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BronchiectasisPhase 1NCT02058407

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), Pharmacodynamics (PD) and Food Effect of Single or Repeat Doses of GSK2793660 in Healthy Subjects

A Phase 1 study testing GSK2793660 solution and GSK2793660 capsule in people with Bronchiectasis, run by GlaxoSmithKline at 1 site in United Kingdom.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This study is the first administration of GSK2793660 to humans and will evaluate the safety, tolerability, PK and PD of single oral ascending doses of GSK2793660, and of repeat oral doses of GSK2793660 in healthy subjects. The study will comprise two parts (Part A and Part B). Read more about this study

Who is it for?
Ages 18 to 55 yearsHealthy volunteers can take part
Conditions the study is for
Bronchiectasis
What is being tested?
GSK2793660 solution and GSK2793660 capsule
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
33 participants
Where
1 siteUnited Kingdom
Study dates
28 Jan 2014to 31 Oct 2014
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 55 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, and laboratory tests. A subject with a clinical abnormality or laboratory parameters outside the reference range, and which is not a part of an eligibility criterion, for the population being studied may be included only if the Investigator and GSK medical monitor consider the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures and outcome.
  • Male or female between 18 and 55 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, removal of both ovaries or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >21.7 International units per liter (IU/L) and oestradiol <110 picomole per liter (pmol/L) 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 listed in the protocol 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 should 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.
  • Male subjects with female partners of child-bearing potential must agree to use one of the approved contraception methods as detailed in the protocol. This criterion must be followed from the time of the first dose of study medication until the follow-up visit.
  • Body weight >=50 Kilogram (kg) and Body Mass Index (BMI) within the range 19.9-30.0 kg/meter square (m^2) (inclusive).
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
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  • Based on averaged QT duration corrected for heart rate by Fridericia's formula (QTcF) values of triplicate ECGs obtained over a brief recording period: Average QTcF <450 milliseconds (msec)
  • Systolic blood pressure <=130 millimeters of mercury (mmHg) and diastolic blood pressure 80 mmHg based on average values of triplicate blood pressure readings obtained over a brief period.
  • Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin <=1.5x Upper Limit of Normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

Who cannot join

  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • ECG finding of second or third degree heart block.
  • 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 gram of alcohol: a half-pint (approximately 240 milliliter [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
  • 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.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
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  • Urinary cotinine or exhaled breath carbon monoxide (CO) levels indicative of current smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
  • A positive pre-study drug/alcohol screen.
  • A positive test for human immunodeficiency virus (HIV) antibody.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period. Blood donation will not exceed 500 mL for the entire study.
  • 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.

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site

  • GSK Investigational Site

    London, NW10 7EW

Other trials in United Kingdom

About this study

Official title: A Randomised, Double-blind (Sponsor Unblind), Placebo-controlled, Two Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of Single or Repeat Doses of GSK2793660 in Healthy Subjects

This study is the first administration of GSK2793660 to humans and will evaluate the safety, tolerability, PK and PD of single oral ascending doses of GSK2793660, and of repeat oral doses of GSK2793660 in healthy subjects. The study will comprise two parts (Part A and Part B). Part A will consist of two cohorts of subjects, each taking part in a three-way cross over study, with ascending doses of GSK2793660 and placebo. Available safety, PK and PD data will be reviewed before each dose escalation. This will be followed by a food-effect arm in the cohort that received what is deemed to be the target clinical dose. Part B is planned to consist of up to two cohorts of subjects, each taking part in one 14 day repeat dose study period. Subjects will be dosed on Day 1 and then on Days 3-15. It is planned that two doses will be evaluated. The dose(s) to be tested will be selected based on safety, PK, and PD from Part A. The study is intended to provide sufficient confidence in the safety profile of the molecule and information on target engagement to allow progression to further studies.

Conditions
Bronchiectasis
Being tested
GSK2793660 solution, GSK2793660 capsule, Placebo solution, Placebo capsule
Keywords
food effect, pharmacokinetics, GSK2793660, FTIH, pharmacodynamics, safety
Medical subject headings
Bronchiectasis

What participants receive

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

  • GSK2793660 solutionDrug

    Clear, colourless solution at a unit dose strength of 0.1 mg/mL, in a glass bottle

  • GSK2793660 capsuleDrug

    Size zero swedish orange capsule at a unit dose of 3 mg, 10 mg, 20 mg and 50 mg

  • Placebo solutionDrug

    Matching placebo to GSK2793660 solution

  • Placebo capsuleDrug

    Matching placebo to GSK2793660 capsule

Study groups in NCT02058407
Study groupRoleWhat they receive
Cohort 1- Part AExperimentalThis cohort will follow an interlocking design with Cohort 2 - Part A. Out of the 9 healthy subjects in this cohort, 3 subjects will receive placebo and 6 subjects will receive GSK2793660 according to randomization schedule in three single-dose study periods. Drug administration will be staggered over 2 days in each period. On Day 1, only 1 subject will receive GSK2793660 and 1 subject will receive placebo. The remaining subjects will be dosed on Day 2 of each treatment period assuming adequate safety from Day 1. Placebo administration and an escalation of GSK2793660 from 0.5 mg, to 3 mg, and 20 mg in the subsequent periods, will be done with a minimum washout period of 13 days between doses. If the target clinical dose is determined as being one of the doses administered to this cohort, they will have an additional study period for the administration of target clinical dose GSK2793660 following the standard Food and drug administration (FDA) high fat/high calorie meal.
Receives: Drug: GSK2793660 solution; Drug: GSK2793660 capsule; Drug: Placebo solution; Drug: Placebo capsule
Cohort 2- Part AExperimentalThis cohort will follow an interlocking design with Cohort 1 - Part A. Out of the 9 healthy subjects in this cohort, 3 subjects will receive placebo and 6 subjects will receive GSK2793660 according to randomization schedule in three single-dose study periods. Drug administration will be staggered over 2 days in each period. On Day 1, only 1 subject will receive GSK2793660 and 1 subject will receive placebo. The remaining subjects will be dosed on Day 2 of each treatment period assuming adequate safety from Day 1. Placebo administration and an escalation of GSK2793660 from 1 mg, to 10 mg, and 50 mg in the subsequent periods, will be done with a minimum washout period of 13 days between doses. If the target clinical dose is determined as being one of the doses administered to this cohort, they will have an additional study period for the administration of target clinical dose GSK2793660 following the standard FDA high fat/high calorie meal.
Receives: Drug: GSK2793660 solution; Drug: GSK2793660 capsule; Drug: Placebo solution; Drug: Placebo capsule
Cohort 3- Part BExperimentalIt is planned that up to two doses evaluated in Part A will be taken through to Part B. In this cohort, the lower dose (which will be the likely clinically efficacious dose) will be given for 14 days. The dosing frequency (once a day or twice daily) will be based on a review of the safety, tolerability, PK and PD data from Part A. It is planned that 10 subjects will receive GSK2793660 and 5 subjects will receive placebo. Subjects will be dosed on Day 1 and then on Days 3-15 (assuming once-daily dosing). If dosing is twice-daily, doses will be administered in the morning and evening from Day 1-14.
Receives: Drug: GSK2793660 capsule; Drug: Placebo capsule
Cohort 4- Part BExperimentalIt is planned that up to two doses evaluated in Part A will be taken through to Part B. In this cohort, the higher dose (maximum tolerated or safe dose) will be given for 14 days. The dosing frequency (once a day or twice daily) will be based on a review of the safety, tolerability, PK and PD data from Part A. It is planned that 10 subjects will receive GSK2793660 and 5 subjects will receive placebo. Subjects will be dosed on Day 1 and then on Days 3-15 (assuming once-daily dosing). If dosing is twice-daily, doses will be administered in the morning and evening from Day 1-14. Cohort 4 will commence only after Cohort 3 is completed and data is reviewed. Also there will be no Cohort 4, if only one dose is to be evaluated in Part B.
Receives: Drug: GSK2793660 capsule; Drug: Placebo capsule

What is being measured

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

  1. Safety and tolerability of GSK2793660 as assessed by vital signs in Part A and Part B

    Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, respiratory rate and oral body temperature

    Measured: Part A: Screening (SCR), Day 1 (Pre-dose, 0.25 hours (h), 0.5 h, 1.5 h, 2 h, 3 h, 4 h, 12 h), Day 2 (24 h), Day 3 (48 h), Day 4 (72 h) in each period and at follow-up (7-14 days post last dose); Part B: SCR, Day 1 to Day 18 and at follow-up

  2. Safety and tolerability of GSK2793660 as assessed by cardiac telemetry in Part A and Part B

    Continuous cardiac telemetry will be performed in Part A and Part B of the study

    Measured: Part A: From 1 h pre-dose on Day 1 until 24 h post dose on Day 2 in each period. Part B: From 1 h prior to dosing on Day 3 until pre-dose on Day 5

  3. Safety and tolerability of GSK2793660 as assessed by electrocardiograms (ECGs) in Part A and Part B

    Cardiac safety will be assessed by 12-lead ECGs

    Measured: Part A: SCR, Day 1 (Pre-dose, 0.25 h, 0.5 h, 1.5 h, 2 h, 3 h, 4 h, 12 h), Day 2 (24 h), Day 3 (48 h), Day 4 (72 h) in each period and at follow-up (7-14 days post last dose); Part B: SCR, Day 1 to Day 18 and at follow-up

  4. Safety and tolerability of GSK2793660 as assessed by laboratory data in Part A and Part B

    Laboratory assessments will include hematology, clinical chemistry and urinalysis parameters

    Measured: Part A: SCR, Day -1, Day 1 (8 h), Day 2 (24 h), Day 4 (72 h) in each period and at follow-up (7-14 days post last dose); Part B: SCR, Day -1, Day 2, Day 4, Day 10, Day 15, Day 18 and at follow-up

  5. Safety and tolerability of GSK2793660 as assessed by adverse events (AEs) in Part A and Part B

    Measured: Part A: Approximately 22- 24 weeks. Part B: Approximately 9 weeks

Secondary outcomes (3)

  1. Composite of PK parameters for GSK2793660 in Part A and Part B

    PK parameters for GSK2793660 in plasma will include: area under the plasma concentration-time curve (AUC[0-t], AUC[0-infinity]), maximum observed plasma concentration (Cmax), time to Cmax (Tmax), apparent terminal phase half-life (T1/2).

    Measured: Part A: Pre-dose, 0.25, 0.5, 1.5, 2, 3, 6, 8, 12, 16, 24, 30, 48 and 72 h; Part B: Days 1 and 15 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 6, 8 and 12 h), Days 2 and 16 (16, 24 and 30 h), Days 3 and 17 (48 h), Day 18 (72 h), Days 4, 7, 9, 11, 13 (pre-dose)

  2. To evaluate biomarker activity following oral administration of GSK2793660 in Part A and Part B

    Blood biomarkers that will provide information on target engagement and downstream PD activity will be assessed. Biomarker endpoints including, but not limited to, cathepsin C enzyme activity in whole blood following single dose administration. Neutrophil serine protease activity (i.e. neutrophil elastase, cathepsin G, proteinase 3 [PR3]) following repeat dose administration. Other endpoints may include LL37 in cell extracts and surface expression of PR3 on neutrophils following repeat dose administration.

    Measured: Part A: Pre-dose, 1 h, 2 h, 3 h, 6 h, 8 h, 12 h, 24 h, 30 h, 48 h, 72 h, 144 h in each period; Part B: Day 1 and Day 15 (Pre-dose, 1 h, 3 h, 6 h, 8 h and 12 h), Day 2 and Day 16 (24 h and 30 h), Day 3 and Day 17 (48 h), Day 18 (72 h)

  3. Effect of food on PK of GSK2793660 in Part A

    PK parameters for GSK2793660 in plasma will include: AUC(0-t), AUC(0-infinity), Cmax, Tmax, and T1/2.

    Measured: Pre-dose, 0.25, 0.5, 1.5, 2, 3, 6, 8, 12, 16, 24, 30, 48 and 72 h

Timeline

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

  1. First posted10 Feb 2014 (estimated)
  2. Study start28 Jan 2014
  3. Primary completion31 Oct 2014
  4. Study completion31 Oct 2014

Why it stopped: Drug related AEs observed upon repeat dosing that with longer treatment duration could become worse. Required action on some biomarkers not observed.

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
Single group
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
33 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02058407
Sponsor's protocol ID
200186
Status last verified
Sep 2018
First submitted
9 Jan 2014
Last updated
13 Sep 2018
Results posted
No
Data monitoring committee
No
Individual data sharing
Yes: IPD for this study will be made available via the Clinical Study Data Request site.

Publications

  • Miller BE, Mayer RJ, Goyal N, Bal J, Dallow N, Boyce M, Carpenter D, Churchill A, Heslop T, Lazaar AL. Epithelial desquamation observed in a phase I study of an oral cathepsin C inhibitor (GSK2793660). Br J Clin Pharmacol. 2017 Dec;83(12):2813-2820. doi: 10.1111/bcp.13398. Epub 2017 Sep 20.

    PubMed 28800383

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing GSK2793660 solution and GSK2793660 capsule in people with Bronchiectasis, run by GlaxoSmithKline at 1 site in United Kingdom.

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 9 inclusion and 12 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: stopped early, as of the sponsor's last update on 13 Sep 2018. 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 Kingdom. 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 was stopped early (reason given: Drug related AEs observed upon repeat dosing that with longer treatment duration could become worse. Required action on some biomarkers not observed.). Results are not available in the source record.

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?

Safety and tolerability of GSK2793660 as assessed by vital signs in Part A and Part B (time frame: Part A: Screening (SCR), Day 1 (Pre-dose, 0.25 hours (h), 0.5 h, 1.5 h, 2 h, 3 h, 4 h, 12 h), Day 2 (24 h), Day 3 (48 h), Day 4 (72 h) in each period and at follow-up (7-14 days post last dose); Part B: SCR, Day 1 to Day 18 and at follow-up). The study lists 5 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 NCT02058407, 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 13 Sep 2018.

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