Pharmacokinetic Study of Ravulizumab Administered Subcutaneously With Recombinant Human Hyaluronidase PH20 (rHuPH20) in Healthy Adult Volunteers

Healthy Clinical Trial

Official title:

A Partially Randomized, Sequential Cohort, Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Subcutaneous Ravulizumab Coadministered With rHuPH20 in Healthy Adult Volunteers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05396742
• Other study ID #: ALXN1210-HV-105
• Secondary ID: 2017-004931-35
• Status: Completed
• Phase: Phase 1
• Start date: August 9, 2018
• Est. completion date: May 21, 2019

Study information

• Verified date: April 2023
• Source: Alexion Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The main objectives of this study were to estimate the absolute bioavailability of ravulizumab/rHuPH20 subcutaneous (SC) and to assess the safety and tolerability of ravulizumab/rHuPH20 SC.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 49
• Est. completion date: May 21, 2019
• Est. primary completion date: May 21, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Key Inclusion Criteria:

• Body weight between 60 and 90 kilogram (kg), inclusive, and body mass index within the range 18 through 29.9 kg/square meter, inclusive.

• Negative serum pregnancy test at screening and Day -1

• Male participants and females 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) while on treatment and for up to 8 months after last dose of study drug.

• QT interval corrected using the Fridericia's formula (QTcF) =450 milliseconds (msec) for male participants and =470 msec for female participants at screening and prior to dosing on Day 1.

• Documented vaccination with meningococcal conjugate vaccine (MCV4) at least 56 days and not more than 2 years, 4 months prior to dosing.

• Vaccination with serogroup B meningococcal vaccine at least 56 days prior to dosing on Day 1, with a booster administered at least 28 days prior to dosing on Day 1, with at least 28 days between the first and second injections.

Key Exclusion Criteria:

• Current or recurrent disease (for example, cardiovascular, hematological, neurological, endocrine, immunological, rheumatological, renal, hepatic or gastrointestinal or other conditions) that or could affect clinical assessments or clinical laboratory evaluations.

• Current or relevant history of physical or psychiatric illness that are not stable or may require a change in treatment, use of prohibited therapies during the study or make the participant unlikely to fully comply with the requirements of the study or complete the study, or any condition that presents undue risk from the investigational product or study procedures.

• Any other significant disease or disorder which, in the opinion of the Investigator, may put the participant at risk.

• Documented history of allergy to penicillin or cephalosporin.

• History of significant allergic reaction (for example, anaphylaxis or angioedema) to any product (for example, food, pharmaceutical).

• Use of prescription medications (excluding oral contraceptives) within 14 days prior to dosing on Day 1, except with prior approval of the Sponsor.

• Regular use of nonprescription, over-the-counter medications, including herbal remedies and supplements, within 14 days prior to dosing on Day 1. Multivitamins, paracetamol (acetaminophen) =2 grams (g) per day, and topical skin products without significant systemic absorption are allowed.

• Positive urine drug toxicology screen at screening or on Day -1.

• Alcohol consumption within 48 hours prior to study drug administration or positive alcohol breath test on Day -1.

• Donation of plasma within 7 days prior to dosing on Day 1. Donation or loss (excluding volume drawn at screening) of more than 50 milliliters (mL) of blood within 30 days prior to dosing or more than 499 mL of blood within 56 days prior to dosing on Day 1.

• Female participants who are breastfeeding.

• Participants who are in intimate and prolonged contact with (defined as living under the same roof or providing personal care to) people younger than 2 years of age or older than 65 years of age, or who are either immunocompromised or have one of the following 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); or human immunodeficiency virus (HIV).

• Participants who are one of the following:

1. Professionals exposed to environments of greater risk for meningococcal disease

2. Research, industrial, and clinical laboratory personnel who are routinely exposed to N meningitidis

3. Military personnel during recruit training

4. Daycare center workers

5. Those living on a college or university campus

6. Those who plan to travel during the course of the study to or have travelled to endemic areas for meningococcal meningitis (for example, India, Sub-Saharan Africa, pilgrimage to Saudi Arabia for Hajj) within 6 months prior to dosing

• Immunization with a live-attenuated vaccine 28 days prior to dosing on Day 1 or planned vaccination during the course of the study (except for the vaccination planned by the study protocol). Immunization with inactivated or recombinant influenza vaccine is permitted.

• Prior exposure to ravulizumab or eculizumab.

• Major surgery or hospitalization within 90 days prior to dosing on Day 1.

• History of allergy or hypersensitivity to excipients of ravulizumab (for example, polysorbate 80), rHuPH20, or other hyaluronidases.

• Currently smokes >10 cigarettes daily (former smokers may be permitted to enroll at the Investigator's discretion) and is unwilling to refrain from smoking while a resident in the clinical research unit or comply with the smoking restrictions.

• History of illicit drug abuse, history of significant alcohol abuse within 1 year prior to the screening visit, or clinical evidence of substance and/or alcohol abuse within the 2 years before screening.

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• Ravulizumab
Solution for infusion or injection, as applicable
• rHuPH20
Solution for infusion

Locations

Country	Name	City	State
United Kingdom	Clinical Trial Site	London

Sponsors (1)

Lead Sponsor	Collaborator
Alexion Pharmaceuticals, Inc.

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Absolute Bioavailability Of Ravulizumab Subcutaneous (SC)/rHuPH20	Dose-normalized area under the serum concentration versus time curve from 0 extrapolated to infinity (AUC0-inf) and body weight-adjusted AUC0-inf for the ravulizumab/rHuPH20 SC cohorts were compared with the 400 mg ravulizumab intravenous (IV) cohort to determine absolute bioavailability. Geometric mean ratios of the AUC0-inf parameter were calculated for each group. Absolute bioavailability is reported as the geometric mean ratio, which was defined as the ratio of geometric means for the dose-normalized AUC0-inf parameter (with and without body-weight adjustment) for the ravulizumab SC cohort divided by that for the ravulizumab IV cohort.	Day 1 (after first dose) to Day 200
Primary	Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs)	An AE was reported as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. Serious AEs (SAEs) were defined as any untoward medical occurrence that, at any dose resulted in death, life threatening, required hospitalization, resulted in persistent disability or incapacity, resulted in birth defect, or other situations. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.	Day 1 (after first dose) up to Day 200 (including safety follow up)
Secondary	Relative Bioavailability Of Ravulizumab SC/rHuPH20 Compared With Ravulizumab SC	Dose-normalized AUC0-inf and body weight-adjusted AUC0-inf for the ravulizumab/rHuPH20 SC cohorts were compared with the 400 mg ravulizumab SC cohort to determine relative bioavailability. Geometric mean ratios of the AUC0-inf parameter were calculated for each group. Relative bioavailability is reported as the geometric mean ratio, which was defined as the ratio of the geometric means for the dose-normalized AUC0-inf parameter (with and without body-weight adjustment) for the ravulizumab/rHuPH SC cohort divided by that for the ravulizumab SC cohort.	Day 1 (after first dose) to Day 200
Secondary	Maximum Percent Change From Baseline (PCFB) In Serum Levels Of Total Complement Component 5 (C5) Concentrations	The highest (maximum difference) mean (standard deviation [SD]) PCFB at up to Day 200 is reported. Baseline was defined as the last available value prior to the first drug administration. Change from Baseline was calculated as observed value minus the baseline value. PCFB was calculated as change from baseline divided by baseline multiplied by 100.	Baseline, Up to Day 200
Secondary	Maximum PCFB In Serum Levels Of Free C5 Concentrations	The highest (maximum difference) mean (SD) PCFB at up to Day 200 is reported. Baseline was defined as the last available value prior to the first drug administration. Change from Baseline was calculated as observed value minus the baseline value. PCFB was calculated as change from baseline divided by baseline multiplied by 100.	Baseline, Day 200
Secondary	Maximum PCFB In Ex Vivo Chicken Red Blood Cell (cRBC) Hemolysis Activity	The highest (maximum difference) mean (SD) PCFB at up to Day 200 is reported. Baseline was defined as the last available value prior to the first drug administration. Change from Baseline was calculated as observed value minus the baseline value. PCFB was calculated as change from baseline divided by baseline multiplied by 100.	Baseline, Up to Day 200