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Trial registered on ANZCTR


Registration number
ACTRN12618000896279
Ethics application status
Approved
Date submitted
18/05/2018
Date registered
28/05/2018
Date last updated
19/03/2019
Date data sharing statement initially provided
19/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study to investigate the safety of ACH-0145548 in Healthy Participants
Scientific title
A Randomized, Double-Blind, Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACH-0145548 in Healthy Participants
Secondary ID [1] 294775 0
ACH548-001
Universal Trial Number (UTN)
U1111-1213-0533
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Complement-mediated diseases 307684 0
Condition category
Condition code
Inflammatory and Immune System 306752 306752 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A total of 28 healthy volunteers (18 active and 10 placebo) are planned for three treatment groups and will receive a single oral dose of ACH-0145548 or placebo.
The first dose group (Cohort 1) will have 12 subjects randomized to ratio of 1:1 to active and placebo (6 active: 6 placebo), the remaining dose groups (Cohort 2 and 3) will have 8 subjects per cohort randomized 3:1 to active and placebo (6 active and 2 placebo).
For each cohort, a sentinel group consisting of one active and one placebo subject will be dosed 24 hours before the remaining subjects. If no significant drug related toxicity is identified in the first 24 hours, then remainder of each cohort may be dosed. All dose escalation decisions will be made based on the review of data through Day 4 from the preceding dose.
Safety will be evaluated by monitoring and assessing AEs, clinical laboratory tests, physical examination findings, vital signs measurements, and 12-lead ECG recordings at specified time points during the study.
The starting minimum dose of ACH-0145548 will be 20 mg for Cohort 1, 60 mg for Cohort 2, and 120 or 180 mg for Cohort 3. The maximum dose will be 180 mg. All dose escalation decisions will be made based on the review of data through at least Day 4 from the preceding dose.
The mode of administration will be Powder in Capsule (PIC) taken orally. Subjects will take their dose at the study site under direct observation by trained study personnel.
Intervention code [1] 301081 0
Treatment: Drugs
Comparator / control treatment
Placebo composed of Microcrystalline cellulose, Size 00 white opaque hypromellose capsules.
Control group
Placebo

Outcomes
Primary outcome [1] 305750 0
The primary objective of this study is to demonstrate the safety and tolerability of single ascending oral doses of ACH-0145548 in healthy volunteers.
This outcome is assessed by the number and incidence of serious adverse events (SAEs), Grade 3 or 4 adverse events (AEs), AEs leading to discontinuation from the study, Grade 3 or 4 laboratory abnormalities, and treatment-emergent vital signs, physical exam results, and ECG abnormalities.
Timepoint [1] 305750 0
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.
On-site assessments to occur from dosing day 1, day 2, 3, 4, 7, and 14 with a follow up visit on Day 28. Telephone calls will occur on Day 5 and 6 to inquire about adverse events.
Secondary outcome [1] 346361 0
To evaluate the PK profile of ACH-0145548 in healthy volunteers following the administration of single ascending oral doses.
Single-dose PK parameters of ACH-0145448 , including time after administration of a drug when the maximum plasma concentration is reached time, maximum plasma concentration (Cmax), and area under the plasma concentration-time curve from time of administration to last observed concentration at time t [AUC(0-t)] will be determined at each dose level using validated bio analytical methods. Attainment of steady state will be evaluated by comparison of pre-dose (trough) and dose concentrations over time.
Timepoint [1] 346361 0
This outcome is assessed using the following tests:
Pharmacokinetic Assessments: Serial blood plasma samples will be collected to determine plasma
concentrations of ACH-0145548 and any potential metabolites.
Day 1, 2, 3, 4, and 7. Serial draws on Day 1, then at Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours) and Day 7 (144 hours).
Pharmacokinetic Urine samples will also be collected on Day 1 and 2 at 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 12 hours and 12 to 24 hours post dose.
Secondary outcome [2] 346362 0
To investigate the pharmacodynamic (PD) profile of ACH-0145548 in healthy volunteers following administration of single ascending oral doses.
Pharmacodynamics will be evaluated using serum or plasma collected during the study with the following:
CH50 assay to assess for classical pathway function
AP Wieslab assay for the determination of the alternative pathway function
Complement factor D (fD) enzyme-linked immunosorbent assay (ELISA)
Bb fragment of complement factor B (Bb) ELISA
C3 (a component shared by all 3 complement pathways and C4 (an early component of classical pathway)
These assays will be conducted to assess the Baseline complement classical and alternative pathway functions and representative pathway-specific component concentrations as well as their restoration, if changed, after dosing.
Timepoint [2] 346362 0
This outcome will be assessed using CH50 assay, AP Wieslab assay, Complement factor D (fD) enzyme-linked immunosorbent assay (ELISA), Bb fragment (Bb) ELISA, C3 and C4.
Day 1, 2, 3, 4, and 7. Serial draws on Day 1, then at Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours) and Day 7 (144 hours).
Secondary outcome [3] 346363 0
To evaluate the relationship between single-dose PK and PD effects of ACH-0145548 through inhibition of complement alternative pathway (AP) activity (PK/PD).
Timepoint [3] 346363 0
This outcome is assessed using the following tests: AP Wieslab assay for the determination of the alternative pathway function and Pharmacokinetic Assessments. This outcome is assessed by the relationship between ACH-0145548 concentration and selected PD markers over time.
Day 1, 2, 3, 4, and 7. Serial draws on Day 1, then at Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours) and Day 7 (144 hours).

Eligibility
Key inclusion criteria
1. Participant must be 25 to 55 years of age, inclusive, at the time of signing the informed consent.
2. Participants who are overtly healthy as determined by medical evaluation including detailed medical history, physical examination, blood pressure (BP) and heart rate measurements, 12-lead ECG, and clinical laboratory tests.
3. Body weight of at least 50 kg and body mass index (BMI) within the range 18 to 30 kg/m2 (inclusive).
4. Male or Female
Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
a. Male participants
Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days (a spermatogenesis cycle) after administration of study drug:
Refrain from donating sperm
PLUS either:
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
Must agree to use a highly effective method of contraception with their partner(s) of childbearing potential. Their female partner(s) of childbearing potential must also agree to use a highly effective form of contraception for the same period.
b. Female participants:
Female participants must be of non-childbearing potential as defined by one of the following:
Surgical sterilization by hysterectomy removal of uterus), bilateral salpingo-oophorectomy (removal of both ovaries and fallopian tubes) or bilateral oophorectomy (removal of both ovaries) at least 6 months prior to dosing
Post-menopausal with amenorrhea (absence of menstrual periods) for at least 1 year prior to dosing and follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status
5. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Minimum age
25 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Have a history or presence of/significant history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrinological, hematological, or neurological disorders or conditions capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data.
2. Have a history of febrile illness, or other evidence of infection, within 14 days prior to first study drug administration
3. Have a history of meningococcal infection, or a first-degree relative with a history of meningococcal infection
4. Current or chronic history of liver disease or known hepatic or biliary abnormalities (including biliary cholestasis or Gilbert's syndrome)
5. Subjects with a female partner who is pregnant, nursing, or planning to become pregnant during the confinement phase of the study or within 90 days of study drug administration.
6. Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study
7. History of hypersensitivity reactions to beta-lactams, penicillin, aminopenicillins, fluoroquinolones, cephalosporins, and carbapenems
8. Use of prohibited over-the-counter or prescription medications as follows:
Prescription medications (systemic and topical) within 14 days prior to first study drug administration (or when known, 5 half-lives, whichever is longer) through study completion, including follow-up visits
Non-prescription medications (including lipid-soluble vitamins A, D, E, and K [water-soluble vitamins B and C are not prohibited], herbal supplements, and dietary supplements) within 14 days of first study drug administration
Medications known to induce or inhibit hepatic microsomal enzyme cytochrome P450 (CYP450) activity (e.g., quinines) within 28 days of first study drug administration
Hormonal therapy/replacement medications within 28 days of first study drug administration
9. Live attenuated vaccine within 30 days or other vaccine within 14 days of first study drug administration
10. Donated blood or lost more than 500 ml of blood within 3 months prior to first study drug administration, or received a blood transfusion or blood products within 6 months prior to first study drug administration
11. Current enrolment or past participation within the last 30 days before study drug administration in any clinical study involving an investigational study intervention or any other type of medical research
12. Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to dosing
13. Positive hepatitis C antibody test result at screening or within 3 months prior to starting study intervention.
14. Positive human immunodeficiency virus (HIV) antibody test
15. Positive serum hCG (female participants only)
16. Have clinically significant laboratory abnormalities, including any of the following, at either screening or Day -1 :
Serum creatinine greater than ULN and/or creatinine clearance less than 80 mL/minute estimated by the Cockcroft-Gault formula [(140 - age) × weight (kg) / 72 × serum creatinine (mg/dL)]
Alanine transaminase greater than ULN
Aspartate transaminase greater than ULN
Alkaline phosphatase greater than ULN
Total bilirubin greater than 1.5 × ULN
Absolute neutrophil count (ANC) less than lower limit of normal (LLN)
Absolute lymphocyte count (ALC) less than LLN
Abnormal coagulation profile, including platelet count less than LLN, partial thromboplastin time (PTT) greater than ULN, INR greater than the upper limit of the normal reference range (greater than 1.3) or prothrombin time (PT) greater than ULN
Hemoglobin (Hb) less than LLN
17. Clinically significant findings on a 12-lead ECG, as judged by the Principal Investigator (PI) or the PI’s designee, at screening or prior to dosing on Day 1. Clinically significant findings should be based on the average of 3 recordings and include any of the following:
QTcF greater than or equal to 450 msec
PR interval greater than 220 msec
QRS interval greater than 120 msec
18. Positive urine drug screen at screening or Day -1. The urine drug screen should include, at a minimum, amphetamines, barbiturates, cotinine, cocaine metabolites, opiates, benzodiazepines, and cannabinoids
19. Have C3 or C4 complement protein (C4) greater than 110% of the upper limit or less than 90% of the lower limit of the reference ranges at screening
20. Have alternative pathway function (AH50) or classical pathway function (CH50) results outside the reference ranges at screening
21. Have a body temperature greater than or equal to 38 degrees Celsius (°C) on Day -1 or Day 1, Hour 0
22. Have consumed any alcohol within 72 hours before first study drug administration or have a history of regular alcohol consumption exceeding 21 drinks/week (1 drink = 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 6 months of screening
23. Current tobacco users or smokers (defined as the use of any tobacco or nicotine-containing product within 3 months prior to first study drug administration) or a positive cotinine test at screening or Day -1
24. Consume an average of more than 8 cups of coffee or other caffeinated beverage, or 7 cans of cola per day

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 will be responsible for dispensing according to the randomisation 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, using a randomized block design, will be generated by Statistical Analysis System (SAS) software procedure Plan which assigns subjects to active versus placebo treatment for each cohort, including the 2 sentinel subjects for each cohort. The randomization schedule will then be loaded into the electronic data capturing (EDC) system which is utilized to create the study database. An unblinded pharmacist (or other qualified individual) at the study site(s) who is responsible for preparing the
study drugs to be dispensed for each subject will enter the appropriate subject’s information to the EDC system and obtain the treatment assignment of either active drug or placebo.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis
Due to the exploratory nature of this first in human study, no power or sample size calculations have been performed. The number of subjects was chosen on an empirical basis, based on experience with other Phase 1 first-in-human studies.
There are 3 analysis populations for this study: Safety Population, Pharmacokinetic Population, and Pharmacodynamic Population.
The safety population is defined as all subjects randomized and treated with at least 1 dose of ACH-0145548 or placebo. All safety data collected up to the end of the study are included in the safety analysis. Subjects not treated according to the randomization schedule will be analyzed according to the treatment received rather than the randomized treatment.
The Pharmacokinetic (PK) population will include all subjects treated with ACH-0145548 and for whom PK parameters can be calculated.
The Pharmacodynamic (PD) population will include all subjects treated with ACH-0145548
or placebo and for whom PD markers can be evaluated.
Pharmacokinetic analysis will be done using a validated computer program for the PK population. Based on the individual plasma concentration time data, using the scheduled sampling times, appropriate including, but not limited to, standard PK parameters of ACH-0145548 will be derived from the
bioanalytical results. Descriptive statistics (number of subjects, mean/geometric mean, SD, med, min, and max) will be used to summarize the calculated PK parameters by dose levels.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
26/06/2018
Actual
30/06/2018
Date of last participant enrolment
Anticipated
24/07/2018
Actual
27/09/2018
Date of last data collection
Anticipated
21/08/2018
Actual
4/02/2019
Sample size
Target
28
Accrual to date
Final
28
Recruitment outside Australia
Country [1] 10373 0
New Zealand
State/province [1] 10373 0
Auckland

Funding & Sponsors
Funding source category [1] 299382 0
Commercial sector/Industry
Name [1] 299382 0
Achillion Pharmaceuticals. Inc
Country [1] 299382 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] 298660 0
Commercial sector/Industry
Name [1] 298660 0
Clinical Networks Services (CNS) Ltd
Address [1] 298660 0
PO Box 78312
Grey Lynn
Auckland 1245
New Zealand
Country [1] 298660 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300283 0
Northern A - Health and Disability Ethics Committee (HDEC)
Ethics committee address [1] 300283 0
Ethics committee country [1] 300283 0
New Zealand
Date submitted for ethics approval [1] 300283 0
01/05/2018
Approval date [1] 300283 0
12/06/2018
Ethics approval number [1] 300283 0

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

Contacts
Principal investigator
Name 83154 0
Dr Paul Hamilton
Address 83154 0
Auckland Clinical Studies Ltd
Ground Floor
ACS House
3 Ferncroft Street
Auckland 1010
Country 83154 0
New Zealand
Phone 83154 0
+64 9 373 3474
Fax 83154 0
Email 83154 0
[email protected]
Contact person for public queries
Name 83155 0
Glenn Schulman
Address 83155 0
Achillion Pharmaceuticals. Inc.
300 George Street
New Haven, CT 06511
Country 83155 0
United States of America
Phone 83155 0
+12037525510
Fax 83155 0
Email 83155 0
[email protected]
Contact person for scientific queries
Name 83156 0
Paul Hamilton
Address 83156 0
Auckland Clinical Studies Ltd
Ground Floor
ACS House
3 Ferncroft Street
Auckland 1010
Country 83156 0
New Zealand
Phone 83156 0
+64 9 373 3474
Fax 83156 0
Email 83156 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Trial data will be made public via the CSR and potential publication. No participant identifying information will be shared with the public.


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
No additional documents have been identified.