CALCification as an early marker of vasculopathy and organ involvement in Systemic Sclerosis CALC-SSc study

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2018-001719-65-NL
• Date of registration: 09/07/2018
• Prospective Registration: Yes
• Primary sponsor: University Medial Center Groningen
• Public title: CALCification as an early marker of vasculopathy and organ involvement in Systemic Sclerosis CALC-SSc study
• Scientific title: CALCification as an early marker of vasculopathy and organ involvement in Systemic Sclerosis CALC-SSc study - CALC-SSc study
• Date of first enrolment: 10/12/2018
• Target sample size: 120
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-001719-65
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: no Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Netherlands

Contacts

• Name: D.J. Mulder
• Affiliation: University Medical Center Groningen

• Name: D.J. Mulder
• Affiliation: University Medical Center Groningen

Key inclusion & exclusion criteria

Inclusion criteria:
SSc patients:
In order to be eligible to participate in this study as an SSc patient, a subject must meet all of the following criteria:
• 18-80 years
• Formal diagnosis of Systemic Sclerosis, as determined by a total of =9 from adding the maximum weight (score) in each of the following categories (2013 ACR/EULAR criteria):
o Skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints (sufficient criterion) (9 points)
o Skin thickening of the fingers (only count the higher score)
? Puffy fingers (2 points)
? Sclerodactyly of the fingers (distal to the metacarpophalangeal joints but proximal to the proximal interphalangeal joints) (4 points)
o Fingertip lesions (only count the higher score)
? Digital tip ulcers (2 points)
? Fingertip pitting scars (3 points)
o Telangiectasia (2 points)
o Abnormal nailfold capillaries (2 points)
o Pulmonary involvement (maximum score is 2)
? Pulmonary arterial hypertension (2 points)
? Interstitial lung disease (2 points)
o Raynaud’s phenomenon (3 points)
o SSc-related autoantibodies (maximum score is 3)
? Anticentromere (3 points)
? anti–topoisomerase I [anti–Scl-70] (3 points)
? anti–RNA polymerase III (3 points)
• Written informed consent

Controls:
In order to be eligible to participate in this study as a patient with primary Raynaud’s phenomenon, a subject must meet all of the following criteria:
• 18-80 years
• Negatieve antinuclear antibodies (ANA)
• Normal nailfold capillairies
• No underlying disease
• Written informed consent

Healthy controls:
In order to be eligible to participate in this study as a healthy control, a subject must meet all of the following criteria:
• 18-80 years
• No apparent underlying chronic disease
• No signs and symptoms suggesting Raynaud phenomenon or other vascular disease
• Written informed consent
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 120
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
A potential subject who meets any of the following criteria will be excluded from participation in this study:
• Women who are currently pregnant, planning to become pregnant, breastfeeding women, or women with child bearing potential not using appropriate contraceptive measures
• Patients who are mentally incompetent and cannot sign a Patient Informed Consent or are unwilling to sign a Patient Informed Consent
• Vascular event in the preceding 3 months (33)
• Chemotherapy in the preceding 3 months (33)
• Inflammation of unknown origin, sepsis, or vasculitis (34)

The next criteria will also be used for the substudy concerning 18F-NaF PET/CT:
• Current active bone malignancy or in the previous 6 months (35)
• Fractures or metastases within the evaluated bone regions, as well as metallic implants (33)
• Disorders affecting bone metabolism, e.g. hyperparathyroidism, Paget’s disease (33)
• Patients who have claustrophobia (16)
• Prior or present bisphosphonate therapy (33)
• Prior or present calcium or vitamin D therapy


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Systemic sclerosis (SSc) is a rare progressive autoimmune disease hallmarked by severe vasculopathy. Patients are prone to enhanced calcification of skin and the vasculature. Active calcifications may not only occur in the skin of patients with clinically overt calcinosis cutis, but also in SSc patients without. Since calcification is strongly associated with local inflammation, it may very well occur in internal organs and serve as an early proxy for long-term SSc-related complications.

Therapeutic area: Diseases [C] - Skin and Connective Tissue Diseases [C17]

Intervention(s)

Product Name: Sodium fluoride 18F
Product Code: EMA/CHMP/212874/2015
Pharmaceutical Form: Injection

Primary Outcome(s)

Main Objective: 1. To assess serum calcification propensity (T50) in SSc patients compared with healthy age and gender-matched controls;

Timepoint(s) of evaluation of this end point: At baseline

Secondary Objective: 2. To assess serum T50 in SSc patients with overt calcinosis cutis as compared to age and gender-matched SSc patients without;
3. To assess other serum markers of the calcification process in SSc patients compared with healthy age and gender-matched controls as compared to age and gender-matched SSc patients without;
4. To assess serum T50 and other serum markers of the calcification process compared with established markers of the underlying disease process;
5. To assess serum T50 compared with non-invasive markers of micro- and macrovasculopathy in patients with SSc;
6. To assess serum T50 compared with SSc-related skin and internal organ complications;
7. To study associations with expression of markers involved in the calcification process in skin biopsies by immunohistochemistry;
8. To assess whether AGEs/HMGB1-RAGE interactions lead to increased IFN-1 signature and profibrotic and osteogenic differentiation of fibroblasts isolated from skin biopsies;

Primary end point(s): 1. Degree of serum T50;

Secondary Outcome(s)

Secondary end point(s): 2. Degree of other serum markers of the calcification process: calcium; phosphorus; parathormone; fetuin-A; FGF23; aKlotho;
3. Degree of blood markers involved in inflammation, calcification and endothelial dysfunction: plasma AGEs (CML, pentosidine and MG-H1); HMGB1; carbonyl markers; skin AF as marker of dermal AGE accumulation (biomarkers of the AGE-RAGE axis); ET-1; C-reactive protein, erythrocyte sedimentation rate (ESR), IL-6, whole blood IFN- I signature (biomarkers of endothelial activation and inflammation); VEGF, IL-8, angiogenic T cells, TIE2 positive monocytes (biomarkers of angiogenesis);
4. Degree of vascularopathy measured by: capillary microscopy; arterial stiffness measured by PWV; digital artery involvement assessed with ultrasound;
5. Degree of cardiac involvement by cardiac ultrasound, pulmonary involvement by conventional lung function (FVC, DLCO), and subsequent HRCT upon indication, renal involvement by kidney function (24-hours creatinine clearance, proteinuria, and glomerular erythrocyturia) and gastro-intestinal involvement by conventional oesophageal motility scan;
6. Degree of markers involved in the calcification process as well as biomarkers of progression to SSc in skin biopsies: degree of fibrosis (TGFß, collagen); aKlotho; FGF23; myxovirus resistance gene A (MxA) which is a marker for IFNa, TLR 4 and TLR 8;
7. Degree of fibroblasts sensitivity to calcification and proinflammatory mechanisms by: CML-modified-bovine serum albumin (BSA); HMGB1, RAGE, and TGFß.

Timepoint(s) of evaluation of this end point: At baseline

Secondary ID(s)

CALC-SSc

Source(s) of Monetary Support

University Medical Center Groningen

Ethics review

Status: Approved
Approval date:
Contact: