First in Human Study: LIS1, an Induction Treatment in Kidney Transplanted Patients

NCT04431219 | Completed Phase 1 DMC

• 1 other identifier: XT-1901
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

This first in human study aims at evaluating LIS1, a stabilized solution of purified anti-T lymphocytes polyclonal glyco-humanized swine IgG with immunosuppressive activity, in regards of safety, T cell depletion, and pharmacokinetics / pharmacodynamics in 10 kidney transplant recipients.

Conditions

Kidney Transplant

Keywords

immunosuppression; polyclonal IgG; allograft transplantation; induction treatment; acute graft rejection

Outcome Measures

Primary Outcomes (12)

• Safety of the treatment with LIS1: Blood pressure

  Clinical safety parameters (1): Systolic and diastolic blood pressure (mm Hg).

  up to 3 months after the transplant

• Safety of the treatment with LIS1: Pulse rate

  Clinical safety parameters (2): Pulse rate (beats per minute \[bpm\]) .

  up to 3 months after the transplant

• Safety of the treatment with LIS1: Body temperature

  Clinical safety parameters (3): Body temperature (Celsius degrees).

  up to 3 months after the transplant

• Safety of the treatment with LIS1: Graft rejection

  Clinical safety parameters (4): Graft rejection (yes/no).

  up to 3 months after the transplant

• Safety of the treatment with LIS1: Infection

  Clinical safety parameters (5): Viral infections (namely Cytomegalovirus \[CMV\], BK virus) (yes/no).

  up to 3 months after the transplant

• Safety of the treatment with LIS1: Re-admission

  Clinical safety parameters (6): Re-admission after patient discharge (yes/no).

  up to 3 months after the transplant

• Safety of the treatment with LIS1: Hospitalization

  Clinical safety parameters (7): Prolonged stay in hospital for \>4 weeks (days).

  up to 3 months after the transplant

• Safety of the treatment with LIS1: CRP

  Laboratory parameters (1): C-Reactive Protein (CRP, mg/L).

  up to 3 months after the transplant

• Safety of the treatment with LIS1: LDH

  Laboratory parameters (2): Lactate Dehydrogenase (LDH, µkat/L).

  up to 3 months after the transplant

• Safety of the treatment with LIS1: aPTT

  Laboratory parameters (3): activated Partial Thromboplastin Time (aPTT, seconds).

  up to 3 months after the transplant

• Safety of the treatment with LIS1: Complete Blood Count (CBC)

  Laboratory parameters (4): Platelets (10\^9/L), white blood cells (10\^9/L), absolute neutrophil count (10\^9/L), absolute lymphocyte count (10\^9/L), absolute monocyte count (10\^9/L), absolute eosinophil count (10\^9/L), absolute basophil count (10\^9/L).

  up to 3 months after the transplant

• Pharmacodynamics (depletion of T lymphocytes) of LIS1

  Absolute T lymphocyte counts (10\^9/L).

  up to 3 months after the transplant

Secondary Outcomes (7)

• Pharmacokinetics of LIS1 (1): swine IgG

  up to 3 months after the transplant

• Pharmacodynamics of LIS1 (2): cytokines

  up to 3 months after the transplant

• Biology of LIS1 (1): electrolytes plasma concentration

  up to 3 months after the transplant

• Biology of LIS1 (2): urea and creatinine

  up to 3 months after the transplant

• Biology of LIS1 (3): total plasma proteins

  up to 3 months after the transplant

Study Arms (2)

Ascending Dose Cohort

EXPERIMENTAL

The AD cohort will be first recruited and will include 5 patients: 1 patient per dose, sequentially recruited, the recruitment of the next dose level patient will be assessed by Data Safety Monitoring Board : * Patient 1: 0.6 mg/Kg/day * Patient 2: 1 mg/Kg/day * Patient 3: 3 mg/Kg/day * Patient 4: 6 mg/Kg/day * Patient 5: 8 mg/Kg/day Once the 5 AD patients complete LIS1 treatment, the sponsor and the DSMB will rule on the LIS1 dose to obtain an optimal CD3+ cells depletion, with a good safety profile and will determine the therapeutic dose.

Biological: LIS1

Therapeutic Dose Cohort

EXPERIMENTAL

The TD cohort will be recruited once the therapeutic dose is defined. This cohort will be divided in 2 subgroups of respectively 2 and 3 patients sequentially recruited. DSMB will review the safety and efficacy profile of the first 2 patients (Subgroup1) and decide: * To continue at the same dose and recruit the next 3 patients of Subgroup 2 * To recruit the next 3 patients with a lower dose, estimated from AD as bringing efficient depletion * To recruit the next patient with a higher dose (+2 mg/kg), if the depletion is not considered satisfactory and if the safety profile is considered acceptable * To end the trial if LIS1 toxicity is too important vs its efficacy in CD3+ depletion. If the decision to increase the dose after the first two TD patients is made, an additional DSMB review will be planned after patient 8. The DSMB will decide to maintain the dose for the last 2 patients or to get back to the previous dose

Biological: LIS1

Interventions

LIS1 BIOLOGICAL

LIS1 is an induction treatment on top of maintenance immunosuppressive regimen. All patients from AD and TD cohort will receive the conventional immunosuppressive regimen: tacrolimus (0.2 mg/kg) / mycophenolic acid (MMF, 2x1000 mg) / prednisone (20 mg from day 2). This conventional treatment should be started and monitored for all patients independently of their participation in the clinical trial. Methylprednisolone 500 mg / 100 mL saline / 30 minutes will be administered before reperfusion during the surgery and on post operation day 1 just before LIS1 administration.

Ascending Dose Cohort; Therapeutic Dose Cohort

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must be listed for kidney transplantation,
• AD cohort participants: First transplantation, Panel Reactive Antibody (PRA) \< 20%, negative Donor Specific Antibody (DSA), no anti-HLA antibodies, Epstein-Barr Virus positive (EBV+) serology,
• TD cohort participants: First transplantation, 0-50 % PRA, negative DSA, negative flow cytometry crossmatch (FCXM) for any patients with anti-HLA antibodies on screening is mandatory, Epstein-Barr Virus positive (EBV+) serology
• Participants must weigh at least 50 kg and have a Body Mass Index (BMI) 18.0 ≤ BMI \< 35.0 kg/m2,
• White Blood Cells \> 3000/mm3, platelets \> 75000/mm3,
• Female participants (WOCBP) must have a negative pregnancy test at screening and use a highly effective birth control until 90 days after the last administration of study drug,
• Non-vasectomized male subjects having a female partner of childbearing potential must agree to the use of a highly effective method of contraception until 90 days after the last administration of study drug,
• Participants must be capable of giving signed informed consent.

You may not qualify if:

• Patients with an active cancer or a history of kidney cancer,
• Patients who have previously been exposed to other anti-lymphocyte globulins,
• Patients with previous organ transplantation,
• Patients with a history of specific viral infection that would contraindicate depleting antibody therapy (Hepatitis B and C, HIV),
• Patients with a positive HIV and/or Hepatitis B and C tests
• Patients who have uncontrolled concomitant bacterial or viral infections (unresolved during screening), mycosis and/or parasitosis,
• Patients with a significant liver function impairment: enzyme (AST and/or ALT) values must not exceed 1.5 times upper limit of normal,
• Patients with positive testing for tuberculosis (using QuantiFERON-TB test), Patients with CMV D+/R- constellation at transplant,
• Patients with seronegative EBV prior to transplantation,
• Patients who have previously been exposed to antibodies of swine origin,
• Expanded Criteria Donor (ECD) defined as donor older than 60 years,
• Participants who have participated in another research study involving an investigational product in the previous 3 months,
• Patients with cardiovascular or severe respiratory comorbidities (severe chronic respiratory failure, severe pulmonary fibrosis, obesity-ventilation syndrome, severe idiopathic pulmonary arterial hypertension) not allowing general anesthesia,
• Patients with type 1 diabetes,
• Participants who are pregnant, breast feeding or planning pregnancy during the study,

Sponsors & Collaborators

• Xenothera SAS: lead

Study Sites (1)

Institut klinické a experimentální medicíny

Prague, 140 21, Czechia

Location

Related Publications (1)

• Viklicky O, Slatinska J, Janousek L, Rousse J, Royer PJ, Toutain PL, Cozzi E, Galli C, Evanno G, Duvaux O, Bach JM, Soulillou JP, Giral M, Vanhove B, Blancho G. First-in-human Study With LIS1, a Next-generation Porcine Low Immunogenicity Antilymphocyte Immunoglobulin in Kidney Transplantation. Transplantation. 2024 Jul 1;108(7):e139-e147. doi: 10.1097/TP.0000000000004967. Epub 2024 Feb 29.

  PMID: 38421879 DERIVED

Study Officials

• Dr Ondrej Viklicky

  Institut klinické a experimentální medicíny, Praha 4, Czech Republic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a phase I/II interventional, uncontrolled, single center, open-label study with an adaptive design conducted in two cohorts: Ascending Dose (AD) cohort and Therapeutic Dose (TD) cohort.

Study Record Dates

• First Submitted: May 28, 2020
• First Posted: June 16, 2020
• Study Start: November 26, 2019
• Primary Completion: March 28, 2022
• Study Completion: March 28, 2022
• Last Updated: August 17, 2022

Record last verified: 2022-08

Locations

CZ (1)