title: Randomised controlled trial for emphysema with a selective agonist of the γ-type retinoic acid receptor.
abstract: Palovarotene is an oral γ-selective retinoid agonist. In animal emphysema models, palovarotene reduced inflammation, promoted structural repair and functional improvement. REPAIR (Retinoid treatment of Emphysema in Patients on the α(1)-antitrypsin International Registry), was an investigator-initiated, double-blind, placebo-controlled randomised study to assess the safety and efficacy of 5 mg·day(-1) palovarotene given for 1 year to 262 patients with severe α(1)-antitrypsin deficiency and emphysema confirmed by computed tomography. Change in volume-adjusted 15th percentile point lung density from baseline in 1 year was the primary end-point; functional end-points were also regularly assessed. We randomly assigned 133 and 129 patients to placebo or palovarotene, respectively. Both groups were well matched for all baseline characteristics, including respiratory medications. 88% and 85% of patients completed 1 year of treatment with placebo and palovarotene, respectively. Palovarotene was generally well tolerated. In the study completers population, the placebo-corrected difference of lung density was -0.45 HU at week 28 (p=0.64) and -0.25 HU at week 52 (p=0.94). A nonsignificant treatment difference in most functional parameters of the lung in favour of the drug was observed over time suggesting potential pharmacological effects of palovarotene. Palovarotene 5 mg·day(-1) over 1 yr failed to show a significant benefit on lung density in moderate-to-severe emphysema secondary to severe α(1)-antitrypsin deficiency.
authors.affiliation: Dept of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands. j.stolk.long@lumc.nl
authors.forename: Jan
authors.initials: J
authors.lastname: Stolk
authors.forename: Robert A
authors.initials: RA
authors.lastname: Stockley
authors.forename: Berend C
authors.initials: BC
authors.lastname: Stoel
authors.forename: Brendan G
authors.initials: BG
authors.lastname: Cooper
authors.forename: Eeva
authors.initials: E
authors.lastname: Piitulainen
authors.forename: Niels
authors.initials: N
authors.lastname: Seersholm
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chapman
authors.forename: Jonathan G W
authors.initials: JG
authors.lastname: Burdon
authors.forename: Marc
authors.initials: M
authors.lastname: Decramer
authors.forename: Raja T
authors.initials: RT
authors.lastname: Abboud
authors.forename: Gregorius P M
authors.initials: GP
authors.lastname: Mannes
authors.forename: Emiel F
authors.initials: EF
authors.lastname: Wouters
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Garrett
authors.forename: Juan C
authors.initials: JC
authors.lastname: Barros-Tizon
authors.forename: Erich W
authors.initials: EW
authors.lastname: Russi
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: William A
authors.initials: WA
authors.lastname: MacNee
authors.forename: Alexis
authors.initials: A
authors.lastname: Rames
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D004311:Double-Blind Method; D004646:Emphysema / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005541:Forced Expiratory Volume; D005740:Gases; D005838:Genotype; D006801:Humans; D007249:Inflammation; D016018:Least-Squares Analysis; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011720:Pyrazoles / Q000627:therapeutic use; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D012907:Smoking; D013267:Stilbenes / Q000627:therapeutic use; D014057:Tomography, X-Ray Computed; D000097768:Retinoic Acid Receptor gamma
chemical_list: D005740:Gases; D010919:Placebos; D011720:Pyrazoles; D018168:Receptors, Retinoic Acid; D013267:Stilbenes; D000097768:Retinoic Acid Receptor gamma; C546535:Palovarotene