Clinical trial NCT02149966: A Phase I Study of AG-348 in Healthy Volunteers
Official title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose, Safety, Pharmacokinetic, and Pharmacodynamic Study of Orally Administered AG-348 in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteer
Keywords: safety and tolerability
pharmacokinetic study
Lead sponsor: Agios Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2014-05-29
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a dose escalation study that will be conducted in healthy volunteers. Multiple cohorts of volunteers will receive ascending (increasingly higher) oral doses of AG-348 daily for 14 days to evaluate the safety and tolerability of multiple oral doses of AG-348, the pharmacokinetics (PK) of multiple doses of AG-348, and the pharmacodynamic profile of AG-348 with specific biomarkers assessed in the blood.


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 (coffee, tea, chocolate) for 48 hours prior to dosing through discharge from the clinical facility.
* Subjects must agree to refrain from strenuous exercise starting 72 hours prior to admission through final follow-up visit.
* Subjects must refrain from use of alcohol starting 7 days (14 days for red wine) prior to admission through final follow-up 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 who are not post-menopausal.
* Subjects with recent use of prescription, over the counter (OTC), herbal and/or dietary medications and/or supplements.
* 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.

Primary outcomes:
measure: Incidence of adverse events
timeFrame: 29 days
Secondary outcomes:
measure: Pharmacokinetics parameters of AG-348
timeFrame: 17 days
measure: Pharmacodynamic (PD) relationship of AG-348 and metabolic biomarkers
timeFrame: 17 days
Other outcomes:
Locations:
city: Baltimore,
country: United States
state: Maryland
Study officials:
affiliation: Agios Pharmaceuticals, Inc.
name: Samuel Agresta, MD, MPH & TM
role: STUDY_DIRECTOR
References:
citation: Yang H, Merica E, Chen Y, Cohen M, Goldwater R, Kosinski PA, Kung C, Yuan ZJ, Silverman L, Goldwasser M, Silver BA, Agresta S, Barbier AJ. Phase 1 Single- and Multiple-Ascending-Dose Randomized Studies of the Safety, Pharmacokinetics, and Pharmacodynamics of AG-348, a First-in-Class Allosteric Activator of Pyruvate Kinase R, in Healthy Volunteers. Clin Pharmacol Drug Dev. 2019 Feb;8(2):246-259. doi: 10.1002/cpdd.604. Epub 2018 Aug 9.