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Trial registered on ANZCTR


Registration number
ACTRN12612001086853
Ethics application status
Approved
Date submitted
8/10/2012
Date registered
10/10/2012
Date last updated
10/10/2012
Type of registration
Retrospectively registered

Titles & IDs
Public title
A study to compare the effects of different formulations of epoprostenol for injection.
Scientific title
A single-center, open label, two-part study in healthy male subjects, with each part having a two-period, two-treatment, crossover, ascending dose design to assess the pharmacokinetics and pharmacodynamics of different formulations of epoprostenol.
Secondary ID [1] 281359 0
Nil
Universal Trial Number (UTN)
U1111-1135-5434
Trial acronym
AC-066-102
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pharmacokinetics in healthy male volunteers 287581 0
Pharmacodynamics in healthy male volunteers 287582 0
Condition category
Condition code
Other 287908 287908 0 0
Conditions of unknown or disputed aetiology (such as chronic fatigue syndrome/myalgic encephalomyelitis)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In addition to epoprostenol sodium formulated with glycine-mannitol (epoprostenol GM; Flolan (Registered Trademark); GlaxoSmithKline, North Carolina, USA), 2 other formulations of epoprostenol sodium for injection were recently approved by US FDA for treatment of PAH. All 3 formulations contain the same active ingredient (epoprostenol sodium) but differ with regard to excipients. These modifications confer to the 2 new formulations of epoprostenol sodium, one formulated with arginine-mannitol (epoprostenol AM; Veletri (Registered Trademark) first generation, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland 8) and one formulated with arginine-sucrose (epoprostenol AS, Veletri (Registered Trademark) second generation, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland), an improved stability after reconstitution and dilution when compared to epoprostenol GM.
Epoprostenol AM and epoprostenol AS were infused via an intravenous (i.v.) catheter (on the dominant arm) using an ambulatory infusion pump (CADD-Legacy (Registered Trademark) 1, ambulatory infusion pump Model 6400 for continuous delivery) at room temperature. Epoprostenol GM was administered with the pump contained in a special pouch using frozen gel packs to maintain its stability.
In each study part, the pharmacokinetics, pharmacodynamics, safety, and tolerability of two different formulations of epoprostenol sodium for injection were assessed, epoprostenol AM and epoprostenol AS in part 1 and epoprostenol AS and epoprostenol GM in part 2. A total of 40 healthy male subjects were enrolled, i.e., 20 in part 1 and 20 different subjects in part 2. Each subject, enrolled either in Part 1 or Part 2, attended two periods separated by a 7-day washout period.
Over the two treatment periods of Part 1, treatments with epoprostenol AM and epoprostenol AS were administered in the sequence epoprostenol AM/epoprostenol AS or epoprostenol AS/epoprostenol AM, with 10 subjects per sequence as determined by randomization. Over the two treatment periods of Part 2, treatments with epoprostenol AS and epoprostenol GM were administered in the sequence epoprostenol AS/epoprostenol GM or epoprostenol GM/epoprostenol AS, with 10 subjects per sequence as determined by randomization.
In part 1 and part 2 of the study, for each treatment period, subjects entered the clinic on day -1. On day 1, according to the randomization scheme, epoprostenol AM or epoprostenol AS in part 1 and epoprostenol AS or epoprostenol GM in part 2, was administered as sequential i.v. infusions of 2, 4, 6, and 8 ng/kg/min for 2 hours (h) each, followed by an observation period of 40 h. On day 2, 24 h after the infusion start, the subjects left the clinic after completion of the scheduled assessments. Subjects returned to the clinic on day 3, 48 h after the infusion start, to complete the assessments of the end of period visit. For study part 1 and part 2, the end of period visit of the last treatment period was considered the end of study (EOS) visit.
Throughout the study, safety of the subjects was assessed by means of physical examinations, clinical laboratory tests (hematology, including coagulation screen, and serum chemistry), electrocardiograms, vital signs performed at regular intervals from predose to EOS. Concomitant medications and treatment-emergent adverse events occurring at any time during each treatment period were recorded. Pharmacokinetic and pharmacodynamic measurements were performed at predefined time points from predose to 24 h after infusion start.
Intervention code [1] 285821 0
Treatment: Drugs
Comparator / control treatment
Epoprostenol GM; Flolan (Registered Trademark); GlaxoSmithKline, North Carolina, USA
Control group
Active

Outcomes
Primary outcome [1] 288125 0
Pharmacokinetics of 3 different formulations of epoprostenol sodium for injection.
Timepoint [1] 288125 0
For pharmacokinetic assessments, serial blood samples of 4 mL were collected into ethylenediaminetetraacetic acid (EDTA)-containing tubes, at 0 (predose) and several time points up to 24 h after start of drug infusion.
In detail, blood samples were collected at predose and post dose at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.25, 6.5, 6.75, 7, 7.5, 8, 8.03, 8.07, 8.1, 8.13, 8.17, 8.2, 8.25, 8.33, 8.5, 8.75, 9, 10, 12, 14, 24 h.
Secondary outcome [1] 299459 0
Pharmacodynamics (cardiovascular markers: cardiac output measured by echocardiography, cardiac index, heart rate, and blood pressure) of 3 different formulations of epoprostenol sodium for injection.
Timepoint [1] 299459 0
Pharmacodynamic assessments were performed immediately before and at pre-defined time points up to 24 h after start of drug infusion, i.e., at predose and 2, 4, 6, 8, 9, 12, 24 h post dose.

Eligibility
Key inclusion criteria
1. Signed informed consent prior to any study-mandated procedure.
2. Male subjects between 18 and 45 years (inclusive) at screening.
3. No clinically significant finding on the physical examination at screening.
4. Body mass index (BMI) between 18.0 and 28.0 kg/m2 (inclusive) at screening.
5. Systolic blood pressure (SBP) 100–145 mmHg, diastolic blood pressure (DBP) 60–90 mmHg, and hear rate (HR) 45 90 bpm (inclusive), measured on the leading arm (leading arm = writing arm), after 5 minutes in the supine position at screening.
6. 12-lead electrocardiogram (ECG) without clinically relevant abnormalities measured after 5 minutes in the supine position at screening.
7. Hematology, coagulation, and clinical chemistry results not deviating from the normal range to a clinically relevant extent at screening.
8. Negative results from urine alcohol and urine drug screen at screening.
9. Ability to communicate well with the investigator and to understand and comply with the requirements of the study.
Minimum age
18 Years
Maximum age
45 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Known allergic reactions or hypersensitivity to any excipients of the drug formulation.
2. Treatment with another investigational drug within 3 months prior to screening.
3. Excessive caffeine consumption, defined as > 800 mg per day at screening.
4. History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the distribution, metabolism or excretion of the study drug.
5. Veins unsuitable for i.v. puncture on either arm (e.g., veins that are difficult to locate, access or puncture; veins with a tendency to rupture during or after puncture).
6. Coagulation screen, (i.e., activated partial thromboplastin time [aPTT], prothrombin time [PT], and International normalized ratio [INR]) out of the normal range.
7. Abnormal hematology test results, especially platelet count and hemoglobin (Hb) lower than the lower limit of the reference range.
8. History or clinical evidence of any disorder of hemostasis, hemorrhagic diathesis, nose or gingival bleeding, history of bleeding complications after surgical procedures such as dental extraction.
9. Previous history of fainting, collapses, syncope, orthostatic hypotension, or vasovagal reactions (orthostatic hypotension defined as a reduction in SBP from supine to standing position of > 20 mmHg, or in DBP > 10 mmHg).
10. Previous treatment with any prescribed or over-the-counter (OTC) medications (including herbal medicines such as St. John's wort) within 2 weeks prior to first study drug administration, except for acetaminophen.
11. Loss of 250 mL or more of blood within 3 months prior to screening.
12. Positive results from the hepatitis B/C serology, except for vaccinated subjects, at screening.
13. Smoking within the last month prior to screening.
14. Positive results from the HIV serology at screening.
15. Legal incapacity or limited legal capacity at screening.
16. History or clinical evidence of alcoholism or drug abuse.
17. Alcohol consumption of > 21 units/week or > 3 units/day.
18. Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.

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)
This was not a controlled trial but each subject was randomized 1:1 to a treatment sequence using SAS.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization schemes were generated using SAS.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
This was a single-center, open-label, two-part study in healthy male subjects, with each part having a randomized, two-period, two-treatment, crossover, ascending dose design. A total of 40 healthy male subjects were enrolled, i.e., 20 in part 1 and 20 different subjects in part 2.
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
12/01/2011
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment outside Australia
Country [1] 4586 0
United States of America
State/province [1] 4586 0
Florida

Funding & Sponsors
Funding source category [1] 286116 0
Commercial sector/Industry
Name [1] 286116 0
Actelion Pharmaceuticals Ltd.
Country [1] 286116 0
Switzerland
Primary sponsor type
Commercial sector/Industry
Name
Actelion Pharmaceuticals Ltd.
Address
Actelion Pharmaceuticals Ltd.
Gewerbestrasse 16
CH-4123 Allschwil, Switzerland
Country
Switzerland
Secondary sponsor category [1] 284928 0
None
Name [1] 284928 0
Address [1] 284928 0
Country [1] 284928 0
Other collaborator category [1] 277115 0
Commercial sector/Industry
Name [1] 277115 0
Cetero Research Miami
Address [1] 277115 0
Cetero Research,
1405 NW 167th Street,
Miami Gardens,
FL 33169,
USA
Country [1] 277115 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288164 0
IRB services
Ethics committee address [1] 288164 0
Ethics committee country [1] 288164 0
Canada
Date submitted for ethics approval [1] 288164 0
19/11/2010
Approval date [1] 288164 0
02/12/2010
Ethics approval number [1] 288164 0

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

Contacts
Principal investigator
Name 34800 0
Address 34800 0
Country 34800 0
Phone 34800 0
Fax 34800 0
Email 34800 0
Contact person for public queries
Name 18047 0
Laurent B. Nicolas
Address 18047 0
Actelion Pharmaceuticals Ltd.
Clinical pharmacology
Gewerbestrasse 16
CH-4123 Allschwil, Switzerland
Country 18047 0
Switzerland
Phone 18047 0
+41 61 5656945
Fax 18047 0
+41 61 5656200
Email 18047 0
laurent.nicolas@actelion.com
Contact person for scientific queries
Name 8975 0
Laurent B. Nicolas
Address 8975 0
Actelion Pharmaceuticals Ltd.
Clinical pharmacology
Gewerbestrasse 16
CH-4123 Allschwil, Switzerland
Country 8975 0
Switzerland
Phone 8975 0
+41 61 5656945
Fax 8975 0
+41 61 5656200
Email 8975 0
laurent.nicolas@actelion.com

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What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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