A Study to investigate the safety and tolerability of sirolimus in patients with primary immunodeficiency

JRCT ID: jRCTs031230296

Registered date:18/08/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: primary immunodeficiency
• Date of first enrollment: 20/09/2023
• Target sample size: 20
• Study type: Interventional

Intervention(s)

<If sirolimus is being administered at the start of sirolimus administration in this study [extended administration cohort]>
As a general rule patients will continue to receive sirolimus at the dose most recently registered in this study. Sirolimus is administered once a day on an empty stomach or after a meal, and the dose can be increased or decreased as appropriate while monitoring the patient's condition.
<When sirolimus was not administered at the start of sirolimus administration in this study [initial administration cohort]>
[Initial dose]
1) If you are 12 years old or older (tablet);2 mg as sirolimus
2) 6 months or older and under 12 years old (granules*);0.07 mg/kg x 0.7 as sirolimus (maximum initial dose: 1.4 mg)
*If body weight is 28.6 kg or more, tablet administration may be considered for compliance.
3) Less than 6 months old (granules);0.05 mg/kg x 0.7 as sirolimus
For patients who are on sirolimus withdrawal, administration should be resumed at the dose before the withdrawal or at a reduced dose.

Outcome(s)

• Primary Outcome: Frequency and rate of adverse events (or diseases, etc.)

Secondary Outcome

The following items at 12 weeks*, 52 weeks, and 2 years (104 weeks) of administration
(1) Frequency and rate of improvement in main symptoms at each evaluation point
(2) Improvement frequency and rate of each symptom (lymphoid swelling, enteritis, cytopenia) at each evaluation time point
*: First dose cohort only

Key inclusion & exclusion criteria

• Age minimum: >= 2month old
• Age maximum: Not applicable
• Gender: Both

Include criteria

Patients who meet the following 1) or 2) and all other criteria are included in this clinical study.
1.Patients enrolled in a phase II clinical trial (RALPID trial) to evaluate the efficacy and safety of sirolimus in patients with primary immunodeficiency and who received sirolimus.
2.In this study, patients who will start administration of sirolimus will be selected from those who satisfy all of the following criteria.
(1)Patients enrolled in PIDJ*
*Patients who have been diagnosed with a definitive diagnosis by appropriate genetic testing, etc., based on the diagnosis support of the Japanese Society for Immunodeficiency and Autoinflammation and the judgment of a doctor who has sufficient experience in diagnosing and treating primary immunodeficiency disease (PID). are treated in the same manner as PIDJ registered patients. In that case, we will allow enrollment in this study prior to PIDJ enrollment, but enroll this patient in PIDJ as soon as it becomes possible. This agreement is valid only during the period when PIDJ registration is not possible.
(2)Patients diagnosed with any of the following diseases by flow cytometry or genetic testing
a.Activated PI3K-delta syndrome (APDS)
b.CTLA4 haploinsufficiency
c.LRBA deficiency
d.IPEX syndrome, IPEX-like
e.Autoimmune lymphoproliferative syndrome (ALPS), ALPS-like
f.Unclassifiable immunodeficiency disease (CVID) **
g.Other primary immunodeficiencies**
**Only patients judged by each research institution to have mTOR pathway enhancement in the background are eligible.
(3)Patients who show any of the following symptoms, who are not sufficiently effective despite steroid therapy for 3 months or longer, or whose side effects make continuation of steroid therapy undesirable.a.Patients with evaluable lymphoproliferative symptoms
a. Patients with evaluable lymphoproliferative symptoms
-Hepatomegaly 3.0 cm or more palpable below the costal arch
-Splenomegaly palpable
-Measurable lymph node lesions or extranodal lesions CT or MRI with a major axis of 2.0 cm or more
b.Patients with enteritis (16 years old or older CDAI score equal or greater 220, under 16 years old wPCDAI score equal or greater 40)
c.Patients with 2 or more autoimmune cytopenias* that fall under any of the following
-Hemoglobin concentration less than 10.0g/dL
-Neutrophil count less than 1500/micro L
-Platelet count less than 75,000/micro L
*Autoimmune cytopenia cytopenia without decreased blood cell production, with a history of response to treatment with immunosuppressants, or with autoantibodies
(4)Patients aged 0 years and 2 months or older at the time of informed consent
(5)Patients who can take granules or tablets
3.Patients who can comply with the provisions of the research plan
4.Patients who have obtained written consent from the patient or their legal representative regarding participation in this clinical study

Exclude criteria

Patients who meet any of the following criteria will not be included in this clinical study.
1.Patients who are judged by the principal investigator or co-investigator (hereinafter referred to as principal investigator, etc.) not to continue administration of sirolimus from the viewpoint of efficacy and safety.
2.Patients who meet any of the following criteria for starting sirolimus administration in this study will not be included in this study.
(1)Patients with secondary immunodeficiency
(2)Patients with idiopathic interstitial pneumonia
(3)Patients with uncontrolled hyperlipidemia or uncontrolled diabetes
(4)Patients with clinically significant signs and symptoms of infection (infections requiring iv such as antibiotics)
(5)Patients with a serum creatinine level of 3 times or more, the upper limit of normal at screening (institutional reference values for adults, reference values shown in Appendix 2 for children)
(6)HBs antigen-positive patients, HBs antibody-positive or HBc antibody-positive patients with HBV-DNA detected, or active hepatitis C patients (HCV antibody-positive patients are inactive and have normal liver function values except)
(7)QFT/T-SPOT positive patients
(8)Patients who underwent surgery (invasion into the body cavity or hand requiring 3 or more stitches, including biopsy) within 2 weeks before registration
(9)Patients scheduled for surgery during study drug administration period
(10)Patients who underwent hematopoietic stem cell transplantation
(11)Patients who received blood transfusion or high-dose immunoglobulin therapy within 12 weeks prior to study entry
(12)Patients who received G-CSF formulation within 1 week before enrollment in this study (within 4 weeks for long-acting G-CSF formulation)
(13)Patients who have taken an angiotensin-converting enzyme inhibitor within 4 weeks prior to enrollment in this study
(14)Patients who have taken any other investigational drug within 4 weeks prior to enrollment in this study (excluding patients enrolled in the RALPID study)
(15)Patients who have been treated with the following drugs in the past
a.History of treatment with mTOR inhibitors (everolimus, temsirolimus) or PI3K delta inhibitors outside of the RALPID trial
b.reatment history of rituximab within 24 weeks before enrollment
c.History of treatment with abatacept or other biological immunosuppressants with monoclonal antibodies (etanercept, infliximab, tocilizumab, certolizumab, adalimumab, golimumab, canakinumab, etc.) within 8 weeks before registration
d.Other immunosuppressants (cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, mercaptopurine, methotrexate, JAK inhibitors <tofacitinib, baricitinib, etc.>, etc. within 2 weeks prior to enrollment. However, doses of 1 mg/kg or less history of treatment with systemic steroids and topical steroids (excluding topical steroids)
(16)Patients who received a live vaccine within 4 weeks prior to enrollment in this study
(17)Patients with NYHA class II-IV congestive heart failure
(18)Patients with a history of myocardial infarction within 6 months prior to enrollment
(19)Patients with symptomatic arrhythmias requiring treatment
3.If there is an active malignant tumor at the time of screening (However, depending on the disease, it is difficult to judge malignancy, so it will be judged comprehensively)
4.Patients who are of childbearing potential or have a partner of childbearing potential who cannot consent to adequate contraception from the time consent is obtained until 12 weeks after the last dose of study drug.
5.Patients who are pregnant, breastfeeding, or may be pregnant
6.Other patients who are deemed inappropriate for participation in this study by the principal investigator, etc

Related Information

• Primary Sponsor: Imai Kohsuke
• Source(s) of Monetary Support: Japan Agency for Medical Research and Development