Evaluation of Siplizumab Versus Rabbit Anti-Thymocyte Globulin in Induction Therapy for de novo Renal Transplant Recipients
- Trial ID
- 2023-507895-36-00
- Protocol
- TCD601B101
- Sponsor
- Itb-Med AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **safety**, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of siplizumab compared to rabbit anti-thymocyte globulin (rATG) in de novo renal transplant recipients over a 12-month period post-transplant. This evaluation is clinically relevant as it aims to determine the potential of siplizumab as an induction therapy, which could offer an alternative to existing treatments, potentially improving patient outcomes and reducing adverse effects associated with current therapies.
Secondary objectives include:
- Measuring changes in peripheral lymphocyte immunophenotype.
- Assessing the time-course and duration of siplizumab-induced lymphocyte depletion and time to recovery.
- Evaluating peripheral CD2-RO following siplizumab administration over time.
- Assessing the incidence of treated biopsy-proven acute rejection (tBPAR) over 12 months.
- Evaluating the incidence of treatment-emergent de novo donor-specific antibodies (DSA) over 12 months.
- Assessing the incidence of antibody-mediated rejection over 12 months.
- Evaluating renal function via eGFR using the MDRD equation at months 3, 6, and 12.
Participants
The clinical trial involves a total of **13 participants** who are recipients of a **de novo renal allograft**. The study population includes both male and female subjects, aged between **18 to 70 years**. Participants were selected based on their ability to understand the study requirements and provide written informed consent. The trial includes recipients of a kidney from a heart-beating deceased, living unrelated, or non-human leukocyte antigen (HLA) identical living related donor, with a cold ischemia time (CIT) of less than 30 hours. The study population is characterized by individuals who have undergone **renal transplantation** and are considered a vulnerable population. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The selection criteria ensure that participants are suitable for assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of siplizumab compared to rabbit anti-thymocyte globulin (rATG) over a 12-month period post-transplant.
Plans and Procedures
The clinical trial is designed as a **randomized**, controlled, open-label, dose escalation study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the investigational drug **siplizumab** compared to rabbit anti-thymocyte globulin (rATG) in de novo renal transplant recipients. The trial is set to last for 12 months post-transplant, with an estimated end date of April 28, 2026. Participants will be involved in the study for the entire duration unless early termination is warranted due to adverse events or other protocol-specified conditions.
The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age (18-70 years), ability to provide informed consent, and specific transplant conditions. Following the screening, participants will undergo regular follow-up visits to monitor safety and efficacy endpoints, including adverse events, serious adverse events, and changes in clinical chemistry and hematology. The primary endpoints also include the assessment of **siplizumab** PK, immunophenotyping, CD2 receptor occupancy, and estimated glomerular filtration rate (eGFR). Secondary endpoints involve further immunophenotyping, lymphocyte counts, and incidence of transplant-related complications.
The trial will conclude with an end-of-study visit, where final assessments will be conducted to evaluate the long-term effects of the treatment. Participants may be withdrawn from the study if they experience significant adverse reactions or if they fail to comply with the study protocol. The trial's design ensures rigorous monitoring and data collection to achieve its primary objective of assessing the investigational drug's safety and efficacy in preventing renal transplant rejection.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Cetirizine dihydrochloride** is provided as a film-coated tablet under the name "Cetirizina Mylan 10 mg comprimidos revestidos por película." It is administered orally with a maximum daily dose of 10 mg, and the treatment period is limited to one day. This medication is not a pediatric formulation and is chemically derived.
**Prednisolone** is administered in the form of soluble tablets, marketed as "Prednisolone 5mg Soluble Tablets" by Morningside Healthcare Ltd. The oral administration allows for a maximum daily dose of 150 mg, with a total treatment period extending up to 336 days. This medication is also chemically derived and not formulated for pediatric use.
**Siplizumab**, an experimental medication, is provided as a solution for injection/infusion under the sponsor product code TCD601. It is administered intravenously with a maximum daily dose of 5 mg/kg and a total dose of 10 mg/kg over a treatment period of 4 days. Siplizumab is a protein-based substance and is designated as an orphan drug.
**Rabbit anti-human thymocyte immunoglobulin** is available as a solution for infusion, marketed as "THYMOGLOBULINE 5 mg/ml, poeder voor oplossing voor infusie" by Sanofi B.V. It is administered intravenously with a maximum daily dose of 1.5 mg/kg and a total dose of 4.5 mg/kg over a 3-day treatment period. This medication is derived from structurally diverse blood-derived substances.
**Tacrolimus** is provided in the form of hard capsules, marketed as "Adport 0,5 mg, capsules, hard" by Sandoz B.V. It is administered orally with a maximum daily dose of 36 mg and a total treatment period of 336 days. Tacrolimus is chemically derived and not intended for pediatric use.
**Mycophenolate mofetil** is administered as hard capsules under the name "CellCept 250 mg capsules" by Roche Registration GmbH. The oral administration allows for a maximum daily dose of 2000 mg, with a treatment period extending up to 336 days. This medication is chemically derived and not formulated for pediatric use.
**Paracetamol** is provided as film-coated tablets, marketed as "Paracetamol 500 mg Film Coated Tablets" by Haleon Ireland Limited. It is administered orally with a maximum daily dose of 1000 mg, and the treatment period is limited to one day. Paracetamol is chemically derived and not intended for pediatric use.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the experimental medication, siplizumab, compared to the comparator treatment, rabbit anti-thymocyte globulin, in de novo renal transplant recipients.
Efficacy
The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. Primary endpoints include the evaluation of adverse events (AEs), serious adverse events (SAEs), and clinically significant changes in clinical chemistry, hematology, vital signs, and serology. Additionally, the pharmacokinetics (PK) of **siplizumab**, immunophenotyping, CD2 receptor occupancy (RO), estimated glomerular filtration rate (eGFR) via the Modification of Diet in Renal Disease (MDRD) equation, and the presence of anti-siplizumab antibodies will be measured.
Secondary endpoints will focus on further immunophenotyping via fluorescence-activated cell sorting (FACS), lymphocyte counts, CD2 RO, incidence of tBPAR, de novo-DSA/anti-human leukocyte antigen (HLA) antibody measurement, incidence of AMR, and eGFR. These parameters will be collected and analyzed at specified intervals throughout the 12-month study period to determine the efficacy of **siplizumab** compared to rabbit anti-thymocyte globulin (rATG) in de novo renal transplant recipients.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Able to understand the study requirements and provide written informed consent before any study assessment is performed.
- Male or female patients ≥ 18 to 70 years of age.
- Recipients of a de novo renal allograft from a heart-beating deceased, living unrelated or non-human leukocyte antigen (HLA) identical living related donor.
- Recipients of a kidney with a cold ischemia time (CIT) < 30 hours; hypothermic machine perfusion within the same timeframe is acceptable.
Exclusion Criteria
- Transplant recipients seronegative for Epstein-Barr virus (EBV).
- Multi-organ transplant recipients.
- Subjects who have received a kidney allograft previously (e.g. re-transplant).
- Recipient of a kidney from an HLA identical living related donor
- Recipient of a kidney from a donor after cardiac death
- Subjects at high immunological risk for rejection as determined by local practice (e.g., presence of pre-existing donor-specific antibodies [DSA], recipient of high Kidney Donor Profile Index ≥ 85 kidney (where assessed).
- Subjects with anti-HLA donor specific antibody as measured by complement-dependent cytotoxicity (CDC) assay, enzyme-linked immunosorbent assay (ELISA), or flow cytometry within 90 days prior to transplant or as performed per the center's local practice.
- Complement-dependent cytotoxicity (CDC) crossmatch positive transplant (isolated positive B cell crossmatches are not an exclusion criterion).
- ABO incompatible recipient
- History of malignancy of any organ system, except for localized excised non-melanomatous skin lesions or carcinoma in situ of the cervix.
- Subjects with clinically significant laboratory abnormality that would preclude participation in the study. For example: >2.5 × upper limit of normal (ULN) values for: - Liver function chemistries (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP]) - Bilirubin - Coagulation studies (International Normalized Ratio [INR]/prothrombin time [PT], activated partial thromboplastin time [aPTT]).
- Subjects with any of the following: • Hemoglobin (Hgb) < 8 mg/dL • White blood cell (WBC) count ≤ 2,000/mm3 • Platelet count ≤ 75,000/mm3.
- Seropositive for human immunodeficiency virus (HIV) or hepatitis B surface antigen (HBsAg). Subjects who are seropositive for hepatitis C virus (HCV) are excluded without proof of sustained viral response (SVR) after anti-HCV treatment.
- Recipient of a kidney from a donor who tests positive for HIV, HBsAg/hepatitis B core antigen (HBcAg) positive or HCV.
- History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes (e.g., siplizumab, anti-thymocyte globulin [ATG], tacrolimus [TAC], mycophenolate mofetil [MMF], corticosteroifs [CS]).
- Any additional contraindication to the use of TAC or MMF according to the national labeling information of these products (refer to the local product label).
- Evidence of tuberculosis (TB) infection (after anti-TB treatment, patients with history of latent TB may become eligible according to national guidelines).
- Subjects with severe systemic infections, current or within the two weeks prior to randomization.
- Subjects with any other clinically significant medical condition, active infection or laboratory abnormality that would, in the judgment of the Investigator, interfere with the subject’s ability to participate in the study.
- Subjects who, in the opinion of the investigator, are not capable of giving informed consent for the study or who are unable or unwilling to adhere to the study requirements outlined in the protocol.
- Use of other investigational products or enrollment in another investigational drug study within 30 days of screening or 5 half-lives of the medication, whichever is longer.
- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
- Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 24 weeks after the study medications have been stopped. Highly effective contraception methods include: Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential. Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject. Any of the following: Use of oral, injected, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%); for example, hormone vaginal ring or transdermal hormone contraception. Placement of long-acting reversible contraceptives, an intrauterine device, or intrauterine system. In case of use of oral contraception, women should have been stable on the same brand (or generic equivalent) for a minimum of 3 months before taking study treatment. Additionally, total abstinence, when in line with the preferred and usual lifestyle of the subject, may be an acceptable form of contraception. Withdrawal and period abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) are not acceptable forms of contraception. Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment if she is considered not of childbearing potential.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 21 Jul 2021 | 13 |
 Spain | Not Recruiting | 21 Jul 2021 | 7 |
 Sweden | Not Recruiting | 21 Jul 2021 | 13 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Cetirizina Mylan 10 mg comprimidos revestidos por película | Other | COMPRIMIDOS REVESTIDOS POR PELÍCULA | ORAL | 10 | 1 | PRD7619722 |
Prednisolone 5mg Soluble Tablets | Other | SOLUBLE TABLETS | ORAL | 150 | 336 | PRD10020964 |
THYMOGLOBULINE 5 mg/ml, poeder voor oplossing voor infusie | Comparator | POEDER VOOR OPLOSSING VOOR INFUSIE | INTRAVENOUS | 1.5 | 3 | PRD440677 |
Thymoglobuline, pulver til infusionsvæske, opløsning | Comparator | PULVER TIL INFUSIONSVÆSKE, OPLØSNING | INTRAVENOUS | 1.5 | 3 | PRD441339 |
Adport 0,5 mg, capsules, hard | Other | CAPSULES, HARD | ORAL | 36 | 336 | PRD768375 |
CellCept 250 mg capsules | Other | CAPSULES | ORAL | 2000 | 336 | PRD364726 |
Thymoglobuline
5 mg/ml, Pulver zur Herstellung einer Infusionslösung. | Comparator | PULVER ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS | 1.5 | 3 | PRD440934 |
Paracetamol 500 mg Film Coated Tablets | Other | FILM COATED TABLETS | ORAL | 1000 | 1 | PRD8757963 |