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

NCT04164849 | Completed Phase 1 DMC

• 1 other identifier: twostepala
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

Brief 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).

Conditions

Crohn Disease

Keywords

Crohns Disease; Photopheresis; 5-aminolevulinic acid; Gliolan; UVA-PIT

Outcome Measures

Primary Outcomes (35)

• 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 Outcomes (8)

• CD4+ and CD8+ T cell subpopulations

  Week 0, 10 (all patients) and 50 (patients of the first 5 subjects eligible for study extension)

• 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.

• 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

Study Arms (1)

5-ALA photopheresis

EXPERIMENTAL

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; Procedure: Blue light photopheresis; Procedure: Transfusion; Procedure: Continuous Mononuclear Cell Collection (CMNC)

Interventions

5-aminolevulinic acid DRUG

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

5-ALA photopheresis

Blue light photopheresis PROCEDURE

The mononuclear cells incubated with 5-aminolevulinic acid for 1 hour will be exposed to blue light.

5-ALA photopheresis

Transfusion PROCEDURE

The treated cells are transferred back to the patient as a standard blood transfusion

5-ALA photopheresis

Continuous Mononuclear Cell Collection (CMNC) PROCEDURE

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.

5-ALA photopheresis

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Hospital, Akershus: lead
• Oslo University Hospital: collaborator

Study Sites (1)

Akershus University Hospital

Lorenskog, Akershus, 1478, Norway

Location

MeSH Terms

Conditions

Crohn Disease

Interventions

Aminolevulinic Acid; Blood Transfusion

Condition Hierarchy (Ancestors)

Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Levulinic Acids; Keto Acids; Carboxylic Acids; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Biological Therapy; Therapeutics

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Masking Details: all patients will receive active treatment
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: A combined phase 1/2 pilot study with emphasize on safety/tolerability but also clinical efficacy/effect

Study Record Dates

• First Submitted: November 8, 2019
• First Posted: November 15, 2019
• Study Start: November 22, 2019
• Primary Completion: October 31, 2023
• Study Completion: October 31, 2023
• Last Updated: January 30, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

NO (1)