Hematopoietic Stem Cell Transplantation in Chronic Inflammatory Demyelinating Polyneuropathy

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Brief Title

Hematopoietic Stem Cell Transplantation in Chronic Inflammatory Demyelinating Polyneuropathy

Official Title

Non-myeloablative Autologous Hematopoietic Stem Cell Transplantation in Patients With Chronic Inflammatory Demyelinating Polyneuropathy: A Phase II Trial

Brief Summary

      Chronic inflammatory demyelinating polyneuropathy is disease believed to be due to immune
      cells, cells which normally protect the body, but are now attacking the nerves in the body.
      As a result, the affected nerves fail to respond, or respond only weakly, to stimuli causing
      numbing, tingling, pain, and progressive muscle weakness.The likelihood of progression of the
      disease is high. This study is designed to examine whether treating patients with high dose
      cyclophosphamide (a drug which reduces the function of the immune system) and ATG (a protein
      that kills the immune cells that are thought to be causing disease), followed by return of
      the previously collected blood stem cells will stop the progression of CIDP. Stem cells are
      undeveloped cells that have the capacity to grow into mature blood cells, which normally
      circulate in the blood stream. The purpose of the high dose cyclophosphamide and ATG is to
      destroy the cells in the immune system. The purpose of the stem cell infusion is to evaluate
      whether this treatment will produce a normal immune system that will no longer attack the
      body.
    

Detailed Description

      Selection of the Regimen for Immunosuppressive Therapy

      Cyclophosphamide with ATG is a common conditioning regimen with two decades of experience in
      the treatment of aplastic anemia, and has been used safely without reported mortality in the
      treatment of autoimmune diseases such as systemic lupus erythematosus and rheumatoid
      arthritis.Cy / ATG is not associated with late malignancies or cataracts. Both
      cyclophosphamide and anti-thymocyte globulin (horse or rabbit ATG) are potent
      immunosuppressive agents. ATG contributes additional immunosuppression without additional
      cytotoxicity. ATG given shortly pre-transplant will contribute to the elimination of host T
      lymphocytes that survive cyclophosphamide SLE, an autoimmune disease responsive to
      cyclophosphamide, responds well to a CY / ATG conditioning regimen, but we have recently
      found that patients with either systemic lupus erythematosus (SLE) or neuromyelitis optica
      respond faster and may have more durable remissions to a regimen of "rituxan sandwich" in
      which rituxan is infused before and after standard cytoxan, rATG. For these reasons, "rituxan
      sandwich" will be the conditioning regimen utilized in this study.

      5.2 Method of Harvesting Stem Cells

      Based on the experience of the pilot studies, the current protocol will mobilize stem cells
      with granulocyte-colony stimulating factor (G-CSF) and collect stem cells by apheresis, with
      subsequent bone marrow harvest performed only if needed to supplement the peripheral blood
      stem cells (PBSC). Based on experience of autoimmune flares in patients receiving G-CSF alone
      for mobilization, patients will be mobilized with cyclophosphamide 2.0 g/m2 and G-CSF 5-10
      mcg/kg.

      5.3 Cyclophosphamide

      Cyclophosphamide (CY) is an active agent in patients with a wide variety of malignancies. It
      is used frequently in the therapy of lymphoid malignancies and has potent immunosuppressive
      activity. It is frequently used as a cytotoxic and immunosuppressive agent in patients
      undergoing marrow transplants and as a treatment for patients with autoimmune diseases. It is
      an alkylating agent that requires hepatic metabolism to the active metabolites, phosphoramide
      mustard and acrolein. These active metabolites react with nucleophilic groups. It is
      available as an oral or intravenous preparation. Bioavailability is 90% when given orally.
      The half-life of the parent compound is 5.3 hours in adults, and the half-life of the major
      metabolite phosphoramide mustard is 8.5 hours. Liver or renal dysfunction will lead to
      prolonged serum half-life. CY is administered intravenously at a dosage of 50 mg/kg on each
      of 4 successive days (use adjusted ideal body weight if patient's actual body weight is
      greater than 100% ideal body weight). The major dose limiting side effect at high doses is
      cardiac necrosis. Hemorrhagic cystitis can occur and is mediated by the acrolein
      metabolite.This can be prevented by co-administration of MESNA or bladder irrigation. Other
      notable side effects include nausea, vomiting, alopecia, myelosuppression and SIADH. Refer to
      institutional manuals for more information about administration, toxicity and complications.

      5.4 Rabbit-Derived Anti-Thymocyte Globulin (rATG)

      Rabbit-derived anti-human thymocyte globulin (rATG) is a gamma globulin preparation obtained
      from hyperimmune serum of rabbits immunized with human thymocytes. rATG has been used
      predominately in solid organ transplant immunosuppressive regimens. rATG is a predominantly
      lymphocyte-specific immunosuppressive agent. It contains antibodies specific to the antigens
      commonly found on the surface of T cells. After binding to these surface molecules, rATG
      promotes the depletion of T cells from the circulation through mechanisms which include
      opsonization and complement-assisted, antibody-dependent, cell-mediated cytotoxicity. The
      plasma half-life ranges from 1.5 12 days. rATG is administered intravenously at a dose of 0.5
      mg/kg recipient body weight on day -6 and at a dose of 1.0 mg/kg recipient body weight on
      days -5, -4, -3, -2, and -1. Unlike equine ATG, rabbit ATG does not require a pre-infusion
      skin test to check for hypersensitivity. Methylprednisolone 250 mg will be given before every
      dose of rATG. Additional medications such as diphenhydramine may be given at the discretion
      of the attending physician. Although rare, the major toxicity is anaphylaxis; chills, fever,
      pruritus or serum sickness may occur.

      5.5 Rituxan Rituximab is a chimeric monoclonal antibody used in the treatment of B cell
      non-Hodgkin's lymphoma, B cell leukemia, and numerous autoimmune disorders. The recommended
      adult dosage for patients with low grade or follicular non-Hodgkin's lymphoma (NHL) is 375
      mg/m2 infused intravenously and for adult patients with autoimmune diseases a standard 500 mg
      is generally given intravenously. The infusion may be given at weekly intervals for four
      total dosages or once every 2 weeks and repeated 2-3 times. Acetaminophen and diphenhydramine
      hydrochoride are given 30-60 minutes before the infusion to help reduce side effects. If
      given as a retreatment the dosage is the same. The majority of side effects occur after or
      during the first infusion of the drug. Some common side effects include dizziness, feeling of
      swelling of tongue or throat, fever and chills, flushing of face, headache, itching, nausea
      and vomiting, runny nose, shortness of breath, skin rash, and fatigue.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Number of Participants With Survival

Secondary Outcome

 Disease Improvement - Medication Free Remission

Condition

Chronic Inflammatory Demyelinating Polyneuropathy

Intervention

hematopoietic stem cell transplantation

Study Arms / Comparison Groups

 Hematopoietic Stem Cell Transplantation in CIDP
Description:  Autologous hematopoietic stem cell transplantation will be performed after conditioning regimen of cyclophosphamide 200 mg/kg/intravenously(IV), rATG(thymoglobulin) 5.5 mg/kg/IV and rituximab 1000mg/IV.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

80

Start Date

February 21, 2005

Completion Date

November 4, 2019

Primary Completion Date

January 14, 2017

Eligibility Criteria

        Inclusion criteria:

          -  Definite CIDP according to the European Federation of Neurological
             Societies/Peripheral Nerve Society (EFNS/PNS) criteria

        AND

          -  Clinically typical or atypical CIDP

        AND

          -  Failure to tolerate or respond to, or an incomplete response to, or relapse after at
             least 3 months of conventional treatment consisting of corticosteroids (equivalent
             dosage of prednisone 1.0/mg/day to 0.75mg/kg/day to start with adequate tapering
             trials of no less than 0.5mg/kg/day), and/or either intravenous immunoglobulin (IVIg)
             or plasmapheresis or cytoxan or rituxan

          -  Failure to respond to therapy is defined by:

               1. Persistent muscle weakness Grade 3/5 or worse (MRC) in at least one muscle or
                  grade 4/5 in at least two muscle groups OR

               2. Persistent dysphagia documented by either aspiration or insufficient clearing on
                  videofluoroscopic examination.

                  OR

               3. Persistent incapacitating sensory loss (e.g. gait ataxia, falls > 1/month)

                  AND

               4. If patients are on IVIG or plasmapheresis, neurologic condition is documented to
                  deteriorate (for example, new or increase finger tip paresthesias or increased
                  leg heaviness) upon stopping IVIG (or plasmapheresis)@

          -  Monoclonal gammopathy of undetermined significance (MUGS) (in which the pathogenesis
             of are thought to be the same as CIDP) will be allowed provided bone marrow aspirate
             and biopsy rules out multiple myeloma.

          -  Other immune mediated or suspected immune mediated neuropathies such as multifocal
             motor neuropathy or anti-myelin-associated glycoprotein (anti-MAG) neuropathy may be
             treated but will be analyzed and reported separately.

        Exclusion Criteria:

          -  Any evidence of hereditary cause for neuropathy that is known or likely hereditary
             demyelination neuropathy because of family history, foot deformity, mutilation of
             hands or feet, retinitis pigmentosa, ichthyosis, or liability to pressure palsies.

          -  Diphtheria, drug, or toxin exposure likely to be cause of neuropathy

          -  Conditions in which the pathogenesis of the neuropathy may be different from CIDP such
             as: Lyme disease (Borrelia burgdorferi infection), POEMS syndrome, Osteosclerotic
             myeloma, malignancies such as Waldenstrom macroglobulinemia, and Castleman's)

          -  Multiple myeloma

          -  HIV positive

          -  Insulin dependent Diabetes mellitus

          -  Chronic active hepatitis

          -  Age > 65 years old or < 18 years old

          -  Significant end organ damage such as (not caused by CIDP):

               1. Left ventricular ejection fraction (LVEF) <40% or deterioration of LVEF during
                  exercise test on multigated acquisition scan (MUGA) or echocardiogram.

               2. Untreated life-threatening arrhythmia.

               3. Active ischemic heart disease or heart failure or myocardial infarction within
                  the last 6 months

               4. Diffusing capacity of lung for carbon monoxide (DLCO) <40% or forced expiratory
                  volume at one second (FEV1) / forced expiratory volume (FEV) < 50%

               5. Serum creatinine >2.0.

               6. Liver cirrhosis, transaminases > 2 x of normal limits or bilirubin >2.0 unless
                  due to Gilbert disease.

          -  Prior history of malignancy except localized basal cell or squamous skin cancer or
             other localized cancer considered cured only by surgery

          -  Positive pregnancy test, inability or unwillingness to pursue effective means of birth
             control, or failure to willingly accept or comprehend irreversible sterility as a side
             effect of therapy.

          -  Psychiatric illness or mental deficiency making compliance with treatment or informed
             consent impossible.

          -  Inability to give informed consent.

          -  Major hematological abnormalities such as platelet count less than 100,000/ul or
             absolute neutrophil count (ANC) less than 1000/ul.

          -  Failure to collect at least 2.0 x 106 cluster of differentiation 34 (CD34+) cells by
             apheresis and, if necessary, bone marrow harvest is a contraindication to treatment,
             i.e., receiving the conditioning regimen.
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

Richard Burt, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00278629

Organization ID

NU FDA CIDP.AUTO2003


Responsible Party

Principal Investigator

Study Sponsor

Northwestern University


Study Sponsor

Richard Burt, MD, Principal Investigator, Northwestern University


Verification Date

June 2020