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Hepatic ImpairmentPhase 1NCT03627754

A Study to Evaluate the Effect of Hepatic Impairment on the Pharmacokinetics of Glasdegib

A Phase 1 study testing Glasdegib 100 mg single oral dose in people with Hepatic Impairment, run by Pfizer at 3 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This is a Phase 1, open-label, parallel group, single dose study to investigate the effect of moderate or severe hepatic impairment on the PK of glasdegib, compared to subjects with normal hepatic function. Read more about this study

Who is it for?
Ages 18 to 75 yearsHealthy volunteers can take part
Conditions the study is for
Hepatic Impairment
What is being tested?
Glasdegib 100 mg single oral dose
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
24 participants
Where
3 sitesUnited States
Study dates
5 Nov 2018to 11 Apr 2019
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • Healthy or hepatically impaired female subjects of non-child bearing potential and/or male subjects who, at the time of Screening, are between the ages of 18 and 75 years, inclusive.
  • Female subjects of nonchildbearing potential must meet at least 1 of the following criteria:
  • Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; with a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
  • Have undergone a documented hysterectomy and/or bilateral oophorectomy;
  • Have medically confirmed ovarian failure. All other female subjects (including females with tubal ligations) are considered to be of childbearing potential.
  • Body mass index (BMI) of 17.5 to 40 kg/m2; and a total body weight >50 kg (110 lb).
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  • Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
  • Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures.
  • Additional Inclusion Criteria for Subjects With Normal Hepatic Function:
  • Subjects in the normal hepatic function cohort (Cohort 3) must be considered healthy and meet all of the following additional inclusion criteria to be eligible for enrollment into the study:
  • No known or suspected hepatic impairment based on liver function tests, albumin and prothrombin time, defined as the following:
  • ALT and AST <= upper limit of normal (ULN);
  • Total bilirubin <= 1.5 × ULN; subjects with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is not greater than 0.5 mg/dL;
  • Alkaline phosphatase <= ULN;
  • Albumin within the normal range (local lab ranges);
  • Prothrombin time (PT) within the normal range (local lab ranges).
  • Subjects must fit the demographic-matching criteria, including:
  • A total body weight that is +/- 10 kg of the population median of the pooled hepatic impairment cohorts (Cohorts 1 and 2).
  • An age that is +/- 5 years of the population median of the pooled hepatic impairment cohorts (Cohorts 1 and 2).
  • No known or suspected hepatic impairment.
  • Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure (BP) and pulse rate (PR) measurement, 12 lead ECG or clinical laboratory tests.
  • Additional Inclusion Criteria for Subjects with Impaired Hepatic Function:
  • Subjects in the hepatic impairment cohorts (Cohorts 1 and 2) must meet the following additional inclusion criteria to be eligible for enrollment into the trial:
  • Satisfy the criteria for Class B, or C of the modified Child-Pugh Classification.
  • A diagnosis of hepatic dysfunction due to hepatocellular disease (and not secondary to any acute ongoing hepatocellular process) documented by medical history, physical examination, liver biopsy, hepatic ultrasound, computerized tomography (CT) scan, or magnetic resonance imaging (MRI).
  • Known stable hepatic impairment, defined as no evidence of clinically significant change in disease status within the last 30 days, as documented by the subject's recent medical history (eg, no worsening clinical signs of hepatic impairment, or no worsening of total bilirubin or prothrombin time by more than 50%).
  • Stable drug regimen defined as not starting a new drug or changing dosage within seven days or five half-lives (whichever is longer) prior to the dosing of investigational product. History of alcohol abuse is permissible providing that the results of alcohol test are negative at Screening and on Day -1, and the subject is willing and able to abide by the lifestyle guidelines.

Who cannot join

  • Any condition possibly affecting drug absorption (eg, gastrectomy).
  • A positive urine drug test. Subjects with hepatic impairment (Cohorts 1 and 2) will be eligible to participate if their urine drug test is positive with a drug for a prescribed substance that is not expected to interfere with the PK of glasdegib.
  • Pregnant female subjects; breastfeeding female subjects; fertile male subjects who are unwilling or unable to use at least one highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 90 days after the glasdegib dose and, refrain from sperm donation for the duration of the Study and for at least 90 days after the glasdegib dose.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • Blood donation of approximately 1 pint (500 mL) or more within 56 days prior to dosing.
  • Unwilling or unable to comply with the Lifestyle Requirements.
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  • Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees directly involved in the conduct of the study.
  • History of known sensitivity to glasdegib.
  • Treatment with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives preceding the dose of glasdegib (whichever is longer).
  • Subjects with a history of or current positive results for human immunodeficiency virus (HIV).
  • Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
  • Additional Exclusion Criteria for Subjects with Normal Hepatic Function:
  • In addition, subjects in the normal hepatic function cohort (Cohort 3) presenting with any of the following will not be included in the trial:
  • Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies deemed relevant for participation in this study, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
  • History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) within 6 months of Screening.
  • Screening supine BP => 140 mm Hg (systolic) or => 90 mm Hg (diastolic), following at least 5 minutes of supine rest. If BP is => 140 mm Hg (systolic) or => 90 mm Hg (diastolic), the BP should be repeated two more times and the average of the three BP values should be used to determine the subject's eligibility.
  • 12-lead ECG demonstrating QTcF >450 msec or a QRS interval >120 msec at Screening. If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated two more times and the average of the three QTcF or QRS values should be used to determine the subject's eligibility.
  • Use of prescription or nonprescription drugs and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of lasdegib. As an exception, acetaminophen/paracetamol may be used at doses of =<1 g/day. Limited use of nonprescription medications that are not believed to affect subject safety or the overall results of the study may be permitted on a case by case basis following approval by the sponsor. Herbal supplements and hormone replacement therapy must have been discontinued at least 28 days prior to the dose of investigational product.
  • Subjects with a history of or current positive results for hepatitis B or hepatitis C, including hepatitis B surface antigen (HepBsAg), hepatitis B core antibody (HepBcAb), or hepatitis C antibody (HCVAb).
  • Additional Exclusion Criteria for Subjects With Impaired Hepatic Function:
  • In addition, subjects in the hepatic impairment cohorts (Cohorts 1 and 2) presenting with any of the following will not be included in the trial:
  • Other clinically significant disease that contraindicates study drug or that may affect the PK of glasdegib (stable, chronic, controlled disorders such as hypertension and diabetes may be acceptable).
  • Hepatic carcinoma and hepatorenal syndrome or life expectancy <1 year.
  • Undergone porta-caval shunt surgery. NOTE: Subjects with a transjugular intrahepatic portosystemic shunt (TIPS) are permitted provided that they meet the Child-Pugh Classification criteria
  • History of gastrointestinal hemorrhage either due to esophageal varices or peptic ulcers less than one month prior to study entry.
  • Any clinically significant laboratory abnormality except for those parameters influenced by hepatic impairment. Due to potential for alteration of hepatic function in renally impaired patients, subjects must have an estimated glomerular filtration rate (eGFR) corrected for their body surface area of => 75 mL/min based on the Modification of Diet in Renal Disease (MDRD) equation, with a single repeat permitted to assess eligibility, if needed.
  • Presence of clinically active stage 3 or 4 encephalopathy.
  • Severe uncontrolled ascites and/or pleural effusion.
  • Screening blood pressure => 160 mm Hg (systolic) or => 90 mm Hg (diastolic), following at least 5 minutes of supine rest. If initial BP is => 160 mm Hg (systolic) or => 90 mm Hg (diastolic), the BP should be repeated two more times and the average of the three BP values should be used to determine the subject's eligibility.
  • Screening supine 12-lead ECG demonstrating QTcF >470 msec or a QRS interval >120 msec. If initial QTcF exceeds 470 msec, or QRS exceeds 120 msec, the ECG should be repeated two more times and the average of the three QTcF or QRS values should be used to determine the subject's eligibility.
  • Use of food, drugs, or dietary supplements that may affect the PK of glasdegib within 7 days or 5 half-lives (whichever is longer) prior to the dose of glasdegib. Use of medications that are not believed to affect subject safety and are medically necessary for the treatment and maintenance of hepatic disease and other pre-existing and/or concurrent stable comorbid conditions are permitted with approval by the sponsor. Limited use of nonprescription medications that are not believed to affect subject safety or the overall results of the study may be permitted on a case by case basis with approval by the sponsor. Herbal supplements and hormone replacement therapy must have been discontinued at least 28 days prior to the dose of investigational product.
  • Concurrent use of any of the following food or drugs known to inhibit CYP3A4 (consult the sponsor if in doubt whether a food or a drug falls into any of the above categories) within 7 days or 5 half-lives (whichever is longer) prior to the dose of glasdegib, until the completion of the last PK sample collection. Use of strong or moderate CYP3A4 inhibitors includes but is not limited to: amprenavir, aprepitant, atazanavir, boceprevir, ciprofloxacin, clarithromycin, conivaptan, darunavir, delavirdine, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, verapamil, voriconazole, grapefruit juice or grapefruit/grapefruit-related citrus fruits (eg, Seville oranges, pomelos). The topical use of these medications (if applicable), such as 2% ketoconazole cream, is allowed. All concomitant medications must be approved by the sponsor.
  • Concurrent use of any of the following food or drugs known to induce CYP3A4 (consult the sponsor if in doubt whether a food or a drug falls into any of the above categories) within 12 days or 5 half-lives (whichever is longer) prior to the dose of investigational product, until the completion of the last PK sample collection. Strong or moderate CYP3A4 inducers includes but is not limited to: avasimibe, bosentan, carbamazepine, efavirenz, etravirine, felbamate, modafinil, nafcillin, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John's wort. All concomitant medication must be approved by the sponsor.
  • Subjects with congenital long QT syndrome, medical history of Torsades de Pointes or clinically significant ventricular arrhythmias.
  • Use of PPIs, including but not limited to esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole, within 5 days prior to the day of glasdegib dose (Day 1).
  • Subjects will abstain from taking lactulose or other medications which could result in diarrhea or have excessive (>2) bowel movements per day within 12 hours prior to glasdegib dosing and 12 hours post dosing.

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • Investigational Drug Services (IDS) University of Miami Hospitals and Clinics, Research Pharmacy

    Miami, Florida, 33136

  • University of Miami Division of Clinical Pharmacology

    Miami, Florida, 33136

  • Orlando Clinical Research Center

    Orlando, Florida, 32809

Other trials in United States

About this study

Official title: A PHASE 1, OPEN LABEL, SINGLE DOSE, PARALLEL GROUP STUDY TO EVALUATE THE PLASMA PHARMACOKINETICS OF GLASDEGIB (PF-04449913) IN HEALTHY SUBJECTS WITH NORMAL HEPATIC FUNCTION AND IN SUBJECTS WITH IMPAIRED HEPATIC FUNCTION

This is a Phase 1, open-label, parallel group, single dose study to investigate the effect of moderate or severe hepatic impairment on the PK of glasdegib, compared to subjects with normal hepatic function.

Read the detailed description

This is a Phase 1, open-label, parallel group, single dose study to investigate the effect of hepatic impairment on the PK of glasdegib after administration of a single oral 100 mg dose. Subjects with moderate or severe hepatic impairment will be enrolled, followed by healthy subjects with normal hepatic function who serve as matched controls.

Being tested
Glasdegib 100 mg single oral dose
Keywords
Glasdegib, PF-04449913, Pharmacokinetics, Hepatic Impairment

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Glasdegib 100 mg single oral doseDrug

    A single dose of 100 mg glasdegib tablet will be administered after an overnight fast, followed by serial PK collection, discharge and follow-up.

Study groups in NCT03627754
Study groupRoleWhat they receive
Moderate Hepatic Impairment GroupExperimentalSubjects with Child-Pugh Classification B (score 7-9)
Receives: Drug: Glasdegib 100 mg single oral dose
Severe Hepatic Impairment GroupExperimentalSubjects with Child-Pugh Classification C (score 10-15)
Receives: Drug: Glasdegib 100 mg single oral dose
Normal Hepatic Function GroupExperimentalHealthy subjects with normal hepatic function
Receives: Drug: Glasdegib 100 mg single oral dose

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Area under the plasma concentration-time curve from time 0 to infinity (AUCinf) of glasdegib

    PK parameter of glasdegib to be calculated from the plasma concentration-time data

    Measured: Day 1 to Day 6

  2. Maximum observed plasma concentration (Cmax) of glasdegib

    PK parameter of glasdegib to be calculated from the plasma concentration-time data

    Measured: Day 1

Secondary outcomes (4)

  1. Incidence of adverse events

    Safety and tolerability of glasdegib, including monitoring of adverse events (AE) and addition of concomitant medications; an AE is any untoward medical occurrence in a study subject administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage

    Measured: Day 1 to Day 35

  2. Incidence of clinical laboratory abnormalities

    Safety and tolerability of glasdegib including blood chemistry, hematology, coagulation, and urinalysis parameters

    Measured: Day 1 to Day 35

  3. Incidence of vital sign abnormalities

    Safety and tolerability of glasdegib including monitoring of blood pressure and pulse rate

    Measured: Day 1 to Day 35

  4. Incidence of clinical ECG abnormalities

    Safety and tolerability of glasdegib including monitoring of QT interval, RR, QTc, QTS, and PR

    Measured: Day 1 to Day 35

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Aug 2018
  2. Study start5 Nov 2018
  3. Primary completion11 Apr 2019
  4. Study completion11 Apr 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
24 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03627754
Sponsor's protocol ID
B1371016
Status last verified
May 2019
First submitted
31 Jul 2018
Last updated
6 May 2019
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.

Publications

  • Masters JC, LaBadie RR, Salageanu J, Li J, Shaik N. Pharmacokinetics and Safety of Glasdegib in Participants With Moderate/Severe Hepatic Impairment: A Phase I, Single-Dose, Matched Case-Control Study. Clin Pharmacol Drug Dev. 2021 Jul;10(7):707-717. doi: 10.1002/cpdd.897. Epub 2020 Dec 23.

    PubMed 33356019

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Glasdegib 100 mg single oral dose in people with Hepatic Impairment, run by Pfizer at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 27 inclusion and 36 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 May 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Area under the plasma concentration-time curve from time 0 to infinity (AUCinf) of glasdegib (time frame: Day 1 to Day 6). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03627754, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 May 2019.

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