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Trial registered on ANZCTR


Registration number
ACTRN12614000102673
Ethics application status
Approved
Date submitted
20/01/2014
Date registered
28/01/2014
Date last updated
10/07/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessment of the trial drugs ACH­-0143102 and ACH-0142684, when taken by healthy men and women.
Scientific title
A Phase 1, Double Blind, Randomized, Placebo Controlled, Parallel Design Pharmacokinetic Drug Interaction Study of ACH-0143102 and ACH-0142684 in Healthy Volunteers.
Secondary ID [1] 283931 0
None
Universal Trial Number (UTN)
U1111-1152-3190
Trial acronym
ACH786-­001
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Phase 1 study (Healthy volunteers). Results to support research in Hepatitis C. 290947 0
Condition category
Condition code
Infection 291295 291295 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Adminstration of ACH-0142684 at 200mg per day and ACH-0143102 at 25mg per day together. Group 1 subjects will receive 21 days of ACH-0142684 and 14 days of ACH-0143102 (introduced at Day 8). Group 2 subjects will receive 21 days of ACH-0143102 and 7 days of ACH-0142684 (introduced at Day 15). ACH-0142684 will be a 2ml solution administered orally via a syringe. ACH-0143102 will be a single capsule administered orally.
Medication compliance and adherence will be monitored by weighing, counting and calculating both of the remaining product and monitoring the source documentation regarding drug administration. All drug will be taken in clinic under staff supervision and recorded in the subject notes / source documentation.
Intervention code [1] 288626 0
Treatment: Drugs
Comparator / control treatment
Placebo (no active therapeutic ingredient).
For ACH-0142684: The placebo is the vehicle in which ACH-0142684 would be reconstituted, and also administered orally as a 2 ml solution in a syringe.
The inactive ingredients for the vehicle are Water; Kolliphor (Trademark) P 407 micro (Microprilled Poloxamer 407); Cremophor (Registered Trademark) RH40 (Polyoxyl 40 hydrogenated castor oil/Macrogol glycerolhydroxystearat); Ethanol; Sodium benzoate; Raspberry Flavor; Vanilla Flavor; Prosweet (Registered Trademark) Natural and Artificial Flavor Enhancer.
For ACH-0143102: The placebo is alo a liquid filled capsule with no active ingredients. The inactive ingredients are Super Refined (Registered Trademark) Polysorbate 80, EP/NF; Capmul (Registered Trademark) MCM, NF (mono & diglycerides of caprylic/capric fatty acids); LiCaps (Registered Trademark) and is a hard gelatin capsule which is opaque white, size ‘00’.
In both groups 6 of the 18 subjects will be randomised to placebo. In Group 1, the 6 subjects will receive placebo ACH-0142684 alone once per day for 7 days, followed by placebo ACH-0142684 once per day and placebo ACH-0143102 once per day for 14 days.
In Group 2, the 6 subjects will receive placebo ACH-0143102 alone once per day for 14 days, followed by placebo ACH-0143102 once per day and placebo ACH-0142684 once per day for 7 days.
Control group
Placebo

Outcomes
Primary outcome [1] 291292 0
1. To determine if the steady state pharmacokinetic properties of ACH-0142684 are changed when co-administered with ACH-0143102.
Timepoint [1] 291292 0
Group 1: PK assays assessed from Days 8, 11 and 14 at hours 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose
Goup 2: PK assays assessed from Days 15 and 17 at hours 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose
Primary outcome [2] 291328 0
2. To determine if steady state pharmacokinetic properties of ACH-0143102 are changed when co-administered with ACH-0142684.
Timepoint [2] 291328 0
Group 1: PK assays assessed from Days 8, 11 and 14 at hours 1, 2, 4, 6, 8, 10, 12, 14 and 24 hours post dose
Goup 2: PK assays assessed from Days 15 and 17 at hours 1, 2, 4, 6, 8, 10, 12, 14 and 24 hours post dose
Primary outcome [3] 291329 0
3. To evaluate the safety and tolerability of ACH-0143102 and ACH-0142684 when administered together in healthy volunteers.
Timepoint [3] 291329 0
Day 35 all data (vitals, safety blood tests, physical exams, ECGs) and adverse events collected and reviewed
Secondary outcome [1] 306436 0
None
Timepoint [1] 306436 0
None

Eligibility
Key inclusion criteria
1. Healthy, adult, male or female subjects, 18 to 55 years of age, inclusive.
2. Continuous non smokers who have not used nicotine containing products for at least 3 months prior to the first dose.
3. Weigh at least 50kg and have a Body Mass Index (BMI) in the range 18 to 30.
4. Medically healthy with no clinically significant laboratory profiles, vital signs or ECGs; as assessed by the PI.
5. Liver function tests (serum alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase [ALP]) and serum bilirubin (total and direct) must be below or equal to the upper limit of normal (ULN) at screening.
6. Females must be of non childbearing potential, defined as having undergone one of the following sterilization procedures at least 6 months prior to Day 1:
hysterectomy;
bilateral oophorectomy
bilateral tubal ligation or fallopian tube inserts or be postmenopausal with amenorrhea for at least 1 year prior to Day 1 and have follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status.
7. Males must use a condom with spermicide when engaged in sexual activity from first check in through 90 days beyond the last dose.
8. Males must agree to refrain from sperm donation from first check in through 90 days beyond the last dose.
9. Give voluntary written informed consent to participate in the study.
10. Able to effectively communicate with the Investigator and other center personnel, and willing to comply with all study requirements and restrictions.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease in the opinion of the PI.
2. History or presence of alcoholism and/or drug abuse within the past 2 years.
3. History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds.
4. History or presence of diabetes mellitus or hyperglycemia, in the opinion of the PI.
5. Female subjects who are pregnant or lactating.
6. Have positive results for the urine drug screen at screening or check in.
7. Have positive urine cotinine at screening.
8. Have positive results at screening for HIV, HBsAg or HCV.
9. Seated sustained blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.
10. Heart rate is lower than 40 bpm or higher than 99 bpm at screening.
11. 12 lead ECGs which have clinically significant findings as judged by the PI or the PI’s designee at screening and prior to dosing, including:
QTcB interval is >450 msec;
PR interval > 200 msec.
QRS interval > 120 msec.
12. Has an estimated creatinine clearance < 90 mL/min based on the Cockcroft Gault equation at the screening visit.
13. Have used any drugs or substances known to be significant inhibitors of CYP enzymes and/or significant inhibitors or substrates of P gp and/or OATP within 14 days prior to the assigned first dose of study drug.
14. Have used any drugs or substances known to be significant inducers of CYP enzymes and/or P gp within 28 days prior to the assigned first dose of study drug.
15. Have been on a special diet within the previous 28 days which, in the opinion of the investigator, would interfere with subject safety or compliance with the protocol.
16. Have a hemoglobin level below the lower limit of normal at screening and first check in.
17. Have made a donation of blood or had significant blood loss within 56 days prior to the assigned first dose of study drug.
18. Have participated in another clinical trial within 28 days prior to the assigned first dose of study drug.

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)
The participants will be randomly assigned to active treatment or placebo in a ratio of 2:1 (for every subject allocated to placebo there will be 2 subjects allocated to active drug). The unblinded pharmacist will know the allocation and dispense the appropriate product. All other staff are blinded. i.e. No staff assessing the subject will know to which treatment the subject was randomised.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation script will be sent to the unblinded pharmacist before the enrollment date. Pre-allocated random participant numbers will be assigned active drug or placebo.
The method of sequence generation used is a permuted block randomisation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Non compartmental pharmacokinetic parameters will be calculated for ACH-0143102 and ACH-0142684. The drug interaction will be assessed using an analysis of variance (ANOVA) approach on ln transformed plasma PK parameters Cmax, AUC(0-24), and AUC(0-24) of ACH-0143102 and ACH-0142684.
Results of the ANOVA will be used for the calculation of the ratios of least squares means (LSM) of the ln transformed PK parameters following co administration of ACH 0142684 and ACH-0143102 (Day 21) over ACH-0142684 alone (Day 7) to determine the effect of ACH-0143102 on the PK of ACH-0142684 in Group1; and following co-administration of ACH-0142684 and ACH-0143102 (Day 21) over ACH-0143102 alone (Day 14) in Group 2.
Plasma concentrations of ACH-0143102 and ACH-0142684 will be listed by subject. Descriptive statistics (arithmetic mean, standard deviation [SD], coefficient of variation [CV], standard error of the mean [SEM], number [N], minimum, maximum, median, geometric mean, and geometric SD) will be calculated for plasma concentrations and PK parameters. Geometric mean and geometric SD will be provided only for Cmax and AUC(0-24).
Other PK evaluations may be conducted as needed. Baseline characteristics, demographic data, and safety measurements will be listed by subject and summarized by descriptive statistics (for continuous variables) or incidence of occurrence (for categorical variables).
AEs will be summarized by system organ class and high level term using the Medical Dictionary for Regulatory Activities (MedDRA 'Registered Trademark') for active treatment and placebo within Group 1 and Group 2. Likewise, within each Group, changes from baseline for clinical laboratory evaluation, vital signs and ECG will also be computed for active treatment and placebo subjects.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
3/02/2014
Actual
3/02/2014
Date of last participant enrolment
Anticipated
4/04/2014
Actual
28/02/2014
Date of last data collection
Anticipated
Actual
Sample size
Target
36
Accrual to date
Final
Recruitment outside Australia
Country [1] 5759 0
New Zealand
State/province [1] 5759 0
Auckland

Funding & Sponsors
Funding source category [1] 288573 0
Commercial sector/Industry
Name [1] 288573 0
Achillion Pharmaceuticals, Inc
Country [1] 288573 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Achillion Pharmaceuticals, Inc
Address
300 George Street
New Haven, CT 06511
Country
United States of America
Secondary sponsor category [1] 287284 0
Commercial sector/Industry
Name [1] 287284 0
Clinical Network Services Ltd
Address [1] 287284 0
142 Broadway c/o Alliot Ltd, Newmarket, Auckland
(PO Box 78312, Grey Lynn, Auckland 1245)
Country [1] 287284 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290436 0
Health and Disability Ethics Committee
Ethics committee address [1] 290436 0
Deloitte House
10, Brandon Street
Wellington
6011
Ethics committee country [1] 290436 0
New Zealand
Date submitted for ethics approval [1] 290436 0
03/12/2013
Approval date [1] 290436 0
24/12/2013
Ethics approval number [1] 290436 0
13/STH/188

Summary
Brief summary
This is a Phase 1 study designed to assess the pharmacokinetics and safety of ACH-0143102 in combination with ACH-0142684 when administered to healthy volunteers. In each of 2 groups, a monotherapy phase of each drug will precede the addition of the second drug. The duration of each monotherapy arm is designed to ensure that steady state conditions are achieved before the second drug is added. Given the observed half life and associated variability for ACH-0142684 200mg, the 7 day duration of monotherapy in Group 1 ensures that steady state conditions are achieved prior to initiation of ACH-0143102. The plasma terminal half life of ACH-0143102 is considerably longer, approximately 250 hours, and the duration of the monotherapy phase in Group 2 is therefore increased to 14 days in order to achieve near steady state conditions. In this study, a full PK profile (0-24 hr) is obtained for each drug when administered alone at steady state (last day of monotherapy phase), after one dose of the other drug when the other drug is at steady state (first day of co-administration period), and after both drugs have achieved steady state conditions (last day of co-administration period). The use of a fairly large control group (active:control = 2:1) will decrease the likelihood that random safety events are erroneously attributed to the study drug. In order to obtain the intensive pharmacokinetic evaluations needed and optimally manage subject safety, all subjects will remain in house during the entire study. Safety evaluations will be performed on subjects daily, and safety laboratory assessments will be reviewed in real time to facilitate early intervention for any safety issues identified during the study. Assuming that data from this study demonstrate no insurmountable pharmacokinetic issues, and that no important safety issues are identified, the results of this Phase 1 study will be used to support initiation of a proof of concept study with HCV patients.
Trial website
Trial related presentations / publications
No citations have been published to date.
Public notes

Contacts
Principal investigator
Name 45682 0
Dr Christian Schwabe
Address 45682 0
Auckland Clinical Studies
ECOM House
3, Ferncroft Street
Grafton
Auckland
1010
Country 45682 0
New Zealand
Phone 45682 0
+64 (0)9 373 3474
Fax 45682 0
Email 45682 0
[email protected]
Contact person for public queries
Name 45683 0
John Lahey
Address 45683 0
Achillion Pharmaceuticals, Inc.
300 George Street
New Haven, CT 06511
Country 45683 0
United States of America
Phone 45683 0
+1 203 752 5437
Fax 45683 0
Email 45683 0
[email protected]
Contact person for scientific queries
Name 45684 0
Robert Hindes
Address 45684 0
Achillion Pharmaceuticals, Inc.
300 George Street
New Haven, CT 06511
Country 45684 0
United States of America
Phone 45684 0
+1 908-431-0250
Fax 45684 0
Email 45684 0
[email protected]

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No Supporting Document Provided



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