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

Crohn Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04164849
• Other study ID #: twostepala
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: November 22, 2019
• Est. completion date: October 31, 2023

Study information

• Verified date: January 2024
• Source: University Hospital, Akershus
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7
• Est. completion date: October 31, 2023
• Est. primary completion date: October 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Provision of informed consent

2. Age above 18

3. Male or female patient with active Crohn's disease (6)

4. Women of childbearing potential (WOCBP) will have to use highly effective methods of contraception throughout the entire study.

5. 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

6. Active inflammation in the gut documented by

1. Harvey Bradshaw Index >5 and

2. 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

3. Inflammatory marker; fecal calprotectin > 250 and/or C reactive protein > 5

Exclusion Criteria:

1. Photosensitive comorbidities, porphyria or known hypersensitivity to 5-aminolevulinic acid or porphyrins

2. Patients with aphakia

3. 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.

4. 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

5. Subjects with polyneuropathy

6. Uncontrolled infection or fever

7. History of heparin-induced thrombocytopenia, absolute neutrophil count <1x109, platelet count <20x10 9

8. Body weight below 40 kg

9. Investigator considers subject unlikely to comply with study procedures, restrictions and requirements.

10. Presence of other gastrointestinal diseases potentially influencing the study endpoints

11. 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.

Related Conditions & MeSH terms

• Crohn Disease

Intervention

Drug:
• 5-aminolevulinic acid
5-aminolevulinic acid (30 mg/ml) will be added to mononuclear cells in a dose of 3 millimolar and incubated for 1 hour

Procedure:
• Blue light photopheresis
The mononuclear cells incubated with 5-aminolevulinic acid for 1 hour will be exposed to blue light.
• Transfusion
The treated cells are transferred back to the patient as a standard blood transfusion
• Continuous Mononuclear Cell Collection (CMNC)
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.

Locations

Country	Name	City	State
Norway	Akershus University Hospital	Lorenskog	Akershus

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Akershus	Oslo University Hospital

Country where clinical trial is conducted

Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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	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)
Secondary	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)
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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