Extracorporeal Photopheresis of Patients With Crohn's Disease Using 5-aminolevulinic Acid

Study Overview
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Brief Summary
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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 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).

Official Title
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Extracorporeal Photopheresis of Patients With Crohn's Disease Using 5-aminolevulinic Acid

Conditions
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Crohn Disease

Intervention / Treatment
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* Drug: 5-aminolevulinic acid
* Procedure: Blue light photopheresis
* Procedure: Transfusion
* Procedure: Continuous Mononuclear Cell Collection (CMNC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: A combined phase 1/2 pilot study with emphasize on safety/tolerability but also clinical efficacy/effect
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5-ALA photopheresis<br>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. | Drug: 5-aminolevulinic acid<br>* 5-aminolevulinic acid (30 mg/ml) will be added to mononuclear cells in a dose of 3 millimolar and incubated for 1 hour<br>Procedure: Blue light photopheresis<br>* The mononuclear cells incubated with 5-aminolevulinic acid for 1 hour will be exposed to blue light.<br>Procedure: Transfusion<br>* The treated cells are transferred back to the patient as a standard blood transfusion<br>Procedure: Continuous Mononuclear Cell Collection (CMNC)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response | Clinical response (Harvey Bradshaw Index change > 3 from baseline or less than 4 points) | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD4+ and CD8+ T cell subpopulations | Number of CD4+ and CD8+ T cell subpopulations before and after treatment assessed by flow cytometry. | 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 | Week 0, 10 (all patients) and 50 (patients of the first 5 subjects eligible for study extension) | 
| Clinical remission | Harvey Bradshaw Index < 5 points | 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) | 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 | 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 | 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. | 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) | Change of both total and subscores of IBDQ from baseline. Min 32 Max 224. Higher value is better quality of life. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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UVA-PIT, Crohns Disease, Photopheresis, 5-aminolevulinic acid, Gliolan