Baminercept, a Lymphotoxin-Beta Receptor Fusion Protein, for Treatment of Sjögren's Syndrome

Study Overview
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Brief Summary
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The purpose of the study is to find out if the experimental study agent, baminercept, is effective in treating patients with Sjögren's syndrome. The study will also determine if the study agent can be safely given to patients with Sjögren's syndrome; examine how it affects symptoms of the disease; and attempt to understand how baminercept affects the underlying mechanisms of Sjögren's syndrome and the immune system.

Detailed Description
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Sjögren's syndrome is an autoimmune disorder in which a person's own immune cells attack the body's tear and salivary glands. This disease is the second most common autoimmune disorder, affects close to four million people in the U.S., and has no known cause. About one-third of patients with Sjögren's syndrome have enlarged parotid glands (the largest salivary glands, the glands that make saliva); inflammation of organs such as the lungs and joints may also occur. There is no known effective treatment other than measures that can relieve symptoms. One of the most bothersome symptoms is dryness of the eyes and mouth. Eye drops and saliva stimulants (which help make more saliva) are common treatments. When other organs are affected, symptoms are treated with corticosteroids (prednisone), non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen and naproxen), hydroxychloroquine (Plaquenil®) or other medications that suppress the immune system. These drugs may curb or kill cells of the immune system, but they are not always helpful, do not cure Sjögren's syndrome, and can have many side effects.

Official Title
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A Randomized, Double-blind, Placebo-controlled Phase II Clinical Trial of Baminercept, a Lymphotoxin-beta Receptor Fusion Protein, for the Treatment of Primary Sjögren's Syndrome (ASJ02)

Conditions
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Primary Sjögren's Syndrome

Intervention / Treatment
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* Biological: Baminercept
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has provided written informed consent; Between the ages of 18-75 years (inclusive); Body weight ≥ 40 kg; Meets the revised European criteria proposed by the American-European Consensus Group for primary Sjögren's Syndrome at screening. These criteria include 3 of the following 4 items: ocular symptoms; oral symptoms; Schirmer's I test showing less than 6 mm of wetting per five minutes in at least one eye, or filamentary keratitis on slit lamp examination, or positive lissamine green staining; or diminished salivary production (unstimulated whole salivary flow rate ≤ 1.5 mL/15 min); PLUS, either: a positive test for serum SS-A and/or SS-B antibodies, or focal lymphocytic sialadenitis, with a focus score ≥ 1.0 per 4 millimeters ^2(mm^2) on minor salivary biopsy. Stimulated salivary flow of ≥ 0.1 mL/minute (min) (at screening); Has one or more of the following systemic manifestations of Sjögren's Syndrome that are not life-threatening: fatigue (as measured by > 50 mm on a 100 mm VAS); joint pain (as measured by > 50 mm on a 100 mm VAS); peripheral neuropathy (documented by nerve conduction velocity study); interstitial lung disease (documented by radiography and/or altered pulmonary function tests; leukocytoclastic vasculitis; renal tubular acidosis; interstitial nephritis; severe parotid swelling; other extraglandular manifestations causing organ system dysfunction. If taking prednisone (or equivalent corticosteroid), the dose must be ≤ 10 mg/day and stable for at least 4 weeks prior to Screening; If taking hydroxychloroquine, the dose must be stable for at least 12 weeks prior to Screening; If taking a cholinergic stimulant (e.g. pilocarpine, cevimeline), the dose must be stable for at least 4 weeks prior to Screening; Subjects must agree not to become pregnant or to impregnate a female. Because of the risk involved, participants and their partners (if of reproductive potential) must use two methods of birth control. They must continue to use both methods until 6 months after stopping study drug. Two of the birth control methods listed below may be chosen: Hormonal contraception; Male or female condoms with or without spermicide; Diaphragm or cervical cap with a spermicide; Intrauterine device (IUD). Exclusion Criteria: Has an active infection excluding superficial cutaneous fungal or viral infections; Has a chronic or persistent infection that might be worsened by immunosuppressive treatment (e.g., human immunodeficiency virus [HIV], hepatitis B, hepatitis C, or tuberculosis); History of TB or positive intradermal skin test for purified protein derivative (PPD); positive Mantoux test defined as 10 mm of induration (size of raised bump, not redness), or equivalent positive TB test result, as per country clinical standards, during the screening period. Subjects whose PPD induration is ≥ 5 mm but < 10 mm are eligible for the study if they had a negative chest x-ray during the screening period. There must be no other clinical evidence of TB on physical examination of the subject. Note: Subjects who have had prior adequate prophylaxis treatment for latent TB with an appropriate course of isoniazid or equivalent, per country standards, are not excluded from study participation. PPD should not be administered within 6 weeks of a live-virus vaccine; 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; Receipt of live vaccine within six weeks prior to Day 0; History or presence of primary or secondary immunodeficiency; History of any life-threatening allergic reactions; Is a pregnant or nursing female; Ongoing anticoagulant therapy, which is a contraindication for labial salivary biopsy or tonsil biopsy; 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 Screening: 2 years for rituximab; 24 weeks for cyclophosphamide; 8 weeks for azathioprine, cyclosporine, methotrexate, or mycophenolate mofetil; 4 weeks for intravenous immunoglobulin; 4 weeks for etanercept; 8 weeks for adalimumab; 12 weeks for infliximab. Prednisone (or equivalent corticosteroid) > 10 mg/day; A definite diagnosis of RA, SLE, systemic sclerosis, or dermatomyositis; A history of alcohol or substance abuse within 12 months of the screening visit; 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; Severe pulmonary disease as manifested by one of the following at Screening: Resting oxygen saturation < 92%; Force vital capacity (FVC) < 50% predicted; Diffusion lung capacity for carbon monoxide (DLCO) < 50%; Abnormal laboratory results for the following parameters at the screening visit: Absolute neutrophil count (ANC): < 1,500/mm^3; Platelets: < 100,000/mm^3; Hemoglobin: < 9 grams (g)/deciliter (dL); Serum creatinine: ≥ 2.0 mg/dL; AST: > 1.5x upper limit of normal, or 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; Rochester substudy subjects who meet the following criteria are disqualified from enrolling in the tonsil biopsy substudy if they: Have any side effects to local anesthetics (e.g., lidocaine); Have any side effects to silver nitrate; Do not have tonsils; Are not able to go 48 hours without any NSAIDS; Are not able to go 2 weeks without acetylsalicylic acid (aspirin).

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Baminercept<br>Subcutaneous injections of 100 mg every week for 24 weeks | Biological: Baminercept<br>* Subjects randomized to baminercept (2:1) will receive 24 weekly injections of 100 mg administered subcutaneously starting at the Day 0 visit and ending at Week 23.<br>* Other names: lymphotoxin-beta receptor-immunoglobulin fusion protein;|
| Placebo Comparator: Placebo<br>Subcutaneous injections of matched placebo every week for 24 weeks | Other: Placebo<br>* Subjects randomized to placebo will receive 24 weekly injections of 100 mg administered subcutaneously starting at the Day 0 visit and ending at Week 23.<br>* Other names: baminercept placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Screening in Stimulated Whole Salivary Flow at Week 24 | After an unstimulated salivary flow assessment the participant was administered a single 5-mg dose of pilocarpine to stimulate saliva production. One hour after the administration of pilocarpine the participant spit into a preweighed 50-cm centrifuge tube for 15 minutes. The sample was weighed to determine the volume (1 g = 1 mL) of saliva. The volume of saliva (mL) was divided by the duration of the test (minutes) to calculate the stimulated salivary flow rate (mL/min). Change from screening was computed as the value at Week 24 minus the screening value. A positive value in change from screening indicates an improvement and a negative value indicates worsening. | Screening to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Screening in Stimulated Whole Salivary Flow at Week 48 | After an unstimulated salivary flow assessment the participant was administered a single 5-mg dose of pilocarpine to stimulate saliva production. One hour after the administration of pilocarpine the participant spit into a preweighed 50-cm centrifuge tube for 15 minutes. The sample was weighed to determine the volume (1 g = 1 mL) of saliva. The volume of saliva (mL) was divided by the duration of the test (minutes) to calculate the stimulated salivary flow rate (mL/min). Change from screening was computed as the value at Week 48 minus the screening value. A positive value in change from screening indicates an improvement and a negative value indicates worsening. | Screening to Week 48 | 
| Change From Screening in Unstimulated Whole Salivary Flow at Week 24 | The participant spit into a preweighed 50-cm centrifuge tube for 15 minutes. The sample was weighed to determine the volume (1 g = 1 mL) of saliva. The volume of saliva (mL) was divided by the duration of the test (minutes) to calculate the unstimulated salivary flow rate (mL/min). Cholinergic stimulants such as pilocarpine or cevimeline were discontinued for 48 hours prior to the assessment and nothing was taken by mouth for 60 minutes or longer before or during saliva collection. Change from screening was computed as the value at Week 24 minus the screening value. A positive value in change from screening indicates an improvement and a negative value indicates worsening. | Screening to Week 24 | 
| Change From Screening in Unstimulated Whole Salivary Flow at Week 48 | The participant spit into a preweighed 50-cm centrifuge tube for 15 minutes. The sample was weighed to determine the volume (1 g = 1 mL) of saliva. The volume of saliva (mL) was divided by the duration of the test (minutes) to calculate the unstimulated salivary flow rate (mL/min). Cholinergic stimulants such as pilocarpine or cevimeline were discontinued for 48 hours prior to the assessment and nothing was taken by mouth for 60 minutes or longer before or during saliva collection. Change from screening was computed as the value at Week 48 minus the screening value. A positive value in change from screening indicates an improvement and a negative value indicates worsening. | Screening to Week 48 | 
| Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) at Week 24 | The ESSDAI is a clinical index that measures Sjogren's syndrome disease activity. A physician scores the disease activity level of twelve organ-specific domains in 3 or 4 levels according to their severity. For example, for no disease activity the domain score equals 0 and for high disease activity the domain score equals 3 or 4. Each domain is assigned a weight between 1 and 6, and the domain score is multiplied by the domain weight. The sum of the weighted domain scores is the overall score, which can range from 0 to 123. A higher score indicates more disease activity. Change from baseline was computed as the value at Week 24 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening. | Baseline to Week 24 | 
| Percent of Subjects Classified as Responders According to the Patient Self-Assessment of Fatigue, Overall Dryness, and Joint Pain at Week 24 | Response is defined by 30% or more improvement (decrease) from baseline to week 24 in at least two of the three Visual Analog Scale (VAS) scores for patient self-assessment of symptoms of overall dryness, fatigue, and joint pain. On a 100-mm horizontal line the participant places a vertical mark to indicate a response. The range is 0 to 100, with 100 as the highest perceived overall fatigue, overall dryness, or joint pain. | Week 24 | 
| Percent of Subjects Classified as Responders According to the Patient Self-Assessment of Fatigue, Overall Dryness, and Joint Pain at Week 48 | Response is defined by 30% or more improvement (decrease) from baseline to week 48 in at least two of the three Visual Analog Scale (VAS) scores for patient self-assessment of symptoms of overall dryness, fatigue, and joint pain. On a 100-mm horizontal line the participant places a vertical mark to indicate a response. The range is 0 to 100, with 100 as the highest perceived overall fatigue, overall dryness, or joint pain. | Week 48 | 
| Change From Baseline in Visual Analog Scale (VAS) Scores for Sjogren's Syndrome Symptom Survey at Week 24 | On a 100-mm horizontal line the participant places a vertical mark to indicate responses to 14 questions about salivary and ophthalmic function. The range is 0 to 100, with 100 as the highest perceived difficulty, dryness, discomfort, swelling, thirst, dryness, severity, or sensitivity. Change from baseline was computed as the value at Week 24 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening. | Week 24 | 
| Change From Baseline in Visual Analog Scale (VAS) Scores for Sjogren's Syndrome Symptom Survey at Week 48 | On a 100-mm horizontal line the participant places a vertical mark to indicate responses to 14 questions about salivary and ophthalmic function. The range is 0 to 100, with 100 as the highest perceived difficulty, dryness, discomfort, swelling, thirst, dryness, severity, or sensitivity. Change from baseline was computed as the value at Week 48 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening. | Week 48 | 
| Change From Baseline in Patient Self-Assessment of Fatigue, Overall Dryness, and Joint Pain at Week 24 | Three Visual Analog Scale (VAS) scores for patient self-assessment of symptoms of overall dryness, fatigue, and joint pain. On a 100-mm horizontal line the participant places a vertical mark to indicate responses to 3 questions. The range is 0 to 100, with 100 as the highest perceived tiredness, dryness, or joint pain. Change from baseline was computed as the value at Week 24 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening. | Week 24 | 
| Change From Baseline in Patient Self-Assessment of Fatigue, Overall Dryness, and Joint Pain at Week 48 | Three Visual Analog Scale (VAS) scores for patient self-assessment of symptoms of overall dryness, fatigue, and joint pain. On a 100-mm horizontal line the participant places a vertical mark to indicate responses to 3 questions. The range is 0 to 100, with 100 as the highest perceived tiredness, dryness, or joint pain. Change from baseline was computed as the value at Week 48 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening. | Week 48 | 
| Change From Baseline in Patient and Physician Global Assessments of Disease Activity at Week 24 | A participant's overall rating of Disease Activity and a physician's rating of the participant's disease activity. A vertical mark made on a 100 mm line rated 0 (no symptoms) to 100 (severe symptoms) determines the score. Change from baseline was computed as the value at Week 24 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening. | Week 24 | 
| Change From Baseline in Patient and Physician Global Assessments of Disease Activity at Week 48 | A participant's overall rating of Disease Activity and a physician's rating of the participant's disease activity. A vertical mark made on a 100 mm line rated 0 (no symptoms) to 100 (severe symptoms) determines the score. Change from baseline was computed as the value at Week 48 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening. | Week 48 | 
| Change From Baseline in Tear Secretion as Measured by Schirmer's I Test at Week 24 | A paper strip was placed within each lower eyelid and the participant's eyes were closed for 5 minutes. The wet paper was removed after 5 minutes and the length of wetting was recorded to the nearest 0.5 mm. Change from baseline was computed as the value at Week 24 minus the baseline value. A positive value in change from Baseline indicates an improvement and a negative value indicates worsening. | Week 24 | 
| Change From Baseline in Tear Secretion as Measured by Schirmer's I Test at Week 48 | A paper strip was placed within each lower eyelid and the participant's eyes were closed for 5 minutes. The wet paper was removed after 5 minutes and the length of wetting was recorded to the nearest 0.5 mm. Change from baseline was computed as the value at Week 48 minus the baseline value. A positive value in change from Baseline indicates an improvement and a negative value indicates worsening. | Week 48 | 
| Change From Baseline in Tear Secretion as Measured by Lissamine Green Staining at Week 24 | Lissamine green stain was dropped into the participant's eyes and then an ophthalmologist used a slit lamp to examine the eye surface. Six areas of the eye surface were evaluated and scored from 0 to 3, with 0 being no tear film damage to 3, extensive tear film damage. The scores of all six areas in both eyes were totaled to obtain an overall score between 0 and 18. A higher score indicates insufficient tear flow and excessive dryness. Change from baseline was computed as the value at Week 24 minus the baseline value. A negative value in change from Baseline indicates an improvement and a positive value indicates worsening. | Week 24 | 
| Change From Baseline in Tear Secretion as Measured by Lissamine Green Staining at Week 48 | Lissamine green stain was dropped into the participant's eyes and then an ophthalmologist used a slit lamp to examine the eye surface. Six areas of the eye surface were evaluated and scored from 0 to 3, with 0 being no tear film damage to 3, extensive tear film damage. The scores of all six areas in both eyes were totaled to obtain an overall score between 0 and 18. A higher score indicates insufficient tear flow and excessive dryness. Change from baseline was computed as the value at Week 48 minus the baseline value. A negative value in change from Baseline indicates an improvement and a positive value indicates worsening. | Week 48 | 
| Change From Baseline in the Short Form 36 (SF-36) Physical and Mental Health Component Summary Scores (PCS and MCS) at Week 24 | The SF-36 questionnaire completed by the subject measures health-related quality of life across multiple disease states. It has 36 questions with 8 subscale scores and 2 summary scores: PCS=physical functioning, role-physical, bodily pain, and general health; MCS=vitality, social functioning, role-emotional, and mental health. Scoring is done for both subscores and summary scores. For both, 0=worst score (or quality of life) and 100=best score. Summary measures were standardized to have a mean of 50 and a standard deviation of 10 in the 1998 general US population. Change from baseline is computed as the value at Week 24 minus the baseline value. A positive value in change from Baseline indicates an improvement and a negative value indicates worsening. | Week 24 | 
| Change From Baseline in the Short Form 36 (SF-36) Physical and Mental Health Component Summary Scores (PCS and MCS) at Week 48 | The SF-36 questionnaire completed by the subject measures health-related quality of life across multiple disease states. It has 36 questions with 8 subscale scores and 2 summary scores: PCS=physical functioning, role-physical, bodily pain, and general health; MCS=vitality, social functioning, role-emotional, and mental health. Scoring is done for both subscores and summary scores. For both, 0=worst score (or quality of life) and 100=best score. Summary measures were standardized to have a mean of 50 and a standard deviation of 10 in the 1998 general US population. Change from baseline is computed as the value at Week 48 minus the baseline value. A positive value in change from Baseline indicates an improvement and a negative value indicates worsening. | Week 48 | 
| Percent of Participants With Adverse Events of Grade 3 or Higher | Grades are based on National Cancer Institute--Common Terminology Criteria (NCI-CTCAE) Version 4.0 over the duration of the study. Participants who experienced at least one grade 3 or higher adverse event (AE) are counted only once. The adverse events are treatment-emergent, which means that the AE occurred after taking the first dose of study drug. | From the time of administration of the first dose of study drug until the participant completed study participation, an average of 48 weeks. | 
| Percent of Participants With Grade 3 or Higher Infection Adverse Event | Grades are based on National Cancer Institute--Common Terminology Criteria (NCI-CTCAE) Version 4.0 over the duration of the study. Participants who experienced at least one grade 3 or higher infection adverse event (AE) are counted only once. The adverse events are treatment-emergent, which means that the AE occurred after taking the first dose of study drug. | From the time of administration of the first dose of study drug until the participant completed study participation, an average of 48 weeks. | 
| Percent of Participants With Injection Site Reaction or Any Grade 2 or Higher Adverse Event Within 24 Hours of Injection | Grades are based on National Cancer Institute--Common Terminology Criteria (NCI-CTCAE) Version 4.0 over the duration of the study. Participants who experienced at least one injection site reaction or Grade 2 or higher adverse event within 24 hours of injection are counted only once. The adverse events are treatment-emergent, which means that the AE occurred after taking the first dose of study drug. | From the time of administration of the first dose of study drug until the participant completed study participation, an average of 48 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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baminercept treatment