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Trial registered on ANZCTR


Registration number
ACTRN12616001017415
Ethics application status
Approved
Date submitted
14/07/2016
Date registered
2/08/2016
Date last updated
4/05/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
A study to determine the relative bioavailability of ACH-0144471 after administration of a tablet or softgel and capsule vs. a liquid filled capsule in healthy volunteers.
Scientific title
A Phase 1 Study to Determine the Relative Bioavailability of ACH-0144471 After Administration of a Tablet or Softgel Capsule Versus a Liquid Filled Capsule in Healthy Volunteers
Secondary ID [1] 289620 0
ACH471-006
Universal Trial Number (UTN)
U1111-1184-3143
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Complement-mediated diseases 299406 0
Condition category
Condition code
Inflammatory and Immune System 299386 299386 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Subjects will receive ACH-0144471 as Liquid Filled Capsule (LFC), tablet or Softgel capsules.
A total of 26 healthy subjects, between the ages of 18 and 55 years inclusive, will be enrolled into 2 groups. The first group, (Group 1), will have 18 subjects, and each will receive 3 single dose treatments.
The second group, (Group 2), will have 8 subjects, and each will receive 2 single dose treatments.

Subjects in Group 1 will be randomised to receive 1 of 3 treatments in an open label and 3-period crossover study design.
The three treatments are:
A single dose of the LFC, fasted, followed by a 4-day (96 hour) washout.
A single dose of the tablet, fed medium fat meal, followed by a 4-day (96 hour) washout.
A single dose of the tablet, fasted, followed by a 4-day (96 hour) washout.

Subjects in Group 2 will be randomised to receive 1 of 2 treatments in an open label and 2-period crossover study design.
The two treatments are:
A single dose of the LFC, fasted, followed by a 4-day (96 hour) washout.
A single dose of the softgel capsule, fasted, followed by a 4-day (96 hour) washout.

The ACH-0144471 dose to be used for all three formulations will be the same and will be determined based upon review of data from the ongoing single and multiple ascending
dose studies. The ACH-0144471 daily dose will not exceed 1600 mg.
The current ongoing studies are registered under the following ACTRN identifiers:
Single Ascending Dose study ACH471-001 ACTRN 12616000082404
Multiple Ascending Dose study ACH471-002 ACTRN 12616000568415
All doses of ACH-0144471 will be administered orally and taken under direct observation of research staff. Dosing should be at the same time each day and the time of dose administration will be recorded.
Intervention code [1] 295231 0
Treatment: Drugs
Comparator / control treatment
ACH-0144471 Liquid Filled Capsule (LFC), will be the reference comparator for this study.
The LFC dose will be determined based upon review of data from the ongoing single and multiple ascending dose studies.
Control group
Active

Outcomes
Primary outcome [1] 298848 0
To determine the relative bioavailability of ACH-0144471 after administration of a tablet versus LFC in healthy volunteers.

The outcome would be assessed by collection of PK blood samples after treatment with each of the three formulations.
Timepoint [1] 298848 0
The single-dose PK profile of ACH-0144471 after treatment with each of the three formulations.
PK collection time points will be collected as listed below:
Group 1 and 2
0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours.
48 and 72 hour post-dose PK samples collected on an outpatient basis.

Group 1 - Following the third treatment, subjects return to the clinic for the 96-hour PK sample
Group 2 - Following the second treatment, subjects will also return to the clinic for a collection of 96-hour PK sample.
Primary outcome [2] 298849 0
To determine the relative bioavailability of ACH-0144471 after administration of a softgel capsule versus LFC in healthy volunteers.
The outcome would be assessed by collection of PK blood samples after treatment with each of the three formulations.
Timepoint [2] 298849 0
The single-dose PK profile of ACH-0144471 after treatment with each of the three formulations.

PK collection time points will be collected as listed below:
Group 1 and 2
0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours.
48 and 72 hour post-dose PK samples collected on an outpatient basis.

Group 1 - Following the third treatment, subjects return to the clinic for the 96-hour PK sample
Group 2 - Following the second treatment, subjects will also return to the clinic for a collection of 96-hour PK sample.
Secondary outcome [1] 325427 0
To assess the safety of ACH-0144471 after single dose administration as a tablet, softgel capsule, or the LFC in healthy volunteers.
The safety of each formulation of ACH-0144471 as determined by number and incidence of serious adverse events (SAEs), Grade 3 or 4 adverse events (AEs); AEs leading to discontinuation of the study; and the number and incidence of clinically significant laboratory and ECG abnormalities.
Timepoint [1] 325427 0
Adverse Events and Serious Adverse events will be assessed at the following visits for each group.
Group 1: Day -1, to Day 39/End of study follow up.
Group 2: Day -1 to Day 35/End of study follow up.
Secondary outcome [2] 325428 0
To evaluate the effect of concomitant food intake on ACH-0144471 pharmacokinetics (PK) after administration as a tablet in healthy volunteers.
Plasma ACH-0144471 concentration-time data will be analyzed by non-compartmental methods with PK software programs. Calculations will be based on the actual
sampling times recorded during the study. From the plasma concentration-time data, the following plasma PK parameters of ACH-0144471 will be determined for each treatment: Cmax, tmax, AUC0-t, and AUC0-8, and t1/2. Additional PK parameters may be calculated.
PK parameters for ACH-0144471 will be summarized for each treatment group using descriptive statistics. Analyses of variance (ANOVA) for cross-over design techniques will be performed on the ln-transformed PK parameters, e.g., Cmax, AUCs. Ninety percent (90%) confidence intervals (CIs) for the difference between the treatment means for each parameter will be calculated to determine the relative bioavailability of the tablet or soft-gel capsule formulations vs. the reference formulation LFC.
For Tmax, non-parametric technique will be utilized to assess the comparability of the tablet or softgel capsule formulations with reference formulation LCF.
Food effect on tablet formulation will also be assessed.
Timepoint [2] 325428 0
The single-dose PK profile of ACH-0144471 after treatment with each of the three formulations.
PK collection time points will be collected as listed below:
Group 1 and 2
0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours.
48 and 72 hour post-dose PK samples collected on an outpatient basis.

Group 1 - Following the third treatment, subjects return to the clinic for the 96-hour PK sample
Group 2 - Following the second treatment, subjects will also return to the clinic for a collection of 96-hour PK sample.
Secondary outcome [3] 325429 0
Exploratory Objective
To assess the effect of each formulation on the pharmacodynamic (PD) effect (percent CAP inhibition) of ACH-0144471, as determined by the AP Wieslab assay (Group 1 only)
Timepoint [3] 325429 0
Serum samples will be analyzed to determine % inhibition of Alternative Pathway activity by the AP Wieslab assay at selected time-points (e.g., 0, 2, 4, 6, and 12 hours after dosing) after each treatment in Group 1 only.

Eligibility
Key inclusion criteria
Healthy adult male or female subjects. Females must be of non-child bearing potential. Healthy is defined as having no clinically relevant abnormalities identified by a detailed medical history, physical exam, blood pressure and pulse rate measurements, 12-lead ECG, and clinical laboratory tests.
Healthy volunteers must have a normal weight defined as minimum body weight of 50 kg and a BMI of 18 to 30kg/m2.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
If participants have any of the following criteria, they will be excluded from the study.
- Smokers and have a clinically significant disease or allergy,
- An active infection
- Consume more than 21 alcoholic drinks/week.
- Evidence of drug abuse or have taken prescription medications (systemic and topical) within 14 days prior to dosing.

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer-generated randomization schedule will be prepared by a clinical research organization (CRO) to assign subjects to a treatment sequence. The randomization schedule will be provided to the sponsor,
study site, and bioanalytical laboratory. Subjects will not be replaced if at least 16 subjects are enrolled in
Group 1 and at least 6 subjects are enrolled in Group 2.

Part 1 will follow an open label, 3-treatment, and 3-period crossover study design. Eligible subjects will be assigned, in a 1:1:1 ratio, to 1 of 3 sequences according to a randomization scheme.
Period A. A single dose of the LFC, fasted
Period B. A single dose of the tablet, fed medium fat meal
Period C. A single dose of the tablet, fasted

Sequence 1 consists of the following periods A, B, C
Sequence 2 = consists of the following periods B, C, A
Sequence 3 = consists of the following periods C, A, B
There is a 4-day washout between each period.

Group 2 (8 subjects)
Part 2 will follow an open label, 2-treatment, and 2-period crossover study design.
Eligible subjects will be assigned, in a 1:1 ratio, to 1 of 2 sequences according to a randomization scheme.
Period D. A single dose of the LFC, fasted
Period E. A single dose of the softgel capsule, fasted

Sequence 1 consists of the following periods D, E
Sequence 2 consists of the following periods E, D
There is a 4-day washout between each period.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
This is a Phase 1, randomized, crossover, open-label study to assess the relative bioavailability, PK,
and safety of ACH-0144471 in normal, healthy volunteers. A total of 26 healthy subjects, between the ages of
18 and 55 years inclusive, will be enrolled into 2 groups.
The randomization schedule will be provided to the sponsor, study site, and bioanalytical laboratory.
Subjects will not be replaced if at least 16 subjects are enrolled in Group 1 and at least 6 subjects are enrolled in Group 2.
Phase
Phase 1
Type of endpoint/s
Bio-availability
Statistical methods / analysis
Statistical and Analytical Plans
Data from Group 1 and Group 2 will be presented and analyzed separately. Specific information about the statistical analysis will be provided in a statistical analysis plan (SAP) that will be developed before final database lock.

There are three analysis populations for this study.
1. Safety population
The safety population is defined as all subjects randomized and treated with at least one dose of ACH-0144471. All safety data collected up to the end of the study (i.e., through the last follow-up evaluation) are included in the safety analysis.
2. Pharmacokinetic population
The PK population will include all subjects for whom PK parameters can be calculated.
3. Pharmacodynamic population
The PD population will only include Group 1 subjects for whom AP-Wieslab measurements can be evaluated

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
1/08/2016
Date of last participant enrolment
Anticipated
31/08/2016
Actual
16/09/2016
Date of last data collection
Anticipated
2/10/2016
Actual
6/04/2017
Sample size
Target
26
Accrual to date
Final
26
Recruitment outside Australia
Country [1] 8017 0
New Zealand
State/province [1] 8017 0
Auckland

Funding & Sponsors
Funding source category [1] 294010 0
Commercial sector/Industry
Name [1] 294010 0
Achillion Pharmaceuticals Inc.
Country [1] 294010 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Achillion Pharmaceuticals Inc.
Address
300 George Street
New Haven, CT 0651
Country
United States of America
Secondary sponsor category [1] 292825 0
Commercial sector/Industry
Name [1] 292825 0
Clinical Network Services (CNS) Ltd
Address [1] 292825 0
PO Box 78312
Grey Lynn
Auckland 1245
Country [1] 292825 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295420 0
Health and Disability Ethic Comittee (HDEC)
Ethics committee address [1] 295420 0
Ground Floor
Room G.04
Freyberg Building
20 Aitken Street
Wellington 6011
Ethics committee country [1] 295420 0
New Zealand
Date submitted for ethics approval [1] 295420 0
21/06/2016
Approval date [1] 295420 0
26/07/2016
Ethics approval number [1] 295420 0
16/NTB/117

Summary
Brief summary
ACH-0144471 is an orally administered, small molecule, fD inhibitor that inhibits the alternative pathway of complement. Its alternative pathway inhibitory activity has been established in nonclinical studies, as well as in human healthy subjects in the single ascending dose study in healthy subjects (ACH471-001) that is ongoing in New Zealand. ACH-0144471 has the potential to treat multiple complement mediated diseases
including paroxysmal nocturnal hemoglobinuria (PNH).
In both the ACH471-001 (SAD) and ACH471-002 (MAD) clinical trials of ACH-0144471,
an extemporaneously prepared LFC have been used. For continued development,
more formulations of ACH-0144471 are being developed. The aim of this study is to determine the relative bioavailability and clinical safety of these two new formulations (tablet and softgel capsule) under fed and fasted conditions compared to the reference LFC formulation. The effect of food on the bioavailability of ACH-0144471 in the LFC will have been determined in the SAD study.
The results from this study will provide quantitative information that will be used to determine doses of the new formulations that will provide similar exposures to those achieved by the LFC.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67214 0
Dr Paul Hamilton
Address 67214 0
Auckland Clinical Studies Ltd
Ground Floor
MEDACS House
3 Ferncroft Street
Auckland 1010
Country 67214 0
New Zealand
Phone 67214 0
+64 9 373 3474
Fax 67214 0
Email 67214 0
[email protected]
Contact person for public queries
Name 67215 0
Mr Glenn Schulman
Address 67215 0
Achillion Pharmaceuticals, Inc.
300 George Street
New Haven, CT 06511
Country 67215 0
United States of America
Phone 67215 0
+12037525510
Fax 67215 0
Email 67215 0
[email protected]
Contact person for scientific queries
Name 67216 0
Dr Paul Hamilton
Address 67216 0
Auckland Clinical Studies Ltd
Ground Floor
MEDACS House
3 Ferncroft Street
Auckland 1010
Country 67216 0
New Zealand
Phone 67216 0
+64 9 373 3474
Fax 67216 0
Email 67216 0
[email protected]

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