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BACKGROUND:

Steroid-resistant (SR) acute graft-versus-host disease (aGVHD) lacks standard second-line treatment. Mesenchymal stromal cells (MSCs) have potential efficacy in SR aGVHD. We aimed to assess the efficacy and safety of MSCs combined with basiliximab and calcineurin inhibitor as second-line therapy for SR aGVHD.

METHODS:

A randomized phase 3 trial involved 203 SR aGVHD patients at nine centers in China (September 2014-March 2019). Participants were randomized at a 1:1 ratio to receive second-line therapy with (n = 101) or without (n = 102) MSCs. The primary endpoint was the overall response (OR) at day 28. Secondary and safety endpoints included durable OR at day 56, failure-free survival, overall survival (OS), chronic GVHD (cGVHD), infection, hematological toxicity and relapse.

RESULTS:

Of 203 patients, 198 (97.5%; mean age, 30.1 years; 40.4% women) completed the study. The OR at day 28 was higher in the MSC group than the control group (82.8% [82 patients] vs. 70.7% [70]; odds ratio, 2.00; 95% confidence interval [CI], 1.01-3.94; P = 0.043). The durable OR at day 56 was also higher in the MSC group (78.8% [78 patients] vs. 64.6% [64]; odds ratio, 2.02; 95% CI, 1.08-3.83; P = 0.027). The median failure-free survival was longer in the MSC group compared with control (11.3 months vs. 6.0 months; hazard ratio (HR) 0.68; 95% CI, 0.48-0.95, P = 0.024). The 2-year cumulative incidence of cGVHD was 39.5% (95% CI, 29.3-49.4%) and 62.7% (51.4-72.1%) in the MSC and control groups (HR 0.55, 95% CI, 0.36-0.84; P = 0.005). Within 180 days after study treatments, the most common grade 3 and 4 adverse events were infections (65 [65.7%] in the MSC group vs. 78 [78.8%] in the control group) and hematological toxicity (37 [37.4%] vs. 53 [53.5%]). The 3-year cumulative incidence of tumor relapse was 10.1% (95% CI, 5.2-17.1) and 13.5% (7.5-21.2%) in the MSC and control groups, respectively (HR 0.75, 95% CI, 0.34-1.67, P = 0.610).

CONCLUSIONS:

MSCs plus second-line treatments increase the efficacy of SR aGVHD, decrease drug toxicity of second-line drugs and cGVHD without increasing relapse, and are well-tolerated. MSCs could be recommended as a second-line treatment option for aGVHD patients. Trial registration clinicaltrials.gov identifier: NCT02241018. Registration date: September 16, 2014, https://clinicaltrials.gov/ct2/show/NCT02241018 .

INTERVENTION:

Trade Name: MabCampath Product Name: Campath‐1H Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed

INN:

Alemtuzumab CAS Number: 216503‐57‐0 Other descriptive name: Campath‐1H Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 30‐ Trade Name: Simulect Product Name: Basiliximab Pharmaceutical Form: Powder and solvent for solution for infusion INN or Proposed

INN:

Basiliximab CAS Number: 152923‐56‐3 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 4‐ Trade Name: Rapamune Product Name: Sirolimus Pharmaceutical Form: Tablet INN or Proposed

INN:

Sirolimus CAS Number: 53123‐88‐9 Concentration unit: mg milligram(s) Concentration type: range Concentration number: 1‐2 Trade Name: Prograf Product Name: Tacrolimus Pharmaceutical Form: Capsule, hard INN or Proposed

INN:

Tacrolimus CAS Number: 104987‐11‐3 Concentration unit: mg milligram(s) Concentration type: range Concentration number: 0.5‐5

CONDITION:

Renal transplantation. ; MedDRA version: 14.1 Level: LLT Classification code 10023438 Term: Kidney transplant System Organ Class: 100000004865

PRIMARY OUTCOME:

Main Objective: The primary aims of the 3C Study are to investigate, in people receiving a kidney transplant, whether: 1) using Campath‐1H as induction therapy (i.e. given around the time of transplant surgery) reduces the incidence of acute rejection of the kidney transplant at 6 months after surgery, compared to standard basiliximab‐based induction therapy; and 2) whether sirolimus‐based maintenance immunosuppression (i.e. the drugs they have to take every day to prevent their body's immune system from attacking ('rejecting') the transplant) improves the function of their kidney transplant, compared to using tacrolimus‐based maintenance therapy at 2 years after transplantation. Primary end point(s): There are two primary outcomes: (i) effect of Campath‐1H on the incidence of acute rejection at six months post‐transplantation; and (ii) effect of sirolimus on transplant function (assessed be estimated glomerular filtration rate) at two years after transplantation. Secondary Objective: The secondary objectives of the 3C study are to investigate in people receiving a kidney tranplant: 1) whether the use of Campath‐1H induction therapy (i.e. given around the time of transplant surgery) improves the long‐term function and survival of the transplant, compared to using standard induction therapy; 2) whether Campath‐1H has a similar safety profile to standard induction therapy (e.g. number and/or severity of infections, malignancy, patient survival) 3) whether using sirolimus as maintenance therapy improves the long‐term survival of the transplant, compared to using standard maintenance therapy 4) whether sirolimus has a similar safety profile to standard maintenance therapy (similar to (2) above) In addition a health economic analysis will be performed to estimate the average costs and effectiveness within each study arm, and incremental cost‐effectiveness of CAMPATH induction compared to basiliximab induction, and of sirolimus‐based maintenance therapy compared to

INCLUSION CRITERIA:

INDUCTION THERAPY RANDOMISATION INCLUSION CRITERIA:

‐ age 18 or over; ‐ scheduled to receive kidney transplant in next 24 hours ‐ negative pregnancy test (if female and able to pass urine [not required if unable to pass urine as per standard practice]). MAINTENANCE THERAPY INCLUSION CRITERIA (at 6 months after transplantation): ‐ patient and managing doctors remain willing to randomise between tacrolimus‐ and sirolimus‐based maintenance therapy Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 0 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 0

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This study is designed to evaluate whether tacrolimus dose reduction in de novo renal recipients receiving everolimus can preserve renal function while maintaining efficacy.

INTERVENTION:

Trade Name: SIMULECT 20 mg polvo y disolvente para sol. iny. o sol. para perfusión Pharmaceutical Form: Solution for infusion INN or Proposed

INN:

BASILIXIMAB CAS Number: 179045‐86‐4 Other descriptive name: BASILIXIMAB Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 20‐ Trade Name: MYFORTIC 180 mg comprimidos gastrorresistentes Pharmaceutical Form: Gastro‐resistant tablet INN or Proposed

INN:

MICOFENOLICO ACIDO Other descriptive name: MYCOPHENOLIC ACID Concentration unit: mg milligram(s) Concentration type: up to Concentration number: 360‐ Trade Name: ADVAGRAF 0,5 mg cápsulas duras de liberación prolongada Pharmaceutical Form: Prolonged‐release capsule, hard INN or Proposed

INN:

TACROLIMUS Other descriptive name: TACROLIMUS Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 0.5‐ Trade Name: ADVAGRAF 1 mg cápsulas duras de liberación prolongada Pharmaceutical Form: Prolonged‐release capsule, hard INN or Proposed

INN:

TACROLIMUS Other descriptive name: TACROLIMUS Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 1‐ Trade Name: ADVAGRAF 3 mg cápsulas duras de liberación prolongada Pharmaceutical Form: Prolonged‐release capsule, hard INN or Proposed

INN:

TACROLIMUS Other descriptive name: TACROLIMUS Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 3‐ Trade Name: ADVAGRAF 5 mg cápsulas duras de liberación prolongada Pharmaceutical Form: Prolonged‐release capsule, hard INN or Proposed

INN:

TACROLIMUS Other descriptive name: TACROLIMUS Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 5‐

CONDITION:

En casos de trasplantes renales en pacientes añosos, los injertos tienen una incidencia mayor de necrosis tubular aguda, y mayor sensibilidad a los efectos de las drogas nefrotóxicas, implicando una peor recuperación después del daño renal sufrido con la administración al inicio del trasplante de pautas inmunosupresoras nefrotóxicas. ; MedDRA version: 11 Level: LLT Classification code 10038533 Term: Trasplante renal

PRIMARY OUTCOME:

Main Objective: Comparar la función renal a los 6 meses después del trasplante en pacientes tratados con un régimen inmunosupresor basado en basiliximab, micofenolato sódico, esteroides, e introducción inmediata versus introducción retardada de tacrolimus de liberación prolongada a dosis reducidas Primary end point(s): Función renal medida por el aclaramiento calculado de creatinina (fórmula de cockroft‐gault) a los 6 meses después del trasplante.; variables secundarias:1 porcentaje de pacientes que presentan un episodio de rechazo agudo probado por biopsia.; 2 tiempo medio transcurrido hasta la aparición del primer episodio de rechazo agudo probado por biopsia.; 3 supervivencia del injerto y del paciente a los 6 primeros meses post‐trasnplante.; 4 porcentaje de pacientes para cada uno de los grados de gravedad histológica del rechazo agudo probado por biopsia (basados en criterios de banff07); 5 porcentaje de pacientes que presentan rechazo agudo resistente a corticoides.; 6 tiempo medio transcurrido hasta la aparición del primer episodio de rechazo agudo resistente a corticosteroides.; 7 función renal evaluada por la creatinina sérica y tfg(tasa de filtrado glomerular) evaluada por mdrd‐4, a los 7 dias y a los 6 meses después del trasplante.; 8 porcentaje de pacientes que presentan no función primaria del injerto(muerte o retransplante) en las 2 primeras semanas post‐trasplante.; 9 porcentaje de pacientes que requieren diálisis durante la primera semana post‐trasplante.; 10 tiempo medio de ingreso hospitalario por fri.; 11 número y días de duración de diálisis realizadas en los 6 primeros meses post‐trasplante.; 12 porcentaje de pacientes con valores de creatinina sérica por debajo de la media nadir.; 13 porcentaje de pacientes con reacciones adversas para cada grupo de tratamiento. Secondary Objective: 1. Determinar el porcentaje de pacientes que presentan un episodio de rechazo agudo probado por biopsia.; 2. Determinar el tiempo medio transcurrido hasta la aparición del primer episodio de rechazo agudo probado por biopsia; 3. Conocer la supervivencia del injerto y del paciente a los 6 primeros meses post‐trasplante.; 4. Determinar el porcentaje de pacientes para cada uno de los grados de gravedad histológica del rechazo agudo probado por biopsia (basados en criterios de Banff 07).; 5. Determinar el porcentaje de pacientes que presentan rechazo agudo resistente a corticoides.; 6. Determinar el tiempo medio transcurrido hasta la aparición del primer episodio de rechazo agudo resistente a corticosteorides.; 7. Conocer la función renal evaluada por la creatinina sérica y TFG (Tasa de Filtrado Glomerular) evaluada por MDRD‐4, a los 7 días y a los 6 meses después del trasplante. ; 8. Determinar el porcentaje de pacientes que presentan no función primaria del injerto.; 9. Determinar el po

INCLUSION CRITERIA:

Pacientes de ambos sexos con una edad mínima de 60 años. Pacientes con enfermedad renal terminal que cumplen los criterios para trasplante renal primario. Pacientes que reciben un trasplante renal de un donante cadáver con una edad mínima de 55 años y con grupo sanguíneo AB0 compatible. Pacientes que sean capaces de entender el objetivo y riesgos del ensayo y que han sido completamente informados y han otorgado el Consentimiento Informado por escrito de acuerdo con ICH‐GCP. Los pacientes que no puedan leer o escribir pero que entiendan adecuadamente la información verbal proporcionada por el investigador (o representante designado) otorgarán el consentimiento informado verbal frente a un testigo independiente que firmará el documento de consentimiento informado. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years

AIMS:

Effect of early steroid withdrawal protocol using basiliximab in kidney transplantation (KTx) on the clinical outcomes was investigated as compared with triple regimen.

METHODS:

Kidney transplant patients in group 1 (n = 62) were treated with 8 mg/kg of cyclosporine (CsA), 2000 mg of MMF, two bolus IV injections of 20 mg of basiliximab and 500 mg of methylprednisolone (MP) rapidly tapered and withdrawn at 14 postoperative days (POD). Group 2 (n = 56) was treated with same dose of CsA and MMF, and 250 mg of MP tapered and continued. Acute rejection (AR) episodes were treated with MP pulse therapy followed by muromonab CD3 (OKT3) in case of steroid-resistant rejection.

RESULTS:

In 46 of 62 cases (74.2%) in group 1, steroid was successfully withdrawn at 13.7 +/- 1.7 POD. Graft survival at 3, 6, and 12 months in group 1 was 100%, 100%, and 98.4% (one death with functioning graft), and 100%, 98.2%, and 96.4% in group 2, respectively. The incidence of AR was 12.9% for group 1 and 42.9% for group 2, among which 21 cases in group 2 were treated with ALG or OKT3; no patient needed ALG or OKT3 in group 1. Fifteen cases in group 1 and 13 cases in group 2 developed CMV antigenemia, among which febrile episode was exhibited in 3 cases (4.8%) in group 1 and 5 cases (8.9%) in group 2.

CONCLUSIONS:

Early steroid withdrawal protocol using basiliximab is promising for reducing the incidence of AR (especially steroid-resistant rejection), CMV diseases, and steroid-related complications.

The aim of the study is to assess the short-term benefit of the combination of basiliximab, EC-MPS and cyclosporine microemulsion with C2 monitoring on the prophylaxis of acute rejection in a population of de novo renal transplant patients at potential high risk of DGF.

INTERVENTION:

Trade Name: Rapamune 1mg Coated Tablets Product Name: Rapamune 1mg Coated Tablets Pharmaceutical Form: Coated tablet INN or Proposed

INN:

Sirolimus CAS Number: 53123‐88‐9 Current Sponsor code: 0468 Other descriptive name: Rapamycin Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 1‐ Trade Name: Rapamune 2mg Coated Tablets Product Name: Rapamune 2mg Coated Tablets Pharmaceutical Form: Coated tablet INN or Proposed

INN:

Sirolimus CAS Number: 53123‐88‐9 Current Sponsor code: 0468 Other descriptive name: Rapamycin Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2‐ Trade Name: Rapamune 5mg Coated Tablets Product Name: Rapamune 5mg Coated Tablets Pharmaceutical Form: Coated tablet INN or Proposed

INN:

Sirolimus CAS Number: 53123‐88‐9 Current Sponsor code: 0468 Other descriptive name: Rapamycin Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 5‐ Trade Name: Rapamune 1mg/ml Oral Solution Product Name: Rapamune 1mg/ml Oral Solution Pharmaceutical Form: Oral solution INN or Proposed

INN:

Sirolimus CAS Number: 53123‐88‐9 Current Sponsor code: 0468 Other descriptive name: Rapamycin Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 1‐

CONDITION:

The rationale for the present study is to assess whether a CNI‐free regimen including antibody induction, sirolimus, and mycophenolate mofetil (MMF) results in improved long‐term renal function without having a negative impact on safety or immunosuppressive efficacy, and to further examine the potential of sirolimus to reduce the severity and/or progression of Chronic allograft nephropathy (CAN), which could represent a major advance in the field of transplantation.

INCLUSION CRITERIA:

1. Age > 13 years and weight > 40 kg (age > 18 years in some regions per local regulations; see section H of this application form for requested subject age range in the region reviewing the application). 2. Subjects on dialysis with end‐stage renal disease (ESRD) who will receive a primary renal allograft from a deceased donor, a living‐unrelated donor, or a human leukocyte antigen (HLA)‐mismatched living‐related donor. An HLA mismatch is the number of HLA antigens that a donor has that a recipient does not share. 3. Subjects who receive a primary transplant before the initiation of maintenance dialysis, where the calculated creatinine clearance (CrCl) of the native kidney(s) must be <20 mL/min within 24 hours before transplantation from a deceased donor, a living‐unrelated donor, or an HLA‐mismatched living‐related donor. 4. All female subjects at risk for pregnancy (ie are not surgically sterile or postmenopausal) must have a negative qu

PRIMARY OUTCOME:

Main Objective: Efficacy: to demonstrate superiority of the sirolimus regimen versus Cyclosporine by intent‐to‐treat (ITT) analysis of renal function at 52 weeks, measured by mean calculated glomerular filtration rate (GFR). ; ; Safety: to demonstrate non‐inferiority at 52 weeks in the composite endpoint of the incidence of the first occurrence of graft loss or death. Primary end point(s): The primary efficacy endpoint of this study is renal function at 52 weeks, measured by mean calculated GFR (Nankivell method), to be analyzed in accordance with the ITT principles. The ITT group is defined as all subjects who are randomly assigned to study therapy and undergo transplantation. ; ; The following secondary efficacy endpoints will also be evaluated:; ; ‐ The incidence and severity of BCAR at 12, 24, 52, 104, 156 and 208 weeks. The histologic grade of severity of BCAR will also be evaluated at these time points.; ; ‐ The mean on‐therapy calculated Nankivell GFR at 12, 24, 52, 104, 156 and 208 weeks.; ; ‐ Mean Nankivell GFR at 24, 104, 156 and 208 weeks for all randomly assigned subjects in both groups (ITT).; ; ‐ Slopes of 1/creatinine versus time at 24, 52, 104, 156 and 208 weeks (on‐therapy and ITT).; ; ‐ Slopes of Nankivell GFR versus time at 24, 52, 104, 156 and 208 weeks (on‐therapy and ITT).; ; ‐ Mean GFR as measured by radionuclide or comparable methodology at 24, 52, and 104 weeks (on‐therapy) (at centers that elect to participate).; ; ‐ Progression of chronic allograft nephropathy at 52 weeks (protocol‐mandated biopsies at centers that elect to participate).; ; ‐ Quality of life outcomes at 24, 52, and 104 weeks. Secondary Objective: Secondary Efficacy objectives include:; 1. Incidence of the first occurrence of biopsy‐confirmed acute rejection (BCAR) at 12, 24, 52, 104, 156 and 208 weeks.; 2. Histologic grade of severity of BCAR at 12, 24, 52, 104, 156 and 208 weeks.; 3. Mean on‐therapy calculated Nankivell GFR at 24, 52, 104, 156 and 208 weeks.; 4. Mean Nankivell GFR at 24, 104, 156 and 208 weeks for all randomly assigned subjects in both groups (ITT).; ; Secondary Safety objectives include:; 1. Incidence of patient survival and graft survival at 12, 24, 104, 156 and 208 weeks.; 2. Mean systolic and diastolic blood pressure at 52 and 104 weeks.; 3. Incidence of infection at 52 and 104 weeks. ; 4. Incidence of malignancy (including histologically confirmed lymphoproliferative disease) at 52, 104 and 208 weeks.; ; (See protocol for full list of secondary efficacy and safety objectives).