Evaluating Gut Imaging and Stool Biomarkers in Patients With Scleroderma-associated Gastrointestinal Disease

• Conditions: Scleroderma; Systemic Sclerosis
• Interventions: Diagnostic Test: PET-MRI scan

• Registration Number: NCT04630782
• Lead Sponsor: Singapore General Hospital

Brief Summary

Systemic sclerosis (SSc) is characterized by autoimmunity and vasculopathy resulting in fibrosis of the skin and internal organs including the Gastrointestinal (GI) tract. Key unmet clinical needs are the availability of non-invasive biomarkers for early diagnosis of SSc-GI, further characterization of different stages of SSc-GI and SSc-GI treatment response. The investigators propose combining MRI FDG-PET with MRI T1-MOLLI mapping, which has been applied to cardiac imaging to quantify histologically correlated cardiac fibrosis. T1-MOLLI enables detection and quantification of diffuse fibrosis without the need for contrast.

Aim 1: FDG-PET-MRI imaging (primary biomarker) and stool markers (secondary biomarker) will be compared between patients with VEDOSS/early SSc and those with late SSc not on immunosuppressive treatment.

Aim 2: Evaluation of change in biomarker levels from pre-treatment baseline to 6 months (primary end-point) and 12-months (secondary end-point) following MMF treatment, in early SSc patients

Using precision medicine approach in diagnosis and treatment evaluation, the investigators anticipate that this study will contribute significantly to advance management strategies for, and improve outcomes of SSc-GI disease.

Detailed Description

1. Aim 1 Determine if FDG-PET-MRI imaging biomarkers differentiate patients with VEDOSS/ early SSc (predominantly inflammatory) from those with late SSc (predominantly fibrosis). Stool markers will be used as secondary biomarkers supporting inflammation.

Study design: cross-sectional; The investigators will compare biomarkers between patients with VEDOSS/early SSc and those with late SSc not on immunosuppressive treatment.

2. Aim 2 Evaluate FDG-PET-MRI imaging biomarker change over a 6- and 12-month treatment period with mycophenolate mofetil (MMF) in patients with early SSc. Stool markers will be used as secondary biomarkers supporting inflammation.

Study design: longitudinal; In early SSc patients, the investigators will determine change in biomarker levels from pre-treatment baseline to 6 months (primary end-point) and 12-months (secondary end-point) following MMF treatment.

3. Exploratory Aim: In patients with VEDOSS/early SSc not on immunosuppressive treatment, the investigators will characterize imaging and stool biomarker changes over one year.

Study Timeline

• Study First Submitted: 2020-03-12
• Study Start: 2020-04-09
• Status Verified: 2020-11
• Study First Submitted QC: 2020-11-13
• Study First Posted: 2020-11-16
• Last Update Submitted: 2020-11-23
• Last Update Posted: 2020-11-24
• Primary Completion: 2023-01-31
• Study Completion: 2023-01-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 70

Inclusion Criteria

(i) ≥ 21 years old (ii) SSc fulfilling the American College of Rheumatology/European League Against Rheumatism (EULAR) 2013 criteria or VEDOSS fulfilling proposed criteria by EULAR

Aim 1 subject stratification:

(i) VEDOSS/ early SSc (≤3 years) or late SSc (> 5 years), with disease duration defined from onset of first non-Raynaud's symptom (ii) Not on any immunosuppressive treatment or prednisolone >10 mg /day 8 weeks before recruitment

Aim 2 subject stratification:

(i) early SSc (≤3 years) and (ii) starting on immunosuppressive treatment either

1. MMF + Prednisolone or
2. Other immunosuppressive treatment in combination with MMF + Prednisolone

Exploratory aim subject stratification:

(i) VEDOSS or early SSc (≤3 years) with disease duration defined from onset of first non-Raynaud's symptom (ii) Not on any immunosuppressive treatment or prednisolone >10 mg /day 8 weeks before recruitment

Exclusion Criteria

(i) Lactating or pregnancy (ii) Allergy or contraindications to hyoscine butylbromide (e.g. myasthenia gravis, prostatic enlargement with urinary retention, clinically significant GI obstruction or ileus) (iii) Contraindications to MRI (iv) Infections 4 weeks before baseline measurements (v) On antibiotics 4 weeks before baseline measurements, unless given for treatment of small intestinal bacterial overgrowth (SIBO), a complication of SSc.

(vi) Malignancy or suspected malignancy within the last 2 years (vii) Diabetes on treatment

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Aim 1	PET-MRI scan	The investigators will compare PET-MRI imaging and stool biomarkers between patients with VEDOSS/early SSc (n=40) and those with late SSc (n=20) not on immunosuppressive treatment. Participants will undergo a PET-MRI scan once at baseline.
Aim 2	PET-MRI scan	In early SSc patients (n=35), the investigators will determine change in biomarker levels from pre-treatment baseline to 6 months (primary end-point) and 12-months (secondary end-point) following MMF treatment. Participants will undergo PET-MRI scans at baseline, 6-month and 12-month.
Exploratory aim	PET-MRI scan	In patients with VEDOSS/early SSc (n=15) not on immunosuppressive treatment, the investigators will characterize imaging and stool biomarker changes over one year. Participants will undergo PET-MRI scans at baseline and 12-month.

Primary Outcome Measures

Name	Time	Method
Inflammatory or fibrosis FDG-PET-MRI imaging biomarkers in VEDOSS/early SSc or late SSc patients not on immunosuppresive treatment	Baseline	PET-MRI imaging biomarkers: Inflammatory biomarker: PET SUV tissue to background ratio (TBR); fibrosis biomarker: native T1-MOLLI value.
Inflammatory biomarkers on FDG-PET-MRI imaging after 6 months (primary endpoint) and 12 months (secondary endpoint) of Mycophenolate mofetil treatment.	Baseline, 6-month and 12-month	Change in PET SUV TBR from baseline at 6 months (Primary endpoint) and 12 months (secondary endpoint) following Mycophenolate mofetil treatment

Secondary Outcome Measures

Name	Time	Method
FDG-PET-MRI imaging over one year in patients with VEDOSS/early SSc not on immunosuppresive treatment	Baseline and 12-month	Change in PET SUV TBR, Native T1-MOLLI value, GIT score from baseline at 12 months.
Stool biomarkers	baseline, 6 and 12 months	Faecal-calprotectin, stool microbiota diversity, relative abundance according to taxonomic classifications.

Trial Locations

Locations (5)

Singapore General Hospital; 🇸🇬 Singapore, Singapore

Tan Tock Seng Hospital; 🇸🇬 Singapore, Singapore

Changi General Hospital; 🇸🇬 Singapore, Singapore

National University Hospital; 🇸🇬 Singapore, Singapore

Sengkang General Hospital; 🇸🇬 Singapore, Singapore