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AsthmaPhase 1NCT01266941

A Study to Assess the Effects of Fluticasone Furoate and GW642444M Combination in Healthy Subjects and in Subjects With Mild, Moderate or Severe Hepatic Impairment.

A Phase 1 study testing Inhaled FF 200mcg/GW642444M 25mcg in people with Asthma, run by GlaxoSmithKline at 3 sites in 2 countries.

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

In relation to their severity, hepatic diseases can significantly modify drug absorption and disposition and consequently can interfere with drug efficacy and/or produce toxicity. Read more about this study

Who is it for?
Ages 18 to 70 yearsHealthy volunteers can take part
Conditions the study is for
Asthma
What is being tested?
Inhaled FF 200mcg/GW642444M 25mcg
Could I receive a placebo?
No, everyone receives an active treatment
How many people
35 participants
Where
3 sitesin 2 countries
Study dates
18 Oct 2010to 15 Jul 2011
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
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • A subject will be eligible for inclusion in this study only if all of the following criteria apply:
  • Male or female between 18 and 70 years of age inclusive, at the time of signing the informed consent.
  • A female subject is eligible to participate if she is of:
  • Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) (healthy subjects only) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
  • Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until completion of the follow-up visit.
  • BMI within the range 19 - 33 kg/m^2.
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  • Able to satisfactorily use the dry powder inhalation inhaler.
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
  • Single QTcF < 450 msec; or QTcF < 480 msec in subjects with Bundle Branch Block.
  • Able to satisfactorily use the dry powder inhaler.
  • Healthy subjects:
  • AST, ALT, alkaline phosphatase and bilirubin ≤1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures or outcome.
  • Hepatically Impaired Subjects:
  • Hepatically impaired.
  • To be classified as hepatically impaired, subjects must have:
  • Known medical history of liver disease with or without a known history of alcohol abuse; and A Child-Pugh score of 5-15 to cover all severities (Mild = 5-6 points; Moderate = 7-9 points; Severe = 10-15 points). The components that contribute to the CP score should be directly related to the underlying hepatic disease and not to non-hepatic disease.
  • Subjects with no significant abnormality, apart from impaired hepatic function and related symptoms, or clinical examination. A subject with a clinical abnormality may be included only if the Investigator considers that the abnormality will not introduce additional risk factors and will not interfere with the study procedures. Hepatically impaired subjects with other laboratory parameters outside the reference ranges will only be included if, in the opinion of the Investigator, the result is not clinically important and introduces no additional risk factors.

Who cannot join

  • A subject will not be eligible for inclusion in this study if any of the following criteria apply:
  • Suffered a lower respiratory tract infection in the 4 weeks before the screening visit.
  • Taken oral corticosteroids less than 8 weeks before the screening visit.
  • Taken inhaled, intranasal or topical steroids less than 4 weeks before the screening visit.
  • Have a known sensitivity to corticosteroids and/or long acting beta agonists.
  • A positive pre-study drug/alcohol screen.
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  • A positive test for HIV antibody.
  • 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 longer).
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  • 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 GSK Medical Monitor, contraindicates their participation.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
  • Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.
  • Lactating females.
  • The subject has been treated for or diagnosed with depression within six months of screening or has a history of significant psychiatric illness.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Subject is mentally or legally incapacitated.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • Subjects who have asthma or a history of asthma.
  • History of severe milk protein allergy.
  • Subjects with a smoking history of >10 cigarettes per day or regular use of tobacco- or nicotine-containing products, within 6 months prior to screening.
  • Consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication.
  • Healthy subjects
  • If, in the opinion of the examining physician, an unstable cardiovascular, renal, hepatic, pulmonary, endocrine, metabolic, neurological, haematological or gastrointestinal condition is present or any other medical condition which the investigator considers sufficiently serious to interfere with the conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject.
  • Subjects with any predisposing condition that might interfere with the absorption, distribution, metabolism or excretion of drugs or any previous gastrointestinal (GI) surgery (except appendectomy or cholecystectomy more than three months prior to the study) condition which the investigator considers sufficiently significant to interfere with the conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject.
  • Haemoglobin values <12.9g/dL for males and <11.4g/dL for females.
  • A past history or current symptoms of significant hepatic or renal disease, pancreatitis or acute cholecystitis which the investigator considers sufficiently significant to interfere with the conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject.
  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • History of regular alcohol consumption within 6 months of the study defined as:
  • An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.
  • Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inhibitor) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. In particular subjects taking steroids or medications that significantly inhibit P450 CYP3A4 (e.g. ketoconazole) must not be included in this study.
  • Hepatically Impaired Subjects
  • If in the opinion of the examining physician, an unstable cardiovascular, renal, pulmonary, endocrine, metabolic, neurological, haematological or gastrointestinal condition is present or any other significant medical condition which the investigator considers sufficiently serious to interfere with the conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject.
  • Severe ascities (Child-Pugh ascites score of 3) upon clinical exam, including physical exam and abdominal ultrasound at screening. Subjects identified to have moderate ascities by ultrasound examination may be included at the discretion of the Investigator with prior agreement from the sponsor.
  • History of oesophageal bleeding within the last 6 months before dosing.
  • Significant hepatic encephalopathy, degree of CNS impairment or other signs of hepatic function deterioration which the investigator considers sufficiently serious to interfere with the informed consent, conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject.
  • Patients at risk of requiring a transfusion during the study period, or has haemoglobin < 9 g/dL, or has underlying coronary artery disease (or other clinical condition) in which a reduction in haemoglobin associated with FF/GW642444M administration might be expected to cause clinical deterioration.
  • Evidence of current significant infection (e.g. spontaneous bacterial peritonitis, pneumonia etc.).
  • Subjects who develop symptoms such as infections or haemorrhage between screening and dosing must not be included in the study.
  • Fluctuating or rapidly deteriorating hepatic function (such as, but not limited to, rapidly increasing ascites, rapidly deteriorating mental status, deteriorating hepatic function based on prothrombin time [PT], albumin, total bilirubin). Assessment of the stability of the subject's hepatic function will be at the discretion of the Principal Investigator.
  • Subjects with significant renal insufficiency as defined by estimated creatinine clearance of <50 ml/min, using the Cockcroft and Gault equation.
  • Subjects with a diagnosis of primary biliary disease such as cholestasis or sclerosing cholangitis.
  • Subjects who need to take any concomitant medication, either prescribed or over-the-counter, which may in the opinion of the Investigator, interfere in any way with the study procedure or be a safety concern (see Section 9 for the list of permitted concurrent medications). In particular subjects taking medications that significantly inhibit P450 CYP3A4 (e.g. ketoconazole) must not be included in this study.
  • Subjects who, within the past six months, have had a history of significant drug abuse or alcohol abuse.

Trial locations and contacts

3 sites in 2 countries.

3 sites in 2 countries

Czechia2 sites

  • GSK Investigational Site

    Hradec Králové, 500 05

  • GSK Investigational Site

    Prague, 170 00

Other trials in Czechia

Slovakia1 site

  • GSK Investigational Site

    Bratislava, 833 05

Other trials in Slovakia

About this study

Official title: An Open-label, Non-randomized, Pharmacokinetic and Safety Study of Repeat Doses of Fluticasone Furoate and GW642444M Combination in Healthy Subjects and in Subjects With Mild, Moderate or Severe Hepatic Impairment

In relation to their severity, hepatic diseases can significantly modify drug absorption and disposition and consequently can interfere with drug efficacy and/or produce toxicity. The purpose of this study will be to aid in deciding whether a dose adjustment is required in subjects with hepatic impairment and in estimating any such adjustments.

Read the detailed description

In relation to their severity, hepatic diseases can significantly modify drug absorption and disposition and consequently can interfere with drug efficacy and/or produce toxicity. Pathological modifications of liver structure or functionality might result in complex modifications of various factors including liver blood flow, hypoalbuminaemia, indirectly affect renal function and reduce the hepatic drug metabolizing capability including the microsomal oxidase system [Howden, 1989].

Although FF/GW642444M is delivered directly to the site of action, i.e. the lungs, a large portion of the administered dose is swallowed. For both FF and GW642444 any drug absorbed from the GI tract undergoes first pass metabolism via CYP3A4. In addition, drug absorbed into the systemic circulation is metabolised in the liver and removed by biliary clearance. Hence, there is a possibility that when used by patients with impaired liver function the pharmacokinetics of inhaled FF and/or GW642444 may be changed due to reduced first pass metabolism and/or reduced clearance. The results of this study will aid in deciding whether a dose adjustment is justified and in estimating any such adjustments in patients with impaired hepatic function.

This is an open-label, non-randomized study which will assess the pharmacokinetics and safety of inhaled FF 200mcg/GW642444M 25mcg in subjects with hepatic impairment following 7 days once daily dosing. Subjects with mild, moderate and severe hepatic impairment (as defined by a Child-Pugh score of 5-15) will be recruited along with healthy control subjects matched to the moderate subjects (matched on gender, ethnicity, body mass index +/-15%, age +/-5 years).

Approximately thirty-six subjects will be recruited: 9 subjects for each severity and 9 matched healthy subjects. All subjects are scheduled to receive FF 200mcg/GW642444M 25mcg once daily for 7 days. The dose for subjects with severe hepatic impairment may be adjusted to FF 100mcg/GW642444M 12.5mcg after review of the PK and safety data from the moderate and healthy matched control subjects. The results of this study will aid in deciding whether a dose adjustment is required in subjects with hepatic impairment and in estimating any such adjustments.

Conditions
Asthma
Being tested
Inhaled FF 200mcg/GW642444M 25mcg
Keywords
pharmacokinetics, hepatic impairment, heart rate, serum potassium, serum cortisol, GW642444M, Fluticasone furoate (GW685698)
Medical subject headings
Asthma

What participants receive

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

  • Inhaled FF 200mcg/GW642444M 25mcgDrug

    All subjects are scheduled to receive FF 200mcg/GW642444M 25mcg once daily for 7 days. The dose for subjects with severe hepatic impairment may be adjusted to FF 100mcg/GW642444M 12.5mcg after review of the PK and safety data from the moderate and healthy matched control subjects.

Study groups in NCT01266941
Study groupRoleWhat they receive
Mild Hepatic ImpairmentExperimentalMild and moderate hepatic patients will be recruited first, approximately 9 subjects should complete each of these treatment arms.
Receives: Drug: Inhaled FF 200mcg/GW642444M 25mcg
Moderate Hepatic ImpairmentExperimentalMild and moderate hepatic patients will be recruited first, approximately 9 subjects should complete each of these treatment arms.
Receives: Drug: Inhaled FF 200mcg/GW642444M 25mcg
Matched healthy volunteersExperimentalOnce a moderate subject has been recruited, a healthy control subject should be recruited (matched to the moderate subject on gender, ethnicity, body mass index +/-15%, age +/-5 years). In total there will be 9 matched healthy volunteers 1 for each subject with moderate hepatic impairment.
Receives: Drug: Inhaled FF 200mcg/GW642444M 25mcg
Severe Hepatic ImpairmentExperimentalSevere subjects will not be enrolled into the study until 9 moderate subjects and their matched control subjects have completed the study and the safety and PK data have been reviewed.
Receives: Drug: Inhaled FF 200mcg/GW642444M 25mcg

What is being measured

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

  1. Fluticasone furoate and GW642444 pharmacokinetics (AUC(0-t), AUC (0-8), Cmax, tmax) on Day 1 and 7 and AUC(0-24) and t½ on Day 7.

    Measured: 1 Month

Secondary outcomes (4)

  1. Serum cortisol weighted mean over 24 hours on Days -1 and 7.

    Measured: 1 Month

  2. Maximum heart rate over time period 0-4 hours on Day 7.

    Measured: 1 Month

  3. Minimum serum potassium concentration over time period 0-4 hours on Day 7.

    Measured: 1 Month

  4. General safety and tolerability endpoints: adverse events, blood pressure, heart rate, 12-lead ECG, clinical laboratory safety tests.

    Measured: 1 Month

Timeline

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

  1. First posted24 Dec 2010 (estimated)
  2. Study start18 Oct 2010
  3. Primary completion15 Jul 2011
  4. Study completion15 Jul 2011

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
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
35 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01266941
Sponsor's protocol ID
111789
Status last verified
Jul 2017
First submitted
23 Dec 2010
Last updated
21 Jul 2017
Results posted
No
Data monitoring committee
No
Individual data sharing
Yes: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Publications

  • Allen A, Davis A, Hardes K, Tombs L, Kempsford R. Influence of renal and hepatic impairment on the pharmacokinetic and pharmacodynamic properties and tolerability of fluticasone furoate and vilanterol in combination. Clin Ther. 2012 Dec;34(12):2316-32. doi: 10.1016/j.clinthera.2012.11.001. Epub 2012 Nov 30.

    PubMed 23200625

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Inhaled FF 200mcg/GW642444M 25mcg in people with Asthma, run by GlaxoSmithKline at 3 sites in 2 countries.

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 18 inclusion and 44 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 21 Jul 2017. 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 Czechia, Slovakia. 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?

Fluticasone furoate and GW642444 pharmacokinetics (AUC(0-t), AUC (0-8), Cmax, tmax) on Day 1 and 7 and AUC(0-24) and t½ on Day 7. (time frame: 1 Month). 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 NCT01266941, 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 21 Jul 2017.

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