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Prediction of disease progression, treatment response and dropout in chronic obstructive pulmonary disease (COPD).

Musuamba FT, Teutonico D, Maas HJ, Facius A, Yang S, Danhof M, Della Pasqua O - Pharm. Res. (2014)

Bottom Line: Two parameters were necessary to model the dropout patterns, which was found to be partly linked to the treatment failure.Disease severity at baseline, previous use of corticosteroids, gender and height were significant covariates on disease baseline whereas disease severity and reversibility to salbutamol/salmeterol were significant covariates on Emax for salmeterol active arm.Incorporation of the various interacting factors into a single model will offer the basis for patient enrichment and improved dose rationale in COPD.

View Article: PubMed Central - PubMed

Affiliation: Gorlaeus Laboratories, Division of Pharmacology, Leiden Academic Centre for Drug Research, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.

ABSTRACT

Purpose: Drug development in chronic obstructive pulmonary disease (COPD) has been characterised by unacceptably high failure rates. In addition to the poor sensitivity in forced expiratory volume in one second (FEV1), numerous causes are known to contribute to this phenomenon, which can be clustered into drug-, disease- and design-related factors. Here we present a model-based approach to describe disease progression, treatment response and dropout in clinical trials with COPD patients.

Methods: Data from six phase II trials lasting up to 6 months were used. Disease progression (trough FEV1 measurements) was modelled by a time-varying function, whilst the treatment effect was described by an indirect response model. A time-to-event model was used for dropout

Results: All relevant parameters were characterised with acceptable precision. Two parameters were necessary to model the dropout patterns, which was found to be partly linked to the treatment failure. Disease severity at baseline, previous use of corticosteroids, gender and height were significant covariates on disease baseline whereas disease severity and reversibility to salbutamol/salmeterol were significant covariates on Emax for salmeterol active arm.

Conclusion: Incorporation of the various interacting factors into a single model will offer the basis for patient enrichment and improved dose rationale in COPD.

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Related in: MedlinePlus

Simulations (n = 1000) of four scenarios based on the final model. In blue: median and 95% prediction intervals for the placebo and in black: median and 95% prediction intervals for the active arm. (a) left panel: non-reversible and severe patients, right panel: reversible and non-severe patients; (b) patients with height >172 cm and previous use of inhaled corticosteroids, right panel: patients with height >172 cm and no previous use of inhaled corticosteroids. To ensure appropriate comparisons between the groups, the remaining covariates were kept in a balanced manner in each group.
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Fig5: Simulations (n = 1000) of four scenarios based on the final model. In blue: median and 95% prediction intervals for the placebo and in black: median and 95% prediction intervals for the active arm. (a) left panel: non-reversible and severe patients, right panel: reversible and non-severe patients; (b) patients with height >172 cm and previous use of inhaled corticosteroids, right panel: patients with height >172 cm and no previous use of inhaled corticosteroids. To ensure appropriate comparisons between the groups, the remaining covariates were kept in a balanced manner in each group.

Mentions: One of the interesting findings from our analysis is that the change in FEV1 values over time was found to be dependent on the baseline characteristics. For instance, as shown in Fig. 5, patients with a more severe disease status and unfavourable covariate characteristics at baseline will have a slower evolution over time and will be less sensitive to drug effects (see Fig. 5(a) and (b)). The correlation between change in FEV1 values over time and baseline characteristics is consistent with indirect drug effects, as described by increasing zero-order processes. This is particularly relevant for salmeterol, given that baseline severity status shows a higher effect on the disease slope than the active treatment itself when salmeterol is administered at 50 μg doses according to a twice daily-dosing regimen. On the other hand, higher sensitivity to the drug effects was more pronounced in patients who show reversibility to salbutamol/salmeterol at baseline.Fig. 5


Prediction of disease progression, treatment response and dropout in chronic obstructive pulmonary disease (COPD).

Musuamba FT, Teutonico D, Maas HJ, Facius A, Yang S, Danhof M, Della Pasqua O - Pharm. Res. (2014)

Simulations (n = 1000) of four scenarios based on the final model. In blue: median and 95% prediction intervals for the placebo and in black: median and 95% prediction intervals for the active arm. (a) left panel: non-reversible and severe patients, right panel: reversible and non-severe patients; (b) patients with height >172 cm and previous use of inhaled corticosteroids, right panel: patients with height >172 cm and no previous use of inhaled corticosteroids. To ensure appropriate comparisons between the groups, the remaining covariates were kept in a balanced manner in each group.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4300418&req=5

Fig5: Simulations (n = 1000) of four scenarios based on the final model. In blue: median and 95% prediction intervals for the placebo and in black: median and 95% prediction intervals for the active arm. (a) left panel: non-reversible and severe patients, right panel: reversible and non-severe patients; (b) patients with height >172 cm and previous use of inhaled corticosteroids, right panel: patients with height >172 cm and no previous use of inhaled corticosteroids. To ensure appropriate comparisons between the groups, the remaining covariates were kept in a balanced manner in each group.
Mentions: One of the interesting findings from our analysis is that the change in FEV1 values over time was found to be dependent on the baseline characteristics. For instance, as shown in Fig. 5, patients with a more severe disease status and unfavourable covariate characteristics at baseline will have a slower evolution over time and will be less sensitive to drug effects (see Fig. 5(a) and (b)). The correlation between change in FEV1 values over time and baseline characteristics is consistent with indirect drug effects, as described by increasing zero-order processes. This is particularly relevant for salmeterol, given that baseline severity status shows a higher effect on the disease slope than the active treatment itself when salmeterol is administered at 50 μg doses according to a twice daily-dosing regimen. On the other hand, higher sensitivity to the drug effects was more pronounced in patients who show reversibility to salbutamol/salmeterol at baseline.Fig. 5

Bottom Line: Two parameters were necessary to model the dropout patterns, which was found to be partly linked to the treatment failure.Disease severity at baseline, previous use of corticosteroids, gender and height were significant covariates on disease baseline whereas disease severity and reversibility to salbutamol/salmeterol were significant covariates on Emax for salmeterol active arm.Incorporation of the various interacting factors into a single model will offer the basis for patient enrichment and improved dose rationale in COPD.

View Article: PubMed Central - PubMed

Affiliation: Gorlaeus Laboratories, Division of Pharmacology, Leiden Academic Centre for Drug Research, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.

ABSTRACT

Purpose: Drug development in chronic obstructive pulmonary disease (COPD) has been characterised by unacceptably high failure rates. In addition to the poor sensitivity in forced expiratory volume in one second (FEV1), numerous causes are known to contribute to this phenomenon, which can be clustered into drug-, disease- and design-related factors. Here we present a model-based approach to describe disease progression, treatment response and dropout in clinical trials with COPD patients.

Methods: Data from six phase II trials lasting up to 6 months were used. Disease progression (trough FEV1 measurements) was modelled by a time-varying function, whilst the treatment effect was described by an indirect response model. A time-to-event model was used for dropout

Results: All relevant parameters were characterised with acceptable precision. Two parameters were necessary to model the dropout patterns, which was found to be partly linked to the treatment failure. Disease severity at baseline, previous use of corticosteroids, gender and height were significant covariates on disease baseline whereas disease severity and reversibility to salbutamol/salmeterol were significant covariates on Emax for salmeterol active arm.

Conclusion: Incorporation of the various interacting factors into a single model will offer the basis for patient enrichment and improved dose rationale in COPD.

Show MeSH
Related in: MedlinePlus