| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic active antibody mediated rejection of renal transplants |
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| E.1.1.1 | Medical condition in easily understood language |
| Kidney transplants that have rejection present |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10023439 |
| E.1.2 | Term | Kidney transplant rejection |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The principle research question is to assess the efficacy of fostamatinib administered orally for 52 weeks to subjects with chronic antibody mediated rejection of kidney transplants.
Efficacy will be determined principally by changes of inflammation and antibody mediated injury in biopsy specimens of the study patients. A biopsy showing CAMR is a prerequisite to enrol in the study. This biopsy will be compared to subsequent biopsies taken at 26 and 52 weeks, following commencement of fostamatinib.
Efficacy will also be determined by change in kidney transplant function (determined by a blood test), change in proteinuria (protein leak in the urine) and change in the level of donor specific antibodies (antibodies made against the transplant, which can be measured by a blood test).
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| E.2.2 | Secondary objectives of the trial |
| The secondary research question is to investigate the safety and tolerability of fostamatinib administered orally for 52 weeks to subjects with chronic antibody mediated rejection of kidney transplants. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent prior to any study specific screening procedures.
2. Male or female, at least 18 years of age.
3. Females must be either post-menopausal (defined as no menses for 12 months without an alternative medical cause), surgically sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy), or, if of child-bearing potential, must not be pregnant or lactating. If sexually active, must agree to use a highly effective methods of birth control, which include: combined (estrogen and progestogen containing) hormonal contraception via the oral, intravaginal or transdermal route, progestogen only hormonal contraception via the oral, injectable or implantable route, an intrauterine device (IUD), an intrauterine hormone releasing system (IUS), bilateral tubal occlusion, vasectomised partner or sexual abstinence throughout the duration of the trial and for 30 days following the last dose. In males, there are no restrictions on sex or sperm donation during the study. This is based on a study which found that extremely low amounts of fostamatinib were present in human semen of healthy male volunteers who took the drug. In addition, animal studies have found that fostamatinib does not affect sperm. There are also no restrictions on males impregnating females during the course of the study.
4. Patients must be established on tacrolimus maintenance immunosuppression
5. A pre-study renal biopsy obtained within 3 months prior to Screening (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
Chronic tubulo-interstitial scarring ≤30%
Glomerular global obsolescence ≤50%
The sample contains at least 7 glomeruli and 1 artery
A flow diagram showing the histological inclusion and exclusion criteria can be shown in appendix 1.
6. Anti-HLA DSA positive (Mean fluorescence intensity MFI ≥500)
7. eGFR ≥30 mL/min/1.73 m2 (using the MDRD equation) at Screening (Visit 1) and ≤15% fall from baseline GFR during the run in period (Visit 5)
8. UPCR ≥50mg/mol
9. 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.
10. 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.
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| E.4 | Principal exclusion criteria |
1. Co-existing Banff Category 4 T-cell mediated rejection.
2. 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.
3. 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.
4. 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 2).
5. Acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea) at Baseline (Visit 2). The subject may be reassessed after full recovery from the acute gastrointestinal illness.
6. Co-existing BK nephropathy or pyelonephritis on screening biopsy.
7. 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.
8. Evidence of active or previous invasive fungal infection.
9. 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).
10. Have active malignancy.
11. 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 2).
12. Are unable or unwilling to follow instructions, including participation in all study assessments and visits.
13. 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.
14. 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.
15. Have a known allergy and/or sensitivity to the study drug or its excipients.
16. 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).
17. Women who are breastfeeding.
18. Patients with rapid loss of kidney function because they may need other medical interventions: therefore: exclusion of patient with a fall of eGFR by more than 15% from baseline within the first 21 days of the run in period.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measure will be determined by improvement of histological features of CAMR, as measured on the histological appearances of biopsies (at 26 weeks ± 52 weeks).
1. Change from pre-treatment to post-treatment of g+ptc (MI) score on renal biopsies
2. Change from pre-treatment to post-treatment in C4d score on renal biopsies
3. Change from pre-treatment to post-treatment in cg score on renal biopsies
4. Change from pre-treatment to post-treatment in segmental or global glomerulosclerosis on renal biopsies
5. Change from pre-treatment to post-treatment in tubulointerstitial scarring on renal biopsies
6. Change from pre-treatment to post-treatment in glomerular and peritubular capillary basement membrane multilayering
7. Change from pre-treatment to post-treatment in cAMR -associated and other immune related (including syk-associated) transcript levels (expressed as individual transcript levels and/or as aggregate scores).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Renal biopsy taken at 26 weeks (optional for patient to have a further biopsy at 52 weeks). |
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| E.5.2 | Secondary end point(s) |
1. Mean change, or stabilisation from Baseline (Visit 2) of proteinuria as measured by sPCR at 12, 26, 36 and 52 weeks (Visits 13,17,20 and 24)
2. Mean change, or stabilisation from Baseline (Visit 2) of eGFR at 12, 26, 38 and 52 weeks (Visit 13, 17, 20 and 24).
3. Change in donor specific antibody [DSA] status from Baseline (Visit 2) at 12, 26, 36 and 52 weeks. Change in the number of DSA and mean fluorescence intensity (MFI), of DSA present.
4. Change from pre-treatment baseline to post-treatment in ABMR-associated and other immune-related (including Syk-associated) transcript levels
5. Allograft survival [dialysis independent] at 52 weeks (visit 24).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Proteinuria will be measured at 12, 26, 36 and 52 weeks (Visits 13,17,20 and 24)
eGFR will be measured at 12, 26, 36 and 52 weeks (Visits 13,17,20 and 24)
Donor specific antibody status will be measured at 12, 26, 36 and 52 weeks (Visits 13,17,20 and 24)
ABMR associated and other immune related transcript levels will be measured on biopsy samples taken at 26 weeks (and at 52 weeks if patient agrees to this optional biopsy)
Allograft survival will be measured at 52 weeks |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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