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Trial registered on ANZCTR


Registration number
ACTRN12617001521314
Ethics application status
Approved
Date submitted
24/10/2017
Date registered
31/10/2017
Date last updated
3/09/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Single Dose Study to investigate the safety of ACH-0145228 in Healthy Volunteers.
Scientific title
A Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACH-0145228 in Healthy Volunteers
Secondary ID [1] 293157 0
ACH228-001
Universal Trial Number (UTN)
U1111-1203-1371
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Complement-mediated diseases 305136 0
Condition category
Condition code
Inflammatory and Immune System 304457 304457 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A total of 28 healthy volunteers (18 active, 10 placebo) are planned for three treatment groups and will receive a single oral dose of ACH-0145228 or placebo.
The first dose group (Group 1) will have 12 subjects randomized to 1:1 to active and placebo (6 active:6 placebo), the remaining dose groups will have 8 subjects per cohort randomized 3:1 to active and placebo (6 active and 2 placebo).
For each group, 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 remaining subjects 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-0145228 will be 40mg and the maximum dose will be 160mg. The mode of administration will be Powder in Capsule (PIC) taken orally.
Intervention code [1] 299407 0
Treatment: Drugs
Comparator / control treatment
Placebo composed of Microcrystalline cellulose, Size 00 white opaque hypromellose capsules.
Control group
Placebo

Outcomes
Primary outcome [1] 303710 0
To demonstrate the safety and tolerability of single ascending oral doses of ACH-0145228 in healthy volunteers
Timepoint [1] 303710 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 on Day 5 and 6 to inquire about adverse events.
Secondary outcome [1] 339946 0
To evaluate the PK profile of ACH-0145228 in healthy volunteers following the administration of single ascending oral doses.
Single-dose PK parameters of ACH-0145228, 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] 339946 0
This outcome is assessed using the following tests:
Pharmacokinetic Assessments: Serial blood plasma samples will be collected to determine plasma concentrations of ACH-0145228 and any potential metabolites.
Day 1, 2, 3, 4 and 7. Serial draws on Day 1 (0; 0.5; 1; 1.5; 2; 2.5; 3; 4; 6; 8; 10; 12; 16hrs), 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 1/2 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] 339947 0
To investigate the pharmacodynamic (PD) profile of ACH-0145228 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:
AH50 assay to assess for alternative pathway function
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] 339947 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 (0; 0.5; 1; 1.5; 2; 2.5; 3; 4; 6; 8; 10; 12; 16hrs), then at Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours) and Day 7 (144 hours).
Secondary outcome [3] 339948 0
To evaluate the relationship between ACH-0145228 single-dose PK and PD effects through inhibition of complement alternative pathway (AP) activity (PK/PD).
This will be evaluated by AP Wieslab assay for the determination of the alternative pathway function. After dosing, the AP Wieslab and Bb will be conducted to assess the inhibitory effect of ACH-0145228 ex vivo and in vivo on AP activity.
Timepoint [3] 339948 0
This outcome is assessed using the following tests: AP Wieslab and Pharmacokinetic Assessments.
Day 1, 2, 3, 4 and 7. Serial draws on Day 1 (0; 0.5; 1; 1.5; 2; 2.5; 3; 4; 6; 8; 10; 12; 16hrs), then at Day 2 (24 hours), Day 3 (48 hours), Day 4 (72 hours) and Day 7 (144 hours).

Eligibility
Key inclusion criteria
1. Be a healthy male or female of any ethnic origin between the ages of 25 and 55 years, inclusive. Healthy is defined as having no clinically relevant abnormalities identified by a detailed medical history, physical examination, blood pressure (BP) and heart rate measurements, 12-lead ECG, and clinical laboratory tests
2. Have a body mass index (BMI) of 18 to 30 kg/m2 with a minimum body weight of 50 kg
3. Female subjects must be of non childbearing potential, as defined by 1 of the following:
Surgical sterilization by hysterectomy, bilateral salpingo-oophorectomy or bilateral oophorectomy at least 6 months prior to dosing
Postmenopausal with amenorrhea for at least 1 year prior to dosing and follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status
4. Male subjects must agree to abstinence or use a condom when engaged in sexual activity, and agree to refrain from sperm donation, from check-in through at least 90 days after administration of study drug. Male subjects’ female partners of child-bearing potential must agree to use a highly effective form of contraception for the same time period
5. Be willing to answer inclusion and exclusion criteria questions
6. Give voluntary written informed consent to participate in the study
7. Be willing and able to comply with the visit schedule, treatment plan, laboratory tests, PK sampling schedule, and other study procedures
Minimum age
25 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Have a history or clinically relevant evidence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease in the opinion of the PI
2. Have any condition possibly affecting drug absorption (including gastrectomy and cholecystectomy)
3. Test positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV)
4. Have C3 or C4 complement protein (C4) > 110% of the upper limit or < 90% of the lower limit of the reference ranges at screening
5. Have alternative pathway function (AH50) or classical pathway function (CH50) results outside the reference ranges at Screening
6. Have a body temperature greater than or equal to 38 degrees Celsius (°C) on Day -1 or
Day 1, Hour 0
7. Have a history of febrile illness, or other evidence of infection, within 14 days prior to first study drug administration
8. Have a history of meningococcal infection, or a first-degree relative with a history of meningococcal infection
9. Have a history of seizures or any disorder of the brain
10. Have a history of hypersensitivity reactions to beta-lactams, penicillin, aminopenicillins, fluoroquinolones, cephalosporins, and carbapenems
11. Have a 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
12. Be 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
13. 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
14. Have participated in a clinical study within 30 days prior to first study drug administration
15. Have a 12-lead ECG with clinically significant findings as judged by the 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 > 450 msec
PR interval > 220 msec
QRS interval > 120 msec
16. Have clinically significant laboratory abnormalities, including any of the following, at either screening or Day -1:
Serum creatinine > 1.5 × ULN or creatinine clearance < 80 mL/minute estimated by the Cockcroft-Gault formula [(140 - age) × weight (kg) / 72 × serum creatinine (mg/dL)]
Alanine transaminase > ULN
Aspartate transaminase > ULN
Alkaline phosphatase > ULN
Total bilirubin > 1.5 × ULN at screening
Absolute neutrophil count (ANC) < lower limit of normal (LLN)
Abnormal coagulation profile, including platelet count < LLN, partial thromboplastin time (PTT) > ULN, INR greater than the upper limit of the normal reference range
(> 1.3) or prothrombin time (PT) > ULN
Hemoglobin (Hb) < LLN
Have a history or current evidence of biliary cholestasis
18. Have used prohibited 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
19. Consume an average of more than 8 cups of coffee or other caffeinated beverage, or
7 cans of cola per day
20. Have donated blood or lost more than 500 mL of blood within 3 months prior to first study drug administration
21. Have a clinically significant history of drug allergy as determined by the Investigator
22. Be unwilling or unable to comply with the study protocol for any reason
23. Have received a live attenuated vaccine within 30 days or other vaccine within 14 days of first study drug administration
24. Have received a blood transfusion or blood products within 6 months prior to first study drug administration
25. Have a diagnosis or history of Gilbert’s Syndrome, in the Investigator’s opinion


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)
Safety
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-0145228 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-0145228 and for whom PK parameters can be calculated.


The Pharmacodynamic (PD) population will include all subjects treated with ACH-0145228 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-0145228 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
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 9304 0
New Zealand
State/province [1] 9304 0
Auckland

Funding & Sponsors
Funding source category [1] 297784 0
Commercial sector/Industry
Name [1] 297784 0
Achillion Pharmaceuticals, Inc.
Address [1] 297784 0
300 George Street
New Haven, CT 06511
Country [1] 297784 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] 296820 0
Commercial sector/Industry
Name [1] 296820 0
Clinical Network Services (CNS) Ltd
Address [1] 296820 0
PO Box 78312
Grey Lynn
Auckland 1245
Country [1] 296820 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298842 0
Northern A - Health and Disability Ethics Committee (HDEC)
Ethics committee address [1] 298842 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 298842 0
New Zealand
Date submitted for ethics approval [1] 298842 0
05/10/2017
Approval date [1] 298842 0
26/10/2017
Ethics approval number [1] 298842 0

Summary
Brief summary
ACH0145228 is a new orally (by mouth) administered complement factor D (fD) inhibitor being developed by Achillion Pharmaceuticals Inc.for the treatment of complement mediated diseases. Many diseases are associated with inefficient control of complement or too much activity of the complement system. This study will help determine the correct dose, whether this medication has any side effects and how effective it is at controlling the
complement system.
A total of 28 subjects (18 active, 10 placebo) are planned for three treatment groups. Each healthy volunteer will receive a single dose of ACH0145228 or placebo. Subjects will remain inpatient from Day 1 to Day 4 with telephone calls on Day 5 and 6, and follow up visits (days 7, 14 and 28). The total duration of participation for each of these subjects will be approximately 28 days, not including screening.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 78414 0
Dr Paul Hamilton
Address 78414 0
Auckland Clinical Studies Ltd
Ground Floor
ACS House
3 Ferncroft Street
Auckland 1010
Country 78414 0
New Zealand
Phone 78414 0
+64 9 373 3474
Fax 78414 0
Email 78414 0
Paul.Hamilton@clinicalstudies.co.nz
Contact person for public queries
Name 78415 0
Mr Glenn Schulman
Address 78415 0
Achillion Pharmaceuticals, Inc.
300 George Street
New Haven, CT 06511
Country 78415 0
United States of America
Phone 78415 0
+12037525510
Fax 78415 0
Email 78415 0
gschulman@achillion.com
Contact person for scientific queries
Name 78416 0
Dr Paul Hamilton
Address 78416 0
Auckland Clinical Studies Ltd
Ground Floor
ACS House
3 Ferncroft Street
Auckland 1010
Country 78416 0
New Zealand
Phone 78416 0
+64 9 373 3474
Fax 78416 0
Email 78416 0
Paul.Hamilton@clinicalstudies.co.nz

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary