None listed
Conditions
Brief summary
We are studying the drug candidate, PF329, as a potential new medicine to treat pain, that is less easily abused than other pain medications. In early research studies, combinations of PF329 and the compound nafamostat showed the potential to provide protection from people taking too many pills at once. This study is intended to test the effects of various doses of nafamostat mesilate on the way the human body uses the drug PF329.
Interventions
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
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
Sponsors
Signature Therapeutics, Inc.
Study design
Allocation
Randomised controlled trial
Intervention model
Crossover
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 50 Years
Healthy volunteers
Yes
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
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
Outcome results
None listed