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Safety, Tolerability and Pharmacokinetics of FTX-6058

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ClinicalTrials.gov Identifier: NCT04586985
Recruitment Status : Recruiting
First Posted : October 14, 2020
Last Update Posted : August 9, 2021
Sponsor:
Information provided by (Responsible Party):
Fulcrum Therapeutics

Brief Summary:
This is a study to evaluate the safety, tolerability and pharmacokinetics of FTX-6058 in healthy adult subjects.

Condition or disease Intervention/treatment Phase
Healthy Adult Subjects Drug: FTX-6058/placebo oral capsule(s) Drug: FTX-6058 oral capsule(s) - Two dosing periods Drug: FTX-6058 oral capsule(s) / Midazolam Syrup Phase 1

Detailed Description:

This study is a Phase 1 randomized, double-blind, placebo-controlled, single- and multiple-dose study evaluating safety, tolerability, and pharmacokinetics, with an open label initial food effect and CYP3A drug-drug interaction study, of FTX-6058 in healthy adult subjects.

This study will comprise 4 parts and will be conducted in healthy adult subjects.

Part A will be a randomized, double-blind, placebo-controlled, single ascending dose (SAD) study in up to 8 cohorts of healthy adult subjects. Part B will be a randomized, double-blind, placebo-controlled, multiple ascending dose (MAD) study in up to 6 cohorts of healthy adult subjects dosed once daily for 14 days. Part C will be an open label pilot food effect study in healthy adult subjects randomized to take FTX-6058 with and without a high-fat meal, and Part D will be an open label study to evaluate the potential of FTX-6058 to induce CYP3A (using midazolam) in healthy adult subjects.

The primary endpoint of the study is to evaluate the safety and tolerability of FTX-6058 in healthy adult subjects as measured by the frequency of adverse events. Secondary endpoints include evaluation of the pharmacokinetics of single dose and multiple dose FTX-6058, assessing target engagement of FTX-6058, evaluation of the potential effect of food on FTX-6058, evaluating the potential for CYP3A induction by FTX-6058 in healthy adult subjects.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 96 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Single ascending dose escalation and multiple ascending dose escalation study followed by an evaluation of food effects on absorption and CYP3A induction
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Randomized double-blind
Primary Purpose: Treatment
Official Title: A Phase 1 Randomized, Double-Blind, Placebo-Controlled, Single-and Multiple-Dose Study Evaluating Safety, Tolerability, and Pharmacokinetics, With an Open Label Initial Food Effect and CYP3A Drug-Drug Interaction Study, of FTX-6058 in Healthy Adult Subjects
Actual Study Start Date : October 26, 2020
Estimated Primary Completion Date : December 19, 2021
Estimated Study Completion Date : December 19, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Midazolam

Arm Intervention/treatment
Experimental: Single ascending dose (SAD) cohorts in healthy subjects (Part A)
Subjects will be randomized to receive a single dose FTX-6058 or placebo. Cohorts 1 and 2 will enroll 5 subjects per cohort randomized 3:2. Cohorts 3-8 will enroll up to 7 subjects per cohort randomized 5:2. Planned doses are 2 mg (Cohort 1), 4 mg (Cohort 2), 10 mg (Cohort 3), 20 mg (Cohort 4), 30 mg (Cohort 5), 40 mg (Cohort 6), 60 mg (Cohort 7), and 90 mg (Cohort 8).
Drug: FTX-6058/placebo oral capsule(s)
Subjects will receive FTX-6058 or matching placebo.

Experimental: Multiple ascending dose (MAD) cohorts in healthy subjects (Part B)
Subjects will be randomized 6:2 to receive once daily FTX-6058 or placebo by mouth for 14 days. Up to 6 cohorts of 8 subjects per cohort will be enrolled. Planned doses are 2 mg (Cohort 1), 6 mg (Cohort 2), 10 mg (Cohort 3), 20 mg (Cohort 4), 30 mg (Cohort 5), and 40 mg (Cohort 6).
Drug: FTX-6058/placebo oral capsule(s)
Subjects will receive FTX-6058 or matching placebo.

Experimental: Pilot Food Effect Cohort in healthy subjects (Part C)

Ten subjects will be randomized to receive two single 20 mg doses of FTX-6058 with and without a high fat meal.

Dosing Period 1: Single dose within 30 minutes of high-fat meal.

Washout Period: Interval of 7 ± 2 days

Dosing Period 2: Single dose without high fat meal.

Drug: FTX-6058 oral capsule(s) - Two dosing periods
Subjects will receive FTX-6058 in two dosing periods

Experimental: Potential for CYP3A Induction Cohort (Part D)
Sixteen subjects will receive 3 mg midazolam once by mouth on Day 1. On Days 3-12, subjects will receive FTX-6058 once daily. On Day 12, 3 mg midazolam will be given once by mouth. The dose of FTX-6058 will be the highest tolerated dose from Part B.
Drug: FTX-6058 oral capsule(s) / Midazolam Syrup
Subjects will receive FTX-6058 and midazolam syrup




Primary Outcome Measures :
  1. Treatment-Emergent Adverse Events [ Time Frame: Up to approximately 4 weeks of monitoring ]
    To evaluate the safety and tolerability of FTX-6058 in healthy adult subjects based on the frequency of adverse events (AEs), frequency of serious adverse events (SAEs), and clinically significant laboratory test results, electrocardiograms (ECGs), and vital signs.


Secondary Outcome Measures :
  1. Plasma Concentrations of FTX-6058 [ Time Frame: Study Part A: Days 1 and 2 ]
    Blood samples will be collected to measure the plasma concentration of FTX-6058 at specified timepoints by liquid chromatography with tandem mass spectrometry.

  2. Plasma Concentrations of FTX-6058 [ Time Frame: Study Part B: Days 1, 2, 7, 8, and 12-15 ]
    Blood samples will be collected to measure the plasma concentration of FTX-6058 at specified timepoints by liquid chromatography with tandem mass spectrometry

  3. Plasma Concentrations of FTX-6058 [ Time Frame: Study Part C: Days 1 and 2 ]
    Blood samples will be collected to measure the plasma concentration of FTX-6058 at specified timepoints by liquid chromatography with tandem mass spectrometry.

  4. Plasma Concentrations of for Midazolam [ Time Frame: Study Part D: Days 1, 2, 12 and 13 ]
    Blood samples will be collected to measure the plasma concentration of Midazolam at specified timepoints by liquid chromatography with tandem mass spectrometry

  5. Plasma Concentrations of for 1-OH-Midazolam [ Time Frame: Study Part D: Days 1, 2, 12 and 13 ]
    Blood samples will be collected to measure the plasma concentration of 1-OH-Midazolam at specified timepoints by liquid chromatography with tandem mass spectrometry.


Other Outcome Measures:
  1. Predictive Model of the Relationship between QTc Interval and FTX-6058 Concentration [ Time Frame: Study Part A: Days 1 and 2 and Study Part B: Days 1, 2, and 7-15 ]
    A model of the relationship between time-match FTX-6058 plasma concentrations QTc intervals may be developed and will include simulations to predict potential QT risk.

  2. Change in F Reticulocytes [ Time Frame: Study Part B: Days 1, 7, 14 and 7-10 days after last dose of study drug. ]
    Change from baseline in the percentage of F reticulocytes, a fetal hemoglobin pharmacodynamic biomarker that may be measured in peripheral whole blood by flow cytometry.

  3. Change in Globin Gene mRNA [ Time Frame: Study Part B: Days 1, 7, 14 and 7-10 days after last dose of study drug. ]
    Change from baseline in the globin gene mRNA, a fetal hemoglobin pharmacodynamic biomarker that may be measured in peripheral whole blood by digital drop polymerase chain reaction (ddPCR).

  4. Target Engagement of FTX-6058 [ Time Frame: Study Part B: Days 1, 2, 7-10 and 14 ]
    Change from baseline in H3K27me3/Total Histone H3 ratio in circulating monocytes will be evaluated by fluorescence-activated cell sorting (FACS).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy male / female subjects, 18 to 55 years of age, inclusive at screening.
  • Good health, based upon the opinion of the investigator and the results of medical history, physical examination, vital signs, ECG, and laboratory profiles of both blood and urine at screening.
  • Body mass index (BMI) between 18 and 32 kg/m2, inclusive at screening, and with a minimum weight of 50 kg.
  • Willingness of men and women of reproductive potential to use two effective means of contraception throughout study participation until 90 days after dose administration.
  • Females with hematocrit >35% and <45% or hemoglobin >11.7/dL and <15.5/dL and males with hematocrit >38.5% and <50% or hemoglobin >13.2/dL and <17.1/dL.
  • Signed and dated written informed consent.
  • Willing and able to comply with all study procedures.

Exclusion Criteria:

  • History of any illness or any clinical condition that, in the opinion of the investigator/subinvestigator, might confound the results of the study or pose an additional risk in administering study drug to the subject. This may include, but is not limited to, history or presence of gastrointestinal conditions including Crohn's disease, ulcerative colitis, frequent episodes of diarrhea, or irritable bowel syndrome; history of relevant drug or food allergies; history of cardiovascular or central nervous system disease; history or presence of clinically significant pathology; clinically significant history of mental disease; concurrent active malignancy; and history of cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical carcinoma in situ (all 3 with no recurrence for the last 5 years).
  • History of febrile illness within 1 week prior to the baseline visit.
  • Acute or chronic history of liver disease or current alanine aminotransferase ≥2 × ULN or total bilirubin >1.5 × ULN at screening (note: subjects with Gilbert's syndrome are permitted to enroll in the trial).
  • Known renal impairment (defined as glomerular filtration rate of <60 mL/min/1.73 m2).
  • Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or antibodies against human immunodeficiency viruses 1 and 2 (HIV1/HIV2 Abs) at screening.
  • Any condition possibly affecting drug absorption (e.g., gastrectomy, cholecystectomy, or other gastrointestinal tract surgery, except appendectomy).
  • Standard 12 lead ECG demonstrating QTcF >450 msec for male subjects and QTcF >470 msec for female subjects at screening. If QTcF exceeds 450 msec for males or 470 msec for females, the ECG will be repeated 2 more times, and the average of the 3 QTcF values will be used to determine the subject's eligibility.
  • History of cardiac dysrhythmias requiring anti-arrhythmia treatment(s) or history or evidence of abnormal ECGs that, in the opinion of the investigator or medical monitor, would preclude the subject's participation in the study.
  • Blood or blood product (e.g., plasma/serum) donation (of approximately 1 pint [500 mL] or more) or any significant loss of blood within 8 weeks prior to screening or intention to donate blood or blood products during the study as determined by the investigator.
  • History of abuse of addictive substances such as drug abuse, or regular user of sedatives, hypnotics, tranquillizers, or any other addictive agent within 6 months prior to screening.
  • History of regular alcohol consumption within 6 months prior to screening defined as:

    • An average weekly intake of greater than 21 units. One unit is equivalent to a 285 mL glass of full-strength beer or 425 mL of light beer or 1 (30 mL) measure of spirits or 1 glass (100 mL) of wine.
  • History of demonstrating an excess in xanthine or caffeine consumption (more than 8 cups of coffee or equivalent per day).
  • Use of another investigational product within 30 days or 5 half-lives (whichever is longer), or according to local regulations, or currently participating in a prospective study with an investigational product or medical device.
  • Use of any medication (prescription or over-the-counter [OTC]) within 14 days of study drug administration, or use of herbal supplements, dietary supplements or multivitamins within 7 days of study drug administration or less than 5 half-lives (whichever is longer), with the exception of paracetamol (up to 3 g/day). Other exceptions will only be made if the rationale is clearly documented by the investigator. Note: Any vaccination, including COVID-19 vaccine, cannot be administered within 14 days prior to initial dose of study drug until the end of study participation.
  • History of sensitivity to the study drug or placebo, or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation.
  • Female subject who is pregnant, trying to become pregnant, or is breastfeeding or male subject whose partner is pregnant, trying to become pregnant, or is breastfeeding.
  • Subject is mentally or legally incapacitated.
  • Abnormal laboratory results indicative of any significant medical disease that, in the opinion of the investigator, would preclude the subject's participation in the study at screening or prior to first dose.
  • Subject, or close relative of the subject, is the investigator or a subinvestigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study at that site.
  • Positive test for drugs of abuse at screening or baseline.
  • Positive test for COVID-19 prior to admission to the study site, as required per local regulations.
  • Subject smokes cigarettes (or equivalent) and/or has used nicotine-based products within 3 months prior to screening. Note: Cotinine test is not required per protocol but may be performed at the discretion of the Investigator to confirm non-smoker status.
  • Consumption of any alcohol within the 48-hour period prior to study drug administration.
  • Plans for hospitalization, surgery, or other major procedures during the study duration or between screening and baseline.
  • Part D only: Any contraindication to the use of midazolam.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04586985


Contacts
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Contact: Call Center 617-651-8853 clinicaltrials@fulcrumtx.com

Locations
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United States, Kansas
Altasciences Clinical Kansas, Inc. Recruiting
Overland Park, Kansas, United States, 66212
Sponsors and Collaborators
Fulcrum Therapeutics
Investigators
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Study Director: John Ziegler, MD, FASA Fulcrum Therapeutics
Publications:
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Responsible Party: Fulcrum Therapeutics
ClinicalTrials.gov Identifier: NCT04586985    
Other Study ID Numbers: FIS-002-2020
First Posted: October 14, 2020    Key Record Dates
Last Update Posted: August 9, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Fulcrum Therapeutics:
Healthy Adult Subjects
Additional relevant MeSH terms:
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Midazolam
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action