TELO-SCOPE study: a randomised, double-blind, placebo-controlled, phase 2 trial of danazol for short telomere related pulmonary fibrosis

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Abstract

Introduction

Recent discoveries have identified shortened telomeres and related mutations in people with pulmonary fibrosis (PF). There is evidence to suggest that androgens, including danazol, may be effective in lengthening telomeres in peripheral blood cells. This study aims to assess the safety and efficacy of danazol in adults and children with PF associated with telomere shortening.

Methods and analysis

A multi-centre, double-blind, placebo-controlled, randomised trial of danazol will be conducted in subjects aged >5 years with PF associated with age-adjusted telomere length ≤10th centile measured by flow fluorescence in situ hybridisation; or in children, a diagnosis of dyskeratosis congenita. Adult participants will receive danazol 800 mg daily in two divided doses or identical placebo capsules orally for 12 months, in addition to standard of care (including pirfenidone or nintedanib). Paediatric participants will receive danazol 2 mg/kg/day orally in two divided doses or identical placebo for 6 months. If no side effects are encountered, the dose will be escalated to 4 mg/kg/day (maximum 800 mg daily) orally in two divided doses for a further 6 months. The primary outcome is change in absolute telomere length in base pairs, measured using the telomere shortest length assay (TeSLA), at 12 months in the intention to treat population.

Ethics and dissemination

Ethics approval has been granted in Australia by the Metro South Human Research Ethics Committee (HREC/2020/QMS/66385). The study will be conducted and reported according to Standard Protocol Items: Recommendations for Interventional Trials guidelines. Results will be published in peer-reviewed journals and presented at international and national conferences.

Trial registration numbers

NCT04638517; Australian New Zealand Clinical Trials Registry (ACTRN12620001363976p).

Related collections

Most cited references 44

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Next-generation DNA sequencing (NGS) projects, such as the 1000 Genomes Project, are already revolutionizing our understanding of genetic variation among individuals. However, the massive data sets generated by NGS--the 1000 Genome pilot alone includes nearly five terabases--make writing feature-rich, efficient, and robust analysis tools difficult for even computationally sophisticated individuals. Indeed, many professionals are limited in the scope and the ease with which they can answer scientific questions by the complexity of accessing and manipulating the data produced by these machines. Here, we discuss our Genome Analysis Toolkit (GATK), a structured programming framework designed to ease the development of efficient and robust analysis tools for next-generation DNA sequencers using the functional programming philosophy of MapReduce. The GATK provides a small but rich set of data access patterns that encompass the majority of analysis tool needs. Separating specific analysis calculations from common data management infrastructure enables us to optimize the GATK framework for correctness, stability, and CPU and memory efficiency and to enable distributed and shared memory parallelization. We highlight the capabilities of the GATK by describing the implementation and application of robust, scale-tolerant tools like coverage calculators and single nucleotide polymorphism (SNP) calling. We conclude that the GATK programming framework enables developers and analysts to quickly and easily write efficient and robust NGS tools, many of which have already been incorporated into large-scale sequencing projects like the 1000 Genomes Project and The Cancer Genome Atlas.

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ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data

Kai Wang, Mingyao Li, Hakon Hakonarson (2010)

High-throughput sequencing platforms are generating massive amounts of genetic variation data for diverse genomes, but it remains a challenge to pinpoint a small subset of functionally important variants. To fill these unmet needs, we developed the ANNOVAR tool to annotate single nucleotide variants (SNVs) and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP. ANNOVAR can utilize annotation databases from the UCSC Genome Browser or any annotation data set conforming to Generic Feature Format version 3 (GFF3). We also illustrate a ‘variants reduction’ protocol on 4.7 million SNVs and indels from a human genome, including two causal mutations for Miller syndrome, a rare recessive disease. Through a stepwise procedure, we excluded variants that are unlikely to be causal, and identified 20 candidate genes including the causal gene. Using a desktop computer, ANNOVAR requires ∼4 min to perform gene-based annotation and ∼15 min to perform variants reduction on 4.7 million variants, making it practical to handle hundreds of human genomes in a day. ANNOVAR is freely available at http://www.openbioinformatics.org/annovar/ .

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ClinVar: improving access to variant interpretations and supporting evidence

Melissa J. Landrum, Jennifer Lee, Mark Benson … (2017)

Abstract ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) is a freely available, public archive of human genetic variants and interpretations of their significance to disease, maintained at the National Institutes of Health. Interpretations of the clinical significance of variants are submitted by clinical testing laboratories, research laboratories, expert panels and other groups. ClinVar aggregates data by variant-disease pairs, and by variant (or set of variants). Data aggregated by variant are accessible on the website, in an improved set of variant call format files and as a new comprehensive XML report. ClinVar recently started accepting submissions that are focused primarily on providing phenotypic information for individuals who have had genetic testing. Submissions may come from clinical providers providing their own interpretation of the variant (‘provider interpretation’) or from groups such as patient registries that primarily provide phenotypic information from patients (‘phenotyping only’). ClinVar continues to make improvements to its search and retrieval functions. Several new fields are now indexed for more precise searching, and filters allow the user to narrow down a large set of search results.

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Author and article information

Journal

Journal ID (nlm-ta): BMJ Open Respir Res

Journal ID (iso-abbrev): BMJ Open Respir Res

Journal ID (hwp): bmjresp

Journal ID (publisher-id): bmjopenrespres

Title: BMJ Open Respiratory Research

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2052-4439

Publication date Collection: 2021

Publication date (Electronic): 2 December 2021

Volume: 8

Issue: 1

Electronic Location Identifier: e001127

Affiliations

[1 ]departmentQueensland Lung Transplant Service, Department of Thoracic Medicine , The Prince Charles Hospital , Chermside, Queensland, Australia

[2 ]departmentFaculty of Medicine , University of Queensland , Brisbane, Queensland, Australia

[3 ]departmentMenzies Institute for Medical Research , University of Tasmania , Hobart, Tasmania, Australia

[4 ]departmentChildren's Medical Research Institute , University of Sydney , Westmead, New South Wales, Australia

[5 ]departmentDepartment of Respiratory Medicine , The Children's Hospital at Westmead , Sydney, New South Wales, Australia

[6 ]departmentDiscipline of Paediatrics and Child Health , The University of Sydney , Sydney, New South Wales, Australia

[7 ]departmentDepartment of Respiratory Medicine , John Hunter Hospital , Newcastle, New South Wales, Australia

[8 ]departmentRespiratory and Sleep Medicine Department , Austin Health , Heidelberg, Victoria, Australia

[9 ]Institute for Breathing and Sleep , Melbourne, Victoria, Australia

[10 ]departmentFaculty of Medicine, Dentistry and Health Sciences , University of Melbourne , Melbourne, Victoria, Australia

[11 ]departmentDepartment of Allergy and Respiratory Medicine , Alfred Hospital , Melbourne, Victoria, Australia

[12 ]departmentDepartment of Respiratory Medicine , Royal Adelaide Hospital , Adelaide, South Australia, Australia

[13 ]departmentAdvanced Lung Disease Unit , Fiona Stanley Hospital , Murdoch, Western Australia, Australia

[14 ]departmentDepartment of Medicine , University of Notre Dame , Perth, Western Australia, Australia

[15 ]departmentSchool of Women's and Children's Health, Faculty of Medicine , University of New South Wales , Sydney, New South Wales, Australia

[16 ]departmentRespiratory Medicine , Royal Prince Alfred Hospital , Camperdown, New South Wales, Australia

[17 ]departmentFaculty of Medicine and Health , University of Sydney , Sydney, New South Wales, Australia

Author notes

[Correspondence to ] Dr John A Mackintosh; john.mackintosh@ 123456health.qld.gov.au

Author information

John A Mackintosh http://orcid.org/0000-0002-5254-4144

Article

Publisher ID: bmjresp-2021-001127

DOI: 10.1136/bmjresp-2021-001127

PMC ID: 8640666

PubMed ID: 34857525

SO-VID: b3d16ca7-c849-47d1-bed7-b62f4566ee38

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 14 October 2021

Date accepted : 15 November 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;

Award ID: MRFF APP1199373

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Keywords: interstitial fibrosis

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Keywords: interstitial fibrosis

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TELO-SCOPE study: a randomised, double-blind, placebo-controlled, phase 2 trial of danazol for short telomere related pulmonary fibrosis

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Abstract

Introduction

Methods and analysis

Ethics and dissemination

Trial registration numbers

Related collections

ChemSpider related publications

Most cited references 44

The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.

ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data

ClinVar: improving access to variant interpretations and supporting evidence

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Author notes

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Cited by 8

Most referenced authors 904