Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability.
- 2023-02-28
- EBioMedicine 90
- Anoop Nambiar
- Dean Kellogg
- Jaime Justice
- Martin Goros
- Jonathan Gelfond
- Rodolfo Pascual
- Shahrukh Hashmi
- Michal Masternak
- Larissa Prata
- Nathan LeBrasseur
- Andrew Limper
- Stephen Kritchevsky
- Nicolas Musi
- Tamara Tchkonia
- James Kirkland
- PubMed: 36857968
- DOI: 10.1016/j.ebiom.2023.104481
Study Design
- Type
- Randomized Controlled Trial (RCT)
- Population
- Twelve participants with IPF aged >50 years
- Methods
- randomized placebo-controlled pilot trial (RCT; NCT02874989), three weeks of D+Q (D: 100 mg/d and Q: 1250 mg/d, three consecutive days per week) or matching placebo
- Blinding
- Double-blind
- Duration
- three weeks
- Funding
- Independent
- Highly Cited
Background
Idiopathic pulmonary fibrosis (IPF) is an age-related, chronic, irreversible fibrotic lung disease. IPF is associated with increased senescent cells burden, which may be alleviated with administration of senescent cell targeting drugs termed 'senolytics'. We previously conducted an open-label single-arm pilot study of the senolytic combination of dasatinib and quercetin (D + Q) in patients with IPF but lack of control group limited interpretation and next-stage trial planning. The primary objective of this confirmatory randomized placebo-controlled pilot trial (RCT; NCT02874989) was to report adverse events with D + Q and inform study feasibility for future efficacy trials.Methods
Twelve participants with IPF aged >50 years were blinded and randomized at a 1:1 ratio to either receive three weeks of D + Q (D: 100 mg/d and Q: 1250 mg/d, three consecutive days per week) or matching placebo.Findings
All participants completed the scheduled drug dosing regimen (108/108 doses) and planned assessments (60/60). While the placebo arm reported fewer overall non-serious AEs (65 vs 22), there were no serious adverse events related to D + Q. Most AEs in the D + Q arm are common in IPF patients or anticipated side effects of D. Sleep disturbances and anxiety were disproportionately represented in the D + Q arm (4/6 vs 0/6). Frailty, pulmonary, or physical function were explored before and after intermittent D + Q; though under-powered to evaluate change, these measures do not appear to differ meaningfully between groups.Interpretation
Intermittently-dosed D + Q in patients with IPF is feasible and generally well-tolerated. Further prospective studies, such as a larger RCT, are needed to confirm the safety and efficacy of D + Q in patients with IPF.Funding
This work was supported by National Institutes of Health grants R33AG61456 (JLK, TT), Robert and Arlene Kogod (JLK, TT), the Connor Fund (JLK, TT), Robert J. and Theresa W. Ryan (JLK, TT), and the Noaber Foundation (JLK, TT) San Antonio Claude D. Pepper Older Americans Independence Center's (OAIC)Pilot/Exploratory Studies Core (PESC) Grant (AMN, NM); NIHK01 AG059837 (JNJ), P30 AG021332 (SBK, JNJ); NIHR37 AG013925 (JLK), the Connor Group (JLK), Glenn/AFAR BIG Award (JLK), Robert J. and Theresa W. Ryan (JLK), and the Noaber and Ted Nash Long Life Foundations (JLK).Research Insights
Frailty, pulmonary, or physical function were explored before and after intermittent D+Q; though under-powered to evaluate change, these measures do not appear to differ meaningfully between groups.
- Effect
- Neutral
- Effect size
- Small
- Dose
- 1250 mg/d
Frailty, pulmonary, or physical function were explored before and after intermittent D+Q; though under-powered to evaluate change, these measures do not appear to differ meaningfully between groups.
- Effect
- Neutral
- Effect size
- Small
- Dose
- 1250 mg/d
Frailty, pulmonary, or physical function were explored before and after intermittent D+Q; though under-powered to evaluate change, these measures do not appear to differ meaningfully between groups.
- Effect
- Neutral
- Effect size
- Small
- Dose
- 1250 mg/d
Adverse Events Reported
Sleep disturbances and anxiety were disproportionately represented in the D+Q arm (4/6 vs 0/6).
- Finding
- Increased risk
- Magnitude
- 4/6 vs 0/6
Sleep disturbances and anxiety were disproportionately represented in the D+Q arm (4/6 vs 0/6).
- Finding
- Increased risk
- Magnitude
- 4/6 vs 0/6
While the placebo arm reported fewer overall non-serious AEs (65 vs 22), there were no serious adverse events related to D+Q.
- Finding
- Reported