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Investigators aim to develop an effective and safe treatment of autoimmune diseases through adoptive T regulatory cells transfer. Our objectives are to evaluate the safety and efficacy of autologous adoptive Treg (CD4CD25FoxP3 CD127 low regulatory) cell transfer to patients with refractory autoimmune diseases: Refractory lupus Nephritis, and adults' type1 diabetes mellitus. Patients and Methods: This is Non randomized open label phase 1 pilot study including ten patients with refractory lupus nephritis and ten patients with Type 1 diabetic patients. All patients will be subjected to Full history taking, clinical examination and pretreatment investigations according to the type of autoimmune disease then regulatory T cells (Tregs) identification and count, Treg isolation and expansion and finally administration of T reg cells and follow-up of adverse events and outcomes.
Full description
Autoimmune disorders are chronic diseases caused by the breakdown of tolerance against self-antigens
; one hypothesis involves a failure in central and peripheral tolerance with the latter being associated with reduced Treg (CD4+CD25+FpxP3CD127- T- Regulatory )cells number or failure in their function (6).
In preclinical studies, human CD4+CD25+CD127- Treg cells have been shown to be effective in preventing Graft vs. Host Disease (GvHD) (7, 23), autoimmune diseases (13,22) and delaying graft rejection (19, 26).
The positive outcomes gave the rationale to apply Treg cells for the treatment of human diseases and results from the first clinical trials with adoptively transferred Treg cells investigators published in 2009 (24).
What does this study add? This is the first interventional study on adoptive Treg cell transfer in Egypt as a therapeutic trial for patients with refractory autoimmune diseases who do not respond to base line of care treatment available in the institute. Separation of this Treg cells was done in Egyptian patients but as a descriptive study only (as mentioned below).
investigators choose two diseases in order to give some chance for success for getting fund of our research, as its cost is expensive. Investigators chose these two diseases (refractory lupus nephritis and type 1 diabetes in adults, as they are the commonest trials in international publication).
investigators will evaluate the safety and efficacy of autologous adoptive Treg(CD4CD25FoxP3 CD127 low regulatory) cell transfer to patients with refractory autoimmune diseases: Refractory lupus Nephritis and adults type1 diabetes mellitus.
2.STUDY QUESTION/AIM / OBJECTIVES investigators will evaluate the safety and efficacy of autologous adoptive Treg (CD4CD25FoxP3 CD127low regulatory ) cell transfer to SLE patients with refractory lupus nephritis and patients with adult type1 diabetes mellitus.
Monitoring plan of AE is documented in the protocol checking for systemic and local adverse events using CTCAE(5).Safety assessments will consist of continuous monitoring and reporting of adverse events (AEs) (with monthly visits or as clinically indicated by mobile contact or out patients visits); monitoring of vital signs, , physical examinations and laboratory assessments. Precise documentation and proper management will be done for any AE that may occur (in the outpatient and inpatient units as indicated).Patients will be seen monthly for detection of any adverse event or as clinically evaluated by Mobil contact The following will be assessed:
White blood cell count (WBC) with differential count , red blood cell count (RBC), platelet count (PLT), hemoglobin (Hb) and hematocrit (Hct).
Liver functions, kidney functions tests and electrolytes measurement.
Efficacy of adoptive Treg cell transfer:
Clinical Evaluation: Full history taking and thorough clinical examination with assessment of disease activity score (clinically and laboratory) to compare with baseline data.
Laboratory testing according to the type autoimmune disease:
Radiological evaluation if needed according to the type of autoimmune disease:
Researchers will detect the efficacy of T reg cells infusion after 3 months, after 6 months and after one year of administration.
METHODOLOGY:
Type of Study : Non randomized open label phase 1 pilot study Study Setting: Table of responsibilities (Table 1) :see below Study duration: Two years.
Study Population:
Sampling Method:
Purposive samples following pre-set inclusion and exclusion criteria.
Sample Size:
Researchers will include ten patients in each autoimmune disease as a pilot study.
Study Procedures:
All Patients will be subjected to the following:
In the first visit
SLE patients:
T1D Patients:
Regarding blood samples: our plan as regards frequency and amount of blood samples as following:
A- Frequency:
B- Amount:
Cryopreservation of Expanded Tregs:
In order to allow infusion of the cell product several times, the feasibility of Treg cryopreservation will be used. Cryopreservation of Tregs allows flexibility in administration to assist with clinical pathways and facilitates completion of all required release assays. ( 10 ) Administration of T reg cells and follow-up of adverse events Results of blood chemistries and hematology will be reviewed, and a history of any recent illness or fever will be obtained before infusion of the cells. Patients will receive premedication with paracetamol and diphenhydramine. Poly t regs will be infused via a peripheral intravenous line over 10 to 30 min.
Vital signs will be taken before and after infusion, then every 15 min for at least 1 hour, then every hour for the first 4 hours, and every 4 hours for 20 hours. Chemistries and complete blood count with differential blood count will be repeated the next day before discharge from the clinical research unit. Patients will be seen for follow-up assessments on day 4 after infusion, then weekly for 4 weeks, then after 13weeks, and then after 26 weeks. Telephone monitoring for adverse events will continue one year after infusion followed by a final clinic visit.
The dose of ex-vivo expanded T reg will be the same for all patients. It will be administered in increasing doses of 5x10^6-1x10^8 cells I V infusion I V infusion. It is the minimum dose in previous international therapeutic cohorts in order to achieve safety (14).
ETHICAL CONSIDERATIONS
RISKS and MINIMIZATION OF RISKS:
Possible Risks of Ultrasound Medical Imaging: Ultrasound medical imaging is a fast and safe way to evaluate patients that do not represent any risk and do not lead to side effects. They do not lead to any change in the patient's original condition, but there may be rare problems such as: pain or bruising.
Complications of venipuncture: hematoma formation, nerve damage, pain, hemoconcentration, extravasation, iatrogenic anemia, arterial puncture, petechiae, infection, syncope and fainting, excessive bleeding, edema and thrombus. To minimize these risks it will be taken under aseptic conditions by qualified nurses.
Risk of infection: T reg cell isolation and expansion will be done under strict sterilized environment. Frequent sterility techniques will be followed during expansion and Quality control, and release assays will be done before adoptive T cell transfer.
● Side effects of taking 400 cc of blood from patients: like that of blood donation which are rare and include the development of a local traumatic hematoma when the needle is removed from the vein. Holding local pressure and application of ice or cold compresses to the area can help to prevent the development or progression of hematomas. These hematomas are usually small and do not cause major problems. Development of dizziness, sweating and syncope might also occur, and can be avoided by requiring the patient to sit in a reclined position for a few minutes, and when able, slowly moving to the upright position and moving to an area where they will be given something to eat and drink. Increased fluid intake will be encouraged over the few hours following taking the blood. Patient Hb level must be not less than 11g/dl before withdrawal of blood for Treg isolation. investigators will prepare packed RBCs before blood withdrawal in order to be given if indicated clinically.
Risk of infection / inflammation: Treg cell isolation and expansion will be done under strict sterilized environment. Frequent sterility techniques will be followed during expansion and Quality control, and release assays will be done before adoptive T cell transfer .The accepted release criteria include: Phenotype>60%, , viability :> 70%, sterility and negative mycoplasma.
DISCONTINUATION CRITERIA (STUDY AND ENROLLMENT TERMINATION) Safety Stopping Rules for Individual Subjects
Treatment will be discontinued in any subject who experiences any one of the following:
Study Stopping Rules
This clinical trial will be paused for any of the following reasons:
BENEFITS:
Direct benefits for patients:
Indirect benefits
PRIVACY AND CONFIDENTIALITY investigators will deal in complete confidentiality, and no one has right to read our patient medical information except the main researcher. After the research is complete, our patient's research results and also further information regarding our patient's health status will be informed .Individuals' confidentiality will be maintained in all published and written data resulting from the study.
Alternatives to participating:
Patient has the right to refuse or withdraw from the study at any time. In case of refusing to participate in this research, the patient will be followed up and will receive his treatment as planned. Patient can stop participation in the study at any time without plenty or loss of patients medical care.
CONSENT PROCEDURES:
Rheumatology and endocrinology investigators (ASU) hospitals will obtain a written consent. The consent will be conducted to the patient by the mentioned investigator during the first visit. Literate individuals will be left to read the consent followed by its explanation by the mentioned investigator, while illiterate individuals will have the consent read and explained to them as well.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
Group 1: refractory lupus nephritis
Inclusion Criteria:
Exclusion Criteria:
Group 2: type 1 diabetes Meletus
Inclusion criteria:
Exclusion criteria:
Primary purpose
Allocation
Interventional model
Masking
20 participants in 1 patient group
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Central trial contact
Zeinab Ashour, Professor
Data sourced from clinicaltrials.gov
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