A PH I Pilot Imaging Study to Evaluate Molecular Imaging Methods in HVs and pSS Pts

A Pilot Study to Evaluate Molecular Imaging Methods in Primary Sjögren's Syndrome

This is a pilot imaging study to determine whether molecular imaging with 18^F fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT), 11^C-Methionine (MET) PET/CT, and salivary gland magnetic resonance imaging (MRI) with Dotarem (gadoterate meglumine) have the potential to characterize and quantify disease manifestations in primary Sjögren's syndrome (pSS) subjects. This will be achieved by assessing the associations and consistency between the imaging techniques studied, clinical assessments (salivary and tear flow and clinical scores), laboratory biomarkers, and histological findings on minor salivary gland biopsy.

In this study, healthy volunteers will be enrolled in Group A and pSS subjects in Group B. The subjects will be required to undergo screening and baseline assessments including unstimulated and stimulated salivary flow and Schirmer's test; an imaging visit (Visit 1); a sample collection visit (Visit 2) for repeat of selected baseline assessments and a minor salivary gland biopsy for pSS subjects only; and a follow-up visit. The total duration of participation in the study will be up to 11 weeks.

Inclusion Criteria:

• GROUP A: Healthy Volunteers Subjects for both PET/CT and MRI: Aged >=40 years inclusive at the time of signing the informed consent.

Subjects for MRI, without PET/CT: Aged >=30 years inclusive at the time of signing the informed consent Healthy as defined by the investigator, or medically qualified designee, based on a medical evaluation including medical history, physical examination, and laboratory tests.

• Group B: Primary Sjögren's Syndrome Patients Age >=30 years, at the time of signing the informed consent. Diagnosis of pSS according to the American-European Consensus Group criteria Baseline unstimulated salivary flow >0.0 mL/min or evidence of glandular reserve function (stimulated baseline salivary flow >0.05 mL/min).

Systemically active disease, ESSDAI >=5 points

• All Subjects Body weight >=50 kilogram (kg) and body mass index within the range 18.5 to 35 kg/m^2 (inclusive)

Male or Female, where one of the following conditions apply:

A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin test) at screening, and a negative urine pregnancy test 4-7 days prior to Visit 1, on the day of Visit 1 (on each day of scanning), on Visit 2, is not lactating, and at least one of the following conditions applies: non-reproductive potential or reproductive potential and agrees to use contraceptive methods listed in the protocol from 28 days prior to Visit 1 until follow up.

• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form.

Exclusion Criteria:

• Diagnosis of secondary Sjögren's Syndrome.
• Diagnosis of another systemic autoimmune disease, apart from pSS, including but not limited to, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis or systemic vasculitis. For Group B subjects, autoimmune conditions associated with pSS (for example autoimmune thyroiditis, primary biliary cirrhosis or coeliac disease), are not included in this exclusion, but should be described in the medical history taken baseline. If in doubt please consult the medical monitor.
• Subjects with active life-threatening or organ-threatening effects of pSS meaning that they may not be able to complete the study visits according to the protocol (as determine by the investigator) (Group B).
• History of coagulation or bleeding disorders which would increase the risk of minor salivary gland biopsy (for example, but not limited to, Hemophilia A or B, Von Willibrand's disease, platelet function disorders; Group B).
• History of malignancy within 5 years of screening that, in the view of the investigator, in consultation with the medical monitor if required, could confound the results of the 18F-FDG PET/CT scan (including lymphoma associated with pSS). This does not include cervical carcinoma in situ or non-melanoma skin malignancy that has been treated with curative surgical treatment.
• History of unresolved acute or chronic infection that, in the view of the investigator in consultation with the medial monitor, if required, could confound the results of the 18F-FDG PET/CT.
• Subject with diabetes mellitus requiring insulin therapy
• Contraindications to MRI scanning (as assessed by MRI safety questionnaire).
• History of, or suffers from, claustrophobia or feel that they will be unable to lie still in the PET or MRI scanner for a period of up to 1 to 2 hours.
• Where participation in the study would result in donation of blood or blood products in excess of 500mL within a 56 day period.
• Previous inclusion in a research protocol involving nuclear medicine, PET or radiological investigations, or as a result of occupational exposure with a significant radiation burden (a significant radiation burden being defined as 10mSv in addition to natural background radiation, in the previous 3 years including the dose from this study). A clinical procedure where the subject received a direct benefit (eg diagnostic test) will not be included in the calculation of exposure.
• Lack of adequate peripheral venous access for cannulation.
• Current participation in a study with an investigational product, or recent participation within 5 half lives of discontinuation the drug, or within twice the duration of the biological effect of the drug, whichever is longer
• Group A: Healthy volunteers Subject is unable to refrain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 days prior to Visit 1 until completion of Visit 2, unless in the opinion of the investigator and Sponsor the medication will not interfere with the study.
• Group B: pSS subjects taking immunomodulatory treatment at screening are excluded unless they have been on stable doses of these medicines for 6 weeks prior to Screening/Baseline and are expected to remain on stable doses of these medications until the Follow up visit. This would include drugs such as glucocorticoids, immunosuppressive agents (for example, hydroxychloroquine, azathioprine, methotrexate, mycophenolate mofetil, and biologic therapies). If in doubt, to be discussed with the Medical Monitor.
• Group B: pSS subjects receiving treatment with anti-coagulant medications, including but not limited to warfarin, heparin, thrombin inhibitors, and Factor Xa inhibitors, and aspirin, unless the subjects is able to discontinue these medications one week prior to minor salivary gland biopsy, or according to local guidelines. The treatment may be restarted 3 days after the biopsy, or according to local guidelines.
• History of alcohol, prescription or non-prescription drug abuse which could interfere with participation in the trial according to the protocol, or in the opinion of the investigator impacts on the physical or mental wellbeing of the subject
• History of allergy/hypersensitivity to study medications including local anesthesia (Group B), radio-isotopes or gadolinium-containing contrast agents (all subjects).
• Contraindications to gadolinium-containing contrast agents in accordance with product labeling and local guidelines
• Estimated GFR (Modification of Diet in Renal Disease calculation) of less than 60 mL/min/1.73m^2 at screening.
• Platelet count below the laboratory normal range at screening, or prothrombin time above the laboratory normal range at screening (Group B).
• Subject with a fasting blood sugar >11.1 millimoles (mmol)/Liters (L) at screening (defined as fasting for a minimum of 6 hours, excluding unflavored water).