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出境医 / 临床实验 / Low-dose Interleukin-2 in Women With Unexplained Miscarriages (FaCIL-2)

Low-dose Interleukin-2 in Women With Unexplained Miscarriages (FaCIL-2)

Study Description
Brief Summary:
The purpose of this study is to demonstrate the ability of low dose IL-2 to stimulate peripheral blood Tregs of women with unexplained repeated early spontaneous miscarriages for development of a therapy to prevent fetal rejection by low dose IL-2.

Condition or disease Intervention/treatment Phase
Recurrent Miscarriage Drug: low-dose IL-2 Phase 1 Phase 2

Detailed Description:

About 1 to 3% of women of childbearing age have repeated early spontaneous miscarriages that may be related to parental chromosomal abnormalities, uterine abnormalities, hormonal causes, infectious etiology, thrombophilia ... When one of these known causes is excluded, it is unexplained miscarriages of which half would be due to an immunological deregulation of the mother causing a decrease of the tolerance to the fetus.

In this context, the stimulation of regulatory T cells (Tregs) by low dose IL-2 is a therapeutic option with a rational, preclinical and clinical data very favorable.

In humans, low dose IL-2 allows preferential activation of Tregs and is very well tolerated. Several therapeutic trials have shown its efficiencies.

These elements make it possible to envisage the development of a therapeutic to prevent fetal rejection by IL2-fd on the women with spontaneous miscarriages by an immunological deregulation.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Regulatory T-cell Induction by Low-dose Interleukin-2 in Women With Unexplained Repeated Spontaneous Early Miscarriages
Actual Study Start Date : January 5, 2021
Estimated Primary Completion Date : February 5, 2024
Estimated Study Completion Date : February 5, 2025
Arms and Interventions
Arm Intervention/treatment
Experimental: 1
Low-dose IL-2
Drug: low-dose IL-2
Subcutaneous injection of low dose of IL-2 for induction course of 5 days, the 10th day after the beginning of periods. At most 5 courses of low dose of IL-2.
Other Name: interleukin-2

Outcome Measures
Primary Outcome Measures :
  1. Variation of rate of blood circulating T regulator lymphocytes(expressed in % of CD4 and total) [ Time Frame: At the day 38 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1] ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2

  2. Variation of rate of blood circulating T regulator lymphocytes(expressed in % of CD4 and total) [ Time Frame: At the day 66 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2

  3. Variation of rate of blood circulating T regulator lymphocytes(expressed in % of CD4 and total) [ Time Frame: At the day 94 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2

  4. Variation of rate of blood circulating T regulator lymphocytes(expressed in % of CD4 and total) [ Time Frame: At the day 122 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2

  5. Variation of rate of blood circulating T regulator lymphocytes(expressed in % of CD4 and total) [ Time Frame: At the day 150 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 11 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2


Secondary Outcome Measures :
  1. Variation of rate of blood circulating T regulator lymphocytes(expressed in absolute numbers) [ Time Frame: At the day 38 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2

  2. Variation of rate of blood circulating T regulator lymphocytes(expressed in absolute numbers) [ Time Frame: At the day 66 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2

  3. Variation of rate of blood circulating T regulator lymphocytes(expressed in absolute numbers) [ Time Frame: At the day 94 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2

  4. Variation of rate of blood circulating T regulator lymphocytes(expressed in absolute numbers) [ Time Frame: At the day 122 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2

  5. Variation of rate of blood circulating T regulator lymphocytes(expressed in absolute numbers) [ Time Frame: At the day 150 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 11 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Woman with at least 5 consecutive early miscarriages less than 14 weeks of amenorrhea and unexplained after the usual check-up;
  • Volunteer to participate in the trial and having given written consent after appropriate information.

Exclusion Criteria:

  • Uterine or pelvic abnormality: uterine malformation, intracavitary fibroid, synechiae, polyp, hydrosalpinx;
  • Balanced translocations in both spouses;
  • Diabetes type I or II;
  • Sickle cell disease;
  • Contraindication to pregnancy;
  • Constitutional or acquired thrombophilia (protein deficit C, S, ATIII, homozygous factor V or II deficiency, antiphospholipid syndrome, antithyroid antibodies positive, celiac disease, hyperhomocysteinemia);
  • Ovarian insufficiency (AMH <1 μg/ml);
  • Active HIV or HCV infection;
  • Main known contraindications to treatment with IL-2:
  • Hypersensitivity to the active substance or to any of the excipients;
  • Signs of progressive infection requiring antibiotic therapy;
  • History of organ allograft;
  • Pre-existing autoimmune disease;
  • Leukocytes <4000 / mm3; platelets <100,000 / mm3; hematocrit <30%;
  • hepatic or renal insufficiency;
  • depression;
  • heart failure (ECG);
  • patients with autoimmune disease;
  • patients with an infection (septicemia, bacterial endocarditis, septic thrombophlebitis, peritonitis and pneumonia);
  • pregnancy;
  • Treatment with immunomodulators, immunosuppressants (class L04A of the ATC classification), in particular systemic corticosteroids, as well as aspirin and low molecular weight heparin;
  • No affiliation to a social security;
  • Person who has already been included in this study or in another at the same time;
  • Major incapacitated patient (tutorship / curatorship);
  • Patient with an allergy to taking IL2-fd;
  • Participants who would present professional risk factors (eg ionizing exposure);
Contacts and Locations

Contacts
Layout table for location contacts
Contact: David Klatzmann, Pr +331 42 16 74 61 david.klatzmann@upmc.fr
Contact: Arsène Mékinian, Dr +33 1 48 02 63 96 arsene.mekinian@aphp.fr

Locations
Layout table for location information
France
Mekinian Recruiting
Paris, Hopital Saint Antoine, France, 75012
Contact: Arsene Mekinian, Dr         
Sub-Investigator: Olivier Fain, Pr         
Sub-Investigator: roberta Lorenzon, Dr         
Principal Investigator: Arsene Mekinian, DR         
Bornes Not yet recruiting
Paris, Hopital Tenon, France, 75020
Contact: Marie Bornes, Pr         
Principal Investigator: Marie Bornes, Pr         
Sub-Investigator: Audrey rosefort, Pr         
Kayem Not yet recruiting
Paris, Hopital Trousseau, France, 75012
Contact: Gilles Kayem, Pr         
Principal Investigator: Gilles Kayem, Pr         
Sub-Investigator: lucille cedille, Dr         
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Iltoo Pharma
Investigators
Layout table for investigator information
Principal Investigator: David Klatzmann, Pr Pitié Salpètrière APHP Paris
Study Director: Arsene Mékinian, Dr Saint Antoine APHP Paris
Study Director: Gilles Kayem, Pr Trousseau APHP Paris
Tracking Information
First Submitted Date  ICMJE March 14, 2019
First Posted Date  ICMJE June 3, 2019
Last Update Posted Date March 9, 2021
Actual Study Start Date  ICMJE January 5, 2021
Estimated Primary Completion Date February 5, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 29, 2019)
  • Variation of rate of blood circulating T regulator lymphocytes(expressed in % of CD4 and total) [ Time Frame: At the day 38 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1] ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2
  • Variation of rate of blood circulating T regulator lymphocytes(expressed in % of CD4 and total) [ Time Frame: At the day 66 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2
  • Variation of rate of blood circulating T regulator lymphocytes(expressed in % of CD4 and total) [ Time Frame: At the day 94 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2
  • Variation of rate of blood circulating T regulator lymphocytes(expressed in % of CD4 and total) [ Time Frame: At the day 122 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2
  • Variation of rate of blood circulating T regulator lymphocytes(expressed in % of CD4 and total) [ Time Frame: At the day 150 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 11 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 29, 2019)
  • Variation of rate of blood circulating T regulator lymphocytes(expressed in absolute numbers) [ Time Frame: At the day 38 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2
  • Variation of rate of blood circulating T regulator lymphocytes(expressed in absolute numbers) [ Time Frame: At the day 66 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2
  • Variation of rate of blood circulating T regulator lymphocytes(expressed in absolute numbers) [ Time Frame: At the day 94 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2
  • Variation of rate of blood circulating T regulator lymphocytes(expressed in absolute numbers) [ Time Frame: At the day 122 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 1 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2
  • Variation of rate of blood circulating T regulator lymphocytes(expressed in absolute numbers) [ Time Frame: At the day 150 of Cycle 2 (each cycle is 28 days) compared from the day 10 of Cycle 11 ]
    Change of Tregs at Day 14 of cycles under low dose of IL-2 compared to the baseline of the first cycle without low dose of IL-2
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Low-dose Interleukin-2 in Women With Unexplained Miscarriages
Official Title  ICMJE Regulatory T-cell Induction by Low-dose Interleukin-2 in Women With Unexplained Repeated Spontaneous Early Miscarriages
Brief Summary The purpose of this study is to demonstrate the ability of low dose IL-2 to stimulate peripheral blood Tregs of women with unexplained repeated early spontaneous miscarriages for development of a therapy to prevent fetal rejection by low dose IL-2.
Detailed Description

About 1 to 3% of women of childbearing age have repeated early spontaneous miscarriages that may be related to parental chromosomal abnormalities, uterine abnormalities, hormonal causes, infectious etiology, thrombophilia ... When one of these known causes is excluded, it is unexplained miscarriages of which half would be due to an immunological deregulation of the mother causing a decrease of the tolerance to the fetus.

In this context, the stimulation of regulatory T cells (Tregs) by low dose IL-2 is a therapeutic option with a rational, preclinical and clinical data very favorable.

In humans, low dose IL-2 allows preferential activation of Tregs and is very well tolerated. Several therapeutic trials have shown its efficiencies.

These elements make it possible to envisage the development of a therapeutic to prevent fetal rejection by IL2-fd on the women with spontaneous miscarriages by an immunological deregulation.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Recurrent Miscarriage
Intervention  ICMJE Drug: low-dose IL-2
Subcutaneous injection of low dose of IL-2 for induction course of 5 days, the 10th day after the beginning of periods. At most 5 courses of low dose of IL-2.
Other Name: interleukin-2
Study Arms  ICMJE Experimental: 1
Low-dose IL-2
Intervention: Drug: low-dose IL-2
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 29, 2019)
10
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 5, 2025
Estimated Primary Completion Date February 5, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Woman with at least 5 consecutive early miscarriages less than 14 weeks of amenorrhea and unexplained after the usual check-up;
  • Volunteer to participate in the trial and having given written consent after appropriate information.

Exclusion Criteria:

  • Uterine or pelvic abnormality: uterine malformation, intracavitary fibroid, synechiae, polyp, hydrosalpinx;
  • Balanced translocations in both spouses;
  • Diabetes type I or II;
  • Sickle cell disease;
  • Contraindication to pregnancy;
  • Constitutional or acquired thrombophilia (protein deficit C, S, ATIII, homozygous factor V or II deficiency, antiphospholipid syndrome, antithyroid antibodies positive, celiac disease, hyperhomocysteinemia);
  • Ovarian insufficiency (AMH <1 μg/ml);
  • Active HIV or HCV infection;
  • Main known contraindications to treatment with IL-2:
  • Hypersensitivity to the active substance or to any of the excipients;
  • Signs of progressive infection requiring antibiotic therapy;
  • History of organ allograft;
  • Pre-existing autoimmune disease;
  • Leukocytes <4000 / mm3; platelets <100,000 / mm3; hematocrit <30%;
  • hepatic or renal insufficiency;
  • depression;
  • heart failure (ECG);
  • patients with autoimmune disease;
  • patients with an infection (septicemia, bacterial endocarditis, septic thrombophlebitis, peritonitis and pneumonia);
  • pregnancy;
  • Treatment with immunomodulators, immunosuppressants (class L04A of the ATC classification), in particular systemic corticosteroids, as well as aspirin and low molecular weight heparin;
  • No affiliation to a social security;
  • Person who has already been included in this study or in another at the same time;
  • Major incapacitated patient (tutorship / curatorship);
  • Patient with an allergy to taking IL2-fd;
  • Participants who would present professional risk factors (eg ionizing exposure);
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 40 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: David Klatzmann, Pr +331 42 16 74 61 david.klatzmann@upmc.fr
Contact: Arsène Mékinian, Dr +33 1 48 02 63 96 arsene.mekinian@aphp.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03970954
Other Study ID Numbers  ICMJE APHP 180256
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Iltoo Pharma
Investigators  ICMJE
Principal Investigator: David Klatzmann, Pr Pitié Salpètrière APHP Paris
Study Director: Arsene Mékinian, Dr Saint Antoine APHP Paris
Study Director: Gilles Kayem, Pr Trousseau APHP Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP