A Study of a Single Dose of ALXN1210 in Healthy Participants

Study Overview
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Brief Summary
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This study evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single dose of ALXN1210 in healthy participants, as assessed by electrocardiograms, physical examination, vital signs, laboratory analysis, and assessment of adverse events (AEs).

Detailed Description
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The participants were randomized in a 2:1 ratio (4 active and 2 placebo) to receive a single dose of ALXN1210 or placebo in the 200-milligram (mg) dose cohort and in a 3:1 ratio (6 active and 2 placebo) to receive a single dose of ALXN1210 or placebo in the 400-mg dose cohort, administered by intravenous (IV) infusion. A 150-day observation period was performed for safety, pharmacokinetic, and pharmacodynamic assessments after study drug administration. Antidrug antibody (ADA) levels were monitored in study participants for the duration of the 150-day follow-up period.

Official Title
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A Phase 1, Randomized, Blinded, Placebo Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Single Dose of ALXN1210 Administered Intravenously to Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: ALXN1210
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index from 18 through 29.9 kilogram (kg)/square meter, inclusive, and weight between 50 and 100 kg, inclusive. QT interval (Fridericia's correction); ≤450 milliseconds (msec) for males and ≤470 msec for females at screening and pre-dose on Day 1. Willing and able to give written informed consent and comply with the study visit schedule. Male participant and his female spouse/partner who was of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (at least 1 of which must be a barrier method), starting at screening and continuing until at least 5 months after the last dose of ALXN1210. Documented vaccination with meningococcal conjugate vaccine (MCV4) at least 14 days and not more than 3 years prior to dosing. Exclusion Criteria: Participants in intimate and prolonged contact (defined as living under the same roof or providing personal care) with individuals who are either immunocompromised, or with a specific underlying medical conditions (anatomic or functional asplenia [including sickle cell disease]; congenital complement, properdin, factor D, or primary antibody deficiencies; acquired complement deficiencies [for example, those receiving eculizumab]; and human immunodeficiency virus [HIV]), people younger than 2 years old and older than 65 years old, and professionals exposed to environments of greater risk for meningococcal disease (research, industrial, and clinical laboratory personnel who are routinely exposed to Neisseria meningitidis, military personnel during recruit training [military personnel may be at increased risk when accommodated in close quarters], daycare center workers, or those living on a college or university campus). Participants living or working in the Saguenay-Lac-St-Jean area (due to increased incidence of meningococcal infections in that specific area). Female participants of childbearing potential, including any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or who was pregnant, breastfeeding, or was not postmenopausal. Positive serum pregnancy test at screening or Day -1. Serum creatinine greater than the upper limit of normal (ULN) of the testing laboratory at screening and Day -1. Alanine aminotransferase or aspartate aminotransferase >ULN of the testing laboratory at screening and Day -1. Any of the following hematology tests: hemoglobin <135 grams (g)/L for males and <120 g/L for females; hematocrit <0.41 L/L for males and <0.36 L/L for females; white blood cells <3.5*10^3/microliter (μL) or >ULN of the testing laboratory; absolute neutrophils <1.5*10^3/μL (<1.0*10^3/μL for black race volunteers) or >ULN of the testing laboratory; and platelets <the lower limit of normal of the testing laboratory or >450*10^3/μL at screening and Day -1. HIV infection (evidenced by HIV-1 or HIV-2 antibody titer). Acute or chronic hepatitis B virus (HBV) infection (evidenced by the presence of HBV surface antigen or immunoglobulin M antibodies against HBV core antigen). Acute or chronic hepatitis C virus infection (evidenced by antibody titer). Active systemic bacterial, viral, or fungal infection within 14 days prior to dosing. Positive QuantiFERON-TB test, indicating possible tuberculosis (TB) infection. History of complement deficiency. History of malignancy other than basal cell carcinoma. Participated in a clinical trial within 30 days before initiation of dosing on Day 1, or used any experimental small-molecule therapy within 30 days prior to dosing on Day 1, or biologic therapy within 90 days prior to initiation of dosing on Day 1 or within 5 half-lives of the product, whichever is greater. Major surgery within the last 90 days prior to dosing. History of any Neisseria infection; history of unexplained, recurrent infection; or infection requiring treatment with systemic antibiotics within the last 90 days prior to dosing. Contraindication to receiving MCV4, including severe (life-threatening) allergic reaction to a previous dose of MCV4; severe (life-threatening) allergy to any vaccine component; previous diagnosis of Guillain-Barré Syndrome. History of allergy to excipients of ALXN1210 (that is, polysorbate 80) History of allergy to penicillin or cephalosporin, or history of significant allergic reaction to other products (anaphylaxis and angioedema). Positive urine drug toxicology screen. Donation of plasma within 7 days prior to dosing. Donation or loss of blood of more than 50 mL of blood within 30 days of dosing, or more than 499 mL of blood within 56 days of dosing. Clinical diagnosis of any autoimmune or rheumatologic disease (for example, systemic lupus erythematosus, and rheumatoid arthritis) or other condition or medical history that, in the opinion of the Investigator, might interfere with the participant's participation in the study, poses an added risk for the participant, or confounds the assessment of the participant or outcome of the study. History of latent or active TB or exposure to endemic areas within 8 weeks prior to the TB test performed at screening. Immunization with a live attenuated vaccine 1 month prior to dosing or planned vaccination during the course of the study (except for the vaccination planned by the study protocol). Presence of fever (body temperature > 37.6°C) (for example, a fever associated with a symptomatic viral or bacterial infection) within 2 weeks prior to the first dosing.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALXN1210 200 mg<br>ALXN1210 was administered intravenously. | Drug: ALXN1210<br>* All doses of ALXN1210 were administered by IV infusion, using programmable IV infusion pump and IV sets with in-line filters, at a fixed rate of 686 mg/hour (equivalent to 137 milliliters [mL]/hour), excluding interruption for safety or technical reason.<br>* Other names: Ravulizumab;|
| Experimental: ALXN1210 400 mg<br>ALXN1210 was administered intravenously. | Drug: ALXN1210<br>* All doses of ALXN1210 were administered by IV infusion, using programmable IV infusion pump and IV sets with in-line filters, at a fixed rate of 686 mg/hour (equivalent to 137 milliliters [mL]/hour), excluding interruption for safety or technical reason.<br>* Other names: Ravulizumab;|
| Placebo Comparator: Placebo<br>Placebo was administered intravenously. | Drug: Placebo<br>* All doses of placebo were administered by IV infusion, using programmable IV infusion pump and IV sets with in-line filters, at a fixed rate of 686 mg/hour (equivalent to 137 mL/hour), excluding interruption for safety or technical reason.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAEs were defined as AEs that occurred on or after the date and time of study drug administration, or those that first occurred before dosing but worsened in frequency or severity after study drug administration. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. | Baseline up to Day 150 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration (Cmax) of ALXN1210 | Blood samples were collected for estimation of Cmax by noncompartmental analyses using Pharsight Knowledgebase Server 4.0.2 and Phoenix WinNonlin 5.3. | Predose, 30 minutes, 4, 8, 24, 48, 96 hours postdose, then at Days 8, 15, 22, 29, 36, 43, 50, 57, 71, 90, 120 and 150 | 
| Time To Maximum Observed Serum Concentration (Tmax) of ALXN1210 | Blood samples were collected for estimation of Tmax by noncompartmental analyses using Pharsight Knowledgebase Server 4.0.2 and Phoenix WinNonlin 5.3. | Predose, 30 minutes, 4, 8, 24, 48, 96 hours postdose, then at Days 8, 15, 22, 29, 36, 43, 50, 57, 71, 90, 120 and 150 | 
| Area Under The Serum Concentration Versus Time Curve From Time Zero To The Time of The Last Quantifiable Concentration (AUC0-t) of ALXN1210 | Blood samples were collected for estimation of AUC0-t by noncompartmental analyses using Pharsight Knowledgebase Server 4.0.2 and Phoenix WinNonlin 5.3. | Predose, 30 minutes, 4, 8, 24, 48, 96 hours postdose, then at Days 8, 15, 22, 29, 36, 43, 50, 57, 71, 90, 120 and 150 | 
| Area Under The Serum Concentration Versus Time Curve From Time Zero (Dosing) To Infinity (AUCinf) of ALXN1210 | Blood samples were collected for estimation of AUCinf by noncompartmental analyses using Pharsight Knowledgebase Server 4.0.2 and Phoenix WinNonlin 5.3. | Predose, 30 minutes, 4, 8, 24, 48, 96 hours postdose, then at Days 8, 15, 22, 29, 36, 43, 50, 57, 71, 90, 120 and 150 | 
| Terminal Elimination Rate Constant (λz) of Serum ALXN1210 | Blood samples were collected for estimation of λz by noncompartmental analyses using Pharsight Knowledgebase Server 4.0.2 and Phoenix WinNonlin 5.3. | Predose, 30 minutes, 4, 8, 24, 48, 96 hours postdose, then at Days 8, 15, 22, 29, 36, 43, 50, 57, 71, 90, 120 and 150 | 
| Terminal Elimination Half-life (t½) of Serum ALXN1210 | Blood samples were collected for estimation of t½ by noncompartmental analyses using Pharsight Knowledgebase Server 4.0.2 and Phoenix WinNonlin 5.3. | Predose, 30 minutes, 4, 8, 24, 48, 96 hours postdose, then at Days 8, 15, 22, 29, 36, 43, 50, 57, 71, 90, 120 and 150 | 
| Total Clearance (CL) of ALXN1210 | Blood samples were collected for estimation of CL by noncompartmental analyses using Pharsight Knowledgebase Server 4.0.2 and Phoenix WinNonlin 5.3. | Predose, 30 minutes, 4, 8, 24, 48, 96 hours postdose, then at Days 8, 15, 22, 29, 36, 43, 50, 57, 71, 90, 120 and 150 | 
| Volume of Distribution (Vd) of ALXN1210 | Blood samples were collected for estimation of Vd by noncompartmental analyses using Pharsight Knowledgebase Server 4.0.2 and Phoenix WinNonlin 5.3. | Predose, 30 minutes, 4, 8, 24, 48, 96 hours postdose, then at Days 8, 15, 22, 29, 36, 43, 50, 57, 71, 90, 120 and 150 | 
| Percent Change From Baseline in Free Complement Component 5 (C5) | Blood samples were collected for analysis of free C5 concentrations. | Baseline, Day 150 | 
| Percent Change From Baseline in Total Complement C5 | Blood samples were collected for analysis of total C5 concentrations. | Baseline, Day 150 | 
| Percent Change From Baseline in Complement C5b-9 | Blood samples were collected for analysis of C5b-9 concentrations. | Baseline, Day 8 | 
| Percent Change From Baseline in Chicken Red Blood Cell Hemolysis | Blood samples were collected for analysis of cRBC hemolysis. | Baseline, Day 150 | 
| Percent Change From Baseline In Complement Classical Pathway (CCP) Activity | Blood samples were collected for analysis of CCP. | Baseline, Day 150 | 
| Percent Change From Baseline In Complement Alternative Pathway (CAP) Activity | Blood samples were collected for analysis of CAP. | Baseline, Day 150 | 
| Percentage of Participants With Positive Anti-Drug Antibody (ADA) | Blood samples were collected to evaluate antibody response through development of ADAs. | Baseline up to Day 150 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetic, Pharmacodynamic, Safety, Immunogenicity, ALXN1210