Clinical trial NCT02282514: Stem Cell Transplantation for Stiff Person Syndrome (SPS)
Official title: Non-myeloablative Hematopoietic Stem Cell Transplantation for Stiff Person Syndrome (SPS) and Anti-GAD Antibody Variants: Progressive Encephalomyelitis With Rigidity and Myoclonus (PERM), and Adult Onset Autoimmune Anti-GAD Positive Cerebellar Ataxia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Stiff-Person Syndrome
Keywords: Autoimmune Diseases
Autologous Hematopoietic Stem Cell Transplantation
Lead sponsor: Northwestern University
Sponsor class: OTHER
First posted: 2014-11-04
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Non-myeloablative regimens (as the investigators use herein) are designed to maximally suppress the immune system without destruction of the bone marrow stem cell compartment.

When using a non-myeloablative regimen recovery occurs without infusion of stem cells and the stem cells are autologous. While not necessary for recovery, stem cell infusion may shorten the interval of neutropenia and attendant complications. Thus in reality there is no transplant only an autologous supportive blood product.

Based on our encouraging results of non-myeloablative hematopoietic stem cell transplantation, for patients with multiple sclerosis and chronic inflammatory demyelinating polyneuropathy, the investigators will investigate the role of non-myeloablative hematopoietic stem cell transplantation for patients with SPS who require assistance to ambulate.

Detailed description: Pre-study Testing

1. History and physical
2. Electrocardiogram (EKG)
3. Dobutamine stress echocardiogram
4. High-resolution computed tomography of the chest (HRCT)
5. Blood draw for laboratory tests- these tests will include a complete blood count, evaluating liver and kidney function, assessing immune system, tissue typing, and checking for certain germs that can cause infections, including a pregnancy test for females and prostate-specific antigen (PSA) for male as well as testing for HIV
6. Pulmonary Function Test (PFT)
7. Electromyography (EMG)
8. Magnetic Resonance Imaging (MRI) of the Abdomen and Pelvis
9. Magnetic Resonance Imaging (MRI) of the Spinal Cord
10. Magnetic Resonance Imaging (MRI) of the Brain with Gadolinium (only if PERM of cerebellar ataxia)
11. Colonoscopy
12. Mammogram (if female)
13. Timed ambulation
14. Quality of Life Questionnaires \[ Short Form (36) Health Survey (SF36) and Barthel Index\]
15. Chronic Pain Acceptance Questionnaire (CPAQ)
16. Rankin Functional Scale
17. Modified Ashworth Scale
18. Purkinje Cell Cytoplasmic Antibody, Type 1 (PCA-1), Purkinje Cell Cytoplasmic Antibody, Type 2 (PCA-2) antibody (only if cerebellar ataxia)
19. Spinocerebellar ataxia (SCA) 1, 2, 3, 4, 5, 6, 7, 8 genes (only if ataxia)

Study Treatment

Stem Cell Collection: Cyclophosphamide 2.0 gm/m2 will be given on day 0, G-CSF 5-10 mcg/kg/day subcutaneous (SQ) will start on day +5 and will continue until apheresis is discontinued. Apheresis will begin when the absolute neutrophil count (ANC) \> 1.0 x 109/L and continue until \>2.0 x 106 cluster of differentiation 34 (CD34)+ cells/kg patient weight are cryopreserved. A 10-15 liter apheresis will be performed unless stopped earlier for clinical judgment of toxicity (e.g., numbness, tetany). A maximum of four apheresis will be performed.

Eligibility criteria: Inclusion Criteria:

1. Diagnosis of Stiff-person Syndrome and

   * Age between 18 and 60 years old
   * Failure of medically tolerable doses (20-40 mg/day) of diazepam
   * Failure of either intravenous immunoglobulin (IVIg) and or plasmapheresis
   * Stiffness in the axial muscles, prominently in the abdominal and thoracolumbar paraspinal muscle leading to a fixed deformity (hyperlordosis)
   * Superimposed painful spasms precipitated by unexpected noises, emotional stress, tactile stimuli
   * Confirmation of the continuous motor unit activity in agonist and antagonist muscles by electromyography when off diazepam and anti-spasmatic medications
   * Absence of neurological or cognitive impairments that could explain the stiffness
   * Inability to run or walk, or abnormal gait
2. Diagnosis of a SPS variant- Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM) defined as:

   Acute onset of painful rigidity and muscle spasms in the limbs and trunk
   * Brainstem dysfunction (nystagmus, opsoclonus, ophthalmoparesis, deafness, dysarthria, dysphagia)
   * Profound autonomic disturbance.
   * Positive serology for GAD65 (or amphiphysin) autoantibodies, assessed by immunocytochemistry, western blot or radioimmunoassay (\>1000 u/ml)
   * MRI may show increased signal intensity throughout the spinal cord and the brainstem
3. Diagnosis of a SPS variant - anti-GAD positive cerebellar ataxia

   * Subacute or chronic onset of cerebellar symptoms-gait or limb ataxia, dysarthria, nystagmus
   * Positive serology for GAD65 (or amphiphysin) autoantibodies, assessed by immunocytochemistry, western blot or radioimmunoassay (\>1000 u/ml)
   * Anti-GAD antibody in cerebrospinal fluid
   * Abnormal MRI imaging of brainstem or cerebellum other than cerebellar atrophy
   * Negative history of toxin or alcohol
   * Absence of Vitamin B12 or Vitamin E deficiency
   * Absence of positive HIV, syphilis or whipple disease
   * Absence of consanguinity, positive family history for ataxia or positive genetic screen for spinocerebellar ataxia (SCA) 1, SCA 2, SCA 3, SCA 6, SCA 7 or SCA 8 mutation

Exclusion Criteria:

* Current or prior history of a malignancy or paraneoplastic syndrome
* Inability to sign and understand consent and be compliant with treatment
* Positive pregnancy test
* Inability to or comprehend irreversible sterility as a possible side effect
* Amphiphysin antibody positive
* Left ventricular ejection fraction (LVEF) \< 45% or ischemic coronary artery disease on dobutamine stress echocardiogram
* Diffusing capacity of the lungs for carbon monoxide (DLCO) \< 60% predicted
* Serum creatinine \> 2.0 mg/dl
* Bilirubin \>2.0 mg/dl
* Platelet count \< 100,000 / ul, white blood cell count (WBC) \< 1,500 cells/mm3
* History of toxin or alcohol abuse
* History of Vitamin B12 or Vitamin E deficiency
* Positive HIV, syphilis, or whipple disease
* Consanguinity, positive family history for ataxia or positive genetic screen for SCA1, SCA2, SCA3, SCA6, SCA 7 or SCA8 mutation (if ataxia present)
* Absence of at least one SPS associated antibody such as anti-GAD, or gamma-aminobutyric acid (GABA)-A receptor associated protein, or synaptophysin, or gephyrin, or GABA-transaminase

Primary outcomes:
measure: Overall Survival
timeFrame: Mean 3.6 years
Secondary outcomes:
measure: Reduction of Muscle Relaxation Anti-spasmatic Medications
timeFrame: Mean 3.6 years
measure: Short-form 36 Quality of Life Questionnaire (SF-36 QOL)
timeFrame: mean 3.6 years
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
Study officials:
affiliation: Northwestern University
name: Richard Burt, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Burt RK, Balabanov R, Han X, Quigley K, Arnautovic I, Helenowski I, Rose J, Siddique T. Autologous Hematopoietic Stem Cell Transplantation for Stiff-Person Spectrum Disorder: A Clinical Trial. Neurology. 2021 Feb 9;96(6):e817-e830. doi: 10.1212/WNL.0000000000011338. Epub 2020 Dec 14.