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Drug InteractionsPhase 1NCT02706535

A Cross-over Study to Evaluate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics (PK) of GSK525762 in Healthy Female Subjects of Non Child Bearing Potential

A Phase 1 study testing GSK525762 Besylate Tablets, Itraconazole 200 mg and Rifampicin 300 mg in people with Drug Interactions and Neoplasms, run by GlaxoSmithKline at 1 site 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 I, single center, two-part, randomized, open label, cross-over study. Part 1 of this study will evaluate the PK, safety, and tolerability of GSK525762 when administered alone and when co-administered following repeat dosing of itraconazole, a known strong inhibitor of Cytochrome P450 3A4 (CYP3A4) and a… Read more about this study

Who is it for?
Ages 18 to 70 years, women onlyHealthy volunteers can take part
Conditions the study is for
Drug Interactions, Neoplasms
What is being tested?
GSK525762 Besylate Tablets, Itraconazole 200 mg and Rifampicin 300 mg
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
29 participants
Where
1 siteUnited States
Study dates
5 May 2016to 6 Jan 2017
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 70 years
  • Women only
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • Between 18 and 70 years of age inclusive, at the time of signing the informed consent.
  • Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, and laboratory tests.
  • A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator in consultation with the Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
  • Body Weight >=45 Kilograms (Kg) and body mass index within the range 18.0 - 29.9 Kilograms/squared meter (kg/m^2) (inclusive) at time of screening.
  • Only female subjects of non child bearing potential are eligible for screening; men are not eligible for this study. Female subjects: are eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin (hCG) test at screening and serum or urine hCG prior to dosing), is not lactating, and lacks reproductive potential, defined as:
  • Pre-menopausal females with one of the following:
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  • Documented tubal ligation
  • Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
  • Hysterectomy
  • Documented Bilateral Oophorectomy
  • Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)].
  • Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

Who cannot join

  • ALT and bilirubin >1.5xupper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent).
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • Cardiac abnormalities as evidenced by any of the following:
  • History or current untreated clinically significant uncontrolled arrhythmias.
  • Clinically significant conduction abnormalities or arrhythmias, subjects with Bundle Branch Block
  • Presence of cardiac pacemaker
Show all 26Show fewer
  • History or evidence of current >=Class II congestive heart failure as defined by New York Heart Association (NYHA).
  • History of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting.
  • Any of the following ECG findings:
  • Baseline QT duration corrected for heart rate by Fridericia's formula (QTcF) interval >450 miliseconds.
  • History of major gastrointestinal bleeding within the last 6 months. Any evidence of active gastrointestinal bleeding excludes the subject.
  • An unwillingness to abstain from all concomitant medications (excluding acetaminophen).
  • History of regular alcohol consumption within 3 months of the study defined as:
  • •An average weekly intake of >7 drinks for females. One drink is equivalent to 12 grams of alcohol: 12 ounces (360 millilitre [ml]) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.
  • A positive test for alcohol at screening or on admission to the clinical unit.
  • A positive urine drug test at screening or on admission to the clinical unit.
  • Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 3 months prior to screening.
  • An unwillingness to abstain from caffeine- and xantheine- containing products for 24 hours prior to GSK525762 dosing until collection of the final PK sample during each PK session.
  • An unwillingness to abstain from ingestion of any food or drink containing grapefruit and grapefruit juice, Seville oranges, blood oranges, or pomelos within 7 days prior to the first dose of study treatment(s) or until the end of the study.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
  • Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. A positive pre-study drug/alcohol screen.
  • A positive test for Human Immunodeficiency Virus antibody.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
  • The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longest).
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • GSK Investigational Site

    Baltimore, Maryland, 21225

Other trials in United States

About this study

Official title: A Single Center, Two Part, Randomized, Open Label Cross-over Study to Evaluate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics of GSK525762 in Healthy Female Subjects of Non Child Bearing Potential

This is a Phase I, single center, two-part, randomized, open label, cross-over study. Part 1 of this study will evaluate the PK, safety, and tolerability of GSK525762 when administered alone and when co-administered following repeat dosing of itraconazole, a known strong inhibitor of Cytochrome P450 3A4 (CYP3A4) and a Para-glycoprotein (Pgp) inhibitor. Part 1 will consist of 2 Cohorts with preliminary PK and safety data obtained from Cohort 1 informing Cohort 2. Part 2 (one Cohort) of the study will evaluate the PK, safety, and tolerability of GSK525762 when administered alone and when co-administered following repeat dosing of rifampicin, a known potent inducer of CYP3A4. In vitro inhibition data indicate CYP3A4 may be the major route of clearance for GSK525762 and co-administration of drug therapies which modulate CYP3A4 (i.e.CYP3A4 inhibitors and inducers) is likely to alter the exposure of GSK525762 (i.e. increase or decrease exposure, respectively). The data generated from this current study to justify exclusion criteria on concomitant medications which affect CYP3A4 or Pgp and also inform potential dose modification in case of co-administration with medication affecting CYP3A4 activity. All subjects will undergo a screening visit within 28 days of the first dose of study drug followed by one treatment period and a follow-up visit 7-10 days after the last dose of GSK525762. Subjects in Part 1 will participate in the study for up to 45 days and subjects in Part 2 will participate for up to 56 days.

Being tested
GSK525762 Besylate Tablets, Itraconazole 200 mg, Rifampicin 300 mg
Keywords
Itraconazole, Rifampicin, Pharmacokinetics, Cross-over
Medical subject headings
Neoplasms

What participants receive

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

  • GSK525762 Besylate TabletsDrug

    GSK525762 is available as a film-coated, white to slightly colored round, biconvex tablets with no markings. It is available in unit dose strength of 5 mg.

  • Itraconazole 200 mgDrug

    Itraconazole is available as a clear yellow solution with unit dose strength of 10 mg/mL

  • Rifampicin 300 mgDrug

    Rifampicin is available as a red capsule with printed markings and as a 300 mg unit dose strength.

Study groups in NCT02706535
Study groupRoleWhat they receive
Part 1 Cohort 1ExperimentalSubjects will receive a single dose of GSK525762 10 mg on Day 1 followed by 200 mg Itraconazole two times a day (BID) on Day 3. On Day 4 to Day 6 inclusive subjects will receive a single dose of itraconazole 200 mg in the morning. On Day 7 subjects will receive a single dose of GSK525762 5 mg one hour after receiving 200 mg dose of itraconazole. On day 8 and 9 subjects will receive a single dose of 200 mg itraconazole in the morning.
Receives: Drug: GSK525762 Besylate Tablets; Drug: Itraconazole 200 mg
Part 1 Cohort 2ExperimentalSubjects will receive a single dose of GSK525762 10 mg on day 1 followed by 200 mg Itraconazole BID on day 3. On day 4 to day 6 inclusive subjects will receive a single dose of itraconazole 200 mg in the morning. On day 7 subjects will receive a single dose of GSK525762 5 mg or GSK525762 10 mg one hour after receiving 200 mg dose of itraconazole. On day 8 and 9 subjects will receive a single dose of 200 mg itraconazole in the morning.
Receives: Drug: GSK525762 Besylate Tablets; Drug: Itraconazole 200 mg
Part 2ExperimentalSubjects will receive a single dose of GSK525762 10 mg on day 1. From day 3 to 17 inclusive, subjects will receive a single dose of 600 mg rifampicin in fasting conditions. On day 18 subjects will receive single dose of GSK525762 either 20 or 30 mg along with 600 mg dose of rifampicin. On day 19 subjects will receive a single dose of rifampicin 600 mg.
Receives: Drug: GSK525762 Besylate Tablets; Drug: Rifampicin 300 mg

What is being measured

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

  1. Part 1: Area under the plasma concentration-time curve (AUC) from pre dose to time 't' (AUC[0-t]) and pre dose to infinite time (AUC[0-infinity]) of GSK525762 and metabolites in the presence and absence of itraconazole

    Measured: Day 1: Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr , 36 hr, and 48 hr post dose. Day 7:Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr, 36 hr, 48 hr and 72 hr.

  2. Part 1: Maximum plasma concentration (Cmax) of GSK525762 and metabolites in the presence and absence of itraconazole

    Measured: Day1 (Pre dose and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr, 36 hr, and 48 hr post dose) and Day7 (Pre dose and 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr, 36 hr, 48 hr and 72 hr post dose) of each cohort

  3. Part 1: Time to maximum plasma concentration (tmax) of GSK525762 and metabolites in the presence and absence of itraconazole

    Measured: Day1 (Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr , 36 hr, and 48 hr) and Day7 (Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr, 36 hr, 48 hr and 72 hr) of each cohort

  4. Part 2: (AUC[0-t]) and (AUC[0-infinity]) of GSK525762 and metabolites in the presence and absence of rifampicin

    Measured: Blood samples will be collected on Day1 and Day 18 at Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr (Day 19), 36 hr, and 48 hr (Day 20) post dose

  5. Part 2: Cmax of GSK525762 and metabolites in the presence and absence of rifampicin

    Measured: Blood samples will be collected on Day 1 and Day 18 at Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr (Day 19), 36 hr, and 48 hr (Day 20) post dose

  6. Part 2: tmax of GSK525762 and metabolites in the presence and absence of rifampicin

    Measured: Blood samples will be collected on Day 1 and Day 18 at Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr (Day 19), 36 hr, and 48 hr (Day 20) post dose

Secondary outcomes (14)

  1. Part 1: Number of subjects with adverse event (AE) and serious adverse event (SAE)

    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement will be categorized as SAE

    Measured: Up to 45 days

  2. Part 1: Number of subjects having abnormal haematology parameters as a measure of safety.

    Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 6 and at follow-up visit to analyze platelet counts, red blood cells (RBC) count, white blood cells (WBC) count (absolute), haemoglobin, hematocrit and differential WBC count ( neutrophils, lymphocytes, monocytes, eosinophils, and basophils).

    Measured: Up to 45 days

  3. Part 1: Number of subjects having abnormal clinical chemistry parameters as a measure of safety

    Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 6 and at follow-up visit to analyze blood urea nitrogen (BUN), creatinine, glucose (fasting), sodium, c peptide, potassium, chloride, magnesium, ionized calcium, aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase (ALP) levels, gamma-glutamyltransferase (GGT), total and direct bilirubin, total carbon dioxide, total protein and albumin

    Measured: Up to 45 days

  4. Part 1: Number of subjects having abnormal urine parameters (using dipstick test) as a measure of safety

    Urine samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 6 and at follow-up visit to analyze specific gravity, pH, glucose, protein, blood and ketone bodies by dipstick method, microscopic examination (if blood or protein is abnormal) WBCs, RBCs, hyaline casts, granular casts and cellular casts.

    Measured: Up to 45 days

  5. Part 1: Electrocardiogram (ECG) assessment as a measure of safety and tolerability

    ECGs will be measured in supine position after 5 minutes rest using a standard 12-lead ECG machine that automatically calculates the HR and measures PR, QRS, QT and QTcF intervals.

    Measured: Up to 45 days

  6. Part 1: Blood pressure assessment as a safety measure.

    Systolic and diastolic blood pressure will be measured on each day in supine or semi-supine position after 5 minutes rest.

    Measured: Up to 45 days

  7. Part 1: Heart rate assessment as a safety measure.

    Heart rate will be measured on each day in supine or semi-supine position after 5 minutes rest.

    Measured: Up to 45 days

  8. Part 2: Number of subjects with adverse event (AE) and serious adverse event (SAE)

    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement will be categorized as SAE.

    Measured: Up to 56 days

  9. Part 2: Number of subjects having abnormal haematology parameters as a measure of safety.

    Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 4, Day 17 and at follow-up to analyze platelet counts, RBC count, WBC count (absolute), haemoglobin, hematocrit and differential WBC count ( neutrophils, lymphocytes, monocytes, eosinophils, and basophils).

    Measured: Up to 56 days

  10. Part 2: Number of subjects having abnormal clinical chemistry parameters as a measure of safety.

    Blood samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 4, Day 17 and at follow-up visit to analyze BUN, creatinine, glucose (fasting), sodium, c peptide, potassium, chloride, magnesium, ionized calcium, AST/SGOT, ALT/SGPT, ALP levels, GGT, total and direct bilirubin, total carbon dioxide, total protein and albumin

    Measured: Up to 56 days

  11. Part 2: Number of subjects having abnormal urine parameters (using dipstick test) as a measure of safety.

    Urine samples will be collected at screening, pre dose (Day 1), and post dose on Day 3,Day 4, Day 17 and at follow-up visit to analyze specific gravity, pH, glucose, protein, blood and ketone bodies by dipstick method, microscopic examination (if blood or protein is abnormal) WBCs, RBCs, hyaline casts, granular casts and cellular casts.

    Measured: Up to 56 days

  12. Part 2: ECG assessment as a measure of safety and tolerability.

    On Day 1 and Day 18 ECGs will be measured in supine position after 5 minutes rest at screening, pre-dose, 1 hr, 24 hr and 48 hrs.

    Measured: Up to 56 days

  13. Part 2: Blood pressure assessment as a safety measure.

    Systolic and diastolic blood pressure will be measured on each day in supine or semi-supine position after 5 minutes rest.

    Measured: Up to 56 days

  14. Part 2: Heart rate assessment as a safety measure.

    Heart rate will be measured on each day in supine or semi-supine position after 5 minutes rest.

    Measured: Up to 56 days

Timeline

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

  1. First posted11 Mar 2016 (estimated)
  2. Study start5 May 2016
  3. Primary completion6 Jan 2017
  4. Study completion6 Jan 2017

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
Treatment
Allocation
Randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
29 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02706535
Sponsor's protocol ID
204946
Status last verified
Nov 2020
First submitted
7 Mar 2016
Last updated
16 Nov 2020
Results posted
No
Data monitoring committee
No
Individual data sharing
Yes: IPD for this study is available via the Clinical Study Data Request site.

Publications

  • Riddell K, Patel A, Collins G, Zhou Y, Schramek D, Kremer BE, Ferron-Brady G. An Adaptive Physiologically Based Pharmacokinetic-Driven Design to Investigate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics of Molibresib (GSK525762) in Healthy Female Volunteers. J Clin Pharmacol. 2021 Jan;61(1):125-137. doi: 10.1002/jcph.1711. Epub 2020 Aug 20.

    PubMed 32820548

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing GSK525762 Besylate Tablets, Itraconazole 200 mg and Rifampicin 300 mg in people with Drug Interactions and Neoplasms, run by GlaxoSmithKline at 1 site 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 12 inclusion and 26 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 16 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site 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?

Part 1: Area under the plasma concentration-time curve (AUC) from pre dose to time 't' (AUC[0-t]) and pre dose to infinite time (AUC[0-infinity]) of GSK525762 and metabolites in the presence and absence of itraconazole (time frame: Day 1: Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr , 36 hr, and 48 hr post dose. Day 7:Pre dose, 15 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 8 hr, 12 hr, 24 hr, 36 hr, 48 hr and 72 hr.). The study lists 6 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 NCT02706535, 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 16 Nov 2020.

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