None listed
Conditions
Brief summary
ACH-0145228 is a small molecule, orally administered complement factor D(fD) inhibitor being developed by Achillion Pharmaceuticals, Inc. for the treatment of complement alternative pathway (AP) mediated diseases. Many inflammatory, autoimmune, neurodegenerative and age-related diseases are associated with inefficient complement regulation or excessive 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 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 (MAD) or a single dose 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 total duration of participation for each participant in multiple-dose cohorts will be approximately 42 days, not including screening, and for each participant in single-dose cohorts will be approximately 28 days, not including screening.
Interventions
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
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.
Sponsors
Achillion Pharmaceuticals. Inc
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver)
Eligibility
Sex/Gender
All
Age
25 Years to 55 Years
Healthy volunteers
Yes
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
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
Outcome results
None listed