A Double-Blind, Double-Dummy, Placebo- and Active-Controlled Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-Inflammatory Effects of GSK1399686 in Patients With Mild to Moderately Active Ulcerative Colitis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Number of Participants With Any Adverse Events (AE) or Serious Adverse Events (SAE)
研究概览
简要总结
This study is the first-time-in-patient trial of GSK1399686, a novel locally-acting anti-inflammatory compound, aimed at obtaining initial information on the tolerability, safety, pharmacokinetics (including concentrations in colon mucosa) and anti-inflammatory activity of GSK1399686 upon oral dosing in patients with active ulcerative colitis.
The study is designed as a randomized, double-blind, double-dummy, placebo-controlled, sequential dose escalating trial, with an active control (ASACOL) group as internal control. Up to three cohorts (Cohorts 1-3), each consisting of approximately 20 patients with mild-moderately active ulcerative colitis not limited to the rectum, will be included, one for each dose level of GSK1399686 to be tested. Within a cohort, patients will be randomized in a 3:1:1 ratio to receive GSK1399686 (once daily over 4 weeks, followed by 2 weeks dosing with placebo), placebo, or ASACOL (t.i.d. for 6 weeks), respectively.
An interim analysis of fecal markers and disease activity data will be performed by the end of Cohort 3. Based upon results, the study may be stopped or continued by recruiting either Cohort 4 (if data on an additional dose level would be warranted to establish or clarify a dose-response relationship) or, in the case of a robust efficacy signal at any dose level previously studied, Cohort 5 (to expand the sample size for given dose level in order to evaluate the efficacy of GSK1399686). The number of patients and randomization allocation ratio may be altered in Cohort 5 and it may not include an active control arm. If Cohort 4 is initiated upon interim analysis, then a second interim analysis may be performed at the end of Cohort 4, to assess whether progression into Cohort 5 (as defined above) would be justifiable.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female of non-childbearing potential between 18 and 65 years of age inclusive.
- •Presence of mild-to-moderately active ulcerative colitis spread beyond the rectum as evidenced by clinical signs and endoscopy.
- •UCDAI score 4-10 (inclusive) with rectal bleeding score ≥ 1, endoscopy score ≥ 1 and Physician's rating of disease activity <
- •Body weight > or = to 50 kg and BMI within the range 18.5-29.9 kg/m2 (inclusive).
- •Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
排除标准
- •History of sensitivity to any component of study medications, history of hypersensitivity to ACTH, or a history of drug or other allergy that, in the opinion of the Investigator, contraindicates patient's participation in the study.
- •History of renal sensitivity to 5-ASA or presence of nephritis, nephropathia or renal function impairment.
- •Presence or a history of asthma or presence or history of other serious allergic disorder.
- •Presence or history of chronic liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- •A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
- •Presence of significant hematologic disorder, or significant bleeding or immune system disorder.
- •QTcB or QTcF >450 msec; or QTc >480 msec in patients with Bundle Branch Block, based on an average QTc value of triplicate ECGs, if the first ECG showed an abnormal value.
- •Presence of a significant cardiac, pulmonary, metabolic or infectious disease or mental disorder that, in the opinion of the Investigator, represents an unacceptable safety risk for participation in this trial.
- •History of malignant neoplastic disease within the past 5 years other than localized basal cell skin cancer, squamous cell skin cancer or cancer in situ that has been resected.
- •History of regular alcohol consumption within 6 months of the study or presence of recreational drug abuse or dependence.
- •Presence of infectious colitis as evidenced by stool culture positive for enteric pathogens or positive Clostridium difficile cytotoxin assay.
- •Suspicion of Crohn's disease, indeterminate colitis, microscopic colitis, ischaemic colitis or radiation-induced colitis, based on medical history, endoscopy and/or histological findings.
- •Bowel surgery within last 12 months.
- •Treatment with oral aminosalicylates at dose ≥ 2.4 g/day and/or with topical aminosalicylates at any dose within 2 weeks prior to Day 1 visit.
- •Treatment with systemic or topical corticosteroids within 4 weeks prior to Day 1 visit.
- •Treatment with TNF-α inhibitors or other biologics within 2 months prior to Day 1 visit.
- •Treatment with immunosuppressants (azathioprine or 6-mercaptopurine), if initiated within 3 months prior to Day 1 visit, or if changed in terms of drug or dose within 3 months prior to Day 1 visit.
- •Regular use of probiotic or prebiotic preparations, if initiated within 4 weeks prior to Day 1 visit.
- •Regular daily use of non-steroidal anti-inflammatory drugs (NSAIDs), except low dose aspirin (325 mg/day) for cardioprotection, within 7 days prior to Day 1 visit.
- •Treatment with medications known to be strong inducers of CYP3A4/5 (e.g. carbamezipine, phenobarbital, phenytoin, rifabutin, rifampin, troglitazone) or regular use of St. John's Wort within 14 days prior to Day 1 visit.
- •Treatment with medications known to be strong inhibitors of CYP3A4/5 (e.g. ketoconazole, itraconazole, fluconazole, mibefradil, clarithromycin, erythromycin, diltiazem, verapamil), or regular use of grapefruit juice within 7 days prior to Day 1 visit.
- •Treatment with medications known to be sensitive CYP3A4 substrates with a narrow therapeutic index (e.g. alfentanil, astemizole, cisapride, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfenadine) within 7 days prior to Day 1 visit.
- •Participation in a clinical trial and treatment with an investigational product within the following time period prior to the Day 1 visit: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
- •Prior enrolment in the present trial.
- •For Canadian sites only:
- •Patients with existing gastric or duodenal ulcers.
- •Patients with urinary tract obstruction
研究组 & 干预措施
Group 2
ASACOL 800mg t.i.d.
干预措施: GSK1399686 (Drug)
Group 1
GSK1399686 at 3-4 dose levels
干预措施: GSK1399686 (Drug)
Group 3
Placebo
干预措施: GSK1399686 (Drug)
结局指标
主要结局
Number of Participants With Any Adverse Events (AE) or Serious Adverse Events (SAE)
时间窗: Up to Week 6
An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase \>=3 x upper limit of normal (ULN), and total bilirubin \>=2 x ULN or international normalized ratio \>1.5.
Number of Participants With Hematology Data Outside the Reference Range
时间窗: Screening (Day -7 to -1), Day 1, Week 1, 2, 3, 4 and 6
Normal reference range for clinical chemistry parameters include: basophils 0 - 0.2 giga cells (GI)/L; eosinophils 0 - 0.4 GI/L; lymphocytes 1 - 4.8 GI/L; monocyte 0 - 0.8 GI/L; total neutrophils (total absolute neutrophils count) 1.8 - 7.7 GI/L; platelet count 150 - 400 GI/L; red blood cell count 4.5 - 5.9 GI/L; white blood cell count 3.9 - 10.6 GI/L; hemoglobin 135 - 175 g/L; hematocrit 0.41 - 0.53 ratio; mean corpuscle hemoglobin concentration 310 - 370 g/L; mean corpuscle hemoglobin 26 - 34 picogram (PG); mean corpuscle volume 80 - 100 femtoliter (FL); reticulocytes 0.05 - 0.1 trillion cells (TI)/L. Number of participants with high and low values compared to the reference range is presented. Only those parameters for which at least one value outside the reference range was reported at any visit are summarized.
Number of Participants With Clinical Chemistry Data Outside the Reference Range
时间窗: Screening (Day -7 to -1), Day 1, Week 1, 2, 3, 4 and 6
Normal reference range for clinical chemistry parameters include: alanine amino transferase (ALT) 0-41 international units per liter (IU/L); aspartate amino transferase (AST) 10 - 38 IU/L; alkaline phosphatase 40 - 129 IU/L; gamma glutamyl transferase (GGT) 10 - 66 IU/L; albumin 39 - 48 gram per liter (g/L); total protein 66 - 87 g/L; direct bilirubin 0 - 5.13 micromole per liter (µmol/L); total bilirubin 0 - 17.1 µmol/L; creatinine 61.88 - 106.08 µmol/L; uric acid 202.232 - 416.36 µmol/L; calcium 2.0958 - 2.42015 millimole per liter (mmol/L); cholesterol 2.8446 - 5.9478 mmol/L; chloride 98 - 106 mmol/L; glucose 2.2204 - 11.102 mmol/L; potassium 3.4 - 4.5 mmol/L; magnesium 0.6576 - 1.0686 mmol/L; sodium 0 - 2.26 mmol/L; urea/ blood urea nitrogen (BUN) 0 - 17.85 mmol/L. Number of participants with high and low values compared to the reference range is presented. Only those parameters for which at least one value outside the reference range was reported at any visit are summarized.
Mean Concentration of GSK1399686 in Colon Biopsy Obtained Within 24 h After the Last Dose
时间窗: Week 4
The assessment was done on the samples collected from the sigmoid colon and from the rectum obtained within 24 hour after the last dose on Week 4 visit after endoscopic evaluation of respective area for determination of GSK1399686 concentration. Non-quantifiable (NQ) concentration values were imputed as 0.
Number of Participants of Abnormal Urinalysis Dipstick Results
时间窗: Screening (Day -7 to -1), Week 2, 4 and 6
The urinalysis parameters included urine occult blood, urine general, glucose, ketones and protein by dipstick analysis. The assessments were done on screening, Week 2, Week 4 and Week 6.The number of participants with results of 0, 0.3, 1, 1+, 1.5, 10, 2+, 3+, 30, 4+, 5+, 55, not rated (NR), positive (pos) and trace is presented.
Mean Treatment Effects on Basal Morning Cortisol and Adrenocorticotropic Hormone (ACTH) Stimulated Cortisol Levels at Week 4 in Comparison With Baseline
时间窗: Baseline (Day 1, pre dose) and Week 4
Treatment effects was assessed using a low-dose ACTH stimulation test which was performed on Day 1 pre dose (Baseline) and at Week 4 visit. A blood sample for plasma cortisol was taken immediately, before and 30 minutes after an intravenous injection of 1 microgram (μg). tetracosactide acetate, a synthetic peptide displaying the same physiological properties as ACTH. The change from morning basal cortisol was calculated for Day 1 pre-dose (ACTH1) and Week 4 (ACTH2) using the equation: ACTH1 = Day 1 post ACTH - Day 1 pre ACTH; ACTH2 = Week 4 post ACTH - Week 4 pre ACTH. The change from morning basal cortisol between Week 4 and Day 1 (ACTH effect) was calculated as : ACTH effect = ACTH2 - ACTH1. The difference in morning basal cortisol between Week 4 and Day 1 (ACTH morning) was calculated as:- ACTH morning = Week 4 pre ACTH - Day 1 pre ACTH. Adrenocorticol function was classed as normal if the change from post ACTH to pre ACTH (using ACTH1 and ACTH2) was \>= 200 nanomoles per liter.
Number of Participants With Vital Sign Outside Range of Potential Clinical Importance (PCI)
时间窗: Screening (Day -7 to -1), Week 2, 4 and 6
Vital signs assessment included systolic blood pressure (SBP), Diastolic blood pressure (DBP) and heart rate (HR). Criteria for vital sign values meeting PCI included: SBP \< 85 and \> 160 millimeter of mercury (mmHg); DBP \< 45 and \> 100 mmHg and HR \< 40 and \> 110 beats per minute (bpm). The assessments were done on screening, Week 2, Week 4 and Week 6. The participants with values higher and lower than the PCI range is presented. Only those parameters for which at least one value of PCI was reported at any visit are summarized.
Number of Participants With Abnormal Electrocardiography (ECG) Findings
时间窗: Screening (Day -7 to -1), Week 2, 4 and 6
Single 12-lead ECGs were obtained at each timepoint during the study using an ECG machine that automatically calculated the HR and measured PR, QRS, QT, and QTc intervals. Criteria for ECG parameter values meeting PCI included absolute QTc interval \>500 millisecond (msec); increase from Baseline QTc \>60 msec; PR interval \<110 and \>220 msec; QRS interval \<75 and \>110 msec. Only those participants for whom at least one value of abnormal clinically significant or abnormal not clinically significant ECG findings were reported at any visit are summarized.
次要结局
- Mean Simple Clinical Colitis Activity Index (SCCAI) Score(Up to Week 6)
- Pre-dose Trough Concentration at the End of the Dosing Interval (Cτ) on Day 28 Derived From Observed Plasma Concentrations of GSK1399686 After Repeated Oral Dosing(Day 28 (Week 4 at pre dose, 1 hour, 2 hour, 3 hour and 4 hour morning post dose))
- Mean Fecal Calprotectin Levels Over Time(Up to Week 6)
- Mean Fecal Lactoferrin Levels Over Time(Up to Week 6)
- Volume of Distribution Estimated Based on Population Pharmacokinetic Analysis of Healthy Volunteers (Historical Data) and Patient Data(Day 1 (1 hour, 2 hour, 3 hour post dose), Week 1 (anytime relative to the last dose), Week 2 (anytime relative to the last dose) and Day 28 (Week 4 at pre dose, 1 hour, 2 hour, 3 hour and 4 hour morning post dose))
- Number of Participants With Clinical Response and Clinical Remission at Week 4 and Week 6(Week 4 and Week 6)
- Median Time to Clinical Response and Clinical Remission(Up to Week 6)
- Mean Maximum Observed Concentration (Cmax) on Day 1 and Day 28 Derived From Observed Plasma Concentrations of GSK1399686 After Repeated Oral Dosing(Day 1 (1 hour, 2 hour, 3 hour post dose) and Day 28 (Week 4 at pre dose, 1 hour, 2 hour, 3 hour and 4 hour morning post dose))
- Plasma Clearance Estimated Based on Population Pharmacokinetic Analysis of Healthy Volunteers (Historical Data) and Patient Data(Day 1 (1 hour, 2 hour, 3 hour post dose), Week 1 (anytime relative to the last dose), Week 2 (anytime relative to the last dose) and Day 28 (Week 4 at pre dose, 1 hour, 2 hour, 3 hour and 4 hour morning post dose))