The ProVee Urethral Expander System Clinical Study
Phase: NA
Conditions: BPH With Symptomatic Lower Urinary Tract Symptoms
Sponsor: ProVerum Medical

  
The ProVIDE Study
Clinical Investigation Plan 
Protocol Number:
CIP 002 Rev 04
NCT Number:                       NCT05186740
Product: 
ProVee Urethral Expander System
Protocol Ref: 
CIP 002 
IDE Study Sponsor:
ProVerum Inc.
1101 Sylvan Ave
Suite A1A Modesto
CA 95350
Global P.I:
Date of Issue:
28 September 2023
Statement of Confidentiality:
The investigation described in this protocol involves a significant risk device as defined by the Investigational Device Exemption 
(IDE) regulation, Part 12, of the Code of Federal Regulations, Food and Drug Administration (FDA). This protocol contains 
confidential and proprietary information and shall not be duplicated, disclosed to others, or used for purposes other than to carry 
out the intent for which this document is delivered. This protocol is for use by the Investigators and their designated representatives 
participating in this clinical investigation. Do not copy of distribute without written permission from ProVerum Inc.
 
 

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The ProVIDE Study Clinical Investigation Plan 
Investigational site number:  ___________________________________
I, the undersigned, have read and understand the protocol specified above and agree on its content. 
I agree to perform and conduct the study as described in the clinical investigation plan and in 
accordance with the relevant parts of the ICH Guidelines for Good Clinical Practice (GCP), 
applicable United States (US) Code of Federal Regulations (CFR) including but not limited to 45 
CFR Part 46, 21 CFR parts 812, 50, 54, 56, the International Standard ISO 14155 (Clinical 
Investigation of Medical Devices for Human Subjects), ethical principles that have their origins in 
the Declaration of Helsinki, and pertinent individual country laws and regulations. In addition, 
when applicable, I agree to enlist sub-investigators who also agree to perform and conduct the 
study as described in the protocol. 
Principal Investigator (Print Name):
Principal Investigator (Signature):
Date :
Sponsor (Signature):
Date :

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Table of Contents
Protocol Signature Page.................................................................................................................. 1
Study Contacts ................................................................................................................................ 3
1.0
Protocol Summary ............................................................................................................... 7
1.1.
Study Synopsis.....................................................................................................7
1.2.
Patient Flow Chart and Schedule of Activities ..................................................15
2.0
Introduction........................................................................................................................ 17
2.1.
Study Rationale ..................................................................................................17
2.2.
Background ........................................................................................................18
2.3.
Risk/Benefit Assessment....................................................................................23
3.0
Objectives And Endpoints ................................................................................................. 24
3.1.
Study Objective..................................................................................................24
3.2.
Primary Endpoints..............................................................................................24
3.3.
Secondary Safety Endpoints...............................................................................25
4.0
Study Design...................................................................................................................... 27
4.1.
Overall Design....................................................................................................27
4.2.
Cohort Description .............................................................................................27
5.0
Study Population................................................................................................................ 29
5.1.
Inclusion Criteria................................................................................................29
5.2.
Exclusion Criteria...............................................................................................29
5.3.
Strategies For Recruitment And Retention ........................................................32
5.4.
Screen Failures ...................................................................................................32
6.0
Study Assessments And Procedures .................................................................................. 32
6.1.
Informed Consent...............................................................................................32

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6.2.
Screening Assessment........................................................................................33
6.3.
Study Randomization.........................................................................................36
6.4.
Index Procedure (Treatment) .............................................................................36
6.5.
Post-procedure / Discharge ................................................................................36
6.6.
Performance of Assessments and Procedures ....................................................37
6.7.
Follow-up Assessments......................................................................................39
6.8.
Study Follow-up Timepoints..............................................................................39
6.9.
Cross Over following 3 month Follow-up .........................................................42
6.10. Subject Retreatment ...........................................................................................46
6.11. End Of Study Definition ....................................................................................47
6.12. Adverse Events And Serious Adverse Events....................................................47
7.0
Preparation/Handling/Storage/Accountability................................................................... 51
7.1.
Acquisition And Accountability.........................................................................51
7.2.
Formulation, Appearance, Packaging, And Labeling ........................................52
7.3.
Product Storage And Stability............................................................................52
7.4.
Preparation .........................................................................................................53
8.0
Measures To Minimize Bias: Randomization And Blinding............................................. 55
8.2.
Study Intervention Compliance..........................................................................57
8.3.
Concomitant Therapy.........................................................................................57
9.0
Study Intervention Discontinuation And Participant Discontinuation/Withdrawal .......... 58
9.1.
Participant Discontinuation/Withdrawal From The Study.................................58
9.2.
Lost To Follow-Up.............................................................................................59
10.0
Statistical Considerations................................................................................................... 59
10.1. Study Success.....................................................................................................59
10.2. Analysis Cohorts ................................................................................................61

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10.3. Derived Data ......................................................................................................62
10.4. Statistical Methods.............................................................................................62
10.5. Handling of Dropouts and Missing Data............................................................63
10.6. Poolability ..........................................................................................................64
10.7. Sensitivity Analyses...........................................................................................65
10.8. Subgroup Analyses.............................................................................................66
10.9. Sample Size Determination................................................................................66
10.10. Power to Pass Both Co-Primary Objectives Simultaneously.............................67
10.11. Sample Size Justification – Safety .....................................................................68
11.0
Supporting Documentation And Operational Considerations ........................................... 68
11.1. Regulatory, Ethical, And Study Oversight Considerations................................68
11.2. Abbreviations .....................................................................................................73
11.3. Protocol Amendment History.............................................................................77
12.0
Study Definitions ............................................................................................................... 78
13.0
References.......................................................................................................................... 81

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19. Taking androgens, unless eugonadal state for at least 3 months or greater with 
a stable dosage for at least 2 months as documented by the Investigator
20. Use of 5-alpha-reductase inhibitors (e.g., dutasteride, finasteride) within 6
months of baseline assessment
21. Use of Phenylephrine / Pseudoephedrine within 24 hours of baseline 
assessment
22. Use of alpha-blockers (e.g., Terazosin, Doxazosin, Alfuzosin, Tamsulosin) 
within 2 weeks of baseline assessment
23. Use of estrogen or drug-producing androgen suppression (e.g. gonadotropin-
releasing hormonal analogues) within 1 year of baseline assessment
24. Use of antihistamines, anticonvulsants, and antispasmodics within 1 week of 
baseline assessment unless there is documented evidence that the patient was 
on the same drug dose for at least 6 months with a stable voiding pattern (the 
drug dose should not be altered or discontinued for entrance into or 
throughout the study)
25. Use of anticholinergics or cholinergic medication within 2 weeks of baseline 
assessment
26. Use of beta-blockers where the dose is not stable. (Stable dose is defined as 
having the same medication and dose in the last 6 months)
27. Use of Phosphodiesterase-5 Enzyme Inhibitors in doses for BPH within 2 
weeks of baseline assessment 
28. Current treatment with anticoagulants (e.g., coumadin or enoxaparin) or 
antiplatelet medications other than aspirin (e.g., clopidogrel, or alternative and 
ASA). Patient unable to stop taking anticoagulants and/or antiplatelets within 
3 days prior to the procedure or coumadin at least 5 days prior to the 
procedure. Low dose aspirin
100mg/day not prohibited
29. Future fertility concerns 
30. Previous prostate surgery, balloon dilatation, stent implantation, laser 
prostatectomy, hyperthermia, or any other invasive treatment to the prostate; 
including penile implants
31. Previous pelvic irradiation or radical pelvic surgery
32. Previous rectal surgery (other than hemorrhoidectomy) or known history of 
rectal disease

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1.2. Patient Flow Chart and Schedule of Activities 
The patient flow chart is provided in Figure 1 and the schedule of study activities in contained in 
Table 1. 

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2.0 Introduction 
 
 
 
 
  
2.1.  Study Rationale  
Benign prostatic hyperplasia (BPH) refers to the non-malignant proliferation of smooth muscle 
and epithelial cells within the prostatic transition zone resulting in an enlargement of the prostate 
gland. It is estimated to occur in more than 50% of men in their 60s, growing to 90% of men in 
their 80s, and is the fourth most common diagnosed disease in men above 50 years old, ranking 
behind coronary artery disease, hypertension and type 2 diabetes1. Patients often present with 
lower urinary tract symptoms (LUTS), secondary to BPH. These symptoms, which include 
urgency, frequency, retention of urine, difficulty in voiding/emptying of the bladder and problems 
following urination such as post void dribbling, have a major impact on quality of life and require 
treatment1–3. 
The main goal of BPH treatment is to alleviate LUTS in order to improve the patient’s quality of 
life,  options are drug therapy or surgical intervention. 
 Drug Therapy - Whilst there is no pharmacological cure for BPH, drug therapy is often 
the first line treatment option and is used to manage symptoms by either shrinking the 
prostate (5-alpha reductase inhibitors) or relaxing muscles surrounding the prostate (alpha 
blockers). In some instances, patients may be prescribed a combination of both drugs 
(CombiRx)3. While medication can provide relief for some men, limited efficacy4 and 
negative side effects contribute to poor compliance, with up to 82% of men electing to 
discontinue drug therapy within one year5. 
 Surgical Intervention – Traditionally, surgical intervention has involved removal of the 
obstructing tissue from the prostate gland typically via resection.  Whilst invasive, this 
Transurethral Resection of the Prostate (TURP) and surgical equivalents are considered to 

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be the cornerstone of LUTS surgical treatment delivering durable outcomes as shown by 
studies with a follow-up of 8-22 years6.  Despite generally providing longer lasting 
symptomatic relief, less than 3% of BPH patients elect to undergo resective surgery due to 
the potential side effects, such as urinary incontinence, erectile dysfunction and ejaculatory 
dysfunction, associated with the procedures6.  More recently Minimally Invasive Surgical 
Therapies (MISTs) are recommended for the treatment of LUTS.  These non-resective 
procedures re-shape the prostate by means of a medical device and offer patients a 
treatment solution with greater efficacy than medication and fewer complications than 
resective surgery6,7.  
 
 
2.2. Background
2.2.1. Benign Prostatic Hyperplasia (BPH)
Benign prostatic hyperplasia is a histologic diagnosis that refers to the proliferation of smooth 
muscle and epithelial cells within the prostatic transition zone. In clinical BPH abnormal prostate 
anatomy will result from the excessive proliferation, resulting in a varying degree of benign 
prostatic obstruction (BPO) and benign prostatic enlargement (BPE)1.
It is the lower urinary tract symptoms (LUTS), secondary to BPH, due to BPO and BPE that are a 
common problem among men with a major impact on quality of life (QoL), and substantial 
economic burden. Symptoms increase in frequency and severity with age and include symptoms 
prior to urination related to frequency, urgency, retention of urine and difficulty voiding/emptying 
of the bladder and problems following urination related to post void dribbling1,3.
2.2.2. Current Treatment Options
 
 

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.
2.2.3.
Drug Therapy
The two main class of medications are
-blockers) and
-
reductase inhibitors (5-ARIs):
-blockers aim to inhibit the effect of endogenously released noradrenaline on smooth 
muscle cells in the prostate and thereby reduce prostate tone and bladder outlet 
obstruction.  
-reductase inhibitors reduce levels of dihydrotestosterone (DHT) inducing apoptosis of 
prostate epithelial cells leading to a reduction in prostate size.
 
 
 
 
 
2.2.4. BPH Surgery
Surgical treatment of symptomatic BPH has classically involved removal of the obstructing 
adenomatous tissue from the prostate gland typically via Transurethral Resection of the Prostate 
(TURP) using monopolar electroconductivity where tissue is cored out with a heated wire loop, 
simultaneously cutting and cauterizing the tissue. In addition to TURP there are a variety of 
modifications and alternatives technologies that all involve tissue resection or ablation. These 
procedures include bipolar TURP (BTURP), water vapor thermal therapy known as transurethral 
vaporisation of the prostate (TUVP), laser enucleation and resection of the prostate using holmium 
laser(HoLEP),
thulium:yttrium-aluminium-garnet
laser(Tm:YAG) 
or
a
Photoselective
Vaporization of the Prostate (PVP) Greenlight laser.

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2.2.6. Design Verification and Biocompatibility Studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.2.7. Clinical Experience (First in Man)  
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
   
 

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2.3. Risk/Benefit Assessment 
To evaluate device related risk, ProVerum performed a risk analysis in accordance with the 
harmonized European standard ISO 14971 “Medical Devices – Application of Risk Management 
to Medical Devices”. 
2.3.1. Known Potential Risks
Risk associated with the use of a minimally invasive devices such as the ProVee device include 
but are not limited to:
Dysuria 
Haematuria 
Urge Incontinence 
Urinary Calculus
Pain Pelvic and/ or with Ejaculation
Acute Urinary Retention
Urinary Tract Infection
Urinary Incontinence
Micturition Urgency
Pollakiuria
Nocturia
Temporary Prostatic Urethral Inflammation

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Urethral Stricture
2.3.2.
Known Potential Benefits
 
 
 
 
 
 
2.3.3. Assessment Of Potential Risks And Benefits
 
 
 
 
 
 
 
3.0 Objectives And Endpoints
3.1. Study Objective 
To evaluate the safety and effectiveness of the ProVee Device in subjects with lower urinary tract 
symptoms secondary to Benign Prostatic Hyperplasia (BPH). The primary endpoints are defined 
in section 3.2 and the secondary endpoints are specified in section 3.3. 
3.2. Primary Endpoints
3.2.1. Primary Safety Endpoint 
1. Adverse Events (time frame: procedure to 12 months)
Rate of device or procedure related serious adverse events through 12-months.

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2. Need for urinary catheterization (time frame: >7 days post procedure)
The rate of extended post-operative urinary catheterization (> 7 days from treatment) for 
inability to void among patients treated with the ProVee Device.
3.2.2. Primary Effectiveness Endpoints
1.
Reduction in BPH Symptoms compared to Sham (time frame: procedure to 3 months)
The ProVee Treatment Arm will be considered superior to the Sham Treatment Arm when 
the mean 3-month improvement from baseline score for the IPSS symptom questionnaire 
demonstrates a minimum statistical margin of 25% compared to mean improvement from 
baseline for the Sham Treatment Arm alone.
2.
Symptoms Improvement (time frame: Procedure to 12 months)
The mean percent change in IPSS in the treatment arm is at least 30% improvement over the 
patient's pre-treatment baseline score.
3.3. Secondary Safety Endpoints  
  
 

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3.3.2. Secondary Effectiveness Endpoints  
1. Long
 
 
 
 
 

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6.
 
 
4.0 Study Design
4.1. Overall Design
This is a prospective, multi-center, 2:1 randomized, double-blind, sham-controlled study to 
evaluate the safety, performance, and effectiveness of the ProVee Device (Investigational Device) 
when used in subjects with symptomatic urinary obstruction related to benign prostatic hyperplasia 
(BPH).  
The primary endpoints will be assessed up to the 1 year follow-up. To assess the long term safety 
and effectiveness, all subjects randomized to the treatment arm will be monitored for adverse 
events and continued assessment through 5 years post procedure. 
4.2.
Cohort Description 
The study design has 2:1 randomization (Investigational Device: Sham Procedure) stratified by 
Investigational Sites. As a result, the study includes 3 subject cohorts – Sham Treatment Group
(Control Arm), ProVee Treatment Group (Investigational Arm) and Cross-Over Arm. The subject 
will be blinded as to whether he is in the control or treatment group. Unblinding will occur at 3 
months post procedure after follow-up assessments are completed.
4.2.1. Sham Treatment Group (Control Arm) 
 
 
 

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Following unblinding after the 3-month visit, subjects assigned to the Control Arm (sham
procedure) may elect to be treated with the ProVee Device (crossover to treatment). Refer to 
section 4.2.3 for further details.  The subjects choosing not to crossover and receive the ProVee 
Device will be exited from the study.  
4.2.2. ProVee Treatment Group (Investigational Arm)   
The ProVee Treatment Group subjects will receive the ProVee Device. All subjects in the ProVee 
Treatment Group will be followed at a minimum of 5 years per the assessment schedule (Table 
7).
4.2.3. Cross Over Group 
Specific to the Control Arm, after unblinding, upon completion of the 3 month follow-up 
assessments, qualifying subjects who are willing to comply with the required follow-up can be 
offered treatment with the ProVee Device if they meet the retreatment or crossover enrollment 
criteria specified in 6.9. After being treated, Crossover Subjects will be followed using the same 
schedule used with the ProVee Treatment Arm. From 12 months onward, the Crossover Cohort 
shall be analyzed with the Treatment Arm Cohort in the assessment of long-term safety and 
effectiveness.  Control Arm subjects choosing not to receive the ProVee Device will be exited 
from the study.

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5.0 Study Population
The patient population is male subjects who are 45 years and older with lower urinary tract 
symptoms (LUTS) related to symptomatic benign prostatic hyperplasia (BPH).
5.1. Inclusion Criteria
1. Males > 45 years of age
2.
, IPSS V/S > 1 at baseline assessment
3.
4.
by TRUS
5. Failed, intolerant, or subject choice to not take a medication regimen for the treatment of 
LUTS
5.2. Exclusion Criteria
1. Void volume <125 ml; Qmax > 12ml/s; PVR > 250 ml
2. Obstructive median lobe defined by EITHER >10mm protrusion on sagittal mid-prostate 
plane as measured by TRUS OR an obstructive median lobe seen on cystoscopy e.g., ‘ball 
valve’’
3. High bladder neck, with the absence of lateral lobe encroachment indicating a high 
likelihood of primary bladder neck obstruction
4. Anatomy that would prevent the apices of the ProVee from engaging with the lateral lobes 
e.g., high degree of bladder neck angulation such that the anterior bladder neck is not 
visible
5. Acute urinary retention
6. Known immunosuppression
7. History of or suspected prostate or bladder cancer 
8. Baseline PSA > 10 ng/mL or confirmed or suspected prostate cancer (Subjects with a PSA 
level above 2.5 ng/mL, or age specific, or local reference ranges should have prostate 
cancer excluded to the Investigator's satisfaction, including a SOC biopsy if indicated). 

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9. Recent urinary tract stones OR widespread calcifications on the prostatic urethral wall, 
within 3 months of index procedure
10. A history of prostatitis within the last two years
11. Active or history of epididymitis within the past 3 months 
12. Neurogenic bladder and/or sphincter abnormalities due to Parkinson's disease, multiple 
sclerosis, cerebral vascular accident, diabetes’
13. History of urinary retention within 12 months of baseline assessment
14. Requiring self-catheterization to void
15. An active urinary tract infection (UTI) at time of index procedure 
16. Gross haematuria, within 3 months of index procedure
17. Subjects with known allergy to nickel or titanium
18. Life expectancy estimated to be less than 60 months
19. Taking androgens, unless eugonadal state for at least 3 months or greater with a stable 
dosage for at least 2 months as documented by the Investigator
20. Use of 5-alpha-reductase inhibitors (e.g., dutasteride, finasteride) within 6 months of 
baseline assessment
21. Use of Phenylephrine / Pseudoephedrine within 24 hours of baseline assessment
22. Use of alpha-blockers (e.g., Terazosin, Doxazosin, Alfuzosin, Tamsulosin) within 2 weeks 
of baseline assessment
23. Use of estrogen or drug-producing androgen suppression (e.g. gonadotropin-releasing 
hormonal analogues) within 1 year of baseline assessment
24. Use of antihistamines, anticonvulsants, and antispasmodics within 1 week of baseline 
assessment unless there is documented evidence that the patient was on the same drug dose 
for at least 6 months with a stable voiding pattern (the drug dose should not be altered or 
discontinued for entrance into or throughout the study)
25. Use of anticholinergics or cholinergic medication within 2 weeks of baseline assessment
26. Use of beta-blockers where the dose is not stable. (Stable dose is defined as having the 
same medication and dose in the last 6 months)
27. Use of Phosphodiesterase-5 Enzyme Inhibitors in doses for BPH within 2 weeks of baseline 
assessment 

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5.3. Strategies For Recruitment And Retention
 
 
 
 
  
 
 
.
5.4. Screen Failures
 
 
 
  
 
 
 
 
 
.    
6.0 Study Assessments And Procedures
6.1. Informed Consent 
The subject will be given and asked to read and sign the approved Informed Consent Form (ICF). 
The subject is entitled to a minimum of twenty-four (24) hours to review the ICF. The subject is 
entitled to take the ICF home to discuss with a relative, friend or their local doctor. If the subject 

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is interested, an appointment to return to the clinic to meet with the investigator and staff will be 
arranged.
The Investigator and/or delegate must fully explain to the subject all aspects of the study that are 
relevant to the decision of participation in the study. Any questions will be addressed and if they 
wish to proceed, the subject’s informed consent is documented by means of a written, signed, and 
dated ICF prior to the start of the study. Subjects who do not have decision making capacity to 
consent will be excluded from the Study.
Subject enrolment occurs at the time of ICF execution. Once the subject has completed the 
informed consent procedure and signed the ICF, the Investigator or delegated Study research staff 
can complete the screening process with the subject. Every subject that signs a ICF will be 
considered enrolled in the Study. If a subject has provided consent and completed screening, and 
for any reason does not complete the assessment phases, the subject will be exited from the Study.  
Any subjects that screen fail prior treatment with the investigational device or sham control device, 
will not be counted in the data analysis.
The eCRF for each subject will document that informed consent was obtained prior to participation 
in the Study. The original signed consent forms must remain in each subject’s Study file and must 
be available for verification by Study monitors at any time. Medical records will also retain and 
scan an original ICF.
6.2. Screening Assessment 
 
 
 
 
 

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6.3. Study Randomization 
 
    
 
 
 
   
6.4. Index Procedure (Treatment)
 
  
 
 
  
 
 
 
6.5. Post-procedure / Discharge 
 
 
 

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6.6. Performance of Assessments and Procedures 
 
6.6.1. Questionnaires
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.6.9. Assessment of Concomitant Medications 
 
 
 
 
6.7. Follow-up Assessments 
 
 
 
 
 
 
6.8. Study Follow-up Timepoints 
 
 
 
 
 

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6.8.1. 1-Month (± 7 days) Follow-up 
 
 
 
 
 
6.8.2. 3-month (± 14 days) Follow-up
 
 
 
 
 
 

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o
 
 
 
6.8.3. 6-month (± 1 month) Follow-up
 
  
 
 
 
6.8.4. 12-month (± 1 month) Follow-up
 
 
 

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6.8.5. 2-year (± 1 month) to 5-year (± 1 month) Follow-up 
 
 
 
 
 
6.9. Cross Over following 3 month Follow-up 
 
 
 
 

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The Inclusion and Exclusion criteria for cross over eligibility are as follow: 
Inclusion
1. Males > 45 years of age
2. Failed, intolerant, or subject choice to not take a medication regimen for the treatment of 
LUTS
2 Sham procedure will not count as a prostate surgery under this exclusion definition. Other prostate surgery will result in exclusion 
from crossover

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of baseline assessment
19. Use of estrogen or drug-producing androgen suppression (e.g. gonadotropin-releasing 
hormonal analogues) within 1 year of baseline assessment
20. Use of antihistamines, anticonvulsants, and antispasmodics within 1 week of baseline 
assessment unless there is documented evidence that the patient was on the same drug dose 
for at least 6 months with a stable voiding pattern (the drug dose should not be altered or 
discontinued for entrance into or throughout the study)
21. Use of anticholinergics or cholinergic medication within 2 weeks of baseline assessment
22. Use of beta-blockers where the dose is not stable. (Stable dose is defined as having the 
same medication and dose in the last 6 months)
23. Use of Phosphodiesterase-5 Enzyme Inhibitors in doses for BPH within 2 weeks of baseline 
assessment 
24. Current treatment with anticoagulants (e.g., warfarin or enoxaparin) or antiplatelet 
medications other than aspirin (e.g., clopidogrel, or alternative and ASA). Patient unable 
to stop taking antiplatelet/ASA within 7 days prior to the procedure or warfarin at least 5 
days prior to the procedure. ASA <100mg/day not prohibited
25. Future fertility concerns 
26. Previous pelvic irradiation or radical pelvic surgery
27. Previous rectal surgery (other than hemorrhoidectomy) or known history of rectal disease
28. Urethral strictures, bladder neck contracture, or other potentially confounding bladder 
pathology 
29. Urethral pathologies that may prevent insertion of delivery system
30. Uncontrolled diabetes mellitus including Hgb AIC >8%
31. Overactive bladder (OAB) requiring treatment by OAB medication
32. Urinary incontinence
33. Patients taking tri-cyclic antidepressants.
34. Compromised renal function (i.e., serum creatinine >1.8 mg/dl or upper tract disease)

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6.11. End Of Study Definition
A study subject is considered to have completed the study if he/she has completed all phases of 
the study including the last follow up assessment as shown in Table 1. The end of the study is 
defined as completion of the last follow up assessment in the study. Once this has occurred, the 
declaration of the end of study will be submitted to the IRB/IEC, as required. Following this, the 
Sponsor will advise the study sites on the procedures for closing the study.
With the end of the study being declared, no more prospective subject data will be collected, and 
sites must cooperate addressing any data queries regarding existing data to allow for data lock, and 
analysis. 
6.12. Adverse Events And Serious Adverse Events
Once a patient is randomized, all AEs must be reported for follow-up period (as designated for 
treatment, control or crossover arms).All AEs irrespective of their relatedness to the device and/or 
procedure which occur throughout the duration of the study shall be reported. The Investigator will 
monitor the occurrence of adverse events for each subject during the course of the study.  All 
adverse events reported by the subject, observed by the Investigator, or documented in medical 
records will be documented on the Adverse Event Case Report Forms (CRFs), whether believed 
by the Investigator to be related or unrelated to the investigational device.  All pre-existing medical 
conditions will be recorded in the subject’s medical record and/or baseline CRFs.  Beginning with 
subject enrollment, any new event that was not present at baseline, or worsening of a pre-existing 
condition, is considered an adverse event.
 
6.12.1. Definition Of Adverse Events (AE)
Adverse Events are defined as any undesirable treatment emergent signs or symptoms.  

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6.12.2. Adverse Device Effect (ADE)
An Adverse Device Effect is defined as any AE that is considered device-related.  All ADEs are 
further classified as anticipated or unanticipated.
6.12.3. Anticipated Adverse Device Effect (AADE)
An Anticipated Adverse Device Effect is defined as any undesirable health related experience 
occurring to a subject whether or not it is considered related to the investigational product or drug 
regimen prescribed as part of the protocol, predefined in the protocol and/or Instruction for Use 
(IFU) that is identified or worsens during a clinical study.
6.12.4. Unanticipated Adverse Device Effect (UADE)
Unanticipated Adverse Device Effect is defined as any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, the Device, if that effect 
was not previously identified in nature, severity, or degree of incidence (frequency) in the 
investigational plan, subject informed consent, IFU, or any other unanticipated serious problem 
associated with a device that relates to the rights, welfare and safety of the subject.
6.12.5. Serious Adverse Event (SAE)
Serious Adverse Events are a subset of Adverse Events and are defined as an event which leads 
to:
1. Death due to any cause
2. Life-threatening condition
3. Results in persistent or significant disability/incapacity
4. Requires in-patient hospitalization or prolonged hospitalization. 
5. Is an important medical event that may not result in death, be life-threatening, or require 
hospitalization but may be considered serious when, based upon appropriate medical 
judgment, may jeopardize the subject and/or may require intervention to prevent one of the 
outcomes listed in this definition

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6.12.6. Classification Of An Adverse Event
 
 
6.12.7. Adverse Event Reporting
 
 
 
 
 
 
  
 
  
 
 
 
6.12.8. Reporting of Device Failures and Malfunctions
 
 
 
 
  
 
 

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7.0 Preparation/Handling/Storage/Accountability
7.1.
Acquisition And Accountability
 
 
 
 
 
 
 
 
 
 
 
 
 

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a)
 
 
 
 
7.2.
Formulation, Appearance, Packaging, And Labeling
 
 
 
 
 
 
 
 
 
 
 
  
7.3.
Product Storage And Stability
 
 
 
 

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8.1.2. Subject randomization
 
 
 
 
8.1.3. Study Blinding
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
    
 
  
 
 
 
 

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. 
8.2. Study Intervention Compliance
The study will be conducted in accordance with the Declaration of Helsinki, International 
Conference on Harmonization Good Clinical Practice (ICH GCP), ISO 14155, applicable United 
States (US) Code of Federal Regulations (CFR) including but not limited to 21 CFR parts 812, 50, 
54, 56 and the pertinent individual country laws and regulations. The study will comply with local 
national legislations and requirements regarding Institutional Review Boards (IRB) / Ethics 
Committees (EC). The study may only begin once authorizations have been granted by the FDA, 
EC and IRB for the Clinical Investigational Plan, informed consent form and other adjunctive 
material. Treatment refusals will be minimized by careful and thoughtful informed consent. Loss 
to follow up will be minimized through regular and routine follow-up with subjects.
8.3. Concomitant Therapy
 
 
 
 
 

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9.0 Study Intervention Discontinuation And Participant 
Discontinuation/Withdrawal
9.1. Participant Discontinuation/Withdrawal From The Study
A subject is free to withdraw from participation in the study at any time upon request and for any 
reason without prejudice to his or her future medical care by the physician or the institution.  The 
subject shall notify the Investigator of the request to withdraw in writing.  Study withdrawal by a 
subject is the withdrawal of consent from further participation in the study.  A subject who 
withdraws consent after enrollment will be evaluated to the time of withdrawal.  Withdrawal of 
consent precludes any further study-related treatment or data collection.  At a minimum, every 
effort shall be made to document subject outcome at the time of withdrawal including a review of 
adverse events that may have occurred since the last follow-up visit.  
An investigator may discontinue or withdraw a subject from the study if the Investigator feels the
subject can no longer fully comply with the requirements of the study or based on his/her medical 
judgement.  Every effort shall be made to document at the time of withdrawal any adverse events 
that have occurred since the last follow-up visit.  
The reason for subject or investigator discontinuation or withdrawal from the study will be 
recorded on the eCRF. 
 
 
 
 

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9.2. Lost To Follow-Up
The Investigator will encourage subjects to return for all required follow-up visits. If a subject 
refuses to return for follow-up visits, the Investigator shall make every effort to obtain the subject’s 
vital status. In the event of subject death, a death certificate or autopsy report shall be obtained to 
confirm the cause of death and recorded on the eCRF. 
 
 
  
 
 
 
 
 
 
 
10.0 Statistical Considerations
10.1. Study Success
 
 
 
 
 
 
  

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10.2. Analysis Cohorts
Different groups of subjects, or Analysis Cohorts, will be identified depending on the type and 
extent of analysis being performed.
10.2.1. Screening Cohort (Enrolled)
 
  
 
 
 
 
10.2.2. Safety/Intent-to-Treat (ITT) Cohort
 
 
 
 
10.2.3. Per-Protocol Cohort
 

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10.2.4. Cohort for Procedure Success Endpoints
10.2.5. Cohort for Primary and Secondary Effectiveness Endpoints
 
.
10.2.6. Cohort for Safety Endpoints
10.3. Derived Data 
 
 
 
10.4. Statistical Methods
 
 
 
 
 
 
 
 

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10.5. Handling of Dropouts and Missing Data 
Every effort will be made to collect all data points in the study. The sponsor plans to minimize 
the amount of missing data by appropriate management of the prospective clinical trial, proper 
screening of study subjects, and training of participating investigators, monitors and study 
coordinators. Specific details regarding handling of missing data are included in ProVIDE 
Statistical Analysis Plan. 
 
 
 
All other endpoints will be analyzed “as-is” without any special data imputation methods used to 
replace missing data.

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10.6. Poolability  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
3 Meinert, C. (1986). Clinical Trials: Design, Conduct, and Analysis.  Oxford University Press, New York.

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10.7. Sensitivity Analyses
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 

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10.8. Subgroup Analyses
 
 
 
 
10.9. Sample Size Determination
 
 
   
 
 
 

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10.10. Power to Pass Both Co-Primary Objectives Simultaneously
 
 
 
 

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.
10.11. Sample Size Justification – Safety
 
 
11.0 Supporting Documentation And Operational Considerations
11.1. Regulatory, Ethical, And Study Oversight Considerations
The study will be conducted in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP), ISO 14155-2020, applicable United States (US) Code of Federal 
Regulations (CFR) including but not limited to 21 CFR parts 812, 50, 54, 56 and applicable local 
regulations for OUS sites. This study will be conducted in accordance with the ethical principles that 
have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice and 
applicable regulatory requirements. 
11.1.1. IRB/ EC Information 
The protocol, informed consent document, and relevant supporting information will be submitted to 
the IRB/EC for review and be approved before the study is initiated. In addition, any subject 
recruitment materials will be approved by the IRB/EC prior to use. The study will be conducted in 
accordance with the regulations of the United Stated Food and Drug Administration (FDA) as 
described in 21 CFR 50 and 56, applicable laws and the IRB/EC requirements.
The Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the sponsor, and documented approval from the Institutional Review 
Board (IRB)/Ethics Committee (EC), except where necessary to eliminate an immediate hazard(s) 
to the study participants. All personnel involved in the conduct of this study have completed 
Human Subjects Protection and ICH GCP Training. 

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The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB/EC 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/EC before the changes are implemented to the study. All 
changes to the consent form will be IRB/EC 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.
11.1.2. Informed Consent Process
The principles of informed consent described in FDA Regulations (21 CFR Part 50) must be followed. 
The background of the proposed study and the potential benefits and risks shall be carefully explained 
to the subject. Before undergoing protocol required assessments the subject or their legal representative 
must give witnessed written consent to participate in the study using the informed consent form 
approved by the clinical site’s IRB/EC. A copy of the signed consent form shall be given to the subject, 
an original shall be filed in the subject’s medical record, and a copy maintained with the site’s research 
documentation. The informed consent form is written in compliance with the current Health Insurance 
Portability and Accountability Act (HIPAA) regulations. 
11.1.3. Confidentiality And Privacy
All information and data sent to the Sponsor, and its authorized representatives, concerning 
subjects or their participation in this study will be considered confidential.  All data used in the 
analysis and reporting of this evaluation will be used in a manner without identifiable reference to 
the study subject.
11.1.4. Safety Oversight
 
 
 

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11.1.5. Clinical Monitoring
The responsibilities of the clinical monitors include ensuring that IRB/EC approval is obtained 
prior to initiating the study, investigators understand and comply with the investigational plan, all 
subject consent forms are properly completed, Case Report Forms are accurate and supported by 
appropriate source verified documents, and all reports are filed in accordance with the protocol 
and the appropriate regulations. If a monitor finds that an investigator is not complying with the 
executed study agreements, the investigational plan, Government regulations, or the requirements 
of the reviewing IRB/EC, prompt action will be taken to secure compliance. In addition, shipment 
of the device may be stopped or the participation of the investigator may be terminated (21 CFR 
812.46). 
Clinical monitors may also be responsible for assessing the adequacy of the facilities, training, and 
technical support.
 
 
11.1.6. Data Handling And Record Keeping
Investigators will be trained on the appropriate records to maintain and reports to file. ProVerum 
Ltd. will maintain records relating to the clinical investigation and file the reports within the 
appropriate timeframes in accordance with 21 CFR 812, Subpart G. 

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11.1.7. Protocol Amendments 
 
 
 
 
  
 
 
.
11.1.8. Emergency Actions 
 
 
 
 
11.1.9. Financial Disclosure 
All investigators must provide the study Sponsor with documentation of financial interest related 
to ProVerum Ltd.  Investigator’s will need to complete a Financial Disclosure in compliance with 
21CFR 54 and send it to the study Sponsor during the approval process of the site and upon study 
close-out.

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11.1.10.
Publication And Data Sharing Policy
 
 
 
 
 

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12.0 Study Definitions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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.

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13.0 References
1.
Chughtai, B. et al. Benign prostatic hyperplasia. Nat. Rev. Dis. Primer 2, 16031 (2016).
2.
Foster, H. E. et al. Surgical Management of Lower Urinary Tract Symptoms Attributed to 
Benign Prostatic  Hyperplasia: AUA Guideline Amendment 2019. J. Urol. 202, 592–598 
(2019).
3.
Gravas, S. et al. EAU Guidelines on Management of Non-Neurogenic Male Lower Urinary 
Tract Symptoms (LUTS), incl. Benign Prostatic Obstruction (BPO) 2018. in European 
Association of Urology Guidelines. 2018 Edition. vol. presented at the EAU Annual Congress 
Copenhagen 2018 (European Association of Urology Guidelines Office, 2018).
4.
Roehrborn, C. G. et al. The effects of combination therapy with dutasteride and tamsulosin on 
clinical  outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from  
the CombAT study. Eur. Urol. 57, 123–131 (2010).
5.
Cindolo, L. et al. Patient’s adherence on pharmacological therapy for benign prostatic 
hyperplasia  (BPH)-associated lower urinary tract symptoms (LUTS) is different: is 
combination  therapy better than monotherapy? BMC Urol. 15, 96 (2015).
6.
Kaplan, S. A. DeMISTifying less-invasive solutions for BPH. Urology Times
https://www.urologytimes.com/view/demistifying-less-invasive-solutions-bph (2019).
7.
Das, A. K., Leong, J. Y. & Roehrborn, C. G. Office-based therapies for benign prostatic 
hyperplasia: a review and update. Can. J. Urol. 26, 2–7 (2019).
8.
Djavan, B., Chapple, C., Milani, S. & Marberger, M. State of the art on the efficacy and 
tolerability of alpha1-adrenoceptor antagonists  in patients with lower urinary tract symptoms 
suggestive of benign prostatic  hyperplasia. Urology 64, 1081–1088 (2004).

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9.
Cornu, J.-N. et al. A Systematic Review and Meta-analysis of Functional Outcomes and 
Complications  Following Transurethral Procedures for Lower Urinary Tract Symptoms 
Resulting from  Benign Prostatic Obstruction: An Update. Eur. Urol. 67, 1066–1096 (2015).
10. Reich, O. et al. Morbidity, mortality and early outcome of transurethral resection of the 
prostate: a  prospective multicenter evaluation of 10,654 patients. J. Urol. 180, 246–249 
(2008).
11. Roehrborn, C. G. et al. Five year results of the prospective randomized controlled prostatic 
urethral L.I.F.T. study. Can. J. Urol. 24, 8802–8813 (2017).
12.
Lower Urinary Tract Symptoms Associated With Benign Prostatic Hyperplasia: 4-Year 
Results From Randomized Controlled Study. Urology 126, 171–179 (2019).