PMID- 35233731
OWN - NLM
STAT- MEDLINE
DCOM- 20220727
LR  - 20231226
IS  - 1573-904X (Electronic)
IS  - 0724-8741 (Print)
IS  - 0724-8741 (Linking)
VI  - 39
IP  - 8
DP  - 2022 Aug
TI  - Improved Confidence in a Confirmatory Stage by Application of Item-Based 
      Pharmacometrics Model: Illustration with a Phase III Active Comparator-Controlled 
      Trial in COPD Patients.
PG  - 1779-1787
LID - 10.1007/s11095-022-03194-1 [doi]
AB  - PURPOSE: The current study aimed to illustrate how a non-linear mixed effect 
      (NLME) model-based analysis may improve confidence in a Phase III trial through 
      more precise estimates of the drug effect. METHODS: The FULFIL clinical trial was 
      a Phase III study that compared 24 weeks of once daily inhaled triple therapy 
      with twice daily inhaled dual therapy in patients with chronic obstructive 
      pulmonary disease (COPD). Patient reported outcome data, obtained by using The 
      Evaluating Respiratory Symptoms in COPD (E-RS:COPD) questionnaire, from the 
      FULFIL study were analyzed using an NLME item-based response theory model (IRT). 
      The change from baseline (CFB) in E-RS:COPD total score over 4-week intervals for 
      each treatment arm was obtained using the IRT and compared with published results 
      obtained with a mixed model repeated measures (MMRM) analysis. RESULTS: The IRT 
      included a graded response model characterizing item parameters and a Weibull 
      function combined with an offset function to describe the COPD symptoms-time 
      course in patients receiving either triple therapy (n = 907) or dual therapy 
      (n = 894). The IRT improved precision of the estimated drug effect compared to 
      MMRM, resulting in a sample size of at least 3.64 times larger for the MMRM 
      analysis to achieve the IRT precision in the CFB estimate. CONCLUSION: This study 
      shows the advantage of IRT over MMRM with a direct comparison of the same primary 
      endpoint for the two analyses using the same observed clinical trial data, 
      resulting in an increased confidence in Phase III.
CI  - (c) 2022. The Author(s).
FAU - Llanos-Paez, Carolina
AU  - Llanos-Paez C
AD  - Department of Pharmacy, Uppsala University, BMC, Box 580, 751 23, Uppsala, 
      Sweden.
FAU - Ambery, Claire
AU  - Ambery C
AD  - Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline plc, London, UK.
FAU - Yang, Shuying
AU  - Yang S
AD  - Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline plc, London, UK.
FAU - Beerahee, Misba
AU  - Beerahee M
AD  - Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline plc, London, UK.
FAU - Plan, Elodie L
AU  - Plan EL
AD  - Department of Pharmacy, Uppsala University, BMC, Box 580, 751 23, Uppsala, 
      Sweden.
FAU - Karlsson, Mats O
AU  - Karlsson MO
AUID- ORCID: 0000-0003-1258-8297
AD  - Department of Pharmacy, Uppsala University, BMC, Box 580, 751 23, Uppsala, 
      Sweden. mats.karlsson@farmaci.uu.se.
LA  - eng
GR  - GSK funded this research in the form of a Research payment to Uppsala 
      University/GSK/
GR  - 2018-03317/Vetenskapsradet/
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20220301
PL  - United States
TA  - Pharm Res
JT  - Pharmaceutical research
JID - 8406521
RN  - 0 (Bronchodilator Agents)
SB  - IM
MH  - Administration, Inhalation
MH  - Bronchodilator Agents/therapeutic use
MH  - Humans
MH  - Patient Reported Outcome Measures
MH  - *Pulmonary Disease, Chronic Obstructive/drug therapy
PMC - PMC9314306
OTO - NOTNLM
OT  - chronic obstructive pulmonary disease
OT  - item response theory
OT  - mixed model repeated measures
OT  - non-linear mixed effect model
OT  - patient-reported outcomes
EDAT- 2022/03/03 06:00
MHDA- 2022/07/28 06:00
PMCR- 2022/03/01
CRDT- 2022/03/02 06:16
PHST- 2021/09/23 00:00 [received]
PHST- 2022/02/09 00:00 [accepted]
PHST- 2022/03/03 06:00 [pubmed]
PHST- 2022/07/28 06:00 [medline]
PHST- 2022/03/02 06:16 [entrez]
PHST- 2022/03/01 00:00 [pmc-release]
AID - 10.1007/s11095-022-03194-1 [pii]
AID - 3194 [pii]
AID - 10.1007/s11095-022-03194-1 [doi]
PST - ppublish
SO  - Pharm Res. 2022 Aug;39(8):1779-1787. doi: 10.1007/s11095-022-03194-1. Epub 2022 
      Mar 1.