Study to Assess Safety, Tolerability and Phamacokinetics of KAE609 Administered Intravenously in Healthy Subjects

A Randomized, Subject and Investigator-blinded, Placebo Controlled, Single and Multiple Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of KAE609 Administered Intravenously in Healthy Subjects

This was a randomized, subject and investigator-blinded, placebo-controlled, single and multiple ascending intravenous (iv) dose study in healthy subjects to assess the safety and tolerability of KAE609 given in the vein.

Study Overview

• Status: Completed
• Conditions: Malaria
• Intervention / Treatment: Drug: KAE609; Drug: Placebo

Detailed Description

The study consisted of 2 parts: single-ascending dose (SAD) part and multiple ascending dose (MAD) part.

In Part A (Single-ascending dose (SAD) part), it was planned to recruit 6 active, 2 placebo subjects in each cohort:

• Cohort A1: 10.5 mg/placebo
• Cohort A2: 30 mg/placebo
• Cohort A3: 75 mg/placebo
• Cohort A4: 120 mg/placebo
• Cohort A5: 210 mg/placebo

In Part B (Multiple-ascending dose (MAD) part), Subjects were assigned to one of the following treatment arms in a ratio of 2:1 (6 active, 3 placebo):

• Cohort B1: 60 mg/placebo, every 24 hours (q24h) × 5 days
• Cohort B2: 120 mg/placebo, every 24 hours (q24h) × 5 days

Eligible subjects were randomized to receive a single or q24h x 5 doses of either KAE609 or placebo. Safety, tolerability and pharmacokinetics were assessed over the period of 8 days for single dose and 12 days for multiple dose up to end of study visit for each subject.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium, B-2060
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Healthy male and female subjects 18 to 55 years of age inclusive, and in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests.
• Subjects must weigh at least 50 kg to participate in the study, and must have a body mass index (BMI) within the range of 18.0 - 30.0 kg/m2.

Key Exclusion Criteria:

• Use of other investigational drugs within 5 half-lives of Screening, or within 30 days of dosing, whichever is longer; or longer if required by local regulations.
• Significant illness which has not resolved within two (2) weeks prior to initial dosing.
• Pregnant or nursing (lactating) women.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant.
• Sexually active males unwilling to use a condom during intercourse while taking investigational drug and for at least 2 weeks after last dose of investigational drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A1: 10.5 mg/placebo; Single iv bolus dose of KAE609 or placebo administered at the clinical site by the study personnel.	Drug: KAE609; iv bolus administration over approximately 2 min for doses < 75 mg (Cohorts A1, A2 and B1); iv infusion over approximately 10 min for doses ≥ 75 mg (Cohorts A3, A4, A5 and B2); Drug: Placebo; matching placeo for iv administration
Experimental: Cohort A2: 30 mg/placebo; Single iv bolus dose of KAE609 or placebo administered at the clinical site by the study personnel.	Drug: KAE609; iv bolus administration over approximately 2 min for doses < 75 mg (Cohorts A1, A2 and B1); iv infusion over approximately 10 min for doses ≥ 75 mg (Cohorts A3, A4, A5 and B2); Drug: Placebo; matching placeo for iv administration
Experimental: Cohort A3: 75 mg/placebo; Single iv infusion dose of KAE609 or placebo administered at the clinical site by the study personnel.	Drug: KAE609; iv bolus administration over approximately 2 min for doses < 75 mg (Cohorts A1, A2 and B1); iv infusion over approximately 10 min for doses ≥ 75 mg (Cohorts A3, A4, A5 and B2); Drug: Placebo; matching placeo for iv administration
Experimental: Cohort A4: 120 mg/placebo; Single iv infusion dose of KAE609 or placebo administered at the clinical site by the study personnel.	Drug: KAE609; iv bolus administration over approximately 2 min for doses < 75 mg (Cohorts A1, A2 and B1); iv infusion over approximately 10 min for doses ≥ 75 mg (Cohorts A3, A4, A5 and B2); Drug: Placebo; matching placeo for iv administration
Experimental: Cohort A5: 210 mg/placebo; Single iv infusion dose of KAE609 or placebo administered at the clinical site by the study personnel.	Drug: KAE609; iv bolus administration over approximately 2 min for doses < 75 mg (Cohorts A1, A2 and B1); iv infusion over approximately 10 min for doses ≥ 75 mg (Cohorts A3, A4, A5 and B2); Drug: Placebo; matching placeo for iv administration
Experimental: Cohort B1: 60 mg/placebo, every 24 hours (q24h) × 5 days; Multiple iv bolus doses of KAE609 or placebo administered at the clinical site by the study personnel.	Drug: KAE609; iv bolus administration over approximately 2 min for doses < 75 mg (Cohorts A1, A2 and B1); iv infusion over approximately 10 min for doses ≥ 75 mg (Cohorts A3, A4, A5 and B2); Drug: Placebo; matching placeo for iv administration
Experimental: Cohort B2: 120 mg/placebo, every 24 hours (q24h) × 5 days; Multiple iv infusion doses of KAE609 or placebo administered at the clinical site by the study personnel.	Drug: KAE609; iv bolus administration over approximately 2 min for doses < 75 mg (Cohorts A1, A2 and B1); iv infusion over approximately 10 min for doses ≥ 75 mg (Cohorts A3, A4, A5 and B2); Drug: Placebo; matching placeo for iv administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With On-Treatments Adverse Events, Serious Adverse Events, and Deaths	The distribution of adverse events was done via the analysis of frequencies for Adverse Event (AEs), Serious Adverse Event (SAEs) and Deaths, through the monitoring of relevant clinical and laboratory safety parameters.	From study treatment start date till 30 days safety follow-up, assessed for up to 4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A - Pharmacokinetic of KAE609: Maximum Observed Plasma Concentration (Cmax)	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)
Part A - Pharmacokinetic of KAE609: Time to Reach the Maximum Concentration After Drug Administration (Tmax)	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Tmax was calculated from plasma concentration-time data using non-compartmental methods based on the actual time of sample collection and summarized using descriptive statistics.	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)
Part A - Pharmacokinetic of KAE609: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast)	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. AUClast was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)
Part A - Pharmacokinetic of KAE609: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. AUCinf was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)
Part A - Pharmacokinetic of KAE609: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC0-24hrs)	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. AUC0-24hrs was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)
Part A - Pharmacokinetic of KAE609: Terminal Elimination Half-life (T1/2)	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. T1/2 was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)
Part A - Pharmacokinetic of KAE609: Clearance From Plasma (CL) Following Drug Administration	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. CL was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)
Part A - Pharmacokinetic of KAE609: Apparent Volume of Distribution During Terminal Phase (Vz)	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Vz was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)
Part B - Pharmacokinetic of KAE609: Maximum Observed Plasma Concentration (Cmax)	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.	Days 1 and 5 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)
Part B - Pharmacokinetic of KAE609: Time to Reach the Maximum Concentration After Drug Administration (Tmax)	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Tmax was calculated from plasma concentration-time data using non-compartmental methods based on the actual time of sample collection and summarized using descriptive statistics.	Days 1 and 5 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)
Part B - Pharmacokinetic of KAE609: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast)	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. AUClast was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.	Day 5 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)
Part B - Pharmacokinetic of KAE609: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC0-24hrs)	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. AUC0-24hrs was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.	Days 1 and 5 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)
Part B - Pharmacokinetic of KAE609: Terminal Elimination Half-life (T1/2)	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. T1/2 was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.	Days 1 and 5 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)
Part B - Pharmacokinetic of KAE609: Clearance From Plasma (CL) Following Drug Administration	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. CL was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.	Day 5 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)
Part B - Pharmacokinetic of KAE609: Apparent Volume of Distribution During Terminal Phase (Vz)	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Vz was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.	Day 5 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: Wellcome Trust

Study record dates

Study Major Dates

• Study Start (Actual): July 22, 2020
• Primary Completion (Actual): November 10, 2020
• Study Completion (Actual): November 10, 2020

Study Registration Dates

• First Submitted: March 23, 2020
• First Submitted That Met QC Criteria: March 23, 2020
• First Posted (Actual): March 25, 2020

Study Record Updates

• Last Update Posted (Actual): December 13, 2021
• Last Update Submitted That Met QC Criteria: October 27, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: tolerability; safety; pharmacokinetics; phase 1; iv; healthy volunteers; malaria; Placebo; intravenous; KAE609
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria
• Other Study ID Numbers: CKAE609X2111; 2019-000405-71 (EudraCT Number); 217692/Z/19/Z (Other Grant/Funding Number: Wellcome Trust and EDCTP within the PAMAFRICA Grant)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No