Optimizing Anti-IL17 Antibody Therapy by Associating Fiber Supplementation to Correct Treatment-aggravated Gut Dysbiosis in Axial Spondyloarthritis - RESPOND-IL17

Axial Spondyloarthritis Clinical Trial

— RESPOND-IL17  

Official title:

Optimization of Anti-IL17 Antibody Therapy by Associating Fiber Supplementation to Correct Treatment-aggravated Gut Dysbiosis in Axial Spondyloarthritis - RESPOND-IL17

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05812157
• Other study ID #: IDRCB : 2022-A00135-38
• Status: Recruiting
• Phase: N/A
• Start date: October 2, 2023
• Est. completion date: December 1, 2026

Study information

• Verified date: October 2023
• Source: Centre Hospitalier Universitaire de Nimes
• Contact: Cédric LUKAS, Professor
• Phone: +334 67 33 87 10
• Email: c-lukas[@]chu-montpellier.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Fiber is the main source of energy for colonic bacteria and its consumption favorably modifies the composition of the microbiota in only a few days. Their fermentation in the colon releases short-chain fatty acids (SCFAs). Clostridiales contain many strains producing SCFAs. These SCFAs can restore the intestinal barrier and promote certain anti-inflammatory cells, including regulatory T cells (Tregs), which are essential to the mechanisms in tolerance of the self. Fibers could therefore correct the intestinal abnormalities present in patients with axial spondyloarthritis (AxSpA) and aggravated by anti-IL-17 drugs and thus improve the therapeutic response to these treatments.

The hypothesis is that dietary fiber will correct the dysbiosis in AxSpA patients and increase the release of SCFAs, which favorably modulate the immune response and improve AxSpA.

Description:

Axial spondyloarthritis (AxSpA) is the second most common chronic inflammatory rheumatic disease, which develops preferentially in young subjects and results in a significant impairment of quality of life, particularly due to painful symptoms. The importance of the digestive system has long been recognized, since this disease is considered to be part of a larger group of diseases including Crohn's disease and ulcerative colitis because of their frequent association in the same patient, and because leaky gut disorders and alterations of the intestinal microbiota (dysbiosis) have been described in these patients. These abnormalities may stimulate the immune system and therefore be involved in inflammatory processes (especially Th17). The available treatments are based on non-steroidal anti-inflammatory drugs, and in the event of failure or intolerance, biomedicines targeting TNF can be used. Therapeutic monoclonal antibodies against IL-17 have recently enriched the therapeutic arsenal. Although most anti-TNF agents have a beneficial effect on the rheumatologic and digestive aspects of these diseases, anti-IL-17 agents are not expected to be effective in inflammatory bowel diseases.

Indeed, a deleterious role of anti-IL-17 on the intestinal microbiota has even been demonstrated, which could result in a reduction of the systemic anti-inflammatory effect expected from these molecules, and consequently of the clinical benefit felt by the patient. In fact, anti-IL-17s lead to a significant decrease in Clostridiales, bacteria that participate in intestinal homeostasis.

Fiber is the main source of energy for colonic bacteria and its consumption favorably modifies the composition of the microbiota in just a few days. Their fermentation in the colon releases short-chain fatty acids (SCFAs). Clostridiales contain many strains producing SCFAs. These SCFAs can restore the intestinal barrier and promote certain anti-inflammatory cells, including regulatory T cells (Tregs), which are essential to the mechanisms in tolerance of the self. Fibers could therefore correct the intestinal abnormalities present in AxSpA patients and aggravated by anti-IL-17 drugs and thus improve the therapeutic response to these treatments.

The hypothesis is therefore that dietary fiber will correct the dysbiosis in AxSpA patients and increase the release of SCFAs, which favorably modulate the immune response and thus improve AxSpA.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: December 1, 2026
• Est. primary completion date: December 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

Inclusion criteria:

• Patients with spondyloarthritis meeting the ASAS criteria

• Patient considered by the treating rheumatologist for anti-IL-17 biomedication

• Patients aged between 18 and 90 years of age

• Patients who are affiliated to a French social security system or beneficiaries of such a system

• Patients with no desire to become pregnant during the study period (Effective contraception for women of childbearing age during the study period (surgical sterilization, hormonal contraceptives, barrier method, intrauterine device))

Exclusion Criteria:

• Lack of written informed consent after a time of reflection

• Patients participating in other therapeutic research or having participated in research for which the exclusion period has not ended

• Patient under court protection, guardianship or curatorship.

• Patient unable to give consent.

• Pregnant or breastfeeding woman

• Patients with digestive disorders for which a chronic inflammatory bowel disease has not been excluded

• Patients with fructose intolerance or glucose or galactose malabsorption

• Patients with known intolerance to inulin or maltodextrin

Related Conditions & MeSH terms

• Axial Spondyloarthritis
• Dysbiosis
• Spondylarthritis
• Spondylitis

Intervention

Dietary Supplement:
• Daily dietary supplementation with Fibruline
Supplementation with 12 grams per day of Fibruline reconstituted with 60mL of water, once a day

Drug:
• Anti-IL-17 therapy
Patients in both groups will be on anti-IL-17 therapy

Locations

Country	Name	City	State
France	Montpellier University Hospital	Montpellier	Hérault
France	Nîmes University Hospital	Nîmes	Gard
France	Tours Regional University Hospital (Bretonneau)	Tours	Indre-et-Loire

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Nimes

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clostridial changes in the Experimental group	Patients will receive fiber supplementation with inulin (Fibruline® Instant, Fagron laboratory) at a rate of 12 grams of powder per day reconstituted with approximately 60mL of water and consumed in one intake per day. To confirm the efficacy of treatment, the percentage of patients with a >10% decrease in Clostriadiales in their stools at 3 months after initiation of anti-IL-17 will be recorded. This percentage will be based on the distribution of bacteria analyzed by 16S RNA sequencing.	Week 0
Primary	Clostridial changes in Controls	Patients will receive a placebo consisting of Maltodextrin (Fagron laboratories), packaged in jars identical to those used for inulin, with a volumetric equivalent, an energy contribution and very similar color. Patients will consume 12 grams of powder per day reconstituted with approximately 60mL of water and consumed in one intake per day. The percentage of patients with a >10% decrease in Clostriadiales in their stools at 3 months after initiation of anti-IL-17 will be recorded. This percentage will be based on the distribution of bacteria analyzed by 16S RNA sequencing.	Week 0
Primary	Clostridial changes in the Experimental group	Patients will receive fiber supplementation with inulin (Fibruline® Instant, Fagron laboratory) at a rate of 12 grams of powder per day reconstituted with approximately 60mL of water and consumed in one intake per day. To confirm the efficacy of treatment, the percentage of patients with a >10% decrease in Clostriadiales in their stools at 3 months after initiation of anti-IL-17 will be recorded. This percentage will be based on the distribution of bacteria analyzed by 16S RNA sequencing.	Week 12
Primary	Clostridial changes in Controls	Patients will receive a placebo consisting of Maltodextrin (Fagron laboratories), packaged in jars identical to those used for inulin, with a volumetric equivalent, an energy contribution and very similar color. Patients will consume 12 grams of powder per day reconstituted with approximately 60mL of water and consumed in one intake per day. The percentage of patients with a >10% decrease in Clostriadiales in their stools at 3 months after initiation of anti-IL-17 will be recorded. This percentage will be based on the distribution of bacteria analyzed by 16S RNA sequencing.	Week 12
Secondary	Effect of fiber supplementation on clinical therapeutic response in the experimental group: Delta BASDAI	Clinical response rates observed in patients treated with anti-IL-17 with fiber supplementation will be recorded as a percentage.; The BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) will be used to measure the percentage of patients responding positively to treatment.	Week 0
Secondary	Effect of fiber supplementation on clinical therapeutic response in the experimental group: Delta BASDAI	Clinical response rates observed at 3 months in patients treated with anti-IL-17 with fiber supplementation will be recorded as a percentage.; The BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) will be used to measure the percentage of patients responding positively to treatment.	Week 12
Secondary	Effect of fiber supplementation on clinical therapeutic response in the experimental group: ASAS20	Clinical response rates observed in patients treated with anti-IL-17 with fiber supplementation will be recorded as a percentage.; The ASAS20 will be used to measure the percentage of patients responding positively to treatment. This tool was developed by the Assessment of SpondylArthritis international Society (ASAS). The ASAS Response Criteria (ASAS 20) is defined as an improvement in at least 20% and an absolute improvement in at least 10 units on a 0-100 scale in at least three of the following domains: Patient global assessment, Pain assessment, Function, and Inflammation (last 2 questions of BASDAI).	Week 0
Secondary	Effect of fiber supplementation on clinical therapeutic response in the experimental group: ASAS20	Clinical response rates observed at 3 months in patients treated with anti-IL-17 with fiber supplementation will be recorded as a percentage.; The ASAS20 will be used to measure the percentage of patients responding positively to treatment. This tool was developed by the Assessment of SpondylArthritis international Society (ASAS). The ASAS Response Criteria (ASAS 20) is defined as an improvement in at least 20% and an absolute improvement in at least 10 units on a 0-100 scale in at least three of the following domains: Patient global assessment, Pain assessment, Function, and Inflammation (last 2 questions of BASDAI).	Week 12
Secondary	Effect of fiber supplementation on clinical therapeutic response in the experimental group: ASAS40	Clinical response rates observed in patients treated with anti-IL-17 with fiber supplementation will be recorded as a percentage.; The ASAS40 will be used to measure the percentage of patients responding positively to treatment. This tool was developed by the Assessment of SpondylArthritis international Society (ASAS). The ASAS Response Criteria (ASAS 40) is defined as an improvement in at least 40% and an absolute improvement in at least 10 units on a 0-100 scale in at least three of the following domains: Patient global assessment, Pain assessment, Function, and Inflammation (last 2 questions of BASDAI).	Week 0
Secondary	Effect of fiber supplementation on clinical therapeutic response in the experimental group: ASAS40	Clinical response rates observed at 3 months in patients treated with anti-IL-17 with fiber supplementation will be recorded as a percentage.; The ASAS40 will be used to measure the percentage of patients responding positively to treatment. This tool was developed by the Assessment of SpondylArthritis international Society (ASAS). The ASAS Response Criteria (ASAS 40) is defined as an improvement in at least 40% and an absolute improvement in at least 10 units on a 0-100 scale in at least three of the following domains: Patient global assessment, Pain assessment, Function, and Inflammation (last 2 questions of BASDAI).	Week 12
Secondary	Effect of fiber supplementation on clinical therapeutic response in the experimental group: ASDAS	Clinical response rates observed at 3 months in patients treated with anti-IL-17 with fiber supplementation will be recorded as a percentage.; The ASDAS (Ankylosing Spondylitis Disease Activity Score) will be used to measure the percentage of patients responding positively to treatment. This tool is an index to assess disease activity in Ankylosing Spondylitis. The preferred score uses CRP (C-reactive protein) rather than ESR (erythrocyte sedimentation rate).	Week 0
Secondary	Effect of fiber supplementation on clinical therapeutic response in the experimental group: ASDAS	Clinical response rates observed at 3 months in patients treated with anti-IL-17 with fiber supplementation will be recorded as a percentage.; The ASDAS (Ankylosing Spondylitis Disease Activity Score) will be used to measure the percentage of patients responding positively to treatment. This tool is an index to assess disease activity in Ankylosing Spondylitis. The preferred score uses CRP (C-reactive protein) rather than ESR (erythrocyte sedimentation rate).	Week 12
Secondary	Effect of fiber supplementation on clinical therapeutic response: GIQLI	Clinical response rates in patients treated with anti-IL-17 with fiber supplementation will be recorded as a percentage.; Digestive symptoms will be assessed using the Gastrointestinal Quality of Life Index (GIQLI) questionnaire at Week 0 and Week 12. The GIQLI is a measure of the subjective perception of well-being by a patient, which may vary unexpectedly between diagnostic groups. The GIQLI was initiated in Germany and includes 36 items asking about symptoms, physical status, emotions, social dysfunction, and effects of medical treatment. The Questions cover the following 5 dimensions : symptoms, physical condition, emotions, social integration and medical treatment.	Week 0
Secondary	Effect of fiber supplmentation on clinical therapeutic response: GIQLI	Clinical response rates observed at 3 months in patients treated with anti-IL-17 with fiber supplementation will be recorded as a percentage.; Digestive symptoms will be assessed using the Gastrointestinal Quality of Life Index (GIQLI) questionnaire at Week 0 and Week 12. The GIQLI is a measure of the subjective perception of well-being by a patient, which may vary unexpectedly between diagnostic groups. The GIQLI was initiated in Germany and includes 36 items asking about symptoms, physical status, emotions, social dysfunction, and effects of medical treatment. The Questions cover the following 5 dimensions : symptoms, physical condition, emotions, social integration and medical treatment.	Week 12
Secondary	Effect at 12 weeks of placebo on clinical therapeutic response: Delta BASDAI	Clinical response rates observed in patients treated with anti-IL-17 without fiber supplementation will be recorded as a percentage.; The BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) will be used to measure the percentage of patients responding positively to treatment.	Week 0
Secondary	Effect at 12 weeks of placebo on clinical therapeutic response: Delta BASDAI	Clinical response rates observed at 3 months in patients treated with anti-IL-17 without fiber supplementation will be recorded as a percentage.; The BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) will be used to measure the percentage of patients responding positively to treatment.	Week 12
Secondary	Effect at 12 weeks of placebo on clinical therapeutic response: ASA20	Clinical response rates observed in patients treated with anti-IL-17 without fiber supplementation will be recorded as a percentage.; The ASAS20 will be used to measure the percentage of patients responding positively to treatment.This tool was developed by the Assessment of SpondylArthritis international Society (ASAS). The ASAS Response Criteria (ASAS 20) is defined as an improvement in at least 20% and an absolute improvement in at least 10 units on a 0-100 scale in at least three of the following domains: Patient global assessment, Pain assessment, Function, and Inflammation (last 2 questions of BASDAI).	Week 0
Secondary	Effect at 12 weeks of placebo on clinical therapeutic response: ASA20	Clinical response rates observed at 3 months in patients treated with anti-IL-17 without fiber supplementation will be recorded as a percentage.; The ASAS20 will be used to measure the percentage of patients responding positively to treatment.This tool was developed by the Assessment of SpondylArthritis international Society (ASAS). The ASAS Response Criteria (ASAS 20) is defined as an improvement in at least 20% and an absolute improvement in at least 10 units on a 0-100 scale in at least three of the following domains: Patient global assessment, Pain assessment, Function, and Inflammation (last 2 questions of BASDAI).	Week 12
Secondary	Effect at 12 weeks of placebo on clinical therapeutic response: ASA40	Clinical response rates observed in patients treated with anti-IL-17 without fiber supplementation will be recorded as a percentage.; The ASAS40 will be used to measure the percentage of patients responding positively to treatment.This tool was developed by the Assessment of SpondylArthritis international Society (ASAS). The ASAS Response Criteria (ASAS 40) is defined as an improvement in at least 40% and an absolute improvement in at least 10 units on a 0-100 scale in at least three of the following domains: Patient global assessment, Pain assessment, Function, and Inflammation (last 2 questions of BASDAI).	Week 0
Secondary	Effect at 12 weeks of placebo on clinical therapeutic response: ASA40	Clinical response rates observed at 3 months in patients treated with anti-IL-17 without fiber supplementation will be recorded as a percentage.; The ASAS40 will be used to measure the percentage of patients responding positively to treatment.This tool was developed by the Assessment of SpondylArthritis international Society (ASAS). The ASAS Response Criteria (ASAS 40) is defined as an improvement in at least 40% and an absolute improvement in at least 10 units on a 0-100 scale in at least three of the following domains: Patient global assessment, Pain assessment, Function, and Inflammation (last 2 questions of BASDAI).	Week 12
Secondary	Effect at 12 weeks of placebo on clinical therapeutic response: ASDAS	Clinical response rates observed at 3 months in patients treated with anti-IL-17 without fiber supplementation will be recorded as a percentage. The ASDAS (Ankylosing Spondylitis Disease Activity Score) will be used to measure the percentage of patients responding positively to treatment. This tool is an index to assess disease activity in Ankylosing Spondylitis. The preferred score uses CRP (C-reactive protein) rather than ESR (erythrocyte sedimentation rate).	Week 0
Secondary	Effect at 12 weeks of placebo on clinical therapeutic response: ASDAS	Clinical response rates observed at 3 months in patients treated with anti-IL-17 without fiber supplementation will be recorded as a percentage. The ASDAS (Ankylosing Spondylitis Disease Activity Score) will be used to measure the percentage of patients responding positively to treatment. This tool is an index to assess disease activity in Ankylosing Spondylitis. The preferred score uses CRP (C-reactive protein) rather than ESR (erythrocyte sedimentation rate).	Week 12
Secondary	Effect of placebo on clinical therapeutic response: GIQLI	Clinical response rates observed in patients treated with anti-IL-17 without fiber supplementation will be recorded as a percentage.; Digestive symptoms will be assessed using the Gastrointestinal Quality of Life Index (GIQLI) questionnaire at Week 0 and Week 12. The GIQLI is a measure of the subjective perception of well-being by a patient, which may vary unexpectedly between diagnostic groups. The GIQLI was initiated in Germany and includes 36 items asking about symptoms, physical status, emotions, social dysfunction, and effects of medical treatment. The Questions cover the following 5 dimensions : symptoms, physical condition, emotions, social integration and medical treatment.	Week 0
Secondary	Effect of placebo on clinical therapeutic response: GIQLI	Clinical response rates observed at 3 months in patients treated with anti-IL-17 without fiber supplementation will be recorded as a percentage.; Digestive symptoms will be assessed using the Gastrointestinal Quality of Life Index (GIQLI) questionnaire at Week 0 and Week 12. The GIQLI is a measure of the subjective perception of well-being by a patient, which may vary unexpectedly between diagnostic groups. The GIQLI was initiated in Germany and includes 36 items asking about symptoms, physical status, emotions, social dysfunction, and effects of medical treatment. The Questions cover the following 5 dimensions : symptoms, physical condition, emotions, social integration and medical treatment.	Week 12
Secondary	Tolerance of anti-IL17 intervention and treatment in the experimental group: Permeability	Changes in serum concentrations of intestinal permeability markers (zonulin, claudin-3, iFABP); and endotoxemia (LBP, CD14s) will be measured by ELISA in ng/ml	Month 0
Secondary	Tolerance of anti-IL17 intervention and treatment in controls: Permeability	Changes in serum concentrations of intestinal permeability markers (zonulin, claudin-3, iFABP); and endotoxemia (LBP, CD14s) will be measured by ELISA in ng/ml	Month 3
Secondary	Tolerance of anti-IL17 intervention and treatment in the experimental group	The distribution and diversity of different germs will be measured by 16S RNA sequencing.; Quantitative	Month 3
Secondary	Tolerance of anti-IL17 intervention and treatment in controls	The distribution and diversity of different germs will be measured by 16S RNA sequencing.; Quantitative	Month 3
Secondary	Presence of candida in patients in the experimental group	YES/NO	Month 3
Secondary	Presence of candida in patients in the control group	YES/NO	Month 3
Secondary	Tolerance of treatment in the experimental group	All adverse events related or not to anti-IL17 treatment and potentially associated with the consumption of high doses of fiber (bloating, flatulence, diarrhea, abdominal pain) will be recorded	Month 3
Secondary	Tolerance of treatment in the control group	All adverse events related or not to anti-IL17 treatment and potentially associated with the consumption of high doses of fiber (bloating, flatulence, diarrhea, abdominal pain) will be recorded	Month 3
Secondary	Complete blood count: Red blood cells in the experimental group	Red blood cells will be measured in millions/mm3	Month 0
Secondary	Complete blood count: Red blood cells in the control group	Red blood cells will be measured in millions/mm3	Month 0
Secondary	Complete blood count: Red blood cells in the experimental group	Red blood cells will be measured in millions/mm3	Month 3
Secondary	Complete blood count: Red blood cells in the control group	Red blood cells will be measured in millions/mm3	Month 3
Secondary	Complete blood count: White blood cells in the experimental group	White blood cells will be measured in millions/mm3	Month 0
Secondary	Complete blood count: White blood cells in the control group	White blood cells will be measured in millions/mm3	Month 0
Secondary	Complete blood count: White blood cells in the experimental group	White blood cells will be measured in millions/mm3	Month 3
Secondary	Complete blood count: White blood cells in the control group	White blood cells will be measured in millions/mm3	Month 3
Secondary	Complete blood count: Hemoglobin in the experimental group	Hemoglobin will be measured in g/L	Month 0
Secondary	Complete blood count: Hemoglobin in the control group	Hemoglobin will be measured in g/L	Month 0
Secondary	Complete blood count: Hemoglobin in the experimental group	Hemoglobin will be measured in g/L	Month 3
Secondary	Complete blood count: Hemoglobin in the control group	Hemoglobin will be measured in g/L	Month 3
Secondary	Complete blood count: Hematocrit in the experimental group	Hematocrit will be measured as a % of whole blood	Month 0
Secondary	Complete blood count: Hematocrit in the control group	Hematocrit will be measured as a % of whole blood	Month 0
Secondary	Complete blood count: Hematocrit in the experimental group	Hematocrit will be measured as a % of whole blood	Month 3
Secondary	Complete blood count: Hematocrit in the control group	Hematocrit will be measured as a % of whole blood	Month 3
Secondary	Complete blood count: Platelets in the experimental group	Platelets will be measured in K/µL	Month 0
Secondary	Complete blood count: Platelets in the control group	Platelets will be measured in K/µL	Month 0
Secondary	Complete blood count: Platelets in the experimental group	Platelets will be measured in K/µL	Month 3
Secondary	Complete blood count: Platelets in the control group	Platelets will be measured in K/µL	Month 3
Secondary	T-lymphocytes in the experimental group	The phenotype of T-lymphocytes (Treg, Thelpers) will be measured as % of total white blood cells	Month 0
Secondary	T-lymphocytes in the control group	The phenotype of T-lymphocytes (Treg, Thelpers) will be measured as % of total white blood cells	Month 0
Secondary	T-lymphocytes in the experimental group	The phenotype of T-lymphocytes (Treg, Thelpers) will be measured as % of total white blood cells	Month 3
Secondary	T-lymphocytes in the control group	The phenotype of T-lymphocytes (Treg, Thelpers) will be measured as % of total white blood cells	Month 3
Secondary	Monocytes in the experimental group	Monocytes will be measured by flow cytometry (CD25, CD127, CXCR3, CCR6, CD294, CD14, CD16, TNF, IL-6) as % of total white blood cells	Month 0
Secondary	Monocytes in the control group	Monocytes will be measured by flow cytometry (CD25, CD127, CXCR3, CCR6, CD294, CD14, CD16, TNF, IL-6) as % of total white blood cells	Month 0
Secondary	Monocytes in the experimental group	Monocytes will be measured by flow cytometry (CD25, CD127, CXCR3, CCR6, CD294, CD14, CD16, TNF, IL-6) as % of total white blood cells	Month 3
Secondary	Monocytes in the control group	Monocytes will be measured by flow cytometry (CD25, CD127, CXCR3, CCR6, CD294, CD14, CD16, TNF, IL-6) as % of total white blood cells	Month 3
Secondary	Aspartate aminotransferase (ASAT) in the experimental group	Aspartate aminotransferase (or ASAT) will be measured in international units per liter	Month 0
Secondary	Aspartate aminotransferase (ASAT) in the experimental group	Aspartate aminotransferase (or ASAT) will be measured in international units per liter	Month 3
Secondary	Aspartate aminotransferase (ASAT) in the control group	Aspartate aminotransferase (or ASAT) will be measured in international units per liter	Month 0
Secondary	Aspartate aminotransferase (ASAT) in the control group	Aspartate aminotransferase (or ASAT) will be measured in international units per liter	Month 3
Secondary	Alanine aminotransferase (ALAT) in the experimental group	Alanine aminotransferase (ALAT) will be measured in international units per liter	Month 0
Secondary	Alanine aminotransferase (ALAT) in the experimental group	Alanine aminotransferase (ALAT) will be measured in international units per liter	Month 3
Secondary	Alanine aminotransferase (ALAT) in the control group	Alanine aminotransferase (ALAT) will be measured in international units per liter	Month 0
Secondary	Alanine aminotransferase (ALAT) in the control group	Alanine aminotransferase (ALAT) will be measured in international units per liter	Month 3
Secondary	Alkaline phosphatase in the experimental group	Alkaline phosphatase (ALP) will be measured in units per liter	Month 0
Secondary	Alkaline phosphatase in the experimental group	Alkaline phosphatase (ALP) will be measured in units per liter	Month 3
Secondary	Alkaline phosphatase in the control group	Alkaline phosphatase (ALP) will be measured in units per liter	Month 0
Secondary	Alkaline phosphatase in the control group	Alkaline phosphatase (ALP) will be measured in units per liter	Month 3
Secondary	Calcium in the experimental group	Calcium will be measured in mmol/L	Month 0
Secondary	Calcium in the experimental group	Calcium will be measured in mmol/L	Month 3
Secondary	Calcium in the control group	Calcium will be measured in mmol/L	Month 0
Secondary	Calcium in the control group	Calcium will be measured in mmol/L	Month 3
Secondary	Creatinine in the experimental group	Calcium will be measured in µmol/L	Month 0
Secondary	Creatinine in the experimental group	Calcium will be measured in µmol/L	Month 12
Secondary	Creatinine in the control group	Calcium will be measured in µmol/L	Month 0
Secondary	Creatinine in the control group	Calcium will be measured in µmol/L	Month 12
Secondary	Albumin in the experimental group	Albumin will be measured in g/liter	Month 0
Secondary	Albumin in the experimental group	Albumin will be measured in g/liter	Month 12
Secondary	Albumin in the control group	Albumin will be measured in g/liter	Month 0
Secondary	Albumin in the control group	Albumin will be measured in g/liter	Month 12
Secondary	Urea in the experimental group	Urea will be measured in mmol/L	Month 0
Secondary	Urea in the experimental group	Urea will be measured in mmol/L	Month 12
Secondary	Urea in the control group	Urea will be measured in mmol/L	Month 0
Secondary	Urea in the control group	Urea will be measured in mmol/L	Month 12
Secondary	Bilirubin in the experimental group	Bilirubin will be measured in µmol/L	Month 0
Secondary	Bilirubin in the experimental group	Bilirubin will be measured in µmol/L	Month 12
Secondary	Bilirubin in the control group	Bilirubin will be measured in µmol/L	Month 0
Secondary	Bilirubin in the control group	Bilirubin will be measured in µmol/L	Month 12
Secondary	C-Reactive Protein in the experimental group	C-Reactive Protein will be measured in mg/L	Month 0
Secondary	C-Reactive Protein in the experimental group	C-Reactive Protein will be measured in mg/L	Month 12
Secondary	C-Reactive Protein in the control group	C-Reactive Protein will be measured in mg/L	Month 0
Secondary	C-Reactive Protein in the control group	C-Reactive Protein will be measured in mg/L	Month 12