ClinicalTrials.gov
ClinicalTrials.gov Menu

Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Effect of GSK2646264 in Cutaneous Lupus Erythematosus Subjects

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02927457
Recruitment Status : Completed
First Posted : October 7, 2016
Last Update Posted : August 13, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:

This study is designed to examine safety, tolerability, pharmacokinetics, pharmacodynamics and clinical effect of repeat dosing of GSK2646264 in patients with subacute and chronic cutaneous lupus erythematosus (CLE) lesions and in acute CLE like lesions induced by photoprovocation (PV).

Current study is two group study. In Group A, Patients with fewer than two active lesions will be enrolled and exposed to photoprovocation (PV) for 3 consecutive days. Patients that develop PV lesions at any time during this period, as determined by the local investigative team, will receive 1% strength GSK2646264 on 1 lesion and placebo on 1 lesion daily and either 1% strength GSK2646264 or placebo on an area of uninvolved skin, for skin pharmacokinetic (PK) of study drug, for 28 days.

In Group B, Patients that have a minimum of 2 active existing CLE lesions as determined by the investigators will be enrolled into group B and have one lesion treated with 1% GSK2646264 and 1 lesion with placebo.

A completed patient will be defined as a subject who receives at least 25 days of study drug and completes the end of treatment biopsy (at day 28) and assessment. Thereafter patients will be followed for 28 days in Group A only or until complete resolution of induced PV lesions, as determined by the investigator.


Condition or disease Intervention/treatment Phase
Lupus Erythematosus, Cutaneous Drug: GSK2646264 1% Drug: Placebo Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Double-blind (Sponsor Unblinded) Study to Investigate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Effect of Repeat Dosing of GSK2646264 in Cutaneous Lupus Erythematosus Patients
Actual Study Start Date : January 13, 2017
Actual Primary Completion Date : June 12, 2018
Actual Study Completion Date : June 12, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Group A1- Skin Sites A/C/D (A/P/A)
Skin areas A to E in group A are identified skin areas across the back of the subject. Subjects will be receiving GSK2646264 1% (A) for Area A- PV lesion, Placebo (P) for Area C- PV lesion and GSK2646264 1% for Area D- uninvolved skin once daily for 28 days according to randomisation. Skin areas B- PV lesion and E- uninvolved skin will not be assigned any treatment and will be used for the baseline biopsy.
Drug: GSK2646264 1%
A cream for topical application with a concentration of 1% GSK2646264.

Drug: Placebo
Subjects will receive matching Placebo topically.

Experimental: Group A2- Skin Sites A/C/D (A/P/P)
Skin areas A to E in group A are identified skin areas across the back of the subject. Subjects will be receiving GSK2646264 1% for Area A- PV lesion, Placebo for Area C- PV lesion and Placebo for Area D- uninvolved skin once daily for 28 days according to randomisation. Skin areas B- PV lesion and E- uninvolved skin will not be assigned any treatment and will be used for the baseline biopsy.
Drug: GSK2646264 1%
A cream for topical application with a concentration of 1% GSK2646264.

Drug: Placebo
Subjects will receive matching Placebo topically.

Experimental: Group A3- Skin Sites A/C/D (P/A/A)
Skin areas A to E in group A are identified skin areas across the back of the subject. Subjects will be receiving Placebo for Area A- PV lesion, GSK2646264 1% for Area C- PV lesion and GSK2646264 1% for Area D- uninvolved skin once daily for 28 days according to randomisation. Skin areas B- PV lesion and E- uninvolved skin will not be assigned any treatment and will be used for the baseline biopsy.
Drug: GSK2646264 1%
A cream for topical application with a concentration of 1% GSK2646264.

Drug: Placebo
Subjects will receive matching Placebo topically.

Experimental: Group A4- Skin Sites A/C/D (P/A/P)
Skin areas A to E in group A are identified skin areas across the back of the subject. Subjects will be receiving Placebo for Area A- PV lesion, GSK2646264 1% for Area C- PV lesion and Placebo for Area D- uninvolved skin once daily for 28 days according to randomisation. Skin areas B- PV lesion and E- uninvolved skin will not be assigned any treatment and will be used for the baseline biopsy.
Drug: GSK2646264 1%
A cream for topical application with a concentration of 1% GSK2646264.

Drug: Placebo
Subjects will receive matching Placebo topically.

Experimental: Group B1- Skin Sites F/ G (A/P)
In group B, two chosen lesions will be labeled F and G based on size (F >G). Subjects will be receiving GSK2646264 1% for lesion F and Placebo for lesion G once daily for 28 days according to randomisation. Skin area H- uninvolved skin will not be assigned any treatment and will be used for the baseline biopsy.
Drug: GSK2646264 1%
A cream for topical application with a concentration of 1% GSK2646264.

Drug: Placebo
Subjects will receive matching Placebo topically.

Experimental: Group B2- Skin Sites F/ G (P/A)
In group B, two chosen skin lesions will be labeled F and G based on size (F >G). Subjects will be receiving Placebo for lesion F and GSK2646264 1% for lesion G once daily for 28 days according to randomisation. Skin area H- uninvolved skin will not be assigned any treatment and will be used for the baseline biopsy.
Drug: GSK2646264 1%
A cream for topical application with a concentration of 1% GSK2646264.

Drug: Placebo
Subjects will receive matching Placebo topically.




Primary Outcome Measures :
  1. Number of participants with abnormal hematology parameters in Group A [ Time Frame: Approximately 14 weeks ]
    The hematology parameters included are platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), neutrophils, lymphocytes, monocytes, eosinophils, basophils.

  2. Number of participants with abnormal hematology parameters in Group B [ Time Frame: Approximately 12 weeks ]
    The hematology parameters included are platelet count, RBC count, hemoglobin, hematocrit, MCV, MCH, neutrophils, lymphocytes, monocytes, eosinophils, basophils.

  3. Number of participants with abnormal clinical chemistry parameters in Group A [ Time Frame: Approximately 14 weeks ]
    Clinical chemistry parameters included are blood urea nitrogen (BUN), creatinine, glucose, potassium, sodium, calcium, Aspartate transaminase (AST), Alanine transaminase (ALT), alkaline phosphatase, total and direct bilirubin, total protein, albumin, thyroid-stimulating hormone (TSH), free T4, free T3

  4. Number of participants with abnormal clinical chemistry parameters in Group B [ Time Frame: Approximately 12 weeks ]
    Clinical chemistry parameters included are BUN, creatinine, glucose, potassium, sodium, calcium, AST, ALT, alkaline phosphatase, total and direct bilirubin, total protein, albumin, TSH, free T4, free T3

  5. Number of participants with abnormal urinalysis parameters in Group A [ Time Frame: Approximately 14 weeks ]
    Urinalysis parameters included are specific gravity, potential of hydrogen (pH), protein, blood and ketones by dipstick, microscopic examination (if blood or protein is abnormal)

  6. Number of participants with abnormal urinalysis parameters in Group B [ Time Frame: Approximately 12 weeks ]
    Urinalysis parameters included are specific gravity, pH, protein, blood and ketones by dipstick, microscopic examination (if blood or protein is abnormal)

  7. Change from baseline in body temperature-Group A [ Time Frame: Approximately 14 weeks ]
  8. Change from baseline in body temperature-Group B [ Time Frame: Approximately 12 weeks ]
  9. Change from baseline in systolic and diastolic blood pressure (BP)-Group A [ Time Frame: Approximately 14 weeks ]
  10. Change from baseline in systolic and diastolic BP-Group B [ Time Frame: Approximately 12 weeks ]
  11. Change from baseline in pulse rate-Group A [ Time Frame: Approximately 14 weeks ]
  12. Change from baseline in pulse rate-Group B [ Time Frame: Approximately 12 weeks ]
  13. Change from baseline in respiratory rate-Group A [ Time Frame: Approximately 14 weeks ]
  14. Change from baseline in respiratory rate-Group B [ Time Frame: Approximately 12 weeks ]
  15. Changes from Baseline in Electrocardiogram (ECG) parameters-Group A [ Time Frame: Approximately 14 weeks ]
    A 12 lead ECG will be measured using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals.

  16. Changes from Baseline in ECG parameters-Group B [ Time Frame: Approximately 12 weeks ]
    A 12 lead ECG will be measured using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.

  17. Number of participants experiencing adverse events (AEs) and serious adverse events (SAE) in Group A [ Time Frame: Approximately 14 weeks ]
    An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity or is a congenital anomaly/birth defect, at any dose

  18. Number of participants experiencing AEs and SAE in Group B [ Time Frame: Approximately 14 weeks ]
    An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity or is a congenital anomaly/birth defect, at any dose


Secondary Outcome Measures :
  1. Change from baseline of components of a modified RCLASI- composite clinical activity score [ Time Frame: Baseline, Day 14 and Day 28 ]
    The RCLASI (Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index) will be used to assess disease activity.

  2. Change from baseline in interferon (IFN) Messenger-Ribonucleaic Acid (mRNA) signature in skin biopsies in PV and existing CLE lesions [ Time Frame: Baseline and Day 28 ]
    Lesional inflammation in lupus erythematosus is driven through the activation of IFN via the innate pathway. SYK mRNA is known to be stimulated by the IFN pathway.

  3. Cmax of GSK2646264 [ Time Frame: Day 1, Day 2-13, Day 14, Day 21-27, Day 28, Day 29-42, Day 43-56 ]
    PK parameter will include maximum observed concentration (Cmax)

  4. AUC(0- Tau) of GSK2646264 [ Time Frame: Day 1, Day 2-13, Day 14, Day 21-27, Day 28, Day 29-42, Day 43-56 ]
    PK parameter will include area under the concentration-time curve (AUC) over the dosing interval (0- Tau)

  5. t1/2 of GSK2646264 [ Time Frame: Day 1, Day 2-13, Day 14, Day 21-27, Day 28, Day 29-42, Day 43-56 ]
    PK parameter will include Terminal phase half life (t1/2)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Between 18 and 70 years of age inclusive, at the time of signing the informed consent.
  • Subject values for the following parameters thyroid-stimulating hormone (TSH), free thyroxine (T4), and free triiodothyronine (T3) within the normal range.
  • Subject has confirmed diagnosis of Lupus Erythematosus Tumidus (LET) (group A only), subacute or chronic CLE as determined by the investigators.
  • Body weight >= 50 kg and body mass index (BMI) within the range 19.9 - 35 kilogram (kg)/meter square (m^2) (inclusive)
  • Male OR Female.

Females: Non-reproductive potential defined as:

  • Pre-menopausal females with one of the following: 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). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods 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 enrolment.

Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 28 days prior to the first dose of study medication and until 12 days after the last dose of study medication and completion of the follow-up visit.

  • Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
  • All subjects must be free from scarring or skin markings (e.g. tattoos or piercings) and open wounds on the defined areas of the body that cream will be applied onto or that will be exposed to PV, unless in the opinion of the investigator it will not compromise the subjects' safety and quality of data.
  • Able to refrain from exposure to extended and direct sunlight during the study period, from screening until follow up, especially the area that is under treatment during the study.
  • Able to refrain from using self-tanning products on the areas on which the study cream will be applied for the duration of the study from screening to follow-up.
  • Able to refrain from shaving and waxing the areas on which the study cream will be applied during the duration of the study from screening to follow up.
  • Patient stable on either no treatment or on :

    • Corticosteroids (=<7.5milligram [mg]/day prednisone or prednisone equivalent or less) for a minimum of 30 days prior to screening and through to Day 28.
    • and /or hydroxychloroquine (=<400mg daily dose) for a minimum of 60 days prior to the initial photoprovocation for group A or Randomisation Visit for group B through to day 28.
    • Topical steroids applied to the defined areas of the body that are not exposed to photoprovocation or study cream from screening to Day 28.
    • Topical calcineurin inhibitors and retinoids applied to the defined areas of the body that are not exposed to photoprovocation or study cream from screening to Day 28.

Exclusion Criteria

  • ALT >2xupper limit of normal (ULN);
  • Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
  • QTcF > 450 millisecond (msec), or QTcF > 480 msec in subjects with Bundle Branch Block
  • History of any past or present benign or malignant skin conditions and disease, unless in the opinion of the investigator it will not compromise the subjects safety and quality of data.
  • Subjects with a history of Graves disease
  • Subjects with a history of thyroid cancer.
  • Unable to refrain from vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half lives (whichever is longer) prior to the screening visit until the completion of the follow-up assessments, unless in the opinion of the Investigator, in consultation with the GlaxoSmithKline (GSK) Medical Monitor if required, the medication will not interfere with the study procedures or compromise subject safety.
  • Clinically significant abnormality in the hematological, clinical chemistry, or urinalysis screen, as judged by the investigator after discussion with the medical monitor.
  • Subjects who start prohibited medications or therapies at any time during the study may be withdrawn from the study. Subjects who start prohibited medications or therapies may remain in the study only with the approval of the Medical Monitor and at the discretion of the Sponsor.
  • The following medications and therapies are prohibited at any time during the study:

    • Use of other investigational agents (biologic or non-biologic; investigational applies to any drug not approved for sale in the country in which it is used).
    • Co-enrolment into another study of an investigational agent or non-drug therapy.
    • Use of biological agents (e.g., alemtuzumab [ATG], rituximab,) during the clinical study or within 12 months to first dose of study treatment.
    • Use of other immunosuppressive drugs commonly used in Systemic lupus erythematosus (SLE) including Azathioprine, Methotrexate, Mycophenolate, Cyclophosphamide within 3 months to first dose of study treatment.
  • History of regular alcohol consumption within 3 months of the study defined as:

Alcohol will be allowed but limited to an average weekly intake of <21 units for males or <14 units for females).

  • Direct exposure to ultraviolet (UV) light (e.g. sunbathing) to the testing areas within 2 weeks of study entry.
  • 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 (refer to the Investigator Brochure for a list of excipients).
  • 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 screen.
  • Where participation in the study would result in donation of blood or blood products in excess of 450 milliliter (ml) within 3 months.
  • 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 4 investigational medicinal products within 12 months prior to the first dosing day.

Country Specific Exclusion criteria wording for Germany:

  • Subjects that are employees of either GlaxoSmithKline (sponsor) or one of the study centres (investigators).
  • Subjects who live in detention on court order or on regulatory action.
  • Oral Prednisolone

    • Greater than 7.5 mg by mouth daily.
    • Any increase in dose from screening to Day 28
  • Hydroxychloroquine

    • Greater than 400 mg oral daily.
    • Any increase in dose from screening to Day 28.
  • Photosensitizing drugs within 5 half-lives prior to the photoprovocation visit.

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): NCT02927457


Locations
Germany
GSK Investigational Site
Tuebingen, Baden-Wuerttemberg, Germany, 72076
GSK Investigational Site
Erlangen, Bayern, Germany, 91054
GSK Investigational Site
Bonn, Nordrhein-Westfalen, Germany, 53127
GSK Investigational Site
Muenster, Nordrhein-Westfalen, Germany, 48149
GSK Investigational Site
Wuppertal, Nordrhein-Westfalen, Germany, 42283
GSK Investigational Site
Mainz, Rheinland-Pfalz, Germany, 55131
GSK Investigational Site
Berlin, Germany, 10117
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02927457     History of Changes
Other Study ID Numbers: 204860
First Posted: October 7, 2016    Key Record Dates
Last Update Posted: August 13, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com

Keywords provided by GlaxoSmithKline:
Cutaneous Lupus Erythematosus-CLE
Spleen Tyrosine Kinase-SYK
Photoprovocation-PV
GSK2646264

Additional relevant MeSH terms:
Lupus Erythematosus, Systemic
Lupus Erythematosus, Cutaneous
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Skin Diseases