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

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 1

Conditions: Lupus Erythematosus, Cutaneous

Treatments: Drug: Placebo; Drug: GSK2646264 1%

Study type: Interventional

Funder types: Industry

Identifiers

NCT02927457

2016-000277-20 (EudraCT Number)

204860

Details and patient eligibility

About

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.

Enrollment: 11 patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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11 participants in 6 patient groups

Group A1- Skin Sites A/C/D (A/P/A)

Experimental group

Description:

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.

Treatment:

Drug: GSK2646264 1%

Drug: Placebo

Group A2- Skin Sites A/C/D (A/P/P)

Experimental group

Description:

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.

Treatment:

Drug: GSK2646264 1%

Drug: Placebo

Group A3- Skin Sites A/C/D (P/A/A)

Experimental group

Description:

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.

Treatment:

Drug: GSK2646264 1%

Drug: Placebo

Group A4- Skin Sites A/C/D (P/A/P)

Experimental group

Description:

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.

Treatment:

Drug: GSK2646264 1%

Drug: Placebo

Group B1- Skin Sites F/ G (A/P)

Experimental group

Description:

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.

Treatment:

Drug: GSK2646264 1%

Drug: Placebo

Group B2- Skin Sites F/ G (P/A)

Experimental group

Description:

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.

Treatment:

Drug: GSK2646264 1%

Drug: Placebo