Clinical trial NCT02927457: Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Effect of GSK2646264 in Cutaneous Lupus Erythematosus Subjects
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lupus Erythematosus, Cutaneous
Keywords: Cutaneous Lupus Erythematosus-CLE
Spleen Tyrosine Kinase-SYK
Photoprovocation-PV
GSK2646264
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2016-10-07
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Number of Participants With Emergent Chemistry Results by Potential Clinical Importance (PCI) Criteria
timeFrame: Day 14, Day 28 and follow-up (up to Day 56)
measure: Number of Participants With Emergent Hematology Results by PCI Criteria
timeFrame: Day 14, Day 28 and follow-up (up to Day 56)
measure: Change From Baseline in Urine Potential of Hydrogen (pH)
timeFrame: Baseline (Day 1), Day 14, Day 28 and follow-up (up to Day 56)
measure: Change From Baseline in Urine Specific Gravity
timeFrame: Baseline (Day 1), Day 14, Day 28 and follow-up (up to Day 56)
measure: Number of Participants With Emergent Vital Sign Results by PCI Criteria
timeFrame: Day 14 and Day 28
measure: Change From Baseline in Electrocardiogram (ECG); HR
timeFrame: Baseline (Day 1), Day 14 and follow-up (up to Day 56)
measure: Change From Baseline in ECG; PR Interval, QRS Duration, QT Interval and QTcF
timeFrame: Baseline (Day 1), Day 14 and follow-up (up to Day 56)
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Day 56
Secondary outcomes:
measure: Change From Baseline in Erythema, Scaling Hyperkeratosis, Edema/Infiltration, Dyspigmentation, Modified Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI) Activity Score and Overall RCLASI Modified Score.
timeFrame: Baseline (Day 1), Day 14 and Day 28
measure: Maximum Observed Concentration (Cmax) of GSK2646264 in Participants With Cutaneous Lupus Erythematosus (CLE)
timeFrame: Day 1 (pre-dose and 5 hours post-dose), Day 2 to Day 13, Day 14 (pre-dose), Day 21 to Day 27, Day 28 (post-dose), Day 29 to Day 42 and Follow-up (up to Day 56)
measure: Time to Reach Maximum Observed Concentration (Tmax) of GSK2646264 in Participants With CLE
timeFrame: Day 1 (pre-dose and 5 hours post-dose), Day 2 to Day 13, Day 14 (pre-dose), Day 21 to Day 27, Day 28 (post-dose), Day 29 to Day 42 and Follow-up (up to Day 56)
measure: Mean Fold Change in Messenger Ribonucleic Acid (mRNA) Expression of Interferon (IFN) Signatures in Skin Biopsies
timeFrame: Baseline (Day -5 to -3) and Day 28
Other outcomes:
Locations:
city: Tuebingen
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Bonn
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Muenster
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Wuppertal
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Berlin
country: Germany
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Walker A, Erwig L, Foster K, Nevin K, Wenzel J, Worm M, Williams N, Ratia N, Hoang B, Schneider-Merck T, Gisbert S, Carnarius H, Dickson M. Safety, pharmacokinetics and pharmacodynamics of a topical SYK inhibitor in cutaneous lupus erythematosus: A double-blind Phase Ib study. Exp Dermatol. 2021 Nov;30(11):1686-1692. doi: 10.1111/exd.14253. Epub 2020 Dec 17.