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Trial registered on ANZCTR


Registration number
ACTRN12612000880842
Ethics application status
Approved
Date submitted
13/08/2012
Date registered
20/08/2012
Date last updated
24/02/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Single-Center, Dose-Ranging, Multi-Treatment Study to Determine the Safety and Pharmacokinetics of Single Oral Dose Combinations of PF329 and Nafamostat Mesilate in Healthy Subjects
Scientific title
A Phase 1, Single-Center, Dose-Ranging, Multi-Treatment Study to Determine the Safety and Pharmacokinetics of Single Oral Dose Combinations of PF329 and Nafamostat Mesilate in Healthy Subjects
Secondary ID [1] 280848 0
Signature Therapeutics, Inc. Study PF329-102
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
The compound PF329 is intended for eventual use in patients for the treatment of pain. This current study is being conducted in healthy volunteers to learn about the way this drug behaves in the body when it is given in combination with nafamostat. The combination of PF329 and nafamostat may provide safeguards against either intentional overdose (abuse) or unintentional overdose (misuse or error). This study will provide the information needed to determine the feasibility and utility of this combination for the intended use. 286915 0
Condition category
Condition code
Anaesthesiology 287243 287243 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is designed to assess the effects of varying doses of nafamostat mesilate on the pharmacokinetics ("PK") of PF329. PF329 is a prodrug of the currently used opioid hydromorphone. An understanding of the dose-response relationship of PF329 and nafamostat combinations is the key first step in demonstrating the viability of the MPAR concept in humans (MPAR = Multi-Pill Abuse-Resistance, or overdose protection). Data from this study will inform later assessments to confirm that there is a combination of the agents that will have a minimal effect on the conversion of PF329 to hydromorphone when administered as prescribed, but will substantially reduce that conversion when multiple pills are taken in an overdose or abuse situation. Subjects will receive PF329 alone and in combination with nafamostat at doses sufficient to characterize the dose response curve of the impact of nafamostat on the pharmacokinetics of a dose of PF329. Both PF329 and nafamostat will be given as oral solutions during the study. During each treatment with PF329, subjects will receive naltrexone to block the opioid effects.

The study is a 4 to 6 treatment open-label, single-dose, crossover in up to 14 subjects to determine the dose-response curve of nafamostat co-administered with PF329 and the effects on the "PK" of PF329. The following treatments will be administered with a washout period of at least 7 days between treatments. Safety and "PK" data will be reviewed between treatments (for treatments 1(a) and 1(b) the review will be conducted after the complete crossover) to determine nafamostat doses for subsequent treatments.
1. Baseline PK and maximal effect dose of nafamostat: All subjects will receive treatment 1(a) and treatment 1(b) in random order, followed by treatment 1(c) if indicated:
1(a): 4 mg PF329 to determine baseline "PK" of hydromorphone
1(b): 4 mg PF329 co-administered with 10 mg nafamostat to achieve a reduction of at least 50% (maximal effect) in the AUC (AUC = Area under the Curve, or amount) of hydromorphone produced from PF329 as compared to baseline.
1(c): If the maximal effect is not achieved in Treatment 1(b) with 10 mg nafamostat, an additional treatment will be administered with 4 mg PF329 and 20 mg of nafamostat.
2. Minimal effect dose of nafamostat (dose that results in hydromorphone AUC that is > 80% of baseline):
2(a): 4 mg PF329 co-administered with 1/10th the nafamostat dose shown to have maximal effect on hydromorphone AUC in Treatment 1.
2(b): If the minimal effect is not observed at the 1/10th dose the nafamostat dose will be reduced by 10-fold and the treatment will be repeated.
3. Intermediate effect dose of nafamostat: 4 mg PF329 co-administered with a dose of nafamostat that is midway (in the log domain) between the maximal and minimal effect doses determined in 1 and 2 above.
3(a): 4 mg PF329 + 3X the nafamostat dose from treatment 2 that produced no / minimal effect on the "PK" of a 4 mg dose of PF329.
3(b): If the effect is not intermediate, then the dose of nafamostat will be adjusted up or down 1.8 fold
Intervention code [1] 285274 0
Treatment: Drugs
Comparator / control treatment
Comparator / control treatment: This is a cross-over study. Subjects serve as their own control. Pharmacokinetics from a dose of PF329 alone (identified as “treatment 1a” – the “baseline” or “control” treatment) will be compared to pharmacokinetics of PF329 with varying doses of nafamostat mesilate. This comparison will enable analysis of the effect of nafamostat on PF329 pharmacokinetics as compared to baseline.
Control group
Active

Outcomes
Primary outcome [1] 287642 0
SAFETY, assessed by measurement of vital signs and assessment of reported adverse events.
The risks associated with PF329 include low blood pressure, slow breathing and lower levels of oxygen in the blood.
In general, nafamostat mesilate is well tolerated and the most significant adverse reactions tend to be allergic reactions with the IV product. Exacerbation of bleeding may occur with nafamostat mesilate. This risk will be monitored via blood clotting tests.
The risks associated with naltrexone include difficulty sleeping, anxiety, nervousness, abdominal pains/cramps, nausea and/or vomiting, low energy, joint and muscle pain, increased appetite, weight loss, yawning, somnolence, fever, dry mouth, cold feet, hot spells, light sensitivity, palpitations, tachycardia, sneezing and headache. Subjects will be observed for these adverse events. Should any of these events occur, they should occur within hours of naltrexone administration, during which the subjects will be under continuous observation in the clinic.
Timepoint [1] 287642 0
Vital signs, including heart rate, blood pressure, and respiratory rate as well as oxygen saturation will be recorded prior to dosing and every 15 minutes during the 3 hour period following study drug administration. During the time period of 3 hours through 24 hours after study drug administration, vitals will be recorded every hour and then every 4 hours until the subject is discharged, 72 hours following drug administration
Primary outcome [2] 287643 0
PHARMACOKINETICS, assessed by measurement of drug in plasma or blood samples.
Timepoint [2] 287643 0
Blood samples (8 mL) will be collected from the venous catheter at pre-dose (within 30 minutes prior to dosing), and approximately 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 12 hr, 24 hr, 36 hr, 48 hr and 72 hr post-dose administration.
Primary outcome [3] 287644 0
TOLERABILITY, assessed by reported adverse events.
The risks associated with PF329 include low blood pressure, slow breathing and lower levels of oxygen in the blood.
In general, nafamostat mesilate is well tolerated and the most significant adverse reactions tend to be allergic reactions with the IV product. Exacerbation of bleeding may occur with nafamostat mesilate. This risk will be monitored via blood clotting tests.
The risks associated with naltrexone include difficulty sleeping, anxiety, nervousness, abdominal pains/cramps, nausea and/or vomiting, low energy, joint and muscle pain, increased appetite, weight loss, yawning, somnolence, fever, dry mouth, cold feet, hot spells, light sensitivity, palpitations, tachycardia, sneezing and headache. Subjects will be observed for these adverse events. Should any of these events occur, they should occur within hours of naltrexone administration, during which the subjects will be under continuous observation in the clinic.
Timepoint [3] 287644 0
Up to 72 hours following drug administration
Secondary outcome [1] 298572 0
Nil
Timepoint [1] 298572 0
Nil

Eligibility
Key inclusion criteria
1. Males or females, ages 18-50 years in good general health
2. Body Mass Index (BMI) between 18 and 30 kg/m2 (inclusive)
3. Subjects must have a negative screen for drugs of abuse, alcohol, hepatitis B-surface antigen, hepatitis C and HIV.
4. Female subjects must have a negative serum pregnancy test at screening and a negative urine pregnancy test at randomization.
5. Female subjects must use a medically acceptable method of birth control (oral or transdermal contraceptives, condom, spermicidal foam, IUD, progestin implant or injection, abstinence, vaginal ring, or sterilization of partner) from the time of screening through two weeks after the last study treatment.
6. Subjects must have normal findings in a physical examination and a 12-lead ECG, and normal vital signs (respiratory rate between 12 and 20 breaths per minute, blood pressure (sitting) between 100-140/60-90 mmHg, heart rate (sitting) between 48-99 beats per minute, temperature between 35.8 degrees C and 37.8 degrees C) as well as SpO2 > 96% in the absence of supplemental oxygen.
7. Clinical laboratory values must be within the normal limits as defined by the clinical laboratory, unless the Investigator decides that out-of-range values are not clinically significant.
8. Subjects must be able to provide meaningful written informed consent
9. Subjects must be willing and able to follow study instructions and be likely to complete all study requirements, which include participation in up to 7 study treatment sessions
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History of allergy or sensitivity to hydromorphone or nafamostat
2. History of blood clotting disorders
3. History of loud snoring or sleep apnea
4. History of medical problems encountered with opioid therapy other than nausea and/or vomiting
5. History of alcoholism or drug abuse (prescription or illicit drugs)
6. Use of prescription or over-the-counter medications within 14 days of study drug administration except for contraceptive medications used by female subjects
7. Use of any opiate within 30 days prior to screening
8. Donation of blood within 30 days prior to screening
9. Donation of plasma or participation in a plasmapheresis program within 7 days prior to screening
10. Acute illness (e.g. gastrointestinal illness, infection such as influenza, upper respiratory tract infection, or known inflammatory process) at admission to the clinical study unit
11. History of gastrointestinal disturbance requiring frequent use of antacid
12. Anticipated need for surgery or hospitalization during the study
13. Enrollment in an investigational drug study within 30 days prior to screening
14. Any condition, that in the Investigator’s opinion, (i) puts the subject at significant risk, (ii) could confound the study results or (iii) may interfere significantly with the subject’s participation in the study

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)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
17/09/2012
Actual
24/09/2012
Date of last participant enrolment
Anticipated
Actual
24/09/2012
Date of last data collection
Anticipated
Actual
Sample size
Target
14
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 2130 0
The Alfred - Prahran

Funding & Sponsors
Funding source category [1] 285735 0
Commercial sector/Industry
Name [1] 285735 0
Signature Therapeutics, Inc.
Country [1] 285735 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Signature Therapeutics, Inc.
Address
Signature Therapeutics, Inc.
1731 Embarcadero Road
Suite 220
Palo Alto, CA 94303 USA
Country
United States of America
Secondary sponsor category [1] 284560 0
None
Name [1] 284560 0
Address [1] 284560 0
Country [1] 284560 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287739 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 287739 0
Ethics committee country [1] 287739 0
Australia
Date submitted for ethics approval [1] 287739 0
01/08/2012
Approval date [1] 287739 0
27/08/2012
Ethics approval number [1] 287739 0

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

Contacts
Principal investigator
Name 34438 0
A/Prof Peter Hodsman
Address 34438 0
The Alfred Hospital
Nucleus Network Ltd.
Level 5, Burnet Tower
89 Commercial Road
Melbourne, Victoria 3004
Country 34438 0
Australia
Phone 34438 0
+61 3 9076 8900
Fax 34438 0
Email 34438 0
P.Hodsman@nucleusnetwork.com.au
Contact person for public queries
Name 17685 0
Judy Magruder
Address 17685 0
Signature Therapeutics, Inc.
1731 Embarcadero Road
Suite 220
Palo Alto, CA 94303 USA
Country 17685 0
United States of America
Phone 17685 0
1-650-331-4004
Fax 17685 0
1-650-641-3704
Email 17685 0
jmagruder@signaturerx.com
Contact person for scientific queries
Name 8613 0
Judy Magruder
Address 8613 0
Signature Therapeutics, Inc.
1731 Embarcadero Road
Suite 220
Palo Alto, CA 94303 USA
Country 8613 0
United States of America
Phone 8613 0
1-650-331-4004
Fax 8613 0
1-650-641-3704
Email 8613 0
jmagruder@signaturerx.com

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No Supporting Document Provided



Results publications and other study-related documents

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