Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000082404
Ethics application status
Approved
Date submitted
5/01/2016
Date registered
27/01/2016
Date last updated
2/03/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to investigate the safety of ACH-0144471 in healthy volunteers.
Scientific title
ACH471-001; A Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACH-0144471 in Healthy Volunteers.
Secondary ID [1] 288133 0
Nil known.
Universal Trial Number (UTN)
U1111-1177-3305
Trial acronym
ACH471-001
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Complement-mediated diseases. 297012 0
Condition category
Condition code
Inflammatory and Immune System 297259 297259 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Subjects will receive either active (ACH-0144471) or placebo. At least three dose groups are planned. Group 1 will receive a single 200mg dose (consisting of two 100mg capsules), Group 2 will receive a single dose up to 600 mg and Group 3 will receive a dose up to 1500mg. ACH-0144471 may be given as divided doses over a 24-hour period. The maximum daily dose for this study will be calculated so that the predicted Cmax and ACH-0144471 AUC0-24 do not exceed the NOAEL observed in nonclinical studies, and may be adjusted upward or downward based on emerging nonclinical and clinical safety, PK, and PD data.
Treatment compliance will be observed by the research staff to ensure the subjects have taken his/her dose, and the time will be recorded in the source notes.
In order to ensure adequate placebo subjects for comparison at the first dose, the first dose group (Group 1) will have will have 12 subjects, randomized 1:1 to active and placebo (six active and six placebo subjects); the remaining dose groups will have eight subjects per group randomized 3:1 to active and placebo (six active and two placebo subjects per group).
In Group 1, a sentinel group consisting of one active and one placebo subject will be dosed before the other ten subjects in Group 1. If no significant drug-related toxicity is identified in the first 24 hours in the opinion of the PI, then remainder of Group 1 may be dosed. All dose escalation decisions will be made based on review of safety data through at least Day 4 from the preceding dose. However, after review of emerging data, the planned doses may be reduced, or a prior dose may be repeated. Higher than planned doses may also be considered, provided that previous doses were well-tolerated, and projected exposures at the higher than planned doses do not exceed the pre-specified exposure limits of the study, and do not exceed three times (3X) the corresponding exposures at the highest dose already studied.
Based on emerging data from the first three dose groups, it will be determined if additional dose groups are warranted, and if so, at which doses and/or regimens (fed or fasted). These additional groups may be used to ensure adequate study of potential therapeutic doses, and/or to study the effect of food on the PK of ACH-0144471.

A Dose Escalation Team (DET) consisting of, at a minimum, Principal Investigator, Medical Monitor, Clinical Pharmacologist, will review available safety, PK and PD data from preceding groups to decide whether the next group will proceed, and if so, at which dose level, and if at single administration or divided doses over 24 hours."
Intervention code [1] 293443 0
Treatment: Drugs
Comparator / control treatment
The ACH-0144471 LFC and placebo for ACH-0144471 LFC dosage forms will be extemporaneously prepared by the clinical site and/or an alternate approved site.
The excipients used in the placebo for ACH-0144471 LFCs will be the same as the excipients used in the active ACH-0144471 LFCs. All excipients will be precedented and have regulatory acceptance. The number of capsules required will be adjusted based on the final doses chosen for each group.
Control group
Placebo

Outcomes
Primary outcome [1] 296850 0
To evaluate the Safety and tolerability of single ascending oral doses of ACH-0144471 in healthy volunteers. This outcome is assessed using the following tests and assessments:
Assessment of AEs/SAEs, recording concomitant medications, obtaining vitals, ECGs and collection of blood and urine samples.
Timepoint [1] 296850 0
Group 1;
A sentinel group consisting of one active and one placebo subject will be dosed before the other ten subjects in Group 1. If no significant drug-related toxicity is identified in the first 24 hours in the opinion of the PI, then remainder of Group 1 may be dosed. All dose escalation decisions will be made based on review of safety data through at least Day 4 from the preceding dose.
Post dose assessment time points for Groups 1, 2 and 3.
Vitals and ECGs at 1, 2, 4, 8, 12, and 16 hours.

Days 2 and 3 (Hours 24-60)
Vitals, ECGs , blood and urine tests at 24 and 48 hours post dose.

Day 4 (Hour 72)
Vitals, ECGs , blood and urine tests at 72 hours post dose.

Groups 2, 3 +;
All dose escalation decisions will be made based on review of safety data through at least Day 4 from the preceding dose. However, after review of emerging data, the planned doses may be reduced, or a prior dose may be repeated.
Secondary outcome [1] 319516 0
To evaluate the pharmacokinetic (PK) profile of ACH-0144471 in healthy volunteers following administration of single ascending oral doses. This outcome is assessed using the following tests: Pharmacokinetic Assessments: Serial blood samples will be collected throughout Days -1 to 4 and concentrations of ACH-0144471 and any potential metabolites will be determined in serum and plasma using validated methods.
Timepoint [1] 319516 0
Upon completion of the first three dose groups, all available safety, pharmacokinetic (PK), and pharmacodynamics (PD) data through at least Day 4 from the first three groups will be reviewed to determine if additional dose groups are warranted.

Post dose assessment time points for Groups 1, 2 and 3.
PK assessments 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12 and 16 hours after dosing.
Urine samples for ACH-0144471 PK analysis at 0 (pre-dose), 0-2, 2-4, 4-6, 6-12 and 12-24 hours after dosing.

Days 2 and 3 (Hours 24-60)
PK sample collection at 24 and 48 hours post dose.

Day 4 (Hour 72)
PK sample collection at 72 hours post dose.
Secondary outcome [2] 319517 0
To evaluate the relationship between ACH-0144471 pharmacokinetics and inhibition of alternative pathway activity (PK/PD) as measured by the AP Wieslab assay.
Timepoint [2] 319517 0
Based on emerging data from the first three dose groups, it will be determined if additional dose groups are warranted, and if so, at which doses and/or regimens (fed or fasted). These additional groups may be used to ensure adequate study of potential therapeutic doses, and/or to study the effect of food on the PK of ACH-0144471.

Post dose assessment time points for Groups 1, 2 and 3. PK and PD assessments 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12 and 16 hours after dosing.
Separate blood sample for AH50, CH50, C3, and C4 at 1 and 12 hours after dosing.
Separate blood sample for retention for future testing of additional complement biomarkers at 1 and 12 hours after dosing; these samples will not be used for any genetic testing.

Days 2 and 3 (Hours 24-60)
PK and PD sample collection at 24 and 48 hours post dose.

Day 4 (Hour 72)
PK and PD sample collection at 72 hours post dose.

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, 12lead 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
21 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Healthy volunteers must not be smokers and not have a clinically significant disease or allergy, an active infection, or consume more than 21 alcoholic drinks/week. Volunteers must refrain from alcohol use for at least 72 hours prior to dosing (Day 1) and for the duration of the study.
Volunteers must not have any evidence of drug abuse or 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)
Study drug components will be shipped to the study center in open-label fashion. An unblinded pharmacist and the associated pharmacy staff at the study site will be responsible for dispensing according to the randomization schedule provided. The unblinded pharmacy staff will affix a blinded, unit-dose label to the drug identifying which study subject should receive which dose. All doses will be administered by blinded site staff.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A randomization schedule assigning subjects to active versus placebo treatment for each Group will be provided to an unblinded pharmacist (or other qualified individual) at the study site(s) that will be responsible for preparing the study drugs to be dispensed for each subject. The randomization schedule will also be provided to the bioanalytical laboratory responsible for analysis of PK samples.

The Method of assigning subjects to treatment groups:
Subjects in each Group will be randomized to receive either active treatment or placebo as follows:
*Group 1: 12 subjects randomized 1:1 to active or placebo (six active and six placebo)
A sentinel group consisting of one active and one placebo will be dosed before the other ten subjects in Group 1. If no significant drug-related toxicity is identified in the first 24 hours in the opinion of the PI, then remainder of Group 1 may be dosed.
*Group 2: Eight subjects randomized 3:1 to active or placebo (six active and two placebo)
*Group 3: Eight subjects randomized 3:1 to active or placebo (six active and two placebo)
*Group 4 and additional groups, if needed:
Eight subjects randomized 3:1 to active or placebo (six active and two placebo)
The method of sequence generation used is permuted block randomization design. Factors used for stratification within each group will be for dietary status (fed vs. fasted).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
This is a randomized, double-blind (subject and investigator blind, sponsor-open), single-ascending dose (SAD) study in healthy volunteers.

A total of 28 subjects (18 active and 10 placebo) are planned for three treatment groups. Additional subjects may be enrolled to replace discontinued subjects, or if more than three treatment groups are conducted (six active and two placebo subjects per group).
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
All continuous variables will be summarized by dose(s) and placebo using descriptive statistics including number of observations, number of missing data, mean, standard deviation (SD), minimum (min), median (med), and maximum (max). All categorical variables will be summarized by ACH-0144471 dose(s) and placebo using frequency counts and percentages.
Placebo data from each dose level will be combined into one placebo group.
No missing data imputation will be performed.
Subject listings will be provided for all the data collected during the study period.
Specific information about the statistical analysis will be provided in a statistical analysis plan (SAP) that will be developed before final database lock.
Due to the exploratory nature of this first in human study, no power or sample size calculations have been performed. The number of subjects has been chosen on an empirical basis, based on experience with other Phase 1 first-in-human studies.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
10/02/2016
Actual
11/02/2016
Date of last participant enrolment
Anticipated
30/08/2016
Actual
24/05/2016
Date of last data collection
Anticipated
16/08/2016
Actual
20/06/2016
Sample size
Target
36
Accrual to date
Final
44
Recruitment outside Australia
Country [1] 7410 0
New Zealand
State/province [1] 7410 0
Auckland

Funding & Sponsors
Funding source category [1] 292542 0
Commercial sector/Industry
Name [1] 292542 0
Achillion Pharmaceuticals, Inc.
Country [1] 292542 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] 291259 0
Commercial sector/Industry
Name [1] 291259 0
Clinical Network Services (CNS) Ltd
Address [1] 291259 0
PO Box 78312
Grey Lynn
Auckland 1245
New Zealand
Country [1] 291259 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294017 0
Health and Disability Ethic Comittee (HDEC)
Ethics committee address [1] 294017 0
Ethics committee country [1] 294017 0
New Zealand
Date submitted for ethics approval [1] 294017 0
30/11/2015
Approval date [1] 294017 0
30/01/2016
Ethics approval number [1] 294017 0

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

Contacts
Principal investigator
Name 62154 0
Dr Roderick Ellis-Pegler
Address 62154 0
Auckland Clinical Studies Ltd
Ground Floor
MEDACS House
3 Ferncroft Street
Auckland 1010
Country 62154 0
New Zealand
Phone 62154 0
+64 9 373 3474
Fax 62154 0
Email 62154 0
[email protected]
Contact person for public queries
Name 62155 0
Frank Spitters
Address 62155 0
Clinical Network Services (CNS) Ltd
PO Box 78312
Grey Lynn
Auckland 1245
Country 62155 0
New Zealand
Phone 62155 0
+64(0)27 202 2012
Fax 62155 0
Email 62155 0
[email protected]
Contact person for scientific queries
Name 62156 0
Roderick Ellis-Pegler
Address 62156 0
Auckland Clinical Studies Ltd
Ground Floor
MEDACS House
3 Ferncroft Street
Auckland 1010
Country 62156 0
New Zealand
Phone 62156 0
+64 9 373 3474
Fax 62156 0
Email 62156 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
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AINew milestones ahead in complement-targeted therapy2016https://doi.org/10.1016/j.smim.2016.06.001
N.B. These documents automatically identified may not have been verified by the study sponsor.