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NCT Number: NCT03383380

Rapamycin Treatment for Activated Phosphoinositide 3-Kinase δ Syndrome

The purpose of this proposed research is to evaluate the efficacy and safety of the rapamycin therapy in patients with activated phosphoinositide 3-kinase δ syndrome (APDS).

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Key information

Conditions

Activated PI3K-delta Syndrome Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Immune System Diseases Immunodeficiency Primary Immunologic Deficiency Syndromes Primary Immunodeficiency Diseases

Age range

Up to 18 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Children's Hospital of Fudan University, Shanghai, Shanghai Municipality, China

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Rapamycin

Drug

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 names: Sirolimus

Primary outcomes

  1. Frequency of Recurrent Infections

    Time frame: 5 years

    Frequency of recurrent infections of the patients as indicators of rapamycin efficacy.

  2. Hepatosplenomegaly

    Time frame: 5 years

    Changes in hepatosplenomegaly with rapamycin treatment.

  3. Lymphocyte subset

    Time frame: 5 years

    The changes of lymphocytes subset were evaluated by flow cytometry.

Secondary outcomes

  1. Incidence of Adverse Events

    Time frame: 5 years

    Unexpected toxic adverse events during and after using rapamycin

Sponsors and collaborators

Lead sponsor

Children's Hospital of Fudan University

Other

Registry information

Official study title

Efficacy and Safety of Rapamycin Therapy for Patients With Activated Phosphoinositide 3-Kinase δ Syndrome

Important dates

Study start
2017
Primary completion
2022
Study completion
2023
First posted
Dec 26, 2017
Registry last updated
Jul 9, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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