None listed
Conditions
Brief summary
PARTICIPANTS: Children (> 5 years) and adults with pulmonary fibrosis (PF) related to short (<10th centile) telomere length (PF-ST) (n=50). This subgroup have mutation/s in the telomerase enzyme which maintains telomere length. PF-ST patients have a prognosis far worse than their long telomere counterparts. Survival is worse than most cancers, with death within 2 years. INTERVENTION: A synthetic androgen, danazol (400mg capsule bd), or placebo (2:1 randomisation) for 12 months, administered in addition to standard of care. Danazol is a synthetic hormone which augments telomerase activity and hence lengthens telomeres. In a small group of haematology patients with short telomere syndromes (Townsley et al. NEJM 2016) danazol impressively attenuated telomere attrition, and in the subgroup of patients with PF (n=10) there was apparent stabilisation of lung function for up to 2 years, completely at odds with expected PF-ST natural history. COMPARATOR: Identical placebo. OUTCOMES: Change in absolute telomere length (base pairs) and lung function (forced vital capacity) over 12 months; safety (treatment emergent adverse events); survival.
Interventions
TELO-SCOPE is a national, multi-centre, double-blind, placebo-controlled, randomised (2:1) trial of danazol in addition to standard of care in pulmonary fibrosis associated with short telomeres. Consenting participants who meet all other inclusions and no exclusions (n ~ 200) will have their relative telomere length measured (Flow-FISH), with those <10th centile randomised (n=50, 2:1 (danazol:placebo)) to receive danazol or matched placebo, for 12 months in addition to standard of care backgroun
TELO-SCOPE is a national, multi-centre, double-blind, placebo-controlled, randomised (2:1) trial of danazol in addition to standard of care in pulmonary fibrosis associated with short telomeres. Consenting participants who meet all other inclusions and no exclusions (n ~ 200) will have their relative telomere length measured (Flow-FISH), with those <10th centile randomised (n=50, 2:1 (danazol:placebo)) to receive danazol or matched placebo, for 12 months in addition to standard of care background therapy (including background anti-fibrotic therapies in patients with IPF). Adult participants will receive danazol oral capsules at a dose of 800mg daily in two divided doses or identical placebo. If the participant is unable to tolerate the intervention, the dose will be reduced by 200mg per day and side effects reassessed. Further dose reduction to a minimum dose of 200mg daily will be permitted before drug discontinuation. Child participants (aged <18years) will initially receive danazol oral capsules at a dose of 2mg/kg/day in two divided doses rounded to the nearest 100mg with a maximum dose of 800mg daily. After six months, if no side effects are encountered, the dose will be increased to 4mg/kg/day (maximum 800mg daily) in two divided doses rounded to the nearest 100mg.
Sponsors
The University of Queensland
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
5 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Males and females aged >5 years, able to take capsules orally. Fibrosing interstitial pneumonia (Idiopathic PF, idiopathic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, pleuroparenchymal fibroelastosis, unclassifiable interstitial lung disease (ILD)) diagnosed according to the current international guidelines. Age-adjusted peripheral blood leukocyte telomere length < 10th centile on Flow-FISH. FVC > 40% predicted. DLCO > 25% predicted. If receiving background pirfenidone / nintedanib, stable dose for 28 days prior to screening. Able to understand and sign a written informed consent form (or legally authorised representative). Agreement to use a medically approved form of non-hormonal contraception (if of child-bearing potential) (noting that oral contraceptives are advised not to be used concurrently with danazol).
Exclusion criteria
Actively or imminently listed for lung transplantation. Undergone, awaiting, or likely to require bone marrow transplantation within 12 months. Concurrent enrolment in another study. Females with a positive pregnancy test at screening or currently breastfeeding. Pelvic infection. Past jaundice with oral contraceptives. Undiagnosed abnormal genital bleeding. Undiagnosed ovarian/uterine masses Any history of malignancy likely to result in significant disability or likely to require significant medical or surgical intervention within the next 12 months. History of androgen-dependent tumour. Any condition other than PF that, in the opinion of the investigator, is likely to result in the death of the participant within the next 12 months. History of end-stage liver disease or ALT or AST > 3 times the upper limit of normal. History of end-stage kidney disease requiring dialysis. Markedly impaired cardiac function. Known increased risk of or history of thromboembolism (e.g. Factor V Leiden, Protein C or S deficiency). Uncontrolled hypertension. Uncontrolled lipoprotein disorder. Poorly-controlled diabetes mellitus. History of marked or persistent androgenic reaction to previous gonadal steroid therapy. History of epilepsy induced or worsened by previous gonadal steroid therapy. History of raised intracranial pressure. Known intolerance to danazol. Porphyria. Use of any of the following agents within 28 days before screening: danazol or other androgen therapy, warfarin or other anticoagulant, carbamazepine, phenytoin, investigational therapy, cytotoxic therapy, tacrolimus, cyclosporine, simvastatin. Professional singer due to potential for voice change. Competitive athletes. Lactose intolerance.
Outcome results
None listed