Rapamycin Treatment for Activated Phosphoinositide 3-Kinase δ Syndrome
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ClinicalTrials.gov Identifier: NCT03383380 |
Recruitment Status : Unknown
Verified March 2022 by Jinqiao Sun, Children's Hospital of Fudan University.
Recruitment status was: Recruiting
First Posted : December 26, 2017
Last Update Posted : March 23, 2022
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Condition or disease | Intervention/treatment | Phase |
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Activated PI3K-delta Syndrome Immunodeficiency Primary | Drug: Rapamycin | Phase 1 Phase 2 |
Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described autosomal dominant primary immunodeficiency (PID), caused by the mutations in PIK3CD gene. The manifestations of APDS mainly include recurrent respiratory tract infections, persistent Epstein-Barr virus (EBV)/ cytomegalovirus (CMV)infections, lymphadenopathy, splenomegaly, CD4+T cells lymphopenia, and hyper-IgM syndrome. PIK3CD encodes p110δ, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) which mainly expresses in leukocytes, being critical for their proliferation, activation and survival. Gain-of-function (GOF) PIK3CD mutations lead to PI3Kδ hyperactivity, with the downstream mediators Akt and mammilian target of rapamycin (mTOR) hyperphosphorylated. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein. Hyperactivation of mTOR increases phosphorylation of kinases and increased glycolysis that results in enhanced proliferation and senescence of terminally differentiated CD8+ Tcell populations.
The optimal treatment for these APDS patients is not yet determined; however, there are many kinds of therapeutic approaches (anti-infection prophylaxis, immunoglobulin replacement, conventional immunosuppressants, PI3K/mTOR inhibitors and hematopoietic stem cell transplantation). The APDS patients frequently receive treatment with immunoglobulin replacement and antibiotics. Hematopoietic stem cell transplantation (HSCT) has been currently curative in APDS patients; however, longer-term follow-up to determine the degree of donor chimerism and efficacy is required. There are several subjects without a prompt suitable matched donor or for whom the critical disease conditions force to postpone HSCT.The mammalian/mechanistic target of inhibitor rapamycin was reported to improve circulating T-cell profiles. Individual patients in previous studies experienced a decrease in nonneoplastic lymphoproliferation while taking rapamycin.
The investigators in this study hope to evaluate the efficacy and safety of rapamycin in the treatment for carefully selected patients with APDS.
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 20 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | Efficacy and Safety of Rapamycin Therapy for Patients With Activated Phosphoinositide 3-Kinase δ Syndrome |
Actual Study Start Date : | December 1, 2017 |
Estimated Primary Completion Date : | November 30, 2022 |
Estimated Study Completion Date : | November 30, 2022 |
Arm | Intervention/treatment |
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Experimental: Rapamycin
Treatment for patients with activated phosphoinositide 3-kinase δ syndrome
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Drug: Rapamycin
Gain-of-function (GOF) PIK3CD mutations lead to PI3Kδ hyperactivity, with the downstream mediators Akt and mTOR hyperphosphorylated. The mammalian/mechanistic target of rapamycin inhibitor rapamycin may be effective to control the progress of this disease.
Other Name: Sirolimus |
- Frequency of Recurrent Infections [ Time Frame: 5 years ]Frequency of recurrent infections of the patients as indicators of rapamycin efficacy.
- Hepatosplenomegaly [ Time Frame: 5 years ]Changes in hepatosplenomegaly with rapamycin treatment.
- Lymphocyte subset [ Time Frame: 5 years ]The changes of lymphocytes subset were evaluated by flow cytometry.
- Incidence of Adverse Events [ Time Frame: 5 years ]Unexpected toxic adverse events during and after using rapamycin
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Ages Eligible for Study: | up to 18 Years (Child, Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patients with activated phosphoinositide 3-kinase δ syndrome
- No more than 18 years old
Exclusion Criteria:
- Patients with serious fungous infection
- Patients with serious complications
- Lack of parental consent
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03383380
Contact: Jinqiao Sun, Ph.D.,M.D | 86-21-64932909 | jinqiaosun@sina.com | |
Contact: Weili Yan, Ph.D. | 86-21-64931913 | yanwl@fudan.edu.cn |
China, Shanghai | |
Children's Hospital of Fudan University | Recruiting |
Shanghai, Shanghai, China, 201102 | |
Contact: Jinqiao Sun, Ph.D.,M.D jinqiaosun@sina.com | |
Children's Hospital of Fudan University | Recruiting |
Shanghai, Shanghai, China | |
Contact: Weili Yan, Ph.D yanwl@fudan.edu.cn |
Principal Investigator: | Jinqiao Sun, Ph.D.,M.D | Children's Hospital of Fudan University |
Responsible Party: | Jinqiao Sun, Professor, Children's Hospital of Fudan University |
ClinicalTrials.gov Identifier: | NCT03383380 |
Other Study ID Numbers: |
RTAPDS |
First Posted: | December 26, 2017 Key Record Dates |
Last Update Posted: | March 23, 2022 |
Last Verified: | March 2022 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | No |
Studies a U.S. FDA-regulated Device Product: | No |
Activated PI3K-delta Syndrome Immunodeficiency Primary Akt/mTOR pathway Rapamycin Therapy Hyperphosphorylation |
Sirolimus Primary Immunodeficiency Diseases Immunologic Deficiency Syndromes Syndrome Disease Pathologic Processes Immune System Diseases Genetic Diseases, Inborn |
Anti-Bacterial Agents Anti-Infective Agents Antibiotics, Antineoplastic Antineoplastic Agents Antifungal Agents Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |