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Rapamycin Treatment for Activated Phosphoinositide 3-Kinase δ Syndrome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03383380
Recruitment Status : Recruiting
First Posted : December 26, 2017
Last Update Posted : February 18, 2020
Sponsor:
Information provided by (Responsible Party):
Jinqiao Sun, Children's Hospital of Fudan University

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Activated PI3K-delta Syndrome Immunodeficiency Primary Drug: Rapamycin Phase 1 Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
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
Experimental: Rapamycin
Treatment for patients with activated phosphoinositide 3-kinase δ syndrome
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




Primary Outcome Measures :
  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 Outcome Measures :
  1. 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
Criteria

Inclusion Criteria:

  1. Patients with activated phosphoinositide 3-kinase δ syndrome
  2. No more than 18 years old

Exclusion Criteria:

  1. Patients with serious fungous infection
  2. Patients with serious complications
  3. Lack of parental consent

Information from the National Library of Medicine

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


Contacts
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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

Locations
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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   
Sponsors and Collaborators
Children's Hospital of Fudan University
Investigators
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Principal Investigator: Jinqiao Sun, Ph.D.,M.D Children's Hospital of Fudan University

Publications:
Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, Goodlad JR, Farmer G, Steele CL, Leahy TR, Doffinger R, Baxendale H, Bernatoniene J, Edgar JD, Longhurst HJ, Ehl S, Speckmann C, Grimbacher B, Sediva A, Milota T, Faust SN, Williams AP, Hayman G, Kucuk ZY, Hague R, French P, Brooker R, Forsyth P, Herriot R, Cancrini C, Palma P, Ariganello P, Conlon N, Feighery C, Gavin PJ, Jones A, Imai K, Ibrahim MA, Markelj G, Abinun M, Rieux-Laucat F, Latour S, Pellier I, Fischer A, Touzot F, Casanova JL, Durandy A, Burns SO, Savic S, Kumararatne DS, Moshous D, Kracker S, Vanhaesebroeck B, Okkenhaug K, Picard C, Nejentsev S, Condliffe AM, Cant AJ. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study. J Allergy Clin Immunol. 2017 Feb;139(2):597-606.e4. doi: 10.1016/j.jaci.2016.06.021. Epub 2016 Jul 16.

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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: February 18, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Jinqiao Sun, Children's Hospital of Fudan University:
Activated PI3K-delta Syndrome
Immunodeficiency Primary
Akt/mTOR pathway
Rapamycin Therapy
Hyperphosphorylation
Additional relevant MeSH terms:
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Immunologic Deficiency Syndromes
Syndrome
Disease
Pathologic Processes
Immune System Diseases
Sirolimus
Everolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs