Clinical trial NCT05988034: A Study to Assess the Effect of Avacopan at Therapeutic and Supratherapeutic Doses on the QT/QTc Interval in Healthy Participants
Official title: A Multiple-dose, Randomized, Double-blind, Placebo-controlled, Active-Comparator, Parallel Study to Investigate the Effect of Avacopan at Therapeutic and Supratherapeutic Doses on the QT/QTc Interval in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Electrocardiography
Keywords: Complement 5a receptor (C5aR)
Anti-neutrophil cytoplasmic antibody-associated vasculitis
Complement
Vasculitis
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2023-08-14
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The primary objective of this study is to evaluate the effects of therapeutic and supratherapeutic doses of avacopan on the heart rate corrected QT interval, using Fridericia's formula (QTcF).


Eligibility criteria: Inclusion Criteria:

* Be able to verbalize understanding of consent form and able to provide written informed consent;
* Healthy male or female: No known history of a clinically significant medical diagnosis in the opinion of the Investigator and is not receiving prescription medication except birth control therapies; this includes but is not limited to no history of heart or lung disease (including latent tuberculosis), high blood pressure, history of any cardiac or endocrine disease (including thyroid disease and diabetes); appendectomy and cholecystectomy are allowed;
* Aged ≥18 and ≤60 years at the time of screening;
* Body mass index ≥18.0 and ≤30.0 kg/m\^2, and body weight of ≥50 kg, at screening and Day -2;
* Non- or ex-smoker; an ex-smoker is defined as someone who completely stopped using nicotine products for at least 180 days prior to the first study drug administration;
* A female participant meeting 1 of the following criteria: (1) female participants of child-bearing potential using adequate contraception during and for at least 90 days after any administration of study medication; or (2) physiological postmenopausal status, defined as the following: absence of menses for at least 1 year prior to the first study drug administration (not due to amenorrhea secondary to lactation); and follicle stimulating hormone (FSH) levels ≥40 mIU/mL at screening; or (3) surgical postmenopausal status, defined as the following: bilateral oophorectomy; and absence of menses for at least 90 days prior to the first study drug administration; and FSH levels ≥40 mIU/mL at screening; or (4) surgical sterilization including tubal ligation, salpingectomy and hysterectomy. If the postmenopausal participant has an FSH of \<40 mIU/mL, but meets the above criteria in either (1), (2), (3) or (4) (for all aspects other than FSH levels) as well as all the other inclusion criteria, the participant may be included in the study if the estradiol serum level measured at screening is equal to or below 150 pmol/L. If male, non-vasectomized participants with female partners of child-bearing potential must agree to use contraception and agree not to donate sperm during the study period and for 90 days after the last study drug administration;
* Willing to communicate with an investigator and site staff and comply with all study procedures and requirements.

Exclusion Criteria:

* An uninterpretable or abnormal screening electrocardiogram (ECG) indicating a second- or third-degree atrioventricular block, or one or more of the following: QRS interval \>110 msec; QTcF \>450 msec; PR interval \>200 msec; HR \<40 bpm; or any rhythm other than sinus rhythm that is interpreted an investigator to be clinically significant;
* History of risk factors for torsades de pointes, including unexplained syncope, known long QT syndrome, heart failure, myocardial infarction, angina, or clinically significant abnormal laboratory assessments including hypokalemia, hypercalcemia, or hypomagnesemia. Participants will also be excluded if there is a family history of long QT syndrome or Brugada syndrome;
* A sustained supine systolic blood pressure \>150 mm Hg or \<90 mm Hg or a supine diastolic blood pressure \>95 mm Hg or \<50 mm Hg at screening or on Day -1. Blood pressure may be retested more than once in the supine position. The blood pressure abnormality is considered sustained if either the systolic or the diastolic pressure values are outside the stated limits after 3 assessments and the participant may not be randomized;
* A resting HR of \<40 bpm or \>100 bpm when vital signs are measured at screening or on Day -1;
* Unstable cardiovascular disease, including recent myocardial infarction or cardiac arrhythmia;
* History of acquired immunodeficiency syndrome or positive test results for human immunodeficiency virus, hepatitis C virus antibody, or hepatitis B surface antigen at screening;
* Positive urine drug or alcohol screen at screening or on Day -2 (admission);
* Clinically significant illness, including viral syndromes within 3 weeks prior to Day 1;
* Women who are pregnant according to a serum pregnancy test (or planning to become pregnant within the next 6 months) or currently breastfeeding, at screening or according to a urine pregnancy test on Day -2 (admission);
* Participation in another investigational drug or device study or treated with an investigational drug within 30 days or 5 half-lives, whichever is longer, prior to Day 1;
* Received avacopan previously;
* Consumed more than 21 units of ethanol per week at any time in the 6 months prior to Day 1 (1 unit of ethanol is equivalent to 8 ounces of beer, 4 ounces of wine, or 1 ounce of spirits) or history of alcoholism and/or drug/chemical abuse within 5 years;
* Use of prescription medications (with the exception of hormone replacement therapy and hormonal birth control), including nonsteroidal anti-inflammatory drugs or sucralfate and medications known to prolong the QT/QTc interval or herbal preparations within 14 days or 5 half-lives (whichever is longer) prior to Day 1, or use of an over-the-counter medication, vitamins, or supplements (including omega-3 fish oils) within 7 days prior to Day 1;
* Use of alcohol-, caffeine-, or xanthine-containing products, Seville oranges (sour), grapefruit, or grapefruit juice, within 72 hours prior to Day 1;
* Strenuous activity (e.g., sports) from 96 hours (4 days) prior to entry into the clinical research unit (on Day -2) and throughout the study (until the final follow-up visit is conducted);
* Donated more than 500 mL of blood or significant blood loss within 60 days prior to signing the informed consent form;
* Any other medical, psychological, or social condition that, in the opinion of an investigator, would prevent the participant from fully participating in the study, would represent a concern for study compliance, or would constitute a safety concern to the participant;
* An employee of an investigator or study center with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as a family member of the employee or investigator;
* Known hypersensitivity to drugs including moxifloxacin;
* Participants taking strong CYP3A4 inducers (e.g., phenytoin, fosphenytoin, rifampicin, carbamazepine, St. John's Wort, nevirapine, pentobarbital, primidone, rifapentine, enzalutamide, lumacaftor, mitotane, apalutamide, quinine, rimexolone, rifaximin, rifamycin, topiramate, oxcarbazepine) or moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, dexamethasone, etravirine, nafcillin, dabrafenib, methotrexate, bexarotene, mifepristone) within 2 weeks prior to prior to Day 1;
* Positive screening tuberculosis blood test.

Primary outcomes:
measure: Change from Baseline in QTcF
timeFrame: Day -1 (baseline) and up to Day 14
Secondary outcomes:
measure: Change from Baseline in Heart Rate (HR)
timeFrame: Day -1 (baseline) and Days 1, 7, and 14
measure: Change from Baseline in Time Between P and R Wave (PR Interval)
timeFrame: Day -1 (baseline) and Days 1, 7, and 14
measure: Change from Baseline in Complex Between Q and S Wave (QRS Interval)
timeFrame: Day -1 (baseline) and Days 1, 7, and 14
measure: Placebo-corrected Change from Baseline in HR
timeFrame: Day -1 (baseline) and Days 1, 7, and 14
measure: Placebo-corrected Change from Baseline in QTcF
timeFrame: Day -1 (baseline) and Days 1, 7, and 14
measure: Placebo-corrected Change from Baseline in PR Interval
timeFrame: Day -1 (baseline) and Days 1, 7, and 14
measure: Placebo-corrected Change from Baseline in QRS Interval
timeFrame: Day -1 (baseline) and Days 1, 7, and 14
measure: Number of Participants with Categorical Increases in QTcF from Baseline
timeFrame: Day -1 (baseline) and Days 1, 7, and 14
measure: Number of Participants with Categorical Increases in PR Interval from Baseline
timeFrame: Day -1 (baseline) and Days 1, 7, and 14
measure: Number of Participants with Categorical Increases in QRS Interval from Baseline
timeFrame: Day -1 (baseline) and Days 1, 7, and 14
measure: Number of Participants with Categorical Decreases in HR from Baseline
timeFrame: Day -1 (baseline) and Days 1, 7, and 14
measure: Change from Baseline in the Number of T-wave Morphology Findings
timeFrame: Day -1 (baseline) and Days 1, 7, and 14
measure: Change from Baseline in the Number of U-waves
timeFrame: Day -1 (baseline) and Days 1, 7, and 14
measure: Maximum Observed Plasma Concentration (Cmax) of Avacopan
timeFrame: Up to Day 14
measure: Cmax of Avacopan Metabolite M1
timeFrame: Up to Day 14
measure: Time of Cmax (Tmax) of Avacopan
timeFrame: Up to Day 14
measure: Tmax of Avacopan Metabolite M1
timeFrame: Up to Day 14
measure: Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to 6 Hours (AUC0-6h) of Avacopan
timeFrame: Up to Hour 6 post-dose on Days 1, 7, and 14
measure: AUC0-6h of Avacopan Metabolite M1
timeFrame: Up to Hour 6 post-dose on Days 1, 7, and 14
measure: AUC From Time 0 to 12 Hours (AUC0-12h) of Avacopan
timeFrame: Up to Hour 12 post-dose on Days 1, 7, and 14
measure: AUC0-12h of Avacopan Metabolite M1
timeFrame: Up to Hour 12 post-dose on Days 1, 7, and 14
Other outcomes:
Locations:
city: Tempe
country: United States
facility: Celerion
state: Arizona
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References: