Pioglitazone Therapy for Chronic Granulomatous Disease

Chronic Granulomatous Disease Clinical Trial

Official title:

Efficacy and Safety of Pioglitazone Therapy for Chronic Granulomatous Disease Patients With Severe Infection.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03080480
• Other study ID #: PTSICGD
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: September 1, 2017
• Est. completion date: October 20, 2019

Study information

• Verified date: October 2019
• Source: Children's Hospital of Fudan University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 3
• Est. completion date: October 20, 2019
• Est. primary completion date: October 20, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 18 Years

Eligibility

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)

Related Conditions & MeSH terms

• Chronic Granulomatous Disease
• Granuloma
• Granulomatous Disease, Chronic

Intervention

Drug:
• Pioglitazone
Pioglitazone is PPAR? 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.

Locations

Country	Name	City	State
China	Children's Hospital of Fudan University	Shanghai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Children's Hospital of Fudan University

Country where clinical trial is conducted

China, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	efficiency of Pioglitazone	Frequency of infections as indicator for the drug's benefit for the patients; Functional reconstitution of the NADPH oxidase in circulating cells of the peripheral blood (Stimulation Index by DHR analysis).	3 years
Secondary	Incidence of Treatment-Emergent Adverse Events	Frequency and severity of metabolic disorders and unexpected toxic adverse events during and after using pioglitazone	3 years