Clinical trial NCT03503513
Conditions: Urinary Tract Infections Spinal Cord Injuries Spinal Cord Diseases Neurogenic Bladder
Sponsor: University of Michigan
Start date: 2018-08-24; Completion date: 2023-09-30
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A non-randomized study evaluating the efficacy of intravesical gentamicin on the occurrence rate of urinary tract infections and bladder complications in patients after spinal cord injury (SCI), and to assess its effectiveness in promoting overall quality of life (QOL), community living, and participation.

Detailed description:
Intervention: Participants' number of UTIs during the six-month treatment period will be compared to the number they incurred during the six months prior to treatment. Participants complete a baseline visit which consists of medical history, informed consent, urinalysis/culture indicating no active UTIs, metabolic panel, and self-reported measures about complications, symptoms, community participation and quality of life. Similar information is collected at the end of treatment. At a 3-month follow up visit, all available data is obtained through phone interviews and/or medical chart reviews except for self-report measures. Participants begin active treatment using Gentamicin plus saline solution after they have completed all requirements. Instillations of treatment solution occur nightly after the participant's last evening catheterization. Bi-weekly calls are conducted to ensure compliance, answer questions and document adverse events. Participants will stop the trial if they develop an UTI. After receiving treatment for the UTI by their physician, they will go into a washout period of a week before resuming the trial with Gentamicin instillations.

Arms: arm 1: Participants initiate Gentamicin instillations every night for a treatment period of 6 months. Instillations are stopped if they developed a UTI. After receiving treatment for this UTI, they resume the Gentamicin instillations. After baseline screening and being consented, they are instructed on how to do the instillations through a catheter, once they receive the drug and aid equipment (i.e. syringes) to do installations. Remaining drug from syringes are to be disposed after each use. Participants use their own catheters. In-dwelling catheters are not allowed.
Interventions: intervention 1: Gentamicin Sulfate
Intervention descriptions: intervention 1: Gentamicin is compounded by the Michigan Medicine Research Pharmacy in a concentration of 480 milligrams of the active product to 1000 milliliters of normal saline. Pharmacy mails participants treatment drug. Once received, participants will do daily instillations of 30 milliliters of solution after catheterizing their bladder at night.

Protocol documents:
SAP_002.pdf: 
The Effect of Gentamicin Intravesical Instillations on Decreasing Urinary Tract Infections in Patients 
with Neurogenic Bladder after SCI: A Clinical Trial 
National Clinical Trial (NCT) Identified Number: 03503513 
 
 
 
Statistical Analysis Plan 
6/23/2023 


Statistical Analysis Plan 
All data were examined for completeness and outliers before hypothesis testing. Categorical data was 
summarized in terms of frequencies, presented as n (%), and continuous data will be summarized in 
terms of means (standard deviations). Participant demographics and clinical status were evaluated using 
descriptive statistics. All efforts were made to recruit a balanced sample representative of persons with 
SCI/D. Statistical significance was set at p < 0.05 for group comparisons with a 95% confidence interval. 
 
To test for significant differences in the incidence of UTIs across periods (six months pre-treatment, six- 
month treatment, one-month post-treatment, six months post-treatment) an incidence rate per person 
month was determined by comparing the total number of UTIs in relation to duration, reflecting all 
participants across six months. The incidence rate ratio was determined by comparing the different 
timepoint ratios in relation to pre-treatment ratio. Confidence intervals and p values were calculated for 
rates and rate ratios. This approach analytical was used to satisfy small sample size calculations, as 
appropriate with count outcomes data (Hypothesis 1). To assess the impact of the study intervention on 
our Secondary Endpoint, bladder, and bowel complications (Hypothesis 2), and Tertiary Endpoints, QOL 
(Hypothesis 3), paired t tests were used to test differences in scores across survey measures. 

Prot_000.pdf: 
The Effect of Gentamicin Intravesical Instillations on Decreasing Urinary Tract Infections in Patients 
with Neurogenic Bladder after SCI: A Clinical Trial 
Version 6.6
Protocol 589-TATE  
 
 
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The Effect of Gentamicin Intravesical Instillations on Decreasing Urinary Tract Infections in Patients 
with Neurogenic Bladder after SCI: A Clinical Trial 
Protocol Number: 589-TATE (OnCore # 00137086) 
National Clinical Trial (NCT) Identified Number: in03503513 
IND Number: 138946 
Principal Investigator: Denise Tate, PhD 
Co-Principal Investigator: Anne Pelletier Cameron, MD 
Co-Investigator: Gianna Rodriguez 
IND Sponsor: Denise Tate, PhD  
Funded by: National Institute on Disability, Independent Living and Rehabilitation Research (NIDILRR), 
Administration for Community Living, US Department of Health and Human Services 
Version: 6.6 
March 2023 
 
 


The Effect of Gentamicin Intravesical Instillations on Decreasing Urinary Tract Infections in Patients 
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Table of Contents 
Statement of Compliance .............................................................................................................................................. 5 
1 Protocol Summary ...................................................................................................................................................... 6 
1.1 Synopsis ............................................................................................................................................................... 6 
1.2 Schema ................................................................................................................................................................ 7 
1.3 Schedule of Activities (SoA) ................................................................................................................................. 8 
2 Introduction .............................................................................................................................................................. 10 
2.1 Study Rationale .................................................................................................................................................. 10 
2.2 Background ........................................................................................................................................................ 10 
2.3 Risk/Benefit Assessment.................................................................................................................................... 11 
2.3.1 Known Potential Risks 
11 
2.3.2 Known Potential Benefits 
13 
2.3.3 Assessment of Potential Risks and Benefits  
13 
3 Objectives and Endpoints ..................................................................................................................................... 14 
4 Study Design ............................................................................................................................................................. 15 
4.1 Overall Design .................................................................................................................................................... 15 
Key Design Details 
15 
Hypotheses  15 
4.2 Scientific Rationale for Study Design ................................................................................................................. 16 
4.3 Justification for Dose ......................................................................................................................................... 16 
Gentamicin + Saline 16 
4.4 End of Study Definition ...................................................................................................................................... 16 
5 Study Population ...................................................................................................................................................... 17 
5.1 Inclusion Criteria ................................................................................................................................................ 17 
5.2 Exclusion Criteria ............................................................................................................................................... 17 
5.3 Lifestyle Considerations ..................................................................................................................................... 19 
5.4 Screen Failures ................................................................................................................................................... 19 
5.5 Strategies for Recruitment and Retention ......................................................................................................... 19 
Recruitment    19 
Retention 
20 
Remuneration & Incentives 
21 
6.1 Study Intervention(s) Administration ................................................................................................................ 21 
6.1.1 Study Intervention Description 
21 
6.1.2 Dosing and Administration 
22 
6.2 Preparation/Handling/Storage/Accountability .................................................................................................. 23 
6.2.1 Acquisition and accountability 
23 
6.2.2 Formulation, Appearance, Packaging, and Labeling 23 
6.2.3 Product Storage and Stability 
23 
6.2.4 Preparation 
24 
6.3 Measures to Minimize Bias: Randomization and Blinding ................................................................................. 24 
Randomization 
24 
Un-blinding 24 
6.4 Study Intervention Compliance ......................................................................................................................... 24 


The Effect of Gentamicin Intravesical Instillations on Decreasing Urinary Tract Infections in Patients 
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6.5 Concomitant Therapy ........................................................................................................................................ 24 
6.5.1 Rescue Medicine 
25 
7 Study Intervention Discontinuation and Participant Discontinuation/Withdrawal ................................................. 26 
7.1 Discontinuation of Study Intervention .............................................................................................................. 26 
7.2 Participant Discontinuation/Withdrawal from the Study .................................................................................. 26 
7.3 Lost to Follow-Up ............................................................................................................................................... 27 
8 Study Assessments and Procedures ......................................................................................................................... 29 
8.1 Efficacy Assessments ......................................................................................................................................... 29 
8.2 Safety and Other Assessments .......................................................................................................................... 30 
8.3 Adverse Events and Serious Adverse Events ..................................................................................................... 31 
8.3.1 Definition of Adverse Events (AE)      31 
8.3.2 Definition of Serious Adverse Events (SAE)      31 
8.3.3 Classification of an Adverse Event       32 
8.3.4 Time Period and Frequency for Event Assessment and Follow-Up 
34 
8.3.5 Adverse Event Reporting       34 
8.3.6 Serious Adverse Event Reporting       34 
8.3.7 Reporting Events to Participants        35 
8.3.8 Events of Special Interest 
35 
8.3.9 Reporting of Pregnancy       35 
8.4 Unanticipated Problems .................................................................................................................................... 35 
8.4.1 Definition of Unanticipated Problems (UP)      35 
8.4.2 Unanticipated Problem Reporting      36 
8.4.3 Reporting Unanticipated Problems to Participants      36 
9 Statistical Considerations ......................................................................................................................................... 37 
9.1 Statistical Hypotheses ........................................................................................................................................ 37 
9.2 Sample Size Determination................................................................................................................................ 37 
9.3 Populations for Analyses ................................................................................................................................... 37 
9.4 Statistical Analyses............................................................................................................................................. 38 
9.4.1 General Approach 
38 
9.4.2 Analysis of the Primary Efficacy Endpoint(s) 
38 
9.4.3 Analysis of the Secondary Endpoint(s) 
38 
9.4.4 Safety Analyses 38 
9.4.5 Baseline Descriptive Statistics 
39 
9.4.6 Planned Interim Analyses 
39 
9.4.7 Sub-Group Analyses 
39 
9.4.8 Tabulation of Individual Participant Data 39 
9.4.9 Exploratory Analyses 
39 
10 Supporting Documentation and Operational Considerations ................................................................................ 40 
10.1 Regulatory, Ethical, and Study Oversight Considerations ................................................................................ 40 
10.1.1 Informed Consent Process 
40 
10.1.2 Study Discontinuation and Closure 
41 
10.1.3 Confidentiality and Privacy 
41 
10.1.4 Future Use of Stored Specimens and Data 
43 
10.1.5 Key Roles and Study Governance 
43 
10.1.6 Safety Oversight 
43 
10.1.7 Clinical Monitoring 
44 


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10.1.8 Quality Assurance and Quality Control 
44 
10.1.9 Data Handling and Record Keeping 
44 
10.1.10 Protocol Deviations 
45 
10.1.11 Publication and Data Sharing Policy 
46 
10.1.12 Conflict of Interest Policy 
46 
10.2 Additional Considerations ............................................................................................................................... 46 
10.3 Abbreviations ................................................................................................................................................... 46 
10.4 Protocol Amendment History .......................................................................................................................... 47 
11 References .............................................................................................................................................................. 49 
 


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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with good clinical practice, applicable United States (US) Code 
of Federal Regulations (CFR), and the NIDILRR Terms and Conditions of Award. The Principal Investigator 
will assure that no deviation from, or changes to the protocol will take place without prior agreement 
from the Investigational New Drug (IND) sponsor, funding agency and documented approval from the 
Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the 
trial participants. All personnel involved in the conduct of this study have completed human subjects 
training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 


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1 PROTOCOL SUMMARY 
1.1 SYNOPSIS 
Title: 
The Effect of Gentamicin Intravesical Instillations on Decreasing Urinary 
Tract Infections in Patients with Neurogenic Bladder after SCI: A Clinical 
Trial 
Study Description: 
A trial to assess the efficacy of intravesical gentamicin on the occurrence 
rate of urinary tract infections (UTIs) and bladder complications in 
patients after SCI, and to assess its effectiveness in promoting overall 
QOL, community living, and participation. 
Objectives: 
Primary Objective: Evaluate efficacy of intravesical gentamicin in reducing 
the number of urinary tract infections during a six-month period.1 
Secondary Objectives: Examine the effectiveness of gentamicin in 
decreasing associated bladder and bowel complications. 
Tertiary Objective: Examine the effect of gentamicin on improving health-
related quality of life and community participation. 
Endpoints: 
Primary Endpoint: Number of UTIs 
Secondary Endpoints: Number of complications 
Tertiary Endpoints: Quality of life and participation scores 
Study Population: 
Adults with a traumatic or non-traumatic SCI with neurogenic bladder and 
recurrent urinary tract infections 
Phase: 
Phase 2/3 
Description of 
Sites/Facilities Enrolling 
Participants: 
Michigan Medicine (academic medical institution in southeastern 
Michigan affiliated with the University of Michigan) 
Department of Physical Medicine and Rehabilitation 
Department of Urology 
Description of Study 
Intervention: 
Intravesical gentamicin + saline instillations 
Study Duration: 
12 months 
Intervention Duration: 
6 months 
  
 
1 Throughout this document, six months refers to 180 days. 


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1.2 SCHEMA 
 
Figure 1. Study Flowchart; refer to Schedule of Activities (Table 1) for study procedures by visit 
Pre-screening 
Visit 1: 
Baseline  
0 months 
Visit 2: 
6 months 
Completed 
Informed consent, clinical history, current medications,  
CBC, metabolic panel, QOL measures 
End bladder instillations, medical record review, 
demographics, clinical history, current medications, 
urine analysis/culture, CBC, metabolic panel, QOL 
measures, and safety review. 
Bi-weekly 
phone calls 
(UTI, AE, health 
updates, compliance) 
Medical record review, demographics, clinical history, 
current medications, urine analysis/culture, pregnancy 
test 
Screening: 
Day -30 to 0 
Medical record review, clinical history, current 
medications 
Follow-Up 
Interview: 
3-months post-
intervention 
Optional post-intervention survey  


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1.3 SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening 
Visit 1 
Visit 2 
Visit 3 
(Follow-Up 
Interview) 
Optional Post-
Intervention 
Survey 
(Baseline)1 
Day -30 
to 0 
D0 
Day 
180±30 
Day 90 - 30 
/ + 90 post-
intervention 
Day 90 -
30/+365 post-
intervention 
Medical Record Review 
X 
 X 
X 
X 
 
Informed consent 
  
X 
  
  
 
Demographics 
X 
  
  
  
 
Clinical History  
X 
X 
X 
X 
 
Current Medications 
X 
X 
X 
X 
 
Urine Analysis (UA; plus culture 
if needed)2 
X 
  
X 
  
 
Pregnancy test 
X 
  
  
  
 
Complete Blood Count 
  
X 
X 
  
 
Comprehensive Metabolic Panel 
  
X 
X 
  
 
Self-report measures of QOL3 
  
X 
X 
 
 
Safety Review5 
  
  
X 
  
 
Every 30 days +/- 2 business 
days: ship study product 
 
 
 
Schedule bi-weekly phone calls4 
 
 
 
Satisfaction survey6 
 
 
 
 
X 


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1 Participation will commence once eligibility is confirmed via urine analysis (or 
culture for those individuals with a positive UA); an order for study product will be 
faxed/emailed to the Research Pharmacy; intervention start date will be the first 
dose listed on the dosing diary. If the dosing diary is not available, the intervention 
start date will be recorded as the date told to the study team by the participant and 
documented in the REDCap database. 
 
 
2 A rapid UA will be performed as part of standard of care at the time of screening; 
UAs at Visit 2 will be study-paid; positive tests will be followed with a urine culture; 
test results usually take about 4 days 
 
 
3 QOL measures include the following standardized surveys: Neurogenic Bladder 
Symptom Score; Neurogenic Bowel Dysfunction Score; SF-Qualiveen; SCI-QOL 
Measurement System’s Bladder Management Difficulties, Bladder Complications, 
Bowel Management Difficulties, and Satisfaction with Social Roles and Activities; and 
Community Participation Indicators Scale (see Section 8.1, “Efficacy Assessments”) 
 
 
4 Study team will make phone calls every two weeks +/- 3 business days to 
participants throughout the study period to ask about UTIs, adverse events, 
compliance and general health updates.   
 
 
5Study team will conduct this visit, likely over the phone, within 30 days after the 
participant’s final instillation in order to assess any adverse events or reactions 
while the study drug is washing out of the participant’s system 
 
 
6Study team will contact 
participants at least 60 days 
post-intervention for an 
optional survey to assess their 
perception of Gentamicin use, 
challenges and satisfaction with 
study participation. Participants 
may be contacted up to 1 year 
after the end of their 
participation.  
 
 
 


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2 INTRODUCTION 
2.1 STUDY RATIONALE 
This proposal addresses a critical health issue affecting those living with spinal cord injury (SCI), that of 
recurrent urinary tract infections (UTIs) and their effects on health, quality of life (QOL), community 
living and participation. While mortality due to urinary tract complications has decreased during the last 
several decades in persons with SCI, UTIs remain one of the eight leading causes of death among SCI 
patients,1 and their effects on QOL and one’s ability to function in the community are clearly 
documented in the literature.2,3 Although antibiotics have been used to treat UTIs, for those with 
recurrent infections, oral antibiotic treatment is not always effective and can lead to infections that are 
resistant to treatment.4 Intravesical (occurring within the bladder) instillation of a gentamicin solution (a 
generic antibiotic often used to treat UTIs) has been used clinically in adults with SCI for over 20 years.5 
The process is quite simple and requires flushing the bladder with the solution. Yet, the effectiveness of 
intravesical gentamicin in prevention of UTIs has not undergone rigorous efficacy testing in SCI. This 
study proposes a clinical trial of intravesical gentamicin to reduce the incidence of UTIs in persons 
with SCI and to assess its effectiveness in promoting overall QOL, community living and participation. 
Two important reasons guided our decision to study the effects of prevention of UTIs with gentamicin 
on QOL. First, our discussions with colleagues and collaborators show that most SCI patients who use 
gentamicin for prevention of UTIs are very satisfied with results. Second, there is a lack of clear evidence 
in the field for broad outcome measures, shown by the limited use of QOL and community participation 
measures in clinical trials. 
Due to its potential efficacy, a robust trial of intravesical gentamicin in person with SCI having recurrent 
infections is needed. The selection of gentamicin for this Clinical Trial (CT) has several reasons: 1) its 
ongoing use by patients with SCI and recurrent infections; 2) its potential efficacy as an antimicrobial 
treatment that shows good results in persons with neurogenic bladder; and 3) its apparent drug safety 
in this route of administration, with no expected systemic side effects per previous studies. 
2.2 BACKGROUND 
This study addresses a critical health issue for those living with SCI, that of recurrent UTIs and their 
effects on health, QOL, community living and participation. While mortality due to urinary tract 
complications has decreased during the last several decades in persons with SCI, UTIs remain one of 
the eight leading causes of death among SCI patients,1 and their effects on QOL and one’s ability to 
function in the community are clearly documented in the literature.2,3 Although antibiotics have been 
used to treat UTIs, for those with recurrent infections, oral antibiotic treatment is not always 
effective and can lead to infections that are resistant to treatment.4 Intravesical (occurring within 
the bladder) instillation of a gentamicin solution (a generic antibiotic often used to treat UTIs) has 
been used clinically in adults with SCI for over 20 years.5  
 


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Inappropriate bladder management can cause complications including recurrent UTIs, sepsis, and kidney 
damage due to chronic urinary retention.6 The instillation process is quite simple and requires flushing 
the bladder with the solution. However, the effectiveness of intravesical gentamicin in prevention of 
UTIs has not undergone rigorous efficacy testing in SCI. This study will also contribute new knowledge 
by examining the associations between neurogenic bladder and bowel complications. It will also 
examine the impact of this treatment on QOL and community participation among persons with 
SCI.  
 
Risk factors for UTIs include requiring catheterization by a caregiver,7 build-up of urinary calculi in the 
bladder,8 incomplete voiding, elevated intravesical pressure and catheter use.9 There exists little 
consensus on treatment of UTIs in this population. While literature suggests the superiority of clean 
intermittent catheterization (CIC) for those who are able to perform it,10,11 a 2012 systematic review 
suggested that no universal recommendations could be made.12 The dose of gentamicin was selected 
based on similar protocols available in the literature.5,13 
2.3 RISK/BENEFIT ASSESSMENT   
2.3.1 KNOWN POTENTIAL RISKS 
The overall risk of intravesical gentamicin for the management of recurrent UTIs in patients with 
neurogenic bladder is low. The method of daily bladder instillations is a common clinical strategy at 
Michigan Medicine, Department of Urology for specific patients (i.e. those with neurogenic bladder and 
frequent symptomatic UTIs), and it is one that is generally well-received by both patients and care 
givers. A retrospective analysis of Michigan Medicine patients showed mild and rare adverse events 
while using Gentamicin bladder instillations.14 Likewise, Abrams et al.15 and Defoor et al.13 suggest that 
gentamicin as prophylaxis against recurrent UTIs is well-tolerated and of minimal risk. 
 
Urinary tract infection (primary outcome) – Recurrent UTIs are a likely occurrence in this study 
population. Participants will be instructed to contact their physicians at U-M who provide urological care 
in the event of UTI symptoms and can expect to be managed according to standard clinical practice (e.g. 
a course of oral antibiotics). The study team will query participants bi-weekly for any UTI occurrences 
(including symptoms and treated cases) and prompt the participant to follow-up accordingly if they have 
not already done so. 
 
Risks associated with regular bladder catheterization – There is potential for trauma at the site of 
insertion of the catheter.  The risk associated with participation in this study is no greater than 
experienced by these patients as part of their typical catheterization process.  Likewise, there is a risk of 
contamination from using non-sterilized equipment.  Again, this risk is commensurate with participant’s 
risk exposure during their typical catheterization process.  Participants and/or their caregivers will 
typically be experienced in the proper and safe manner of clean intermittent catheterization, but all will 
receive education and guidance in proper and hygienic catheterization practices with their study 
materials. 


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Burden - Cox et al14 describe daily gentamicin instillations as "minimally burdensome" as it only adds one 
additional step to the patient's normal nightly catheterization routine. The expected additional time is 1-
3 minutes.  This burden may be experienced by both the patient and a caregiver. Participants will be told 
that if the additional burden is too great they may withdraw from the study without repercussion to 
them or their normal clinical care.   
 
Bladder spasms – Waites et al reported a small percentage (<5%) of patients with bladder spasms 
related to bladder irrigation using compounds other than gentamicin.16 It is unclear whether these 
experiences were related to the process itself or to the product. There were no reports of bladder 
spasms in the Cox analysis.14 To minimize the likelihood that the instillation process contributes to 
bladder spasms, we will provide standard patient and caregiver education on how to perform the 
instillation and on usual patient experiences. Participants will be told that withdrawal without 
repercussion is an option in the event the study proves more onerous than anticipated or desired. 
 
Allergic reaction or sensitivity to study product – Individuals allergic to gentamicin or any component of 
the study product may experience allergic-type reactions including mild asthmatic episodes to 
anaphylaxis.  The overall prevalence of reactive sensitivities is likely to be low (per product insert and 
clinical experience of Dr. Anne P Cameron, Associate Professor, Michigan Medicine Department of 
Urology, co-investigator on this study).  Individuals with a noted and/or reported history of allergy or 
sensitivity to aminoglycoside antibiotics (including gentamicin) will be excluded.  
 
Antibiotic resistance – It is unlikely that antibiotic resistance will be an issue in this study. The localized 
dosing (as opposed to systemic dosing via an oral or IV administration) used in this study will minimize 
the overall exposure and decrease the likelihood of altered urinary and urethral flora in response to 
antibiotic exposure. In fact, Cox et al actually demonstrated reduced antibiotic resistance while on 
gentamicin instillations.14 
  
Confidentiality breach – The risk of research data or PHI being accessed without study or clinical care 
need is very low given the standard safeguards used by Michigan Medicine as an institution and by 
those on the study team. Access to study-related files is granted on the basis of need by the project 
manager. Electronic files, including electronic consents, are protected by the Michigan Medicine 
information technology infrastructure, which includes digital encryption, and paper files are stored in a 
secure environment including locked file cabinets and restricted access offices. 
 
Toxicity – The likelihood that a participant in this study would experience toxicity is quite low, as toxicity 
as a side effect is more associated with high doses of prolonged systemic therapy and/or in patients with 
impaired renal function.  While high doses of gentamicin and similar compounds can be associated with 
nephro- and ototoxicity, these risks are minimized in this study due to the exclusion of patients with 
renal impairment and because the systemic absorption via the bladder has been found to be 
negligible.5,15  Using rats, canines and humans, Wan (1994) instilled gentamicin and evaluated serum 


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levels 30-minutes post-instillation.5  Only the rat model showed measurable, yet low, non-toxic levels of 
serum gentamicin; neither canine nor human tests showed any detectable concentration.  In studies 
with limited follow-up data, there were no clinically relevant side effects.17 While unlikely based on 
these factors, gentamicin toxicity may manifest in the form of new onset and prolonged numbness, skin 
tingling, dizziness and vertigo. Other side effects include prolonged muscle twitching, tinnitus, roaring in 
the ears or hearing loss. Subjects will be instructed to remain well hydrated during study treatment, and 
to discontinue treatment if they experience any of these symptoms and to contact the study 
coordinator.  
 
Overdosage – Overdosage may increase the risk of toxicity described above. The risk of this is minimal as 
long as subjects take study treatment as directed. As stated above, the localized dosing is unlikely to 
cause any increase in serum gentamicin levels and, additionally, the dose of gentamicin in each syringe 
is far below the threshold at which has been reported to cause adverse reactions. 
 
Fetal Harm – Aminoglycosides such as gentamicin can cause fetal harm when administered to pregnant 
women. A pregnancy test will be administered to females of child-bearing potential at screening. 
Sexually active females of child-bearing age will also be asked to use appropriate contraception 
throughout the study while on the study treatment. Subjects who become pregnant after enrollment 
will be asked to discontinue the study treatment, but may remain in the study, tracking their UTIs and 
completing study interviews. 
2.3.2 KNOWN POTENTIAL BENEFITS 
The potential benefits to patients include: a reduction in symptomatic UTIs, a reduction in use of oral 
antibiotics used to treat UTI, and an improved quality of life.14 Successful treatment is likely to enable 
persons with SCI to live more active, independent and productive lives, contributing to the fabric of 
society.  A 2009 study found that treatments leading to favorable urodynamic results correlated with 
better quality of life in those with SCI.18 Neurogenic bladder in general and UTIs in specific lead to 
increased mortality and morbidity in the SCI population, along with greater incidence of hospitalizations.  
 
Successful treatment can decrease morbidity, mortality and hospitalizations related to UTIs. With fewer 
medical complications associated with neurogenic bladder (i.e. incontinence and leakage) and bowel 
(i.e. constipation and incontinence), patients are more likely to live healthy, happy and fulfilling lives.  
 
The potential for benefit extends to caregivers who might experience reduced stress or concern for UTIs, 
and to clinic staff who might experience fewer telephone encounters from patients related to UTI 
concerns. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
The risk-benefit profile of using daily bladder instillations of gentamicin is favorable. In patients for 
whom frequent UTIs are a problem, intravesical treatment with gentamicin offers a minimally 


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burdensome strategy with minor increase over minimal risk. 
 
3 OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
The use of intravesical gentamicin reduces 
the incidence of UTIs during treatment 
A reduction in the count of UTIs during 
the six months of treatment  
Allows for verification of reduced UTIs 
during the intervention. UTIs are 
associated with major medical, 
psychological, social and economic 
consequences 
Secondary 
Gentamicin treatment will decrease self-
reported bladder complications  
A reduction in scores of the Neurogenic 
Bladder Symptom Severity at six months 
of gentamicin use.  
Allows for validated self-assessment of 
bladder symptoms in patients with SCI 
following the intervention.  
Gentamicin treatment will decrease self-
reported bowel complications 
A reduction in scores of the Neurogenic 
Bowel Dysfunction at six months 
Allows for a validated self-assessment of 
bowel dysfunction severity in patients 
with SCI following the interventions 
Tertiary/Exploratory (other pre-specified analyses) 
The use of intravesical gentamicin will 
enhance overall quality of life  
An increase in SF-Qualiveen scores at six 
months of gentamicin use 
UTIs, associated bladder and bowel 
complications contribute to reduced QOL 
in patients with SCI manifesting in 
negative affect and psychological 
functioning 
The use of intravesical gentamicin will 
enhance quality of life by decreasing 
bladder management difficulties  
An improvement in SCI-QOL: Bladder 
Management scores at six months. 
The use of intravesical gentamicin will 
enhance quality of life by decreasing 
bladder complications  
An improvement in SCI-QOL: Bladder 
Complications scores at six months. 
The use of intravesical gentamicin will 
enhance quality of life by decreasing 
bowel management difficulties  
An improvement in SCI-QOL: Bowel 
Management Difficulties scores at six 
months. 
The use of intravesical gentamicin will 
increase overall community participation 
An improvement in Community 
Participation Indicators Scale scores at 
six months. 
Repeated UTIs, associated bladder and 
bowel complications negatively impact 
patients' interactions with their social 
environments 
The use of intravesical gentamicin will 
increase subject’s satisfaction with roles 
and activities scale 
An improvement in SCI-QOL: Satisfaction 
with roles and activities scale scores at 
six months. 


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4 STUDY DESIGN 
4.1 OVERALL DESIGN 
KEY DESIGN DETAILS 
. 
• 
Hypothesis - The use of intravesical gentamicin will reduce the incidence of UTIs, bladder 
complications, bowel complications, and will enhance subject’s quality of life.  
• 
Pre-post study design, comparing participants number of UTIs during the six-month treatment 
period to the number they incurred during the six months2 prior to treatment. 
• 
Participants will begin with active treatment, using gentamicin + saline solution, after they have 
completed the baseline interview and required urinalysis and bloodwork.    
• 
Phase 2/3 
• 
Single-site - Michigan Medicine in Ann Arbor, MI. 
• 
Dosing – Instillations of treatment solution will occur nightly after the subject’s last evening 
catheterization. 
• 
Interim analysis – The study design and intended sample size preclude meaningful interim analyses. 
HYPOTHESES 
The proposed study is a pre- post CT in which participants receive the study drug for six calendar 
months, and analysis compares their frequency of UTIs during this period to the frequency in the prior 
six months: 
1. The incidence of UTIs will be lower during the treatment period than it had been during the 
previous six calendar months. Occurrence of UTIs throughout this study will be defined as 
having symptoms of a UTI, followed by a positive urine culture and prescribed treatment. 
2. The number of bladder and bowel complications will be likewise decreased during the 
treatment period compared to what was reported during the baseline interview. 
3. Reported health-related quality of life will be higher during the treatment period compared to 
the how it was reported during the baseline interview. 
4. Satisfaction with social roles and activities and community participation will be higher during the 
treatment period than how it had been reported during the baseline interview. 
 
2 Throughout this document, six months refers to 180 calendar days. 


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4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This study’s pre-post design is selected because it provides substantially more statistical power than a 
parallel group design with a similar sample size and allows participants to serve as their own controls, 
without requiring them to use placebo for half of the study. Our prior project experience, using a cross-
over design indicated that subjects are likely to drop out if they think that they are receiving placebo. 
• 
Treatment (gentamicin plus saline) is administered to each study participant for six months. 
• 
This design provides the benefit of a direct comparison within participants (the effect of no 
treatment vs. treatment). 
• 
Superiority trial – this design allows one to determine a clinically relevant difference between no 
intervention and the study intervention. 
4.3 JUSTIFICATION FOR DOSE 
GENTAMICIN + SALINE 
The research pharmacy will send participants premixed bags of 60mg of gentamicin in 50ml of normal 
saline. Participants will draw 25cc with their syringe, switch tips, instill this into the bladder after 
emptying of urine at their last evening catheterization, and discard the remaining 25cc of premixed 
solution. This is equivalent to the 30mg which had been used in the initial study protocol. The solution 
will remain in the bladder until the next catheterization. This is a standard dose that is easily tolerated 
by patients, and one that does not lead to leakage. It is based on the clinical expertise of Co-I, Dr. 
Cameron, and is appropriate for bladders sizes in patients with long-term use of indwelling 
catheterization.16 
4.4 END OF STUDY DEFINITION 
To be considered a "completer" of the study, a participant must: 
1. Be placed into the study treatment.  
2. Complete the 6-month intervention.  
3. Complete both outcome assessments (baseline and 6-months). 
4. Complete the follow-up assessments (3-months post-intervention). 
5. Have available outcome data on UTI occurrences during the study period as well as during the 
six months prior to study participation.  
6. Complete a safety review with a study team member within 30 days after administering last 
study drug dose to assess any adverse health/safety events, as required by the FDA.  
The end of the study data collection will be when the last participant accrued completes their final 
assessment. 


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5 STUDY POPULATION 
Participants who had previously been enrolled in this clinical trial and did not complete the intervention 
due to the study having been put on hold for an extended period will be allowed to re-enroll if they still 
meet the criteria for participation listed below. 
5.1 INCLUSION CRITERIA 
The electronic medical record (EMR) will be pre-screened for all inclusion criteria prior to the baseline 
interview and initial lab work. Criteria will be confirmed by patient or caregiver report at the screening 
assessment. 
 
• 
Provision of signed and dated informed consent form.  
• 
Male or female 18 years or older at time of enrollment. 
• 
History of traumatic SCI or non-traumatic spinal cord disease (SCD), with sustained neurological 
dysfunction. Traumatic and non-traumatic SCI/D are defined according to the International SCI 
Standards and Datasets.20 
• 
At least 6-months post-initial hospital discharge following SCI/D onset. 
• 
Neurogenic bladder. 
• 
Ability to self-perform daily instillation  or with help of others and willingness to adhere to the 
study regiment. 
• 
Negative pregnancy test (for females of childbearing age) and expresses willing and ability to use 
appropriate contraception while enrolled in the study. 
• 
History of at least 2 UTIs documented in the EMR during the previous six months (prior to 
screening). 
• 
Have a designated physician or health care provider for routine urological care who is a member 
of Michigan Medicine. 
• 
Use of clean intermittent catheterization (CIC) or catheterization through a stoma (i.e. 
Mitrofanoff) as their primary method of bladder management 
• 
Agreement to adhere to Lifestyle Considerations (see below) throughout participation in the 
study and to complete the daily dosing log as instructed by the study coordinator. 
5.2 EXCLUSION CRITERIA 
The EMR will be pre-screened for contraindications to participation based on medical history. Criteria 
will be confirmed by patient or caregiver report at the screening assessment. Final eligibility will be 
ascertained at the baseline assessment following confirmation of criteria by patient or caregiver report 
and a urine analysis. 


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• 
Concurrent use of systemic oral or intravesical antibiotic prophylaxis during the previous six 
months. 
o 
Localized antibiotic therapies (i.e. topical antibiotic creams) are permitted 
• 
EMR-documented or self-reported history of gentamicin allergy. 
• 
Patients who are 80 years old or older. 
• 
Positive pregnancy test at screening (for female patients who are of childbearing age). 
o 
Subjects who are not pregnant and who are willing and able to use appropriate 
contraception while enrolled in the study intervention will be permitted. 
• 
Patients with a history of 8th cranial nerve disorder. 
• 
Co-morbidities like cancer and chronic disease that could impact patient safety OR significantly 
affect the rate of UTIs and/or QOL substantially. 
• 
Urological co-morbidities like bladder cancer and history of kidney disease. Co-PI Cameron will 
review all cases where there is any question about possible inclusion of persons with a history of 
kidney disease.  These include: 
o 
Patients with EMR-documented renal impairment (e.g. end-stage renal disease, 
documented glomerular filtration rate (GFR) less than 60 ml/min will be excluded (most 
recent result). 
o 
Patients with active pyelonephritis (patients with a history of pyelonephritis, which has 
been treated and is resolved, will be permitted in the study.) 
• 
Current UTI at screening visit, assessed via urine analysis, culture, and symptoms. 
• 
Concurrent enrollment in a similar clinical trial 
• 
Concurrent use of contraindicated diuretics (ethacrynic acid, furosemide) 
• 
Current use of other contraindicated or disallowed concomitant medications or receiving 
treatments that may influence the results from this study. 
• 
Known allergy to aminoglycoside antibiotics. 
• 
Otological symptoms at baseline (i.e., tinnitus, severe dizziness/vertigo). 
• 
At the discretion of study team, individuals who are unable or unlikely to comply with 
procedures and/or for whom study participation is not recommended (e.g. unable to arrange 
transportation and/or reliable assistance to perform instillations, cognitive and/or behavioral 
challenges that preclude meaningful participation, poor health, etc.) 


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5.3 LIFESTYLE CONSIDERATIONS 
Participants should show indications of health seeking behaviors (i.e. following bladder management 
procedures), and be able to consult with their personal physicians when noticing symptoms related to 
bladder complications and/or UTIs. They should have access to caregivers or family members, as 
needed, to assist them with instillations following regular catheterizations. Healthy behaviors related to 
hygiene when having to catheterize and during bowel management procedures are also important.  
During this study, the management of all ongoing and new bladder or bowel issues will continue to fall 
under the purview of the participant's treating physician or care provider. The study team will not offer 
treatment for any new-onset UTIs, in their role on the study. This means that participants are expected 
to contact their provider about any new symptoms or infections. Since the physicians on the study team 
also provide treatment to SCI/D patients for urinary issues, in this clinician role, they may provide 
participants with care. 
Participants or their assistants should be willing to follow study protocol for storage of the medication 
and preparation of dose for daily instillations as well as complete their dosing diaries.  
Dietary restrictions and activity limitations are not required for participants while they are enrolled in 
this study. Should a participant start one of the contraindicated diuretics above, or become pregnant, 
they will discontinue the study treatment and notify the study team. Female participants will be asked 
about pregnancy and compliance with the use of contraception during their bi-weekly follow up visits. 
5.4 SCREEN FAILURES 
Screen failures are defined as those individuals who consented to participate in the study, but who are 
subsequently deemed ineligible, usually after the screening visit urine analysis and culture.  
 
Individuals who test positive for a UTI at their screening visit may be re-assessed for eligibility after 
prescribed antibiotic use. Individuals who undergo a second positive urine tests with UTI symptoms 
following treatment are ineligible for the study (i.e.; categorized as a screen failure). 
Additionally, females of childbearing potential who have a positive screening pregnancy test will be 
categorized as a screen failure. 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
RECRUITMENT 
This study will use a multi-pronged approach to recruitment that includes physician-referral, weekly 
reviews of the Michigan Medicine Urology and PM&R clinic schedules, use of MiChart Best Practice 
Alerts (BPAs) for satellite outpatient clinics, use of flyers for recruitment at clinics and community based 
agencies, use of UMhealthresearch.org (which may be linked to the patient’s electronic health portal), 
the MSCIS database and UM SCI Research Registry, Neurogenic Bladder Clinical Database, Patient 


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Reported Outcomes for Bladder Management Strategies in Spinal Cord Injury project database, and 
outreach to other related databases and patient advocacy groups in Ann Arbor and surrounding locales.  
Key criteria for targeting appropriate individuals will include: 
• 
Age 
• 
Presence of SCI and neurogenic bladder (evidenced by neurological classification when possible) 
• 
Use of CIC or catheterization through a stoma 
• 
Experience with recurring documented UTIs (2 or more in the prior six months) 
• 
Availability of regular physician for treatment of any UTIs who is affiliated with Michigan 
Medicine 
 
The study team will pre-screen EMRs for pertinent eligibility criteria. The study team will also check 
individuals referred by physicians in clinic, or responses of patients to in-clinic flyers, for eligibility.  
Individuals meeting this first pass at eligibility can be contacted in multiple ways: 
• 
Approached in clinic by a referring physician or by the study coordinator and/or her trained 
assistant. 
• 
Sent an introductory letter about this trial. 
• 
Contacted via email with the same information as contained in the introductory letter. 
 
Interested individuals will be invited to a research interview at which time the consent dialog will be 
initiated and eligibility confirmed. This interview will be conducted through secure, encrypted video 
conferencing or over the phone. 
• 
Individuals will be emailed a copy of the consent document and a study information sheet prior 
to the initial research interview. If the individuals do not have email access, physical copies will 
be mailed. 
• 
Individuals will be invited to review the study information on UMhealthregistry.org prior to the 
initial research interview. 
• 
We will suggest that the individual share their intentions about potential participation with their 
family, caregiver, regular physicians, and/or care team prior to the initial research interview. 
• 
We anticipate the ability to screen at least 30-50 participants in order to obtain a sample of 25 
potential participants following eligibility screening with the goal of enrolling and retaining a 
minimum of 15 participants.. 
• 
Special efforts will be made to recruit minority participants by ensuring that all potential eligible 
minority participants are contacted and invited to participate.  
 
RETENTION 
The study team will strive for an empathetic relationship with participants to promote retention across 
their study participation period.  Strategies for developing this type of relationship include: 
• 
Minimizing distractions and interruptions during research encounters (visits, phone calls, etc.) 
• 
Being present in the moment. 
• 
Engaging in active listening. 


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• 
Being aware of non-verbal cues, i.e. body language, that may turn off an individual. 
• 
Using teach-back methods of communication and information sharing to ensure mutual 
understanding. 
• 
Keeping individuals updated and aware of necessary and useful information. 
• 
Allowing individuals to correct or add to study team responses.  
• 
Engaging on a personal level, when appropriate. 
• 
Being culturally responsive and aware; assess personal implicit biases. 
• 
Addressing questions participants may have about the study. 
 
Study team members will implement the above strategies in all participant encounters whether planned 
or ad hoc.  In addition to regularly scheduled research phone calls or e-visits for outcome assessments, 
participants will be contacted bi-weekly via phone calls.  These bi-weekly encounters, while ostensibly 
for the primary purpose of collecting information about UTI occurrences, adverse events, and other 
symptoms, will also be used to maintain and promote an ongoing relationship with study participants, 
thus facilitating retention. 
 
REMUNERATION & INCENTIVES 
Participants will be paid $90 for participating in the study, $30 at their baseline, six-month, and 3-month 
post-intervention assessments.  Payments will be processed through the Human Subjects Incentive 
Program and will be conveyed via check or gift card.  The precise method of payment will default to 
check, with the other option being offered upon request for a different method of remuneration.   
 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
Section 6.1 makes repeated references to remote interviews, which will be conducted via an 
encrypted, HIPAA-compliant video conferencing platform (e.g., Zoom for Health.) It will be 
standard practice to conduct as many procedures remotely as possible to better protect 
subject/caregiver(s) and staff against the risk of COVID-19. However, in cases where a remote 
video interview is not possible, remote telephone interviews will be conducted and the study will 
follow all UM guidelines for proper consenting. 
6.1.1 STUDY INTERVENTION DESCRIPTION 
Eligible participants will be given the investigational product (gentamicin + saline solute). Those who use 
“a closed system” for catheterizing will also be provided with catheters to insert the investigational 
product into their bladders. Upon the termination of treatment, they will complete a study visit 
consisting of a blood draw, urine sample, and self-reported quality of life (QOL) measures. Additionally, 
a safety review will be conducted within 30 days after treatment termination by a member of the study 
team to assess for any adverse events. Approximately three months following the termination of 
treatment, participants will complete a final study visit to assess current Gentamicin use and UTI 
occurrences. Those interested will complete a brief survey about their perceptions of this treatment and 


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trial during or following the 3 months follow up. The treatment period lasts six months, beginning at the 
time of the first bladder instillation. Data collection will occur at baseline, at the biweekly visits, at the 
end of the treatment, and three-months post-treatment. Participants will be monitored bi-weekly 
throughout the trial through remote video interviews, and/or phone calls. The daily treatment consists 
of each participant and /or caregiver flushing the bladder with the treatment drug via bladder or stoma 
catheterization in the evening, leaving it in overnight, and emptying it the next morning.  
 
Treatment 
Consists of Gentamicin, an aminoglycoside antibiotic indicated for a variety of gram-negative bacterial 
infections and saline. The drug will be sent by the Michigan Medicine Research Pharmacy in a 
concentration of 60mg of the active product to 50ml of normal saline. Participants will receive catheters 
and syringe tips and will withdraw 25ml with their syringe, switch tips, instill, and dispose of remaining 
25ml of solution daily. Participants’ shipments will be ordered every 28 days +/- 2 business days by the 
study team.    
  
6.1.2 DOSING AND ADMINISTRATION 
The study treatment will either be self-administered or administered by a caregiver. During treatment 
participants will be instructed to follow their normal catheter routine for bladder emptying at night, 
before bed.  Once the bladder is empty, participants will attach the syringe containing the study product 
to the end of the catheter and slowly push the solution into the bladder.  Once the full dose is instilled 
into the bladder, the participant will remove the catheter and syringe, leaving the study product in the 
bladder until the following morning.  Participants will be asked to document the date and time of 
instillation and the date and time of bladder emptying the next morning in their daily dosing log, along 
with any other comments related to the process or related observed complications. In summary the 
process involves: 
1. Emptying the bladder as usual at night, before bed 
2. Attaching the catheter tip to the syringe 
3. Flushing the bladder with the solution 
4. Discarding the catheter tip and disposing of used syringe 
5. Leaving the solution in place until next routine bladder emptying 
6. Emptying the bladder with catheter as usual at next routine bladder emptying the next morning 
 
Treatment condition: gentamicin + saline 
• 
Instillation dose of 25mL solution every day; gentamicin dose = 30mg. 
• 
Instillation to occur at night after the last bladder emptying of the day before bed. 
• 
Self or caregiver administered via catheter. 
• 
To remain in the bladder until next catheterization. 
To ensure proper administration, participants and their caregivers will receive training on how to 
conduct the daily instillations. This training and printed information that includes contact information 


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for the study team will be provided to participants. A blank copy of the daily dosing log will be included 
as well. The process will also be explained to them when they enter the study. 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
Michigan Medicine Research Pharmacy will maintain study medication supply (both active and control 
products) and be responsible for dispensing the medication and study supplies (syringes, needles, 
catheter tips, and dosing logs) directly to the participant. Participants will receive their study medication 
in the mail via ground delivery. A signature at delivery is preferred. The Research Pharmacy will maintain 
shipping records and the study team will follow-up with participants to ensure receipt of study materials 
at the appropriate bi-weekly visit. The study participants will be asked to maintain a dosing log and 
review educational materials supplied by the study team. They are not required to save the used 
syringes but should refrain from re-using the syringes.  
  
The Research Pharmacy and Study Team shall retain records of the following: 
• 
Product shipped date. 
• 
Product received date. 
• 
Quantity of product shipped. 
• 
Batch/serial numbers of products. 
• 
Product expiration dates. 
• 
Participant compliance. 
 
The study team will call participants to confirm receipt of study product.  Accommodations will be made 
for vacations and other travel away from home.   
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
The individual mini bags sent to participants will be labeled with study identification, participant 
identifier, a “use-by date”, and contact information for study team. A patient education sheet for 
drawing up and administering the irrigation solution will be included with the shipment. The immediate 
package shall bear a label with the statement "Caution: New Drug--Limited by Federal (or United States) 
law to investigational use." 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
Active products should be stored at room temperature in the packaging they were shipped in.  
 
Participants will be instructed to contact the study team (who will contact the Research Pharmacy) in 
the event that: 1) they receive a damaged parcel or contents, 2) they notice anything unusual about the 
syringes or contents, and 3) if they failed to receive an expected delivery.  Participants will be advised to 
look for: 


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• 
Signs of a mishandled opened parcel. 
• 
Cracks or evidence of tampering with the mini bags. 
• 
Distortions in the solution, e.g., cloudiness, particulates, etc.  
 
6.2.4 PREPARATION 
The active study product (Gentamicin+ saline) will be obtained by the Research Pharmacy from Baxter. 
This is a premixed solution of 60mg of gentamicin in 0.9% NaCl 50 mL. Participants will be shipped 
parcels from the Research Pharmacy every 30 days +/- 2 business days. These parcels include the study 
product in a IVPB bag, IVPB solutions, 18 g 1.5 needles (boxes of 100), syringe catheter tip, alcohol 
swabs, and sharps container (for needles), sufficient to cover at least 28 days of treatment.  
  
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
RANDOMIZATION 
Not Applicable.   
 
UN-BLINDING 
Not Applicable.  
 
6.4 STUDY INTERVENTION COMPLIANCE 
Participants will be asked to complete a daily dosing log to promote and record compliance with the 
treatment protocol. The participants will share these logs during their 6-month outcome assessment. 
This will generally be done by emailing them to the Study Coordinator.  Data captured will include dates 
and items of dosing, as well date and time of the subsequent catheterization (to estimate duration of 
instillation), and any challenges or problems encountered. Participants will be requested to return any 
unused investigational product to the study site at the end of the treatment period for disposal.  
 
Additionally, the Study Coordinator will ask about compliance with the dosing protocol and study log 
completion, along with any barriers at the bi-weekly phone calls. The dates, times, and content of these 
calls will be documented in the study record. 
6.5 CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications, and supplements. 


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During each bi-weekly call, participants will be asked about any changes in medications.. Changes will be 
entered into the CRF. 
Concomitant use of ethacrynic acid and furosemide is not permitted in this protocol due to the 
increased risk of neurotoxicity. Additionally, concurrent use of systemic antibiotics for any reason is not 
permitted. Subjects prescribed a course of systemic antibiotic therapy will discontinue study treatment 
for the duration of their antibiotic course. 
6.5.1 RESCUE MEDICINE 
Participants experiencing a symptomatic UTI may be prescribed an oral antibiotic by their treating 
physician. The name and dose (if available) will be documented in the study record.  It is up to the 
participant and/or their caregiver to seek treatment for an active UTI.  The study will not provide any 
medications other than the study products. 
 
Likewise, it is possible that participants might be prescribed an antibiotic for another reason (i.e. not for 
a UTI).  Regardless of the reason, participants will be instructed to pause their daily instillations while 
undergoing treatment with an antibiotic for any reason.  They are then to resume their study treatment 
upon finishing their outside antibiotic.  The participants will document this in their dosing diaries and the 
information will be maintained in the subject’s research records. This issue will also be discussed during 
the bi-weekly phone calls. 
 
Participants may use non-pharmacologic strategies to help manage their urinary health, such as 
cranberry juice.  The use of these types of treatments will be documented at the study visits, and during 
the bi-weekly phone calls. 
 


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7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
Participants may elect to discontinue the study intervention for any number of reasons (not inclusive 
list): burden of study procedures, side effects, caregiver limitations, etc.  They will be educated on signs 
and symptoms of toxicity (see Section 8.2) and instructed to notify the study team and their physician 
for advice on discontinuation of study treatment. If a participant develops COVID-19 while participating 
in this study, the study team will make every effort to keep the participant in the trial. Participants with 
COVID-19 will remain in the study unless, for medical reasons, they can no longer participate. 
Participants will be asked about the reasons for withdrawal from the study when self-initiated. 
 
Regardless of the reason, discontinuation of the study treatment does not mean withdrawal from the 
study since the study uses an intent –to-treat design. If a participant decides to stop using the study 
product, and they are willing, they will remain enrolled in the study.  This means that study procedures, 
including bi-weekly phone calls and study visits will go on as scheduled. No drug taper is required when 
subjects discontinue the study treatment – they may stop immediately. These subjects will also 
complete the study’s final assessments, if willing. 
 
Regarding the discontinuation of treatment, the following information will be documented in the study 
record: 
• 
Reason for discontinuation of intervention (i.e. treatment). 
• 
Date of last dose. 
• 
Willingness to continue in the study. 
If a participant decides to discontinue the study intervention in light of a new or exacerbated clinical 
finding, we will report the finding on the Adverse Event case report form, and report to the necessary 
entities as outlined in the Events Reporting Schedule. 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants may withdraw from the study at any time; likewise, the study team can withdraw a 
participant from the study given any of the following reasons:  
• 
Individual expresses desire to stop participation. 
• 
A new or exacerbated clinical occurrence or adverse event that precludes safe and meaningful 
participation in the remaining study activities (note: while it may be necessary for a participant 
who experiences an adverse event to discontinue study treatment, they do not necessarily need 
to be withdrawn from the study). 


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o 
This criterion can include, but is not limited to, an adverse event, disease progression, 
other medical condition or lab finding. 
• 
Individual fails to comply with study requirements (e.g., unable or unwilling to complete lab 
exams, outcome assessments, lost-to-follow up, maintain appropriate communications with the 
study team, etc.) 
• 
Study team discretion that continued participation is unlikely to be safe and/or meaningful. 
• 
Participant status changes such that an individual no longer meets eligibility criteria. 
The reason for withdrawal will be documented in the study record (i.e., CRFs and REDCap database). 
Participants will be informed that they have been withdrawn from the study by the study team. 
 
Replacements 
• 
Participants who sign the informed consent form but do not receive the study intervention (for 
whatever reason, e.g., if they change their mind) will be replaced. 
• 
Participants who sign the informed consent form, and receive the study intervention, and 
subsequently are withdrawn or discontinued from the study, may be replaced at the discretion 
of the PI and Co-Is. 
7.3 LOST TO FOLLOW-UP 
Every effort will be made to maintain contact throughout an individual's enrollment. Standard practice 
for participant contact can involve telephone calls, routine emails, and snail mail letters, and will include 
a review of the EMR to check health status prior to attempting contact. The exact number of encounters 
will be based on study team discretion and knowledge of the participants, with consideration of the 
following guidelines: 
 
Schedule baseline visit 
• 
Initial introduction letter and 3 calls without contact. 
• 
Unlimited, yet practical, number of calls in context of contact with individual. 
Bi-weekly phone calls 
• 
5 encounter attempts made at different times. 
• 
Can use email if preferred by participant. 
• 
Send letter asking for participant to call or email study team if no contact made after 3 
attempts. 
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• 
Phone calls in the month preceding the projected follow-up window. 
• 
Can use email if preferred by participant. 
• 
Send letter asking for participant to call or email the study team if no contact is made.  
o 
Provide alternatives to facilitate completing outcome assessments: surveys over phone, 
urine analysis done at a clinic closer to home, etc. 
Since some of the information to be collected for this follow-up may be available in participants’ medical 
records, e.g., documentation of treatment for a UTI, study staff will review records before contacting 
subjects and query subjects if discrepancies are observed. If the follow-up cannot be completed with the 
subject, data from their medical record may be entered into the study database. All encounters will be 
documented in the study record. Individuals who are deemed "unreachable" will be withdrawn from the 
study and categorized as "Lost-to-follow up."   
 
Participants will be asked if they would like to participate in a brief survey about their experience in the 
trial. When possible, these questions will be asked at the end of their follow up. For those who already 
completed their third follow up, the study team will contact them via phone or e-mail asking the same 
questions.  Three to four contact attempts will be made to  participants to gauge  their interest in 
completing this post-intervention survey. Email may be used if preferred by participant. If a participant 
cannot be reached after these attempts they will be considered uninterested in the survey. All 
participants will be thanked for their participation in the study either verbally or by letter.  


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8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 EFFICACY ASSESSMENTS 
Section 8.1 refers to lab visits and study interviews. It will be standard practice to conduct as 
many procedures remotely as possible to better protect subject/caregiver(s) and UM staff against 
the risk of COVID-19. However, in cases where a procedure cannot be conducted remotely (e.g., 
required in-person lab visits for blood draws), the study coordinator will educate study 
participants/caregivers on all of Michigan Medicine’s safety guidelines for entering and being in 
UM buildings (e.g., COVID screenings, PPE, social distancing, etc.). 
 
Demographics, Clinical History and Current Medications will be abstracted from the electronic medical 
record and confirmed with participant and caregiver during study interviews. Co-morbidities, bladder 
and bowel symptoms, and current medications will be recorded.  Elements specific to SCI include age at 
injury and level and completeness of neurological impairment. Changes in health status and medication 
use will be updated during each interview. 
 
Urine analysis – Prior to any MLabs visit, the study coordinator will remind the participant of Michigan 
Medicine’s policies regarding COVID-19 as they relate to the participant and any person whom they 
might need to accompany them. Participants will provide urine samples according to MLabs (Michigan 
Medicine Pathology Handbook) specifications. A clean urine analysis is required for enrollment. 
Minimum volume required is 0.5ml collected in a non-sterile plastic urine cup. Dipstick analysis may be 
performed in the clinic at the time of the baseline visit; results are usually available within 10-15 
minutes.  Tests that come back positive will be sent to the lab for a urine culture.  Specimens can be 
stored at room temperature if received in lab within 2 hours of collection; otherwise the sample should 
be refrigerated for up to 24hr. Results are usually back within 4 days for a culture. 
 
Self-reported quality of life measures will be collected twice: at baseline and after the treatment period 
(approximately six months). Several disease-specific and overall quality of life measures will be used, 
including several scales from the SCI-QOL Measurement System. The SCI-QOL system builds on the 
PROMIS and Neuro-QOL initiatives were developed to address a dearth of valid patient-reported 
outcome measures for patients with spinal cord injury. 
• 
Neurogenic Bladder Symptom Score (NBSS): 22 item validated measure that assesses symptoms 
across three domains (incontinence, storage & voiding, and consequences) plus one overall 
quality of life item. 
• 
Neurogenic Bowel Dysfunction Score (NBD): 10 item validated measure that assesses frequency, 
of defecation and methods of bowel management and complications. 
• 
SF-Qualiveen: 8 item validated measure for urinary disorders that covers four domains (bother 
with limitations, frequency of limitations, fears, and feelings). Participants respond to each item 
using a 5-point Likert scale. 


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• 
SCI-QOL Measurement System’s Bladder Management Difficulties, Bladder Complications and 
Bowel Management Difficulties: these reflect three scales within the SCI-QOL battery that is part 
of the NIH Patient Reported Outcomes Measurement Information System (PROMIS) initiative. 
The short form for each scale will be administered (range 5-9 items).  
• 
SCI-QOL Measurement System’s Satisfaction with Social Roles and Activities is a 10-item short-
form that is also part of the overall SCI-QOL battery. 
• 
Community Participation Indicators Scale: 20 item validated measure of the frequency and 
importance of involvement in various types of activities.  
UTI Query and Adverse Event Occurrences – Study staff will review the participant’s EMR and 
communicate with them to query for UTI symptoms and occurrences, and any adverse events and side 
effects every 2 weeks throughout the study. These contacts also serve to promote protocol adherence 
and compliance with the study schedule, and will occur through remote video interviews, or over the 
phone. In addition, participants are instructed to contact the study team at any time during the trial to 
report UTIs, UTI symptoms, AEs, and any other concerns (e.g. transportation challenges or schedule 
conflicts). Each contact, whether scheduled or ad hoc, will be documented in the study record. Study 
staff will also query for UTI occurrences at Visit 3 (three months after the end of treatment). 
8.2 SAFETY AND OTHER ASSESSMENTS 
• 
The bi-weekly phone encounters and EMR reviews are the primary means of monitoring the 
occurrences of side effects and participant tolerability of the Gentamicin treatment. If a participant 
reports a UTI or UTI symptoms, they will be advised to follow-up with their personal provider for 
management. Any potential manifestation of gentamicin toxicity will also be assessed during these 
phone encounters. These include new onset and prolonged numbness, skin tingling, dizziness, and 
vertigo. They also include prolonged muscle twitching, tinnitus, roaring in the ears or hearing loss. 
The study team will recommend subjects with these symptoms be seen by a physician for otological 
assessment and possible study treatment discontinuation.   
• 
A complete blood count and comprehensive metabolic panel will be administered at baseline and six 
months when treatment is concluded. 
• 
If a study-ordered urine analysis (atscreening, and approximately 6-months later, defined here with 
a window of plus or minus 30 days) reveals an infection, participants will be instructed to follow-up 
with their personal provider to treat the current infection. The results of the urine test will be 
included in the EMR and be available to providers across institutions with EPIC access. 
• 
During the follow-up interview (3-months post-treatment), the participant will also be asked if they 
have used any gentamicin instillations since being off the study drug. If they have used gentamicin, 
they will be asked if they are still using it. If they have not used gentamicin, they will be asked why 
not.  


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After the follow-up interview, participants will be thanked for their participation in the trial and 
asked to participate in a final optional survey. If willing, they will be asked about their perceptions of 
the benefits and/or challenges of using Gentamicin instillations and whether they thought their 
participation in this trial was worthwhile. This information will be recorded in their CRFs.  This option 
will be offered to participants at the end of their 3-months post-treatment interview and/or at a 
different time following this interview, depending on their availability and interest in participating. 
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
This study's definition of AE will align with the FDA definition: "any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related." In practice, this 
means we will consider and document any experience or unfavorable and unintended sign, symptom, or 
disease that arises while an individual is participating in the study. This interpretation includes positive 
test results on urine analysis and urine culture (both those provided by the study and those ordered by 
the participant's treating physician) and reports of UTI symptoms (e.g., malodorous and cloudy urine, 
fatigue, fever, chills, etc.) 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
Similarly, this study will use the FDA definition of SAE: 
 
"An adverse event or suspected adverse reaction is considered "serious" if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: Death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect." 
 
This definition goes on to include any other "important medical events" that may not result in death, 
be life-threatening, or require hospitalization, but may be considered serious when deemed as such by 
medical judgment. These events may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such medical events include 
hospitalization for complications from a UTI (e.g., kidney infection, sepsis), allergic response requiring 
intensive treatment, other side effects or complications that require intensive or ongoing treatment 
and/or admission to the hospital. 
 
AE occurrences can be caused by any of the study products themselves, other aspects of the 
interventions like reactions to the catheter supplies, research procedures, the underlying health status 
of the participant, and any concurrent treatments or therapies not necessarily associated with the study. 
There might be other causes of AEs that we haven't considered. 


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8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
The PI, and Co-Is Dr. Cameron and Dr. Rodriquez will be the final arbiters of AE classification. 
8.3.3.1 SEVERITY OF EVENT 
This study will classify adverse events using the Common Terminology Criteria for Adverse Events 
(CTCAE) v4.0 from 2009: 
• 
Grade 1 - Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2 - Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL; impact on ADLs will be considered within the context of the 
individual participant's usual capacity. 
• 
Grade 3 - Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL*. 
• 
Grade 4 - Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 - Death related to AE. 
Under this classification system, UTIs are a "disorder characterized by an infectious process involving the 
urinary tract, most commonly the bladder or the urethra." The severity classification begins with grade 
2: 
• 
Grade 2 - Localized; local intervention indicated (e.g., topical antibiotic, antifungal, or antiviral) 
• 
Grade 3 - IV antibiotic, antifungal, or antiviral intervention indicated; radiologic or operative 
intervention indicated. 
• 
Grade 4 - Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 - Death 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
DEFINITELY RELATED 
• 
The event is a known effect of the drug, or procedure (e.g., listed in the protocol documents, 
consent, publications). 
• 
The event follows an obvious sequence of time, from the drug’s administration, or procedure, 
for which the event is directly attributed to the administration, implantation, activation, or 
procedure. 
• 
The event ceases with discontinuation of the drug, or procedure (and reoccurs on restarting). 
• 
The event includes data that was only collected for the study. 
• 
The event included disturbing or upsetting questions that the subject was asked for the purpose 
of the research. 
PROBABLY RELATED 


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• 
The event is a lesser known or suspected effect of the drug, or procedure (listed in the protocol 
documents including consent, publications, etc.) 
• 
The event follows a reasonable sequence of time from the drug’s administration, or procedure, 
for which the event may be attributed to the administration, or procedure. 
• 
The event ceases or diminishes with discontinuation of the drug, or procedure. 
POSSIBLE RELATED 
• 
The event is a lesser known or possible effect of the drug, or procedure. 
• 
The event occurred within a sequence of time from the drug’s administration, or procedure, for 
which the event may be attributed to the administration or procedure. 
• 
The event could be explained by the characteristics of the population under study. 
UNLIKELY RELATED 
• 
The event is NOT a previously known or suspected effect of the test drug, or procedure. 
• 
The event does NOT follow a sequence of time from drug administration, or procedure, for 
which the event could be attributed to the administration, or procedure. 
• 
The event can be readily explained by the characteristics of the population under study. 
NOT RELATED 
• 
The event is NOT known to be an effect of the test drug, or procedure. 
• 
The event does NOT follow a sequence of time from drug administration, or procedure, for 
which the event could be attributed to the administration, implantation, activation, or 
procedure. 
• 
The event can be readily and easily explained by the characteristics of the population under 
study. 
• 
Subject never received study drug or underwent research study procedure. 
8.3.3.3 EXPECTEDNESS 
The determination of expectedness is assessed based on the awareness of AEs previously observed, not 
on the basis of what might be anticipated from the properties of the study intervention. An AE will be 
considered "expected" if any of the following conditions are met: 
• 
The event is listed on the informed consent document. 
• 
The event is documented in the proposal to the National Institute on Disability, Independent 
Living and Rehabilitation Research, this protocol document or IRB application. 
• 
The event is listed as a side effect in the respective drug information materials for gentamicin 
and saline. 
• 
The event is identified in published literature or otherwise related to the study population (for 
example, UTIs would be expected, pressure sores would be expected, heart attack would not 
necessarily be expected given the characteristics of the study population, etc.). 


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8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
• 
Study staff will call or otherwise contact participants and/or their caregivers to assess for side 
effects, adverse events, UTI symptoms, etc. every two weeks for the duration of the study 
intervention.   
o 
Staff will ask about changes in health status since enrollment in the study. 
o 
Study staff will ask directed questions regarding specific side effects or difficulties related to 
the bladder instillation. 
• 
The reporting period for AEs will begin when the participant signs the main consent and end 30 days 
after the end of treatment.  
8.3.5 ADVERSE EVENT REPORTING 
 
This study will follow the standard Institutional Review Boards of the University of Michigan Medical 
School (IRBMED) reporting schedule for AEs. Refer to 
https://az.research.umich.edu/sites/default/files/Adverse%20Event%20Reporting%20Guidelines%20for
%20INTERNAL%20AEs%20Occurring%20at%20UM_1152018%20OUTWARD%20facing.pdffor a printable 
version. 
 
Briefly, this reporting schedule precludes reporting to IRBMED all expected non-serious events 
regardless of relatedness. These events will be recorded in the study record and evaluated for 
occurrence rates. If any event seems to occur in greater numbers than expected or are more severe 
than previously known, we will file a report with IRBMED and DSMB. 
8.3.6 SERIOUS ADVERSE EVENT REPORTING 
• 
All SAEs will be reviewed and evaluated by the PI and Dr. Cameron, and reported to the following 
groups: DSMB, IRBMED, and the Sponsor  
• 
SAEs or new clinical findings which meet the reporting requirements under the Federal Food, Drug, 
and Cosmetic Act and/or the Code of Federal Regulations will be reported to the FDA. 
o 
Any unexpected fatal or life-threatening suspected adverse reaction to the study product 
will be reported no later than 7 calendar days after initial receipt of the information. 
o 
Any (1) serious, unexpected suspected adverse reactions, (2) findings from other clinical, 
animal, or in-vitro studies that suggest significant human risk, and (3) a clinically important 
increase in the rate of a serious suspected adverse reaction will be reported no later than 15 
calendar days after determining that the information qualifies for reporting. 
• 
The study team will notify the participant's treating physician of any study product-related SAE. 


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• 
All SAEs will be followed until satisfactory resolution or until Dr. Cameron and/or the participant’s 
treating physician deem the event to be chronic or that the participant is stable. 
• 
The PI and study team will notify all parties of any unexpected fatal or life-threatening suspected 
adverse reaction to the study product as soon as possible, but no later than 7 days after becoming 
aware of the event. 
8.3.7 REPORTING EVENTS TO PARTICIPANTS 
In general, the occurrence of adverse events throughout the study will not be reported back to the 
participants.  Exceptions to this general policy include: 
• 
SAEs that are related to the study product. 
• 
Findings of the DSMB related to patterns of AE/SAE occurrence that might impact one’s decision 
to continue participation. 
 
Phone calls will be the primary method of communication in these cases and will be documented in the 
study record. 
 
8.3.8 EVENTS OF SPECIAL INTEREST 
We will document any challenges, difficulties or complaints associated with the following: 
• 
Delivery of study product. 
• 
Stability of study product. 
• 
Usability of study product and supplies. 
8.3.9 REPORTING OF PREGNANCY 
Pregnancy is not considered an adverse event, but it is an exclusion criterion for the study.  Individuals 
reporting a new pregnancy will discontinue their study intervention and will be withdrawn from the 
study. 
 
8.4 UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
We will use the IRBMED criteria to determine the occurrence of an unanticipated problem. All three 
criteria must be met for an occurrence to be deemed an UP. More guidance from IRBMED regarding UPs 
can be found at the following link: https://research.medicine.umich.edu/office-research/institutional-
review-boards-irbmed/guidance/adverse-events-aes-other-reportable-information-and-occurrences-
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1. The occurrence is unexpected in terms of nature, severity or frequency relative to what is 
written in this protocol document and IRBMED application and considering the characteristics of 
the study population. 
2. The occurrence is related or possibly related to participation in this study with "possibly 
related" defined as there being a "reasonable possibility that the incidence, experience, or 
outcome may have been caused by the procedures. 
3. Suggests that participants or others are at greater risk than previously thought. 
8.4.2 UNANTICIPATED PROBLEM REPORTING 
• 
Unanticipated problems that are also SAEs will follow the SAE reporting schedule and guidelines. 
• 
Unanticipated problems that are not associated with an SAE will be reported to the DSMB, 
IRBMED, the Sponsor within 14 days of the study team becoming aware of the problem. 
• 
Reports will include the following information: 
o 
Description of the problem, i.e., what occurred, how it occurred, any outcome, etc. 
o 
Discussion of why the event is considered an unanticipated problem. 
o 
A corrective action plan. 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
Participants will be notified forthwith about problems that directly impact their current risk level or 
potentially impact their decision to remain enrolled in the study. Examples of problems that would 
require prompt reporting: 
• 
Contamination of study product. 
• 
Problems leading to injury or illness related to study supplies (e.g. catheter tips or syringes). 
• 
Breach of confidentiality. 
Phone calls will be the primary method of communication in these cases, and will be documented din 
the study record. 


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9 STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESES 
Our primary hypothesis (H1) is that during the six-month treatment period, incidence of UTIs will be 
significantly lower than it had been during the six months prior to the treatment period.  Our Secondary 
Hypothesis (H2) states that there will be significantly fewer bladder and bowel complications as 
reported on the various patient-reported outcome measures at the end of treatment than there had 
been on the baseline interview, just prior to the start of treatment. 
 
Our tertiary hypotheses (H3 and H4) center on health-related quality of life and community 
participation. We expect that at the end of the treatment period, QOL will be significantly higher than it 
had been at the time of the baseline interview, prior to treatment (H3). Similarly, we expect that at the 
end of the treatment period, community participation will be significantly better than it had been at the 
time of the baseline interview (H4). 
9.2 SAMPLE SIZE DETERMINATION 
Power calculations were conducted based on the primary hypothesis that incidence of UTIs will be 
significantly lower during the treatment period (gentamicin + saline) than during the prior six months. 
 
In calculating power, we assume that during the study period, there will be a 50% reduction in 
UTIs from the number that participant experienced during the prior six months, which serves 
as the control period. These assumptions are based on the findings of a six-month retrospective study 
of gentamicin.22 Calculations of power were conducted assuming that paired samples t-tests will be used 
to assess the first hypothesis. While we may consider using other additional ways of determining 
differences in UTIs between the baseline and trial periods, paired samples t-tests will be used at least 
initially. Because we are working with count rather than continuous data, the t-tests will be conducted 
using natural log-transformed infection rates rather than the raw rates. Based on our assumptions, the 
sample size needed to have a power of at least 80% will be 15. This is the necessary sample size of 
participants who complete the study. SPSS version 28 was used to conduct this power analysis. 
 
9.3 POPULATIONS FOR ANALYSES 
The primary analyses will be conducted including those participants who have used Gentamicin flushes 
for at least half of the days during their 6-month intervention period if data is available for the number 
of UTIs that they experience during the period when they are using these flushes. Additional analyses 
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9.4 STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
All data will be examined for completeness and outliers before hypothesis testing. Categorical data will 
be summarized in terms of frequencies, presented as n (%), and continuous data will be summarized in 
terms of means (standard deviations). Participant demographics and clinical status will be evaluated 
using descriptive statistics. These analyses will be conducted after all data has been collected. All efforts 
will be made to recruit a balanced sample representative of persons with SCI/D. Missing data will be 
handled using common statistical methods such as multiple imputation and the estimation maximization 
approach. 
 
All statistical procedures will be run using either SPSS28 or the statistical package R.29 Statistical 
significance will be set at p < 0.05 for group comparisons and all models. 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
To test for significant differences in the incidence of UTIs across periods, as mentioned above, paired 
samples t-tests will be conducted using log-transformed infection rates rather than the raw rates. We 
may than subsequently re-analyze this data using a Generalized Linear Mixed Model (GLMM) with log 
link and a Poisson distribution, as is appropriate for count outcomes data.   
9.4.3 ANALYSIS OF THE SECONDARY AND TERITIARY ENDPOINT(S) 
To assess the impact of the study intervention on our Secondary Endpoint, bladder, and bowel 
complications (Hypothesis 2), and Tertiary Endpoints, QOL (Hypothesis 3), and Participation (Hypothesis 
4), a similar analytic approach will be used as was used for Hypothesis 1. The outcomes for these 
hypotheses are all continuous and therefore paired t tests or GLMM will be used. Our plan for handling 
missing data across all study analyses will include the use of common statistical methods to handle 
missing data such as multiple imputation and the estimation maximization approach. As appropriate, we 
may employ sensitivity analysis to assess the effect of data that is not missing at random such as when 
participants stop using the research treatment but continue to be willing to participate in the study’s 
assessments. 
9.4.4 SAFETY ANALYSES 
The study team will ask about adverse events at the bi-weekly phone calls.  The frequency of events will 
be monitored by the study coordinator and reported to the PI and co-Investigators at regular meetings.  
Instances in which the frequency of total events or of any event seem higher than expected will be 
referred to the DSMB for further review. 
 
In the event that any participant dies during their study participation, the investigators will determine if 
this is related to the study intervention and document the cause of death regardless. The DSMB will be 
provided with this information along with that about other adverse events. 


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9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Participants will be characterized using standard demographic variables (e.g. age, sex, etc.) and clinical 
status (age at injury, level of injury, completeness of injury, etc.) 
9.4.6 PLANNED INTERIM ANALYSES 
The use of our study design results in no complete data being ready to be analyzed until at least six 
months into the conduct of the intervention.  Given this, the timeframe for all data collection and the 
intended sample size, meaningful interim analyses will not be viable to conduct. 
9.4.7 SUB-GROUP ANALYSES 
Again, given the small sample size, planned group analyses are unlikely except for review of 
characteristics associated with completion vs. non-completion of the study. 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Available participant data from each time point will be retained in the study dataset. 
9.4.9 EXPLORATORY ANALYSES 
We do not have any exploratory analyses planned. 
 
 


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
Section 10.1 makes repeated references to remote interviews, which will be conducted via an 
encrypted, HIPAA-compliant video conferencing platform (e.g., Blue Jeans, Zoom for Health, etc.) 
It will be standard practice to conduct as many procedures remotely as possible to better protect 
subject/caregiver(s) and staff against the risk of COVID-19. However, in cases where a remote 
video interview is not possible, remote telephone visits will be conducted and the study will follow 
all UM guidelines for proper e-consenting. Baseline interviews may also be completed at U-M 
clinics, if participants prefer, following all U-M COVID-19 guidelines. 
10.1.1 INFORMED CONSENT PROCESS 
The informed consent process will center on providing sufficient and usable information that allows an 
individual to make a choice about whether to participate in the study. A copy of the consent document 
will be provided (e.g., mailed or emailed) prior to the remote or in-person baseline interview. Individuals 
will be encouraged to discuss the merits of participation with their caregiver, families, and physician. 
The actual consent dialog will occur during the remote baseline interview. Baseline visits can also be 
conducted in person, at U-M clinics adjacent to patient appointments, if participants prefer, following all 
U-M COVID-19 guidelines. 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Participants will be provided with either an electronic or physical copy of their signed and dated consent 
document. If consent is obtained using a mailed copy of the consent, which participants send back after 
signing, they will be resent a physical copy after all signatures are included. If consent is provided 
electronically, a physical copy will be mailed to participants, upon their request. The signed consent will 
be uploaded to the participants’ electronic medical record. 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent will be obtained prior to the beginning of the baseline visit. The dialog will follow the 
IRBMED-approved consent document and cover sheet with an emphasis on participant responsibilities, 
the risk-benefit profile, and the voluntary nature of research participation (including the right to 
withdraw without prejudice). A member of the study team will lead the discussion, allowing time for and 
encouraging questions along the way. Visual materials (such as mock study supplies and written 
materials) will be available during the consent dialog to assist the patient and their caregiver in deciding 
about participation. Electronic informed consent signatures will be collected using SignNow. All 
procedures will adhere to the IRBMED Guidance for use of SignNow for Electronic Informed Consent 
Procedures. If subjects are unable to use SignNow for consenting, e.g., if they do not have a computer 
for this purpose, of if they do not wish to, a physical version of the consent document can be mailed to 
them to sign and return, in a provided, stamped envelope. Also, if participants choose to do the baseline 


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interview at a U-M clinic location, e.g., prior to or following a clinic visit, the consent will be provided to 
them at that time, though a copy may be sent to them prior to this appointment to review. 
 
Individuals can elect to withhold informed consent without prejudice and can be rescheduled for 
another baseline appointment if desired. Regardless, study procedures will not be administered without 
a valid documented consent document. 
 
The original electronically signed and dated consent document (or physically singed consent) will 
confirm the provision of voluntary and informed agreement of the participant to enroll in the study. For 
individuals who are unable to sign the consent electronically or physically due to upper extremity 
paralysis, a witness who is unassociated with the study will be made available during the consent 
process. This person will electronically or physically sign the consent document, verifying that they have 
witnessed the individual providing assent. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
If suspension of study activities or a premature end to the study is necessary, relevant parties will be 
notified in writing, and/or via a phone call.  For example, the research team will notify participants by 
phone, e-mail and/or  letter in the event the study is terminated for any reason prior to its conclusion. It 
will be the PI’s responsibility working with his/her study team to follow-up with other invested entities, 
e.g., IRBMED and Sponsor, the FDA, etc., and will provide the reason(s) for the termination or 
suspension. 
 
Circumstances that might result in early termination of the study include: 
• 
Occurrence of unexpected, significant, or unacceptable risks. 
• 
Demonstration of efficacy suggesting further observation is unnecessary. 
• 
Insufficient compliance to protocol rendering insufficient or invalid data for analysis of primary 
outcome. 
• 
Demonstration of futility (e.g., inability to recruit and retain participants). 
• 
Lack of key resources needed for the trial (i.e. drug supply) and funding challenges. 
The study may resume provided reason(s) for early termination have been adequately addressed and 
approved by the relevant oversight agencies. 
10.1.3 CONFIDENTIALITY AND PRIVACY 
This study will follow all national and institutional regulations and safeguards to protect participant 
confidentiality and privacy. An individual's research data (e.g., outcome assessments like surveys and lab 
results), clinical data and demographics (information abstracted from the EMR and patient-report), and 
contact information (e.g. telephone number, address, etc.) are all protected by institutional 
confidentiality practices. 


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• 
Access to study data is granted based on the need for completion of job-role responsibilities and 
to uphold patient safety. The types of data accessible will include but are not limited to data 
collected for research purposes (e.g., patient-reported outcomes), results of urine analysis in the 
EMR, other relevant medical records, Research Pharmacy records, and contact information, etc. 
o 
Data or other participant information will not be released to an unauthorized individual 
or entity (i.e., agents not listed Section 9 of the consent document) without approval 
from the PI and/or participant. 
• 
Research procedures, including the consent process, will be conducted in as private a setting as 
possible. Likely locations include private rooms dedicated to research and exam or conference 
rooms located within the clinic. 
• 
Participants will be assigned a unique alphanumeric code to identify their research records. Case 
report forms will be labeled with this identifier rather than an individual's name. The link 
between an individual and their code will be stored in a HIPAA-compliant database (e.g., 
REDCap, OnCore Clinical Trials Management System, etc.) Both systems allow for role-based 
restrictions on data access and download. 
• 
All files will be in electronic form, unless otherwise specified. 
• 
All electronic files will be maintained behind Michigan Medicine firewalls and require passwords 
for access. 
 
The individuals who are most likely to access all or some of the research data and information include: 
• 
Study team members involved in the day-to-day operations (e.g., project manager, study 
coordinator, PI, research assistant, etc.)  will be responsible for maintaining study databases and 
research files in a manner conducive to preserving participant confidentiality and privacy. 
• 
Research Pharmacy staff - will require access to participant contact information. 
• 
Members of the Data Safety Monitoring Board (DSMB) - will have full access to participant 
information and research data. Specific data will be prepared and provided by the study team 
for review at the DSMB's request. 
• 
Study Monitor (MICHR staff) – will also have widespread access upon request. 
• 
Data analysts & statisticians - will primarily use coded data sets in their day-to-day work, unless 
identifying information is required to evaluate safety endpoints. 
• 
Co-investigators - will have access to full study records upon request. 


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10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA 
As a rule, data generated from this study will be retained for future to-be-determined analyses in the 
development of additional research projects. The electronic and paper files will be housed at Michigan 
Medicine under the PI's oversight. Data will be stored and archived according to federal and institutional 
guidelines (https://research.medicine.umich.edu/office-research/institutional-review-boards-
irbmed/guidance/record-keeping-guidelines). 
• 
In general, consent documentation (including HIPAA authorization) and all research records will 
be retained for 7 years from study completion or publication of the primary manuscript, 
whichever is later. 
• 
Participant contact information and demographics will be preserved in the OnCore clinical trials 
management system and will be retained indefinitely.  Individual subject identifiers will not be 
stored in this system but will be managed in a separate HIPAA-compliant database.  
o 
The link between participant and their unique ID will be severed after publications of 
primary manuscripts. 
• 
Urine samples may be retained for subjects who opt-in (via the consent). These samples may be 
used in future studies for analysis of the microbiome of the urine. 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
DSMB 
Denise Tate, PhD 
Michael Geisser, PhD (chair); Kate Kraft, 
MD; Shokoufeh Khalatbari, MS 
Study Physicians, Prescribers, & Co-
Investigators 
 
Anne Cameron, MD 
 
Gianna Rodriguez, MD 
 
Patricia Maymi-Castrodad, MD 
 
 
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the following expertise and/or qualifications:  
• 
Clinical knowledge of patient population and study intervention products, e.g., urologists, 
pharmacists, PM&R physicians treating patients with SCI, etc. 
• 
Statistics 
• 
Independent from the day-to-day study conduct 


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• 
Generally free of conflicts of interest (COI)  
o 
In the case of appearance of a COI or potential COI, we will put in place adequate 
measures and practices to minimize bias.  
The DSMB will meet on an enrollment-based schedule. For every ten subjects which complete their 6-
month intervention, the DSMB members will convene to assess safety and efficacy when appropriate, 
comparing data from the six-month period prior to enrollment with that obtained during the treatment 
period. The DSMB will operate under the rules of an approved charter that will be written and reviewed 
at the organizational meeting of the DSMB. At this time, each data element that the DSMB needs to 
assess will be clearly defined. The DSMB will provide its input to the study team and the Sponsor, when 
appropriate. They will be provided with periodical updates on study participants, AEs and SAEs as well as 
other issues encountered during the conduct of this trial.   
10.1.7 CLINICAL MONITORING 
Clinical site monitoring will be conducted by Michigan Institute for Clinical and Health Research Study 
Monitoring staff. The assigned individual will review study procedures and documentation to ensure the 
following: 
• 
Participants' rights and well-being are protected. 
• 
Reported data are completed, verified and accurate. 
• 
Trial is being conducted in accordance with good clinical practice. 
• 
Regulatory requirements (e.g., IRBMED and clincialtrials.gov) reporting requirements are up-to-
date. 
• 
The assigned monitor will review periodically at their discretion. 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
The responsibility for upholding quality assurance and control practices will involve an engaged PI and 
project manager in close concert with other study staff. Regular meetings and documented routine 
communications will provide a record of study activities. Meetings of the study team (e.g., PI, Co-
Investigators, project manager and coordinator/research assistants) will focus on accrual and 
withdrawal updates, challenges and problem-solving related to recruitment, AE/ORIO/UP updates, and 
any other issue relating to the day-to-day operations of the study.  Full details of study procedures and 
quality control practices will be described in the Manual of Operations. Minutes will be generated for all 
weekly meetings. 
10.1.9 DATA HANDLING AND RECORD KEEPING 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
Day-to-day data collection and management will be the responsibility of the study coordinator(s) or 
other study staff, with the project manager (Martin Forchheimer, MPP) providing managerial and 
statistical oversight.  Source data are defined as: 
• 
Survey responses of participants whether via electronic direct-entry or using paper and pencil 


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• 
EMR for enumeration of UTIs documented on appropriate case report form (CRF). 
• 
Participant dosing log for compliance with medication protocol. 
• 
Participant-report of clinical status updates and data regarding concomitant medication will be 
recorded on the appropriate case report form. 
• 
Adverse events as reported by participant or as indicated in the EMR will be documented on the 
appropriate case report form. 
 
All CRFs and study documents will be completed electronically except for participants dosing logs, 
reviewed for accuracy, and stored in the participant research record within the secured database.   
 
All study data (e.g., outcome data, encounter records, adverse events, etc.) will be stored in a REDCap 
database supported by the Michigan Medicine IT infrastructure.  Data base quality checks will be 
conducted by the project manager and/or study coordinator to determine missing information, and data 
inconsistencies.  
10.1.9.2 STUDY RECORDS RETENTION 
Data will be stored and archived according to federal and institutional guidelines 
(https://research.medicine.umich.edu/office-research/institutional-review-boards-
irbmed/guidance/record-keeping-guidelines).  
• 
In general, consent documentation (including HIPAA authorization) and all paper research 
records will be retained for 7 years from study completion or publication of the primary 
manuscript, whichever is later. 
• 
Electronic files will be retained indefinitely, though participant identifiers (participant ID, MRN, 
clinic visit dates, etc.) will deleted or adjusted to ensure anonymity after the publications of 
primary manuscripts.  
10.1.10 PROTOCOL DEVIATIONS 
For the purposes of this study, a protocol deviation is defined as any deviation, whether intentional or 
otherwise, from the protocol with respect to eligibility, study procedures and data collection arising 
from actions on the part of the participant, the study team or other entity (e.g., MLabs runs the wrong 
test).  Details related to protocol deviations documentation and reporting will be included in the Manual 
of Operations.  As with AEs, SAEs and unanticipated problems (Ups), the occurrence of protocol 
deviations will be routinely discussed at regular study team meetings.   
• 
Deviations will be documented in the study record. 
• 
Appropriate corrective plans will be developed and implemented where applicable. 
• 
Deviations will be reported according to the Event Reporting schedule and/or IRBMED standard 
reporting guidelines. 
• 
Deviations will be reviewed for frequency and degree of impact on participant safety and data 
integrity at regular study team meetings. 


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10.1.11 PUBLICATION AND DATA SHARING POLICY 
This study will abide by FDA, NIH and IMJE requirements to share information about this study via timely 
registration, updates, and results reporting in clinicaltrials.gov.  The informed consent document will 
include statements to inform participants of this fact.  The results of the primary analyses will be 
submitted to a peer-reviewed journal for digital archiving in PubMed Central upon acceptance for 
publication. 
10.1.12 CONFLICT OF INTEREST POLICY 
The study team will follow the Michigan Medicine policies on conflict of interest.  Conflict of interest 
management plans will be developed and upheld for any member of the study with an actual or 
apparent conflict.  Management plans will include appropriate disclosure and mitigating practices to 
minimize effects on participant well-being and data integrity. 
 
10.2 ADDITIONAL CONSIDERATIONS 
N/A 
10.3 ABBREVIATIONS 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CIC 
Clean Intermittent Catheterization 
CRF 
Case Report Form 
CBC 
Complete Blood Count 
CT 
Clinical Trial 
DSMB 
Data Safety Monitoring Board 
EMR 
Electronic Medical Record 
FDA 
Food and Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IRBMED Institutional Review Boards of the University of Michigan Medical School 
MIAP 
Michigan Institute for Clinical and Health Research Investigator Assistance Program 
MICHR 
Michigan Institute for Clinical and Health Research 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIDILRR National Institute on Disability, Independent Living and Rehabilitation Research 
NIH 
National Institutes of Health 
PI 
Principal Investigator 
QOL 
Quality of Life 
SAE 
Serious Adverse Event 


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SAP 
Statistical Analysis Plan 
SCD 
Spinal Cord Disease 
SCI 
Spinal Cord Injury 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UA 
Urinalysis 
UP 
Unanticipated Problem 
US 
United States 
UTI 
Urinary Tract Infection 
 
10.4 PROTOCOL AMENDMENT HISTORY 
 
 
Date 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
14 MAR 2018 6.3, 10.1.3, 
10.1.7 
Added language on clinical monitoring 
This study is now an FDA IND 
trial and will require clinical 
monitoring 
14 MAR 2018 8.3.6 
Added language on FDA reporting 
FDA reporting is required for 
the same reason as above 
11 JUN 2018 
6.1.2 
Clarified order of instillation process 
Was unclear per MICHR safety 
monitoring group 
09 JUL 2018 
2.3.3, 5.1, 5.5, 
6.1.2, 7.3 
Changed assessment of risk, clarified 
inclusion criteria, training materials, 
recruitment methods 
IRB comments 
09 JUL 2018 
6.3, 7.2 
Clarified using blocking randomization, 
treatment discontinuation 
FDA comments 
25 OCT 2018 
4.4, 5.2, 10.1.5, 
10.1.6 
Clarified washout period, Clarified 
eligibility criteria, Listed DSMB members 
names, revised DSMB meeting schedule 
Per DSMB request 
3 SEP 2019 
4.3 
Clarified dosing instructions 
FDA comments 
28 May 2020 1.3, 6.1.1, 6.2.4 Clarified shipping frequency window 
Per MICHR monitor’s 
suggestion 
13 July 2020 
6.1, 8.1, 10.1 
Included COVID-19 
procedures/precautions 
Per Michigan Medicine, U of 
M, IRB requirements 
13 October 
2020 
1.3, 7.1 
Assigned superscript number to 
schedule of activities SOA), added 
language regarding continued study 
participation of COVID-19 patients 
FDA comments 
17 March 2021 4.1-4.4, 5.1, 6.1, 
6.3 
Change in study design 
Change the study design from 
a randomized cross-over trial 


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to a pre- post design in which 
all participants receive the 
active study drug. The study 
will assess the difference in 
the number of UTIs during 
treatment to the number that 
occurred in the six months 
prior to their start in the trial.  
30 November 
2021 
1.3, 3, 4.4, 5.2, 
6.1 
Addition of study event 
Added 3-month post-
intervention follow-up 
interview 
6 July 2022 
1.3, 8.1 
Remove special contact of participants 
to do COVID screening by study staff 
prior to conduct of laboratory 
assessments 
Such screening is part of 
standard practice for of all in-
person clinical contact and 
thus, does not need to be 
conducted by the study team. 
3 October 
2022 
10.1 
Allow for informed consent and study 
visits to be conducted in person 
Adding these options may 
reduce burden for study 
participants 
5 December 
2022 
1.2, 1.3, 5.2, 5.4, 
6.5, 7.3 
Allow for follow up information to be 
collected from participants’ medical 
records. Clarify screen failure 
assessment.  
Necessary data may be 
collected even if participants 
are lost to follow up 
1 March 2023 1.2, 6.1.1, 8.1, 
8.3.4, 10.1.5 
Reconcile discrepancies in the calendar, 
provide a timeline for AEs, addition of a 
co-investigator 
Clarified which assessments 
will be performed at each visit 
and when AEs will be 
recorded 
 


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