A Study Investigating Intravenous Human Normal Immune Globulin 10% in Adults With Stiff Person Syndrome

A Phase III, Randomized, Double-blind, Placebo-Controlled, Parallel Group, Multicenter Study to Assess the Efficacy and Safety of Intravenous Human Normal Immune Globulin (IGIV) 10% in Adult Patients With Stiff Person Syndrome

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).

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.

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.