphone App.  
● 
Subjects will be asked to complete a questionnaire following completion of the tasks. 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          22 
 
5) 
   Subjects will be observed as they complete the tasks by a research staff member. The research 
staff observer will complete a dedicated post-test questionnaire. 
6) 
    Upon completion of the usability study tasks, the subject will provide the urine sample in the 
device kit urine receptacle to the research staff for further testing. The research staff will perform the 
urine analysis test using the comparator device, the URiSCAN Optima device. The research staff 
performing the urine analysis test with the Optima will be blinded to the results of the ACR | U.S. test, 
until the test with the comparator device is completed.  
7) 
 Only after the urine has been tested with the Optima, can the subject begin the test with a second 
kit on the second smartphone device, provided by the operator in the clinic.  A new ID number will be 
given to the second kit, therefore the lab operator will consider this as new urine and will be kept 
blinded to the urine results. 
8) 
   The results of the ACR | U.S. and the comparator device (the Optima) will be used for study 
purposes only and not for diagnostic or therapeutic purposes of patient management. In the case that 
urinalysis results are required for patient management, urine specimens from the subject will be sent 
independently to the hospital/clinic laboratory for analysis and only the results of the hospital/clinic 
urine analysis will be used for patient care and management. The patient will provide only one urine 
sample for use in both the study and any subsequent clinical urinalysis testing.   
 
● 
Stage VI – Post-test procedures 
Statistical analyses comparing the results from the ACR | U.S. and the Optima will be performed using 
an appropriate statistical program and methodology. 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eSource and all 
source documents that support the data collected from each patient, as well as all study documents as 
specified in ICH/GCP Section 8, Essential, Documents for the Conduct of a Clinical Trial, and all study 
documents as specified by the applicable regulatory requirement(s). The investigator/institution will take 
measures to prevent accidental or premature destruction of these documents. 
 
 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          23 
 
Figure 1 – Method Comparison Study Flow 
 
 
 
8. 
SUBJECT COMPLETION / WITHDRAWAL  
8.1. 
Accuracy Evaluation 
The ACR | U.S. test results will be compared to the Optima test results. The data will be graphically 
presented to compare the percent exact match (agreement) and the percent ±1 block match (agreement) 
between the ACR | U.S. (tested by the lay user) and the comparator device (tested by a healthcare 
professional), for the different tested concentrations (blocks). 
 
8.2. 
Usability Evaluation 
The usability of the ACR | U.S. will be determined by evaluating the percentage of study subjects able to 
complete the device related tasks, including operating the ACR | U.S. with minimal attempts to ask for 
assistance. Measurable usability criteria for specific, critical steps, such as time-to-completion, number 
of requests for assistance, numerical ratings, etc., will be evaluated by observer evaluation and user 
questionnaire responses. 
The device usability information will be compared to identified device risks. Device and user related 
hazards were identified and documented in the ACR | U.S. Risk Analysis file. These specific device and 
user related risks will be evaluated in the usability study, according to the following steps: 
(1) 
Identify device and user related hazards (Risk Analysis) 
(2) 
Identify critical steps to be completed (Task List) 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          24 
 
(3) 
Compare device’s use with identified risks (Observer Evaluation and User Questionnaire) 
(4) 
Apply Criteria - percentage of permissible failures (refer to section 11.6.4) 
(5) 
Link assessment to the overall risk analysis (study conclusions) 
The following measurable usability criteria for specific, critical steps, based on observer evaluation or 
user questionnaire responses, will be assessed through analysis of the data: 
(1) 
Time-to-completion of task; 
(2) 
Number of requests for assistance; 
(3) 
Numerical ratings describing the participants’ level of success in completing tasks will be 
collected through user posttest questionnaire responses; 
Qualitative information regarding specific user errors and inefficiencies will be collected through 
observer evaluation and user posttest questionnaire responses. 
 
In addition, key system errors will be evaluated in some subjects. Examples of key errors may include 
the following: 
1. 
Interruption during the test by an incoming phone call. 
2. 
Interruption during the test by an incoming message. 
3. 
No Internet connection 
The subject will be required to continue device operation according to the user manual.  
 
 
 
 
 
 
 
 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          25 
 
9. 
SUBJECT COMPLETION / WITHDRAWAL  
9.1. 
Completion 
A subject will be considered to have completed the study if the urine sample has been tested.  
A subject will be considered to have passed the usability test if he/she was able to scan the Color-Board 
successfully. In addition, in case a subject failed in his/her first try but identified the problem alone and 
requested a second kit, and then completed the test, the subject will be considered to have passed the 
usability test.  
 
9.2. 
Withdrawal from the study  
A subject will be withdrawn from the study for any of the following reasons: 
1. 
Patient has identified that he/she cannot provide a sufficient urine sample. 
2. 
Withdrawal of consent.  
3. 
Patient is not compliant with requirements of the study, including inclusion and exclusion 
criteria. 
4. 
The study is prematurely stopped or halted (e.g. clinical halt). 
5. 
The investigator believes that for safety reasons (e.g. an adverse event) it is in the best interest of 
the patient to stop the test.  
 
When a patient withdraws before completing the study, the reason for withdrawal will be documented in 
the CRF.  

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          26 
 
10. 
STATISTICAL CONSIDERATIONS 
10.1. Study Design and Objectives 
o 
The study is designed as a comparative, controlled, multi-centered trial to evaluate the accuracy 
and usability performance of ACR | U.S. in the hands of a potential lay user.  
 
10.2. Study Endpoints 
● 
Primary Efficacy Endpoint 
The primary endpoint of the study is to calculate the exact % match (agreement) and the % ±1 block 
match (agreement) of the ACR | U.S. (tested by the lay user) compared to the URiSCAN Optima device 
(tested by a healthcare professional), ), for the tested concentrations (blocks). 
● 
Secondary Efficacy Endpoint  
The secondary endpoint of the study is to evaluate the ACR | U.S. usability, by potential lay users under 
actual use conditions (home environment). 
 
10.3. Sample Size Estimation 
Sample size estimation was determined according to previous method comparison studies performed 
using other urine analyzers with similar Indications for Use (see table 1.0, Performance testing clinical 
evaluation) and based on the EP9-A2 standard. 
Furthermore, based on our experience in a previous, similar study, at least 250 subjects should represent 
a sufficient sample size to cover all concentrations and determine the agreement between the ACR | U.S. 
and the URiSCAN Optima. 
 
10.4. Subject Tracking 
During the subject recruitment, tracking will be performed to evaluate if the data collected covers the 
entire range of concentrations measured by the device. If the data is insufficient, spiked urine samples 
will be used to supplement the missing data. The number of spiked samples will not exceed 15% of the 
total number of samples (all blocks combined).       
 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          27 
 
10.5. Data Analysis Sets 
● 
Efficacy Analysis Set 
The Efficacy analysis set will consist of all subjects without major protocol deviations. Protocol 
deviations will be defined and classified as minor or major.    
● 
Statistical Analysis of Analysis Sets 
The Efficacy analysis set will serve as the main analysis set for the method comparison and usability 
assessments. 
 
10.6. Statistical Analysis 
● 
General Considerations 
Statistical analyses will be performed using an appropriate statistical program and methodology. 
Baseline demographic and safety analyses will be performed on all enrolled subjects.  
● 
Demographic and Other Baseline Variables 
Demographic and baseline condition related characteristics will be tabulated. Continuous variables will 
be summarized by a mean, standard deviation, minimum, median and maximum, and categorical 
variables by a count and percentage. 
● 
Disposition of Subjects 
The number and percent of subjects who fail to complete the study and the number and percent of 
subjects who fail to complete the study because of Adverse Events will be presented. 
● 
Efficacy Analysis 
The % exact match (agreement) of the ACR | U.S. compared to the comparator device, for the same 
Albumin-Creatinine Ratio concentration (block) will be calculated. The % ±1 block match (agreement) 
of the ACR | U.S. compared to the comparator device, for the same Albumin-Creatinine Ratio 
concentration (block) will also be calculated.  
● 
Usability Analysis 
The usability of the ACR | U.S. will be determined by evaluating the percentage of study subjects who 
are able to complete the device-related tasks, including accessing the ACR | U.S. App, providing a urine 
sample in the urine receptacle, dipping the kit urine strip in the urine specimen, positioning the strip on 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          28 
 
the Color-Board and taking a picture using the smartphone App, with minimal attempts to ask for 
assistance.  
Measurable usability criteria for specific, critical steps, such as time-to-completion, number of requests 
for assistance, numerical ratings, etc., will be evaluated by observer evaluation and user questionnaire 
responses. Descriptive statistics will be provided for usability criteria. 
● 
Adverse Event 
In general, there are no anticipated adverse events in this study; however, if any adverse events do occur 
they will be recorded and presented in tables. 
 
RISK / BENEFIT ANALYSIS 
10.7. Risks 
The risks to patients resulting from potential device hazards have been analyzed using the Risk 
Management Standard - ISO 14971. The different types of hazards were identified and evaluated using 
risk assessment numerical parameters. Applicable controls for the risks were analyzed. After the 
implementation of appropriate risk control measures, the level of risk was re-evaluated and found to be 
acceptable. The risks associated with the device are minimal if any. Below is a summary of the risks to 
the subject and the applicable control measures. 
Risk: Urine receptacle material may cause irritation if it comes in contact with the skin. 
Mitigation: The urine receptacle is manufactured from a combination of FDA food grade approved 
materials: Polypropylene and Thermo Plastic Elastomer (TPE) in over-molding / core injection process. 
The receptacle was also subjected to biocompatibility testing in a certified lab according to the ISO 
10993 standard.  
Risk: The urine receptacle is not comfortable for collecting urine or for immersing the urine strip. 
Mitigation: The urine receptacle has been designed taking into consideration human factors analysis. 
The design is such that the urine will flow into the cup and avoid splashing. The cup is designed so that 
the user can immerse the urine strip easily in one quick insertion.  
Risk: The Color-Board gets wet and damaged 
 
Mitigation: The Color-Board is manufactured from sturdy carton material and is designed for one-time 
use.  

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          29 
 
Risk: The user places the urine strip in the wrong position on the Color-Board pad.  
Mitigation: The device App will instruct the subject to reposition the urine strip.   
 
These risks following the mitigation are considered minimal, if not negligible. 
  
10.8. Benefits 
There are no immediate benefits to the subject from their participation in the study. The results of the 
study may provide valuable information and data towards their eventual benefit from the device as a 
new, home-use urine analyzer device.  
 
11. 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies is 
crucial for the protection of patients, investigators and the sponsor, and are mandated by regulatory 
agencies worldwide.  
11.1. Definitions 
Adverse Event Definitions and Classifications 
● 
Adverse Event 
An adverse event is any untoward medical occurrence in a clinical study patient. An adverse event does 
not necessarily have a causal relationship with the treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally 
associated with the use of an investigational product, whether or not it is related to the investigational 
product. (Definition per International Conference on Harmonization [ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test abnormalities. 
● 
Serious Adverse Event 
A serious adverse event as defined by ICH is any untoward medical occurrence that meets any of the 
following conditions: 
● 
Results in death  

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          30 
 
● 
Is life-threatening 
● 
Requires inpatient hospitalization  
● 
Results in persistent or significant disability/incapacity, or 
● 
Is a congenital anomaly/birth defect 
Note: Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in situations other than those listed above. For example, important medical events may 
not be immediately life threatening or result in death or hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the outcomes listed in the definition above. Any adverse 
event is considered a serious adverse event if it is associated with clinical signs or symptoms judged by 
the investigator to have a significant clinical impact. 
● 
Unlisted (Unexpected) Adverse Event 
An unlisted adverse event, the nature or severity of which is not consistent with the applicable product 
information (e.g. Investigator's Brochure for an unapproved investigational product or the package 
insert/summary of product characteristics for an approved product) (ICH) 
● 
Associated with the Use of the Device 
An adverse event is considered associated with the use of the device if the attribution is possible, 
probable, or very likely by the definitions listed below. 
Relationship to Investigational Device  
For all adverse events, the relationship to the study device and / or procedure will be determined by the 
investigator, using the following terms: 
● 
Probably related: 
Follows a reasonable temporal sequence from study device delivery / retrieval, and cannot be reasonably 
explained by known characteristics of the patient’s clinical data or the surgical procedure applied. 
● 
Possibly related:  
Follows a reasonable temporal sequence from study device delivery / retrieval but could have been 
produced by the patient’s clinical state or by the surgical procedures regardless of the study device. 
● 
Probably not related:    
Temporal association is such that the study device is not likely to have had any reasonable association 
with the observed event. 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          31 
 
● 
Not related:  
 
 
 
No relationship to study device activation is perceived. 
11.2. Procedures 
All Adverse Events 
All adverse events will be reported from the time a signed and dated informed consent form is obtained 
until completion of the last study-related procedure. Events meeting the definition of serious adverse 
events must be reported using the Serious Adverse Event Form, including serious adverse events 
spontaneously reported to the investigator within 30 days after the patient has completed the study 
(including post-study follow up).  
All events that meet the definition of a serious adverse event will be reported as serious adverse events, 
regardless of whether they are protocol-specific assessments. All adverse events, regardless of 
seriousness, severity, or presumed relationship to study treatment, must be recorded using medical 
terminology in the source document and the CRF. Whenever possible, diagnoses should be given when 
signs and symptoms are due to a common etiology (e.g., cough, runny nose, sneezing, sore throat, and 
head congestion should be reported as "Upper respiratory infection"). Investigators must record in the 
CRF their opinion concerning the relationship of the adverse event to study treatment. All measures 
required for adverse event management must be recorded in the source document and reported according 
to sponsor instructions.  
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The investigator (or sponsor where required) must report these events to the appropriate 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol, unless 
otherwise required and documented by the IEC/IRB. 
Serious Adverse Events 
All serious adverse events occurring during clinical studies must be reported to the appropriate sponsor 
contact person by investigational staff within 24 hours of their knowledge of event. 
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Form, which must be signed by a member of the investigational staff. The initial report of a 
serious adverse event may be made by facsimile (fax), e-mail or telephone. It is preferable that serious 
adverse events are reported via fax or e-mail. Subsequent to a telephone report of a serious adverse 
event, a Serious Adverse Event Form must be completed by the investigational staff and transmitted to 
the sponsor within one working day. 

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All serious adverse events that have not been resolved by the end of the study, or that have not been 
resolved upon discontinuation of the patient's participation in the study, must be followed until any of 
the following occurs: 
● 
The event resolves 
● 
The event stabilizes 
● 
The event returns to baseline, if a baseline value is available 
● 
The event can be attributed to agents other that the study treatment or to factors unrelated to the 
study conduct 
● 
When it becomes unlikely any additional information can be obtained (i.e. patient or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of due 
diligence with follow-up efforts) 
The cause of death in a clinical study, whether or not the event is expected or associated with the 
investigational agent, is considered a serious adverse event. Any event requiring hospitalization (or 
prolongation of hospitalization) that occurs during the course of a patient's participation in a clinical 
study must be reported as a serious adverse event, except hospitalization for: 
● 
Pre-planned hospitalizations, i.e. before enrollment into the study and which are not related to the 
disease itself 
● 
Social reasons in absence of an adverse event 
● 
Surgery or procedure planned before entry into the study (must be documented in the CRF)  
 
 
 
 
 
 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          33 
 
12. 
ETHICAL ASPECTS 
12.1. Study-Specific Design Considerations 
Only patients who have the capacity to provide informed consent are allowed to enroll in the study. As 
part of the screening of patients for entry into the study, the investigator will assess each patient's ability 
to provide informed consent for participation in the study. 
The protocol includes strict requirements to ensure adequate protection of all patients participating in the 
study, including: 
● 
Patients will be carefully screened using medical history before enrollment. Those who are 
judged to be at a high risk for adverse events will be excluded.  
● 
Patients may withdraw their consent at any time without having to give a reason. 
● 
Patients are fully informed as to the risks of study participation and will be provided with any 
new information about the study testing that might become available during their participation in the 
study. 
● 
Informed consent is obtained from patients without undue enticement. Patients will not be 
coerced in any way to participate in this study. Excessive financial compensation will not be offered to 
patients or to investigators. 
 
12.2. Regulatory Ethics Compliance 
● 
Investigators Responsibilities 
The investigator is responsible for ensuring that the clinical study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory 
requirements. 
GCP is an international ethical and scientific quality standard for designing, conducting, recording, and 
reporting studies that involve the participation of human subjects. Compliance with this standard 
provides public assurance that the rights, safety, and well-being of study subjects are protected, 
consistent with the principles that originated in the Declaration of Helsinki, and that the clinical study 
data are credible. 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          34 
 
● 
Independent Ethics Committee or Institutional Review Board  
Before the start of the study, the investigator will provide the IEC/IRB with current and complete copies 
of the following documents: 
● 
Final protocol and if applicable, amendments 
● 
Informed consent form (and any other written materials to be provided to the patients) 
● 
Investigator's Brochure (or equivalent information) and amendments 
● 
Patient recruiting materials, if applicable 
● 
Information on compensation for study-related injuries or payments to patients for participation 
in the study, if applicable  
● 
Investigator's curriculum vitae or equivalent information (unless not required, as documented by 
IEC/IRB) 
● 
Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for patients 
● 
Any other documents that the IEC/IRB requests to fulfill its obligation 
This study will be undertaken only after IEC/IRB has given full approval of the final protocol, 
amendments (if any), and the informed consent form, applicable recruiting materials, and after the 
sponsor has received a copy of this approval. This approval letter must be dated and must clearly 
identify the documents being approved. 
During the study, the investigator will send the following documents to the IEC/IRB for their review and 
approval, where appropriate: 
● 
Protocol amendments 
● 
Revision(s) to informed consent form and any other written materials to be provided to patients 
● 
If applicable, new or revised patient recruiting materials approved by the sponsor 
● 
Revisions to compensation for study-related injuries or payment to patients for participations in 
the study, if applicable 
● 
Investigator's Brochure amendments or new edition(s) 
● 
Summaries of the status of the study (at least annually or at intervals stipulated in guidelines of 
the IEC/IRB) 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          35 
 
● 
Reports of any serious adverse events  
● 
New information that may adversely affect the safety of the patients or the conduct of the study  
● 
Deviations from or changes to the protocol to eliminate immediate hazards to the patients  
● 
Report of death of patients under investigator's care 
● 
Notification if new investigator is responsible for the study at the site 
● 
Any other requirements of the IEC/IRB 
For protocol amendments that increase patient risk, the amendments and applicable informed consent 
form revisions must be submitted promptly to the IEC/IRB for review and approval before 
implementation of the change(s) 
At least once a year the IEC/IRB will be asked to review and re-approve this clinical study. This request 
and approval should be documented in writing. 
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about the 
study completion. 
● 
Informed Consent 
Each patient must give written consent according to local requirements after the nature of the study has 
been fully explained. 
The consent form must be signed before performance of any study-related activity. The consent form 
used must be approved by both the sponsor and by the reviewing IEC/IRB. The informed consent should 
be in accordance with principles set forth in the Declaration of Helsinki, current ICH and GCP 
guidelines, applicable regulatory requirements, and sponsor policy. 
Before entry into the study, the investigator or an authorized member of the investigational staff must 
explain to potential patients the aims, methods, reasonably anticipated benefits, and potential hazards of 
the study, and any discomfort it may entail. Patients will be informed that their participation is voluntary 
and that they may withdraw consent to participate at any time. They will be informed that choosing not 
to participate will not affect the care they patient will receive for the treatment for his/her disease. 
Patients will be told that alternative treatments are available if they refuse to take part and that such 
refusal will not prejudice future treatment. Finally, they will be told that the investigator will maintain a 
patient identification register for the purposes of long-term follow up if needed and that their records 
may be accessed by health authorities without violating the confidentiality of the patient, to the extent 
permitted by the applicable law(s) or regulations. By signing the informed consent form the patient is 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          36 
 
authorizing such access, and agrees to be re-contacted after the study’s completion, by health authorities 
and authorized sponsor staff, for the purpose of obtaining consent for additional safety evaluations if 
needed. 
The patient will be given sufficient time to read the informed consent form and the opportunity to ask 
questions. After this explanation and before entry into the study, consent should be appropriately 
recorded by name of the patient, patient's signature and date of signature. After having obtained the 
consent, a copy of the informed consent form must be given to the patient. 
If the patient or legally acceptable representative is unable to read or write, an impartial witness should 
be present for the entire informed consent process (which includes reading and explaining all written 
explanations) and should personally date and sign the inform consent form after the oral consent of the 
patient or legally acceptable representative is obtained. 
● 
Privacy of Personal Data 
The collection and processing of personal data from patients enrolled in this study will be limited to 
those data that are necessary to investigate the efficacy, safety, quality, and utility of the investigational 
product(s) used in this study. This data must be collected and processed with adequate precautions to 
ensure confidentiality and compliance with applicable data privacy protection laws and regulations. 
 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          37 
 
13. 
ADMINISTRATIVE REQUIREMENTS 
13.1. Protocol Modifications 
The investigator will not modify this protocol without a formal amendment, if applicable. Protocol 
amendments must not be implemented without prior IEC/IRB approval, or when the relevant competent 
authority has raised any grounds for non-acceptance, except when necessary to eliminate immediate 
hazards to the patients in which case the amendment must be promptly submitted to the IEC/IRB and the 
relevant competent authority. When the change(s) involves only logistic or administrative aspects of the 
study, the IRB (and IEC where required) only needs to be notified. 
The investigator or other physician in attendance will contact the appropriate sponsor representative by 
fax or telephone regarding any situations requiring a departure from the protocol. If possible, contact 
will be made before implementing any departure from the protocol. In all cases contact with the sponsor 
must be made as soon as possible in order to discuss the situation and agree on an appropriate course of 
action. The data recorded in the CRF will reflect any departure from the protocol. 
13.2. Regulatory Documentation 
● 
Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities in each 
respective country, if applicable. A study may not be initiated until all local regulatory requirements are 
met.  
● 
Required Pre-study Documentation  
The following documents must be available and maintained during the study: 
● 
Approved Study Protocol and amendment(s) 
● 
A copy of the dated and written IEC/IRB approval of the protocol, 
amendments, informed consent form, any recruiting materials and if applicable, patient compensation 
programs. This approval must clearly identify the specific protocol by title and number. 
● 
Regulatory authority approval or notification, if applicable 
● 
Documentation of investigator qualifications (e.g., curriculum vitae) 
● 
Completed financial disclosure form  
● 
Signed and dated clinical trial agreement, which includes the financial 
agreements 

ACR-US-MCU-01 Study Protocol Version 1.0 August 02, 2020                                          38 
 
● 
Other documentation required by local regulations 
● 
Patient Identification Register and Patient Screening Log 
The investigator agrees to complete a patient identification register to permit easy identification of each 
patient during and after the study.  
The patient identification register will be treated as confidential. To ensure patient confidentiality, no 
copy will be made. All reports and communications relating to the study will identify patients by initials 
and assigned number only. 
The investigator will also complete a patient-screening log, which reports all patients who were seen to 
determine eligibility for inclusion in the study. 
● 
eSource Completion  
All data relating to the study will be recorded in electronic source documents. Data will be entered into 
eSource in English. The eSource are to be completed at the time of the patient's visit, so that they always 
reflect the latest observations on the patients participating in the study. 
The investigator must verify that all data entries in the eSource are accurate and correct. 
● 
Record Retention  
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eSource and all 
source documents that support the data collected from each patient, as well as all study documents as 
specified in ICH/GCP Section 8, Essential, Documents for the Conduct of a Clinical Trial, and all study 
documents as specified by the applicable regulatory requirement(s). The investigator/institution will take 
measures to prevent accidental or premature destruction of these documents. 
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational products. These documents will be retained for a longer period if 
required by regulatory requirements or by an agreement with the sponsor. It is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a person who will accept the responsibility. 
The sponsor must be notified in writing of the name and address of the new custodian. Under no 

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circumstance shall the investigator relocate or dispose of any study documents before having obtained 
written approval from the sponsor. 
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator must permit access to such report. 
 
13.3. Study Completion/Termination 
● 
Study Completion 
The study is considered completed with the last patient undergoing the study. 
● 
Study Termination 
The sponsor reserves the right to close the investigational site or terminate the study at any time. The 
investigational site will be closed upon study completion. Reasons for the early closure of an 
investigational site or termination of the study may include but are not limited to: 
●        Safety concerns 
● Sufficient data suggesting lack of efficacy 
● Inadequate recruitment of patients by the investigator 
 
 
 
 
 
 

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14. 
APPENDICIES  
STUDY PROTOCOL AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me 
who assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study treatment and the conduct of the study. 
_________________________________________________________________ 
Investigator's Signature                                                       Date (Day Month Year) 
_________________________________________________________________ 
Name of Investigator (Typed or Printed) 
_________________________________________________________________ 
_________________________________________________________________ 
_________________________________________________________________ 
Institution and Address* 
_________________________________________________________________ 
Telephone number* 
 
______________________________________________________________ 
Sponsor's Representative Signature               
     Date (Day Month Year 
_________________________________________________________________ 
Name of Sponsor's Representative (Typed or Printed) 
_________________________________________________________________ 
_________________________________________________________________ 
_________________________________________________________________ 
Sponsor Address* 
_________________________________________________________________ 
Telephone number* 

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* 
If the address or telephone number of the investigator changes during the course of study, written 
notification will be provided by the investigator to the sponsor and will not require protocol amendment(s). 
 
15. 
References