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CompletedNCT03383380Updated Jul 9, 2024

Rapamycin Treatment for Activated Phosphoinositide 3-Kinase δ Syndrome

A Phase 1/2 interventional study of Rapamycin in Activated PI3K-delta Syndrome and Immunodeficiency Primary, sponsored by Children's Hospital of Fudan University. Completed at 2 sites in China. Open to participants aged Up to 18 Years. Per ClinicalTrials.gov, last updated 2024-07-09.

Sponsored by Children's Hospital of Fudan University · Phase 1/2, Interventional, and Treatment

Phase
Phase 1/2
Study type
Interventional
Enrollment
30
Allocation
Not applicable
Ages
Up to 18 Years
Sex
All
01

Study 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).

Read the 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.

02

Conditions studied

  • Activated PI3K-delta Syndrome
  • Immunodeficiency Primary

Keywords

  • Activated PI3K-delta Syndrome
  • Immunodeficiency Primary
  • Akt/mTOR pathway
  • Rapamycin Therapy
  • Hyperphosphorylation
03

In context

Primary Immunodeficiency Diseases

211 studies on the registry are indexed under Primary Immunodeficiency Diseases; 51 are open to participants now.

This study's enrollment of 30 is below the median of 36 across 125 interventional studies indexed under Primary Immunodeficiency Diseases.

Browse Primary Immunodeficiency Diseases studies →

Lead sponsor

Children's Hospital of Fudan University is the lead sponsor of 268 studies on the registry; 95 are open to participants now.

Browse Children's Hospital of Fudan University studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
Up to 18 Years
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

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

Exclusion criteria

Exclusion Criteria:

  1. Patients with serious fungous infection
  2. Patients with serious complications
  3. Lack of parental consent
05

Study design

Phase
Phase 1 / Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
30 participants (actual)

Study arms

  • Experimental
    Rapamycin

    Treatment for patients with activated phosphoinositide 3-kinase δ syndrome

    Drug: Rapamycin

Interventions

  • DrugRapamycin

    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.

    Also known as: Sirolimus

06

What researchers measure

Primary outcomes

  1. Frequency of Recurrent Infections

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

    Time frame: 5 years

  2. Hepatosplenomegaly

    Changes in hepatosplenomegaly with rapamycin treatment.

    Time frame: 5 years

  3. Lymphocyte subset

    The changes of lymphocytes subset were evaluated by flow cytometry.

    Time frame: 5 years

Secondary outcomes

  1. Incidence of Adverse Events

    Unexpected toxic adverse events during and after using rapamycin

    Time frame: 5 years

07

Study locations

2 sites
  • Children's Hospital of Fudan University
    Shanghai, Shanghai 201102, China
  • Children's Hospital of Fudan University
    Shanghai, Shanghai, China
08

References and documents

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 delta 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. PubMed 27555459 ↗
  • Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DM, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliveira JB, Tangye SG, Schwartzberg PL, Lenardo MJ, Uzel G. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nat Immunol. 2014 Jan;15(1):88-97. doi: 10.1038/ni.2771. Epub 2013 Oct 28. PubMed 24165795 ↗
  • Tsujita Y, Mitsui-Sekinaka K, Imai K, Yeh TW, Mitsuiki N, Asano T, Ohnishi H, Kato Z, Sekinaka Y, Zaha K, Kato T, Okano T, Takashima T, Kobayashi K, Kimura M, Kunitsu T, Maruo Y, Kanegane H, Takagi M, Yoshida K, Okuno Y, Muramatsu H, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Kojima S, Ogawa S, Ohara O, Okada S, Kobayashi M, Morio T, Nonoyama S. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase delta syndrome-like immunodeficiency. J Allergy Clin Immunol. 2016 Dec;138(6):1672-1680.e10. doi: 10.1016/j.jaci.2016.03.055. Epub 2016 Jul 14. PubMed 27426521 ↗
  • Vignesh P, Rawat A, Singh S. An Update on the Use of Immunomodulators in Primary Immunodeficiencies. Clin Rev Allergy Immunol. 2017 Apr;52(2):287-303. doi: 10.1007/s12016-016-8591-2. PubMed 27873163 ↗
  • Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR, Baxendale H, Coulter T, Curtis J, Wu C, Blake-Palmer K, Perisic O, Smyth D, Maes M, Fiddler C, Juss J, Cilliers D, Markelj G, Chandra A, Farmer G, Kielkowska A, Clark J, Kracker S, Debre M, Picard C, Pellier I, Jabado N, Morris JA, Barcenas-Morales G, Fischer A, Stephens L, Hawkins P, Barrett JC, Abinun M, Clatworthy M, Durandy A, Doffinger R, Chilvers ER, Cant AJ, Kumararatne D, Okkenhaug K, Williams RL, Condliffe A, Nejentsev S. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013 Nov 15;342(6160):866-71. doi: 10.1126/science.1243292. Epub 2013 Oct 17. PubMed 24136356 ↗
  • Walsh CM, Fruman DA. Too much of a good thing: immunodeficiency due to hyperactive PI3K signaling. J Clin Invest. 2014 Sep;124(9):3688-90. doi: 10.1172/JCI77198. Epub 2014 Aug 18. PubMed 25133419 ↗

Individual participant data

Plan to share: No

09

Timeline

Tracking since Sep 25, 2026
ElapsedEstimatedEstimated, not yet reached

Ran from Dec 2017 to primary completion in Nov 2022, 59 months.

How these figures are worked out, and which studies are left out of them.

Registered
Dec 12, 2017
First posted
Dec 26, 2017
StartActual
Dec 1, 2017
Primary completionActual
Nov 30, 2022
CompletionActual
Nov 30, 2023
Last update
Jul 9, 2024
What these dates mean
Start.
When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.
When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.
When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.
Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.
No changes since tracking began. The registry record was last updated on Jul 9, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT03383380
Lead sponsor
Children's Hospital of Fudan University
Responsible party
Jinqiao Sun (Professor, Children's Hospital of Fudan University) — Principal investigator
First posted
Dec 26, 2017
Start date
Dec 1, 2017
Primary completion
Nov 30, 2022
Completion
Nov 30, 2023
Last update
Jul 9, 2024

Study contacts

Jinqiao Sun, Ph.D.,M.D
principal investigator · Children's Hospital of Fudan University

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Jul 2024. You cannot join it, but the record below documents what was studied.

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