Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001989235
Ethics application status
Approved
Date submitted
29/11/2018
Date registered
12/12/2018
Date last updated
10/10/2019
Date data sharing statement initially provided
12/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Multiple Ascending Dose study of ACH-0145228 in healthy participants.
Scientific title
A Randomized, Double-Blind, Multiple Ascending Dose Study to Assess the
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACH-0145228 in Healthy
Participants
Secondary ID [1] 296645 0
ACH228-002
Universal Trial Number (UTN)
U1111-1222-964
Trial acronym
Linked study record
ACTRN12617001521314
A single dose study to investigate the safety of ACH-0145228 in healthy volunteers.

The current study is the Multiple Ascending Dose study following the linked Single Ascending Dose study with the same Investigational Product.

Health condition
Health condition(s) or problem(s) studied:
Complement-mediated diseases 310472 0
Condition category
Condition code
Inflammatory and Immune System 309186 309186 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A total of at least 54 healthy participants (38 active, 16 placebo) are planned for four separate multiple dose cohorts and one single dose cohort. Each healthy participant will receive either 14 days multiple ascending dose (MAD) or a single dose (S1) of oral doses of ACH-0145228 or placebo. Participants in MAD cohorts will receive a single 500-mg oral dose of ciprofloxacin 7 to 10 days before dosing. One additional single-dose cohort of 8 participants and one additional multiple-dose cohort of 10 participants may be enrolled if needed, for a maximum enrolment of 72 healthy participants.
The first dose group (Cohort 1) will have 16 participants randomized 1:1 to active or placebo (8 active and 8 placebo), Cohort 2, 3, 4, and additional multiple-dose cohorts, if needed will each consist of 10 participants, randomized 4:1 to active or placebo (8 active and 2 placebo). The single-dose cohort (Cohort S1), and additional single-dose cohorts, if needed, will each consist of 8 participants, randomized 3:1 to active or placebo (6 active and 2 placebo). For single-dose cohort, a sentinel group consisting of one active and one placebo subject will be dosed 24 hours before the remaining 6 subjects. If no significant drug-related toxicity is identified in the first 24 hours in the opinion of the PI, then the remaining participants of the same Cohort may be randomized 5:1 to receive either active study medication or placebo treatment.
Cohort 1 to 3 dose escalation decisions will be made based on review of safety data up to Day 14 and PK to Day 7 from the preceding dose. Dose escalation decision for Cohort 4 will be made based on review of safety data up to Day 14 and PK to Day 7 from Cohorts 1-3 and the safety and available PK and PD data to Day 4 from Cohort S1.
For MAD cohorts, escalation to a higher dose may occur if the last dose was well tolerated. The predicted exposure may not exceed that observed at the highest dose evaluated in a single-dose setting.
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 40 mg BID for Cohort 1, 80 mg BID for Cohort 2, 120 mg BID for Cohort 3, and 200 mg BID for Cohort 4. The maximum dose for MAD Cohorts will be 200 mg BID.
Because the available data do not provide single-dose exposures high enough to support the planned 200 mg BID dose in Cohort 4, the single-ascending dose cohort (S1) must be completed before Cohort 4 is enrolled. Cohort S1 will receive a maximum single-dose of 240 mg.
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.

MAD cohort 1 dose is 40 mg BID. This was determined based on the data from the SAD study (ACH228-001) and the available nonclinical toxicology and PK/PD data.
The cohort S1 (SAD) dose for this study is 240 mg. This was determined based on the data from the SAD study (ACH228-001) and the available nonclinical toxicology and PK/PD data. The Cmax and AUC0-24 predicted for this doses is calculated to maintain a 10-fold or greater margin to the exposure observed at the NOAEL observed in nonclinical studies.

MAD cohorts will be enrolled sequentially. Up to Cohort 3, all dose escalation decisions will be made based on review of safety data through at least Day 14 and PK through Day 7 from the preceding dose. The dose escalation decision for Cohort 4 will be made based on review of safety data through at least Day 14 and PK through Day 7 from Cohorts 1-3 and the safety and available PK and PD data up to at least Day 4 from Cohort S1.
Cohort S1 may be enrolled at the convenience of the investigational site, including concurrently with Cohorts 1-3, but must be completed before Cohort 4 is enrolled.
Intervention code [1] 312953 0
Treatment: Drugs
Comparator / control treatment
Placebo composed of Microcrystalline cellulose, Size 00 white opaque hypromellose capsules.
Control group
Placebo

Outcomes
Primary outcome [1] 308163 0
The primary objective is to demonstrate the safety and tolerability of multiple, ascending oral doses of ACH-0145228 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] 308163 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 Day -1 to Day 17 (clinic confinement) with telephone calls on Days 18, 19, and 20. Day 1 to inquire about adverse events, and follow-up visits on Days 21, 28, and 42.
Subjects in SAD cohort will be confined from Day -1 to Day 4 and receive a single dose of ACH-0145228 on Day 1, with telephone calls from the site to inquire about adverse events on Days 5 and 6, and follow-up visits (Days 7, 14, and 28).
Secondary outcome [1] 354122 0
To evaluate the PK profile of ACH-0145228 in healthy volunteers following the administration of multiple oral dose.
ACH-0145228 concentration over time and calculated PK parameters.
Multiple-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] 354122 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.
Serial draws will occur on Day 1, 7, and 14 (taken pre-dose and then 0.5,1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hours post dose (with a sample taken at 16 hours post dose at Day 14.) and also on day 2, 3, 6, 8, 9, 13, 15, 16 and 17.
Pharmacokinetic Urine samples on day 1, 7 and 14 (taken pre-dose and then between 0-2, 2-4, 4-6, 6-8, 8-12 and 12-24 hours post dose), and also on day 2, 3, 4, 10, 16 and 17.

For Single-dose cohorts the PK assessments are as follows:
Day 1 serial draws (taken pre-dose and then 0.5,1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 hours post dose), and also on day 2, 3 and 4.
Pharmacokinetic Urine samples day 1 only (taken pre-dose and then between 0-2, 2-4, 4-6, 6-12, 12-24 hours post dose).
Secondary outcome [2] 354123 0
To investigate the pharmacodynamic (PD) profile of ACH-0145228 in healthy volunteers following administration of multiple oral doses.
Pharmacodynamics will be evaluated using serum or plasma collected during the study with the following:
C3 and C4, Total CP activity, AP Wieslab, AP Hemolysis, fD, Bb.
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] 354123 0
This is assessed by Values for selected PD markers over time.
Outcome will be assessed using C3 and C4, Total CP activity, AP Wieslab assay, AP Hemolysis, fD, Bb.
For multiple-ascending dose Cohorts:
Day 1, 7 and 14 serial draws for AP wieslab and AP hemolysis assay (taken pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 16 hours post dose).
Day 1, 7 and 14; C3 and C4, taken pre-dose only.
Day 1, 7 and 14; Complement classical pathway activity (CP activity) and Complement factor D (fD), taken pre-dose, 2 and 12 hours pose dose. Also collected on day 3, 13, 17, 21 and 28.
Day 1, 7 and 14; Bb fragment (Bb); taken pre-dose, 2, 4, 6, 8, 10, 12 and 16 hours post dose.

AP wieslab and AP hemolysis assay, Bb fragment (Bb), C3 and C4 will also be collected on Day 2, 3, 6, 8, 9, 13, 15, 16, 17, 21 and 28.

For single-dose cohort:
Day 1 serial draws for AP wieslab and AP hemolysis assay (taken pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 16 hours post dose).
Day 1; C3 and C4, taken pre-dose only.
Day 1; Complement classical pathway activity (CP activity) and Complement factor D (fD), taken pre-dose, 2 and 12 hours pose dose.
Day 1; Bb fragment (Bb) taken pre-dose, 2, 4, 6, 8, 10, 12 and 16 hours post dose.

AP wieslab and AP hemolysis assay, Bb fragment (Bb), C3 and C4 collected on Day 2, 3, 4, 7 and at Early termination.
Secondary outcome [3] 354124 0
To evaluate the relationship between multiple-dose PK and PD effects of ACH-0145228 through inhibition of complement alternative pathway (AP) activity (PK/PD).
Timepoint [3] 354124 0
This is assessed by the relationship between ACH-0145228 concentration and selected PD markers over time.
PD markers to be assessed are; C3, C4, Total CP activity, AP Wieslab assay, fD, Bb.
For multiple-ascending dose Cohorts:
Day 1, 7 and 14 serial draws for AP wieslab and AP hemolysis assay (taken pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 16 hours post dose) and collected on Day 2, 3, 6, 8, 9, 13, 15, 16, 17, 21 and 28.
For single-dose cohort:
Day 1 serial draws for AP wieslab and AP hemolysis assay (taken pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 16 hours post dose) and collected on Day 2, 3, 4, 7 and at Early termination.

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 of 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.
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.
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 as described in Appendix 1 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 clinically relevant evidence of current cardiovascular, pulmonary, hepatic (including biliary cholestasis or Gilbert's syndrome), renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric 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. Have a history of seizures or any disorder of the brain
5. Participants 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 (including a history of hypersensitivity reactions to ciprofloxacin or other antibiotics, including beta-lactams, penicillin, aminopenicillins, other fluoroquinolones, cephalosporins, and/or carbapenems) that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
7. Use of prohibited over-the-counter or prescription medications as follows (other than ciprofloxacin, administered as part of this study for nasopharyngeal decolonization 7 to 10 days before dosing):
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.
8. Live attenuated vaccine within 30 days or other vaccine within 14 days of first study drug administration.
9. 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.
10. 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.
11. Test positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV) at screening.
12. Positive serum hCG (female participants only).
13. Have clinically significant laboratory abnormalities, including any of the following, at either screening or Day -1:
Serum creatinine >ULN and/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 > ULN
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
14. 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 >220 msec
QRS interval >120 msec
15. 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
16. Have C3 or C4 complement protein (C4) >120% of the upper limit or <80% of the lower limit of the reference ranges at screening
17. Have total complement classical pathway activity (total CP activity assay) or complement alternative pathway activity (AP Wieslab assay) <LLN or >120% of ULN at screening
18. Have a body temperature greater than or equal to 38 degrees Celsius (°C) on Day -1 or Day 1, Hour 0
19. 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
20. 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
21. 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 a single-dose 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 studies.
There are 5 analysis populations for this study: Enrolled participants, Randomly Assigned to Study Intervention participants, 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
31/01/2019
Actual
31/01/2019
Date of last participant enrolment
Anticipated
22/05/2019
Actual
23/05/2019
Date of last data collection
Anticipated
14/07/2019
Actual
3/07/2019
Sample size
Target
54
Accrual to date
Final
61
Recruitment outside Australia
Country [1] 21051 0
New Zealand
State/province [1] 21051 0
Auckland

Funding & Sponsors
Funding source category [1] 301223 0
Commercial sector/Industry
Name [1] 301223 0
Achillion Pharmaceuticals. Inc
Country [1] 301223 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Achillion Pharmaceuticals. Inc
Address
Achillion Pharmaceuticals, Inc 1777 Sentry Pkwy West Suite 200, Bld 14 Blue Bell, Pa 19422
Country
United States of America
Secondary sponsor category [1] 300857 0
Commercial sector/Industry
Name [1] 300857 0
Clinical Networks Services (CNS) Ltd
Address [1] 300857 0
PO Box 78312
Grey Lynn
Auckland 1245
New Zealand
Country [1] 300857 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301967 0
Central - Health and Disability Ethics Committee (HDEC)
Ethics committee address [1] 301967 0
Ethics committee country [1] 301967 0
New Zealand
Date submitted for ethics approval [1] 301967 0
09/11/2018
Approval date [1] 301967 0
09/12/2018
Ethics approval number [1] 301967 0

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

Contacts
Principal investigator
Name 88702 0
Dr Paul Hamilton
Address 88702 0
Auckland Clinical Studies Ltd
Ground Floor
ACS House
3 Ferncroft Street
Auckland 1010
Country 88702 0
New Zealand
Phone 88702 0
+64 9 373 3474
Fax 88702 0
Email 88702 0
[email protected]
Contact person for public queries
Name 88703 0
Kevin Malibosky
Address 88703 0
Achillion Pharmaceuticals, Inc
1777 Sentry Pkwy West
Suite 200, Bld 14
Blue Bell, Pa 19422
Country 88703 0
United States of America
Phone 88703 0
+1 215 709 3037
Fax 88703 0
Email 88703 0
[email protected]
Contact person for scientific queries
Name 88704 0
Paul Hamilton
Address 88704 0
Auckland Clinical Studies Ltd
Ground Floor
ACS House
3 Ferncroft Street
Auckland 1010
Country 88704 0
New Zealand
Phone 88704 0
+64 9 373 3474
Fax 88704 0
Email 88704 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


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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