Pilot Trial of Ustekinumab for Primary Sjögren's Syndrome

Study Overview
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Brief Summary
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This pilot study will make a preliminary determination of the safety of ustekinumab in patients with Primary Sjogren's Syndrome (PSS) and assess the response of systemic measures of inflammation (biomarkers).

Detailed Description
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This is a single-center, open label, pilot trial of ustekinumab in patients with Primary Sjögren's Syndrome (PSS). Up to 15 subjects will receive an infusion loading dose of 6 mg/kg of ustekinumab at baseline, and 90 mg of ustekinumab subcutaneously at week 4, week 12 and week 20. Subjects will be followed for 24 weeks.

Official Title
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Pilot Trial of Ustekinumab for Primary Sjögren's Syndrome

Conditions
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Primary Sjögren Syndrome

Intervention / Treatment
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* Drug: Ustekinumab


Participation Criteria
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Eligibility Criteria
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A subject who has met all of the following criteria is eligible for participation in the study: Has provided written informed consent Between the ages of 18-75 years (inclusive) Body weight ≥ 40 kg Meets the 2016 ACR EULAR criteria (score >4) 3 points- Labial salivary gland with focal lymphocytic sialadenitis and focus score of >1 foci/4 mm2‡ 3 Points- Anti-SSA/Ro positive 1 Point- Ocular Staining Score >5 in at least 1 eye 1 Point- Schirmer's test <5 mm/5 minutes in at least 1 eye 1 Point- Unstimulated whole saliva flow rate <0.1 ml/minute If taking prednisone (or equivalent corticosteroid), the dose must be ≤ 10 mg/day and stable for at least 4 weeks prior to baseline visit If taking hydroxychloroquine, the dose must be stable for at least 12 weeks prior to baseline. If taking a cholinergic stimulant (e.g. pilocarpine, cevimeline), the dose must be stable for at least 4 weeks prior to baseline. If a male of reproductive potential, must agree to practice two highly effective forms of contraception during the study (one of which must be a barrier method) and be able to continue contraception for 20 weeks after his last dose of study agent Subject must also agree not to donate sperm up to 20 weeks after his last dose of study agent. If a female of childbearing potential, must agree to practice two highly effective forms of contraception during the study (one of which must be a barrier method) and able to continue contraception for 20 weeks after her last dose of study agent. A subject who meets any of the following criteria is disqualified from participation in the study: Has a chronic or persistent infection that might be worsened by immunosuppressive treatment (e.g., HIV, hepatitis B, hepatitis C, or tuberculosis). History of untreated TB or positive QuantiFERON TB-Gold during screening period. If a subject has previously received an adequate course of therapy for either latent (9 months of isoniazid in a locale where rates of primary multi-drug resistant TB infection are <5%) or active TB infection, a QuantiFERON TB-Gold test need not be obtained, but a chest radiograph or other appropriate image must still be obtained if not done so within the prior 3 months. History of recurrent significant infections or occurrence of a serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., pneumonia, septicemia) within twelve weeks prior to Day 0. Active symptomatic infection within two weeks prior to Day 0. Receipt of live vaccine within four weeks prior to Day 0. History or presence of primary or secondary immunodeficiency. History of any life-threatening allergic reactions to pilocarpine or any components of ustekinumab. Pilocarpine will be used to stimulate salivary flow in order to assess flow rate. Is currently pregnant or nursing. Concurrent use of anticholinergic agents, such as tricyclic antidepressants, antihistamines, phenothiazines, antiparkinsonian drugs, anti-asthmatic medications, or gastrointestinal (GI) medications that cause xerostomia in more than 10% of patients. Treatment with any of the following within the defined period prior to the screening and Day 0 visits: 12 months for rituximab 24 weeks for cyclophosphamide 8 weeks for azathioprine, cyclosporine, methotrexate, and mycophenolate mofetil 4 weeks for intravenous immunoglobulin 4 weeks for etanercept 8 weeks for adalimumab 12 weeks for infliximab 8 weeks Golimumab 8weeks Certolizumab pegol 16 weeks Abatacept 4 weeks Tocilizumab SQ 16 weeks Tocilizumab IV 4 weeks Tofacitinib and Tofacitinib XR Prednisone (or equivalent corticosteroid) > 10 mg/day. A definite diagnosis of RA, SLE, systemic sclerosis, or dermatomyositis. A history of alcohol or substance abuse. A history of head and neck radiation therapy, sarcoidosis, or graft-versus-host disease. A history of malignancy, except for a resected basal or major squamous cell carcinoma, cervical dysplasia, or in situ cervical cancer Grade I, within the last five years. Abnormal laboratory results for the following parameters at the baseline visit: Absolute neutrophil count (ANC): < 1500/mm3 Platelets: < 100,000/mm3 Hemoglobin: < 9 grams (g)/deciliter (dL) Serum creatinine: ≥ 2.0 mg/dL AST: > 1.5x upper limit of normal ALT: > 1.5x upper limit of normal. A psychiatric disorder rendering the subject incapable of providing informed consent. Plans for foreign travel to countries other than Canada or Western Europe within the treatment period. Inability or unwillingness to follow the protocol Any condition or treatment that, in the opinion of the investigator, places the subject at an unacceptable risk as a participant in the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Up to 15 subjects will receive an infusion loading dose of 6 mg/kg of ustekinumab at baseline, and 90 mg of ustekinumab subcutaneously at week 4, week 12 and week 20. Subjects will be followed for 24 weeks.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ustekinumab<br>All subjects will receive an intravenous loading dose of 6 mg/kg at their baseline visit. 650mg acetaminophen and 60mg allegra will be given as premedication to the infusion. All patients will receive 90mg ustekinumab by a subcutaneous injection at all subsequent dosing visits. Subcutaneous injections do not require any premedication. Drug will be administered by qualified personnel. | Drug: Ustekinumab<br>* Up to 15 subjects will receive an infusion loading dose of 6 mg/kg of ustekinumab at baseline, and 90 mg of ustekinumab subcutaneously at week 4, week 12 and week 20. Subjects will be followed for 24 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in The European League Against Rheumatism (EULAR) Sjogren's Syndrome Patient Reported Index (ESSPRI) score from Baseline to Week 24 | The primary endpoint is a well-established, patient reported questionnaire for use in PSS, the ESSPRI. The ESSPRI is composed of 3 scales - dryness, fatigue, and pain. Each scale is measured 0 - 10, 0 being no symptoms, 10 being maximal imaginable dryness, fatigue or pain. The total score is the mean score of the three scales. Baseline ESSPRI total score will be compared to week 24, end of treatment, ESSPRI total score. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Short Form Health Survey (SF-36) Patient Reported Outcome Measure between day 0 and week 24 | The SF-36 is a measure of health-related quality-of-life. It's a 36-item patient-reported questionnaire that covers 8 health domains. Scores for each domain range from 0 to 100, with a higher score defining a more favorable health state. Changes in total scores in each domain from BL to week 24 will be measured. | 24 weeks | 
| Change in serum biomarkers of inflammation from baseline to week 24 | To determine whether the standard dosing schedule for ustekinumab lowers serum biomarkers of inflammation in patients with PSS blood will be collected at baseline, week 12 and week 24 for the following mechanistic studies: Serum levels of TNFα, IL-6, IL17, IL17A, IL17F, IL22, IL12, IL23, BAFF, B and T cell, blood interferon signature. Means, medians, standard deviations, minimums and maximums will be computed for each continuous mechanistic endpoint. | 24 weeks | 
| Number of participants with treatment-emergent adverse events as defined by ICH definition of AE. | Safety of ustekinumab in PSS patients will be measured by incidence of serious and non-serious adverse events per ICH definitions from prior to treatment and after the first dose of study drug. Number of events and number (%) of participants experiencing events will be summarized by system organ class and preferred term for each. In addition, AEs will be summarized by maximum severity and relationship to study drug. | 24 weeks | 
| Change in total score of the EULAR Sjogren's syndrome disease activity index (ESSDAI) from baseline to week 24. | The ESSDAI is a disease activity measurement that has 12 domains. The score of each domain is the product of the weight of the domain by the level of activity. Activity levels are 0 - 3, 0 being no activity, 3 being high activity. The total score is the sum of the score of all domains. Change in total score from BL to week 24 will be measured. | 24 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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primary sjogren syndrome, PSS, SjS, Sjogren, Ustekinumab, SS