Pioglitazone Therapy for Chronic Granulomatous Disease

NCT ID: NCT03080480

Last Updated: 2019-10-22

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-01
• Study Completion Date: 2019-10-20

Brief Summary

The purpose of this proposed research is to investigate the efficacy and safety of the therapy with pioglitazone for chronic granulomatous disease (CGD) patients severe infection.

Detailed Description

Chronic granulomatous disease (CGD) is a rare genetic disease caused by defects in genes encoding the subunits of the nicotinamide adenine dinucleotide（NADPH）phosphate oxidase complex. In normal phagocytes peroxisome proliferator-activated receptor gamma (PPARγ) activation links NADPH oxidase activity with enhanced mitochondrial reactive oxygen species (ROS) production. There is deficient mitochondrial ROS production in CGD，due to the lack of this upstream signaling by the NADPH oxidase and PPARγ. These patients are susceptible to bacterial and fungal infections, as well as extensive tissue granuloma formation. X-chromosome-linked CGD (X-CGD) is most frequently. And it generally produces a severe phenotype, with a mortality rate of 3% to 5% per year despite state-of-the-art prophylaxis and intensive multimodal treatment.

At present the most curative treatment for patients with X-CGD is hematopoietic stem cell transplantion (HSCT). But for many patients without an HLA-matched donor and active infections/inflammatory complications still require novel approches.

PPARγ agonist such as pioglitazone, approved for type 2 diabetes, was reported to bypass the need for the NADPH oxidase for enhanced mtROS production and partially restored host defense in CGD. What's more, some animal models and several clinical cases have proved its efficacy. The investigators propose to study the efficacy and safety of the therapy with pioglitazone for children with severe infection of CGD, and its long-term effects.

Through this study the investigators hope to confirm the benefits of pioglitazone in the treatment of this rare disease especially for those patients without a prompt suitable matched donor or for whom the critical disease conditions force to postpone HSCT.

Conditions

Chronic Granulomatous Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Pioglitazone

Treatment for chronic granulomatous disease patients with severe infection.

Group Type: EXPERIMENTAL

Pioglitazone

Intervention Type: DRUG

Pioglitazone is PPARγ agonist that may be enhance ROS production and partially restore host phagocytes in CGD.

pioglitazone is administered at a starting dose of 1 mg/kg and given the absence of adverse effects is progressively increased up to 3 mg/kg or 30 mg/daily.

Interventions

Pioglitazone

Pioglitazone is PPARγ agonist that may be enhance ROS production and partially restore host phagocytes in CGD.

pioglitazone is administered at a starting dose of 1 mg/kg and given the absence of adverse effects is progressively increased up to 3 mg/kg or 30 mg/daily.

Intervention Type: DRUG

Other Intervention Names

ACTOS

Eligibility Criteria

Inclusion Criteria

1. Age：1 months to 18 years

2. Chronic Granulomatous Disease

3. with severe infections

Exclusion Criteria

1. > 18 years of age

2. infections are treatable by conventional therapy (antibiotics, antimycotics, allogeneic granulocytes)

• Minimum Eligible Age: 1 Month
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Children's Hospital of Fudan University

OTHER

Sponsor Role: lead

Responsible Party

Jinqiao Sun

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Children's Hospital of Fudan University

Shanghai, Shanghai Municipality, China

Countries

China

References

Migliavacca M, Assanelli A, Ferrua F, Cicalese MP, Biffi A, Frittoli M, Silvani P, Chidini G, Calderini E, Mandelli A, Camporesi A, Milani R, Farinelli G, Nicoletti R, Ciceri F, Aiuti A, Bernardo ME. Pioglitazone as a novel therapeutic approach in chronic granulomatous disease. J Allergy Clin Immunol. 2016 Jun;137(6):1913-1915.e2. doi: 10.1016/j.jaci.2016.01.033. Epub 2016 Apr 4. No abstract available.

Reference Type: BACKGROUND

PMID: 27056268 (View on PubMed)

Fernandez-Boyanapalli RF, Falcone EL, Zerbe CS, Marciano BE, Frasch SC, Henson PM, Holland SM, Bratton DL. Impaired efferocytosis in human chronic granulomatous disease is reversed by pioglitazone treatment. J Allergy Clin Immunol. 2015 Nov;136(5):1399-1401.e3. doi: 10.1016/j.jaci.2015.07.034. Epub 2015 Sep 18. No abstract available.

Reference Type: BACKGROUND

PMID: 26386811 (View on PubMed)

Fernandez-Boyanapalli RF, Frasch SC, Thomas SM, Malcolm KC, Nicks M, Harbeck RJ, Jakubzick CV, Nemenoff R, Henson PM, Holland SM, Bratton DL. Pioglitazone restores phagocyte mitochondrial oxidants and bactericidal capacity in chronic granulomatous disease. J Allergy Clin Immunol. 2015 Feb;135(2):517-527.e12. doi: 10.1016/j.jaci.2014.10.034. Epub 2014 Dec 10.

Reference Type: BACKGROUND

PMID: 25498313 (View on PubMed)

Hui X, Liu D, Wang W, Hou J, Ying W, Zhou Q, Yao H, Sun J, Wang X. Low-Dose Pioglitazone does not Increase ROS Production in Chronic Granulomatous Disease Patients with Severe Infection. J Clin Immunol. 2020 Jan;40(1):131-137. doi: 10.1007/s10875-019-00719-z. Epub 2019 Nov 19.

Reference Type: DERIVED

PMID: 31745699 (View on PubMed)

Other Identifiers

PTSICGD

Identifier Type: -

Identifier Source: org_study_id