A Phase I Study of AG-348 in Healthy Volunteers

Study Overview
=================
Brief Summary
-----------------
This is a dose escalation study that will be conducted in healthy volunteers. Multiple cohorts of volunteers will receive ascending oral doses of AG-348 to evaluate the safety and tolerability of a single oral dose of AG-348, the pharmacokinetics (PK) of a single dose of AG-348, and the pharmacodynamic profile of AG-348 with specific biomarkers assessed in the blood.

Official Title
-----------------
A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Safety, Pharmacokinetic and Pharmacodynamic Study of Orally Administered AG-348 in Healthy Volunteers

Conditions
-----------------
Healthy Volunteer

Intervention / Treatment
-----------------
* Drug: AG-348
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy adult male or female subjects 18 - 60 years, in good general health who are able to understand consent and complete all study procedures. Female subjects of non-child bearing potential (surgically sterile or post-menopausal as confirmed by age [over 50 years], amenorrhea for 12 consecutive months and FSH). Male subjects who are not vasectomized must agree to use contraception up to 30 days after dosing. Subjects with body weight ≥50 kg; BMI ≥18.5 and ≤32 kg/m2. Subjects who are non-smokers and have not used nicotine containing products for at least 3 months prior to screening. Subjects must be willing to refrain from caffeine- or xanthene containing products (chocolate) prior to dosing through 72 hours after dosing. Subjects must agree to refrain from strenuous exercise prior to admission through final visit. Subjects must refrain from use of alcohol starting 7 days prior to admission through final visit. Subjects must agree not to donate blood products for duration of study participation. Exclusion Criteria: Subjects who have previously received AG-348. Subjects with clinically relevant screening laboratory tests. Female subjects of childbearing potential. Male subjects with QTcF interval ECG > 450 msec,or female subjects with QTcF interval ECG > 470 msec. Subjects with a history of a serious mental illness. Subjects with a clinically relevant medical history or pre-existing medical condition that would interfere with the absorption, metabolism or excretion of the study drug. Subjects with a history of any primary malignancy (cancer). Exceptions are certain skin cancers, cervical cancer in situ or other cancers that have been curatively treated without evidence of disease for a minimum of 1 year. Subjects with glucose-6-phosphate-dehydrogenase (G6PD) deficiency. Subjects who are positive for hepatitis B, hepatitis C or HIV. Subjects who have undergone surgery 6 months prior to screening. Subjects who have a history of illicit drug use or alcoholism within the last year. Subjects who are participating in other concurrent clinical trial of an investigational drug, or have received another investigational agent within the last 2 months. Subjects with any conditions which would make the subject unsuitable for enrollment, or could interfere with the subject's participation in or completion of the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AG-348<br>Single oral dose of AG-348 | Drug: AG-348<br>* A range of doses of AG-348 will be tested based on assessment of safety and tolerability.<br>* Other names: AG-348 will be administered as a single oral dose on Day 1.;|
| Placebo Comparator: Placebo<br>Single oral dose of placebo | Drug: Placebo<br> <br> * Other names: Placebo will be administered as a single oral dose on Day 1.;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | Incidence of adverse events and descriptive statistics for safety laboratory parameters, physical exam findings, vital signs and ECGs. | 11 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of AG-348 | Descriptive statistics will be used to summarize PK parameters of AG-348 for each dose group and, where appropriate, for the entire population. Standard non-compartmental PK parameters will be calculated from individual plasma concentration data. | 4 days | 
| Pharmacodynamic (PD) relationship of AG-348 and metabolic biomarkers | The potential relationship between AG-348 and metabolic biomarkers will be explored with descriptive and graphical methods. Details on the evaluation of exploratory analyses of pyruvate kinase (PKR) activity and other potential PD biomarkers will be described. | 4 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
safety and tolerability, pharmacokinetic study