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

Phase 1

Completed

• Conditions: Malaria
• Interventions: Drug: KAE609; Drug: Placebo

• Registration Number: NCT04321252
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

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.

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 Timeline

• Study First Submitted: 2020-03-23
• Study First Submitted QC: 2020-03-23
• Study First Posted: 2020-03-25
• Study Start: 2020-07-22
• Primary Completion: 2020-11-10
• Study Completion: 2020-11-10
• Status Verified: 2021-10
• Results First Submitted: 2021-10-27
• Results First Submitted QC: 2021-10-27
• Last Update Submitted: 2021-10-27
• Results First Posted: 2021-12-13
• Last Update Posted: 2021-12-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 57

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort B1: 60 mg/placebo, every 24 hours (q24h) × 5 days	Placebo	Multiple iv bolus doses of KAE609 or placebo administered at the clinical site by the study personnel.
Cohort A1: 10.5 mg/placebo	KAE609	Single iv bolus dose of KAE609 or placebo administered at the clinical site by the study personnel.
Cohort A1: 10.5 mg/placebo	Placebo	Single iv bolus dose of KAE609 or placebo administered at the clinical site by the study personnel.
Cohort A2: 30 mg/placebo	KAE609	Single iv bolus dose of KAE609 or placebo administered at the clinical site by the study personnel.
Cohort A2: 30 mg/placebo	Placebo	Single iv bolus dose of KAE609 or placebo administered at the clinical site by the study personnel.
Cohort A3: 75 mg/placebo	KAE609	Single iv infusion dose of KAE609 or placebo administered at the clinical site by the study personnel.
Cohort A3: 75 mg/placebo	Placebo	Single iv infusion dose of KAE609 or placebo administered at the clinical site by the study personnel.
Cohort A4: 120 mg/placebo	KAE609	Single iv infusion dose of KAE609 or placebo administered at the clinical site by the study personnel.
Cohort B1: 60 mg/placebo, every 24 hours (q24h) × 5 days	KAE609	Multiple iv bolus doses of KAE609 or placebo administered at the clinical site by the study personnel.
Cohort A4: 120 mg/placebo	Placebo	Single iv infusion dose of KAE609 or placebo administered at the clinical site by the study personnel.
Cohort A5: 210 mg/placebo	KAE609	Single iv infusion dose of KAE609 or placebo administered at the clinical site by the study personnel.
Cohort A5: 210 mg/placebo	Placebo	Single iv infusion dose of KAE609 or placebo administered at the clinical site by the study personnel.
Cohort B2: 120 mg/placebo, every 24 hours (q24h) × 5 days	KAE609	Multiple iv infusion doses of KAE609 or placebo administered at the clinical site by the study personnel.
Cohort B2: 120 mg/placebo, every 24 hours (q24h) × 5 days	Placebo	Multiple iv infusion doses of KAE609 or placebo administered at the clinical site by the study personnel.

Primary Outcome Measures

Name	Time	Method
Number of Participants With On-Treatments Adverse Events, Serious Adverse Events, and Deaths	From study treatment start date till 30 days safety follow-up, assessed for up to 4 months	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.

Secondary Outcome Measures

Name	Time	Method
Part A - Pharmacokinetic of KAE609: Maximum Observed Plasma Concentration (Cmax)	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.
Part A - Pharmacokinetic of KAE609: Time to Reach the Maximum Concentration After Drug Administration (Tmax)	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.
Part A - Pharmacokinetic of KAE609: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast)	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.
Part A - Pharmacokinetic of KAE609: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.
Part A - Pharmacokinetic of KAE609: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC0-24hrs)	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.
Part A - Pharmacokinetic of KAE609: Terminal Elimination Half-life (T1/2)	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.
Part A - Pharmacokinetic of KAE609: Clearance From Plasma (CL) Following Drug Administration	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.
Part A - Pharmacokinetic of KAE609: Apparent Volume of Distribution During Terminal Phase (Vz)	Day 1 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.
Part B - Pharmacokinetic of KAE609: Maximum Observed Plasma Concentration (Cmax)	Days 1 and 5 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.
Part B - Pharmacokinetic of KAE609: Time to Reach the Maximum Concentration After Drug Administration (Tmax)	Days 1 and 5 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.
Part B - Pharmacokinetic of KAE609: Terminal Elimination Half-life (T1/2)	Days 1 and 5 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.
Part B - Pharmacokinetic of KAE609: Clearance From Plasma (CL) Following Drug Administration	Day 5 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.
Part B - Pharmacokinetic of KAE609: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast)	Day 5 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.
Part B - Pharmacokinetic of KAE609: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC0-24hrs)	Days 1 and 5 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.
Part B - Pharmacokinetic of KAE609: Apparent Volume of Distribution During Terminal Phase (Vz)	Day 5 (-1 hr, 2 min, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 12 hr)	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.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇧🇪 Antwerpen, Belgium