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Incidence and clinical significance of elevated liver function tests in cystic fibrosis clinical trials.

ABSTRACT: Emergence of elevated liver function tests (LFTs) during a clinical trial may be due to underlying disease factors of the participants, thus cofounding safety assessments of therapies. Limited data exist addressing the frequency of elevated LFTs in the chronic disease setting of cystic fibrosis (CF). The objectives of this study were to characterize emergence rates of elevated LFTs in CF trials and their association with clinical outcomes.The cohort was comprised of participants of three completed multicenter CF trials. LFTs were collected as safety endpoints, and hospitalization rates and changes in pulmonary function and weight were used to assess the association between elevated LFTs and clinical outcome.93/376 (25%) participants had ?1 emergent elevated LFT exceeding the normal reference range over an average 8.3 month follow-up, and only 12/93 (13%) had a value determined by the physician as clinically significant. The emergence of an elevated LFT was not significantly associated with a greater rate of decline in pulmonary function or weight as compared to participants with normal LFTs. The emergence of an elevated LFT value was however associated with a higher hospitalization risk (relative risk:1.67, 95% confidence interval:1.11, 2.53).Elevated LFTs are common among CF trials, although in most cases they are not deemed clinically significant. These elevated LFTs are associated with more frequent hospitalizations, but additional studies are needed to determine the causality of this association. Therapeutic trials in CF must define a priori criteria for clinical significance of elevated LFTs to enable unbiased safety assessments.

SUBMITTER: Mayer-Hamblett N

PROVIDER: S-EPMC3948320 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Incidence and clinical significance of elevated liver function tests in cystic fibrosis clinical trials.

Mayer-Hamblett Nicole N Kloster Margaret M Ramsey Bonnie W BW Narkewicz Michael R MR Saiman Lisa L Goss Christopher H CH

Contemporary clinical trials 20121129 2

<h4>Rationale</h4>Emergence of elevated liver function tests (LFTs) during a clinical trial may be due to underlying disease factors of the participants, thus cofounding safety assessments of therapies. Limited data exist addressing the frequency of elevated LFTs in the chronic disease setting of cystic fibrosis (CF). The objectives of this study were to characterize emergence rates of elevated LFTs in CF trials and their association with clinical outcomes.<h4>Methods</h4>The cohort was comprise ...[more]

PMID: 23200843

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Project description:Background and Aims: Cystic fibrosis-related liver disease (CFLD) is one of the leading causes of morbidity and mortality in cystic fibrosis (CF). Several non-invasive diagnostic methods have been proposed as screening tools for CFLD. Our aim was to rank all available non-invasive modalities for diagnostic performance. Methods: A systematic search was performed in five medical databases to find studies which reported on any single or composite non-invasive diagnostic test (as an index test) compared to the Debray, the EuroCare or the Colombo criteria (as a reference standard). Ranking was carried out with a Bayesian diagnostic test accuracy network meta-analysis based on superiority indices, calculated for pooled sensitivity (Se) and specificity (Sp) with a 95% confidence interval (CI). The study was registered under CRD42020155846 in PROSPERO. Results: Fifteen studies with 15 index tests and a combination of them were included. The New criteria proposed by Koh et al. - which represent a composite diagnostic definition for CFLD including liver biochemistry, ultrasonography, transient elastography and fibrosis markers-had the best performance for detecting CFLD (Se:94%[CI:58-100], Sp:72%[CI:52-84]); while transient elastography (Se:65%[CI:56-74], Sp:88%[CI:84-91]) and a combination of it with a tissue inhibitor of metalloproteinase-4 measurement (Se:78%[CI:30-100], Sp:64%[CI:18-95%]) proved to be the second and third best options, respectively. In the imaging techniques subgroup, transient elastography (Se:66%[CI:57-72], Sp:88%[CI:85-91%]), acoustic radiation force impulse in the right lobe (Se:54%[CI:33-74], Sp:88%[CI:66-96]) and that in the left lobe (Se:55%[CI:23-81], Sp:82%[CI:50-95]) were ranked the highest. Comparing biochemical markers/fibrosis indices, the measurement of the Forns index (Se:72%[CI:25-99], Sp:63%[CI:16-94]), the aspartate aminotransferase-to-platelet ratio (Se:55%[CI:41-68], Sp:83%[CI:66-89]) and alkaline phosphatase (Se:63%[CI:18-93], Sp:64%[CI:19-95]) were ranked the highest. Conclusion: The New criteria show the best diagnostic performance. In clinical practice, transient elastography seems to be a simple, cheap and non-invasive tool, outperforming imaging, biochemical and fibrosis tests for detecting CFLD. Further studies are needed to validate our findings.

Dataset Information

Incidence and clinical significance of elevated liver function tests in cystic fibrosis clinical trials.

Publications

Incidence and clinical significance of elevated liver function tests in cystic fibrosis clinical trials.

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