Extracorporeal Photopheresis of Patients With Crohn's Disease Using 5-aminolevulinic Acid
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 7
- 试验地点
- 1
- 主要终点
- Clinical response
研究概览
简要总结
In the clinical trial the investigators will assess efficacy, safety and tolerability after single and multiple doses of 3 millimolar 5 aminolevulinic acid (Gliolan®) in combination with blue-light (405 nanometer) photopheresis in patients with active crohns disease. The study is a proof-of-concept pilot with up to 10 included patients where every patient will get active treatment. The use of 5-aminolevulinic acid in combination with blue-light photopheresis is a first-in-human trial. Primary endpoints include clinical response and adverse events (safety). Secondary endpoints include endoscopic improvement, quality of life questionnaires, faecal calprotectin, C-reactive protein and mechanisms of action (differences in t-cells and other cells before and after treatment). All patients will get treatment every 2 weeks for 10 weeks (6 treatments-induction) with evaluation at week 13. If any effect on week 13 eligible for study extension with treatment every 4 weeks for up to 12 months for the first 5 patients. The latter 5 patients will be referred to standard of care on the week 13 visit. Through the study the investigators will see if this kind of photopheresis is safe and can be an option for a larger randomized-controlled-trial. In addition the investigators will see if photopheresis as an option can be further developed for other diseases as well (ie other T-cell mediated diseases or patients already receiving photopheresis as a treatment).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
all patients will receive active treatment
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provision of informed consent
- •Age above 18
- •Male or female patient with active Crohn's disease (6)
- •Women of childbearing potential (WOCBP) will have to use highly effective methods of contraception throughout the entire study.
- •Inadequate response (a) or intolerance to biological therapy
- •a. Inadequate response on ongoing treatment is defined as: i. Progressive disease: increasing Harvey Bradshaw Index/Calprotectin/Simple Endoscopic Score for Crohns Disease and/or worsening of radiologic images after 6 months.
- •ii. Stable disease: no-response after 6 months
- •Active inflammation in the gut documented by
- •Harvey Bradshaw Index >5 and
- •Endoscopy with Simple Endoscopic Score for Crohns Disease equal to or above 6 points or equal to or above 4 points if only isolated ileitis is present and/or
- •Inflammatory marker; fecal calprotectin > 250 and/or C reactive protein > 5
排除标准
- •Photosensitive comorbidities, porphyria or known hypersensitivity to 5-aminolevulinic acid or porphyrins
- •Patients with aphakia
- •Pregnant or breast-feeding women. A negative urine pregnancy test must be demonstrated in female patients of child-bearing potential at the Screening Visit and before every treatment.
- •Ongoing cardiac and pulmonary diseases or aspartate transaminase alanine aminotransferase, Bilirubin or International Normalized Ratio value ≥ 3x upper limit of normal or clinically significant electrocardiogram findings
- •Subjects with polyneuropathy
- •Uncontrolled infection or fever
- •History of heparin-induced thrombocytopenia, absolute neutrophil count <1x109, platelet count <20x10 9
- •Body weight below 40 kg
- •Investigator considers subject unlikely to comply with study procedures, restrictions and requirements.
- •Presence of other gastrointestinal diseases potentially influencing the study endpoints
- •History of any clinically significant disease or disorder which in the opinion of the investigator, may either put the patient at risk because of participation in the study, or influence the result or the patient's ability to participate in the study.
研究组 & 干预措施
5-ALA photopheresis
All patients will receive 5-aminolevulinic acid (5-ALA) in combination with blue light photopheresis. The investigators will collect mononuclear cells by connecting patient to Spectra Optia with CMNC (continuous mononuclear cell collection protocol), and these cells will include active T-lymphocytes. 5-ALA will be incubated for 1 hour to produce photoactive protoporphyrin-IX (PpIX) before light exposure.
干预措施: 5-aminolevulinic acid (Drug)
5-ALA photopheresis
All patients will receive 5-aminolevulinic acid (5-ALA) in combination with blue light photopheresis. The investigators will collect mononuclear cells by connecting patient to Spectra Optia with CMNC (continuous mononuclear cell collection protocol), and these cells will include active T-lymphocytes. 5-ALA will be incubated for 1 hour to produce photoactive protoporphyrin-IX (PpIX) before light exposure.
干预措施: Blue light photopheresis (Procedure)
5-ALA photopheresis
All patients will receive 5-aminolevulinic acid (5-ALA) in combination with blue light photopheresis. The investigators will collect mononuclear cells by connecting patient to Spectra Optia with CMNC (continuous mononuclear cell collection protocol), and these cells will include active T-lymphocytes. 5-ALA will be incubated for 1 hour to produce photoactive protoporphyrin-IX (PpIX) before light exposure.
干预措施: Transfusion (Procedure)
5-ALA photopheresis
All patients will receive 5-aminolevulinic acid (5-ALA) in combination with blue light photopheresis. The investigators will collect mononuclear cells by connecting patient to Spectra Optia with CMNC (continuous mononuclear cell collection protocol), and these cells will include active T-lymphocytes. 5-ALA will be incubated for 1 hour to produce photoactive protoporphyrin-IX (PpIX) before light exposure.
干预措施: Continuous Mononuclear Cell Collection (CMNC) (Procedure)
结局指标
主要结局
Clinical response
时间窗: Week 13, 26 (28 for patients not eligible for study extension and the latter 5 patients), 38, 50, 64 and 3 months after last treatment
Clinical response (Harvey Bradshaw Index change \> 3 from baseline or less than 4 points)
Safety and tolerability Electrocardiogram-PR segment
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in PR segment before and after treatment
Safety and tolerability Electrocardiogram-T wave
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in T wave before and after treatment
Safety and tolerability Electrocardiogram-QRS complex
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in QRS complex before and after treatment
Alkaline phosphatase
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in serum alkaline phosphatase (U/L) before and after treatment
Bilirubin
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Serum Bilirubin (micromol/L) before and after treatment
Safety and tolerability adverse events
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Frequency, seriousness and intensity of adverse events
Safety and tolerability Electrocardiogram-QT interval
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in QT interval before and after treatment
Safety and tolerability Electrocardiogram-PR interval
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in PR interval before and after treatment
Alanine aminotransferase
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in serum alanine aminotransferase (U/L) before and after treatment
Albumin
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Serum Albumin (g/L) before and after treatment
Safety and tolerability blood pressure
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Vital signs (systolic and diastolic blood pressure) before and after treatment
Aspartate transferase
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in serum aspartate transferase(U/L) before and after treatment
White cell count
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Blood White cell count (10\^9/L) before and after treatment
Safety and tolerability Electrocardiogram-ST segment
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in ST segment before and after treatment
Safety and tolerability vital signs
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Vital signs (heart rate) before and after treatment
Gamma glutamyltransferase
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Serum gamma glutamyltransferase (U/L) before and after treatment
Neutrophil granulocytes
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Blood neutrophil granulocytes (10\^9/L) before and after treatment
Lymphocytes
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Blood Lymphocytes (10\^9/L) before and after treatment
Monocytes
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Blood Monocytes (10\^9/L) before and after treatment
Eosinophile granulocytes
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Blood Eosinophile granulocytes (10\^9/L) before and after treatment
Basophile granulocytes
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Blood Basophile granulocytes (10\^9/L) before and after treatment
Platelet count
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Blood Platelet count (10\^9/L) before and after treatment
Mean Cell Volume
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Blood Mean Cell Volume (fL) before and after treatment
Mean Cell hemoglobin
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Blood Mean Cell hemoglobin (picogram) before and after treatment
International Normalized Ratio
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Blood International Normalized Ratio (0,8-1,2) before and after treatment
Hemoglobin
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Blood Hemoglobin (g/dL) before and after treatment
Calcium
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Serum Calcium (millimol/L) before and after treatment
Potassium
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Serum Potassium (millimol/L) before and after treatment
Sodium
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Serum Sodium (millimol/L) before and after treatment
Creatinin
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Serum Creatinine (micromol/L) before and after treatment
Total Protein
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Serum Total Protein (g/L) before and after treatment
Lactate Dehydrogenase
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Serum Lactate Dehydrogenase (U/L) before and after treatment
Cholesterol
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Serum Cholesterol (millimol/L) before and after treatment
Carbamide
时间窗: Before every treatment visit (every second week from week 0-10, every 4th week from week 14-62, week 28 for patients not eligible for study extension and latter 5 patients) in addition to week 64 and 3 months after last treatment.
Changes in Serum Carbamide (millimol/L) before and after treatment
次要结局
- Quality of life questionnaire Short-Form 36 (SF-36)(Week 13, 26 (28 for patients not eligible for study extension and the latter 5 patients), 38, 50, 64 and/or 3 months after last treatment)
- Quality of life questionnaire Inflammatory Bowel Disease Questionnaire (IBDQ)(Week 13, 26 (28 for patients not eligible for study extension and the latter 5 patients), 38, 50, 64 and/or 3 months after last treatment)
- CD4+ and CD8+ T cell subpopulations(Week 0, 10 (all patients) and 50 (patients of the first 5 subjects eligible for study extension))
- Endoscopic efficacy(Week 13 (all patients) and 64 (patients of the first 5 subjects eligible for study extension) with baseline visit as reference.)
- Faecal calprotectin(Week 13, 26 (28 for patients not eligible for study extension and the latter 5 patients), 38, 50, 64 and/or 3 months after last treatment)
- Concentration of C reactive protein in blood(Week 13, 26 (28 for patients not eligible for study extension and the latter 5 patients), 38, 50, 64 and/or 3 months after last treatment)
- Apoptosis and necrosis(Week 0, 10 (all patients) and 50 (patients of the first 5 subjects eligible for study extension))
- Clinical remission(Week 13 and/or sustained/delayed response in week 26 (28 for patients not eligible for study extension and the latter 5 patients), 38, 50, 64 and 3 months after last treatment.)
研究者
Jørgen Jahnsen
Professor
University Hospital, Akershus