FOSTAMR: Fostamatinib in the Treatment of Chronic Active Antibody Mediated Rejection

Sponsor
Imperial College London (Other)
Overall Status
Recruiting
CT.gov ID
NCT03991780
Collaborator
(none)
10
1
1
62.8
0.2

Study Details

Study Description

Brief Summary

A Phase 2, Pilot Study to Assess the Safety and Efficacy of Fostamatinib in the Treatment of Chronic Active Antibody Mediated Rejection in Renal Transplantation

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

The commonest cause of renal transplant failure worldwide is rejection, a process whereby the recipient's immune system recognises the transplant kidney as foreign and attacks it. One common form of rejection is due to the recipient developing antibodies against their kidney transplant. Spleen tyrosine kinase is a molecule present in immune cells which is important in the process of antibody mediated damage. Fostamatinib is a drug which inhibits spleen tyrosine kinase.

This clinical trial will recruit 10 patients who have a renal transplant and a diagnosis of antibody mediated rejection. Patients will be given Fostamatinib for 12 months and will undergo a renal biopsy at 6 months and at a 12 months in order to determine whether the histological signs of antibody mediated rejection have either improved or not progressed.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
10 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Intervention Model Description:
Single centre, not randomised, open labelSingle centre, not randomised, open label
Masking:
None (Open Label)
Masking Description:
Open label
Primary Purpose:
Treatment
Official Title:
A Phase 2, Pilot Study to Assess the Safety and Efficacy of Fostamatinib in the Treatment of Chronic Active Antibody Mediated Rejection in Renal Transplantation
Actual Study Start Date :
May 8, 2019
Anticipated Primary Completion Date :
Jul 31, 2024
Anticipated Study Completion Date :
Jul 31, 2024

Arms and Interventions

Arm Intervention/Treatment
Experimental: Fostamatinib

All patients will be given treatment with Fostamatinib. The initial treatment dose will be 100mg of Fostamatinib (tablet taken orally) twice daily for 8 weeks. If after 8 weeks the participant has not experienced any side effects and are tolerant of this dose, then the dose will increase to 150mg twice daily. This dose will continue for the duration of the study.

Drug: Fostamatinib
All patients will be given treatment with Fostamatinib. The initial treatment dose will be 100mg of Fostamatinib twice daily for 8 weeks. If after 8 weeks the participant has not experienced any side effects and are tolerant of this dose, then the dose will increase to 150mg twice daily. This dose will continue for the duration of the study.
Other Names:
  • Spleen Tyrosine Kinase Inhibitor, TAVALISSE
  • Outcome Measures

    Primary Outcome Measures

    1. Histological changes of antibody mediated rejection assessed by a histopathologist [6 months]

      Pre treatment and Post treatment renal transplant biopsies will be scored by a histopathologist

    Secondary Outcome Measures

    1. Concentration of Protein in urine [6 months and 12 months]

      The Level of proteinuria will be assessed by collected a urine samples which will be sent to the clinical laboratory and the protein/creatinine ratio will be calculated. The normal value of the protein/creatinine ratio should be <10, anything higher than this indicated that the kidney is "leaky" and functioning abnormally. Levels of proteinuria will be compared pre and post treatment

    2. eGFR ( Estimated Glomerular Filtration Rate) assessed by a blood test [6 months and 12 months]

      GFR is Glomerular Filtration Rate and it is a key indicator of renal function. The normal eGFR is 60 or more. If your eGFR is less than 60 for three months or more, your kidneys may not be working well. Th eGFR of participants will be compared pre and post treatment.

    3. Donor specific antibody levels [6 months and 12 months]

      The mean fluorescence intensity (MFI) of donor specific antibody present will be compared pre and post treatment. Each participant will have their Donor specific antibodies measured at baseline pre treatment, this specific antibody or antibodies will be re-measured post treatment and the level (MFI) of the antibody/antibodies will be compared to pre treatment levels.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    Inclusion Criteria

    • Signed informed consent prior to any study specific screening procedures.

    • Male or female, at least 18 years of age

    • Females must be either post-menopausal, surgically sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy), or, if of child-bearing potential, must not be pregnant or lactating.

    • Patients must be established on tacrolimus maintenance immunosuppression

    • A pre-study renal biopsy obtained within 3 months prior to Baseline (Visit 1) will be reviewed by a renal pathologist to ensure subjects meet the following Banff histologic entry criteria: If C4d positive: Microcirculation inflammation score (g+ptc) ≥1 If C4d negative: Microcirculation inflammation score (g+ptc) ≥2 Chronic glomerulopathy (cg) score ≥1b or significant Peritubular Capillary Basement Membrane Multilayering (PTCBML) Chronic tubulo-interstitial scarring ≤50% Glomerular global obsolescence ≤50% Sample must contain at least 7 glomeruli and 1 artery

    • Otherwise in stable health as determined by the Investigator based on medical history and laboratory tests during the screening period. See Exclusion Criteria for specific exclusions.

    • In the Investigator's opinion, understand the duration of the study (up to 52 weeks), including the requirements for renal biopsies, and has the ability to understand the nature of the study and any hazards of participation and to communicate satisfactorily with the Investigator.

    Exclusion Criteria:
    • Co-existing Banff Category 4 T-cell mediated rejection

    • History of or active, clinically significant, respiratory, gastrointestinal (including pancreatitis), hepatic, neurological, psychiatric, musculoskeletal, genitourinary, dermatological, or other disorder that, in the Investigator's opinion, could affect the conduct of the study or the absorption, metabolism or excretion of the study drug.

    • Have had any major cardiovascular event within the 180 days prior to randomisation, including but not limited to: myocardial infarction, unstable angina, cerebrovascular accident, pulmonary embolism, or New York Heart Association Class III or IV heart failure.

    • An absolute neutrophil count of < 1,500/μL, Hgb < 9 g/L, ALT or AST of > 1.5x ULN, total bilirubin > 2.0 mg/dL at Baseline (Visit 1).

    • Acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea) at Baseline (Visit

    1). The subject may be reassessed after full recovery from the acute gastrointestinal illness.

    • Co-existing BK nephropathy or pyelonephritis on screening biopsy.

    • Active bacterial, viral or parasitic infections, including tuberculosis. Where CMV viral infection is defined as replicating DNA ≥3000 copies/ml and EBV viral infection is defined as replicating DNA ≥10000 copies/ml.

    • Evidence of active or previous invasive fungal infection.

    • Positive serologic tests suggestive of active hepatitis B or hepatitis C or hepatitis E(subjects may be included if confirmed hepatitis C recombinant immunoblot assay negative or hepatitis C virus RNA negative [qualitative]) or hepatitis E virus RNA negative by PCR), or subjects with suspected human immunodeficiency virus (HIV).

    • Have active malignancy.

    • Currently enrolled in an investigational drug or device study or have used an investigational drug or device within 30 days or 5 half-lives (whichever is longer) from Baseline (Visit 1).

    • Are unable or unwilling to follow instructions, including participation in all study assessments and visits.

    • Have a history of alcohol or substance abuse that, in the judgment of the Investigator, may impair or risk the subject's full participation in the study.

    • Have a condition or be in a situation that the Investigator feels may put the subject at significant risk, may confound the study results, or may interfere significantly with the subject's participation in the study.

    • Have a known allergy and/or sensitivity to the study drug or its excipients.

    • Pregnancy or for women that are sexually active, unable to take highly effective contraception (please see inclusion criteria 3 for more information regarding what classifies as a highly effective contraception method)

    • Women who are breastfeeding

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Imperial College NHS Healthcare Trust London United Kingdom W12 0HS

    Sponsors and Collaborators

    • Imperial College London

    Investigators

    • Principal Investigator: Frederick Tam, MBBChir, Imperial College London

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Imperial College London
    ClinicalTrials.gov Identifier:
    NCT03991780
    Other Study ID Numbers:
    • 18HH4488
    • 2018-000027-14
    First Posted:
    Jun 19, 2019
    Last Update Posted:
    Oct 4, 2021
    Last Verified:
    Sep 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Keywords provided by Imperial College London

    Study Results

    No Results Posted as of Oct 4, 2021