Primary Sjögren Syndrome
Conditions
Keywords
primary sjogren syndrome, PSS, SjS, Sjogren, Ustekinumab, SS
Brief summary
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
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.
Interventions
DRUGUstekinumab
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.
Sponsors
Janssen, LP
University of Rochester
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in The European League Against Rheumatism (EULAR) Sjogren's Syndrome Patient Reported Index (ESSPRI) Score From Baseline to Week 24 | baseline to 24 weeks | 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 which ranges from 0- 10. Baseline ESSPRI total score will be compared to week 24, end of treatment, ESSPRI total score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Short Form Health Survey (SF-36) Patient Reported Outcome Measure Between Day 0 and Week 24 | baseline to 24 weeks | 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 for physical function, energy/fatigue, pain and general health. |
| Change in Mean Serum Biomarkers of Inflammation From Baseline to Week 24 | baseline to 24 weeks | To determine whether the standard dosing schedule for ustekinumab lowers serum biomarkers of inflammation in patients with PSS blood will be collected at baseline 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. |
| Total Score of the EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) | 24 weeks. | 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. Lower numbers indicate less activity. The total score is the sum of the score of all domains. The total score ranges from 0-123. Mean scores at baseline and week 24 are reported. |
Countries
United States
Participant flow
Pre-assignment details
12 subjects were consented. 4 failed screening.
Participants by arm
| Arm | Count |
|---|---|
| Ustekinumab 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.
Ustekinumab: 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. | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | failed screening | 4 |
Baseline characteristics
| Characteristic | Ustekinumab |
|---|---|
| Age, Continuous | 47.3 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 8 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
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 which ranges from 0- 10. Baseline ESSPRI total score will be compared to week 24, end of treatment, ESSPRI total score.
Time frame: baseline to 24 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ustekinumab | Change in The European League Against Rheumatism (EULAR) Sjogren's Syndrome Patient Reported Index (ESSPRI) Score From Baseline to Week 24 | -0.125 score on a scale |
Secondary
Change in Mean 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 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.
Time frame: baseline to 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ustekinumab | Change in Mean Serum Biomarkers of Inflammation From Baseline to Week 24 | IFNa2 | 6.984 pg/mL | Standard Deviation 0.2922 |
| Ustekinumab | Change in Mean Serum Biomarkers of Inflammation From Baseline to Week 24 | IL12p40 | 12.62 pg/mL | Standard Deviation 0.0893 |
| Ustekinumab | Change in Mean Serum Biomarkers of Inflammation From Baseline to Week 24 | IP-10 | 111.3 pg/mL | Standard Deviation 0.6145 |
| Ustekinumab | Change in Mean Serum Biomarkers of Inflammation From Baseline to Week 24 | IL-17F | 0.02175 pg/mL | Standard Deviation 0.3683 |
| Ustekinumab | Change in Mean Serum Biomarkers of Inflammation From Baseline to Week 24 | IFNg | -0.3912 pg/mL | Standard Deviation 0.9705 |
| Ustekinumab | Change in Mean Serum Biomarkers of Inflammation From Baseline to Week 24 | IL12p70 | 3.054 pg/mL | Standard Deviation 0.0204 |
| Ustekinumab | Change in Mean Serum Biomarkers of Inflammation From Baseline to Week 24 | IL-13 | 1.689 pg/mL | Standard Deviation 0.6965 |
| Ustekinumab | Change in Mean Serum Biomarkers of Inflammation From Baseline to Week 24 | IL17A | -1.236 pg/mL | Standard Deviation 0.4774 |
| Ustekinumab | Change in Mean Serum Biomarkers of Inflammation From Baseline to Week 24 | IL-22 | 0.2963 pg/mL | Standard Deviation 0.2742 |
| Ustekinumab | Change in Mean Serum Biomarkers of Inflammation From Baseline to Week 24 | IL-23 | 1.456 pg/mL | Standard Deviation 0.1801 |
| Ustekinumab | Change in Mean Serum Biomarkers of Inflammation From Baseline to Week 24 | IL-6 | 2.411 pg/mL | Standard Deviation 0.2198 |
| Ustekinumab | Change in Mean Serum Biomarkers of Inflammation From Baseline to Week 24 | TNFa | 1.374 pg/mL | Standard Deviation 0.1252 |
Secondary
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 for physical function, energy/fatigue, pain and general health.
Time frame: baseline to 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ustekinumab | Change in the Short Form Health Survey (SF-36) Patient Reported Outcome Measure Between Day 0 and Week 24 | physical function | 11.1 score on a scale | Standard Deviation 8.9 |
| Ustekinumab | Change in the Short Form Health Survey (SF-36) Patient Reported Outcome Measure Between Day 0 and Week 24 | energy/fatigue | 7.5 score on a scale | Standard Deviation 17.9 |
| Ustekinumab | Change in the Short Form Health Survey (SF-36) Patient Reported Outcome Measure Between Day 0 and Week 24 | pain | 5.25 score on a scale | Standard Deviation 15.5 |
| Ustekinumab | Change in the Short Form Health Survey (SF-36) Patient Reported Outcome Measure Between Day 0 and Week 24 | general health | 0.6 score on a scale | Standard Deviation 20.1 |
Secondary
Total Score of the EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI)
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. Lower numbers indicate less activity. The total score is the sum of the score of all domains. The total score ranges from 0-123. Mean scores at baseline and week 24 are reported.
Time frame: 24 weeks.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ustekinumab | Total Score of the EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) | Baseline | 2.86 score on a scale | Standard Deviation 3.563 |
| Ustekinumab | Total Score of the EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) | Week 24 | 1.75 score on a scale | Standard Deviation 1.5811 |