Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Based on preclinical data, investigators hypothesize that apoptosis resistance in monocyte-derived macrophages (MDMs) have a decisive role in the development of idiopathic pulmonary fibrosis (IPF). Specifically, macrophages from subjects with IPF have increased expression of Bcl-2 in mitochondria. In preclinical models of IPF, a conditional deletion of Bcl-2 in MDMs reverses established fibrosis by inducing apoptosis. Additional evidence to suggest that Bcl-2 expression in MDM mitochondria is a therapeutic target for IPF as administration of the Bcl-2 inhibitor, ABT-199 (Venetoclax), showed marked efficacy in preclinical models of IPF by inducing apoptosis of MDMs and reversing established fibrosis. ABT-199 is an orally available mimetic of the BH3 domain of Bcl-2, which is the domain the anchors Bcl-2 in the mitochondria to inhibit apoptosis. ABT-199 has shown therapeutic efficacy and good safety and tolerability in patients with chronic lymphocytic leukemia. Investigators anticipate that treatment with ABT-199 could result in significant benefit for IPF patients that have a life expectancy of 3-5 years. As there is no curative therapy for IPF, this clinical trial has the potential to substantially alter treatment approaches in patients with IPF.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| treatment | Experimental | Venetoclax 100 mg daily for 3 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Venetoclax | Drug | 100 mg daily by mouth for 3 weeks This drug inhibits a protein (Bcl-2) that protects cells from undergoing programmed cell death. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of participants with treatment-related adverse events as assessed by measuring liver function. | complete metabolic panel | 3 weeks |
| Number of participants with treatment-related adverse events as assessed by measuring blood counts. | complete blood count | 3 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of monocyte-derived macrophages that undergoing apoptosis. | flow cytometry | 3 weeks |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Inhibitors include: pirfenidone, boceprevir, cobicistat, conivaptan, ritonavir, itraconazole, ketoconazole, telaprevir, troleandomycin, voriconazole, clarithromycin, diltiazem, idelalisib, nefazodone, nelfinavir.
Inducers include: carbamazepine, enzalutamide, mitotane, phenytoin, rifampin.
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| TKC | Birmingham | Alabama | 35214 | United States | ||
| UAB |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26921108 | Result | Larson-Casey JL, Deshane JS, Ryan AJ, Thannickal VJ, Carter AB. Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis. Immunity. 2016 Mar 15;44(3):582-596. doi: 10.1016/j.immuni.2016.01.001. Epub 2016 Feb 23. | |
| 25378391 | Result | Larson-Casey JL, Murthy S, Ryan AJ, Carter AB. Modulation of the mevalonate pathway by akt regulates macrophage survival and development of pulmonary fibrosis. J Biol Chem. 2014 Dec 26;289(52):36204-19. doi: 10.1074/jbc.M114.593285. Epub 2014 Nov 5. |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D054990 | Idiopathic Pulmonary Fibrosis |
| ID | Term |
|---|---|
| D011658 | Pulmonary Fibrosis |
| D017563 | Lung Diseases, Interstitial |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C579720 | venetoclax |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Birmingham |
| Alabama |
| 35233 |
| United States |
| 34023385 | Result | Larson-Casey JL, Gu L, Kang J, Dhyani A, Carter AB. NOX4 regulates macrophage apoptosis resistance to induce fibrotic progression. J Biol Chem. 2021 Jul;297(1):100810. doi: 10.1016/j.jbc.2021.100810. Epub 2021 May 21. |
| 34038004 | Result | Larson-Casey JL, Gu L, Davis D, Cai GQ, Ding Q, He C, Carter AB. Post-translational regulation of PGC-1alpha modulates fibrotic repair. FASEB J. 2021 Jun;35(6):e21675. doi: 10.1096/fj.202100339R. |
| 34413485 | Result | Gu L, Surolia R, Larson-Casey JL, He C, Davis D, Kang J, Antony VB, Carter AB. Targeting Cpt1a-Bcl-2 interaction modulates apoptosis resistance and fibrotic remodeling. Cell Death Differ. 2022 Jan;29(1):118-132. doi: 10.1038/s41418-021-00840-w. Epub 2021 Aug 20. |