Reduce Immunosuppression With Atmp in NS ChildrEn
Condition: Nephrotic Syndrome in Children; Steroid-Dependent Nephrotic Syndrome; Idiopathic Nephrotic Syndrome
MeSH terms: Nephrotic Syndrome; Nephrosis; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      A phase II open-label, single arm study aimed to ascertain whether infusions of cord-blood
      mesenchymal stromal cells (CB-MSCs) allow to reduce or suspend the chronic immunosuppressive
      therapy (IS) in steroid-dependent nephrotic syndrome (SDNS).

      We plan to enroll 11 patients aged 3 to 18 with SDNS in remission for at least one month,
      maintained by either ≥2 immunosuppressive drugs or a calcineurin inhibitor.

      Patients are infused with cord-blood allogenic MSC, selected by in-vitro alloreactivity, at a
      dose of 1.5x10^6/kg on days 0, 14, 21. The immunosuppressive treatment is gradually tapered
      starting at the first CB-MSC administration, according to the following scheme: 25% following
      the first administration, 50% following the second administration, and 100% reduction
      following the third administration.

      All patients will be followed-up for 6 months from the last CB-MSC. Study visits are planned
      at baseline during CB-MSC administrations, 2 weeks (follow-up [FU]1) and 6 weeks (FU2) after
      the last infusion, and then every 6 weeks. During follow-up, the patients undergo a physical
      examination (including measurement of height, weight and blood pressure) and laboratory
      evaluations (urinary protein:urinary creatinine ratio, complete blood count, kidney function,
      plasma proteins, liver function, triglycerides and cholesterol). In addition, a blood sample
      is taken for regulatory T lymphocyte quantification, a marker of clinical response to the
      infusions.
    

Detailed description: 
      Background:

      Nephrotic Syndrome (NS) is a rare disease characterized by nephrotic-range proteinuria and
      the need for steroid treatment. About 50% of children will become frequent relapsers (FRNS)
      or steroid dependent (SDNS), requiring higher doses of steroids or other immunosuppressive
      drugs for many years, sometimes up to adulthood. Strong evidence suggests that Idiopathic
      nephrotic syndrome (INS), at least in the steroid-sensitive forms, has an immune
      pathogenesis.

      Mesenchymal Stromal Cells (MSC) are multipotent non-hematopoietic stem cells that produce an
      immunomodulatory activity in-vitro and in-vivo. For this reason, we postulated that SDNS
      patients could benefit with treatment with MSC.

      Objectives:

      The main goal of the present study is to assess whether CB-MSCs have the capacity to regulate
      the immunologic mechanisms involved in the pathogenesis of NS allowing for a reduction or
      suspension of chronic immunosuppressive treatment in SDNS children. The primary objective is
      to evaluate whether CB-MSC therapy is able to prevent NS recurrence for at least 6 months
      after complete withdrawal of immunosuppressive treatment in children with SDNS.

      Primary endpoint: percentage of children without NS recurrence after complete withdrawal of
      immunosuppressive treatment for at least 6 months.

      Population:

      We plan to enroll 11 children (3 to 18 years of age) with SDNS, maintained by chronic
      immunosuppressive treatment and with stable remission for at least two months.

      Study Design:

      Open label single-arm, monocentric trial, with a rescue/second design

      Phase: Phase II

      Inclusion/Exclusion Criteria:

      Inclusion criteria

        1. Age between 3 and 18 years;

        2. Clinical diagnosis of SDNS;

        3. Disease remission maintained by chronic therapy (at least 6 months) with either:

             -  Use of a combination of 2 or more immunosuppressive drugs

             -  use of 1 of the calcineurin inhibitors (Cyclosporin or Tacrolimus);

        4. Absence of proteinuria (urinary protein:urinary creatinine < 0.2 mg/mg) for at least 1
           month;

        5. Estimated glomerular filtration rate greater than or equal to 70 ml/min/1.73 m^2;

        6. Written informed consent from parents or guardians and the child when possible.

      Exclusion criteria

        1. Age < 3 years or ≥ 19 years;

        2. Resistant/refractory NS;

        3. Presence of genetic mutations associated with NS;

        4. eGFR less than 70 ml/min/1.73 m^2;

        5. Thrombophilic condition;

        6. Pregnancy or lactating;

        7. Evidence of an uncooperative attitude;

        8. Any evidence that the patient will be unable to complete the trial follow-up.

      Description of the Intervention:

      The trial will rely on a single advanced therapy medicinal product (ATMP), made by MSC from
      umbilical cord blood (CB) for allogeneic use, produced following a highly standardized
      process, developed and controlled at Cell Factory under the Good Manufacturing Practices
      guidelines.

      After baseline clinical and laboratory evaluation, patients will receive 3 intravenous
      infusions of CB-MSCs at the dosage of 1.5 x 10^6/kg at a time interval of 1 to 2 weeks.

      The immunosuppressive treatment will be gradually tapered off following the first CB-MSC
      administration: 25%, 50% and 100% reduction of the ongoing immunosuppressive treatment
      following the first, second and third administration, respectively.

      At the end of this first part of the trial, a statistical analysis will be performed
      according to the primary end-point. In the case of failure to reach the primary end point an
      extra 11 children with SDNS will be enrolled in a single stage phase 2 study with a 30%
      incremented dose of CB-MSCs.

      Statistical Evaluation:

      A phase II design with a rescue plan B, is adopted to decide whether the proportion
      responding is less than or equal to 0.200 or greater than or equal to 0.600. A sample size of
      10 children is required, considering a drop out of 10%, 11 children will be enrolled: if the
      number of responses is 5 or more, the hypothesis that P ≤ 0.200 is rejected with a target
      error rate of 5%. If the number of responses is 4 or less, the hypothesis that P ≥ 0.600 is
      rejected with a target error rate of 20% (power equal to 80%). The same statistical
      hypothesis will apply for the second part of the study.

      Expected Results:

      The results of this proposal will provide information regarding an innovative cell therapy
      for the treatment of INS. If the hypothesis of this study is confirmed, it will be possible
      to reduce or withdraw immunosuppressive treatment in this vulnerable population of children
      with SDNS, reducing the need for ambulatory visits and hospitalization and therapy-related
      complications. Furthermore, the reduction in the use of immunosuppressive agents as well as
      in the number of outpatient visits and hospital admissions will reduce the financial burden
      to the National Health Service. Above all, the quality of life of children with SDNS would
      clearly be improved, in terms of a reduction in long-term therapy, morbidity and the number
      of visits.
    

Intervention name(s): Cord-blood mesenchymal stromal cells
Intervention type(s): Other
Intervention description(s): The product is packaged in bags suitable for the cryopreservation of cell products. Before administration the cells must be thawed and diluted in an appropriate vol:vol solution: made by saline 78%, human albumin 10%, Acyl-CoA dehydrogenase-A (ACD-A) 12%.
Intervention model: Single Group Assignment
Intervention model description: Open lable, single arm
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Mesenchymal Stromal Cells; Steroid Dependent Nephrotic Syndrome in Children; Proteinuria; Immunosuppressive treatment