Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Effect of GSK2646264 in Cutaneous Lupus Erythematosus Subjects
- Conditions
- Lupus Erythematosus, Cutaneous
- Interventions
- Drug: GSK2646264 1%Drug: Placebo
- Registration Number
- NCT02927457
- Lead Sponsor
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 11
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group A2- Skin Sites A/C/D (A/P/P) Placebo 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. Group A1- Skin Sites A/C/D (A/P/A) Placebo 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. Group A4- Skin Sites A/C/D (P/A/P) GSK2646264 1% 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. Group B2- Skin Sites F/ G (P/A) Placebo 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. Group A2- Skin Sites A/C/D (A/P/P) GSK2646264 1% 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. Group A3- Skin Sites A/C/D (P/A/A) Placebo 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. Group B1- Skin Sites F/ G (A/P) GSK2646264 1% 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. Group B1- Skin Sites F/ G (A/P) Placebo 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. Group A1- Skin Sites A/C/D (A/P/A) GSK2646264 1% 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. Group A3- Skin Sites A/C/D (P/A/A) GSK2646264 1% 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. Group A4- Skin Sites A/C/D (P/A/P) Placebo 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. Group B2- Skin Sites F/ G (P/A) GSK2646264 1% 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.
- Primary Outcome Measures
Name Time Method Change From Baseline in Urine Potential of Hydrogen (pH) Baseline (Day 1), Day 14, Day 28 and follow-up (up to Day 56) Urine samples were collected to monitor the pH. pH is a measure of hydrogen ion concentration and is used to determine the acidity or alkalinity of urine. pH scale ranges from 0 to 14. A neutral pH is 7.0. The higher number indicates the more basic (alkaline) nature of urine and lower number indicates the more acidic urine. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.
Number of Participants With Emergent Hematology Results by PCI Criteria Day 14, Day 28 and follow-up (up to Day 56) PCI ranges were hematocrit \[Hct\] (high: \>0.54 proportion of red blood cell \[RBC\] in blood), hemoglobin \[Hb\] (high: \>180 grams per liter), RBC (low: \<4.2x10\^12 cells per liter and high: \>5.9x10\^12 cells per liter), lymphocytes \[Lympho\] (low: \<0.8x10\^9 cells per liter), monocytes \[Mono\] (low: \<0.14x10\^9 cells per liter and high: \>1.3x10\^9 cells per liter), neutrophils \[Neutro\] (low: \<1.5x10\^9 cells per liter), platelet count \[PC\] (low: \<100x10\^9 cells per liter and high: \>550x10\^9 cells per liter), eosinophils \[Eos\] (high: \>0.55x10\^9 cells per liter), basophils \[Baso\] (high: \>0.22x10\^9 cells per liter), white blood cell \[WBC\] (low: \<3x10\^9 cells per liter and high: \>20x10\^9 cells per liter). All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.
Number of Participants With Emergent Chemistry Results by Potential Clinical Importance (PCI) Criteria Day 14, Day 28 and follow-up (up to Day 56) Blood samples were collected to analyze the clinical chemistry parameters; albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), calcium, glucose, potassium (Pot) and sodium. PCI ranges were albumin (low: \<30 grams per liter), calcium (low: \<2 millimoles per liter \[mmol/L\] and high: \>2.75 mmol/L), glucose (low: \<3 mmol/L and high: \>9 mmol/L), Pot (low: \<3 mmol/L and high: \>5.5 mmol/L), sodium (low: \<130 mmol/L and high: \>150 mmol/L), ALT (high: \>=2 times upper limit of normal \[ULN\] units per liter {U/L}), AST (high: \>=2 times ULN U/L), ALP (high: \>=2 times ULN U/L) and TB (high: \>=1.5 times ULN micromoles per liter). Safety Population comprised of all participants who received at least one dose of study treatment. All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.
Number of Participants With Emergent Vital Sign Results by PCI Criteria Day 14 and Day 28 Vital signs such as diastolic blood pressure (DBP), heart rate (HR) and systolic blood pressure (SBP) were measured in semi-supine position after 5 minutes rest for the participants. PCI ranges were SBP (lower: \<85 millimeters of mercury \[mmHg\] and upper: \>160 mmHg), DBP: (lower: \<45 mmHg and upper: \>100 mmHg) and HR (lower: \<40 beats per minute \[bpm\] and upper: \>110 bpm). All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.
Change From Baseline in Urine Specific Gravity Baseline (Day 1), Day 14, Day 28 and follow-up (up to Day 56) Urine samples were collected to monitor the specific gravity. Specific gravity is a measure of urine concentration and is measured using a chemical test. Specific gravity measurements provide a comparison of the amount of substances dissolved in urine as compared to pure water. If there were no solutes present, the specific gravity of urine would be 1.000 the same as pure water. Specific gravity between 1.002 and 1.035 could be considered as normal. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.
Change From Baseline in Electrocardiogram (ECG); HR Baseline (Day 1), Day 14 and follow-up (up to Day 56) Triplicate 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.
Change From Baseline in ECG; PR Interval, QRS Duration, QT Interval and QTcF Baseline (Day 1), Day 14 and follow-up (up to Day 56) Triplicate 12-lead ECGs were obtained using an ECG machine that automatically measured PR, QRS, QT, and QT interval corrected using Fridericia's formula (QTcF) intervals. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Up to Day 56 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect and other situations according to medical or scientific judgement or events associated with liver injury and impaired liver function.
- Secondary Outcome Measures
Name Time Method Mean Fold Change in Messenger Ribonucleic Acid (mRNA) Expression of Interferon (IFN) Signatures in Skin Biopsies Baseline (Day -5 to -3) and Day 28 Microarray mRNA data was collected from the skin biopsy in both GSK2646264 and placebo treated lesions on Day -5 to -3 visit (Baseline) and Day 28. Fold change represents the change at Day 28 relative to Baseline for each treatment group. Analysis was conducted using mixed model with participant as a random effect and treatment as a fixed effect where treatment is set to "not applicable" at Baseline. Mean fold change and 95% confidence interval is presented for different genes and probesets. IFI16 indicated interferon, gamma-inducible protein 16, IFI44 indicated interferon-induced protein 44, IFIH1 indicated interferon induced with helicase C domain 1, IFIT1 and 3 indicated interferon-induced protein with tetratricopeptide repeats 1 and 3, MX1 indicated myxovirus (influenza virus) resistance 1, interferon-inducible protein p78 (mouse), MX2 indicated myxovirus (influenza virus) resistance 2 (mouse) and OAS indicated 2'-5'-oligoadenylate synthetase.
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. Baseline (Day 1), Day 14 and Day 28 The score ranges for different components were; erythema \[0 (absent) to 3 (dark red, purple/violaceous/crusted/hemorrhagic)\], scaling/hyperkeratosis \[0 (absent) to 2 (verrucous hyperkeratosis)\], edema/infiltration \[0 (absent) to 2 (palpable and visible)\] and dyspigmentation \[0 (absent) to 2 (hypo and hyper pigmentation)\]. For all components, 0 (better) and 3 (worse). Modified RCLASI activity score was derived by adding score for erythema, scaling hyperkeratosis and edema/infiltration. Modified change from Baseline ranged from -7 to 7, 0 (no change), minus (better) and positive (worse). Overall RCLASI modified score was derived by summing the activity and dyspigmentation scores. Overall change from Baseline ranged from -9 to 9, 0 (no change), minus (better) and positive (worse). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Data was not collected for Group A as no participants were dosed.
Time to Reach Maximum Observed Concentration (Tmax) of GSK2646264 in Participants With CLE 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) Blood samples were collected at designated timepoints and PK analysis was performed. Tmax was calculated by non-compartmental analysis using WinNonlin.
Maximum Observed Concentration (Cmax) of GSK2646264 in Participants With Cutaneous Lupus Erythematosus (CLE) 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) Blood samples were collected at designated timepoints and pharmacokinetic (PK) analysis was performed. Cmax was calculated by non-compartmental analysis using WinNonlin. PK Population comprised of all participants in the safety population for whom a PK sample was obtained and analyzed.
Trial Locations
- Locations (1)
GSK Investigational Site
🇩🇪Berlin, Germany