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Trial registered on ANZCTR


Registration number
ACTRN12617000535370p
Ethics application status
Submitted, not yet approved
Date submitted
5/04/2017
Date registered
12/04/2017
Date last updated
12/04/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose, Safety, Tolerability and Pharmacokinetic Study of Topical Pirenzepine in Healthy Volunteers
Scientific title
A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose, Safety, Tolerability and Pharmacokinetic Study of Topical Pirenzepine in Healthy Volunteers
Secondary ID [1] 291587 0
WST-PZP-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetic Peripheral Neuropathy 302719 0
Condition category
Condition code
Neurological 302242 302242 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a Phase 1, first in human, double-blind, randomized, placebo-controlled, multiple dose study consisting of a total of 24 healthy subjects: 3 cohorts of 8 subjects (6 subjects assigned to pirenzepine: 2 assigned to placebo in each cohort).
Each treatment will be administered topically to the lower extremities (right and left calves [i.e., anterior lower leg/shins] and tops of feet) by study staff using gloved hands.
The names of the 2 formulations that will be used are WinF90 (6.5% pirenzepine) and WinFB34 (4.0% pirenzepine).
Cohort 1 will be administered 6.5% pirenzepine topical solution WinF90 or matching placebo – 5 mL applied once daily for 14 days.
Cohort 2 will be administered 4.0% pirenzepine topical solution WinFB34 or matching placebo – 5 mL applied once daily for 14 days.
Cohort 3 will be administered 4.0% pirenzepine topical solution WinFB34/matching placebo or 6.5% pirenzepine topical solution WinF90/matching placebo – administered for 14 days with dose volume and dose frequency to be determined following review of Cohort 1 and 2 data.
Intervention code [1] 297675 0
Treatment: Drugs
Comparator / control treatment
WinF90 and WinFB34 will have matching placebo's containing the same formulations as the active Pirenzepine compositions minus the active ingredient pirenzepine dihydrochloride.
Control group
Placebo

Outcomes
Primary outcome [1] 301651 0
To evaluate the safety and tolerability of 2 different pirenzepine formulations after daily topical dose administrations in healthy subjects for 14 days.
Safety and tolerability will be assessed by ECG and vital sign monitoring, adverse event recording, local skin irritation assessments and Subject assessment of post-dose discomfort at the test site using a Visual Analog Scale.
Timepoint [1] 301651 0
Vital signs will be measured on Day -1, Day 1 (pre-dose and 1, 4, and 8 hours post-dose); pre-dose on Days 2, 4, 6, 8, 10 and 12; Day 14 (pre-dose and 1, 4 and 8 hours post-dose); Day 15 and Day 16.
ECG will be performed on Day -1, Day 1 (pre-dose and 1, 4, and 8 hours post-dose); Day 2 (pre-dose); 1, 4 and 8 hours post-dose on Day 7, and Day 14 (pre-dose and 1, 4 and 8 hours post-dose; Day 15 and Day 16.
Blood samples will be collected on Day 1, Day 7 and Day 14. Subjects will be required to fast for at least 8 hours prior to collection.
Urine samples will be collected prior to dosing on Day 1, Day 7 and Day 14.
Skin irritation (including redness, swelling, itching, pain) at the IP application site will be assessed using a Dermal Rating Scale following IP administration by study center staff on Day -1 through Day 16 at pre-dose; and 1 hour and 4 hours post-dose (+/-30 mins).
Subject Assessment of discomfort via Visual Analog Scale on Day -1 through Day16 at pre-dose; and 1 hour and 4 hours post-dose (+/-30 mins).
Frequency of micturition and urine volume produced by each subject over 0-24 hours post-dose will be measured at Days 1, 7 and 14.
Primary outcome [2] 301652 0
The second primary endpoint for the study is to evaluate the safety and tolerability of an alternative dosing regimen in healthy subjects with 1 of the pirenzepine topical formulations.
Safety and tolerability will be assessed by ECG and vital sign monitoring, adverse event recording, local skin irritation assessments and Subject assessment of post-dose discomfort at the test site using a Visual Analog Scale.
Timepoint [2] 301652 0
Vital signs will be measured on Day -1, Day 1 (pre-dose and 1, 4, and 8 hours post-dose); pre-dose on Days 2, 4, 6, 8, 10 and 12; Day 14 (pre-dose and 1, 4 and 8 hours post-dose); Day 15 and Day 16.
ECG will be performed on Day -1, Day 1 (pre-dose and 1, 4, and 8 hours post-dose); Day 2 (pre-dose); 1, 4 and 8 hours post-dose on Day 7, and Day 14 (pre-dose and 1, 4 and 8 hours post-dose; Day 15 and Day 16.
Blood samples will be collected on Day 1, Day 7 and Day 14. Subjects will be required to fast for at least 8 hours prior to collection.
Urine samples will be collected prior to dosing on Day 1, Day 7 and Day 14.
Skin irritation (including redness, swelling, itching, pain) at the IP application site will be assessed using a Dermal Rating Scale following IP administration by study center staff on Day -1 through Day 16 at pre-dose; and 1 hour and 4 hours post-dose (+/-30 mins).
Subject Assessment of discomfort via Visual Analog Scale on Day -1 through Day16 at pre-dose; and 1 hour and 4 hours post-dose (+/-30 mins).
Frequency of micturition and urine volume produced by each subject over 0-24 hours post-dose will be measured at Days 1, 7 and 14.
Secondary outcome [1] 333442 0
To evaluate the pharmacokinetics (PK) of pirenzepine and its desmethyl metabolite following single and multiple topical doses of 2 different pirenzepine formulations.
Pirenzepine and its desmethyl metabolite concentrations and calculated standard PK parameters including but not limited to; maximum plasma concentration (Cmax), time to maximal concentration (tmax), area under the concentration-time curve (AUC0-last and AUC0-8), apparent terminal elimination rate constant (kel), steady state, and apparent terminal elimination half-life (t1/2).
Timepoint [1] 333442 0
Blood samples will be collected from subjects at the following time points:
Day 1
Within 30 minutes prior to Dose 1 application
Post Dose 1 application:
0.5, 1, 1,5, 2, 3, 4, 6, 8, 12 hours
Day 2
24 hours post Dose 1 application
Day 3
Within 30 minutes prior to Dose 3 application
Day 4
Within 30 minutes prior to Dose 4 application
Day 5
Within 30 minutes prior to Dose 5 application
Day 7
Within 30 minutes prior to Dose 7 application
Day 10
Within 30 minutes prior to Dose 10 application
Day 14
Within 30 minutes prior to Dose 14 application
Post Dose 14 application:
0.5, 1, 2, 3, 4, 6, 8, 12 hours
Day 15
24 hours post Dose 14 application
Day 16
48 hours post Dose 14 application
Secondary outcome [2] 333443 0
Evaluate the PK of pirenzepine and its desmethyl metabolite following an alternative dosing regimen with 1 of the pirenzepine topical formulations.
Pirenzepine and its desmethyl metabolite concentrations and calculated standard PK parameters including but not limited to; maximum plasma concentration (Cmax), time to maximal concentration (tmax), area under the concentration-time curve (AUC0-last and AUC0-8), apparent terminal elimination rate constant (kel), steady state, and apparent terminal elimination half-life (t1/2).
Timepoint [2] 333443 0
Blood samples will be collected from subjects at the following time points:
Day 1
Within 30 minutes prior to Dose 1 application
Post Dose 1 application:
0.5, 1, 1,5, 2, 3, 4, 6, 8, 12 hours
Day 2
24 hours post Dose 1 application
Day 3
Within 30 minutes prior to Dose 3 application
Day 4
Within 30 minutes prior to Dose 4 application
Day 5
Within 30 minutes prior to Dose 5 application
Day 7
Within 30 minutes prior to Dose 7 application
Day 10
Within 30 minutes prior to Dose 10 application
Day 14
Within 30 minutes prior to Dose 14 application
Post Dose 14 application:
0.5, 1, 2, 3, 4, 6, 8, 12 hours
Day 15
24 hours post Dose 14 application
Day 16
48 hours post Dose 14 application

Eligibility
Key inclusion criteria
1. Male or female, 18-65 years old (inclusive).
2. Body mass index (BMI) between 25 and 30 kg/m2 (inclusive).
3. Be in general good health as determined by the Investigator, without clinically significant medical history.
4. Normal or non-clinically significant findings on a physical examination, 12-lead electrocardiogram (ECG) and vital signs, as determined by the Investigator.
5. Adequate hepatic and renal function, as determined by clinical laboratory assessments of blood and urine.
6. Negative serum pregnancy test at Screening and negative urine pregnancy test on Day -1 for females of child bearing potential.
7. Negative screen for drugs of abuse, cotinine, alcohol, hepatitis B surface antigen (HBs Ag), hepatitis C virus antibody (HCV Ab) and Human Immunodeficiency Virus (HIV) at Screening; and negative drugs of abuse, cotinine and alcohol screen on Day -1.
8. Clinical laboratory values within the normal limits as defined by the clinical laboratory, unless the Investigator decides that out-of-range values are not clinically significant.
9. Females of child-bearing potential and males must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 45 days following completion of therapy.
10. Ability to provide written informed consent.
11. Willing and able to follow study instructions and likely to complete all study requirements.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History of allergy or sensitivity to M1 antagonists or any of the components of the investigational product formulations.
2. Known hypersensitivity to pirenzepine or another component of the investigational product.
3. Have sensitive skin, as defined by a requirement to use soap and lotions formulated for ‘sensitive’ skin.
4. Any open wound and/or sunburn(s) in the dosing area. Subjects who have a wound and/or sunburn at Screening which is anticipated to resolve before Day -1 can be enrolled.
5. Any clinically significant central nervous system, cardiac, pulmonary, renal, gastrointestinal, respiratory, metabolic conditions (or history), or other pathological or physiological conditions, including a history of paralytic ileus, glaucoma, prostatic hypertrophy or tachycardia, that might interfere with the trial result in the Investigator’s opinion.
6. Any condition, which in the Investigator’s opinion, puts the subject at significant risk, could confound the study results or may interfere significantly with the subject’s participation in the study.
7. Use of any topical agents (prescription and over-the-counter, including lotions such as sunscreen, cosmetics, moisturizing lotion) at the administration site within a week before randomization and during confinement.
8. History of serious skin diseases (as determined by the Investigator): such as skin cancer, psoriasis, eczema.
9. History of urinary retention, as determined by previous diagnosis or patient self-reporting.
10. Have received a tattoo in the dosing area within 12 months of dosing.
11. Current smoker, or a history of regular (more than weekly) use of tobacco- or nicotine-containing products within 2 months prior to Screening.
12. History of excessive alcohol intake (more than 4 standard drinks daily, on average) or use of recreational drugs within the last 3 months.
13. Use of prescription or over-the-counter medications within 7 days of investigational product administration, with the exception of contraceptive medications, paracetamol, oral non-steroidal anti-inflammatory agents, and vitamins (if they do not exceed recommended daily dose), unless agreed as non-clinically relevant by the Investigator and Sponsor.
14. Donation or loss of blood (excluding volume drawn at Screening) of 50 mL to 499 mL within 30 days of the study.
15. Anticipated need for surgery or hospitalization during the study.
16. Have completed another drug clinical trial within 45 days of dosing, or intend to participate in other drug clinical trials during this study period.
17. Pregnant or nursing females.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer generated randomization schedule will be prepared by an unblinded statistician prior to the start of the study. IP will be prepared in accordance with the randomization schedule.
After signing the informed consent form (ICF), each subject will be given a Screening Number according to the screening order. During the Treatment Period, subjects will be randomized to receive pirenzepine or placebo in a ratio of 3:1 respectively. Subjects will be randomized on Day -1. At the time of randomization, the subject will be assigned a unique Randomization Number, which will be allocated in ascending order from the list of random numbers based on the predetermined randomization schedule, and according to their chronological order of inclusion in the study. Confirmation of the Randomization Number allocated will be documented in the drug accountability records and recorded in the eCRF
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
3 cohorts of 8 subjects (6 subjects assigned to pirenzepine: 2 assigned to placebo in each cohort). The first 2 cohorts will be administered different topical formulations of pirenzepine. The topical formulation, dose volume and dosing frequency to be administered in the third cohort will be selected after completion of the first 2 cohorts.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Descriptive statistics will be used to summarize plasma pirenzepine and its desmethyl metabolite concentrations and resultant PK parameters across study subjects and treatments. Relative bioavailability will be investigated for the 3 pirenzepine treatments relative to each other. Relative bioavailability will be calculated using AUC and Cmax parameters e.g. AUC test/AUC reference or Cmax test/Cmax reference. The similarity of the AUC and Cmax values will be tested statistically, using the analysis of variance method (ANOVA). Further details will be provided in the SAP.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
10/05/2017
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
24
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 7768 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 15701 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 296075 0
Commercial sector/Industry
Name [1] 296075 0
WinSanTor Australia Pty Ltd
Country [1] 296075 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
WinSanTor Australia Pty Ltd
Address
Level 15, 300 Queen Street, Brisbane QLD, 4000
Country
Australia
Secondary sponsor category [1] 294968 0
None
Name [1] 294968 0
None
Address [1] 294968 0
None
Country [1] 294968 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 297333 0
Bellberry Limited
Ethics committee address [1] 297333 0
Ethics committee country [1] 297333 0
Australia
Date submitted for ethics approval [1] 297333 0
12/04/2017
Approval date [1] 297333 0
Ethics approval number [1] 297333 0

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

Contacts
Principal investigator
Name 73734 0
Dr Nicholas Farinola
Address 73734 0
CMAX Clinical Research
Level 5, 18a North Terrace
SA 5000
Country 73734 0
Australia
Phone 73734 0
+61 8 70887900
Fax 73734 0
Email 73734 0
Nicholas.farinola@health.sa.gov.au
Contact person for public queries
Name 73735 0
Jamie Baker
Address 73735 0
CMAX Clinical Research
Level 5, 18a North Terrace, Adelaide SA 5000
Country 73735 0
Australia
Phone 73735 0
+61 8 7088 7938
Fax 73735 0
Email 73735 0
Jamie.Baker@cmax.com.au
Contact person for scientific queries
Name 73736 0
Cecelia Agostinelli
Address 73736 0
INC Research
Level 1, 20 Atherton Road
Oakleigh, VIC, 3166
Country 73736 0
Australia
Phone 73736 0
+61 3 85336878
Fax 73736 0
Email 73736 0
cecelia.agostinellia@incresearch.com

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