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A SAD/MAD to Assess the Safety, PK/PD of FT-4202 in Healthy Volunteers and Sickle Cell Disease Patients

Primary Purpose

Healthy Volunteers, Sickle Cell Disease

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

FT-4202/Placebo

FT-4202

FT-4202/Placebo

FT-4202

About this trial

This is an interventional treatment trial for Healthy Volunteers

Eligibility Criteria

12 Years - 65 Years (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

SCD Key Inclusion Criteria:

Must be between 12 and 65 years of age
Previously diagnosed sickle cell disease (hemoglobin electrophoresis or genotype)
Must have a minimum body weight of 40 kg (88 lbs) at the Screening Visit
Must have the ability to understand and sign written informed consent (and assent where applicable), which must be obtained prior to any study-related procedures being completed
All male and female patients of child bearing potential must agree to use medically accepted contraceptive regimen during study participation and for 90 days after last study drug administration
Must be willing to abide by all study requirements and restrictions

SCD Key Exclusion Criteria:

Had more than 6 episodes of vaso-occlusive crisis (VOC) within the past 12 months that required a hospital, emergency room, or clinic visit
Had a least one episode of acute chest syndrome in the last 6 months
Received any of the following approved therapies for use in SCD:
- Hydroxurea (HU): excluded if started HU < 90 days prior to Day 1 of study treatment
- Adakveo®: excluded if received an infusion within 14 days prior to Day 1 of study treatment
- Oxbryta®: excluded if received a dose within 7 days prior to start of Day 1 of study treatment
Received a red blood cell transfusion within 30 days of starting the study drug
Hemoglobin < 7.0 g/dL or > 10.5 g/dL
Unable to take and absorb oral medications

HEALTHY VOLUNTEER Inclusion Criteria: [NOTE: no longer recruiting subjects for this portion of the study]

Subjects must be between 18 and 60 years of age
Subjects must have the ability to understand and sign written informed consent, which must be obtained prior to any study-related procedures being completed
Subjects must be in general good health, based upon the results of medical history, a physical examination, vital signs, laboratory profile, and a 12-lead ECG
All males and females of child bearing potential must agree to use medically accepted contraceptive regimen during study participation and up to 90 days after
Subjects must be willing to abide by all study requirements and restrictions

HEALTHY VOLUNTEER Exclusion Criteria: [NOTE: no longer recruiting subjects for this portion of the study]

Evidence of clinically significant medical condition or other condition that might significantly interfere with the absorption, distribution, metabolism, or excretion of study drug, or place the subject at an unacceptable risk as a participant in this study
History of clinically significant cardiac diseases including condition disturbances
Abnormal hematologic, renal and liver function studies
History of drug or alcohol abuse

Sites / Locations

Woodland International Research Group (SCD subjects only)
Collaborative Neuroscience Research, LLC (SCD subjects only)
Pacific Research Partners (SCD subjects only)
UCSF Benioff Children's Hospital Oakland (SCD subjects only)
Advanced Pharma CR, LLC (SCD subjects only)
Children's Healthcare of Atlanta (SCD subjects only)
Augusta University Medical Center (SCD subjects only)
University of Illinois at Chicago (SCD subjects only)
University of Maryland, Greenebaum Comprehensive Cancer Center (SCD subjects only)
Columbia University Medical Center (SCD subjects only)
Levine Cancer Institute (SCD subjects only)
Duke University Medical Center (SCD subjects only)
University of Cincinnati Medical Center (SCD subjects only)
Medpace Clinical Pharmacology Unit (Healthy Volunteers only)
Cincinnati Children's Hospital Medical Center (SCD subjects only)
Lynn Institute of Tulsa (SCD subjects only)
St. Jude Children's Research Hospital (SCD subjects only)
The University of Texas Health Science Center at Houston (SCD subjects only)

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Arm Label

Single ascending dose cohorts in healthy subjects

Multiple ascending dose cohorts in healthy subjects

Food Effect Cohort in healthy subjects

Single ascending dose cohorts in SCD subjects

Multiple ascending dose cohorts in SCD subjects

12-week dosing cohort in SCD subjects

Arm Description

Healthy volunteer subject cohorts randomized 6:2 receiving a single dose of FT-4202 or placebo. The first cohort will receive 200 mg of FT-4202 or placebo. Dose escalation will occur if FT-4202 or placebo is tolerated. The maximum dose of FT-4202 or placebo will be 1500 mg.

Healthy volunteer subject cohorts randomized 9:3 to receive FT-4202 or placebo for 14 days continuous dosing. The first cohort will receive 100 mg of FT-4202 or placebo daily X 14 days. The maximum dose of FT-4202/placebo will be 600 mg FT-4202/placebo daily for 14 days.

Health Volunteer subject cohort of 10 subjects who will receive a single dose of FT-4202 with food and without food. Dose will be administered per the protocol defined dose.

Sickle cell disease subject cohort randomized 6:2 receiving a single dose of FT-4202 or placebo. The dose of FT-4202/placebo administered will be a dose that was found to be safe in healthy subjects.

Sickle cell disease subject cohorts randomized 9:3 to receive FT-4202 or placebo for 14 days continuous dosing. The dose of FT-4202/placebo administered will be a dose less than the maximum tolerable dose evaluated in MAD healthy volunteers.

Sickle cell disease subjects cohort to receive up to 84 consecutive daily doses of open-label FT-4202. The dose of FT-4202 administered will not exceed the highest dose evaluated in the MAD SCD subject cohorts

Outcomes

Primary Outcome Measures

Incidence, frequency, and severity of adverse events (AEs) per CTCAE v5.0 of a single ascending dose and multiple ascending doses of FT-4202 in adult healthy volunteers and SCD patients.

Maximum observed plasma concentration (Cmax)

Time to maximum observed plasma concentration (Tmax)

Area under the plasma concentration-time curve from time zero until the 24-hour time point (AUC0-24)

Area under the plasma concentration-time curve from time zero until the last quantifiable time point (AUC0-last)

Area under the plasma concentration-time curve from time zero to infinity (AUC0-inf)

Terminal elimination half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (Vd/F)

Terminal disposition rate constant (Lz)

Renal clearance (ClR)

Secondary Outcome Measures

Change from baseline in the levels of 2,3-diphosphoglycerate (DPG) and adenosine triphosphate (ATP) in the red blood cells (RBCs) of healthy volunteers and SCD patients after single and multiple doses of FT-4202.

Model-based estimate of change from baseline QT interval corrected using Fridericia's correction formula (QTcF) and 90% confidence interval at the estimated Cmax after a single dose of FT-4202 in healthy volunteers

Change from baseline heart rate after a single dose of FT-4202 in healthy volunteers

Change from baseline PR after a single dose of FT-4202 in healthy volunteers

Change from baseline QRS after a single dose of FT-4202 in healthy volunteers

Change from baseline T-wave morphology after a single dose of FT-4202 in healthy volunteers

Full Information

NCT ID

NCT03815695

First Posted

December 21, 2018

Last Updated

July 13, 2022

Sponsor

Novo Nordisk A/S

Collaborators

Medpace, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT03815695

Brief Title

A SAD/MAD to Assess the Safety, PK/PD of FT-4202 in Healthy Volunteers and Sickle Cell Disease Patients

Official Title

A Randomized, Placebo-controlled, Double Blind, Single Ascending and Multiple Ascending Dose Study to Assess the Safety, Pharmacokinetics and Pharmacodynamics of FT-4202 in Healthy Volunteers and Sickle Cell Disease Patients

Study Type

Interventional

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Completed

Study Start Date

December 11, 2018 (Actual)

Primary Completion Date

December 17, 2021 (Actual)

Study Completion Date

December 17, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novo Nordisk A/S

Collaborators

Medpace, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

FT-4202 is an oral small-molecule agonist of pyruvate kinase red blood cell isozyme (PKR) being developed for the treatment of hemolytic anemias. This initial study will characterize the safety, tolerability and the pharmacokinetics/pharmacodynamics (PK/PD) of a single ascending dose and multiple ascending doses of FT-4202 in the context of Phase 1 studies in healthy volunteers and sickle cell disease patients. The effects of food on the absorption of FT-4202 will also be evaluated in healthy volunteers.

Detailed Description

This is a first-in-human (FIH), Phase 1 study of FT-4202 that will characterize the safety, PK and PD of FT-4202 after a single dose and after repeated dosing first in healthy adult volunteers and then in adolescents or adults with sickle cell disease (SCD). Initially, a dose range of FT-4202 in single ascending dose (SAD) escalation cohorts will be explored in healthy subjects. Enrollment of healthy subjects into 2-week multiple ascending dose (MAD) escalation cohorts will be initiated once the safety and PK from at least two SAD cohorts is available to inform the doses for the 2-week MAD portion of the study. The MAD cohorts will then run in parallel to the single dose cohorts. A single dose cohort of healthy subjects is planned to understand food effects (FE) on the PK of FT-4202. After the SAD and FE studies in healthy subjects are completed, the safety, PK, and PD of a single dose of FT-4202 that was found to be safe in healthy subjects will then be evaluated in SCD subjects. Multiple dose studies in SCD subjects will then be initiated upon completion of MAD studies in healthy volunteers.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Healthy Volunteers, Sickle Cell Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Model Description

Single ascending dose escalation and multiple ascending dose escalation study followed by an evaluation of food effects on absorption

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

randomized double blind

Allocation

Randomized

Enrollment

130 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Single ascending dose cohorts in healthy subjects

Arm Type

Experimental

Arm Description

Arm Title

Multiple ascending dose cohorts in healthy subjects

Arm Type

Experimental

Arm Description

Arm Title

Food Effect Cohort in healthy subjects

Arm Type

Experimental

Arm Description

Health Volunteer subject cohort of 10 subjects who will receive a single dose of FT-4202 with food and without food. Dose will be administered per the protocol defined dose.

Arm Title

Single ascending dose cohorts in SCD subjects

Arm Type

Experimental

Arm Description

Sickle cell disease subject cohort randomized 6:2 receiving a single dose of FT-4202 or placebo. The dose of FT-4202/placebo administered will be a dose that was found to be safe in healthy subjects.

Arm Title

Multiple ascending dose cohorts in SCD subjects

Arm Type

Experimental

Arm Description

Arm Title

12-week dosing cohort in SCD subjects

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

FT-4202/Placebo

Intervention Description

Healthy volunteer subjects will receive FT-4202/placebo and monitored for side effects while undergoing pharmacokinetics and pharmacodynamic studies

Intervention Type

Drug

Intervention Name(s)

FT-4202

Intervention Description

Healthy volunteer subjects will receive FT-4202 with or without food and undergo pharmacokinetic studies

Intervention Type

Drug

Intervention Name(s)

FT-4202/Placebo

Intervention Description

SCD subjects will receive FT-4202/placebo and monitored for side effects while undergoing pharmacokinetics and pharmacodynamic studies

Intervention Type

Drug

Intervention Name(s)

FT-4202

Intervention Description

SCD subjects will receive FT-4202 and monitored for side effects while undergoing pharmacokinetics and pharmacodynamic studies

Primary Outcome Measure Information:

Title

Incidence, frequency, and severity of adverse events (AEs) per CTCAE v5.0 of a single ascending dose and multiple ascending doses of FT-4202 in adult healthy volunteers and SCD patients.

Time Frame

Up to 3 weeks of monitoring

Title

Maximum observed plasma concentration (Cmax)

Time Frame

Up to 3 weeks of testing

Title

Time to maximum observed plasma concentration (Tmax)

Time Frame

Up to 3 weeks of testing

Title

Area under the plasma concentration-time curve from time zero until the 24-hour time point (AUC0-24)

Time Frame

Up to 3 weeks of testing

Title

Area under the plasma concentration-time curve from time zero until the last quantifiable time point (AUC0-last)

Time Frame

Up to 3 weeks of testing

Title

Area under the plasma concentration-time curve from time zero to infinity (AUC0-inf)

Time Frame

Up to 3 weeks of testing

Title

Terminal elimination half-life (t1/2)

Time Frame

Up to 3 weeks of testing

Title

Apparent clearance (CL/F)

Time Frame

Up to 3 weeks of testing

Title

Apparent volume of distribution (Vd/F)

Time Frame

Up to 3 weeks of testing

Title

Terminal disposition rate constant (Lz)

Time Frame

Up to 3 weeks of testing

Title

Renal clearance (ClR)

Time Frame

Up to 3 weeks of testing

Secondary Outcome Measure Information:

Title

Time Frame

Up to 3 weeks of testing

Title

Time Frame

up to 7 days

Title

Change from baseline heart rate after a single dose of FT-4202 in healthy volunteers

Time Frame

up to 7 days

Title

Change from baseline PR after a single dose of FT-4202 in healthy volunteers

Time Frame

up to 7 days

Title

Change from baseline QRS after a single dose of FT-4202 in healthy volunteers

Time Frame

up to 7 days

Title

Change from baseline T-wave morphology after a single dose of FT-4202 in healthy volunteers

Time Frame

up to 7 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

12 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

SCD Key Inclusion Criteria: Must be between 12 and 65 years of age Previously diagnosed sickle cell disease (hemoglobin electrophoresis or genotype) Must have a minimum body weight of 40 kg (88 lbs) at the Screening Visit Must have the ability to understand and sign written informed consent (and assent where applicable), which must be obtained prior to any study-related procedures being completed All male and female patients of child bearing potential must agree to use medically accepted contraceptive regimen during study participation and for 90 days after last study drug administration Must be willing to abide by all study requirements and restrictions SCD Key Exclusion Criteria: Had more than 6 episodes of vaso-occlusive crisis (VOC) within the past 12 months that required a hospital, emergency room, or clinic visit Had a least one episode of acute chest syndrome in the last 6 months Received any of the following approved therapies for use in SCD: Hydroxurea (HU): excluded if started HU < 90 days prior to Day 1 of study treatment Adakveo®: excluded if received an infusion within 14 days prior to Day 1 of study treatment Oxbryta®: excluded if received a dose within 7 days prior to start of Day 1 of study treatment Received a red blood cell transfusion within 30 days of starting the study drug Hemoglobin < 7.0 g/dL or > 10.5 g/dL Unable to take and absorb oral medications HEALTHY VOLUNTEER Inclusion Criteria: [NOTE: no longer recruiting subjects for this portion of the study] Subjects must be between 18 and 60 years of age Subjects must have the ability to understand and sign written informed consent, which must be obtained prior to any study-related procedures being completed Subjects must be in general good health, based upon the results of medical history, a physical examination, vital signs, laboratory profile, and a 12-lead ECG All males and females of child bearing potential must agree to use medically accepted contraceptive regimen during study participation and up to 90 days after Subjects must be willing to abide by all study requirements and restrictions HEALTHY VOLUNTEER Exclusion Criteria: [NOTE: no longer recruiting subjects for this portion of the study] Evidence of clinically significant medical condition or other condition that might significantly interfere with the absorption, distribution, metabolism, or excretion of study drug, or place the subject at an unacceptable risk as a participant in this study History of clinically significant cardiac diseases including condition disturbances Abnormal hematologic, renal and liver function studies History of drug or alcohol abuse

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Patrick Kelly, MD

Organizational Affiliation

Novo Nordisk A/S

Official's Role

Study Director

Facility Information:

Facility Name

Woodland International Research Group (SCD subjects only)

City

Little Rock

State/Province

Arkansas

ZIP/Postal Code

72211

Country

United States

Facility Name

Collaborative Neuroscience Research, LLC (SCD subjects only)

City

Long Beach

State/Province

California

ZIP/Postal Code

90806

Country

United States

Facility Name

Pacific Research Partners (SCD subjects only)

City

Oakland

State/Province

California

ZIP/Postal Code

94607

Country

United States

Facility Name

UCSF Benioff Children's Hospital Oakland (SCD subjects only)

City

Oakland

State/Province

California

ZIP/Postal Code

94609

Country

United States

Facility Name

Advanced Pharma CR, LLC (SCD subjects only)

City

Miami

State/Province

Florida

ZIP/Postal Code

33147

Country

United States

Facility Name

Children's Healthcare of Atlanta (SCD subjects only)

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30342

Country

United States

Facility Name

Augusta University Medical Center (SCD subjects only)

City

Augusta

State/Province

Georgia

ZIP/Postal Code

30912

Country

United States

Facility Name

University of Illinois at Chicago (SCD subjects only)

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60612

Country

United States

Facility Name

University of Maryland, Greenebaum Comprehensive Cancer Center (SCD subjects only)

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21201

Country

United States

Facility Name

Columbia University Medical Center (SCD subjects only)

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

Facility Name

Levine Cancer Institute (SCD subjects only)

City

Charlotte

State/Province

North Carolina

ZIP/Postal Code

28204

Country

United States

Facility Name

Duke University Medical Center (SCD subjects only)

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27710

Country

United States

Facility Name

University of Cincinnati Medical Center (SCD subjects only)

City

Cincinnati

State/Province

Ohio

ZIP/Postal Code

45219

Country

United States

Facility Name

Medpace Clinical Pharmacology Unit (Healthy Volunteers only)

City

Cincinnati

State/Province

Ohio

ZIP/Postal Code

45227

Country

United States

Facility Name

Cincinnati Children's Hospital Medical Center (SCD subjects only)

City

Cincinnati

State/Province

Ohio

ZIP/Postal Code

45229

Country

United States

Facility Name

Lynn Institute of Tulsa (SCD subjects only)

City

Tulsa

State/Province

Oklahoma

ZIP/Postal Code

74135

Country

United States

Facility Name

St. Jude Children's Research Hospital (SCD subjects only)

City

Memphis

State/Province

Tennessee

ZIP/Postal Code

38105

Country

United States

Facility Name

The University of Texas Health Science Center at Houston (SCD subjects only)

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

35019238

Citation

Forsyth S, Schroeder P, Geib J, Vrishabhendra L, Konstantinidis DG, LaSalvia K, Ribadeneira MD, Wu E, Kelly P, Kalfa TA. Safety, Pharmacokinetics, and Pharmacodynamics of Etavopivat (FT-4202), an Allosteric Activator of Pyruvate Kinase-R, in Healthy Adults: A Randomized, Placebo-Controlled, Double-Blind, First-in-Human Phase 1 Trial. Clin Pharmacol Drug Dev. 2022 May;11(5):654-665. doi: 10.1002/cpdd.1058. Epub 2022 Jan 12.

Results Reference

derived

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A SAD/MAD to Assess the Safety, PK/PD of FT-4202 in Healthy Volunteers and Sickle Cell Disease Patients

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