Stiff Person Syndrome
Conditions
Keywords
Stiff Person Syndrome, SPS, Neurological Disorders, Autoimmune Disease, Human Immunoglobulin
Brief summary
The purpose of this study is to evaluate the efficacy and safety of QIVIGY (Intravenous Human Normal Immune Globulin 10%) compared with placebo in adult participants with stiff person syndrome (SPS).
Detailed description
This is a phase III, double-blind, placebo-controlled, parallel group, multicenter study to assess the efficacy and safety of QIVIGY in adult participants with stiff person syndrome. Participants will be randomized in a 1:1 ratio, to receive either 2 g/kg of QIVIGY or equivalent volume of placebo. During the randomized phase, study treatment will be administered every 4 weeks for 24 weeks, at which point the primary efficacy endpoint assessment will be performed at an End of Randomized Treatment visit. At this study visit, all participants will be given the option to enter an open-label study extension. Participants who choose to continue in the study will receive 2.0 g/kg QIVIGY every 4 weeks, for a duration of 24 weeks.
Interventions
BIOLOGICALKedrion IVIg 10%
Intravenous human normal immunoglobulin (IVIg) 10%
BIOLOGICALHuman Albumin
Human albumin solution, diluted with saline 0.9% to a final concentration of 0.5% as an intravenous infusion
Sponsors
Kedrion S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, 18-70 years of age. 2. Patient has signed the Informed Consent Form (ICF). 3. Diagnosed with SPS per the following criteria: a. Clinical symptoms (must have 1 of 2) i. Stiffness (axial regions, limbs, or both) ii. Episodic spasms (axial regions, limbs, or both) triggered by noises, tactile stimuli, emotional stress. b. Clinical signs during symptomatic phase of illness (must have 1 of 3) i. Increased muscle tone (axial or limbs) ii. Exaggerated lumbar lordosis iii. Concurrent stiffness of lumbar paraspinal and abdominal muscles. c. Serological findings (must have 1 of 2), based on participant medical history: i. High-titer GAD65-IgG in the serum (e.g. ≥ 20 nmol/L by radio-immunoprecipitation assay or 10,000 IU/mL by enzyme-linked immunoassay \[ELISA\]) or any positive titer in cerebrospinal fluid \[CSF\] ii. Glycine-R-IgG in serum and/or CSF by live cell binding assay. 4. Patients must have paravertebral stiffness and torso/lower extremity predominance. 5. Distribution of stiffness index score of ≥ 2, including stiffness in the legs or trunk. 6. Patient may be Ig-naïve or Ig-pre-treated, however they should not have received Ig within 3 months prior to the time of study entry (Day 0). 1. Includes newly diagnosed patients 2. Includes patients who have received symptomatic treatments only 3. Includes patients who have failed to respond to rituximab. 7. Patients who have received rituximab in the past 18 months must have B-cell reconstitution test results available from within 3 months prior to enrolment that confirms restoration of humoral immunity. 8. Daily symptomatic therapy has been stable for a minimum of two weeks prior to screening and is expected to remain stable throughout the duration of the study. 9. Willing to comply with all requirements of the protocol, including travel to site for scheduled protocol assessments and treatment, and completion of a diary for the study duration. 10. For women of childbearing potential (WOCBP), a negative urine pregnancy test at screening, on enrollment (Day 0), and agreement to employ effective birth control measures during the study until the end of study (EOS) visit. 11. Authorization to access personal health information.
Exclusion criteria
1. Patients incapable of giving informed consent. 2. Patients with SPS-plus or variants of SPS such as paraneoplastic or progressive encephalomyelitis with rigidity and myoclonus (PERM). Patients with pure cerebellar ataxia, ocular motor apraxia. 3. Patients who are bed-bound or wheelchair-dependent. 4. Ongoing/active infection with hepatitis B virus (HBV), hepatitis C virus (HCV) or HIV Type 1/2 infection. Subjects with chronic hepatitis B or hepatitis C infection currently on treatment may participate if they have undetectable viral load within 12 months of screening date. 5. Patient with a history of hypersensitivity to IVIg, other injectable forms of IVIg, or to glycine (used as an excipient). 6. Patient with known Immunoglobulin A (IgA) deficiency and antibodies against IgA. 7. Patients who are planning to receive the following treatments within the coming 12 months, or who have received in the stated timeframe before enrollment (Day 0) 1. Botulinum toxin within 6 months 2. Rituximab within 6 months 3. Steroid-sparing immunosuppressants (azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil) within 1 month 4. Plasmapheresis within 3 months. 8. Prior chimeric antigen receptor (CAR)-T cell therapy or autologous hematopoietic stem-cell transplantation. 9. Received any blood, blood product, or blood derivative within 1 month of the baseline visit. 10. Had therapy with live attenuated virus vaccines within 3 months of the baseline visit. 11. Use of loop diuretics within 1 week of the baseline visit. 12. Patients at high-risk of thrombotic events such as deep vein thrombosis, cerebrovascular accident, pulmonary embolism, transient ischemic attacks, or myocardial infarction. 13. Uncontrolled hypertension (i.e., diastolic blood pressure \[BP\] \> 100 mmHg and/or systolic BP \> 160 mmHg). If a single measure exceeds this limit, a triple repeat measurement may be performed and the average of the three measurements used. 14. Congestive heart failure as per New York Heart Association III/IV, cardiomyopathy, cardiac arrhythmia associated with thromboembolic events (e.g., atrial fibrillation), unstable or advanced ischemic heart disease, hyperviscosity. 15. Patients with significant protein losing enteropathy, nephrotic syndrome, or lymphangiectasia. 16. Patients with hyperproteinemia, increased serum viscosity, and/or hyponatremia. 17. Severe liver or kidney disease (normal reference ranges of laboratory doing the analysis): 1. Alanine aminotransferase (ALT) or aspartate amino transferase (AST) \>2.5x upper limit of normal (ULN) 2. Creatinine \> 120 µmol/L 3. Blood urea nitrogen (BUN) \> 2.5x ULN. 18. Signs of severe anemia: Hemoglobin of less than 7 g/dL, hemodynamically unstable due to active bleeding, and/or when evidence of end-organ ischemia secondary to severe anemia is present. 19. Body mass index \> 35 kg/m2 or an IVIg dose that puts the patient at risk of fluid overload. 20. History of a malignant disease within 3 years of the baseline visit other than properly treated carcinoma in situ of the cervix or basal cell or squamous cell carcinoma of the skin. 21. Patients having participated in an interventional, investigational clinical study within 30 days of the baseline visit, or within 5 half-lives of the investigational medicinal product (IMP) under investigation. 22. Any condition that the Investigator believes is likely to interfere with evaluation of the IMP or with satisfactory conduct of the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Timed 25-Foot Walk (T25-FW) | Baseline to Week 24 | Proportion of participants showing an improvement on the Timed 25-Foot Walk |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Timed 25-Foot Walk (T25-FW) | Baseline up to Week 48 | Change in the Timed 25-Foot Walk from baseline to Week 24 and, for participants entering the study extension, to Week 48 |
| Distribution-of-Stiffness (DSI) | Baseline up to Week 48 | Change in the scores of the distribution-of-stiffness index (DSI) from baseline to Week 24 and, for participants entering the study extension, to Week 48 |
| Heightened Sensitivity Scale (HSS) | Baseline up to Week 48 | Change in heightened sensitivity scale (HSS) from baseline to Week 24 and, for participants entering the study extension, to Week 48 |
| Modified Rankin Scale (mRS) | Baseline up to Week 48 | Change in Modified Rankin scale (mRS) from baseline to Week 24 and, for participants entering the study extension, to Week 48 |
| HRQoL assessments (Neuro-QOL) | Baseline up to Week 48 | Change in score by visit |
| Pain Interference Score | Baseline up to Week 48 | Change in score by visit |
| Change in level of walking aid dependency | Baseline up to Week 48 | Change from baseline in level of walking aid dependency will be assessed by clinician-reported ambulatory status during scheduled clinical outcome assessments. Walking aid use (unaided, cane, or walker) will be recorded at baseline and at each study visit. Improvement is defined as a reduction in level of assistance (e.g., from walker to cane or unaided, or from cane to unaided). |
| Assess Safety | Day 0 to Week 48 | Assess treatment-emergent AEs and SAEs |
| Duration of Response | Week 24 to Week 48 | Participants on QIVIGY in the randomized phase who responded to treatment will be assessed for continued change (duration of response) through 12 months, based on the T25-FW Test |
| Time to response | Week 24 to Week 48 | Participants on placebo in the randomized phase and did not achieve a response will be assessed for time to response to QIVIGY based on the T25-FW Test |
Contacts
CONTACTCecilia Conz
CONTACTNicola Rovai
STUDY_CHAIRMiranda Norton, PhD
Kedrion S.p.A.
Outcome results
None listed