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).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
7
5-aminolevulinic acid (30 mg/ml) will be added to mononuclear cells in a dose of 3 millimolar and incubated for 1 hour
The mononuclear cells incubated with 5-aminolevulinic acid for 1 hour will be exposed to blue light.
The treated cells are transferred back to the patient as a standard blood transfusion
The mononuclear cells are collected using the Spectra Optia with the Continuous Mononuclear Cell Collection protocol. 90 ml of mononuclear cells will be collected and 100 ml of 0,9% saline will be added to dilute the cells before incubation with drug and photopheresis.
Akershus University Hospital
Lorenskog, Akershus, Norway
Clinical response
Clinical response (Harvey Bradshaw Index change \> 3 from baseline or less than 4 points)
Time frame: 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
Safety and tolerability adverse events
Frequency, seriousness and intensity of adverse events
Time frame: 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.
Safety and tolerability Electrocardiogram-PR interval
Changes in PR interval before and after treatment
Time frame: 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.
Safety and tolerability Electrocardiogram-PR segment
Changes in PR segment before and after treatment
Time frame: 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.
Safety and tolerability Electrocardiogram-QT interval
Changes in QT interval before and after treatment
Time frame: 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.
Safety and tolerability Electrocardiogram-ST segment
Changes in ST segment before and after treatment
Time frame: 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.
Safety and tolerability Electrocardiogram-T wave
Changes in T wave before and after treatment
Time frame: 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.
Safety and tolerability Electrocardiogram-QRS complex
Changes in QRS complex before and after treatment
Time frame: 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.
Safety and tolerability vital signs
Vital signs (heart rate) before and after treatment
Time frame: 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.
Safety and tolerability blood pressure
Vital signs (systolic and diastolic blood pressure) before and after treatment
Time frame: 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.
Alkaline phosphatase
Changes in serum alkaline phosphatase (U/L) before and after treatment
Time frame: 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.
Aspartate transferase
Changes in serum aspartate transferase(U/L) before and after treatment
Time frame: 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.
Alanine aminotransferase
Changes in serum alanine aminotransferase (U/L) before and after treatment
Time frame: 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.
Albumin
Changes in Serum Albumin (g/L) before and after treatment
Time frame: 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.
Bilirubin
Changes in Serum Bilirubin (micromol/L) before and after treatment
Time frame: 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.
Gamma glutamyltransferase
Changes in Serum gamma glutamyltransferase (U/L) before and after treatment
Time frame: 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.
White cell count
Changes in Blood White cell count (10\^9/L) before and after treatment
Time frame: 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.
Neutrophil granulocytes
Changes in Blood neutrophil granulocytes (10\^9/L) before and after treatment
Time frame: 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.
Lymphocytes
Changes in Blood Lymphocytes (10\^9/L) before and after treatment
Time frame: 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.
Monocytes
Changes in Blood Monocytes (10\^9/L) before and after treatment
Time frame: 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.
Eosinophile granulocytes
Changes in Blood Eosinophile granulocytes (10\^9/L) before and after treatment
Time frame: 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.
Basophile granulocytes
Changes in Blood Basophile granulocytes (10\^9/L) before and after treatment
Time frame: 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.
Platelet count
Changes in Blood Platelet count (10\^9/L) before and after treatment
Time frame: 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.
Mean Cell Volume
Changes in Blood Mean Cell Volume (fL) before and after treatment
Time frame: 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.
Mean Cell hemoglobin
Changes in Blood Mean Cell hemoglobin (picogram) before and after treatment
Time frame: 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.
International Normalized Ratio
Changes in Blood International Normalized Ratio (0,8-1,2) before and after treatment
Time frame: 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.
Hemoglobin
Changes in Blood Hemoglobin (g/dL) before and after treatment
Time frame: 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.
Calcium
Changes in Serum Calcium (millimol/L) before and after treatment
Time frame: 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.
Potassium
Changes in Serum Potassium (millimol/L) before and after treatment
Time frame: 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.
Sodium
Changes in Serum Sodium (millimol/L) before and after treatment
Time frame: 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.
Creatinin
Changes in Serum Creatinine (micromol/L) before and after treatment
Time frame: 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.
Lactate Dehydrogenase
Changes in Serum Lactate Dehydrogenase (U/L) before and after treatment
Time frame: 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.
Cholesterol
Changes in Serum Cholesterol (millimol/L) before and after treatment
Time frame: 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.
Total Protein
Changes in Serum Total Protein (g/L) before and after treatment
Time frame: 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.
Carbamide
Changes in Serum Carbamide (millimol/L) before and after treatment
Time frame: 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.
CD4+ and CD8+ T cell subpopulations
Number of CD4+ and CD8+ T cell subpopulations before and after treatment assessed by flow cytometry.
Time frame: Week 0, 10 (all patients) and 50 (patients of the first 5 subjects eligible for study extension)
Apoptosis and necrosis
Number of cells in apoptosis or necrosis before and after treatment assessed by flow cytometry
Time frame: Week 0, 10 (all patients) and 50 (patients of the first 5 subjects eligible for study extension)
Clinical remission
Harvey Bradshaw Index \< 5 points
Time frame: 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.
Endoscopic efficacy
Simple Endoscopic Score for Crohns Disease \>49 % improvement or \< 3 (endoscopic remission)
Time frame: Week 13 (all patients) and 64 (patients of the first 5 subjects eligible for study extension) with baseline visit as reference.
Faecal calprotectin
Change from baseline
Time frame: 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
Change from baseline
Time frame: 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 Short-Form 36 (SF-36)
Change of both total and subscores of SF-36 from baseline. Min 0 Max 100. Higher value is better quality of life.
Time frame: 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
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Quality of life questionnaire Inflammatory Bowel Disease Questionnaire (IBDQ)
Change of both total and subscores of IBDQ from baseline. Min 32 Max 224. Higher value is better quality of life.
Time frame: 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