Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000745842p
Ethics application status
Submitted, not yet approved
Date submitted
13/04/2021
Date registered
11/06/2021
Date last updated
11/06/2021
Date data sharing statement initially provided
11/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Safety and Preliminary Efficacy of SIR1-365 in Patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome
Scientific title
A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Safety and Preliminary Efficacy of SIR1-365 in Adult Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome
Secondary ID [1] 299529 0
SIR365-AU-102
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neurodegenerative disease 320618 0
Inflammatory disease 320619 0
Condition category
Condition code
Inflammatory and Immune System 318468 318468 0 0
Other inflammatory or immune system disorders
Neurological 319263 319263 0 0
Other neurological disorders
Renal and Urogenital 319623 319623 0 0
Other renal and urogenital disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
RIP1 mediates the downstream effects of multiple biological activities including inflammatory responses. Therefore RIP1 inhibitors may be advantageous over selective inhibitors for a specific cytokine to reduce inflammatory response. SIR1-365 is a Receptor-Interacting Protein1 (RIP1) inhibitor that is under development as a new investigational drug for the treatment of inflammatory diseases.

Type III prostatitis is also known as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Currently, there is a lack of a clear evidence proved effective treatment.

This will be a multicenter, randomized, double-blinded, placebo-controlled study to evaluate safety and preliminary efficacy of SIR1-365 in patients with CP/CPPS. Enrolled patients will take two 100mg tablets of either SIR1-365 or matching placebo orally, two times a day for 28 consecutive days. Patients will return to the clinical site on Days 7 (±1 day), 14 (±1 day), be contacted by telephone on Day 21 (±1 day), 28 (±2 days) end of treatment and 42 (±5 days) follow up visit/end of study to receive all the activities scheduled for the respective visits. The afternoon dose for Day 28 (±2) or last visit day will not be administered.

Study staff will instruct enrolled patients to take the study medication exactly as instructed as compliance is necessary for patient safety and for the validity of the study. Excluding the follow-up visit, patients will take their morning dose on the days they attend the clinical site. Study staff will contact patients on a weekly basis to schedule their next clinic visit and to remind them to take their study medication. IP bottles will be returned to the clinical site on Days 7, 14 and 28. Study staff will perform a pill count to determine treatment compliance and record the information in the source.
Intervention code [1] 319666 0
Treatment: Drugs
Comparator / control treatment
Placebo tablet which is an excipient match to the SIR1-365 100mg tablet. The placebo tablet is an uncoated compressed tablet.
Control group
Placebo

Outcomes
Primary outcome [1] 327142 0
To evaluate overall safety and tolerability of SIR1-365 in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) when administered orally at 200 mg, two times a day for 28 consecutive days relative to the placebo group.

Primary safety measure:
- Proportion (%) of patients with any treatment-emergent adverse events (TEAEs) during the treatment period (Day 1 to Day 28), assessed by review of adverse event data.
Timepoint [1] 327142 0
Adverse events will be monitored at all visits, Days 1, 7, 14, 21, 28 and 42 post-commencement of intervention.
Secondary outcome [1] 393950 0
To assess the preliminary efficacy of SIR1-365 in patients with CP/CPPS. Clinical efficacy endpoints in patients with different biomarker levels at Baseline will be compared to assess the correlation of biomarker profile to clinical efficacy outcomes.

- Change from Baseline to Days 7, 14, 21, 28 and 42 in NIH-CPSI total score, sub-score for pain, sub-score for urinary symptoms and sub-score for quality of life impact
Timepoint [1] 393950 0
National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) will be completed at Days 1, 7, 14, 21, 28 and 42 (prior to EPS sample collection) post-commencement of intervention.
Secondary outcome [2] 394018 0
To assess the effects of SIR1-365 on multiple biomarkers indicative of inflammation in prostate.

- Change from Baseline to Days 7, 14, and 28 in plasma inflammatory, cytokine and chemokine biomarker levels.

Plasma samples will be collected from all patients for the measurement of biomarkers including white blood cell count, cytokines (IL-6, TNF-a, IFN-gamma, IL-1ß, IL-7, IL-8, IL-9, IL-10, total IL-18, G- CSF, and GM-CSF), and chemokines (CXCL-1, CXCL-9, CXCL-10/IP-10, MCP-1 and MIP-1a) to be carried out at a central laboratory with V-PLEX validated immunoassays of MSD® multi-spot assay system or equivalent method.

Plasma phosphorylated Receptor-interacting protein kinase 1 (pRIP1) and Phosphorylated Mixed Lineage Kinase Domain-Like protein (pMLKL) levels will be measured for target engagement. Peripheral blood mononuclear cell (PBMC) will be prepared at the sites with the necessary equipment for pRIP1 and pMLKL measurement. Additional biomarkers may be assessed as appropriate.
Timepoint [2] 394018 0
Days 1, 7, 14 and 28 post-commencement of intervention. A blood sample for PBMC analysis will be collected on Days 1 and 28 post-commencement of intervention.
Secondary outcome [3] 394019 0
To assess the effects of SIR1-365 on reproductive function in patients with CP/CPPS.

- Change from Baseline to Days 7, 14, and 28 in plasma testosterone, FSH and LH levels.

Collected plasma samples will be used for the measurements of testosterone, FSH and LH levels by routine local laboratory analysis.
Timepoint [3] 394019 0
Fasting routine laboratory tests will be collected before the morning dose on Days 1, 7, 14, 28 and 42 post-commencement of intervention and will include testosterone, FSH (Follicle Stimulating Hormone) and LH (Luteinizing Hormone).
Secondary outcome [4] 394020 0
To assess the effects of SIR1-365 on biomarkers indicative of target engagement in patients with CP/CPPS.

- Change from Baseline to Days 7, 14, and 28 in plasma and PBMC pRIP1 and pMLKL levels

Blood samples will be collected for pRIP1/pMLKL levels measured by target engagement assays to be carried out at a central laboratory.
Timepoint [4] 394020 0
Blood samples will be collected at Days 1, 7, 14 and 28 post-commencement of intervention. A blood sample for PBMC analysis will be collected on Days 1 and 28.
Secondary outcome [5] 394021 0
To measure plasma SIR1-365 levels in patients with CP/CPPS using a validated bioanalytical method following GLP guidance.
Timepoint [5] 394021 0
Blood samples will be collected from each patient within 30 minutes before and 2 hours (±5 min) after the morning dose on Days 1, 7, 14, and 28 post-commencement of intervention. The prepared plasma samples will be divided into 7 parts (2 for drug level analysis, 2 for plasma pRIP1/pMLKL assay and 3 for cytokine assay). Plasma drug and metabolite levels will be measured by validated bioanalytical method following GLP guidance.
Secondary outcome [6] 395432 0
To evaluate overall safety and tolerability of SIR1-365 in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) when administered orally at 200 mg, two times a day for 28 consecutive days.

Secondary safety measures:
- Proportion (%) of patients with any Adverse Events, Serious Adverse Events and drug-related Adverse Events during the study assessed by review of adverse event data.
Timepoint [6] 395432 0
Baseline to Day 42 post-commencement of intervention. Adverse events will be monitored at all visits, Days 1, 7, 14, 21, 28 and 42 post-commencement of intervention.
Secondary outcome [7] 395433 0
To evaluate overall safety and tolerability of SIR1-365 in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) when administered orally at 200 mg, two times a day for 28 consecutive days.

Secondary safety measures:
- Proportion (%) of patients with clinically significant abnormality in clinical laboratory tests and ECG during the study

Safety outcomes in patients with different biomarker levels at baseline will be compared to assess the correlation of biomarker profile to safety outcomes.

Safety will be continuously monitored using composite of data available through physical exam and laboratory assessments.
Clinical Laboratory tests include:
- Blood haematology
- Blood chemistry
- Blood serology (HIV, Hepatitis B and C); screening only
- Urinalysis

A complete physical examination will include but not limited to the evaluation of the following organs or body systems: skin; head, eyes, ears, nose, and throat; thyroid; respiratory, cardiovascular, and central nervous systems; abdomen (liver and spleen); lymph nodes; and extremities.
Timepoint [7] 395433 0
Baseline to Day 42 post-commencement of intervention. A complete physical examination will be completed at Day 28. Complete Vital Signs Measurements and Fasting Clinical Laboratory tests be completed prior to the morning dose on Days 1, 7, 14 & 28 and on Day 42. 12-lead Electrocardiogram (ECG) will be completed prior to the morning dose on Day 1, and within the day of the visit on Days 7, 14, 28 and 42.
Secondary outcome [8] 395434 0
Global Response Assessment score on Days 7, 14, 21, 28 and 42.
Timepoint [8] 395434 0
Global Response Assessment (GRA) will be completed on Days 7, 14, 21, 28 and 42 post-commencement of intervention.
Secondary outcome [9] 395435 0
Change in score from Baseline to Days 28 and 42 in the total Male Sexual Health Questionnaire (MSHQ).
Timepoint [9] 395435 0
MSHQ will be completed on Days 1, 28 and 42 post-commencement of intervention.
Secondary outcome [10] 395440 0
To assess the effects of SIR1-365 on multiple biomarkers indicative of inflammation in prostate.

- Change from Baseline to Day 28 in EPS inflammatory cytokine and chemokine biomarker levels.

Expressed prostatic secretion (EPS) samples will be collected at selected sites from some patients who agree to receive prostatic massage after a period of sexual abstinence of 2-7 days for neutrophil elastase (NE), cytokine (IL-6, TNF-a, IFN-gamma, IL-1ß, IL-7, IL-8, IL-9, IL-10, total IL-18, G- CSF, and GM-CSF), chemokine (CXCL-1, CXCL-9, CXCL-10/IP-10, MCP-1 and MIP-1a) and pRIP1/pMLKL assays to be carried out at a central laboratory with V-PLEX validated immunoassays of MSD® multi-spot assay system or equivalent method.
Timepoint [10] 395440 0
An EPS sample will be collected before the sperm sample at Baseline and Day 28 post-commencement of intervention.
Secondary outcome [11] 395441 0
To assess the effects of SIR1-365 on reproductive function and on multiple biomarkers indicative of inflammation in prostate.

- Change from Baseline to Days 14, and 28 in semen inflammatory, cytokine and chemokine biomarker levels.

Semen samples will be collected at a local laboratory after a period of sexual abstinence of 2-7 days for cytokine (IL-6, TNF-a, IFN-gamma, IL-1ß, IL-7, IL-8, IL-9, IL-10, total IL-18, G- CSF, and GM-CSF), chemokine (CXCL-1, CXCL-9, CXCL-10/IP-10, MCP-1 and MIP-1a) and pRIP1/pMLKL assays to be carried out at a central laboratory with V-PLEX validated immunoassays of MSD® multi-spot assay system or equivalent method.
Timepoint [11] 395441 0
A sperm sample will be collected after the EPS sample at Baseline, Days 14 and 28 post-commencement of intervention.
Secondary outcome [12] 395442 0
To assess the effects of SIR1-365 on reproductive function in patients with CP/CPPS.

- Change from Baseline to Days 14 and 28 in semen routine tests including sperm volume, concentration, total number, total motility, progressive motility, morphology and vitality.

Semen samples will be collected at a local laboratory after a period of sexual abstinence of 2-7 days for routine tests including sperm volume, sperm concentration, total sperm number, total motility, progressive motility, sperm morphology, vitality and pH.
Timepoint [12] 395442 0
A sperm sample will be collected after the EPS sample at Baseline, Days 14 and 28 post-commencement of intervention.
Secondary outcome [13] 395443 0
To assess the effects of SIR1-365 on biomarkers indicative of target engagement in patients with CP/CPPS.

- Change from Baseline to Day 28 in EPS pRIP1 and pMLKL levels

Expressed prostatic secretion (EPS) samples will be collected at selected sites from some patients who agree to receive prostatic massage after a period of sexual abstinence of 2-7 days for pRIP1/pMLKL levels measured by target engagement assays to be carried out at a central laboratory.
Timepoint [13] 395443 0
An EPS sample will be collected before the sperm sample at Baseline and Day 28 post-commencement of intervention.
Secondary outcome [14] 395444 0
To assess the effects of SIR1-365 on biomarkers indicative of target engagement in patients with CP/CPPS.

- Change from Baseline to Days 14 and 28 in semen pRIP1 and pMLKL levels

Semen samples will be collected at a local laboratory after a period of sexual abstinence of 2-7 days for pRIP1/pMLKL levels measured by target engagement assays to be carried out at a central laboratory.
Timepoint [14] 395444 0
A sperm sample will be collected after the EPS sample at Baseline, Days 14 and 28 post-commencement of intervention.

Eligibility
Key inclusion criteria
1. Men 18 to 60 years of age at the time of signing the informed consent.
2. Patient has signed and dated the appropriate Informed Consent document.
3. Patient has pain or discomfort in the pelvic region for at least 3 months in the last 6 months, in the absence of a urinary tract infection or other pelvic/urological cause and have a physician diagnosis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) based on NIH Classification System. If treated with antibiotics, symptoms persist.
4. Patient with NIH-CPSI score of at least 15 at screening,
5. Patient or female partner of patient must agree to use a reliable contraceptive method for sexual intercourse from Screening until at least 90 days after the last dose of study drug, unless they have been surgically sterilized (vasectomy) for a minimum of 6 months.
6. Patient agrees not to participate in another interventional study after signing the informed consent form and until the end of study (EoS) visit has been completed.
Minimum age
18 Years
Maximum age
60 Years
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient has experienced 2 or more UTI in the 12 months prior to screening and facultative Gram negative or enterococcus with a value of greater than or equal to 1000 colony forming units (CFU) /ml in mid-stream urine (VB2) in the last 3 months prior to screening.
2. Patient has a history of or currently has prostate, penile, testicular, bladder, or urethral cancer or has undergone pelvic radiation, systemic chemotherapy, or intravesical chemotherapy.
3. For patients with suspected lower urinary tract malignancy, investigator should make clinical determination based on patient’s overall profiles including positive (micro) hematuria in urine sediment or prostate specific antigen (PSA) >4 ng/mL.
4. Patient with currently active sexually transmittable disease.
5. Patient with symptomatic urethral stricture or symptomatic bladder or urethral calculi, severe bladder outlet obstruction, overactive bladder with incontinence or post void residual volume greater than 150 mL.
6. Patient has unilateral orchialgia without pelvic symptoms, or neurological disease or disorder affecting the bladder.
7. Patient has undergone transurethral prostatectomy, transurethral incision of the prostate, transurethral incision or resection of the bladder neck, transurethral microwave thermotherapy, transurethral needle ablation, balloon dilation of the prostate, open prostatectomy or any other prostate surgery or treatment such as cryotherapy or thermal therapy, or any prior prostate and/or bladder intervention within 3 months prior to screening.
8. Patient with clinically relevant abnormal urine or blood safety laboratory values or active hepatic and/or biliary disease (Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) should be >3 times the upper limit of normal, total bilirubin should be >2 times the upper limit of normal).
9. Patient has a history of moderate or severe hepatic impairment, severe renal sufficiency, severe or unstable cardiovascular (i.e. prolonged QT), respiratory, hematological, endocrinological, neurological or other somatic disorders, which will impact the safety and efficacy evaluation by investigator judgements.
10. Patient with initiation, discontinuation, or variation in the dose of antidepressants, alpha- blockers, 5-alpha reductase inhibitors, antimuscarinics, benzodiazepines, skeletal muscle relaxants, non-steroidal anti-inflammatory drugs, non-opioid analgesics and herbal therapies during the last 4 weeks before screening. Patients should continue these medications at the same stable dose throughout the study.
11. Patient has a neurological impairment or psychiatric disorder preventing his understanding of consent and his ability to comply with the protocol.
12. Patient is taking any medicine that is mainly metabolized by CYP450 2C19. The investigator could provide an alternative medicine that is not mainly metabolized by CYP450 2C19.
13. Patient has a known or suspected hypersensitivity to SIR1-365 or any components of SIR1-365 tablets.
14. Patient has received any investigational drug within 30 days or 5 half-lives, whichever is longer, prior to screening.
15. Patient has any other condition, which makes the patient unsuitable for study participation by investigator’s judgement.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All eligible subjects will be randomised using interactive response technology (central randomisation - computer), developed prior to the initiation of the study. The unblinded site Pharmacist will dispense either SIR1-365 or placebo for the subject as per the randomisation schedule. The dispensed IP label will include the subject's name, randomisation number and will state 'SIR1-365 or matching placebo' and the dose. The label will not contain any unblinded information, to disclose whether the content(s) of the bottle are SIR1-365 or placebo.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
14/06/2021
Actual
Date of last participant enrolment
Anticipated
28/02/2022
Actual
Date of last data collection
Anticipated
10/04/2022
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 19090 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 19091 0
Cabrini Hospital - Malvern - Malvern
Recruitment hospital [3] 19092 0
Emeritus Research - Camberwell
Recruitment postcode(s) [1] 33647 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 33648 0
3144 - Malvern
Recruitment postcode(s) [3] 33649 0
3124 - Camberwell

Funding & Sponsors
Funding source category [1] 304021 0
Commercial sector/Industry
Name [1] 304021 0
Sironax Aus Pty Ltd
Country [1] 304021 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Sironax Aus Pty Ltd
Address
Level 40, 2-26 Park Street, Sydney, NSW 2000
Country
Australia
Secondary sponsor category [1] 304196 0
None
Name [1] 304196 0
Address [1] 304196 0
Country [1] 304196 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 304513 0
Bellberry Limited
Ethics committee address [1] 304513 0
Ethics committee country [1] 304513 0
Australia
Date submitted for ethics approval [1] 304513 0
31/03/2021
Approval date [1] 304513 0
Ethics approval number [1] 304513 0
Ethics committee name [2] 308301 0
St Vincent's Hospital Melbourne
Ethics committee address [2] 308301 0
Ethics committee country [2] 308301 0
Australia
Date submitted for ethics approval [2] 308301 0
06/04/2021
Approval date [2] 308301 0
Ethics approval number [2] 308301 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97214 0
A/Prof Eric Chung
Address 97214 0
Princess Alexandra Hospital
Level 4 Urology Offices
199 Ipswich Road Woolloongabba QLD 4102
Country 97214 0
Australia
Phone 97214 0
+61 7 3832 1168
Fax 97214 0
Email 97214 0
[email protected]
Contact person for public queries
Name 97215 0
Irina Oleinikova
Address 97215 0
Princess Alexandra Hospital
Level 4 Urology Offices
199 Ipswich Road Woolloongabba QLD 4102
Country 97215 0
Australia
Phone 97215 0
+61 7 3176 2217
Fax 97215 0
Email 97215 0
[email protected]
Contact person for scientific queries
Name 97216 0
Irina Oleinikova
Address 97216 0
Princess Alexandra Hospital
Level 4 Urology Offices
199 Ipswich Road Woolloongabba QLD 4102
Country 97216 0
Australia
Phone 97216 0
+61 7 3176 2217
Fax 97216 0
Email 97216 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Combined de-identified participant data may be made publicly available through peer reviewed journal publications or presentations at professional forums.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
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