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Trial registered on ANZCTR


Registration number
ACTRN12610000721000
Ethics application status
Approved
Date submitted
26/08/2010
Date registered
31/08/2010
Date last updated
30/03/2011
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Single-Center, Dose-Escalation and Fixed-Dose Crossover, Cohort Study to Determine the Safety and Pharmacokinetics of a Single Oral Dose of PF329 vs oral hydromorphone hydrochloride (HCl) in Healthy Subjects
Scientific title
A Phase 1, Single-Center, Dose-Escalation and Fixed-Dose Crossover, Cohort Study to Determine the Safety and Pharmacokinetics of a Single Oral Dose of PF329 versus oral hydromorphone hydrochloride (HCl) in Healthy Subjects
Secondary ID [1] 252576 0
Pharmacofore, Inc. Study PF329-101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pain 258063 0
Condition category
Condition code
Anaesthesiology 258223 258223 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a first-in-man Phase 1, partly double-blind, randomized, single oral dose study with two arms: The first arm is a dose escalation of both PF329 and hydromorphone hydrochloride by cohorts. Subjects in the dose escalation cohorts will be fasted overnight from 11:00 PM the night prior to dosing until 4 hours after administration of study medication. All subjects in the dose escalation cohorts will receive oral naltrexone to block the opioid effects of PF329 and hydromorphone hydrochloride. Three doses of naltrexone (50 mg each dosing) will be administered orally with 240 mL of water each at approximately the following times relative to study drug administration: 14 hours before, 2 hours before, and 12 hours after.
The starting dose of PF329 was determined using safety data obtained from nonclinical animal studies, and applying the algorithm for estimating the maximum safe starting dose in initial clinical trials as set forth in the Food and Drug Administration (FDA) guidance on the topic. The hydromorphone hydrochloride starting dose is a fraction of the PF329 dose. Doses will be escalated by cohort based on safety and pharmacokinetic assessments, either 2 or 4 fold from the previous cohort dose. The maximum number of cohorts in this arm is 7, since the smallest increment of dose escalation from the starting dose of 1 mg to the maximum dose of 48 mg is two. If the initial cohorts yield measurable plasma levels of PF329, PF329 doses for each of the 7 cohorts would be: 1 mg, 2 mg, 4 mg, 8 mg, 16 mg, 32 mg and 48 mg. The doses of hydromorphone will start at 0.5 mg, and thereafter will be adjusted to yield plasma concentrations equivalent to the PF329 dose in the next cohort, based on results of hydromorphone plasma assays in previous cohorts.
In the second arm of the study, a separate crossover cohort will receive a dose of PF329 without naltrexone, but 50 mg naltrexone will be given orally with 240 ml water 12 hours after dosing as an added safety precaution. There will be no hydromorphone doses given in the crossover cohort. The PF329 dose for this crossover cohort will be chosen based on data from the dose escalation cohorts in the first arm and will be a dose that is not expected to produce adverse opioid effects. In one treatment session of this cohort, the group will be given a standardized high fat (approximately 50 percent of total caloric content of the meal), high-calorie (approximately 800 to 1000 calories) meal to be started 30 minutes before study drug dosing, and in another treatment session, the cohort will be fasted until 4 hours after dosing. Pharmacokinetics under both conditions will be compared. The subjects may be asked to return for a third treatment session to received half the dose of PF329 as in the previous 2 sessions, to obtain additional pharmacokinetic data. Thus, in this crossover cohort, there is a minimum of two treatment sessions, and a maximum of three treatment sessions. The crossover treatment sessions will be separated by a washout period of at least one week.
The study will evaluate the safety and pharmacokinetics of PF329 as well as the pharmacokinetics of hydromorphone at doses sufficient to characterize the extent to which plasma hydromorphone is produced and maintained following oral ingestion of PF329.
Intervention code [1] 257093 0
Treatment: Drugs
Comparator / control treatment
In study arm 1, the dose escalation cohorts, there will be a parallel study treatment of oral hydromorphone HCl as an active comparator. In study arm 2, the crossover cohort, the effect of a high fat meal versus fasting on the pharmacokinetics of PF329 will be compared.
Control group
Active

Outcomes
Primary outcome [1] 259083 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.
The risks associated with Hydromorphone include low blood pressure, slow breathing and lower levels of oxygen in the blood.
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.
Timepoint [1] 259083 0
Vital signs, including heart rate, blood pressure, and respiratory rate as well as oxygen saturation will be recorded 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] 259100 0
PHARMACOKINETICS, assessed by measurement of drug in plasma samples.
Timepoint [2] 259100 0
Blood samples (6 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, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, 24 hr, 36 hr, 48 hr, 60 hr, and 72 hr post-dose administration.
Primary outcome [3] 259101 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.
The risks associated with Hydromorphone include low blood pressure, slow breathing and lower levels of oxygen in the blood.
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.
Timepoint [3] 259101 0
up to 72 hours following drug administration
Secondary outcome [1] 265372 0
The effects of naltrexone and food on the pharmacokinetics of PF329 will be assessed by measuring plasma levels of drug and metabolites after administration of the drug with and without naltrexone, and with and without food.
Timepoint [1] 265372 0
Blood samples (6 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, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, 24 hr, 36 hr, 48 hr, 60 hr, and 72 hr post-dose administration.

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, nicotine, alcohol, hepatitis B-surface antigen, hepatitis C and Human Immunodeficiency Virus (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, Intra-Uterine Device (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 12-lead Electrocardiogram (ECG), and normal vital signs (respiratory rate between 12 and 20 breaths per minute, blood pressure between 100-140/60-90 mmHg, heart rate between 48-99 beats per minute, temperature between 35.8 degrees Celsius and 37.8 degrees Celsius), and Oxygen Saturation measured by pulse oximetry (SpO2) > 96 percent 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
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 hydromorphoneor sulfites
2. History of loud snoring or sleep apnea
3. History of medical problems encountered with opioid therapy
4. Urinary cotinine levels indicative of smoking or history of regular use of tobacco-containing or nicotine-containing products within 2 months prior to screening
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 opioid 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
Who is / are masked / blinded?



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

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
25/10/2010
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
80
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 257541 0
Commercial sector/Industry
Name [1] 257541 0
PharmacoFore, Inc.
Country [1] 257541 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
PharmacoFore, Inc.
Address
75 Shoreway Road
Suite D
San Carlos, CA 94070
Country
United States of America
Secondary sponsor category [1] 256766 0
None
Name [1] 256766 0
Address [1] 256766 0
Country [1] 256766 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259569 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 259569 0
Ethics committee country [1] 259569 0
Date submitted for ethics approval [1] 259569 0
23/09/2010
Approval date [1] 259569 0
05/10/2010
Ethics approval number [1] 259569 0

Summary
Brief summary
The primary objectives of the study are to assess the safety, tolerability and pharmacokinetics of intact prodrug, PF329, as well as the pharmacokinetics of its pharmaceutically active form, hydromorphone, following increasing doses of a single oral administration of PF329 in healthy adult subjects
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 31575 0
Address 31575 0
Country 31575 0
Phone 31575 0
Fax 31575 0
Email 31575 0
Contact person for public queries
Name 14822 0
Judy Magruder
Address 14822 0
75 Shoreway Road
Suite D
San Carlos, CA 94070
Country 14822 0
United States of America
Phone 14822 0
1-650-331-4004
Fax 14822 0
Email 14822 0
[email protected]
Contact person for scientific queries
Name 5750 0
Judy Magruder
Address 5750 0
75 Shoreway Road
Suite D
San Carlos, CA 94070
Country 5750 0
United States of America
Phone 5750 0
1-650-331-4004
Fax 5750 0
Email 5750 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
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